Clinical aspects of neuronal forms of lysosomal storage disorders. Part 2.
L. B. Jardim • M.M. Villanueva • C.F.M. Souza • C.B.O. Netto
L. B. Jardim ()
Department of Internal Medicine, Universidade Federal do Rio Grande do Sul;
Medical Genetics Service, Hospital de Clinicas de Porto Alegre,
Rua Ramiro Barcelos 2350
90035-903, Porto Alegre, Brazil, e-mail: [email protected]
M.M. Villanueva • C.F.M. Souza • C.B.O. Netto
Medical Genetics Service, Hospital de Clinicas de Porto Alegre, Brazil. “Page 2”
Abstract
The purpose of this review is to describe state of the art related to the neurological phenotypes of lysosomal storage diseases. Primary neuronal involvement is focused and not neurological complications secondary to a disrupted adjacent tissue. This distinction is probably very relevant, in the light of new potential therapies. Clinical presentation and follow-up, genetic and epidemiological data, and pathology were focused. Although prospective studies on the natural history have been hampered by the rarity and short survival of these patients, several longitudinal observations on the neurological manifestations were already published, and received particular attention. Levels of evidence were also included and some have been shown that at least some brain injuries related to lysosomal disease will be prone to therapy. While this goal is not achieved, better clinical studies are necessary in the majority of these disorders. Repeated measurements of disease progression, using responsive scoring systems, in larger samples of cases are needed in order to better clarify natural history of these disorders.
• Take-home message: State of the art on neurological impairment of lysosomal diseases has been reviewed, focusing on the clinical evidences on natural history, genetic determinants and modulating factors.
• Running head: Neuronal findings in LSD
• References to electronic databases
Acetyl-CoA-glucosaminide-N-acetyltransferase deficiency E.C 2.3.1.78 Acid ceramidase deficiency EC 3.5.1.23
Acid sphingomyelinase deficiency EC 3.1.4.12
-fucosidase deficiency EC 3.2.1.51
α-L-iduduronidase deficiency E.C 3.2.1.76
α-mannosidase deficiency EC 3.2.1.24
α-mannosidosis OMIM #248500
α-N-acetylgalactosaminidase deficency EC 3.2.1.49
α-N-acetylglucosaminidase deficiency E.C 3.2.1.50
α -N-acetyl-neuroaminidase EC 3.2.1.18
Arylsulfatase A deficiency EC 3.1.6.8
Aspartylglucosaminuria OMIM +208400
ß-galactosidase and neuraminidase deficiency EC 3.4.16.5
ß-galactosidase deficiency E.C. 3.2.1.23
ß-glucuronidase deficiency E.C 3.2.1.31
ß-mannosidase deficiency EC 3.2.1.25
ß-mannosidosis OMIM #248510
Cathepsin D deficiency EC 3.4.23.5
Ceroid-lipofuscinosis neuronal, 4A, adult form, OMIN %204300
Ceroid-lipofuscinosis neuronal, 4B, adult form, OMIM %162350
Ceroid-lipofuscinosis neuronal, CLN10, congenital form OMIN #610127
Ceroid-lipofuscinosis neuronal, CLN1, infantile form, OMIM #256730
Ceroid-lipofuscinosis neuronal, CLN3, juvenile form, OMIM #204200
Ceroid-lipofuscinosis neuronal, CLN2, late-infantile OMIM #204500
Ceroid-lipofuscinosis neuronal, 8, Northern epilepsy variant OMIM #610003). Farber disease OMIM +228000
Fucosidosis OMIM #230000
Galactocerebrosidase deficiency E.C 3.2.1.46
Galactosialidosis OMIM +256540
Gaucher disease type I OMIN #230800
Gaucher disease type II OMIN #230900
Gaucher disease type III OMIN #231000
Gaucher disease type III C OMIN #231005.
Gaucher disease perinatal lethal OMIN #608013
Glucocerebrosidase E.C. 3.2.1.45.
GM2 activator protein deficiency: OMIM #272750.
GM1 gangliosidosis infantile form OMIM #230500
GM1 gangliosidosis late-infantile form OMIN #230600
GM1 gangliosidosis adult form OMIN #230650.
Heparin-N-sulfatase deficiency E.C 3.10.1.1
Hexosaminidase A deficiency EC 3.2.1.52.
Iduronate-2-sulfatase deficiency E.C 3.1.6.13
Krabbe disease KD OMIM# 245200
Metachromatic leukodystrophy OMIM# 230500
MPS I,Hurler syndrome OMIM #607014.
MPS I, Hurler Scheie syndromeOMIN #607015,
MPS I, Scheie syndrome OMIN #607016
MPS II, Hunter syndrome OMIM +309900
MPS III A, Sanfilippo A syndrome MIM #252900 MPS III B, Sanfilippo B syndrome OMIM #252920
MPS III C, Sanfilippo C syndrome OMIN #252930
MPS III D, Sanfilippo D syndrome OMIN #252940
MPS VII, Sly syndrome OMIM #253220
Mucolipidin gene OMIN *605248
Multiple sulfatase deficiency OMIM #272200
N-acetylglucosamine-1-phosphotransferase alpha/beta-subunits deficiency E.C
2.7.8.15.
N-acetylglucosamine-1-phosphotransferase gamma subunit deficiency E.C
2.7.8.17
N-acetylglucosamine-6-sulfatase deficiency E.C 3.1.6.14
N-aspartyl-beta-glucosaminidase EC 3.5.1.26
Niemann-Pick disease type A OMIN #257200.
Niemann-Pick disease type B OMIN #607616
Niemann-Pick disease type C1 MIM #257220
Niemann-Pick disease type C2 MIN #607625
NPC1 gene *607623
NPC2 gene *601015
Palmitoyl-protein thioesterase-1 deficiency E.C 3.1.2.22
Protein activator saposin B deficiency OMIM# 249900
Sandhoff disease OMIM #268800
Schindler disease OMIM #609241
Sialidosis type I OMIM #256550
٭Sulfatase-modifying factor-1 gene OMIN 607939 Tay-Sachs disease: OMIM #272800.
Tripeptidyl peptidase 1 deficiency1 E.C 3.4.14.9
• Abbreviations
AC acid ceramidase AGU aspartylglucosaminuria ANCL neuronal ceroid-lipofuscinosis, form adult, Kuf's disease ARSA arylsulfatase A ASM acid sphingomyelinase BAER brain auditory evoked response BMT bone marrow transplantation CLP curvilinear profile CNS central nervous system CSF cerebrospinal fluid CT computed tomography EEG electroencephalogram EIKD early infantile Krabbe disease EM electronic microscopy EMG electromyogram ERG electroretinogram ERT enzyme replacement therapy FGE formylglycine-generating enzyme FUCA1 -fucosidase GAGs glycosaminoglycans GALC galactocerebrosidase GD Gaucher disease GLD Globoid cells leukodystrophy GNPTAB alpha/beta-subunits of the N-acetylglucosamine -1-phosphotransferase GNPTG gamma subunit of N-acetylglucosamine-1-phosphotransferase GROD granular osmiophilic deposits (GROD) GUS beta-glucuronidase HDL-C high-density lipoprotein cholesterol Hex A hexosaminidase A HLA-DR major histocompatibility complex, class I 1H-MRSI proton magnetic resonance spectroscopic imaging HSEM horizontal saccadic eye movement INCL infantile neuronal ceroid-lipofuscinosis, Santavuori-Haltia IQ intelligence quotient JNCL juvenile neuronal ceroid-lipofuscinosis, Batten disease, Spielmeyer-Vog KD Krabbe disease LINCL late-infantile neuronal ceroid-lipofuscinosis, Jansky-Bielschowsky LMN lower motor neuron LOKD late-onset Krabbe disease LOTS late-onset Tay-Sachs LSD lysosomal storage disorders MAN2B1 mannosidase, alpha MANBA mannosidase, beta A ML mucolipidosis MLD metachromatic leukodystrophy MPS mucopolysaccharidoses MPS IH Hurler syndrome MPS IH/S Hurler-Scheie syndrome MPS IS Scheie syndrome MPS II Hunter syndrome MPS III Sanfilippo syndrome MRI magnetic resonance imaging MSD multiple sulfatase deficiency NAGA α-N-acetylgalactosaminidase NCL neuronal ceroid lipofuscinosis NCV nerve conduction velocity NE neuronal ceroid-lipofuscinosis, Northern epilepsy variant NEU1 alpha-N-acetyl neuroaminidase NGD neuronopathic Gaucher disease NPA Niemann Pick disease type A NPB Niemann Pick disease type B NPC Niemann Pick disease type C OMA oculomotor apraxia PAS periodic acid-schiff stain PNS peripheral nervous system PPCA protective protein/cathepsin A PPGB beta-galactosidase and neuraminidase PPT1 palmitoyl-protein thioesterase-1 SAP saposins SIF saccade initiation failure SUMF1 sulfatase-modifying factor-1 gene TSD Tay-Sachs disease TNF tumoral necrosis factor TPP1 tripeptidyl peptidase 1 TUNEL TdT-mediated dUTP-biotin nick end-labelling VSEM vertical saccadic eye movement VSPG supranuclear vertical gaze palsy VEP visual evoked potentials BAER WM white matter “Third page”
• Details of the contributions of individual authors,
L.B.Jardim: conception and planning of the manuscript; writing of the first draft of the majority of sphingolipidoses, and of neuronal ceroid lipofuscinosis; review and critique of the final version. L.B. Jardim is the guarantor for the article, accepts full responsibility for the work and/or the conduct of the study, had access to the data, and controlled the decision to publish.
M.M. Villanueva: writing of the first draft of Gaucher and Niemann-Pick diseases sections; review of the final version.
C.F.M.Souza: writing of the first draft of
C.B.O.Netto: writing the first draft of mucopolysaccharidoses; English review.
All authors confirm that they have no competing interests for declaration.
Since this is a review, ethics approval was not required.
Introduction
The lysosomal storage disorders (LSDs) are a family of human genetic diseases caused by the defective activity of lysosomal enzymes and other related proteins: any defect that prevents the catabolism of molecules in the lysosome, or the egress of molecules from the lysosome, induces the storage of undegraded molecules in these subcellular organelles.
The overall frequency of LSD is estimated to be approximately 1 in 8 000 live births. Some of these disorders show founder effects in geographically isolated or demographic transition populations, due to genetic drift. A high incidence of some
LSD in a population can be either due to a genetic proximity between their marriages, or to some selective advantage for the carrier state in the particular settings (Jeyakumar et al 2005).
Many of these disorders are characterized by severe neurological impairment, which is almost always untreatable. Progressive neuronal dysfunction and death occur in these conditions. Contrarily to the former points of view relating signs and symptoms to the mechanical disruption of the cell, secondary to storing of undegradable materials, for most of the neuronal LSD the pathogenesis also involves neuronal dysfunction, sometimes independent from the storage burden
(Wraith 2002; Jeyakumar et al 2005). Neurological involvement can also be secondary to substract accumulation in adjacent tissue, however. This distinction seems to be very pertinent, in the light of new potential therapies. A better understanding about the cascade of events resulting in neuronal involvement will certainly help the development of new therapeutic approaches, and it is possible that clinical information gattered up to now, can help us in achieving this target. Neurological problems which are secondary complications of storage materials, such as spinal cord compressions in
MPS I, IV or VI, or cerebrovascular accidents in Fabry disease, are beyond the scope of the present review. Several recent publications gave accounts on these fields, and appeared elsewhere (Kachur et al 2000; Moore et al 2007; Khanna et al, 2007; Al Sawaf et al 2008; Vougioukas et al 2001; Montaño et a, 2007).
Supportive treatment should not be overlooked: it should be pursued, since it certainly increases quality of life in these disorders.
This review presents the state of art on the neurological phenotypes of the primary neuronal forms of LSD in two parts. Part 1, printed part, includes summaries of the neurological phenotypes as well as genetic characteristics and levels of evidence, as well as some insights gleaned from various clinical observations. Part 2
(electronic) presents a detailed review of the clinical characteristics of each neuronal LSD.
The present review focuses on clinical aspects of the neurological LSD – clinical presentation, genetic and epidemiological data, and pathology, when known.
Established genotype-phenotype correlations in LSD with neuronal involvement were briefly mentioned in Table 2, including those mutations that prevent against neuronal manifestations.
Due to rarity and to the short survival of the majority of the neuronal LSD, prospective studies are very scarce and the knowledge about the natural history or progression rate was inferred from anecdotal reports. Longitudinal observations on the neurological manifestations received particular attention, when available. When natural history studies were lacking, clinical course observations on neurological endpoints after an intervention were also mentioned. The pathogenetic cascades and a review on management will be described with detail elsewhere (Scarpa et al and Schiffman et al, in the present JIMD issue).
1. Sphingolipidosis
Sphingolipids are a class of lipids derived from the aliphatic amino alcohol sphingosine. The three main types of sphingolipids are, from the simplest to the most complex ones: ceramide, sphingomyelin, and the glycosphingolipids
( including cerebrosides and gangliosides). Defects in the degradation of these macromolecules produce the LSD collectively called sphingolipidosis (SL).
Sphingolipids are often found in neural tissue. Sulfatide and galactocerebroside are very important constituents of myelin, being synthetized by olygodendrocytes and
Schwann cells. Several others are synthetized by neurons, and play an important role in both signal transmission and cell recognition. For instance, ceramide modulates either neurite formation and neuronal apoptosis (Buccoliero et al, 2002).
, and gangliosides act as modulators of dendritogenesis (Walkley et al 1999).
Since these lipids are synthetized in neural tissue, the storage produced by a SL most frequently affects the central and peripheral neurvous systems (CNS and
PNS).
Eight SL are neuronopathic: GM2 and GM1 gangliosidoses, Gaucher disease types 2 and 3, Niemann-Pick types A and B, Niemann-Pick type C, Metachromatic leucodistrophy, Krabbe disease (or globoid cell leukodystrophy), and Farber disease.
1. 1 GM2 Gangliosidosis
GM2 gangliosidosis (GM2) are LSD due to the storage of GM2 ganglioside in the lysosomes. Deficient activity of the hexosaminidase A (Hex A) can be secondary to mutations in alpha subunit or in beta subunit of the enzyme. Mutations in the alpha subunit result in GM2 gangliosidosis called Tay-Sachs disease (TSD), or Variant B.
Mutations of the beta-subunit cause Sandhoff disease, or Variant 0. Incomplete degradation of GM2 can also be secondary to a deficiency of the GM2 activator protein, related to the AB variant of GM2 gangliosidosis (Gravel et al 2001;
Sandhoff et al 2001). GM2 is a component of the cell plasma membrane which modulates cell signal transduction events, like synaptic activities and, in neuronal ontogenesis, neurite sprouting. Storage of GM2 ganglioside seemed to be the main cause of neuronal dysfunction, by inducing aberrant dendrite sprouting and synaptic activities during neuronogenesis (Sandhoff et al 1971; Gravel et al 2001; Sandhoff et al 2001).
Variant B, or Tay Sachs disease
This condition is mostly seen in Ashkenazi Jewish communities, where the carrier rate for TSD is about one in 30 and the former incidence of disease was about one in 3 600 live births. As the result of extensive genetic carrier screening programs in this population, the incidence has been reduced by greater than 90% (Kaback
2000). In the general population, the incidence is of 1 in 222 000 live births (Meikle et al 1999)
There are three general subgroups of Variant B, according to ages at onset: (a) the classical infantile form, (b) juvenile, and (c) late onset forms (called chronic or adult forms). Sibs with classical form always present a very similar picture. In contrast, intrafamilial heterogeneity was repeatedly reported among late onset forms, suggesting that factors other than the specific mutation are modulating the clinical presentation (Neudorfer et al 2005; Maegawa et al 2006).
Children with the classical form start with an exaggerated, non-adaptable startle response to stimuli in the first months of life. Soon thereafter, loss of milestones and a pendular nistagmus appear. By the eighth month, there is marked axial hypotonia with limb spasticity and blindness. Eletroretinogram and papillary responses to light are normal. Cherry red spots can be seen in the macula, consisting of a large whitish circular zone, corresponding to ganglion cells storage and degeneration (Figure E-1). Since the fovea is devoid of most inner retinal layers, including ganglion cells, it is spared and appears in the center of the white zone. The size of the cranium increases continuously after birth, due to a true megalencephaly. At the end stages of the disease, ventricles can enlarge in an ex vacuum manner and seizures are present in the second year. End stage is reached with a vegetative state with decerebration and cachexia (Sandhoff et al
2001; Lyon et al 2006). This severe, classical form of Tay Sachs disease can be seen as a stereotype for other early infantile sphingolipidoses, pointing to possible common pathogenetic pathways (Figure 1 and Table 3).
MRI and CSF are unremarkable. There is no evidence of visceral, skeletal, and peripheral nerve involvement. Nerve conduction velocities remain normal, suggesting that ganglioside storage does not affect peripheral myelin. Autopsy findings included enlarged and heavy brain, swollen neurons throughout the CNS, meganeurites, loss of neurons, and GM2 storage (Sandhoff et al 2001; Lyon et al
2006).
In the late onset forms (subacute, juvenile, chronic and adult; LOTS) of variant B, balance problems and difficulty climbing stairs were the most frequent presenting complaints (Neudorfer et al 2005). LOTS can take one or more of the following forms: a lower motor neuron disease, a cerebellar ataxia, a psychiatric syndrome, dementia, a pyramidal and or extrapyramidal syndrome (dystonia), and polyneuropathy (Frey et al 2005; Lyon et al 2006; Shapiro et al 2008). Language and visuospatial skills can be normal for several years, whereas memory and executive functioning were already impaired. This asymmetry raised the hypothesis of a subjacent cerebellar dysfunction (Zaroff et al 2004). Unlike the infantile form, there is no cherry red spot in LOTS. Peculiar abnormalities of saccades, with hypometria, transient decelerations, and premature termination of saccades were seen in patients with varied disease durations, suggesting the involvement of pontine nucleus raphe interpositus or dorsal vermis (Rucker et al 2004) (Table 3).
Loss of vision occurs much later than in the acute infantile form of the disease, due to optic atrophy and/or retinitis pigmentosa. A vegetative state with decerebrate rigidity develops by the end stages of disease. In some cases, the disease pursues a particularly aggressive course, culminating in death in two to four years.
Mild cortical and cerebellar atrophies can be seen by neuroimaging, whereas EMG can reveal lower motor neuron (LMN) involvement (Neudorfer et al 2005; Frey et al
2005). As in the classical Tay Sachs disease, neurophysiological studies of peripheral nerves were always normal.
The rate of progression is not well known. Maegawa et al (2006) presented some estimates, based on a cohort of 21 patients with juvenile GM2. Those authors reported, for instance, a survival estimate of 14.5 years after disease onset (95% confidence interval: 11.7–17.3). Autopsy findings usually show abundant lipid accumulation in CNS neurons and neuronal losses related to the phenotypic manifestations during life. Histochemistry demonstrated diffuse neuronal GM2 storage in the brainstem, in Purkinje and granular cells of the cerebellum, and/or in anterior horns of the spinal cord, in good correlation with clinical observations (Rapin et al 1976; Benninger et al 1993;
Kornfeld 2008).
Variant Zero, or Sandhoff disease
The variant 0 of GM2 gangliosidosis is quite rare, with a carrier frequency of 1/600 in general populations (Cantor and Kaback 1985). Founder effects were found in the Christian Maronite community of Cyprus (Drousiotou et al 2000), and in a
Creole population of Argentina (Dodelson de Kremer et al 1985).
As in Tay Sachs disease, Sandhoff disease can be subdivided in early-onset and juvenile or late onset forms. Ages at onset, disease duration, neurological and ophthalmological pictures are quite similar to those found in Tay Sachs disease, meaning that the GM2 ganglioside is the main storage material in variant 0.
Distinction can be done, sometimes, because some Sandhoff disease patients present with enlarged liver and spleen (Figure 1), skeletal changes similar to GM1 gangliosidosis (Figure E-2), foam cells in bone marrow, and the presence of some oligosaccharides in urine (Sandhoff et al 2001; Lyon et al 2006)).
Due to its rarity, virtually nothing is known about the natural history or intrafamilial variability of Sandhoff disease.
In anatomo-pathology studies, lesions are similar to those found in Tay Sachs disease, except that neuronal inclusions are more polymorphic (Lyon et al 2006).
Variant AB
Rare patients have been diagnosed since the first case was described by Sandhoff
(Sandhoff et al 1971). There is only one report on an adult form, the others shows an early onset form indistinguishable from Tay Sachs disease.
1. 2 GM1 gangliosidosis
GM1 gangliosidosis is due to deficiency of the β-galactosidase enzyme which hydrolyzes the terminal b-galactosyl residues from GM1 ganglioside, glycoproteins, and glycosaminoglycans (Okada and O’Brien 1968). Incidence has been estimated to be 0.5 -1 in 100 000 live births (Sinigerska et al 2006). Increased prevalences ranging from 1:3 700 to 1: 17 000, have been found in South Brazil, Rome, the
Maltese Islands, and in Cyprus, maybe due to founder effects (Lenicker et al 1997;
Severini et al 1999; Georgiou et al 2005; Sinigerska et al 2006). Three different clinical forms have been recognized according to age at onset, being inversely related to the residual activity of mutant b-galactosidase: type 1 or infantile form, type 2 or late infantile or juvenile form, and type 3 or adult form
(Suzuki et al 1978). In a recent metanalysis, reports on 209 patients were found in the literature: 130 were infantile, 23 juvenile, and 56 adult GM1 gangliosidosis
(Brunetti-Pierri and Scaglia 2008).
In type 1, babies present with macrosomy at birth. Macroglossia, hypertelorism, epicanthus, coarse facial features and visceromegaly can also be observed (Figure
E-2). In the following six months of life, patient present a progressive hypotonia, losing or never acquiring motor development. A severe, generalized CNS involvement with macrocephaly, seizures, nystagmus, squint, loss of contact, and blindness supervenes. Cherry-red spots were seen in the majority of affected children (Figure E-1). As time passes, spasticity substitutes hypotonia. Peripheral nerves are spared, as in GM2 Gangliosidosis. Actually, the neurological picture of infantile GM1 Gangliosidosis is quite similar to Tay Sachs disease: the main differences are nonneurologic (Figure 1 and Table 3) (Lyon et al 2006).
Hepatosplenomegaly, facial dysmorphism, and skeletal dysplasia (Figure E-2) are among them, and can be related to the peripheral storage of glycoproteins, and glycosaminoglycans. On MRI, hypointense thalami and diffuse white matter (WM) abnormalities can be seen (Figure E-3 a). Vacuolated lymphocytes can be found in blood, and galactose-containing oligosaccharides and keratan sulfate are excreted in urine. Case series point to a mean survival of 12 months. There is a high rate of birth losses in the sibship, suggesting a low viability of the affected fetuses
(Giugliani et al 1985).
