sign in sign up
<<
Home , Abetalipoproteinemia, Adrenoleukodystrophy, Batten disease, Choreoathetosis, GM2 gangliosidoses, Hunter syndrome

46040ourmal ofNeurology, , and 1995;59:460-470 J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp.59.5.460 on 1 November 1995. Downloaded from NEUROLOGICAL INVESTIGATIONS

Diagnosis of inherited metabolic disorders affecting the

Phillip D Swanson

The number of metabolic disorders that can dominant neurodegenerative . The produce neurological symptoms is daunting. pace of new discoveries in is The clinician cannot simply send off to the incredibly rapid. Many of the new discoveries laboratory a sample and ask for a meta- have led to diagnostic methods that were bolic "screen" that will detect a hypothetical unanticipated only a few years ago. metabolic abnormality. The range of possible Certain terms used by medical geneticists conditions must be narrowed to the most should be familiar to neurological practition- likely before deciding which investigative ers. refers to a beginning approach should be taken. Most biochemical earlier and often being more severe in disorders encountered by neurologists are succeeding generations. In some autosomal genetically determined. Thus one of the most dominant disorders, such as myotonic important elements of the history is the family dystrophy and spinocerebellar 1, this history. It is not sufficient to ask "has anyone phenomenon seems to be related to the in your family had a neurological problem?". length of an expanded trinucleotide repeat in The clinician must be aware of the different the abnormal .4 Penetrance refers to the forms of inheritance patterns (autosomal proportion of subjects with the abnormal dominant, autosomal recessive, X linked, gene who will develop symptoms if they live mitochondrial) and must obtain enough long enough. The degree of expression of a information to construct a meaningful family genetic disease refers to the variation of sever- tree. Directed questions must be asked about ity of the phenotype that is seen in a patient siblings as well as parents, grandparents, population. Mosaicism refers to variation uncles, aunts, cousins, and children. Table 1 among different cells and tissues in the chro- lists features that characterise single gene mosome complement. This occurs normally inheritance patterns.1'3 in women due to lyonisation, in which one of Most of the clear cut genetic diseases are each cell's two X is randomly due to single gene abnormalities.There are inactivated. Mitochondrial disorders (see http://jnnp.bmj.com/ several different mechanisms, however, that later) are associated with heteroplasmy, a term produce abnormal . A point of that refers to variation in the proportion of a single DNA nucleotide can result in a normal or genetically abnormal mitochondria different being coded for in the in different tissues. resulting polypeptide or . There can In autosomal dominant disorders, multiple Department of be deletion of a segment of a gene or insertion generations are usually affected, although this Box one , of or more nucleotides. Duplication of a might not have occurred if the affected on September 27, 2021 by guest. Protected copyright. 356427, University of gene has been reported in Charcot-Marie- Washington School of patient represents a new mutation. Male to , Seattle, WA Tooth disease type IA. Unstable expansions male transmission only occurs with au'toso- 98195, USA of portions of a gene (trinucleotide repeats) mal dominant transmission. Each child of an P D Swanson are being increasingly found in autosomal affected parent will have a 50% chance of having or not having the abnormal gene. Autosomal recessive disorders occur when Table 1 Some characteristics ofsingle gene inheritance expression of the disease requires the abnor- Type ofinheritance Charactenrstics mal gene to be inherited from both parents, so Autosomal dominant Multiple generations affected that the affected person's cells have two Father to son transmission (rules out X linked and abnormal . Many autosomal recessive mitochondrial inheritance patterns) Males and females equally affected disorders are associated with defective Autosomal recessive Only siblings affected . The low level of activity Parental consanguinity common often leads to accumulation of the enzyme Males and females equally affected substrate with resultant toxicity to susceptible X Linked Never father to son transmission Transmission through unaffected mothers cells. The carrier parents seldom manifest Only males affected (rare exceptions) symptoms because the normal gene codes 50% risk to sons of carrier women All daughters of affected men are carriers for normal enzyme that is active enough to Mitochondrial Maternally inherited prevent substrate accumulation. Consan- Never father to child transmission guineous marriages between cousins are more Both sons and daughters can be affected common in families with autosomal recessive Adapted from table 9-1.3 diseases. Diagnosis ofinherited metabolic disorders affecting the nervous system 461 J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp.59.5.460 on 1 November 1995. Downloaded from X Linked disorders are due to abnormal encountered by neurologists. The second genes located on the X . Clinical section contains a discussion of differential disease characteristically occurs in males who diagnoses of metabolic conditions that might have inherited the abnormal gene from a produce particular complexes of neurological carrier mother. Occasionally the mother or symptoms, including mental retardation, daughter with one normal and one abnormal , , , gene will manifest symptoms, which almost movement disorders, and . always are milder than in the affected son or father, who has only one . Male to male transmission cannot occur Categories of metabolic disorders because a son receives the X chromosome AMINOACIDURIAS AND ORGANIC ACIDAEMIAS from his mother. These are the classic disorders of infancy and Mitochondrial disorders are due to abnor- childhood associated with mental retardation malities in genes (deletions, point ) and . The aminoacidurias include located in mitochondrial DNA. Both male , maple syrup urine disease, and female mitochondria are derived from the , and other disorders listed in ovum rather than the sperm. Both males and table 2.5 Screening the urine for amino acids females can be affected by mitochondrial is routinely done in labora- disorders, but father to child transmission tories. Although it would be very unusual for does not occur. Because tissues and cells vary first symptoms to occur in adult life, patients in the proportion of normal and abnormal with treated phenylketonuria eventually will mitochondria they carry (heteroplasmy), the be seen as adults by neurologists. expression of the disorder in different tissues Organic acidaemias, including methyl- and in different subjects can be extremely malonic acidaemia and propionic acidaemia, variable. usually have their onset in infancy. Symptoms This contribution will not include much of dehydration are associated with ketoacido- discussion of diseases that primarily affect sis, hypoglycaemia, and hyperammonaemia. muscle or , as these have been the Diagnosis is made by urinalysis for organic subjects of previous articles in this series. acids, and can be confirmed by measuring Some metabolic conditions, however, includ- activity of the abnormal enzyme in cultured ing metachromatic and fibroblasts. certain mitochondrial disorders that affect These disorders are becoming better both central and peripheral structures, will be understood since the advent of modem mole- included. Non-genetic metabolic conditions cular investigative techniques. For example, it such as hypoglycaemia, hepatic encephalo- is now known that there are three genes pathy, deficiency diseases, and electrolyte located on three different chromosomes (1, 6, disorders will not be discussed. Emphasis will 19) that code for the structural be on conditions that are seen in adults by unique to the deficient enzyme (branched neurologists but many of these disorders will chain ketoacid dehydrogenase complex be variants of diseases that usually have their [BCKAD]) in maple syrup urine disease. first manifestations in infancy or childhood. Mutations in different components of the The first section contains brief discussions of complex can lead to variable clinical mani-