Type 2, late infantile or juvenile, includes cases with onset between 7 months and
3 years. The first sign is difficulty in walking. Purposeful use of hand and speech deteriorates. A spastic quadriparesis associated with pseudobulbar signs can supervene, sometimes with seizures (Brunetti-Pierri and Scaglia 2008). Cherry-red spots were seen in less than 20% of cases. Differently from the infantile form, in type 2 GM1 the macrocephaly, hepatosplenomegaly and the dysmorphisms are less impressive. The most important extraneural involvement is the skeletal abnormalities, consisting mainly of mild anterosuperior hypoplasia of the vertebral bodies at thoracolumbar junction. There is a progressive neurological deterioration: after a stage of decorticate rigidity, death occurs at 3 to 10 years of age (Lyon et al
2006).
Type 3, or the adult or chronic form, is the mildest form of disease, starting at any age after 4 years. The majority of diagnosed cases were of Japanese ancestry.
The picture is either that of a slowly progressive generalized dystonia with prominent facial involvement, or of an akinetic–rigid Parkinsonism (Roze et al
2005). No other LSD has so important extrapyramidal manifestations as GM1 type
3 (Table 3).Dysarthria can be another consequence of basal ganglia involvement.
Intellectual impairment, if present, is moderate. Other neurological manifestations, such as seizures, ataxia, myoclonus, are usually absent. Cheery-red spots, dysmorphisms or visceromegalies were also rare (Lyon et al 2006; Brunetti-Pierri and Scaglia, 2008).
CSF uses to be normal in GM1 gangliosidosis. EEG can be altered but not in any distinctive way. The neuroimaging of the infantile form showed a variety of signs, such as hypointense thalami and diffuse WM abnormality on Flair (Di Rocco et al
2005; Erol et al 2006; Autti et al 2007 (b)), and the radially oriented hypointense stripes in hyperintense cerebral white matter on T2-weighted images (van der
Voorn et al, 2005). In adult form, high signal of posterior putamen was repeatedly described (Uyama et al 1992; Muthane et al 2004).
Neuropathology of GM1 Gangliosidosis consists mainly of abnormal intralysosomal lamellar cytoplasmic bodies in neurons and glial cells. Inclusions were seen in perikarya and also in the initial segment of axons, producing meganeurites.
Whereas diffusely involved in the infantile form, cortical neurons are less affected in late-onset forms. In type 3, storage of ganglioside GM1 predominates in the basal ganglia, mainly in the caudate nucleus (Lyon et al 2006; Brunetti-Pierri and
Scaglia 2008).
Clinical manifestations result from the massive storage of GM1 ganglioside in CNS and related glycoconjugates in different tissues. Any of these stored materials can have a trophic effect that would explain part of macrossomic phenotype. Stored
GM1 ganglioside induces early aberrant dendrite sprouting and activates autophagy. How it correlates to neuronal cell death and demyelination, astrogliosis and microgliosis, will be further explored by Scarpa et al (present issue).
1. 3 Gaucher disease
Gaucher disease (GD) is caused by deficiency of the acid ß glucosidase or glucocerebrosidase, the enzyme that catalyzes the breakdown of the glycolipid glucosylceramide to ceramide and glucose. Neuronopathic Gaucher disease
(NGD) is defined as any GD that presents with neurological symptoms and signs, for which there is no other primary cause (Beutler et al 2001).
GD is one of the most common lysosomal storage diseases (LSD) and its prevalence has been estimated to be 1 per 57 000 births (Meikle et al 1999). NGD is estimated to encompass approximately 6 % of all GD (Charrow et al 2000), corresponding to 1/100 000 live births or less (Vellodi et al 2001). Some populations show higher proportions of neuronopathic (type 3) versus non- neuronopathic form, such as the Polish and the Japanese (Tylki-Szymanska et al
1996). This is partly explained by the absence of the “protective” mutation (non- neuronopathic) 1226A>G (N370S) in these groups. A founder effect for GD type 3 linked to 1448T>C (L444P) mutation was described in Swedish families from the
Norrbotten province (Dreborg et al 1980).
GD has been classically divided into types 1, 2 and 3, based upon the rate of progression and presence or absence of neurologic manifestations. Nowadays, there is a trend to consider GD as a continuum of phenotypes (Goker-Alpan et al
2003; Sidransky 2004; Pastores and Hugues 2008).
Type 2 (acute or infantile)
GD type 2 is the early infantile deterioration syndrome characterized by primary
CNS involvement with a rapid progressive course, loss of psychomotor development, and death by age of two to four years (Figure 1 and Table 3).
According to major case series reported so far, the most frequent initial signs appear between 3 and 6 months of age and include hyperextension of the neck, feeding difficulties, and paralytic strabismus with a variety of oculomotor palsies - all major signs of this brainstem involvement. Whereas enlarged liver and spleen are a constant, there is no skeletal involvement. Other systemic clinical manifestations such as cytopenia, pulmonary disease and dermatologic changes are present. The clinical course is rapid. Marked dysphagia is a striking feature, and is followed by laryngeal stridor, trismus, pyramidal signs and progressive microcephaly. Seizures are rare and there is no startle response, nor a cherry-red spot, as in GM2 (Lyon et al 2006; Mignot et al 2006).
Whereas some authors understand that the clinical picture is homogeneous
(Mignot et al 2006), others propose to divide type 2 in two clinical subgroups, according to the presence of pyramidal signs, because this finding would be associated to an even worse prognosis (Vellodi et al 2001).
Type 3 (subacute or juvenile) Patients with this variant of disease presented with enlarged liver and spleen probably before 2 years of age. The disease progresses slowly, with cytopenia, interstitial lung disease, and skeletal involvement. Usually, neurological signs such as ocular abnormalities or polymyoclonus will appear between 6 and 15 years of age, when the diagnosis of GD type 3 is evidenced (Lyon et al 2006; Tajima et al
2009).
The most characteristic neurological sign is the oculomotor apraxia (OMA) of the horizontal gaze, already described in several different ways (such as “supranuclear saccadic gaze palsy”, “slow horizontal and downward saccades”, “abnormal vestibule-ocular reflexes”, and “saccade initiation failure”, or SIF) (Harris et al 1996 and 1999; Garbutt and Harris 2000; Campbell et al 2003; Lyon et al 2006;
Schiffmann and Vellodi 2007) (Table 3). Dreborg and collaborators (1980) described this finding as,”when the child was running and changed direction, the eyes temporally remained fixed in the original direction. In order to get its eyes in the intended new direction the child had to turn its head towards the side in question.” Children usually adopt a compensatory strategy of head thrusting to shift gaze horizontally and or synkinetic blinking. (Garbutt and Harris 2000). The subjacent mechanism has been described as a failure in the initiation of quick phases of vestibular or optokinetic nystagmus. The involvement of vertical eye movements, when following OMA (or SIF) can be used as sign of progression of this disease (Garbutt and Harris 2000). Other neurological findings appear as the disease progresses, conferring phenotypic heterogeneity to this form of disease. Some features of motor disorder include ataxia, dysarthria, pyramidal signs, polymyoclonus, tonic-clonic seizures, trismus, and dystonia. (Campbell at al 2003; Park et al 2003; Lyon et al 2006;
Shiffmann and Vellodi 2007; Pastores and Hugues 2008). Parkinsonism and psychiatric symptoms were seen in adult sibs with type 3 (Raja et al 2007).
Cognitive deficits are common and dementia has been observed in the later stages of disease.
Patients presenting with a specific combination of a progressive myoclonic encephalopathy and mild systemic involvement, have been classified as a subgroup called type 3a (Beutler et al 2001; Park et al 2003). Myoclonus could originate either in the neocortex, as supported by PEV studies, or in the reticular formation (magnocellular bulbar), as supported by the neuropathological finding of neuronal losses in the dentate nucleus (Verghese et al 2000).
Perinatal lethal form
Children are born with pyramidal signs, arthrogryposis, and icthiosiform or collodion skin changes in the context of non-immune hydrops fetalis. The arthrogryposis was related to the motor neuron apoptosis in the spinal cord (Mignot et al 2006)
Somatosensory (SSER) and brainstem evoked response (BAER) studies on GD types 2 and 3 revealed unspecific alterations (Bamiou et al 2001; Manganotti et al
2001; Campbell et al 2003 and 2004). Peripheral nerve velocity studies on GD type 2 and 3 are usually normal, contrarily to the results found in type 1 (Pastores et al
2003; Mignot et al 2006; Lyon et al 2006; Biegstraaten et al 2008). In patients with myoclonic fits, EEG evidences bilateral, multifocal spikes and spike and wave discharges (Park et al 2003). Neuroimaging can reveal either minimal brain atrophy or normal results, though there were some case reports with other abnormalities
(Hill et al 1996; Chang et al 2000).
Disease progression and severity present an important inter and intrafamilial variability. For instance, one sibling was severely affected during childhood while the other presented a neuronopathic disease during adolescence (Tripp et al 1977;
Dreborg et al 1980; Beutler et al 2001; Koprivica et al 2001; Cox-Brinkman et al
2008).
Studies on the natural history are lacking. One or two longitudinal observations were published, but the obtained data are hard to be generalized (Dreborg et al
1980; Blom et al 1983). Among other findings, splenectomy seemed to accelerate the progression of neurological signs. Neurological outcomes in type 3 patients on enzyme replacement therapy (ERT) have been reported in open label studies: the lack of a control group prevented the results to be either clearly conclusive, or to help understand the natural history (Aoki et al 2000; Davies et al 2007a; Lonser et al 2007). A randomized, controlled trial used as endpoint the vertical saccadic eye movement (VSEM) velocities found no differences between treated groups, but their VSEM worsened steadily in 24 months (Schiffmann et al 2008) (Table 1).
Results using a severity scoring system to assess the neurological features of GD type 3 are waited (Davies et al 2007b). Even with those gaps of knowledge, it was estimated that life span of GD type 3 has changed from the former 12 years of age
(Dreborg et al 1980), to the third or fourth decade, after the advent of enzyme replacement therapy (Schiffmann and Vellodi 2006 and 2007; Pastores and
Hugues 2008).
The pathological hallmark of GD is the perivascular lipid laden macrophage
(Gaucher cell). Usually, there is no storage material in other cell types. However, astrogliosis on hippocampal CA2-4, calcarine cortex 4b, and cerebral cortex 3 and
5 layers have been reported on either non-neuronopathic and neuronopathic GD.
Neuronal loss in both NGD (type 2 and 3) were also observed.
Glucocerebrosidase-specific immunohistochemistry studies showed a high level of glucocerebrosidase expression in hippocampal CA2-4 pyramidal neurons, either in
GD type 1 or in normal controls (Pelled et al 2000; Lloyd-Evans et al 2003; Wong et al 2004). It is possible that increased levels of glucocerebroside in these topographies can be related to neuronal injury (Korkotian 1999; Wong 2004).
Another explanation to the neuronal dysfunction in GD would be the accumulation of glucosylsphingosine (glucosylpsychosine, or deacylated form of glycosilceramide), a compound with neurotoxic function (Schueler et al 2003).
1.4 Niemann-Pick disease types A and B Niemann-Pick disease types A and B are due to deficiency of acid sphingomyelinase (ASM) activity. ASM deficiency causes the accumulation of sphingomyelin within cells of the monocyte-macrophage system and in retinal ganglion cells (Schuchman et al 2001).
The estimated birth rate is of ~0.5–1 per 100 000 ( Meikle et al 1999). Niemann-
Pick disease type A (NPA) is more frequent in the Ashkenazi population, where the carrier frequency is of 1:100. Niemann-Pick disease type B (NPB) is panethnic, but mostly found in Turkish, Arabic, and North African descendants (Simonaro et al
2002).
Niemann-Pick disease type-A (NPA), neuronopathic, infantile or severe early- onset form
NPA manifests usually in the third month of life by hepatosplenomegaly.
Progressive neurological deterioration starts by the 7th month, on average, with loss of head control and of other developmental milestones (Figure 1 and Table 3)
(McGovern et al 2006). Blindness and amaurotic nystagmus can be seen at this stage and cherry-red spots is found in a majority of cases, if not in all (Lyon et al
2006; McGovern et al 2006). With time, the classical combination of axial hypotonia and pyramidal signs are present. There is no startle response. As the disease progresses, liver function tests turn abnormal, with evidence of prolonged jaundice and ascitis. Pulmonary infiltration and enlarged lymph nodes can be present. Cachexia, liver failure and vegetative state mark the end stage of disease.
Foams cells can be seen in bone marrow and vacuolated lymphocytes in the peripheral blood. Other ancillary tests that help are the altered lipid profile
(including total cholesterol and triglycerides, with low HDL-C), mild anaemia, thrombocytopenia and leucopenia. Nerve conduction studies performed in anecdotal cases showed reduced velocities (Gumbinas et al 1975; da Silva et al
1975; Landrieu et al 1984).
A longitudinal observation followed ten affected children since their diagnosis to their death; the median ages at start of several manifestations were published. The mean age of diagnosis was 6 months. The average developmental age did not progress beyond 12 months for adaptive behaviour, expressive language, gross and fine motor skills. The head circumference percentiles did not change over time, even in the few patients presenting with macrocephaly. In contrast, weight attainment began to decline beginning at a median age of 9 months. The median age of death was 21 months, with no children surviving the third year of life
(McGovern et al 2006)(Table 1).
Pathological studies are very rare and included only conjunctiva, liver and nerve biopsies. Dense inclusions were present in the cytoplasm of Schwann cells, myelin sheaths are thin, and myelinated fibres revealed diffuse irregularity of the myelin sheath (Gumbinas et al 1975; da Silva et al 1975; Landrieu et al 1984). Niemann-Pìck disease type B (NPB), chronic visceral form
NPB is usually non-neuronopathic, and is characterized by hepatosplenomegaly with stable liver dysfunction and hypersplenism, gradual pulmonary involvement and typical atherogenic lipid profile. The phenotypic spectrum varies widely, and the age of onset may be from early childhood, adolescence until adulthood
(Schuchman et al 2001; Wasserstein et al 2004; Mihaylova et al 2007; McGovern et al 2008). Some of those patients with ASM deficiency who survive early childhood – excluding the diagnosis of NPA - can have progressive and/or clinically significant neurological manifestations. (Wasserstein et al 2004; Mihaylova et al
2007; McGovern et al 2008).
Case series and surveys have described a wide spectrum of neurological abnormalities in NPB, encompassing neuropsychiatric symptoms, tremor, ataxia, demyelinating neuropathy, pyramidal and extrapyramidal signs, and cherry red spots (Wasserstein et al 2004; Mihaylova et al 2007). A recent cross-sectional study reported that 15 of 59 patients presented with cherry-red spots at a mean age of 23 years. Among them, 5 (or 10% of the overall sample) had cognitive impairment. In the remaining 44 patients without cherry red spots, none had cognitive impairment but five (10%) had peripheral neuropathy (McGovern et al
2008). This association of cherry-red spots with mental handicap, although non- obligate, represents the so called intermediate form of NPD-B, reported since the seventies, which included mainly hypotonia and areflexia, and less frequently, ataxia, with onset of neurologic findings from 2 to 7 years (Wasserstein et al 2004).
Psychiatric symptoms have been described such as hallucinations and psychotic behaviour. They were associated with progressive ataxia, dysarthria, pyramidal signs, athetosis, and cognitive deficits (Mihaylova et al 2007).
In some patients, neuroimaging studies showed cortical and cerebellar atrophy, small pons, and enlargement of the cisterna magna (Obenberg et al 1999; Pavlu-
Pereira et al 2005; Mihaylova et al 2007). In others, neurophysiological studies revealed reduced motor nerve conduction velocities (Mihaylova et al 2007).
Marked intrafamilial heterogeneity has been reported at least once (Obenberg et al
1999). The phenotypic heterogeneity found among gipsies sharing the same homozygous mutation perhaps should be interpreted as a similar phenomenon
(Mihaylova et al 2007).
Neuroanatomophatological studies were performed in nerve biopsies. Schwann cells revealed membranous cytoplasmic bodies on electron microscopy which are similar to the ones that were found in NPA (Takada et al 1987; Lyon et al 2006).
1.5 Niemann-Pick type C Niemann-Pick disease type C (NPC) is a lipid storage disease due to a deficient activity of proteins related to cholesterol trafficking, either NPC1 or NPC2, resulting in storage of cholesterol and glycosphingolipids within late endosomes/lysosomes
(Patterson 2008).
NPC is panethnic. The prevalence in countries from Western Europe is estimated to be about 1/120 000 to 1/150 000 living births. (Vanier and Millat 2003). A founder effect in individuals of Hispanic descendence in Colorado and New Mexico has been described, as well as in French Acadians of Nova Scotia, referred to originally as Niemann–Pick type D (Greer et al 1998; Patersson 2008). This former type should be considered a phenotype variant of NPC (Patterson et al 2001).
The spectrum of manifestations and age of onset ranges from foetal hydrops, neonatal cholestatic, ataxic gait, supranuclear vertical gaze palsy (VSGP) (Table 3) and gelastic cataplexy, to psyquiatric symptoms and extra pyramidal signs in adolescence and adulthood (Patterson et al 2001; Imrie et al 2002; Lyon et al
2006; Sevin et al 2007; Patterson 2008). Prolonged neonatal jaundice was observed in all age group; the degree of neonatal liver involvement is clearly related to the severity of neurological progression (Imrie et al 2007).
Different visceral manifestations between sibs have been recognized (Vanier and
Milat 2003, Imrie et al 2007). However, there is homogeneity in subtypes of neurological presentation (Sevin et al 2007). The late infantile form corresponds to less than one third of all patients with NPC.
Hepatoesplenomegaly and self-limited episodes of jaundice are present in early neonatal period. The first neurological manifestations, which appear at around two years of age, include progressive loss of motor and cognitive functions associated with tremors, pyramidal signs and VSGP without peripheral neuropathy.
Neuroimaging can reveal leukodystrophy. Most infants die between the ages of 3 and 5 years (Patterson et al 2001; Vanier and Millat 2003; Patterson 2008); Lyon et al 2006).
Juvenile NPC is often characterized by the presence of ataxic gait, tremor, dyspraxia, dysarthria and cognitive impairment between the third and eighth year of age. Ocular abnormalities, mainly VSGP, are the major neurological signs in the earlier stages of the disease, being constant after the age of 7 years (Table 3).
Downward saccades are usually impaired before then upward saccades. Other neurological symptoms have been reported, such as dystonia, coreoathetosis and gelastic cataplexy, in approximately 20% of the children (Uc et al 2000; Lyon et al
2006). In later stages, horizontal saccade initiation failure, pyramidal signs and dementia are added to the clinical picture (Fensom et al 1999; Garbutt and Harris
2000; Lyo et al 2006). Neurophysiological studies revealed either demyelinating or axonal forms of polyneuropathy (Uc et al 2000; Zafeiriou et al 2003).
The adult form of NPC was recently reviewed (Sevin et al 2007). The mean age of onset of neurological or psychiatric symptoms in 55 patients was 25 years.
Seventy-six percent of those patients showed cerebellar ataxia; 75%, VSGP; and several had dysarthria, cognitive impairment, extrapyramidal signs, splenomegaly, dysphagia and psychiatric disorders that presents as a bipolar disorder (Sullivan et al 2005).
Brain MRI can be normal in NPC. In the adult forms, however, two MRI patterns have been observed. In patients exhibiting predominant psychiatric or cognitive signs, there was cortical atrophy mainly in the frontal lobes, associated or not with thin corpus callosum. In patients with predominant gait and movement disorders, there were more pronounced brainstem and cerebellar atrophy. At late stages, atrophy was diffuse (Sevin et al 2007). Hyperintense areas on T2 in the periventricular white matter were also described (Grau et al 1997).
Reports on natural history and clinical course of NPC have appeared in literature.
A randomized, controlled trial used as primary endpoint the horizontal saccadic eye movement (HSEM) velocities, as well as dysphagia and an ambulatory index
(Patterson et al 2007). The brain spectroscopy was also used in three patients as an indicator of treatment efficacy (Galanaud et al 2009). Probably better than isolated neurological or neuroimaging signs, at least four clinical severity scales to stage the progression for NPC were also developed (Higgins et al 1992; Iturriaga et al 2006; Klarner et al 2007; Yanjanin et al 2009). The most recent of these scales was applied longitudinally, in prospective and retrospective cohorts of NPC, and their results can inform about the disease progression (Yanjanin et al 2009)
(Table 1). Late-infantile, juvenile and adult forms were recruited. Scores increased linearly as a function of time interval between visits, and nonlinearly as a function of age (Yanjanin et al 2009).
Neuropathology of NPC disease revealed neurons with typical ballooning in the brain and autonomic ganglia, as well as neuronal loss, astrogliosis and demyelisation. At the ultrastructural level, pleomorphic cytoplasmatic inclusions in neurons are identified (Walkley and Suzuki 2004; Lyon et al 2006). Axonal alterations in the form of spheroids were observed, similar to those seen in infantile neuroaxonal dystrophy and Sandhoff disease (Elleder et al 1985; Karten et al
2003; Walkley and Suzuki 2004). Neurofibrillary tangles and the accumulation of amyloid-ß -protein have also been described (Suzuki K et al 1995; Walkley and
Suzuki 2004).
1.6 Metachromatic Leukodystrophy
Metachromatic leukodystrophy (MLD) is a sulfatide storage disease due to the classical deficiency of arylsulfatase A (ARSA) or of the protein activator saposin B
The overall, minimal prevalence of classical MLD varied between 1:40 000 and
1:160 000 in different populations. However, in highly inbred groups like the
Habbanite Jews, Israeli, Christian Israeli Arabs and Navajos, frequencies raise from 1:75 to 1:10 000 (Von Figura et al 2001).
Sulfatide is a normal constituent of myelin. In MLD, sulfatide accumulates in oligodendrocytes and Schwann cells, and leads to progressive demyelization in the CNS and PNS. Three clinical forms can fairly describe MLD phenotypes. Although none of the forms present a stereotyped presentation, the late infantile MLD generally presents pyramidal and neuropathic findings, in any chronological order and in distinct degrees. This phenotype matches well with the primary involvement of oligodendrocytes and Schwann cells (Table 3). On the other hand, juvenile and adult forms show marked inter and intrafamilial heterogeneity. Late infantile MLD is associated with null mutations, whereas juvenile and adult forms are associated with mutations leading to some residual activity of ARSA (Table 2). Clinical heterogeneity of the late onset forms, together with the possible residual activity of
ARSA, suggest the existence of an unknown modifying factor in the definition of phenotypes.