categories of metabolic disease likely to be festations.6 http://jnnp.bmj.com/

Table 2 Aminoacidurias and organic acidaemias Disease Clinicalfeatures Increased substances Enzymne defect Phenylketonuria Mental retardation Phenylalanine Phenylalanine

Phenylpyruvic acid hydroxylase on September 27, 2021 by guest. Protected copyright. Maple syrup urine disease Ketoacidosis Branched chain aminoacids Branched chain ketoacid Infantile seizures (leucine, isoleucine, valine) dehydrogenase complex Characteristic odour (urine: branched chain Progressive ketoacids) Milder variants Homocystinuria Ectopia lentis, stroke Homocystine Cystathionine,B-Synthase Non-ketotic Coma, progressive Glycine Glycine clearance system hyperglycinaemia encephalopathy (4 proteins) Methylmalonic acidaemia Ketoacidosis Methylmalonic acid Methyl-malonyl CoA mutase Hyperammonaemia Propionic acidaemia Ketoacidosis 3-hydroxypropionic acid Propionyl CoA carboxylase Hyperammonaemia Isovaleric acidaemia Ketoacidosis Isovaleric acid Isovaleryl CoA dehydrogenase Hyperammonaemia Glutaric aciduria Progressive encephalopathy Glutaric, 3-hydroxyglutaric Glutaric CoA dehydrogenase Type 1 Spasticity, acids Electron transfer flavoprotein Type 2 Three groups-renal Glutaconic acid (ETF) and ETF ubiquinone cystic dysplasia oxidoreductase Hypoglycaemia, acidosis Muscle weakness y-Hydroxybutyric aciduria Mental retardation y-Hydroxybutyric acid Succinic semialdelyde Seizures dehydrogenase Developmental delay and motor abnormalities 462 Swanson J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp.59.5.460 on 1 November 1995. Downloaded from LYSOSOMAL DISORDERS white blood cells or cultured fibroblasts. The term was proposed by DeDuve Clinical variants are found in each disorder. et al in 1955 for intracellular granules that In MLD some mutations in the arylsul- were rich in hydrolytic enzymes.7 A lysosomal phatase A gene on chromosome 22 have been disease is associated with an abnormal correlated with different phenotypes.II enzyme that results in defective breakdown of Similarly, in Tay-Sachs disease over 20 muta- the enzyme substrate.8 The product accumu- tions including nucleotide insertions, dele- lates and eventually alters cell function. tions, and substitutions on the a subunit Because hydrolytic enzymes are present in (chromosome 15) and the subunit (chro- many tissues, the diagnosis of the accumu- mosome 5) of the enzyme lated product or of the enzyme deficiency have been described.'4 Late onset cases may usually can be made with readily accessible develop weakness, fasciculations, ataxia, and tissues such as peripheral white blood cells or psychiatric symptoms.'5 skin fibroblasts.9-1" Although most of these GM, , due to deficiency of the disorders produce symptoms at a young age, lysosomal enzyme ,B-galactosidase, can some mutations, as in adult onset GM1 produce symptoms in infancy, childhood, or gangliosidosis, lead to onset of symptoms adult life. At least 16 mutations have been later in life.'2 identified in the ,B-galactosidase gene.'2 1617 Lysosomal disorders can be subcategorised Severity of the diseases can be correlated with according to the type of accumulated storage the amount of residual enzyme activity, the product. The two principal groups are lipid infantile form having no demonstrable activ- storage diseases and mucopolysaccharidoses. ity and the adult forms having 4-8% of As these conditions have been more fully normal activity. Leinekugel et al found that characterised, it has become clear that a great 10-15% of,B-hexosaminidase A and arylsul- deal of heterogeneity exists among them, in phatase A activities were sufficient to degrade many cases due to different point mutations substrate. 18 in the gene. Thus these disorders should be The adult form of the disorder is slowly considered in the of progressive and may produce gait disorders, atypical degenerative disorders. involuntary choreoathetoid movements, bradykinesia, or dementia. Storage of GM, Lipid storage diseases can be much more pronounced in Table 3 lists the lipid storage diseases that the than in other parts of the cause neurological dysfunction. These disor- by contrast with younger onset patients, in ders are diagnosed either by finding high whom storage is more widespread.'2 19 concentrations of substrate in tissues or by Diagnosis is confirmed by finding much showing pronounced reduction in concentra- reduced lysosomal acid,B-galactosidase activ- tions of the lysosomal enzyme responsible for ity in leucocytes. Single base mutations can degrading the accumulated storage substance. be found on the ,B-galactosidase gene. The

In each disorder, subtypes have been delin- 5'isoleucine (ATC) -+ threonine (ACC) eated. In Gaucher's disease, associated with mutation in the gene is common in Japanese accumulation of , and in adult onset GM, gangliosidosis.'2 Niemann-Pick disease, with

accumulation, hepatosplenomegaly is promi- Mucopolysaccharidoses http://jnnp.bmj.com/ nent in all types; however, only types 2 and 3 These lysosomal disorders are associated with Gaucher's disease and types A and C accumulation of complex glycosoaminogly- Niemann-Pick disease are associated with cans (mucopolysaccharides), due to genetic neurological deterioration. Globoid leukodys- defects resulting in deficiencies of degradative trophy (Krabbe'6 disease), metachromatic enzymes.20 21 The stored substances include leukodystrophy (MLD) and Tay-Sachs dermatan sulphate, heparan sulphate, keratan disease are inherited as autosomal recessive sulphate, and chondroitin 4/6 sulphates, disorders and can be diagnosed by measure- which are detectable in the urine. Of the 12 on September 27, 2021 by guest. Protected copyright. ment of enzyme concentrations in peripheral described disorders all are autosomal recessive