Late infantile MLD
This is the most common form, affecting around 60 % of MLD patients (Lugowska et al 2005). Gait difficulty is the first clear-cut sign, appearing between 14 and 18 months of age. One of the following three neurological syndromes can be the initial presentation picture: (a) a motor polyneuropathy, combining flaccid paraparesis, hypotonia, absent tendon reflexes, and normal plantar responses, lasting alone for several months before corticospinal involvement is apparent; (b) a paraparesis combining pyramidal signs with a motor neuropathy; or (c) a spastic paraplegia with hyperactive reflexes (Lyon et al 2006). Even in the last form, nerve conduction studies usually show a myelinic involvement of peripheral, motor and sensory nerves. As disease progresses, the child loses the ability to stand and sit up, and there are a progressive appearance of axial hypotonia, intention tremor in the arms, dysarthria, dysphagia, and loss of higher cerebral functions. Later, the appearance of seizures, loss of vision, optic atrophy and, more rarely, cherry-red spot has been described.
CSF presents with high levels of protein, sometimes with elevation of gamma globulins. Leukodystrophy is present in MRI, affecting the periventricular and central white matter and sparing U fibers. From an initial occipitoparietal involvement, the lesions progress rostrally, always without gadolinium enhancement. Sometimes, the diffuse high signal intensity on T2-weighted images of MLD was interrupted by radially oriented stripes of low signal intensity (van der
Voorn et al 2005).
From anecdotal reports, death is estimated to occur after decerebration and a persistent vegetative state, around 3 to 7 years of age (Lyon et al 2006).
Juvenile and adult MLD
The first manifestations of the juvenile MLD start between four and 16 years. Early- and late-juvenile sub-variants are sometimes differentiated, motor difficulties developing first in the earlier-onset cases and behavioral and cognitive issues developing first in the later-onset cases (Von Figura et al 2001). Both extreme phenotypes, sometimes called motor (or spastic-ataxic) and psycho-cognitive (or behavioral), has motivated the search for specific genotype-phenotype correlation.
In at least two studies, p426l/p426l genotype was more frequently found in spastic- ataxic patients, and the I179S allele, in patients with behavioral problems
(Baumann et al 2002; Rauschka et al 2006). In a retrospective study of 41 patients, the ranges of ages at onset and documented disease durations of the two phenotypes were superimposed, although the spastic-ataxic (p426l/p426l) seemed to start earlier (Rauschka et al 2006). Among patients with the I179S mutation, the residual activity of the other mutant allele was clearly associated with age at onset.
Both extreme groups tended to emerge into the other’s phenotype as the disease progresses, although some cases with behavioral phenotype did not develop any motor sign after 7 to 23 years of disease duration (Baumann et al 2002; Rauschka et al 2006). Frontal lobe–type personality with desinhibition, schizophrenic manifestations, optic atrophy, seizures, and localized cortical disturbances such as aphasia, agraphia, acalculia, apraxia or agnosia, were described during the clinical course of some cases (Rauschka et al 2006).
Quite surprisingly, symptoms or clinical signs of PNS damage were generally absent (Rauschka et al 2006). Although mean motor nerve conduction velocities were slower in the spastic-ataxic group than in the behavioral group, they cannot differentiate between phenotypes, and are unrelated to disease duration.
The same MRI signs seen in the infantile form were found in juvenile and adult patients (Figure E-3 b). Two P426L homozygous patients showed signs of long fiber tract degeneration in brainstem MRI images. In the I179S patients, brainstem changes were absent, whereas white matter changes were frontally localized
(Rauschka et al 2006).
Important differences in ages at onset and in phenotype presentations have been reported between siblings of late-onset MLD forms (Clarke et al 1989; Arbour et al
2000), although no modifier factor was suggested, up to now.
Autopsy studies of some forms of MLD revealed storage of sulfatides in oligodendrocytes and macrophages of demyelinated white matter of cerebrum, brainstem, cerebellum, and spinal cord. Some neurons also presented storage material. Myelin sheets were ubiquitously destroyed, as were, to a lesser extent, axons. Sulfatides also accumulated in Schwann cells, and there was segmental demyelination of peripheral nerves. Loss of myelin sheaths was significantly present in the brain stem and spinal cord in the juvenile type than in the late infantile type (Takashima et al 1981; Lyon et al 2006).
Some evidences showed that the accumulated sulfatide is phagocyte by neurons, where it induces apoptosis. This can be related to the pathophysiological cascade of events, in MLD (Scarpa et al, in this issue).
1.7 Krabbe disease Krabbe disease (KD), or globoid cell leukodystrophy (GLD), is an autosomal recessive neurodegenerative disorder due to the lack of the lysosomal enzyme galactocerebrosidase (GALC), which aids in the breakdown and removal of galactolipids from myelin (Wenger et al 2001). When the onset is before 6 months, it is called early infantile KD (EIKD). EIKD is probably the most frequent form of
KD. The later forms of KD are much less common, and have a variable life expectancy. Collectively, they can be called late-onset KD (LOKD). Former estimates pointed that about 90% of all KD were EIKD, and that its incidence would be of 1 in 100,000 (Wenger 2008). The highest incidence, 1 in 6 000, has been reported in a Druze kindred in Israel (Wenger et al 2001; Zlotogora et al 1985). The observed results from the New York State Newborn Screening were rather different from the expected numbers: two EIKD out of 550,000 screened newborns were detected; other two newborns showed low GALC activities, and are being followed up in order to define their clinical status. Therefore, KD incidence can be lower than 1 in 100,000, or, alternatively, EIKD may represent less than 90% (but at least
50%) of all KD patients (Duffner 2009a).
Neuropathology of KD consists of two findings. There is a widespread axonal loss with demyelination and/or arrest of myelination, associated with reactive astrogliosis, relative spare of U fibers, and a marked reduction of number of oligodendrocytes. Demyelization is more pronounced in phylogenetic newer tracts such as those of corona radiata, corpus callosum and cerebellar peduncles (Itoh et al 2002). Secondly, the presence of the “globoid cells” in the demyelinated areas – actually large PAS-positive histiocytes aggregated around capillaries and venules (Lyon et al 2006). Globoid cells appear in the regions of active myelin breakdown, and their occurrence is sparse in late lesions; these cells decrease as the survival became longer. Immunoreactivity for HLA-DR alpha and TNF alpha suggest involvement of immunological responses in KD. (Itoh et al 2002). On EM, cytoplamic inclusions can be seen in globoid and in Schwann cells. Lysosomal storage is absent or negligible.
Deficiency of the galactocerebrosidase is related to increased levels of psychosine
(galactosylsphingosine), a toxic metabolite of galactocerebroside. Psychosine accumulates in GLD causing degeneration of both myelin-producing cells, oligodendrocytes and Schwann cells (Wenger et al 2001). KD phenotype matches well with the primary involvement of these cells (Table 3). The cascade of events will be reviewed in this issue (Scarpa et al,….).
Early onset Krabbe disease
In the EIKD, clinical course is mostly stereotyped. A recent retrospective study designed to establish a severity staging system divided the course in four stages
(Escolar et al 2006) which essentially agreed with former descriptions (Wenger et al 2001; Lyon et al 2006). Stages were established by transversal observations.
Irritability, vomiting and feeding problems as gastroesophageal reflux are among the first signs in stage 1. The first obvious neurologic symptoms (in stage 2) include muscular hypertonia of limbs. Pyramidal signs are definite in this stage, as well as difficult feeding. Stage 3 presents an increase of hypertonia to all limbs and to opisthotonic, spasmodic or sustained recurvation of trunk and neck. Deep tendon reflexes become depressed as time passes, reflecting the subjacent polyneuropathy. Optic atrophy and sluggish pupillary reactions to light are common. In the “burnt out stage 4”, patients are immobile, either hypotonic or decerebrate, and unable to feed. Jerky eye movements, seizures, unexplained fever and startle can also appear (Escolar et al 2006; Lyon et al 2006; Wenger
2008). It is worth remind that sometimes the above mentioned signs did not follow that chronology of events. For instance, in some infants, initial clinical symptom was either seizures or peripheral neuropathy alone for months (Wenger 2008).
Head size gradually diminishes, being in the 2 to 3 lower standard deviations. The reduction in head circumference is not explained only by malnutrition. Global atrophy and high signal intensity on occipital periventricular white matter are usually seen in on brain MRI (Figure E-3 c). Average survival is 12 month or less
(Lyon et al 2006; Wenger 2008).
Staging system was developed to describe the course of EOKD submitted to hematopoietic stem cell transplantation (HSCT). Follow up results show that HSCT in newborns with EIKD prolongs survival, but does not prevent disease progression
(Duffner et al, 2009b).
Late onset Krabbe disease
The rare late-onset forms (LOKD) can start at almost any age, combining three main symptoms: motor weakness, vision loss, and intellectual regression. Late infantile and juvenile forms did not differ significantly, at least in one major case series (Lyon et al 1991). Progressive equinovarus deformity, with walking difficulties, in a previously normal or mildly retarded child, used to be the first signs of disease. A spastic paraparesis supervenes, sometimes associated with cerebellar ataxia and dystonia. Visual failure due to optic atrophy is almost always present with advancing age. In many cases, dementia progresses after the onset of motor signs (Lyon et al 1991). However, some patients did not show this classical progression (Jardim et al 1999). For instance, we have seen two brothers with disease onset in the adolescence, whose major manifestation was cognitive deterioration and temporal seizures, without any motor losses, optic atrophy or visual losses. Survival after disease onset seemed to be directly related with age at onset: in late-infantile forms (onset age six months to three years), death occurred approximately two years after onset. In the juvenile group (onset age three to eight years), survival after disease onset could be longer than seven years (Loonen et al
1985).
Neurophysiologic studies of EOKD show early abnormalities in the disease course.
Nerve conduction studies are reduced in almost all patients since stage 1 (Husain et al 2004; Siddiqi et al 2006), even before the appearance of specific signs. In contrast, peripheral neuropathy is observed in approximately 50% of LOKD patients (Sabatelli et al 2002). NCV studies have been reported to be normal in some adults (Wenger 2008).
In some EOKD patients, VEP and BAER were absent early in the disease, with no clear cut progression according to stage level (Escolar et al 2006; Husain et al 2004). The CSF protein level is high since diagnosis – meaning that, in EOKD, it is high soon after birth. Eletrophoretic pattern is usually normal.
General characteristics of leukodystrophy on MRI were described in a series of 22 patients by a severity score ranging from zero to 32 points (Loes et al 1999). Very good correlation between neurocognitive tests and Loes scores indicated that this scoring system can reasonably help assessing prognosis (Provenzale et al 2009).
In EOKD, the leading imaging findings were signal abnormalities within cerebellar white matter, the deep gray nuclei, and the pyramidal tract. The involvement of the parietooccipital white matter and corpus callosum developed rapidly, along with global atrophy. In five patients, serial MRIs obtained in an 8 months interval, revealed an average increase of 6 points in the score. In LOKD, signal abnormalities were seen in the pyramidal tract, posterior corpus callosum, and parietooccipital white matter. In some cases, CT reveals symmetric hyperdensity involving the cerebellum, thalami, caudate, corona radiata, and brain stem
(Wenger 2008; Jardim et al 1992). Hypertrophy of the optic nerves, optic chiasm, and other cranial nerves were also described (Bussière et al 2006; Patel et al
2008), as well as radial stripes inside demyelinated tracts (van der Voorn et al
2005).
Differently from early onset forms, in LOKD there is intrafamilial variability of age of onset and neurological manifestations (Verdru et al 1991; Bernardini et al 1997;
Wenger 2008). In a case series of 11 families (15 patients), for instance, 4 sibships presented some clinical heterogeneity (Kolodny et al 1991). 1.8 Farber lipogranulomatosis
Farber disease is a rare lysosomal storage disease, characterized by tissue accumulation of ceramide and due to acid ceramidase deficiency (AC). The prevalence of the disease is unknown. Phenotype has been subdivided into seven subtypes. The typical form (type1) is characterized by painful swelling and deformation of the joints, subcutaneous nodules, dysphonia, dyspnea and malnutrition. Symptoms usually appear between ages 2 weeks and 4 months. In the early phases of disease, neurological signs are not prominent and are difficult to detect in view of the severe degree of articular and cutaneous involvement. As the disease progresses, severe motor and mental retardation is evident and reported in most cases. There are usually signs of involvement of the pyramidal tracts, blindness and abnormal grayness of the macula with cherry red spots
(Pellissier et al 1986). Infantile spasms and other types of seizures are occasionally seen. The electromyogram can show signs of denervation and or peripheral nerve lesions. Death occurs by 2 years of age.
The granulomatous infiltration by PAS contains both ceramide and glycolipids, namely gangliosides. In the CNS there is neuronal storage mainly in the anterior horn cells, brain stem nuclei, basal ganglia and ganglion cells of the retina, and in a lesser degree, in cerebral cortex (Burck et al 1985; Moser et al 2001).
2. Mucopolysaccharidoses (MPS) The mucopolysaccharidoses (MPS) are a group of disorders caused by the deficient degradation of glycosaminoglycans (mucopolysaccharides, GAGs).
Lysosomal accumulation of GAGs results in cell, tissue and organ dysfunction. The
MPS share many clinical features, although in variable degrees. These include a progressive course, coarse faces, corneal clouding, hernias, dysostosis multiplex, and hepatosplenomegaly. Profound mental retardation is characteristic of some of them - MPS 1H (Hurler syndrome), the severe form of MPS II (Hunter syndrome), and all subtypes of MPS III (Sanfilippo syndrome). The probable anatomic basis for cerebral dysfunction is the accumulation of gangliosides, most notably GM2 and
GM3, in neurons (Jeyakumar et al 2005; Reuser and Drost 2006). In some patients there is an added tension hydrocephalus resulting from GAGs deposition, histiocytic infiltration, and collagen proliferation in the meninges and arachnoid villi.
(Muenzer 1986; Neufeld and Muenzer 2001; Lyon et al 2006; Clarke 2008). As already mentioned, we will focus on those diseases with primary neuronal involvement.
2.1 MPS I
MPS I is due to an autosomal-recessive α-L-iduduronidase deficiency. MPS I is a panethnic and progressive disease in which degradation of the GAGs dermatan and heparan sulphate is deficient. Three clinical syndromes are often referred to which, from severe through intermediate to mild phenotypes, are termed Hurler
(MPS IH), Hurler-Scheie (MPS IH/S) and Scheie (MPS IS) It is clear however that there is a broad disease spectrum, and attribution to either one of the phenotypes is only possible on clinical basis, not by biochemical investigation (Neufeld and
Muenzer 2001). Although the combination of two severe alleles (nonsense exonic, splice site, deletion, and insertion mutations) is usually related to Hurler syndrome, the ability to accurately predict phenotype based on genotype may be limited
(Terlato and Cox 2003; Rempel et al 2005).
The estimated incidence for MPS I ranges from 1:76 000 (Hurler phenotype) to
1:280 000 or 500 000 (Scheie phenotype) (Lowry et al 1990, Meikle et al 1999,
Poorthuis et al 1999 , Hoffmann and Mayatepeck 2005). Prevalence at birth was of 1: 100 000 (Moore D et al 2008).
Hurler syndrome (MPS I H) affects 47% of all MPS I cases (Pastores et al 2007).
Expert opinions and case series dominate the literature. Neurological development is normal or moderately retarded until the end of the first year, when it arrests and then declines. Social behavior usually is relatively preserved, but in some patients agitation and aggressiveness are troublesome. After some time, signs of corticospinal tract dysfunction appear and there is occasionally evidence of lower motor neuron involvement and or peripheral neuropathy. CNS complications culminate in dementia. A registry which included 302 patients presented its first results recently; data on neurological manifestations should come soon (Pastores et al 2007).
Besides neuronal involvement, several complications in adjacent tissues or sensory organs add to the child’s difficulties, such as obstructive hydrocephalus due to GAG infiltration of the dura matter, defective hearing, corneal clouding, cord compressions, and cervical subluxation. The raised intracranial pressure causes papilledema and progressive enlargement of the head, which may contribute to the mental regression. In addition to the primary, pigmentary degeneration of the retina, the appearance of corneal opacities and optic atrophy (due to pachymeningitis or hydrocephaly), contribute to the visual impairment.
In brain CT and MRI scans, various degrees of ventricular dilatation and white matter hypodensities may be found. Attempts to correlate cerebral MRI findings and mental retardation in patients with MPS I H have failed (Lyon et al 2006;
Vedolin et al 2007b).
Although cohort studies on the natural history are lacking, there are several longitudinal studies on the impact of bone marrow transplantation in neurocognitive functions of MPS I H patients. Intelligence stabilizes and reaches normal values, patients go to school, and the progressive cerebral atrophy or hydrocephalus did not appear after long-term follow-up. Evaluations included standard neuropsychological tests, with no scoring system specifically designed to neurological and motor impact (Souillet et al 2003; Staba et al 2004; Aldenhoven et al 2008).
Irrespective of any treatment, the median survival for MPS I patients in general is of 11.6 years, and for MPS I H is of 8.7 years. The median survival of MPS I H patients who did not receive bone marrow transplantations felled to 6.8 years
(Moore D et al 2008). 2.2 MPS II (HUNTER SYNDROME)
Hunter syndrome, or MPS II, the only X-linked disorder among the MPS, is caused by the deficiency of iduronate-2-sulfatase that results in storage and excretion of excessive quantities of dermatan sulfate and heparan sulfate (Neufeld and
Muenzer 2001).
This is a pan-ethnic disease with an incidence of 1.3 per 100,000 male live births in
Netherlands and Germany (Poorthuis et al 1999; Baehner et al 2005). Several IDS mutations were already associated with different phenotypes. Genotype-phenotype correlations are therefore weak, with the exception of total or partial gene deletion or by gene/pseudogene rearrangement, which usually result in the severe phenotype (Martin et al 2008; Al Sawaf et al 2008).
MPS II is traditionally classified in two clinical subtypes, mild and severe. The severe form of Hunter disease would be similar to Hurler syndrome, except by sparing the cornea, whereas the mild form is analogous to Hurler/Scheie or Scheie syndrome (milder forms of MPSI), with a longer lifespan, a slower progression of somatic deterioration, and retention of intelligence (Neufeld and Muenzer 2001).
These two subtypes may rather represent two ends of a wide spectrum of severity
(Young et al 1982; Wraith et al 2008; Martin et al 2008).
In the severe form of MPS II, clinical features appear before 2 years of age. Age at onset was one of the variables that can be use to anticipate if a child would have the severe form (Young et al 1982; Schwartz et al 2007). The severe phenotype may be up to 3 times more prevalent than the attenuated phenotype. Life expectancy is approximately 12 years for severely affected patients (Schwartz et al
2007; Martin et al 2008).
Primary neuronal involvement seems to be responsible, in part, for cognitive, behavioral and motor deterioration, and for seizures. Retinal dysfunction is also an evidence of direct neuronal involvement. Severe MPS II patients present with verbal IQ worse than the performance component. The highest cognitive score is achieved at around 7 years (Al Sawaf et al 2008). Regression was reported to begin at mean age of 8 years. Neurological impairment progresses towards dementia. Severe behavioral disturbances, such as hyperactivity, obstinacy, and aggression, are commonly seen. Seizures affect between 13% and 50%, in those patients reaching 10 years of age (Schwartz et al 2007; Martin et al 2008) and early onset seizures tended to be found in patients with complete gene deletion
(Wraith et al 1991; Froissart et al 1993). Ophthalmoscopy reveals bilateral pigmentary changes and loss of field of vision in some patients. Retinitis pigmentosa cannot be so evident, due to a loss of pigmentation in the epithelial cells and a moderate degree of gliosis at the nerve fiber layer (Al Sawaf et al
2008). Other findings include disk swelling and optic atrophy. These findings can be due to sclera and meningeal thickening, and to hydrocephalus, which may cause optic nerve compression.
The GAGs storage in adjacent tissues or sensory organs can be one of the main reasons for neurological handicaps. Among these complications, hearing loss, hydrocephalus, spinal cord compression/cervical myelopathy, obstructive sleep apnea, and cerebral infarctions due to cardiac embolism, should be remembered.
These complications can exacerbate or cause seizures, behavioral disturbances, and motor and cognitive deteriorations (Martin et al 2008; Al Sawaf et al 2008).
MRI studies show white matter lesions (WM), brain atrophy, dilated perivascular spaces, hydrocephalus, and spinal canal stenosis. Brain atrophy tended to involve more extensively both frontal and parietal areas. The WM lesion severity was significantly greater in patients with cognitive impairment, as was the hydrocephalus and the brain atrophy (Vedolin et al 2007b). Other common findings have questionable clinical relevance, such as enlargement of the perivascular spaces, whereas others can be either the result of primary neuronal losses or of hydrocephalus – such as ventriculomegaly, megacisterna magna and widening of the subarachnoid spaces (Matheus et al 2004; Vedolin et al 2007a). MR spectroscopy revealed both astrogliosis (Vedolin et al 2007a), and high levels of
GAGs (Takahashi et al 2001).
Peripheral nerve involvement in MPS II is confined primarily to carpal and cubital tunnel syndromes (MacDougal et al 1977; Al Sawaf 2008).
Reports on the occurrence of severe and attenuated brothers in a given family have appeared as a case report in 1977 (Yatziv et al 1977) and in a case series in
1982, where only one heterogeneity was observed in 17 sibships (Young et al
1982). Post-mortem investigations revealed strikingly thickened leptomeninges (Fowler et al 1975; van Aerde et al 1981). Kurihara et al (1992) found neuronal inclusions in the brain stem identified as mucopolysaccharides and gangliosides. There was macroscopic brain atrophy with mild to severe neuronal swelling in the cerebral cortex and Purkinje cells. Neuronal loss and gliosis appeared also in the dorsomedial and dorsal nuclei of the thalamus. Mild occurrence of TUNEL- immunoreactive nuclei, predominantly in swollen neurons in the frontal and temporal cortices, pointed to an underlying apoptotic mechanism. Most of the remaining neurons have storage materials in the cytoplasm in the cerebral cortex and the anterior horn of the spinal cord (Hamano et al 2008).
2.3 MPS III (Sanfilippo syndrome)
MPS III presents as a distinctive group of disorders caused by the deficiency of one of the enzymes required for the degradation of heparan sulfate, which consequently accumulates in several body organs and is excreted in excessive amounts in the urine. The neurological symptoms appear early and are marked, whereas craniofacial, skeletal and other somatic abnormalities are mild. Four phenotypically similar genetic variants of this disease have been recognized, each related to a defect of one of the following enzymes: heparan-N-sulfatase (type A), alpha-N-acetylglucosaminidase (type B), acetyl-CoA:α-glucosaminide-N- acetyltransferase (type C), and N-acetylglucosamine-6-sulfatase (type D) (Neufeld and Muenzer 2001)
MPS III A disease is the most common form and apparently the most severe.
Patients with this disease may be thought to have undifferentiated mental retardation or psychiatric disorder or even primary epilepsy (Lyon et al 2006). MPS
III type B is a very common subtype of MPS and is probably underdiagnosed in adult patients with mental retardation (Moog et al 2007). MPS IIID is one of the rarest of the MPS-III syndromes. To date, the clinical manifestations of very few patients have been reported.
The clinical course of MPS III has been divided into three phases (Valstar et al
2008). In the first phase, between 1 and 4 years of age, a developmental delay becomes apparent. The second phase starts around 3–4 years with severe behavioral problems and progressive mental deterioration. Seizures are not rare and may be an inaugural manifestation. Pigmentary degeneration of the retina and optic atrophy has been described. Insomnia is very frequent, with settling difficulties, early waking, frequent nocturnal waking, and reversal of their day–night rhythm reported in up to 90% (Ruijter et al 2008). In the final stage, behavioral problems slowly disappear, being substituted for apathy, mental deterioration, loss of speech, and a severe dementia. Spasticity, marked amyotrophy, and depressed tendon reflexes are evident. EMG can reveal signs of lower motor neuron disease, and MRI show marked cerebral atrophy (Lyon et al 2006; Valstar et al 2008). Reports on the natural history have appeared in literature (van de Kamp et al 1981;
Nidiffer and Kelly 1983; Meyer et al 2007; Ruijter et al 2008) (Table 1). Clearly
MPS IIIA has an earlier age at onset and a more severe progression than MPS IIIC
(Meyer et al 2007; Ruijter et al 2008). Whereas median age at death was 15 years
(range 8–25) in MPS IIIA, it was 34 years (range 25–48) in MPS IIIC. MPS III C patients loose verbal communication at 16 and stop walking independently at 25
(median values) (Ruijter et al 2008).
Intrafamilial heterogeneity of phenotypes was already reported in MPS III (Andria et al 1979; Valstar et al 2008).
Neuropathological findings are very similar to those described for MPS II (Hamano et al 2008). The extent as well as the distribution of the diverse storage materials varied within and among different neurons as observed in MPS-III A, B, and C syndromes (Jones et al 1997).
2.4 MPS VII (Sly disease)
MPS VII (Sly syndrome), is an autosomal recessive disorder caused by a deficiency of beta-glucuronidase. GUS is required to degrade heparan, dermatan and chondroitin-4,6 sulfates. It is a very rare disorder, with a highly variable phenotype, ranging from severe lethal hydrops fetalis to mild forms with survival into adulthood. Most patients with the intermediate phenotype show hepatomegaly, skeletal anomalies, coarse faces, and variable degrees of mental impairment. The heterogeneity in GUS gene mutations contributes to the extensive clinical variability among patients with MPS VII (Neufeldt and Muenzer 2001; Tomatsu et al 2009).
3. Mucolipidosis
The term mucolipidosis (ML) refers to the observed combination of symptoms of mucopolysaccharidoses and sphingolipidoses in a given syndrome. Four different inborn errors of metabolism are classified as ML: ML type I (also called sialidosis type II, it will be described later in this paper), the homoallelic forms of ML type II and III, and ML type IV (Kornfeld and Sly 2001; Leroy 2007).
3.1 Mucolipidoses type II and III
Mucolipidosis type II (ML-II, or I-cell disease) and mucolipidosis type III alpha-beta
(ML-III, or pseudo-Hurler polydystrophy), are homoalellic genetic diseases. Both are caused by mutations in the gene encoding the alpha/beta-subunits of the lysosomal hydrolase N-acetylglucosamine-1-phosphotransferase (GNPTAB) and phosphorylate target carbohydrate residues on N-linked glycoproteins. Without this phosphorylation, the glycoproteins are not destined for lysosomes, and they escape outside the cell. As a result, the activity of nearly all lysosomal hydrolases is five- to 20-fold higher in plasma than in normal controls, whereas their substrates storage within the lysosomes. A wide spectrum of severity is then seen, from prenatally lethal to progressive MLII alpha/beta and mild adult onset of MLIIIA alpha/beta (Lyon et al 2006; Dierks et al 2009).
Homozygous and compound heterozygous genotypes that predict enzyme inactivation result in ML II (Bargal et al 2006; Dierks et al 2009). The combination of less severe mutations, such as missense and most of the splice-site mutations that may decrease but not abolish enzyme activity, often yield ML III, with later clinical onset (Bargal et al 2006; Kudo et al 2006).
Incidence estimates vary between 1:123 500 to 1:625 500 live births (Poorthuis et al 1999; Pinto et al 2004). A founder effect was described in Québec, where 16 deceased patients were detected (Plante et al 2008).
ML-II or I-cell disease is characterized by many of the clinical features and radiologic changes that are seen in MPS I H, but is more severe, may be evident at birth, and presents as an early infantile deterioration syndrome, with a more rapid neurological deterioration than other LSD (Table 3). Psychomotor retardation is usually obvious by 6 months (Kornfeld and Sly 2001). Speech is not attained and most children do not walk. There is a striking, unique gingival hyperplasia. Brain
MRI showed ventriculomegaly with frontal lobe atrophy and bifrontal leukomalacia
(Breningstall and Tubman 1994). Craniosynostosis may be the first symptom in mucolipidosis II (Aynaci et al 2002). Inter and intrafamilial variability exists (Beck et al 1995).
MLIII alpha/beta (or Pseudo-Hurler polydystrophy) is a much milder disorder.
Psychomotor development ranges from normal to mild delay in reaching motor milestones (Kornfeld and Sly 2001; Lyon et al 2006). Patients typically live into adulthood, when jopint difficulties then manifest. MLIII is genetically heterogeneous: a new form, called ML III gamma, was related to mutations in the gene encoding the gamma subunit of N-acetylglucosamine-1-phosphotransferase
(GNPTG).Therefore, genetic heterogeneity adds to this complex group of LSD.
3.2 Mucolipidosis IV
Mucolipidosis type IV (MLIV), is caused by mutations in MCOLN1, a novel transient receptor potential (TRP) cation channel gene. The lysosomal storage of lipids and water-soluble substances in mucolipidosis IV is attributed to a transport defect in the late steps of endocytosis resulting from abnormal membrane components of endosomes. The diagnosis is based on demonstration of lysosomal inclusions in conjunctival and skin biopsies and on molecular studies.
Over 80% of the MLIV patients are Ashkenazi Jews; the estimated heterozygote frequency in this population is 1/100. The disease is characterized by profound psychomotor retardation and ophthalmological abnormalities, including corneal opacities, retinal degeneration, and strabismus. Ophtalmological problems typically brings the mentally retarded child to diagnostic work out. Facial features are unaltered and there are no skeletal changes or visceromegaly. Severely affected as well as milder patients have been described. In the typical form, neuropsychomotor development is very limited.
Patients use few or no words at all, and use hands poorly. Receptive language is better than expressive language, probably due to the associated dysarthria or anarthria. Not all cases can sit independently or crawl. Patients present with slow chewing, eating and swallowing. Axial hypotonia can be present, but tendon reflexes are hypereactive and there is a spastic diplegia or quadriplegia. This neurologic picture remained static in 7 out of 10 patients, after 5 years, on average
(Altarescu et al 2002) (Table 1). Visual impairment usually becomes evident between 3 and 8 months of age, due to retinal degeneration. Electrophysiologic studies showed that mildly subnormal ERG recordings become nearly flat in five to ten years (Pradhan et al 2002).
On brain MRI, the corpus callosum is thin, and the splenium is sometimes dysplastic or absent. Moderate to severe white matter hyperintensities on T2- weighted images were present, were not related to age, and did not change after a mean of five years. Increased ferritin deposition was present in the basal ganglia and thalamus (Altarescu et al 2002). Low signal intensity of the thalami in T2- wieghted images were also described (Autti et al 2007b). Dysmyelination and corpus callosum dysgenesis indicate that most of the neurologic abnormalities in these patients are developmental, explaining their static picture. Cerebellar atrophy is found in older patients, suggesting a superimposed neuronal degeneration (Frei et al 1998).
Correlation of the genotype with the neurological handicap and corpus callosum dysplasia was found by Altarescu et al (2002).
Lysosomal storage inclusions have been demonstrated in ultrastructural analyses of biopsied tissues. Autopsy of one case revealed neuronal loss in the cerebral cortex, basal ganglia, deep cerebellar nuclei, and brainstem nuclei, substituted by astrocytosis. Residual neurons had brown granules in the cytoplasm, corresponding to lysosomes laden with osmiophilic, amorphous and granular material (Folkerth et al 1995).
4. Multiple Enzyme deficiencies
4.1 Multiple Sulfatase Deficiency (Mucosulfatidosis; Austin Disease)
Multiple sulfatase deficiency (MSD) is caused by a deficient activity of a non- lysosomal protein, the sulfatase-modifying factor-1 gene (SUMF1). MSD has a prevalence of 1 in 1.4 million births. It is characterized by neurovisceral storage of sulfatides, GAGs and other complex sulfa-ester substrates as a result of the depression of the activity of arylsulfatase A and at least 12 other sulfatases
(Santos and Hoo 2009). A predictable genotype-phenotype correlation will be complicated by the fact that 13 defective sulfatases contribute to the complex clinical phenotype in MSD, each of which most likely giving rise to a compensatory response. When attempting to explain the differences in MSD manifestation from the molecular findings, the key approach must be to define the residual functionality of the relevant formylglycine-generating enzyme (FGE) mutants expressed in patients (Dierks et al 2009; Santos and Hoo 2009).
The clinical manifestation of the rare patients described so far is of a neurological syndrome similar to that of early infantile MLD, except that patients tend to be more severely affected. There are features reminiscent of the MPS, like moderate facial and skeletal deformities, and hepatomegaly. An important clinical feature is icthyosis. In about half of the patients the cerebral development during the first year appears to be normal or moderately delayed. Neurologic regression begins between 12 and 18 months of age and is manifested by difficulty in walking. In some cases, earlier development is markedly retarded. The characteristic combination of pyramidal signs and peripheral neuropathy is the norm. Peripheral neuropathy can explain eventually depressed tendon reflexes. Conduction velocities of motor and sensory nerves are always slowed. The mental capacities regress rapidly and generalized and myoclonic seizures are frequent. By the age of
4 years the child is quadriplegic with pseudobulbar signs (Lyon et al 2006; Dierks et al 2009; Santos and Hoo 2009).
Extensive diffuse and symmetrical demyelination was seen in the deep white matter of both cerebral hemispheres, as well as of the subcortical white matter and the brainstem, very similar to those found in MLD. There was additional enlargement of sulci and subdural spaces and mild atrophy (Zafeiriou et al 2008).
The neuropathological findings combine the features of MLD and those of MPS. As in MLD, metachromatic deposits of sulfatides accumulate in glial cells in the demyelinated white matter of the brain, and in Schwann cells and macrophages of peripheral nerves. In addition, there are clear vacuoles in the vascular pericytes in the brain, and lamellated storage substance characteristic of ganglioside, in intracortical neurons (Guerra et al 1990).
4.2 Galactosialidosis
Galactosialidosis is caused by a combined deficiency of lysosomal beta- galactosidase and neuraminidase, due to a primary defect in protective protein/cathepsin A (PPCA) (Galjart et al 1988; Kleijer et al 1996). Three subtypes are recognized: the early infantile type (severe), the late infantile type (mild), and the juvenile/adult type. The clinical features are heterogeneous and include dysmorphism, skeletal dysplasia, visceromegaly, cardiac and renal involvement, progressive neurologic manifestations, ocular abnormalities, angiokeratoma and early death. Most of the juvenile cases have been described in Japanese patients
(Zhou et al 1996). The early infantile type starts between birth and three months of age, although some cases can present as fetal hydrops. There is severe developmental delay, or even its absence. Both hypotonia and pyramidal findings have been reported, besides cherry red spot and corneal clouding (Table 3). There are scarce mentions to survival rates; death usually occurs around the second year of life (Zhou et al 1996; Zammarchi et al 1996; Claeyrs 1999; d`Azzo et al 2001).
The late infantile type has a very similar phenotype, but a milder neurological picture. Seizures and neurologic deterioration have been observed in a few cases
(d`Azzo et al 2001).
The majority of patients with Galactosialidosis present the juvenile/adult type. Age at onset is around 16 years, but may start as late as the 3rd or 4th decade.
Common findings include angiokeratomas, coarse facial features and spinal changes. Neurological manifestation includes ataxia, generalized seizures, myoclonus, cherry-red spot, vision loss, and mental deterioration. Peripheral neuropathy was sometimes detected (Kobayashi 1979; Miyatake et al 1979;
Mochizuki et al 2000; d` Azzo et al 2001).
Unrecordable ERGs and VEPs in two siblings were suggestive of ganglion cell damage (Usui et al 1993).
Neuropathological studies showed neuronal swelling and lamellar inclusions or cytoplasmic vacuoles in anterior horn cells, spinal ganglia, sympathetic ganglia, and in the Schwann cells of peripheral nerves (Mochizuki et al 2000).
5. Oligosaccharidoses and related disorders
Oligosaccharidoses (also known as glucoproteinosis) are LSD due to mutated proteins involved in the hydrolysis of glycoprotein carbohydrate chains, in a stepwise removal of terminal monosaccharides from proteins. The deficient protein may be a glycosidase, a cofactor or a lysosomal membrane carrier which delivers catabolic products to the cytosol (Michalski and Klein 1999). This is a rather rare group of diseases, with birth prevalences around 0.2/100 000 (Poorthuis et al
1999). Case series and anecdotal reports are therefore sparse. In addition to that, each enzymatic deficiency was related to diverse clinical phenotypes.
5.1 Alpha-Mannosidosis
Alpha-mannosidosis results from the deficiency of alpha-mannosidase (Chester et al 1982). The prevalence of the disease is not precisely known, but a study with newborn screening for LDS estimated that it occurs in approximately 1 of 500 000 live births (Meikle et al 2004).
The phenotype resembles a MPS but is generally milder with moderate coarsening of the face becoming apparent after 2-3 years, a lumbar gibbous, sensorineural deafness, hepatomegaly and dysostosis multiplex (Ockerman 1967 and 1969).
Three clinical types have been suggested: the mild form starts after 10 years of age, without skeletal abnormalities and very slow progression; the moderate form starts before 10 years of age, with skeletal abnormalities and development of ataxia at age 20–30; and the severe form presenting skeletal abnormalities and early, progressive deterioration leading to an early death from primary central nervous system involvement or myopathy. Most patients present the moderate form (Malm and Nilssen 2008). These clinical forms should be seen as steps in a continuum of severity. Patients are often born apparently normal, although some had congenital ankle equines. Children are generally clumsy; ataxia is the most characteristic motor disturbance. Walking difficulties result from a combination of joint abnormalities, a metabolic myopathy, and incoordination. Hypotonia, due either to myopathy or to cerebellar dysfunction, is most common. Spastic paraplegia has also been described, but in general, spasticity, rigidity, and dyskinesia are not observed (Kawai et al 1985). Slight strabismus is common.
Some children develop hydrocephalus in the first year of life. Follow-up studies reported the progressive, slow impairment of motor and mental function with age
(Autio et al 1982). In mentally retarded patients, psychiatric symptoms are added to the cognitive and motor disturbances, presenting with acute and recurrent attacks of confusion, anxiety, depression and or hallucinations (Malm and Nilssen 2008).
Vacuolated lymphocytes in the peripheral blood are present, and elevated urinary excretion of mannose-rich oligosaccharides can be demonstrated by thin-layer chromatography (Michalski and Klein 1999). Decreased T2 signal in the thalami were seen (Autti et al 2007b).
Genotype-phenotype correlation has not been described in -mannosidosis
(Nilssen et al 1997; Berg et al 1999; Frostad Riise et al 1999; Baccari et al 2003;
Olmez et al 2003; Sbaragli et al 2005; Lyons et al 2007; Pittis et al 2007).
5.2 Beta-Mannosidosis Beta-mannosidosis is due to a deficiency of beta-mannosidase activity (MANBA).
The prevalence of the disease is unknown, with only 20 cases diagnosed around the world. A wide range of symptoms were reported, with mental retardation appearing in 76% of the cases, associated or not with behavioral problems, hearing loss, recurrent respiratory infections, angiokeratoma, facial dysmorphism, skeletal deformation, seizures, hypotonia, and demyelinating polyneuropathy. The age of symptom onset is variable. A patient was followed-up from his 12 to 26 years of age, with symptoms of progressive cognitive deterioration, cerebellar ataxia, and end-stage spastic tetraplegia and pseudo-bulbar syndrome. A diffuse cortical and subcortical atrophy, on MRI, did not change with time (Labauge et al
2009). The condition might present also as an encephalopathy with intractable seizures, or rarely as a demyelinating neuropathy (Levade et al 1994). Gourrier and co-workers (1997) reported a case with hypertonia and feeding difficulties in infancy.
5.3 Fucosidosis
Fucosidosis is due to a deficiency of lysosomal hydrolase -fucosidase (FUCA1).
Although the disorder is panethnic, the majority of reported patients were originated from Italy and United States (Durand et al 1979; Willelms 1991). The prevalence is unknown, but seems to be a rare and underestimated disorder
(Turkia et al 2008). Two phenotypes have been described, though clinical presentation and outcomes were more consistent with a continuous spectrum (Willelms 1991;Turkia et al
2008). Patients with type I have onset of psychomotor retardation within 6 and 18 month of life, coarse face, growth retardation, dysostosis multiplex, visceromegaly, recurrent bronchopneumonias and rapid neurologic deterioration (Table 3). The chloride content of sweat is markedly increased. Type II is associated with the same symptoms, but begins later and has a low progressive neurologic deterioration. In this form, patients present angiokeratoma and normal sweat sodium chloride. Dementia and spastic quadriplegia are present in more than 85% of the patients. Other neurological findings included seizures, hearing loss, dystonia, intermittent hemiplegia and myoclonus (Sovik et al 1980; Gordon et al
1995). Genotypic differences do not explain the observed phenotypic variability
(Seo et al 1994; Cragg et al 1997).
MRI revealed periventricular white matter abnormalities, and signal abnormalities in the thalamus, globus pallidus and internal capsules (Provenzale et al 1995;
Terespolsky et al 1996; Galluzzi et al 2001; Autti et al 2007b).
The most striking pathologic features are clear vacuoles in the cells of most tissues including neurons, hepatocytes, and kupffer cells. Ultrastructural studies of biopsy material from brain indicate heterogeneous appearance of storage vacuoles. In spite of FUCA deficiency, only oligosaccharides are stored in the brain (Thomas
2001). .
5.4 Schindler and Kanzaki diseases
Schindler disease is caused by the deficient activity of α-N- acetylgalactosaminidase, a lysosomal hydrolase previously known as α- galactosidase B.
Two affected brothers were first reported, in several sequential publications (Van
Diggelen et al 1987 and 1988; Schindler et al 1989; Keulemans et al 1996; Bakker et al 2001). They started with symptoms at 9 months of age and followed a progressive psychomotor deterioration, which included myoclonic seizures, decorticate posture, optic atrophy, blindness, marked long tract signs and total loss of contact with the environment by ages 3 to 4 years. No visceral features were present. A unique abnormal pattern of urinary oligosaccharides was demonstrated by thin-layer chromatography. The levels of NAGA were very low in cultured fibroblasts, leukocytes and plasma, what has identified in those sibs a new LSD
(Van Diggelen et al, 1988). At ultrastructural examination, the rectal mucosa contained dystrophic autonomic axons with 'tubulovesicular' material (Schindler et al 1989). Due to the similarities in clinical course and in neuropathology, this form of Schindler disease was claimed to be one of the infantile forms of neuroaxonal dystrophy (Wang et al 1988). After that, very few – probably one additional
Moroccan patient – have been described. Since NAGA deficiency with neuroaxonal dystrophy had not been reported since 1987, it was suggested that the original German boys may have had 2 disorders: alpha-NAGA deficiency and neuroaxonal dystrophy (Keulemans et al 1996; Bakker et al 2001).
NAGA deficiency is clinically heterogeneous and, in addition to this severe infantile form (type I), two other phenotypes have been identified. Until now, 13 NAGA deficient patients from nine families are known (Chabás et al 2007).
Type II (Kanzaki Disease) disease is an adult-onset disorder characterized by angiokeratoma corporis diffusum and mild intellectual impairment, sensorioneural hearing loss, progressive distal muscle weakness, and recurrent vertigo attacks.
Even though, cases with normal IQ, without neurological symptoms or signs of neuroaxonal dystrophy are reported (de Jong 1994; Chabas et al 1994 and 2007).
The brain MRI from the first case report showed few small lacunar infarctions, without cerebral atrophy (Kanzaki et al 1993).
Type III disease is an intermediate and variable form with manifestations ranging from seizures and moderate psychomotor retardation in infancy to a milder autistic presentation with speech and language delay, and marked behavioral difficulties in early childhood. One proband was an 11-month-old girl with generalized seizures that remained stable up to her 8 years-old (de Jong et al 1994; Bakker et al 2001).
Another case was an autistic boy, with normal neurological examination and brain
MRI scans (Blanchon et al 2002).
Intrafamilial phenotypic variability seems to be very important. In at least two out nine families reported so far, asymptomatic brothers were detected (de Jong et al
1994; Bakker et al 2001). 5.5 Aspartylglucosaminuria
Aspartylglucosaminuria (AGU) is caused by the lysosomal storage of aspartylglucosamine in large amounts, in neurons and glial cells, in visceral organs and in the skin. The estimated prevalence is of 1 in 26 000 in Finland, and of 0.13 in 100 000 in other parts of the world (Tollersrud 1994; Porthuiss et al 1999;
Ambrosetto and Santucci 2009).
According to the observations in Finnish patients, growth spurt in infancy is the earliest sign of the disease. Delayed speech development, attention deficits, clumsiness, aggressive behavior and recurrent respiratory infections appear during the childhood (Autio 1972; Arvio and Arvio 2002). The progression is divided into three phases. The first phase lasts the first 10 years of life, where cognitive measurements classify patients as having mild to moderate mental retardation. In puberty, learning is impaired, and a stable phase begins, during which patients lose some skills and abilities. Cognitive measurements detect moderate to severe mental retardation. Finally, after the age 25-28 years, rapid deterioration occurs.
Generalized tonic, clonic or myoclonic seizures are frequent and appear in case reports (Arvio et al 1993; Ambrosetto and Santucci 2009). Both children and adults with AGU were reported to show several types of sleep disturbances (Lindblom
2006; Ambrosetto and Santucci 2009). The early facial features are described as
"a sagging face with a low nasal bridge and a big mouth". Later in life there is gum hypertrophy and facial angiofibromas similar to those seen in Tuberous sclerosis
(Arvio et al 1999). Liver and cardiac involvements do occur but are uncommon.
Vacuolated lymphocytes are detected in peripheral blood. CT studies revealed diffuse atrophy in adolescent patients. MRI shows abnormalities in the differentiation between gray and white matter and signs of delayed myelination
(Autti 1997). Bilateral abnormal signal intensity of thalamus on T2-weighted images and cysts in the choroid plexus has been described (Malm et al 2004; Autti 2007b).
White matter lesions in T2- and flair-weighted images were stabilized or even improved five years after BMT in two sibs (Malm et al 2004). These findings are difficult to be valued, due to the lack of knowledge on the usual MRI progression in this disease.