Table 3 Common lipid storage diseases Major lipid Enzyme Disease Neurological symptom accumulated defect Gaucher's Hepatosplenomegaly, Glucocerebroside Glucocerebroside- neurological deterioration in type 2 fl-glucosidase Dementia, seizures in type 3 Niemann-Pick Hepatosplenomegaly, psychomotor Sphingomyelin Sphingomyelinase deterioration in types A and C (type C) (type A) Globoid leukodystrophy Progressive encephalopathy, Galactocerebroside Galactocerebroside (Krabbe's) seizures, spasticity, blindness f,-Galactosidase Metachromatic Progressive encephalopathy, Sulphatide Arylsulphatase A leukodystrophy neuropathy, ataxia, spasticity Fabry , rare , X linked, trihexoside Ceramide trihexoside renal insufficiency, skin a-Galactosidase Tay-Sachs Progressive encephalopathy GM2 ganglioside Hexosaminidase A Tay-Sachs variant More rapid progression and GM2 Hexosaminidase A and B GM, gangliosidosis Dementia, progressive ataxia, GM, ganglioside ,B-Galactosidase choreoathetosis 16 point mutations Diagnosis ofinherited metabolic disorders affecting the nervous system 463 J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp.59.5.460 on 1 November 1995. Downloaded from except for Hunter which is X linked have VLCFA concentrations within the usual recessive. Among these conditions are "normal" range.28 Molecular genetic analysis Hurler's, Scheie's, Sanfilippo, Morquio's, and now makes it possible to detect point muta- Maroteaux-Lamy diseases, and fl-glucuro- tions within the gene.29 nidase deficiency. Clinical signs such as coarse facial features, corneal clouding, hearing diffi- MITOCHONDRIAL culties, hepatosplenomegaly, or abnor- A high index of suspicion is aroused for the malities are usually detected during the first presence of a disorder involving an abnormal year of life. Later, developmental delay or mitochondrial gene if there are clinical mental regression may become apparent. features of Leigh's disease (subacute necro- tising encephalomyelopathy), Kearns-Sayre PEROXISOMAL DISORDERS syndrome (progressive external ophthalmo- The is an that is found plegia, retinal pigmentary degeneration, and in most tissues. It contains over 40 enzymes other symptoms), MELAS (mitochondrial including oxidases and catalase. Moser et al encephalomyelopathy with and list 11 disorders attributable to defects in stroke-like episodes), MERRF (myoclonic peroxisomal enzymes.222' These include with ragged red flbres), Leber's disorders of peroxisome biogenesis (Zellweger hereditary optic neuroretinopathy, or NARP syndrome, neonatal adrenoleukodystrophy, (neurogenic muscle weakness, ataxia, and infantile Refsum's syndrome, and hyper- ).'>36 Various other pipecolic acidaemia). The first two of these features have been seen including short disorders can be associated with neonatal stature, deafness, mellitus, peptic seizures, , and developmental delay. ulceration, severe , and . Of the disorders associated with peroxiso- Mutations in mitochondrial DNA have mal enzyme abnormalities, X linked adreno- been discovered in patients with several clini- leukodystrophy is the most likely to be seen cal presentations. Deletions of mitochondrial by neurologists. DNA are common in Kearns-Sayre syn- Adrenoleukodystrophy and adrenomyelo- drome.2 In MELAS, point mutations include neuropathy are X linked disorders and are an A -- G mutation at nt3243 in 80% of associated with raised blood concentrations of cases, as well as T -+ C mutations at nt3271 very long chain fatty acids (VLCFAs) due to and at nt9957, and an A -+ G mutation at impaired peroxisomal fi oxidation. The nt11084. An A-+ G nt8344 mutation has genetic defect seems to result from deletions been found in MERRF, and a T -+ G or in the peroxisomal membrane protein gene.24 T -+ C mutation at nt8993 in Leigh's Some different phenotypes occur.22-26 syndrome.3738 Neurologists are most likely to encounter an Diagnostic laboratory tests include: (a) adult patient with adrenomyeloneuropathy, serum pyruvate and lactate concentrations; with slowly progressive paraparesis as the (b) muscle to assess for the presence of main neurological manifestation and adreno- ragged red fibres, and as a source of mito- cortical failure as a common occurrence. chondria for DNA analysis; and (c) molecular Adult onset cerebral adrenoleukodystrophy is genetic studies on blood or muscle in a manifested by dementia, confusional states, specialised laboratory to assess for known

and sometimes progressive ataxia or psychi- mutations. http://jnnp.bmj.com/ atric disturbances.27 Symptom progression is usually slower in patients with adult onset. DISORDERS ASSOCIATED WITH EXPANDED Assays for VLCFAs (C24:0, C26:0) are TRINUCLEOTIDE REPEATS carried out in specialised lipid laboratories One of the most exciting developments in using gas liquid chromatography or mass neurology has been the discovery of neuro- spectrometry. Although the vast majority of genetic diseases in which the abnormal gene patients have raised plasma concentrations of mutation results in expansion of a repeated these fatty acids, an occasional family will sequence of trinucleotides. Table 4 lists many on September 27, 2021 by guest. Protected copyright.

Table 4 Disorders associated with unstable expanded trinucleotide repeats Number of repeats Extended Translation Disorder Chromosome trinucleotide Normal Disease of repeat X CGG 6-50 Premutation:52-200 No (FRXA) Disease: 200 to > 1000 Fragile X E (FRXE) X GCC 6-25 >200 19q CTG <30 Premutation: 42-180 No Disease: 200->1000 Bulbar spinomuscular Xql 1-12 CAG 17-26 40-52 Yes atrophy (Kennedy's syndrome) Huntington's disease 4p16.3 CAG 11-34 37-121 Yes Autosomal dominant spinocerebellar ataxias 1 6p22-23 CAG 19-36 42-81 Yes Machado-Joseph disease 14q32.1 CAG 13-36 68-79 Yes Dentatorubral- 12p12-ter CAG 7-23 49-75 Yes pallidoluysian atrophy (DRPLA) 464 Swanson J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp.59.5.460 on 1 November 1995. Downloaded from of the presently known disorders of this symptoms in close relatives of affected type.39-50 They are either X linked or auto- patients.62 64 The diagnosis can be made with somal dominant disorders and include the the assistance of the following laboratory dominant spinocerebellar ataxias SCAI and findings.63 (a) increased excretion of Machado-Joseph disease, Huntington's into the urine (normal <30 ptg/24 h; Wilson's disease, fragile X syndrome, myotonic dystro- disease 100-1000 gg/24 h); (b) decreased phy, and spinal bulbar muscular atrophy serum concentration of total copper (normal (Kennedy's syndrome). In many of these 85-145 gg/dl); (c) decreased serum concen- disorders, the length of the expanded trinu- tration of (normal range 25-45 cleotide repeat is unstable. Succeeding gener- mg/dl); about 5% of cases will have normal ations have expansions of greater length ceruloplasmin concentrations.65 which may be associated with earlier onset and more severe disease manifestations. It is likely that additional neurodegenerative disor- Symptomatic approach to the diagnosis ders will be added to this list.43 of inherited metabolic disorders Genetics laboratories have the capability of MENTAL RETARDATION OR DETERIORATION definitively diagnosing the presence or Fragile X syndrome absence of some of these disorders on a single Over 100 X linked mental retardation sample of blood, using molecular genetic are known at the present time.66 techniques. Commercial availability is limited Of these, fragile X syndrome is the leading at this time. genetic cause of mental retardation.67 The syndrome is so named because of the instabil- DISORDERS OF COPPER ity of the X chromosome when incubated in Two diagnosable genetic disorders are associ- folic acid deficient media.68 69 This was the ated with defects in copper metabolism: first neurological disorder to be associated Menkes' disease and Wilson's disease. with an unstable trinucleotide repeat Menkes' "kinky "(steely hair) disease is sequence.70 Clinically, patients may have an X linked disorder with manifestations in prominent ears, large , high arched early infancy.5' 52 Infants feed poorly, become palates, and behavioural deficits. Definitive hypothermic, gain weight slowly, develop diagnosis can be made by the demonstration seizures, and show progressive neurological of an expanded trinucleotide CGG repeat deterioration. They have colourless, friable sequence. Abnormality in the FMR gene results hair which has a characteristic microscopic in lack of production of the FMR1 protein. appearance. Danks et al suggested that the Diagnosis of mental deterioration or disease was due to a disorder of copper progressive encephalopathy in infants may metabolism.53 The gene has been isolated and require various metabolic tests if the is a copper transporting ATPase. Until suspected diagnosis is not already obvious.72 recently, diagnosis if suspected clinically was A metabolic screen of the urine carried out by established by demonstrating low cerulo- a hospital laboratory usually includes a nitro- plasmin and serum copper concentrations prusside-cyanide test, a ferric chloride test, and abnormalities in fibroblast copper tests for ketoacids and mucopolysaccharides, uptake.5455 In the newborn, however, copper and two dimensional amino acid chromatog-