5.6 Sialidosis
Sialidosis, also known as cherry red spot myoclunus syndrome, is a rare lysosomal storage disorder traditionally classified as mucolipidosis type I. The excretion of large quantities of sialy-oligosaccharides glycopeptides occurs due to a deficiency of alpha-N-acetyl neuroaminidase (NEU1). The prevalence around the world is not known, but a study in Netherland estimated the birth rate of 0, 05 per 100,000
(Poorthuis et al 1999). Sialidosis is subdivided into two main variants with different age at onset and severity. The age at onset and severity of the clinical manifestations correlate with the amount of residual sialidase activity (Lowden and
O'Brien 1979; Bonten et al 2000; Thomas 2001).
The very rare sialidosis type II has been the object of case reports. A severe, early-onset, dysmorphic picture dominates, characterized by macular cherry-red spot, Hurler-like phenotype, dystostosis multiplex, mental retardation hepatosplenomegaly, ataxia, spasticity and more rapid progression of the disease process (Cantz and Ulrich-Bott 1990; Thomas 2001). However, later onset forms also exist. Spranger described a patient who presented at age 12 years with muscular hypotonia, ataxia, myoclonus, seizures, coarse faces, spinal deformity, deafness, cherry red spot, and an IQ of 45. This patient had a progressive neurodegenerative course and died at age 21 years (Spranger et al 1977). Other juvenile presentations repeated this clinical picture (Miyatake et al 1979; Amano et al 1983).
Sialidosis type I starts in adolescence or adulthood, and is the prototype of those
LSD characterized by a progressive visual loss, polymyoclonus, and seizures
(Table 3). Polymyoclonus is the most striking feature of this disease. Multiple, irregular, asynchronous, myoclonic jerks are precipitated by action and intentional movements, sensory stimuli or emotional upset, and can be generalized to tonic- clonic seizures. Cherry-red spots are present in the macula. In later stages, there is severe visual impairment associated with punctate opacities of the lens and optic atrophy, plus nystagmus, ataxia and cognitive deterioration (Berkovic et al 1991;
Thomas 2001; Lyon et al 2006). Seventeen Taiwanese patients with type I were followed-up (Lai et al 2009). Mean ages of symptom onset and of disease duration were of 19 (range: 12–33) and 18
(range: 10–31) years, respectively. Action myoclonus was the most common presenting symptom (58.8%), followed by visual defect (23.5%) and seizures
(17.6%). Seizures could be easily controlled by anti-epileptic drugs. Self-applied, modified myoclonus and seizure frequency rating scales were used, in both retrospective and prospective way. The myoclonus score (range: 0 to 5 points) reached 2.71 in 5 years, while the seizure frequency score (range: 0 to 7) decreased from 3 to 1 in 1 year: both stabilized thereafter. The interval from the disease start to the initial falls was 2 years (range, 0–6); to the seizures, 4 years
(range, 0–15 years); and to the blurred vision, 7 years (0–17 years). Cognitive function was preserved in all but one case (Lai et al 2009).
EEG studies were repeatedly normal in a majority of patients (Lai et al 2009). In spite of that, there are evidences that the electrophysiological abnormalities related to the myoclonic seizures are restricted to a level above the brainstem (Huang et al
2008). Abnormal somatosensory evoked and visual evoked potentials were found in virtually all patients, even without visual symptoms (Lai et al 2009). CT and MRI scan demonstrate cerebral, cerebellar and pontine atrophy, which tend to worsen as the time passes (Palmeri et al 2000; Lai et al 2009).
There is considerable molecular heterogeneity, with diversity of clinical phenotypes even within the same homozygous mutation (Seyrantepe et al 2003; Criado et al
2003). The most striking neuropathologic features in type I were a fine cytoplasmatic vacuolation in several neurons of the cortex, basal ganglia and thalamus, and a diffuse neuronal intracytoplasmic storage of lipofuscin-like pigment (Allegranza et al 1989).
6. Neuronal ceroid lipofuscinosis
The neuronal ceroid lipofuscinosis (NCL) constitute a group of at least ten genetically distinct disorders characterized by the intralysosomal aggregation of autofluorescent ceroid and lipofuscin. The NCL genes encode soluble and transmembrane proteins, localized to the endoplasmic reticulum (ER) or the endosomal/lysosomal organelles. The precise function of most of the NCL proteins and its cellular dysfunction remains unclear. NCL exert a profound effect upon the central nervous system (CNS) of affected individuals, by their progressive nature, leading to blindness, neurocognitive decline, untreatable seizures and ultimately premature death. These common clinical and pathological features not only conceptualize NCLs as a group of disorders, but also suggest that the related proteins may be functionally linked (Cooper et al 2003; Kohlschütter and Schulz,
2009; Jalanko and Braulke 2009). Few other LSD are also characterized by a progressive visual loss, polymyoclonus, and seizures (Table 3), such as sialidosis type 1. Collectively, NCL probably constitute the most common group of progressive encephalopathies in children. US incidence has been estimated to be of 1:12 500
(Rider and Rider 1988), whereas some forms are relatively frequent in Northern
European and Newfoundland populations (Uvebrant and Hagberg 1997; Moore et al 2008).
All NCL but one adult form, show an autosomal recessive mode of inheritance.
Clinical forms are broadly classified according to age at onset, in congenital NCL; infantile neuronal ceroid-lipofuscinosis (INCL), Santavuori-Haltia; late-infantile
(LINCL, Jansky-Bielschowsky), juvenile (JNCL, Batten disease, Spielmeyer-Vog), adult (ANCL, Kuf's disease) and Northern epilepsy (NE, progressive epilepsy with mental retardation).
Several different genes are related to NCL, and three of them code for lysosomal enzymes: CLN1, the gene encoding palmitoyl-protein thioesterase-1 (PPT1);
CLN2, the gene of tripeptidyl peptidase 1 (TPP1); CLN3, CLN5 and CLN6, whose mutations affect proteins (probably transmembrane) of unknown function; CLN7 with mutation in the MFSD8 gene, which belongs to the major superfamily of transporter proteins, localized mainly to the lysosomal compartment; CLN8 and the
Northern epilepsy variant of CLN8, another possible transmembrane protein; and
CLN10, coding for cathepsin D. Two forms of CLN have not yet been molecularly characterized: CLN4 and CLN9. With this general picture of multiple complexity, it is natural that several puzzling phenomena in formal genetics have been related to NCL, such as genetic heterogeneity (mutations in a number of genes with similar clinical and histopathological phenotypes), allelic heterogeneity (different mutations in the same gene resulting in markedly different clinical phenotypes), and intrafamilial phenotypic variability.
6.1 Congenital form
Very few patients with congenital NCL have been reported so far. In those genetically defined patients, mutations in cathepsin D (CLN10) alleles were related to phenotype. The congenital form presents at birth with respiratory insufficiency, rigidity, and status epilepticus (possibly intrauterine). Death occurs within hours to weeks after birth. Microcephaly with massive loss of neurons in the cerebral cortex, extensive gliosis, absence of myelin and autofluorescent storage bodies with a granular osmiophilic deposits (GROD) ultrastructure have been observed
(Siintola et al 2006; Steinfeld et al 2006).
6.2 INCL
Infantile neuronal ceroid lipofuscinosis (INCL) is caused by mutations in the CLN1 gene, producing a deficient activity of the palmitoyl-protein thioesterase-1 (PPT1).
Early neural neurodevelopment occur until 12 months of age, although abnormal storage material is known to be present in the fetus. Initial signs start between 6 and 24 months and include deceleration of head growth, delayed development, myoclonic jerks, and/or seizures (Santavuori 1988; Vanhanen et al 1995). Psychomotor abilities deteriorate rapidly. Blindness, due to optic atrophy, macular and retinal changes, is evident by two years of age. Before the age of 3 years the children have lost all their skills. The EEG becomes isoelectric at an average age of 2.7; the ERG (electroretinogram) is unrecordable by age three years. Death usually occurs between 8 and 11 years (Santavuori 1988).
A staging system to describe the clinical course of INCL has been proposed. Both the severity stage and the chronological age were related to progressive abnormalities in longitudinal magnetic resonance spectroscopy (MRS) studies in eight children (Santavuori et al 2000; Vanhanen et al 2004) (Table 1).
MRI findings are variable, and include cerebral atrophy (Figure E-3 d), strong thalamic hypointensity in the white matter and basal ganglia, and thin, hyperintense, periventricular high-signal rims of white matter (Vanhanen et al
1995).
In INCL, there is an autofluorescent lysosomal storage, which takes the form of
GRODs on ultrastructural examination. GRODs are related to PPT1 deficiency.
The major part of the GRODs consists of sphingolipid activator proteins, saposins
A and D (Jalanko and Braulke 2009).
6.3 LINCL
This category of NCL include the classic LINCL or Jansky–Bielschowsky disease, caused by mutations in the CLN2 gene, and patients with virtually the same clinical picture, presenting mutations in CLN1, CLN5 (Finnish variant, fLINCL), CLN6,
CLN7 (Turkish variant, tLINCL), and CLN8 ( Northern epilepsy).
Classical LINCL starts between 2–4 years. Epilepsy uses to be the first manifestation, with myoclonus, generalized tonic-clonic seizures or absence seizures, at a mean age of 3.3 years (Worgall et al 2006). Regression of developmental milestones towards dementia appears soon thereafter. Ataxia, extrapyramidal and pyramidal signs are also present. Visual impairment appears at four to six years of age and rapidly progresses to blindness (Wisniewski 2006;
Kohlschütter and Schulz 2009). Affected children are wheelchair-bound at a mean age of 5.7 years (Worgall et al 2006). The median age at death of children diagnosed with late infantile neuronal ceroid lipofuscinoses was 12 years
(Augestad et al 2006).
Electroencephalogram (EEG) shows spikes in the occipital region in response to photic stimulation at 1-2 Hz (Lyon et al 2006). Electroretinogram (ERG) is usually abnormal at presentation and becomes undetectable soon thereafter. Visual evoked potentials (VEPs) are enhanced for a long period and diminish in the final stage of the disease. MRI shows progressive cerebral and cerebellar atrophy with normal basal ganglia and thalami.
Two scoring systems, combining motor, visual and verbal functions, have been developed, and both were used to describe the disease progression through a limited time. External validation using disease duration, age at onset, MRI volumetries and MRS abnormalities have also been published. No biologically significant differences in rates of progressions according to genotypes were found
(Steinfeld et al 2002; Worgall et al 2006) (Table 1). Disease progression was also followed by MRS markers, in one of those cohorts (Dyke et al 2007).
The hallmark of ultrastructural findings in CLN2 disease is the curvilinear profile
(CLP), found in lysosomal residual bodies. These storage bodies are related to the deficiency of tripeptidyl peptidase 1 (TPP1), the enzyme encoded by CLN2 gene, and contain subunit c of mitochondrial ATP synthase and low amounts of saposins
A and D (Jalanko and Braulke 2009).
6.4 JNCL
JNCL is the most common form of NCL. The majority of affected individuals carry mutations in CLN3 gene which encodes a lysosomal membrane protein with poorly understood function. JNCL can also be due to CLN1 (the gene of the PPT1 enzyme) and CLN2 (the gene of the TPP1 enzyme) mutations.
Disease begins between four and ten years, and pursues a protracted course.
Differently from the former NCLs, the first symptom is failure of vision in the majority (53.5%) of patients (Ju et al 2006). Visual loss can be the only sign for two to five years; children are often totally blind after this period of time. When asked to look straight, some patients actually overlook the target, as if the superior retina was spared. Ophthalmologic examination may reveal macular degeneration (an early sing), pigmentary changes in the retinal periphery, vascular attenuation, appearance of peripheral bone spicules and optic nerve pallor (Spalton et al 1980;
Hainsworth et al 2009). The ERG is extinct early in the disease, due to loss of photoreceptor function.
Intellectual decline, if not present at onset of disease, becomes manifest after two or more years. One study group started to quantify the neuropsychological decline in JNCL; longitudinal results are expected (Adams et al 2007). Short attention span and memory loss are followed by dysarthria, palilalia (stereotyped repetitions of words), festinating stuttering, aphasia and apraxia. In some patients, multiple psychiatric manifestations can also appear (Backman et al 2005). Seizures tend to appear later (but can be the first sign) and are usually of generalized tonic clonic type. Interictal myoclonus can also be present. Later in disease, a parkinsonian rigidity is frequently found. Cerebellar ataxia and pyramidal findings can also supervene. The median age at death was 26 years (95% confidence interval 25-
30) (Augestad et al 2006) (Table 1).
EEG abnormalities are present, but photo stimulation does not evoke occipital spikes, as in LINCL. The presence of vacuolated lymphocytes is a constant feature that can help diagnosis. On neuroradiological imaging, cerebral atrophy appears after 10 years of age, and is followed by cerebellar atrophy. The thalami may show decreased signal intensity from the age of 11 years onwards, on T2-weighted images (Santavuori et al 2000). Longitudinal observations of brain volumetries have shown that the annual rate of the gray matter loss in adolescent JNCL patients is as high as 2.4% (Autti et al 2008). Significant losses were found in the dorsomedial part of the thalami and in the corona radiata, containing cortical efferents and afferents in the transition between the internal capsule and the subcortical white matter (Autti et al 2007a).
Whereas the onset of visual failure and epilepsy was highly concordant, great inter- and intrafamilial heterogeneity was demonstrated in the development of mental and physical handicap (Järvelä et al 1997). Compound heterozygotes for the common 1.02-kb deletion and the point mutation G295K have a more protracted course (Wisniewski 2006).
Pathologic studies reveal severe brain atrophy, with neurons filled with autofluorescent granules. Under the electron microscope, aggregates with fingerprint appearance are prominent; curvilinear inclusions can also be seen.
Inclusions tend to storage between the perikaryon and the axon hillock (Lyon et al
2006).
6.5 ANCL
The adult forms of NCL are quite rare diseases. Also called Kufs disease, ANCL is usually classified in type A (progressive myoclonus epilepsy with dementia) and type B (behavioral abnormalities and dementia, associated with pyramidal and extrapyramidal signs). Although this dichotomy can sometimes be blurred (Zini et al 2008). In any case, there are at least two variants, according to mode of inheritance: an autosomal dominant form without deficient PPT1, in spite of the presence of
GRODs in pathology (Nijssen et al 2003), and an autosomal recessive form with deficient PPT1 enzyme activity, due to CLN1 mutations (van Diggelen et al 2001;
Ramadan et al 2007).
Initial signs and symptoms usually appear around age 30 years, with death occurring about ten years later (Wisniewski 2006). Until recently, ophthalmologic studies were said to be normal in ANCL. Recent publications reported either optic atrophy, absent ERGs, or abnormal PEV on ANCL patients due to CLN1 mutations
(van Diggelen et al 2001; Ramadan et al 2007).
7. Conclusions
Almost all LSD are related to devastating, progressive and untreatable effects in
CNS. The study and comparison of neurological characteristics of LSD address several questions related to the disease process. For instance, the severe forms of the lipidosis result in an almost stereotyped pattern of early (in the first year of life) infantile deterioration (Figure 1 and Table 3), pointing to common pathogenetic pathways. Exceptions to this general early phenotype are quite informative, like the intra-uterine olygodendrocyte cell death related to Krabbe disease, and the dysplastic brains seen in ML IV. Other neurological syndromes may also be suggested in the late-onset forms of LSD, such as those disorders presenting with eye movement disorders, with extrapyramidal manifestations, with upper motor neuron involvement, with gargoilism, or with a combination of myoclonus, seizures and optic atrophy (Table 3).
Clinical differences between most of LSD become more evident when each of the several involved peptides is not completely lacking. Survival into the late infancy allows the appearance of specific dysfunctions, in different neuronal topographies and time spans. The pattern of storage or of the enzyme expression may probably be traced by the evolving phenotypes.
Clinical hetero or homogeneity is another very informative phenomenon. Three main settings can be foreseen from different combinations between this data.
Firstly, interfamilial heterogeneity together with intrafamilial homogeneity can be seen in strict monogenic disorders. Diverse allele combinations can explain it, as is the case of confirmed genotype-phenotype correlations (Table 2). In this setting, the main and still apparently unique determinant of disease is the involved peptide.
For instance, in juvenile MLD the p426l/p426l genotype is associated with a spastic-ataxic phenotype, while I179S mutation is associated with the behavioral phenotype.
The second setting is that of a disease with intrafamilial homogeneity of phenotypes but without genotype-phenotype associations. In this case, phenotype variation is not clearly due to the specific mutations, and some other familial factors
(genetic or environmental) can be influencing the prognosis. For instance, the neurological picture seen in sibs affected by Niemann-Pick disease type C has been always very similar, but the disease course is diverse among unrelated individuals.
The third and last setting is that of the documented intrafamilial heterogeneity of a particular disease, or subtype. It reveals that some factor independent from the causative gene is protecting neurons from damage. Intrafamilial heterogeneity has been reported in several late-onset LSD (Table 1). Although probably uncommon, intrafamilial heterogeneity is a strong evidence in favor of neuroprotective factors acting even in the presence of a LSD.
Studies on the natural history are very important for the evaluation of the long and short-term efficacy of new therapies. Unfortunately, they are rather scarce in LSD, with a few achieving high levels of evidence (Table 1). The advent of new therapies motivated several researchers to perform controlled trials. Actually, the majority of longitudinal studies on LSD are clinical trials; the minorities are observational cohorts. The lack of efficacy on neurological burden did not prevent these studies from being done, due to the benefits they could bring to the general health of patients. Data on the neurological progress of some LSD has been produced from these trials, since placebo groups can be understood as a pursuing the natural history of the disease.
The positive effects on CNS obtained by HSCT in MPS I Hurler and on late onset forms of KD and MLD are promising (Krivit et al 1999; Souillet et al 2003; Staba et al 2004 ; Aldenhoven et al 2008; Peters and Steward, 2003; Boelens , 2006; Lim et al, 2008; Pierson et al, 2008), showing that lysosomal injuries in the brain are prone for therapy. There is no doubt that either better transplantation conditioning or new forms of enzyme delivery are necessary. Good examples are the ongoing studies about the effect of intrathecal administration on cognitive outcome for MPS
I. While no therapy for neuronal LSD is achieved, better clinical studies are necessary in several disorders (Table 1 shows the lack of knowledge on this field).
Repeated measurements of disease progression are needed, using responsive scoring systems, in larger samples of cases.
Finally, it is worth to remember the experience of heterozygous detection programs in Ashkenazi populations. Similar programs directed to other communities may be delineated, according to the best interest of at risk individuals. This should help overburden families to evaluate the role of free information in familial planning and prevention of dramatic diseases, like the lysosomal disorders. 8. Acknowledgements
We are indebted to the patients and their families, who made this study possible.
We also thank Dr. Roberto Giugliani and Dr. Leonardo Vedolin for MRI and patient pictures, and Dr. Gregory Pastores for critical reading of the manuscript. This work was supported by Brazilian funding agencies (CAPES, FAPERGS, FIPE-HCPA,
CNPq). Prof. Jardim is supported by CNPq.
9. References
Adams HR, Kwon J, Marshall FJ, de Blieck EA, Pearce DA, Mink JW (2007)
Neuropsychological symptoms of juvenile-onset batten disease: experiences from
2 studies. J Child Neurol 22(5):621-7. Al Sawaf S; Mayatepek E; Hoffmann B (2008) Neurological findings in Hunter disease: pathology and possible therapeutic effects reviewed. J Inherit Metab Dis
31(4):473-480. Aldenhoven M, Boelens JJ, de Koning TJ (2008) The clinical outcome of Hurler syndrome after stem cell transplantation. Biol Blood Marrow Transplant 14(5):485-
98. Allegranza A, Tredici G, Marmiroli P, di Donato S, Franceschetti S, Mariani C
(1989) Sialidosis type I: pathological study in an adult. Clin Neuropathol. Nov-
(6):266-71. Altarescu G, Sun M, Moore DF, et al (2002) The neurogenetics of mucolipidosis type IV. Neurology. 59(3):306-13. Amano N, Yokoi S, Akagi M et al (1983) Neuropathological findings of an autopsy case of B-galactosidase and neuroaminidase deficiency. Acta Neuropathol 61(3-4):
283-90. Ambrosetto G, Santucci M (2009) Sleep-related hypermotor seizures in aspartylglucosaminuria: A case report. Epilepsia 50(6):1638-40 Andria G, Di Natale P, Del Giudice E, Strisciuglio P, Murino P (1979) Sanfilippo B syndrome (MPS III B): mild and severe forms within the same sibship. Clin Genet
15(6):500-4. Aoki M, Takahashi Y, Miwa Y, Iida S, Sukegawa K, Horai T, Orii T, Kondo N
(2000) Improvement of neurological symptoms by enzyme replacement therapy for
Gaucher disease type IIIb. Eur J Pediatr 160(1):63-4 Arbour LT, Silver K, Hechtman P, Treacy EP, Coulter-Mackie MB (2000) Variable onset of metachromatic leukodystrophy in a Vietnamese family. Pediatr Neurol
23(2):173-6. Arvio M, Oksanen V, Autio S, Gaily E, Sainio K (1993) Epileptic seizures in aspatylglucosaminuria: a common disorder. Acta Neurol Scand 87(5):342-4 Arvio P and Arvio M (2002) Progressive nature of Aspatylglucosaminuria. Acta
Paediatr 91(3):255-57. Arvio P, Arvio M, Kero M, Pirinen S et al (1999) Overgrow of oral mucosa and facial, a novel feature of aspatylglucosaminuria. J Med Genet 36(5):398-404. Augestad LB, Flanders WD (2006) Occurrence of and mortality from childhood neuronal ceroid lipofuscinoses in Norway. J Child Neurol 21(11):917-22. Autio S (1972) Aspatylglucosaminuria: analysis of thirthy –four patients. J Ment defic Res 1(0):1-39.
Autio S, Louhimo T, Helenius M (1982) The Clinical course of mannosidosis. Ann
Clin Res 14:93-97.
Autti T, Hämäläinen J, Aberg L, Lauronen L, Tyynelä J, Van Leemput K. (2007a)
Thalami and corona radiata in juvenile NCL (CLN3): a voxel-based morphometric study. Eur J Neurol 14(4):447-50. Autti T, Joensuu R, Aberg L (2007b). Decreased T2 signal in the thalami may be a sign of lysosomal storage disease. Neuroradiology 49(7):571-578. Autti TH , Hämäläinen J, Mannerkoski M, Van Leemput KV, Aberg LE (2008) JNCL patients show marked brain volume alterations on longitudinal MRI in adolescence.