and ceruloplasmin are normally low, so reli- raphy. Serum analyses for amino acids and http://jnnp.bmj.com/ able detection of abnormally low concentra- organic acids will usually be diagnostic for tions cannot be made until the third or fourth aminoacidurias and organic acidaemias. week of life. The diagnosis can be made by Studies to search for other disorders DNA analysis.56 mentioned (Menkes' disease, lipid storage Wilson's disease is an autosomal recessive diseases) will require special testing by genet- disorder due to an abnormal gene at q14.3 on ics laboratories. chromosome 13. This gene codes for a copper transporting P-type ATPase that is JUVENILE OR ADULT PATIENTS PRESENTING on September 27, 2021 by guest. Protected copyright. presumably important for hepatic incorpora- WITH DEMENTIA tion of copper into ceruloplasmin and for Laboratory investigations are of limited excretion of copper into bile.57-59 The enzyme usefulness in dementia diagnosis. The most is also expressed in the . Twenty five common dementing illnesses such as mutations have been identified in the Alzheimer's disease are not yet diagnosable Wilson's disease gene, accounting for the biochemically on a routine basis. In a few great variability in clinical symptomatology.60 families with familial Alzheimer's disease, The pathogenetic role of reduced synthesis or point mutations have been found in the gene impaired function of the copper transporting on chromosome 21 that codes for the protein ceruloplasmin is not clear.6' In the amyloid precursor protein (APP) gene.7374 course of Wilson's disease, increased storage Most families, however, do not have these of copper occurs in , brain, cornea mutations. In young onset families, linkage (Kayser-Fleischer ring in Descemet's analysis has located the gene defect to a locus membrane), and kidneys. Neurological and on chromosome 14. Ultimately it may be psychiatric symptoms can occur secondary to possible to diagnose the disorder by molecu- deposition of copper in the brain or as a lar genetic techniques. At present, diagnosis result of due to of the rare APP mutation can be carried out copper induced liver damage. The diagnosis only by specialised research laboratories can and should be made before the onset of studying this disorder. Diagnosis ofinherited metabolic disorders affecting the nervous system 465 J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp.59.5.460 on 1 November 1995. Downloaded from In some patients with progressive cognitive as the disorder is X linked. Some heterozy- impairment, a high degree of suspicion based gous women may, however, develop spastic on clinical or radiological clues may justify paraparesis.222 The phenotypes delineated by carrying out further metabolic studies to Moser et al are: childhood cerebral (48%), confirm a suspected diagnosis (table 5). adolescent cerebral (5%), adult cerebral B-12 deficiency rarely produces (3%), adrenomyeloneuropathy (25%), addis- dementia alone but should be excluded. onian only (10%), asymptomatic (8%).26 The disorder is suspected in children with Huntington's disease learning disorders and dementia. Adreno- The diagnosis of Huntington's disease can myeloneuropathy usually begins with progres- now be confirmed by commercially available sive paraparesis. DNA testing. The presence of an extended Pelizaeus-Merzbacher disease-This disorder CAG repeat in the Huntington's disease gene is X linked. Symptoms usually begin in on chromosome 4 establishes the diagnosis. A infancy or childhood, but onset in early adult- normal has less than 35 CAG repeats. hood has been reported.77 Symptoms include The Huntington's disease gene has more than psychomotor delay and later, dementia, 38 repeats in 98-99% of cases.76 , ataxia, spasticity, and involuntary movements. Mutations in the gene coding for proteolipid protein result in defective . In addition to and progres- Mutations in the proteolipid protein gene can sive multifocal leukoencephalopathy, cerebral now be determined in genetics laborato- can be affected by several meta- ries.7879 Prenatal diagnosis is also possible.80 bolic disorders, with dementia as a major Canavan 's disease-Another rare leuko- symptom. These include adult onset dystrophy is Canavan's disease, characterised metachromatic leukodystrophy (MLD), by infantile and juvenile forms with severe adrenoleukodystrophy, Pelizaeus-Merzbacher progressive neurological deterioration. Raised disease, Krabbe's disease, and cerebrotendi- urinary N-acetylaspartic acid and deficiency nous xanthomatosis (CTX). In each disorder, of the enzyme aspartoacyclase in skin fibro- symptoms are progressive, usually over blasts confirm the diagnosis. months to years. Inherited in an autosomal recessive manner, MLD would likely be asso- Lipid storage diseases ciated with clinical or EMG/nerve conduction Metachromatic leukodystrophy (MLD) and velocity evidence of a . Krabbe's disease (globoid leukodystrophy), as Adrenoleukodystrophy might be associated well as other lipid storage diseases such as with and, as it is an X GM, gangliosidosis and type 3 Gaucher's linked disorder, would occur predominantly disease can produce dementia as part of more in males. Patients with cerebrotendinous generalised neurological deterioration. xanthomatosis usually develop prominent Urinary sulphatides will be abnormally in large tendons such as the increased in MLD. In the other conditions, Achilles tendon. confirmation of clinical suspicion will require Adrenoleukodystrophy-This disorder is white blood cell or fibroblast enzyme deter- characterised by varying modes of onset at minations carried out by a specialised labora-