J Neurol 255(8):1226-30. Aynaci FM, Cakir E, Aynaci O (2002) A case of I-cell disease (mucolipidosis II) presenting with craniosynostosis. Childs Nerv Syst 18(12):707-11. Baccari T, Bibi L, Ricci R, et al (2003) Two novel mutation in the gene for human alpha-mannosidase that cause alpha-manosidosis. J Inherit Metab Dis 26(8):819-
20 Backman ML, Santavuori PR, Aberg LE, Aronen ET (2005) Psychiatric symptoms of children and adolescents with juvenile neuronal ceroid lipofuscinosis. J Intellect
Disabil Res; 49(Pt1): 25–32. Baehner F, Schmiedeskamp C, Krummenauer F, et al (2005) Cumulative incidence rates of the mucopolysaccharidoses in Germany. J Inherit Metab Dis 28(6):1011–
1017. Bakker HD, de Sonnaville MLCS, Vreken P, et al (2001) Human alpha-N- acetylgalactosaminidase (alpha-NAGA) deficiency: no association with neuroaxonal dystrophy? Europ J Hum Genet 9(2): 91-96.
Bargal R, Zeigler M, Abu-Libdeh B, et al (2006) When mucolipidois III meets mucolipidosis II: GNPTA gene mutations in 24 patients. Mol Genet metab 88(4):
359-363. Baumann N, Turpin JC, Lefevre M, Colsch B (2002) Motor and psycho-cognitive clinical types in adult metachromatic leukodystrophy: genotype/phenotype relationships?. J Physiol Paris 96(3-4):301-6. Beck M, Barone R, Hoffmann R,et al (1995) Inter- and intrafamilial variability in mucolipidosis II (I-cell disease). Clin Genet 47(4):191-9. Benninger C, Ullrich-BotT B, Zhan SS, Schmitt HP (1993) GM2D gangliosidosis B1 variant in a boy of German/Hungarian descent. Clin Neuropathol 12(4):196-200. Berg T, Riise HM, Hansen GM, Malm D, Tranebjaerg L, Tollersrud OK, Nilssen O
(1999). Spectrum of mutations in alpha-mannosidosis. Am J Hum Genet 64: 77–
88. Berkovic SF, So NK, Andermann F (1991) Progressive myoclonus epilepsies: clinical and neurophysiological diagnosis. Clin Neurophysiol 8(3): 261-74. Bernardini GL, Herrera DG, Carson D, et al (1997) Adult-onset Krabbe's disease in siblings with novel mutations in the galactocerebrosidase gene. Ann Neurol
41(1):111-4. Beutler E, Grabowski GA (2001) Gaucher disease. In Scriver CR, Beaudet AC, Sly
WS, Valle D, eds. The Metabolic and Molecular Basis of Inherited Disease. 8th ed.
New York, NY: McGraw-Hill, 3635-3668. Biegstraaten M, van Schaik IN, Aerts JM, Hollak CE (2008) 'Non-neuronopathic'
Gaucher disease reconsidered. Prevalence of neurological manifestations in a
Dutch cohort of type I Gaucher disease patients and a systematic review of the literature. J Inherit Metab Dis 31(3):337-49. Biffi A, Cesani M, Fumagalli F, et al (2008) Metachromatic leukodystrophy - mutation analysis provides further evidence of genotype-phenotype correlation.
Clin Genet 74(4): 349-57. Blanchon YC, Gay C, Gibert C, Lauras B (2002) A case of N-acetyl galactosaminidase deficiency (Schindler disease) associated with autism. J Autism
Dev Disord 32(2):145-6. Blom S, Erikson A. Gaucher disease (1983) Norrbottnian type. Neurodelopmental, neurological and neurophysiological aspects. Eur J Pediatr 140(4): 316:22 Boelens JJ. Trends in haematopoietic cell transplantation for inborn errors of metabolism. J Inherit Metab Dis 2006;29:413-420. Bonten EJ, Arts WF, Beck M, et al (2000) Novel mutations in lysosomal neuraminidase identify functional domains and determine clinical severity in sialidosis, Hum Mol Genet 9(18): 2715–2725. Breningstall GN, Tubman DE (1994) Magnetic resonance imaging in a patient with
I-cell disease. Clin Neurol Neurosurg May; 96(2):161-3. Brunetti-Pierri N, Scaglia F (2008) GM1 gangliosidosis: review of clinical, molecular, and therapeutic aspects.Mol Genet Metab 94(4):391-6. Burck U, Moser HW, Goebel HH, Grüthner R, Held KR (1985) A case of lipogranulomatosis Farber: some clinical and ultrastructural aspects. Eu J Pediatr
14(3):203-8. Bussière M, Kotylak T, Naik K, Levin S (2006) Optic nerve enlargement associated with globoid cell leukodystrophy. Can J Neurol Sci 33(2):235-6. Campbell PE, Harris CM, Sirimanna T, Vellodi A (2003) A model of neuronophatic
Gaucher disease. J Inherited Metab Dis 26(7):629-639 Cantor RM, Kaback MM (1985) Sandhoff disease (SHD) heterozygote frequencies
(HF) in North American (NA) Jewish (J) and non-Jewish (NJ) populations: implications for carrier (C) screening (Abstract) Am. J. Hum. Genet. 37: A48. Cantz M, Ulrich-Bott B (1990) Disorders of glycoprotein degradation. J Inherit
Metab Dis 13(4):523-37. CEBM.net (updated September 14, 2009) Oxford Centre for Evidence-Based
Medicine (UK)- Copyright, Department of Primary Care, University of Oxford,
United Kingdom. Available at http://www.cebm.net/index.aspx?o=1011. Accessed in September 28, 2009 Chabas A, Coll MJ, Aparicio M, Rodriguez Diaz E (1994) Mild phenotypic expression of alpha-N-acetylgalactosaminidase deficiency in two adult siblings. J
Inherit Metab Dis 17(6): 724-31. Chabas A, Duque j, Gort L (2007) A New infantile case of alpha-N- acetylgalactosaminidase deficiency, cardiomyopathy as a presenting symptom. J
Inherit Metab Dis 30(1):108. Chang Y C, Huang C C, Chen CY, Zimmerman RA (2000) MRI in acute neuropathic Gaucher's disease Neuroradiology 42 (1): 48-50 Charrow J, Andersson H C, Kaplan P, et al (2000) The Gaucher Registry:
Demographics and Disease Characteristics of 1698 Patients With Gaucher
Disease Arch Int Med 160(18): 2835-2843 Chester MA, Lundbladt A, Öckermann PA, Autio S (1982) Mannosidosis. In Duran
P, O’ Brien JF, eds. Genetic Errors of Glyco-Protein Metabolism. Milan: Edi-
Hermes, 89-120. Claeyrs M, Vander Hoeven M, de Die-Smulders C, et al (1999) Early-infantile type of galactosialidosis as a cause of heard failure and neonatal ascites. Inherit Metab
Dis 22(5):666-667. Clarke JT, Skomorowski MA, Chang P (1989) Marked clinical difference between two sibs affected with juvenile metachromatic leukodystrophy. Am J Med Genetics
33 (1):10-3. Clarke LA (2008) The mucopolysaccharidoses: a success of molecular medicine.
Expert Reviews in Molecular Medicine 10;e1:1-18 Cooper JD. Progress towards understanding the neurobiology of Batten disease or neuronal ceroid lipofuscinosis. Curr Opin Neurol. 2003 Apr;16(2):121-8. Cox-Brikman J, Breemen M J, Van Maldegem B T, Bour L, Donker W, Hollak C
EM, Wijburg F A, Aerts M F G (2008) Potential efficacy of enzyme replacement and substrate reduction therapy in three siblings with Gaucher disease type III. J inherited Metab Dis 31(6):745-52. Cragg H, Williamson M, Young E, O'Brien J, Alhadeff J, Fang-Kircher S, Paschke
E, Winchester B (1997) Fucosidosis: genetic and biochemical analysis of eight cases. J Med Genet 34(2): 105-110. Criado GR, Pshezhetsky AV, Rodriguez Becerra A, Gómez de Terreros I (2003)
Clinical variability of type II sialidosis by C808T mutation. Am J Med Genet A
116A(4): 368-71. D´Azzo A, Andria G, Strisciuglio P, Galjaard H (2001) Galactosialidosis. Scriver
CR, Beaudet AC, Sly WS, Valle D, eds. The Metabolic and Molecular Basis of Inherited Disease. 8th ed. New York, NY: McGraw-Hill Book Co: 3811-3826. Da Silva V, Vassella F, Bischoff A, Spycher M, Wiesmann UN, Herschkowitz N
(1975) Niemann-Pick's disease. Clinical, biochemical and ultrastructural findings in a case of the infantile form. J Neurol 211(1):61-8. Davies E H, Surtees R, C Del Vile, Schoon I, Vellodi A (2007b) severity scoring tool to assess the neurological features of neuronophatic Gaucher disease. J inherited Metab Dis 30(5): 768-782 Davies EH, Erikson A, Collin-Histed T, Mengel E, Tylki-Szymanska A, Vellodi A
(2007a) Outcome of type III Gaucher disease on enzyme replacement therapy: review of 55 cases. J Inherit Metab Dis 30(6):935-42
De Gasperi R, Gama Sosa MA, Sartorato E, Battistini S, Raghavan S, Kolodny EH
(1999) Molecular basis of late-life globoid cell leukodystrophy Hum Mutat
14(3):256-62 De Jong J, van den Berg C, Wijburg H, et al (1994) alpha-N- acetylgalactosaminidase deficiency with mild clinical manifestation and difficult biochemical diagnosis. J Pediatr 125(3): 385-391. Di Rocco M, Rossi A, Parenti G, Allegri AE, Filocamo M, Pessagno A, Tortori-
Donati P, Minetti C, Biancheri R (2005) Different molecular mechanisms leading to white matter hypomyelination in infantile onset lysosomal disorders.
Neuropediatrics 36(4):265-9. Dierks T, Schlotawa L, Frese MA, Radhakrishnan K, von Figura K, Schmidt B
(2009) Molecular basis of multiple sulfatase deficiency, mucolipidosis II/III and
Niemann-Pick C1 disesase – Lysosomal storage disorders caused by defects of non-lysosomal proteins. Biochimica et Biophysica Acta 1793(4): 710-725. Dodelson de Kremer, R.; Boldini, C. D.; Capra, A. P.; Levstein, I. M.; Bainttein, N.;
Hidalgo, P. K.; Hliba, H (1985) Sandhoff disease: 36 cases from Cordoba,
Argentina J Inherit Metab Dis 8(1): 46 Dreborg S, Erikson A, Hagberg B (1980) Gaucher disease. Norrbottnian type I.
General clinical descriptions. Eur J Pediatr 133(2):107 118. Drousiotou A, Stylianidou G, Anastasiadou V, et al (2000) Sandhoff disease in
Cyprus: population screening by biochemical and DNA analysis indicates a high frequency of carriers in the Maronite community Hum Genet 107(1): 12-17 Duffner PK, Caggana M, Orsini JJ, et al (2009a) Newborn Screening for Krabbe
Disease:the New York State Model. Pediatr Neurol. 40(4):245-52 Duffner PK, Caviness VS Jr, Erbe RW, Patterson MC, Schultz KR, Wenger DA,
Whitley C. (2009b) The long-term outcomes of presymptomatic infants transplanted for Krabbe disease: report of the workshop held on July 11 and 12,
2008, Holiday Valley, New York. Genet Med. 11(6):450-4. Durand P, Gatti R, Borrone C, et al (1979) Detection of carriers and prenatal diagnosis for fucosidosis in Calabria. Hum Genet 51(2):195-201. Dyke JP, Voss HU, Sondhi D, et al (2007) Assessing Disease Severity in Late
Infantile Neuronal Ceroid Lipofuscinosis Using Quantitative MR Diffusion-Weighted
Imaging. American Journal of Neuroradiology 28(7):1232-1236. Elleder M, Jirfisek A, Smid F, Ledvinovfi J, Besley GT (1985) Niemann-Pick
Disease Type C. Study on the Nature of the Cerebral Storage Process. Acta
Neuropathol 66(4): 325- 336 Erol I, Alehan F, Pourbagher MA, Canan O, Vefa Yildirim S (2006) Neuroimaging findings in infantile GM1 gangliosidosis. Eur J Paediatr Neurol 10(5-6):245-8. Escolar ML, Poe MD, Martin HR, Kurtzberg J (2006) A staging system for infantile
Krabbe disease to predict outcome after unrelated umbilical cord blood transplantation.Pediatrics 118(3):e879-89. Fensom AH, Grant AR, Steinberg SJ, et al (1999) An adult with a non- neuronopathic form of Niemann-Pick C disease. J Inherit Metab Dis 22 (1): 84-6. Fernandez-Valero EM, Ballart A, Iturriaga C, Lluch M, Macias J, Vanier MT, Pineda
M, Coll MJ (2005) Identification of 25 new mutations in 40 unrelated Spanish Niemann-Pick type C patients: genotype-phenotype correlations. Clin Genet 68(3):
245-54 Fluharty AL, Fluharty CB, Bohne W, von Figura K, Gieselmann V (1991) Two new arylsulfatase A (ARSA) mutations in a juvenile metachromatic leukodystrophy
(MLD) patient. Am J Hum Genet 49(6):1340-50 Folkerth RD, Alroy J, Lomakina I, Skutelsky E, Raghavan SS, Kolodny EH (1995)
Mucolipidosis IV: morphology and histochemistry of an autopsy case. J
Neuropathol Exp Neurol 54(2):154-64. Fowler GW, Sukoff M, Hamilton A, Williams JP (1975) Communicating hydrocephalus in children with genetic inborn errors of metabolism. Childs Brain
1(4): 251–254. Frei KP, Patronas NJ, Crutchfield KE, Alterescu G, Schiffmann R (1998)
Mucolipidosis type IV: characteristic MRI findings. Neurology 51(2):565-9. Frey LC, Ringel SP, Filley CM (2005) The natural history of cognitive dysfunction in late-onset GM2 gangliosidosis. Arch Neurol Jun; 62(6):989-94. Froissart R, Blond JL, Maire I, et al (1993) Hunter syndrome: gene deletions and rearrangements. Hum Mutat 2(2): 138–140. Frostad Riise HM, Hansen GM, Tollersrud OK, Nilssen O (1999) Characterization of a novel alpha-mannosidosis-causing mutation and its use in leukocyte genotyping after bone marrow transplantation. Hum Genet; 104: 106–7 Gabrielli O, Coppa GV, Bruni S, Villani GR, Pontarelli G, Di Natale P (2005)An adult Sanfilippo type A patient with homozygous mutation R206P in the sulfamidase gene Am J Med Genet A 133A(1):85-9. Galanaud D, Tourbah A, Lehéricy S, et al (2009) 24 month-treatment with miglustat of three patients with Niemann-Pick disease type C: follow up using brain spectroscopy.Mol Genet Metab 96(2):55-8. Galjart NJ, Gillemans N, Harris A et al (1988) Expression of cDNA encoding the human “protective protein” associated with lysosomal beta-galactosidase and neuroaminidase: homology to yeast proteases. Cell 54(6):755-764. Galluzzi P, Rufa A, Balestri P, Cerase A, Federico A (2001) MR brain imaging of fucosidosis type I. Am J Neuroradiol 22(4): 777-780. Garbutt S, Harris CM (2000) Abnormal vertical optokinetcs nystagmus in infants and chidren. Br J Ophtalmol. 84(5); 451-455 Georgiou T, G. Stylianidou, V. Anastasiadou, et al (2005) The Arg482His mutation in the beta-galactosidase gene is responsible for a high frequency of GM1 gangliosidosis carriers in a Cypriot village. Genet. Test 9(2) 126–132. Giugliani R, Dutra JC, Pereira ML, et al (1985) GM1 gangliosidosis: clinical and laboratory findings in eight families. Hum Genet 70(4):347-54. Goker-Alpan O, Schiffmann R, Park J K, Stubblefield B K, Tayebi N, Sidransky E
(2003) Phenotypic continuum in neuronopathic Gaucher disease: An intermediate phenotype between type 2 and type 3. J. Pediatr 143(2):273-6 Gordon BA, Gordon KE, Seo HC, Yang M, DiCioccio RA, O'Brien JS (1995)
Fucosidosis with dystonia. Neuropediatr 26(6):325-7. Gourrier E, Thomas MP, Munnich A, Poenaru L, Asensi D, Jan D, Leraillez J
(1997). Beta mannposidosis: A new case. Ach Pediatr 4(2):147-51 Grau AJ, Brandt T, Weisbrod M, et al (1997) Adult Niemann-Pick disease type C mimicking features of multiple sclerosis. J Neurol Neurosurg Psychiatry 63(4): 552. Gravel RA, Kaback MM, Proia RL, Sandhoff K, Suzuki K, Suzuki K (2001) The
GM2 gangliosidoses In: Scriver CR, Beaudet AL, Sly WS, Valle D, eds. The metabolic and molecular bases of inherited disease. 8th ed. New York: McGraw-
Hill, 3827-3876
Greer W L,Riddell D C, Gillan T L, et al (1998) The Nova Scotia (Type D) Form of
Niemann-Pick Disease Is Caused by a G3097rT Transversion in NPC1. Am. J.
Hum. Genet 63(1):52–54. Guerra WF, Verity MA, Fluharty AL, Nguyen HT, Philippart M (1990) Multiple sulfatase deficiency: clinical, neuropathological, ultrastructural and biochemical studies. J Neuropathol Exp Neurol 49(4):406-23 Gumbinas M, Larsen M, Mei Liu H (1975) Peripheral neuropathy in classic
Niemann-Pick disease: ultrastructure of nerves and skeletal muscles. Neurology
25(2): 107-13 Hainsworth DP, Liu GT, Hamm CW, Katz ML (2009) Funduscopic and angiographic appearance in the neuronal ceroid lipofuscinoses. Retina.
29(5):657-68. Hamano K, Hayashi M, Shioda K, Fukatsu R, Mizutani S (2008) Mechanisms of neurodegeneration in mucopolysaccharidoses II and IIIB: analysis of human brain tissue. Acta Neuropathol 115(5):547-59. Harris C M, Shawkat F, Russell-Eggitt I, Wilson J, Taylor D (1996) Intermittent horizontal saccade failure ('ocular motor apraxia') in children. British Journal of
Ophthalmology 80(2): 151-158. Harris CM, Taylor DSI, Vellodi A (1999) Ocular motor abnormalities in Gaucher disease. Neuropediatrics 30(6):289-93. Harzer K. Adult Niemann-Pick disease type C mimicking features of multiple sclerosis (1997) J Neurol Neurosurg Psychiatry 63(4): 552. Higgins JJ, Patterson MC, Dambrosia JM, et al (1992) A clinical staging classification for type C Niemann-Pick disease. Neurology 42(12):2286-90.
(abstract) Hill SC, Damasska BM, Tsokos M, Kreps C, Brady RO, Barton NW (1996)
Radiographic findings in type 3b Gaucher disease. Pediatr Radiol 26(12): 852-860 Hoffmann B, Mayatepek E (2005) Neurological manifestations in lysosomal storage disorders - from pathology to first therapeutic possibilities Neuropediatrics
36(5):285-9. Huang YZ, Lai SC, Lu CS, Weng YH, Chuang WL, Chen RS (2008) Abnormal cortical excitability with preserved brainstem and spinal reflexes in sialidosis type I.
Clin Neurophysiol 119(5):1042-50. Husain AM (2006) Neurophysiologic studies in Krabbe disease. Suppl Clin
Neurophysiol 59:289-98. Husain AM, Altuwaijri M, Aldosari M (2004) Krabbe disease: neurophysiologic studies and MRI correlations. Neurology 63(4):617-20. Imrie J, Dasgupta S, Besley G T N, et al (2007) The natural history of Niemann–
Pick disease type C in the UK. J Inherit Metab Dis 30(1):51–59 Imrie J, Vijayaraghaven S, Whitehouse C, et al (2002) Niemann-Pick disease type
C in adults. J Inherit Metab Dis 25(6): 491–500. Itoh M, Hayashi M, Fujioka Y, Nagashima K, Morimatsu Y, Matsuyama H (2002)
Immunohistological study of globoid cell leukodystrophy. Brain Dev 24(5):284-90. Iturriaga C, Pineda M, Fernández-Valero E M, Vanier M T, Coll M J (2006)
Niemann–Pick C disease in Spain: Clinical spectrum and development of a disability scale J Neurol Sci 249(1): 1–6 Jalanko A, Braulke T (2009) Neuronal ceroid lipofuscinoses. Biochimica et
Biophysica Acta 1793(4): 697–709. Jardim LB, Giugliani R, Fensom AH (1992) Thalamic and basal ganglia hyperdensities--a CT marker for globoid cell leukodystrophy? Neuropediatrics
23(1):30-1. Jardim LB, Giugliani R, Pires RF, Haussen S, Burin MG, Rafi MA, Wenger DA
(1999) Protracted course of Krabbe disease in an adult patient bearing a novel mutation. Arch Neurol 56(8):1014-7. Järvelä I, Autti T, Lamminranta S, Aberg L, Raininko R, Santavuori P (1997)
Clinical and magnetic resonance imaging findings in Batten disease: analysis of the major mutation (1.02-kb deletion). Ann Neurol. 42(5):799-802. Jeyakumar M, Dwek RA, Butters TD, Platt FM (2005) . Storage solutions: treating lysosomal disorders of the brain. Nat Rev Neurosci 6(9):713-25. Jeyakumar M, Dwek RA, Butters TD, Platt FM (2005) Storage solutions: treating lysosomal disorders of the brain. Nat Rev Neurosci 6(9):713-25. Jones MZ, Alroy J, Rutledge JC, et al (1997) Human mucopolysaccharidosis IIID: clinical, biochemical, morphological and immunohistochemical characteristics. J
Neuropathol Exp Neurol 56(10):1158-67 Ju W, Wronska A, Moroziewicz DN (2006) Genotype-phenotype analyses of classic neuronal ceroid lipofuscinosis (NCLs): genetic predictions from clinical and pathological findings. Beijing Da Xue Xue Bao 38(1):41-8. Kaback MM (2000) Population-based genetics screening for reproductive counseling: the Tay Sachs experience. Eur J Peds 159: S192–5. Kachur E, Del Maestro R (2000) Mucopolysaccharidoses and spinal cord compression: case report and review of the literature with implications of bone marrow transplantation. Neurosurgery 47(1):223-8. Kanzaki T, Yokota M, Irie F, Hirabayashi Y, Wang AM, Desnick RJ (1993)
Angiokeratoma corporis diffusum with glycopeptiduria due to deficient lysosomal alpha-N-acetylgalactosaminidase activity: clinical, morphologic, and biochemical studies. Arch Derm 129: 460-65. Karten B, Vance D E, Campenot R B, Vance J E (2003) Trafficking of Cholesterol from Cell Bodies to Distal Axons in Niemann Pick C1-deficient Neurons. J Biol
Chem 278(6): 4168–4175 Kawai H, Nishino H, Nishida Y, et al (1985) Skeletal muscle pathology of mannosidosis in two siblings with spastic paraplegia. Acta Neuropath 68: 201-04. Keulemans JLM, Reuser AJJ, Kroos MA, et al (1996) Human alpha-N- acetylgalactosaminidase (alpha-NAGA) deficiency: new mutations and the paradox between genotype and phenotype. J Med Gene 33: 458-64. Khanna G, Van Heest AE, Agel J, et al (2007). Analysis of factors affecting development of carpal tunnel syndrome in patients with Hurler syndrome after hematopoietic cell transplantation. Bone Marrow Transplant 39:331-334. Klarner B, Klünemann HH, Lürding R, Aslanidis C, Rupprecht R (2007)
Neuropsychological profile of adult patients with Niemann-Pick C1 (NPC1) mutations. J Inherit Metab Dis 30(1):60-7 (abstract) Kleijer WJ, Geilen GC, Janse HC, Van Diggelen OP, Zhou XY, Galjart H, D´Azzo A
(1996) Cathepsin A deficiency in galactosialidosis: studies of patients in 16 families. Pediatr Res 39(6): 1067-1071. Kleijer WJ, Keulemans JL, van der Kraan M, Geilen GG, van der Helm RM, Rafi
MA, Luzi P, Wenger DA, Halley DJ, van Diggelen OP (1997) Prevalent mutations in the GALC gene of patients with Krabbe disease of Dutch and other European origin J Inherit Metab Dis 20(4):587-94 Kobayashi T, Ohta M, Goto et al (1979) Adult type mucolipidosis with beta- galactosidase and sialidase deficiency. J Neurol 221(3):137-149. Kohlschütter A, Schulz A (2009) Towards understanding the neuronal ceroid lipofuscinoses. Brain Dev Feb 3. Kolodny EH, Raghavan S, Krivit W (1991) Late-onset Krabbe disease (globoid cell leukodystrophy): clinical and biochemical features of 15 cases. Dev Neurosci 13(4-
5):232-9. Koprivica V, Stone D L, Park J K, et al (2000) Analysis and Classification of 304
Mutant Alleles in Patients with Type 1 and Type 3 Gaucher Disease. Am. J. Hum.
Genet 66(6):1777–1786 Kornfeld M (2008) Neuropathology of chronic GM2 gangliosidosis due to hexosaminidase A deficiency.Clin Neuropathol 27(5):302-8. Kornfeld S, Sly WS (2001) I-cell disease an pseudo-Hurler polydystrophy: disorders of lysosomal enzyme phosporylation and localization. In: Scriver CR,
Beaudet AL, Sly WS, Valle D, eds. The metabolic and molecular bases of inherited disease. 8th ed. New York: McGraw-Hill, 3469-3482. Krivit W, Aubourg P, Shapiro E, Peters C. Bone marrow transplantation for globoid cell leukodystrophy, adrenoleukodystrophy, metachromatic leukodystrophy, and
Hurler syndrome. Curr Opin Hematol. 1999 Nov;6(6):377-82. Kudo M, Brem MS, Canfield WM (2006) Mucolipidosis II (I-cell disease) and mucolipidosis IIIA (classical pseudo-hurler polydystrophy) are caused by mutations in the GlcNAc-phosphotransferase alpha / beta -subunits precursor gene. Am J
Hum Genet. 78(3):451-63. Kurihara M, Kumagai K, Goto K, Imai M, Yagishita S (1992) Severe type Hunter’s syndrome. Polysomnographic and neuropathological study. Neuropediatrics 23(5):
248–256. Labauge P, Renard D, Castelnovo D, Saboardy F, de Champfleur N, Levade T
(2009) Beta-mannosidosis: a new cause of spinocerebellar ataxia. Clin Neurol
Neurosurg 111(1):109-10. Lai SC, Chen RS, Wu Chou YH, et al (2009) A longitudinal study of Taiwanese
Sialidosis type 1: an insight into the concept of cherry-red spot myoclonus syndrome. Eur J Neurol.16(8):912-9 Landrieu P, Said G (1984) Peripheral neuropathy in type A Niemann-Pick disease.
A morphological study. Acta Neuropathol 63(1): 66-71 Lenicker HM, P. Vassallo Agius, E.P. Young, S.P. Attard Montalto (1997) Infantile generalized GM1 gangliosidosis: high incidence in the Maltese Islands, J Inherit.
Metab Dis 20(5) 723–724. Leroy JG (2007) Oligosaccharidoses, disorders allied to the oligosaccharides; Ch
108 in: Rimoin DL, Connor JM, Pyeritz RE, Korf BR , eds Emery and Rimoin’s
Principles and Practice of Medical Genetics, 5 th ed. Philadelphia: Churchill
Livingstone Elsevier, 2413-48. Levade T, Graber D, Flurin V, et al (1994). Human beta- mannosidosidase deficiency associated with peripheral neuropathy. Ann Neurol 35(1):116-9. Levran O, Desnick RJ, Schuchman EH (1992) Identification and expression of a common missense mutation (L302P) in the acid sphingomyelinase gene of
Ashkenazi Jewish type A Niemann-Pick disease patients. Blood 80(8): 2081-7 Levran O, Desnick, RJ, Schuchman EH (1991) Niemann-Pick type B disease.
Identification of a single codon deletion in the acid sphingomyelinase gene and genotype/phenotype correlations in type A and B patients.
J Clin Invest 88(3): 806–810 Li P, Bellows AB, Thompson JN (1999) Molecular basis of iduronate-2-sulphatase gene mutations in patients with mucopolysaccharidosis type II (Hunter syndrome). J Med Genet 36(1): 21-7 Lim ZY, Ho AY, Abrahams S, Fensom A, Aldouri M, Pagliuca A, Shaw C, Mufti GJ.
Sustained neurological improvement following reduced-intensity conditioning allogeneic haematopoietic stem cell transplantation for late-onset Krabbe disease.
Bone Marrow Transplant. 2008 May;41(9):831-2. Lindblom N, Kivinen S, Heiskala H, Laakso ML, Kaski M (2006) Sleep disturbances in aspatylglucosaminuria (AGU): A questionnaire study. J Inherit Metab Dis
29(5):637-646. Lloyd-Evans E, Pelled D, Riebeling C, et al (2003) Glucosylceramide and
Glucosylsphingosine Modulate Calcium Mobilization from Brain Microsomes via
Different Mechanisms. J Biol Chem 27 278(26): 23594–23599. Loes DJ, Peters C, Krivit W. Globoid cell leukodystrophy: distinguishing early-onset from late-onset disease using a brain MR imaging scoring method. AJNR Am J
Neuroradiol. 1999 Feb;20(2):316-23. Lonser RR, Schiffman R, Robison RA, et al (2007) Image-guided, direct convective delivery of glucocerebrosidase for neuronopathic Gaucher disease. Neurology
68(4):254-61. Loonen MC, Van Diggelen OP, Janse HC, Kleijer WJ, Arts WF (1985) Late-onset globoid cell leucodystrophy (Krabbe's disease). Clinical and genetic delineation of two forms and their relation to the early-infantile form. Neuropediatrics 16(3): 137–
42. Lowden JA, O’Brien JS (1979) Sialidosis: a review of human neuraminidase deficiency. Am J Hum Genet 31(1):1-18 Lowry RB, Applegarth DA, Toone JR, MacDonald E, Thunem NY (1990) An update on the frequency of mucopolysaccharide syndromes in British Columbia. Hum
Genet 85(3): 389–90 Lugowska A, Amaral O, Berger J et al (2005) Mutations c.459+1G>A and p.P426L in the ARSA gene: prevalence in metachromatic leukodystrophy patients from European countries. Mol Genet Metab 86(3):353-9. Lyon G, Hagberg B, Evrard P, Allaire C, Pavone L, Vanier M (1991)
Symptomatology of late onset Krabbe’s leukodystrophy: the European experience.
Dev Neurosci 13(4-5):240–244. Lyon G, Kolodny EH, Pastores G (2006) Neurology of hereditary metabolic disease of children. New York, McGraw-Hill, 3rd edition. Lyons MJ, Wood T, Espinoza L, Stenslands HM, Holden KR (2007) Early onset alpha-mannosidosis with slow progression in three Hispanic males. Dev Med Child
Neurol 49(11):854-7. Mac Dougal B, Weeks PM, Wray RC Jr (1977) Median nerve compression and trigger finger in the mucopolysaccharidoses and related diseases. Plast Reconstr
Surg 59(2): 260–263. Maegawa GH, Stockley T, Tropak M, et al (2006) The natural history of juvenile or subacute GM2 gangliosidosis: 21 new cases and literature review of 134 previously reported. Pediatrics 118(5):e1550-62. Malm D, Nilssen O (2008) Alpha–mannosidosis. Orphanet Journal of Rare
Diseases 3: 21. Malm G, Månsson JE, Winiarski J, Mosskin M, Ringdén O (2004) Five-year follow- up of two siblings with aspartylglucosaminuria undergoing allogeneic stem-cell transplantation from unrelated donors. Transplantation 78(3):415-9. Martin R, Beck M, Eng C et al (2008) Recognition and diagnosis of mucopolysaccharidosis II (Hunter syndrome. Pediatrics. 121(2):e377-86 Matheus MG, Castillo M, Smith JK, Armao D, Towle D, Muenzer J (2004) Brain
MRI findings in patients with mucopolysaccharidosis types I and II and mild clinical presentation. Neuroradiology 46(8): 666–672. Mc Govern M M, Aron A, Brodie S E, Desnick R J, and Wasserstein , M P(2006)
Natural history of Type A Niemann-Pick disease Possible endpoints for therapeutic trials. Neurology 66(2): 228-232 Mc Govern M M, Wasserstein M P, Giugliani R, et al (2008) A Prospective, Cross- Sectional Survey Study of the Natural History of Niemann-Pick B Disease.
Pediatrics 122(2): 341–349 (b) Meikle PJ, Hopwood JJ, Clague AE, Carey WF (1999) Prevalence of lysosomal storage disorders. JAMA. 281(3): 249–54 Meikle PJ, Ranieri E, Simonsen H, et al (2004). Newborn screening for lysosomal storage disorders: clinical evaluation of a two-tier strategy. Pediatrics 114(4):909-
916 Meyer A, Kossow K, Gal A et al (2007) Scoring evaluation of the natural course of mucopolysaccharidosis type IIIA (Sanfilippo syndrome type A). Pediatrics 120(5): e1255–e1261. Michalski JC, Klein A (1999) Glycoprotein lysosomal storage disorders: alpha- andbeta-mannosidosis, fucosidosis and alpha-N-acetylgalacto- saminidase deficiency. Biochim Biophys Acta 1455(2-3):69-84. Mignot C, Doummar D, Maire I, De Villemeur T B (2006) The French Type 2
Gaucher Disease Study Group. Type 2 Gaucher disease: 15 new cases and review of the literature. Brain & Development 28(1) 39–48 Mihaylova V,Hantke J, Sinigerska I, et al (2007) Highly variable neural involvement in sphingomyelinase-deficient Niemann-Pick disease caused by an ancestral
Gypsy mutation. Brain 130(Pt 4):1050-1061 Millat G, Marcais C, Rafi MA et al (1999) Niemann–Pick C1 disease: the I1061T substitution is a frequent mutant allele in patients of Western European descent and correlates with a classic juvenile phenotype. Am J Hum Genet: 65(5): 1321–
1329. Millat G, Marcais C, Tomasetto K, et al (2001) Niemann-Pick C1 Disease:
Correlations between NPC1 Mutations, Levels of NPC1 Protein, and Phenotypes
Emphasize the Functional Significance of the Putative Sterol-Sensing Domain and of the Cysteine-Rich Luminal Loop. Am J Hum Genet 68(6):1373–1385, Miyatake T, Atsumi T, ObayashiT et al (1979) Adult type neuronal storage disease with neuroaminidase deficiency. Ann Neurol 6(3): 232-44 Mochizuki A, Motoyoshi Y, Takeuchi M, Sonoo M, Shimizu T (2000) A case of adult type galactosialidosis with involvement of peripheral nerves. J Neurol
247(9):708-10. Montaño AM, Tomatsu S, Gottesman GS, Smith M, Orii T. International Morquio A
Registry: clinical manifestation and natural course of Morquio A disease. J Inherit
Metab Dis. 2007 Apr;30(2):165-74. Moog U, van Mierlo I, van Schrojenstein Lantman-de Valk HM, Spaapen L,
Maaskant MA, Curfs LM (2007) Is Sanfilippo type B in your mind when you see adults with mental retardation and behavioral problems. Am J Med Genet C Semin
Med Genet 145C(3):293-301 Moore D, Connock MJ, Wraith E, Lavery C (2008) The prevalence of and survival in Mucopolysaccharidosis I: Hurler, Hurler-Scheie and Scheie syndromes in the
UK. Orphanet J Rare Dis 3:24 Moore DF, Kaneski CR, Askari H, Schiffmann R (2007) The cerebral vasculopathy of Fabry disease. J Neurol Sci. 257(1-2):258-63. Moore SJ, Buckley DJ, MacMillan A, et al (2008) The clinical and genetic epidemiology of neuronal ceroid lipofuscinosis in Newfoundland. Clin Genet
74(3):213-22. Moser HW, Linke T, Fenson AH, Levade T, Sandhoff K (2001) Acid Ceramidase deficiency: Farber Lipogranulomatosis. In Scriver CR, Beaudet AC, Sly WS, Valle
D, eds. The Metabolic and Molecular Basis of Inherited Disease 8th ed. New York:
McGraw-Hill Book Co, 3573-3588. Muenzer J (1986) Mucopolysaccharidoses Adv Pediatr 33:269-302. Muthane U, Chickabasaviah Y, Kaneski C, et al (2004) Clinical features of adult
GM1 gangliosidosis: report of three Indian patients and review of 40 cases. Mov
Disord 19(11): 1334–1341. Neudorfer O, Pastores GM, Zeng BJ, Gianutsos J, Zaroff CM, Kolodny EH (2005) Late-onset Tay-Sachs disease: phenotypic characterization and genotypic correlations in 21 affected patients. Genet Med 7(2): 119-23. Neufeld EF, Muenzer J (2001) The Mucopoysaccharidoses. In: Scriver CR,
Beaudet AL, Sly WS, Valle D, eds. The metabolic and molecular bases of inherited disease. 8th ed. New York: McGraw-Hill, 3421- 3452. Nidiffer FD, Kelly TE (1983) Developmental and degenerative patterns associated with cognitive, behavioural and motor difficulties in the Sanfilippo syndrome: an epidemiological study. J Ment Defic Res 27 (Pt 3):185-203. Nijssen PC, Ceuterick C, van Diggelen OP, Elleder M, Martin JJ, Teepen JL,
Tyynelä J, Roos RA (2003) Autosomal dominant adult neuronal ceroid lipofuscinosis: a novel form of NCL with granular osmiophilic deposits without palmitoyl protein thioesterase 1 deficiency.Brain Pathol;13(4):574-81. Nilssen O, Berg T, Riise HM, Ramachandran U, Evjen G, Hansen GM, Malm D,
Tranebjaerg L, Tollersrud OK (1997). alpha-Mannosidosis: functional cloning of the lysosomal alpha- mannosidase cDNA and identification of a mutation in two affected siblings. Hum Mol Genet. 6: 717–26. Obenberger J, Seidl Z, Pavlu Ê H, Elleder M (1999) MRI in an unusually protracted neuronopathic variant of acid sphingomyelinase deficiency. Neuroradiology 41(3):
182-184 Ockerman PA (1967) A generalized storage disorder resembling Hurler's syndrome. Lancet 290: 239-241. Ockerman PA (1969) Mannosidosis: isolation of oligosaccharide storage material from brain. J Pediat 75(3): 360-65. Okada S, O’Brien J S(1968) Generalized gangliosidosis: beta-galactosidase deficiency. Science 160 1002–1004. Olmetz A, Nilssen O, Costkun T, Klenow H (2003) Alpha-mannosidosis and mutational analysis in a Turkish patient. Turk J Pediatr 45(1):46-50. Otomo T, Muramatsu T, Yorifuji T, et al (2009) Mucolipidosis II and III alpha/beta: mutation analysis of 40 Japanese patients showed genotype-phenotype correlation. J Hum Genet 54(3): 145-51. Palmeri S, Villanova M, Malandrini A et al (2000) Type I sialidosis: a clinical, biochemical and neuroradiological study. Eur Neurol 43(2):88-94. Park J K, Orvisky E, Tayebi N et al (2003) Myoclonic Epilepsy in Gaucher Disease:
Genotype-Phenotype Insights from a Rare Patient Subgroup. Pediatric Research
53(3): 387-395 Pastores G M, Hugues D A. (Update: March 13, 2008). Gaucher Disease. In
GeneReviews at GeneTests: Medical Genetics Information Resource (database online). Copyright, University of Washington, Seattle. 1997-2009. Available at http://www.genetests.org. Accessed in June 10, 2009. Pastores GM, Arn P, Beck M et al (2007) The MPS I registry: design, methodology, and early findings of a global disease registry for monitoring patients with
Mucopolysaccharidosis Type I. Mol Genet Metab 91(1):37-47. Pastores GM, Barnett NL, Bathan P, Kolodny EH (2003) A neurological symptom survey of patients with type I Gaucher disease. J Inherit Metab Dis 26(7): 641-5. Patel B, Gimi B, Vachha B, Agadi S, Koral K (2008) Optic nerve and chiasm enlargement in a case of infantile Krabbe disease: quantitative comparison with 26 age-matched controls Pediatr Radiol 38(6):697-9. Patterson M C, (Update: July 22, 2008). Niemann-Pick Disease Type C. In
GeneReviews at GeneTests: Medical Genetics Information Resource (database online). Copyright, University of Washington, Seattle. 1997-2009. Available at http://www.genetests.org. Accessed in June 19, 2009. Patterson M C, Vecchio D, Prady H, Abel L, Wraith JE (2007) Miglustat for treatment of Niemann-Pick C disease: a randomised controlled study.Lancet
Neurol 6(9):765-72 Patterson MC, Vanier MT, Suzuki K et al (2001) Niemann–Pick disease type C: a lipid trafficking disorder. In: The metabolic and molecular bases of inherited disease Scriver CR, Beaudet AL, Sly WS, Valle D, eds. New York: McGrawHill,
3611–3634.
Pavlu Pereira, Asfaw B, Poupctova H, et al (2005) Acid sphingomyelinase deficiency. Phenotype variability with prevalence of intermediate phenotype in a series of twenty-five Czech and Slovak patients. A multi-approach study.J. Inherit
Metab Dis 28(2): 203-227 Pelled D, Shogomori H and Futerman A H (2000) The increased sensitivity of neurons with elevated glucocerebroside to neurotoxic agentscan be reversed by imiglucerase J Inherit Metab Dis 23(2): 175-184. Pellissier JF, Berard-Badier M, Pinsard N (1986). Farber's disease in two siblings, sural nerve and subcutaneous biopsies by light and electron microscopy. Acta
Neuropath 72(2): 178-188. Peters C, Steward CG; National Marrow Donor Program; International Bone
Marrow Transplant Registry; Working Party on Inborn Errors, European Bone
Marrow Transplant Group. Hematopoietic cell transplantation for inherited metabolic diseases: an overview of outcomes and practice guidelines. Bone
Marrow Transplant. 2003 Feb;31(4):229-39. Pierson TM, Bonnemann CG, Finkel RS, Bunin N, Tennekoon GI. Umbilical cord blood transplantation for juvenile metachromatic leukodystrophy. Ann Neurol. 2008
Nov;64(5):583-7. Pinto R, Caseiro C, Lemos M, et al (2004) Prevalence of lysosomal storage diseases in Portugal. Eur J Hum Genet 12(2): 87–92. Pittis MG, Montalvo AL, Heikinheimo P, et al (2007) Functional characterization of four novel MAN2B1 mutations causing juvenile onset alpha-mannosidosis. Clin Chim Acta 375(1-2):136-9. Plante M, Claveau S, Lepage P (2008) Mucolipidosis II: a single causal mutation in the N-acetylglucosamine-1-phosphotransferase gene (GNPTAB) in a French
Canadian founder population. Clin Genet 73(3):236-44. Poorthuis BJ, Wevers RA, Kleijer WJ (1999) The frequency of lysosomal storage diseases in The Netherlands. Hum Genet 105 (1-2): 151–6 Pradhan SM, Atchaneeyasakul LO, Appukuttan B et al (2002) Electronegative electroretinogram in mucolipidosis IV Arch Ophthalmol 120(1):45-50. Provenzale JM, Barboriak DP, Sims K (1995) Neuroradiologic findings in fucosidosis, a rare lysosomal storage disease. Am J Neuroradiol 16: 809-13 Provenzale JM, Peddi S, Kurtzberg J, Poe MD, Mukundan S, Escolar M (2009)
Correlation of neurodevelopmental features and MRI findings in infantile Krabbe's disease. AJR Am J Roentgenol 192(1):59-65. Raja M, Azzoni A, Giona F et al (2007) Movement and mood disorder in two brothers with Gaucher disease Clin Genet 72(4): 357-61 Ramadan H, Al-Din AS, Ismail A (2007) Adult neuronal ceroid lipofuscinosis caused by deficiency in palmitoyl protein thioesterase 1. Neurology 68(5):387-8. Rapin I, Suzuki K, Suzuki K, Valsamis MP (1976) Adult (chronic) GM2 gangliosidosis: atypical spinocerebellar degeneration in a Jewish sibship. Arch
Neurol 33(2):120–130. Rauschka H, Colsch B, Baumann N, et al (2006) Late-onset metachromatic leukodystrophy: genotype strongly influences phenotype. Neurology 67(5):859-63. Rempel BP, Clarke LA, Withers SG (2005) A homology model for human alpha-l- iduronidase: insights into human disease. Mol Genet Metab 85(1): 28–37. Reuser AJJ, Drost MR (2006) Lysosomal dysfunction, cellular pathology and clinical symptoms: basic principles. Acta Pediatrica Suppl 95(451):77-82. Rider JA, Rider DL (1988) Batten disease: past, present, and future, Am J Med
Genet Suppl. 5: 21–26. Roze E, Paschke E, Lopez N, et al (2005) Dystonia and parkinsonism in GM1 type 3 gangliosidosis. Mov Disord 20(10): 1366–1369. Rozenberg R, Kok F, Burin MG (2006) Diagnosis and molecular characterization of non-classic forms of Tay-Sachs disease in Brazil. J Child Neurol 21(6): 540-4. Rucker JC, Shapiro BE, Han YH, Kumar AN, Garbutt S, Keller EL, Leigh RJ.