different ages. Most affected people are male, tory. http://jnnp.bmj.com/ Neuronal ceroid lipofuscinosis (Batten's disease and variants)-This is a disorder asso- ciated with storage of a complex lipopigment. Table S Disorders associated with dementia The disease has not yet been characterised Disorder Diagnostic test enzymatically, although linkage analysis has Alzheimer's disease In known families, located the gene for the infantile form genetics laboratory for (CLN1) to chromosome lp32, and that for DNA on September 27, 2021 by guest. Protected copyright. in the APP gene the juvenile form (CLN3) to chromosome B-12 deficiency Serum B-12 level 16p 12.8283 Patients usually develop retinal Schilling test degeneration, , seizures, and Huntington's disease Genetics laboratory for DNA screen dementia. Diagnosis is made by demonstrat- (CAG > 37 repeats) ing accumulated storage product in buffy coat Adrenoleukodystrophy Lipid laboratory for or in skin , which show curvilinear plasma VLCFA bodies or a "fingerprint" pattern on electron Pelizaeus-Merzbacher disease Genetics laboratory for PLP gene microscopy. The early onset forms are auto- Canavan's disease Urine for somal recessive. Both autosomal dominant N-acetylaspartic acid and autosomal recessive inheritance has been Fibroblasts for aspartoacyclase reported in the adult form (Kufs' disease) Metachromatic leukodystrophy Arylsulphatase A which is not associated with pigmentary GM, gangliosidosis fl-galactosidase retinal degeneration.84 85 Globoid leukodystrophy (Krabbe's) Galactocerebrosidase Cerebrotendinous xanthomatosis Lipid laboratory for ATAXIAS cholestanol Progressive ataxia can result from several Ceroid-lipofuscinosis EM of buffy coat for conditions that have metabolic causes. The curvilinear bodies MRI will have assisted in diagnosing multiple VLCFA = very long chain fatty acids; PLP = proteolipid protein; APP = amyloid precursor protein; EM = electron sclerosis, cerebellar neoplasms, and the diag- microscopy. noses of alcoholic cerebellar degeneration and 466 Swanson J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp.59.5.460 on 1 November 1995. Downloaded from paraneoplastic syndromes will have been test will involve contacting a specialised lipid considered. laboratory, but it is important to do, as the Genetic causes are of special importance in disease can be treated by giving chenode- this group of disorders. As yet the diagnosis oxycholic acid.97 Several mutations of the of Friedreich's ataxia is based on clinical, not gene on that codes for the biochemical findings. The genetics laboratory enzyme sterol 27-hydroxylase have been can, however, assist in diagnosing several of found in families with this disorder.98 100 these disorders, including spinocerebellar Presymptomatic cases and heterozygotes can ataxia type I (SCA-1) and Machado-Joseph's now be detected by molecular diagnostic disease.44 86 techniques. 