(2004) Neuro-ophthalmology of late-onset Tay-Sachs disease (LOTS). Neurology
63(10):1918-26. Ruijter GJ, Valstar MJ, Van de Kamp JM, et al (2008) Clinical and genetic spectrum of Sanfilippo type C (MPS IIIC) disease in The Netherlands. Mol Genet
Metab 93(2):104-11. Sabatelli M, Quaranta L, Madia F (2002) Peripheral neuropathy with hypomyelinating features in adult-onset Krabbe's disease. Neuromuscul Disord
12(4):386-91. Sandhoff K (2001) The GM2-gangliosidoses and the elucidation of the beta- hexosaminidase system. Adv Genet 44:67-91. Sandhoff K, Harzer K, Wassle W, Jatzkewitz H (1971) Enzyme alterations and lipid storage in three variants of Tay-Sachs disease J Neurochem 18(12): 2469-
2489 Santavuori P (1988) Neuronal ceroid-lipofuscinoses in childhood. Brain Dev; 10(2):
80–83. Santavuori P, Lauronen L, Kirveskari E, Åberg L, Sainio K, Autti T (2000) Neuronal ceroid lipofuscinoses in childhood. Neurol Sci 21(3 Suppl) S35–41. Santos RP & Hoo JJ (2009) Difficulty in recognizing multiple sulfatase deficiency in an infant. Pediatrics 117(3):955-958 Sbaragli M, Bibi L, Pittis MG, et al (2005) Identification and characterization of five novel MAN2B1 mutations in Italian patients with alpha-mannosidosis. Hum Mutat
25(3):320. Schiffmann R, Fitz Gibbon E J, Harris CM, et al (2008) Randomized, Controlled
Trial of Miglustat in Gaucher’s Disease Type 3. Ann Neurol 64 (5):514–522. Schiffmann R, Vellodi A (2007) Neuronopathic Gaucher Disease. In Futerman A H and Zimran A, eds. Gaucher disease Boca Raton:Taylor & Francis CRC Press, 175-196 Schindler D, Bishop DF, Wolfe DE, et al (1989) Neuroaxonal dystrophy due to lysosomal alpha-N-acetylgalactosaminidase deficiency. New Eng J Med 320(26):
1735-1740. Schlotawa L, Steinfeld R, von Figura K, Dierks T, Gärtner J (2008) Molecular analysis of SUMF1 mutations: stability and residual activity of mutant formylglycine-generating enzyme determine disease severity in multiple sulfatase deficiency. Hum Mutat 29(1): 205 Schuchman EH, Desnick RJ (2001) Niemann-Pick disease types A and B: acid sphingomyelinase deficiencies. In: Scriver CR, Beaudet AL, Sly WS, Valle D, eds.
The Metabolic and Molecular Bases of Inherited Disease. 8th ed. New York:
McGraw Hill:3589–611 Schueler U H, Kolter T, Kaneski CR, Blusztajn J K, Herkenham, M, Sandhoff K, and Brady R O (2003) Toxicity of glucosylsphingosine (glucopsychosine) to cultured neuronal cells: a model system for assessing neuronal damage in
Gaucher disease type 2 and 3. Neurobiol Dis 14(3) 595–601 Schwartz IV, Ribeiro MG, Mota JG, et al (2007) A clinical study of 77 patients with mucopolysaccharidosis type II. Acta Paediatr Suppl 96(455):63-70. Seo HC, Yang M, Tonlorenzi R, et al (1994) A missense mutation (S63L) in alpha-
L-fucosidase is responsible for fucosidosis in an Italian patient. Hum Mol Genet
3(11):2065-6. Severini MH, Silva CD, Sopelsa A, Coelho JC, Giugliani R (1999) High frequency of type 1 GM1 gangliosidosis in southern Brazil. Clin Genet 56(2) 168–169. Sevin M, Lesca G, Baumann N, Millat G, Lyon-Caen O, Vanier MT, Sedel F (2007)
The adult form of Niemann-Pick disease type C. Brain 130(Pt 1):120-33 Seyrantepe V, Poupetova H, Froissart R, Zabot MT, Maire I, Pshezhetsky AV
(2003) Molecular Pathology of Neu 1 Gene in Sialidosis. Hum Mutat 22(5):343-52. Shapiro BE, Logigian EL, Kolodny EH, Pastores GM (2008) Late-onset Tay-Sachs disease: the spectrum of peripheral neuropathy in 30 affected patients. Muscle
Nerve 38(2):1012-1015 Shapiro BE, Pastores GM, Gianutsos J, Luzy C, Kolodny EH (2009) Miglustat in late-onset Tay-Sachs disease: a 12-month, randomized, controlled clinical study with 24 months of extended treatment. Genet Med 11(6):425-33. Shimmoto M, Fukuhara Y, Itoh K, Oshima A, Sakuraba H, Suzuki Y (1993)
Protective protein gene mutations in galactosialidosis. J Clin Invest 91(6): 2393-8 Siddiqi ZA, Sanders DB, Massey JM (2006). Peripheral neuropathy in Krabbe disease: electrodiagnostic findings. Neurology 25;67(2):263-7. Sidransky E, Tsuji S, Martin BM, Stubblefield B, Ginns EI (1992) DNA mutation analysis of Gaucher patients. Am J Med Genet 42(3): 331-6 Sidransky E. Gaucher disease: complexity in a "simple" disorder (2004) Mol Genet
Metab 83(1,2): 6-15. Siintola E, Partanen S, Stromme P, et al (2006) Cathepsin D deficiency underlies congenital human neuronal ceroid-lipofuscinosis. Brain 129(Pt6):1438–45. Simonaro CM, Desnick RJ, McGovern MM, Wasserstein MP, Schuchman E H
(2002)The Demographics and Distribution of Type B Niemann-Pick Disease:Novel
Mutations Lead to New Genotype/Phenotype Correlations Am. J Hum Genet
71(6):1413–1419. Sinigerska I, D. Chandler, V. Vaghjiani, et al (2006) Founder mutation causing infantile GM1-gangliosidosis in the Gypsy population. Mol Genet Metab 88(1): 93–
95. Souillet G, Guffon N, Maire I, et al (2003). Outcome of 27 patients with Hurler's syndrome transplanted from either related or unrelated haematopoietic stem cell sources.Bone Marrow Transplant 31(12):1105-17. Sovik O, Lie SO, Fluge G, Van Hoof F (1980) Fucosidosis: severe phenotype with survival to adult age. Eur J Pediatr 135(2): 211-216. Spalton DJ, Taylor DS, Sanders MD (1980) Juvenile Batten's disease: an ophthalmological assessment of 26 patients. Br J Ophthalmol. 1980 Oct;64(10):726-32. Spranger S, Gehler J, Cantz M (1977) Mucolipidosis I-A sialidosis. Am J Med
Genet 1: 21-29. Staba SL, Escolar ML, Poe M, et al. (2004) Cord-blood transplants from unrelated donors in patients with Hurler’s syndrome. N Engl J Med. 350:1960-1969. Steinfeld R, Heim P, Von GH, et al (2002) Late infantile neuronal ceroid lipofuscinosis: quantitative description of the clinical course in patients with CLN2 mutations. Am J Med Genet 112(4):347–354. Steinfeld R, Reinhardt K, Schreiber K, et al (2006) Cathepsin D deficiency is associated with a human neurodegenerative disorder. Am J Hum Genet 78(6)
988–998. Stone DL, Tayebi N, Orvisky E, Stubblefield B, Madike V, Sidransky E (2000)
Glucocerebrosidase gene mutations in patients with type 2 Gaucher disease Hum
Mutat. 15(2):181-8 Sullivan D, Walterfang M, Velakoulis D (2005) Bipolar disorder and Niemann-Pick disease type C. Am J Psychiatry 162(5): 1021–2. Suzuki K, Parker CC, Pentchev PG, et al (1995) Neurofibrillary tangles in
Niemann–Pick disease type C. Acta Neuropathol 89(3): 227–238. (abstract) Suzuki Y, N. Nakamura, K. Fukuoka (1978) GM1-gangliosidosis: accumulation of ganglioside GM1 in cultured skin fibroblasts and correlation with clinical types.
Hum Genet 43(2)127–131. Suzuki Y, Oshima A, Nanba E (2001) ß-galactosidase deficiency (ß-galactosidosis)
GM1 gangliosidosis and Morquio B disease. In: Scriver CR, Beaudet AL, Sly WS,
Valle D, eds. The metabolic and molecular bases of inherited disease. 8th ed. New
York: McGraw-Hill, 3775- 3809 Tajima A, Yokoi T, Ariga M, et al (2009) Clinical and genetic study of Japanese patients with type 3 Gaucher disease Mol Genet Metab May 10 Takada G, Satoh W, Komatsu K, Konn Y , Miura Y, .Uesaka Y (1987) Transitory
Type of Sphingomyelinase Deficient Niemann-Pick Disease: Clinical and Morphological Studies and Follow-Up of Two Sisters. Tohoku J exp Med153(1):
27-36 Takahashi Y, Sukegawa K, Aoki M, et al (2001) Evaluation of accumulated mucopolysaccharides in the brain of patients with mucopolysaccharidoses by (1)H- magnetic resonance spectroscopy before and after bone marrow transplantation.
Pediatr Res 49(3): 349–355. Takashima S, Matsui A, Fujii Y, Nakamura H (1981) Clinicopathological differences between juvenile and late infantile metachromatic leukodystrophy.
Brain Dev 3(4):365-74. Tayebi N, Stubblefield BK, Park JK, et al (2003) Reciprocal and nonreciprocal recombination at the glucocerebrosidase gene region: implications for complexity in Gaucher disease Am J Hum Genet 72(3):519-34 Terespolsky D, Clarke JTR, Blaser SI (1996) Evolution of the neuroimaging changes in fucosidosis type II. J Inherit Metab Dis 19(6): 775-781. Terlato NJ, Cox GF (2003) Can mucopolysaccharidosis type I disease severity be predicted based on a patient's genotype? A comprehensive review of the literature.
Genet Med 5(4):286-94. Thomas GH (2001) Disordes of Glycoprotein Degradation: -Mannosidosis,
-Mannosidosis, Fucosidosis and Sialidosis. In Scriver CR, Beaudet AC, Sly
WS, Valle D, eds. The Metabolic and Molecular Basis of Inherited Disease.
8th ed. New York: McGraw-Hill Book Co, 3507-3533.
Tollersrud OK, Nilssen O, Tranebjaaerg L, Borud O (1994) Aspatylglucosaminuria in northern Norway: a molecular and genealogical study. J Med Genet 31(5):360-
63. Tomatsu S, Montaño AM, Dung VC, Grubb JH, Sly WS (2009) Mutations and polymorphisms in GUSB gene in mucopolysaccharidosis VII (Sly Syndrome). Hum Mutat 30(4): 511-9 Tripp J H, Lake B D, Young E, Ngu J, Brett E M (1977) Juvenile Gaucher's disease with horizontal gaze palsy in three siblings. Journal Neurol Neurosurg Psychiatry
40(5): 470-478. Turkia HB, Tebib N, Azzouz A et al (2008) Phenotypic spectrum of fucosidosis in
Tunísia. J Inherit Metab Dis Jul 27 Short Report #115 Tylki-Szymańska A, Millat G, Maire I, Czartoryska B (1996) Types I and III Gaucher disease in Poland: incidence of the most common mutations and phenotypic manifestations. Eur J Hum Genet 4(6): 334-7. Uc EY, Wenger DA, Jankovic J (2000) Niemann-Pick disease type C: two cases and an update. Mov Disord 15(6): 1199-203 Usui T, Abe H, Takagi M, Yoshizawa T, Hasegawa S, Iwata K (1993)
Electroretinogram and visual evoked potential in two siblings with adult form galactosialidosis. Metab Pediatr Syst Ophthalmol 16(1-2):19-22. Uvebrant P, Hagberg B (1997) Neuronal ceroid lipofuscinoses in Scandinavia.
Epidemiology and clinical pictures. Neuropediatrics 28(1): 6–8. Uyama E, Terasaki T, Watanabe S, et al (1992) Type 3 GM1 gangliosidosis: characteristic MRI findings correlated with dystonia. Acta Neurol Scand 86(6):609-
15. Vafiadaki E, Cooper A, Heptinstall LE, Hatton CE, Thornley M, Wraith JE (1998)
Mutation analysis in 57 unrelated patients with MPS II (Hunter's disease). Arch Dis
Child 79(3): 237-41 Valstar MJ, Ruitjer GJG, Diggelen OP, Poorthius BJ, Wijburg FA (2008) Sanfilippo syndrome: a mini-review. J Inherit Metab Dis 31: 240-252. Van Aerde J, Plets C, Van der Hauwaert L (1981) Hydrocephalus in Hunter
Syndrome. Acta Paediatr Belg 34(2):93-6. Van de Kamp JJ, Niermeijer MF, Von Figura K, Giesberts MA (1981) Genetic heterogeneity and clinical variability in the Sanfilippo syndrome (types A, B, and C).
Clin Genet 20(2):152-60. Van der Voorn JP, Pouwels PJ, Kamphorst W, et al (2005) Histopathologic correlates of radial stripes on MR images in lysosomal storage disorders. AJNR
Am J Neuroradiol 26(3):442-6. Van Diggelen OP, Schindler D, Kleijer WJ, et al (1987) Lysosomal alpha-N- acetylgalactosaminidase deficiency: a new inherited metabolic disease. (Letter)
Lancet 2(8562): 804. Van Diggelen OP, Schindler D, Willemsen R, Boer M, Kleijer WJ, Huijmans JGM,
Blom W, Galjaard H (1988) Alpha-N-acetylgalactosaminidase deficiency, a new lysosomal storage disorder. J Inherit Metab Dis 11: 349-57. Van Diggelen OP, Thobois S, Tilikete C, et al (2001) Adult neuronal ceroid lipofuscinosis with palmitoyl-protein thioesterase deficiency: first adult-onset patients of a childhood disease. Ann Neurol 50(2): 269–72. Vanhanen SL, Puranen J, Autti T, et al (2004) Neuroradiological findings (MRS,
MRI, SPECT) in infantile neuronal ceroid-lipofuscinosis (infantile CLN1) at different stages of the disease. Neuropediatrics 35(1):27-35. Vanhanen SL, Raininko R, Autti T, Santavuori P (1995) MRI evaluation of the brain in infantile neuronal ceroid-lipofuscinosis. Part 2: MRI findings in 21 patients. J
Child Neurol 10(6): 444–50 Vanier MT, Millat G (2003) Niemann–Pick disease type C. Clin Genet 64(4): 269– 281.
Vedolin L, Schwartz IV, Komlos M, et al (2007a) Correlation of MR imaging and
MR spectroscopy findings with cognitive impairment in Mucopolysaccha- ridosis II.
Am J Neuroradiol 28(6):1029-33 Vedolin L, Schwartz IV, Komlos M, et al (2007b) Brain MRI in mucopolysaccharidosis: effect of aging and correlation with biochemical findings.
Neurology 69(9):917-24. Vellodi A, Bembi B, de Villemeur TB, et al (2001) Management of neuronopathic
Gaucher disease: a European consensus. J Inherit Metab Dis 24(3):319-27. Verdru P, Lammens M, Dom R, Van Elsen A, Carton H (1991) Globoid cell leukodystrophy: a family with both late-infantile and adult type. Neurology
41(9):1382-4. Verghese J, Goldberg R F, Desnick R J, et al (2000) Myoclonus From Selective
Dentate Nucleus Degeneration in Type 3 Gaucher Disease. Arch Neurol 57(3):
389-395 Von Figura K, Gieselmann V, Jacken J (2001) Metachromatic leukodystrophy. In:
Scriver CR, Beaudet AL, Sly WS, Valle D , eds The Metabolic and Molecular
Bases of Inherited Disease. 8th ed. New York: McGraw-Hill Book Co, 3695-3724. Vougioukas VI, Berlis A, Kopp MV, Korinthenberg R, Spreer J, van Velthoven V.
Neurosurgical interventions in children with Maroteaux-Lamy syndrome. Case report and review of the literature. Pediatr Neurosurg. 2001 Jul;35(1):35-8. Walkley S U, Suzuki K (2004) Consequences of NPC1 and NPC2 loss of function in mammalian neurons. Biochimica et Biophysica Acta 1685(1-3): 48– 62 Wang AM, Schindler D, Bishop DF, Lemieux RU, Desnick RJ (1988) Schindler disease: biochemical and molecular characterization of a new neuroaxonal dystrophy due to alpha-N-acetylgalactosaminidase deficiency. Am J Hum Genet
43: A99 only. Wasserstein MP, Desnick RJ, Schuchman EH, et al (2004) The Natural History of
Type B Niemann-Pick Disease: Results From a 10-Year Longitudinal Study.
Pediatrics 114(6): 672-677 Wassertein MP, Aron A, Brodie SE, Simonaro C, Desnick RJ, Mc Govern MM
(2006) Acid sphingomyelinase deficiency prevalence and characterization of an intermediate phenotype o Niemann- Pick. J Pediatr 149(4):554-9 Wenger DA, (Update: August 5, 2008). Krabbe Disease In GeneReviews at
GeneTests: Medical Genetics Information Resource (database online). Copyright,
University of Washington, Seattle. 1997-2009. Available at http://www.genetests.org. Accessed in June 15, 2009. Wenger DA, Suzuki K, Suzuki Y, Suzuki K (2001) Galactosylceramide lipidosis: globoid cell leukodystrophy (Krabbe disease). In: Scriver CR, Beaudet AL, Sly WS,
Valle D, eds. The metabolic and molecular bases of inherited disease. 8th ed. New
York: McGraw-Hill, 3669–3693. Willems PJ, Gatti R, Darby JK, Romeo G, Durand P, Dumon JE, O'Brien JS (1991)
Fucosidosis revisited: a review of 77 patients. Am J Med Genet 38(1): 111-31. Wisniewski KE (Update: May 17, 2006). Neuronal ceroid-lipofuscinoses In
GeneReviews at GeneTests: Medical Genetics Information Resource (database online). Copyright, University of Washington, Seattle. 1997-2009. Available at http://www.genetests.org. Accessed in June 10, 2009. Wisniewski KE, Kida E, Connell F, Zhong N (2000) Neuronal ceroid lipofuscinoses: research update. Neurol Sci 21(3 Suppl):S49-56 Wong K, Sidransky E, Verma A, et al (2004) Neuropathology provides clues to the pathophysiology of Gaucher disease. Molecular Genetics and Metabolism 82(3):
192–207 Worgall S, Kekatpure MV, Heier L, et al (2007)Neurological deterioration in late infantile neuronal ceroid lipofuscinosis. Neurology 69(6):521-35. Wraith JE (2002) Lysosomal disorders. Semin Neonatol 7(1):75-83. Wraith JE, Cooper A, Thornley M, et al (1991) The clinical phenotype of two patients with a complete deletion of the iduronate-2-sulphatase gene
(mucopolysaccharidosis II–Hunter syndrome). Hum Genet 87(2): 205–206. Wraith JE, Scarpa M, Beck M, et al (2008) Mucopolysaccharidosis type II (Hunter syndrome): a clinical review and recommendations for treatment in the era of enzyme replacement therapy. Eur J Pediatr 167(3):267-77. Yanjanin NM, Vélez JI, Gropman A, et al (2009) Linear clinical progression, independent of age of onset, in Niemann-Pick disease, type C. Am J Med Genet B
Neuropsychiatr Genet May 4. Yatziv S, Erickson RP, Epstein CJ (1977) Mild and severe Hunter syndrome (MPS II) within the same sibships. Clin Genet 11(5):319-26. Yogalingam G, Hopwood JJ (2001) Molecular genetics of mucopolysaccharidosis type IIIA and IIIB: Diagnostic, clinical, and biological implications. Hum
Mutat.18(4):264-81. Young ID, Harper PS, Archer IM, Newcombe RG (1982) A clinical and genetic study of Hunter's syndrome. 1. Heterogeneity. J Med Genet 19(6): 401-7. Zafeiriou DI, Triantafyllou P, Gombakis NP, Vargiami E, Tsantali C, Michelakaki E
(2003) Niemann-Pick type C disease associated with peripheral neuropathy.Pediatr Neurol 29(3):242-4. Zafeiriou DI, Vargiami E, Papadopoulou K, et al (2008) Serial magnetic resonance imaging and neurophysiological studies in multiple sulphatase deficiency. E ur J
Paediatr Neurol 12(3):190-4. Zammarchi E, Donati MA, Morrone A, Donzelli GP, Zhou XY, D´Azzo A (1996)
Early-infantile galactosialidosis: clinical, bichemical, and molecular observations in a new patient. Am J Med Genet 64(3):453-458 Zaroff CM, Neudorfer O, Morrison C, Pastores GM, Rubin H, Kolodny EH. (2004)
Neuropsychological assessment of patients with late onset GM2 gangliosidosis.
Neurology 62(12):2283-6. Zhong N, Moroziewicz DN, Ju W, et al (2000) Heterogeneity of late-infantile neuronal ceroid lipofuscinosis. Genet Med 2(6):312-8 Zhou XY, Van der Spoel A, Rottier R, et al (1996) Molecular and biochemical analysis of protective protein/cathepsin A mutations: correlation with clinical severity in galactosialidosis. Hum Mol Genet 5(12):1977-87. Zini A, Cenacchi G, Nichelli P, Zunarelli E, Todeschini A, Meletti S (2008) Early- onset dementia with prolonged occipital seizures: an atypical case of Kufs disease.
Neurology 18;71(21):1709-12. Zlotogora J, Regev R, Zeigler M, Lancu TC, Bach G (1985) Krabbe disease: increased incidence in a highly inbred community. Am J Med Genet 21(4):765–
770. 10. List of tables
Table 1 - Lysosomal storage disorders with primary neuronal involvement, storage materials, enzyme deficiencies, and data on intrafamilial heterogeneity and on the best level of evidence obtained about disease progression (according to Oxford
Centre for Evidence-based Medicine Levels of Evidence)
Table 2 - Established genotype-phenotype correlations in lysosomal storage disorders with neuronal involvement
Table 3 – Characteristical neurological signs found in the neuronal forms of lysosomal storage disorders. Six general syndromes were depicted in grey: (1) the early infantile deterioration syndrome; and the late-onset forms presenting predominantly with (2) eye movement disorders, (3) extrapyramidal (parkinsonian) manifestations, (4) upper motor neuron involvement, (5) gargoilism, and (6) the combination of myoclonus, seizures and optic atrophy syndromes. 11. List of Figures
Figure 1 – Diagram representation of the stereotyped patterns of early infantile deterioration, presented in the severe forms of sphingolipidosis
Figure E-1 – A cherry red spot in the macula.
Figure E-2 - A patient with GM1 gangliosidosis, showing (A) macroglossia, hypertelorism, epicanthus and coarse facial features; and (B) lumbar kyphosis, due to dysplastic vertebrae
Figure E-3 – Some MRI patterns found in patients with lysosomal storage disorders. (A) Hypointense thalami and diffuse WM abnormality in a patient with
GM1 Gangliosidosis. (B) White matter abnormalities affecting the occipital, periventricular and central white matter and sparing U fibers, in a patient with the juvenile form of MLD. (C) Global atrophy and high signal intensity on occipital periventricular white matter, in an infantile patient with Krabbe disease, and (D) cerebral atrophy in a patient with INCL.