101 Ataxia-telangiectasia, an autosomal reces- Ataxia with isolated deficiency sive disorder, is the most common cause of (AVED)-Patients have been described with ataxia in children under the age of 10.72 progressive ataxia and other features of Usually the diagnosis is evident clinically, Friedreich's disease, in which vitamin E with ataxia, nystagmus, choreoathetosis, and concentrations were reduced in the absence characteristic auricular and conjunctival of .'02 In the patient described telangiectases being evident. The abnormal by Stumpf et al, serum vitamin E concentra- gene on chromosome llq22-23, which is tions were below 1 0 (normal 5-20) psg/ml important for DNA repair, has recently been and could be restored to normal with an oral identified.87 The gene product is likely to be a dose of 800 mg/day of DL-a-.'03 phosphatidylinositol-3' kinase. Presumably This disorder is autosomal recessive. The more definitive DNA diagnostic testing will gene maps to chromosome 8q13.'°4105 become available. Symptoms of ataxia-telang- Affected patients have mutations in the a- iectasia can begin in early adult life.88 Some tocopherol transfer protein resulting in serum abnormalities are found in patients impaired ability to incorporate a-tocopherol with this disorder, including raised a-fetopro- into .'06 tein in 95% of cases, alterations in serum A-/B-lipoproteinaemia-Patients with this immunoglobulins, and raised carcinoembry- disorder usually develop in onic antigen concentrations.89 infancy followed in the second decade by Autosomal dominant cerebellar ataxias are progressive ataxia and peripheral being reclassified as their genetic defects neuropathy.72 The patients have absence of are discovered. Abnormal genes have been serum fl-lipoproteins and very low con- found on chromosomes 6, 11, 12, 14, and centrations of a-tocopherol. Dietary supple- 16.42468690-92 Dubourg et al sampled DNA mentation with high doses of vitamin E from 88 families with inherited ataxias and (100 mg/kg/day) may arrest the neurological from 16 patients with sporadic ataxia to manifestations.'07 This condition is associated determine the frequency of the SCAl muta- with defective genes coding for the larger tion on chromosome 6.4 Twelve of the fami- subunit of the microsomal trans- lies and none of the sporadic cases carried the fer protein (MTP), resulting in abnormal SCAl mutation (unstable expanded CAG VLDL secretion and impairing delivery of repeat). vitamin E and other fat soluble substrates.'08 Clinical characteristics do not readily The autosomal recessive disorder

distinguish the subtypes of cerebellar atax- Friedreich's ataxia is associated with an as yet http://jnnp.bmj.com/ ias.93 Many patients will have additional signs unidentified genetic defect on . such as extensor plantar responses, decreased Because of clinical similarities to AVED, it vibration sense, ophthalmoplegias, and has been suggested that the Friedreich's increased or decreased tendon reflexes. In ataxia gene may also be involved in a-toco- SCAl, instability of the mutation is more pherol metabolism.'09 common with male transmission and the age Ataxia associated with mitochondrial of onset of symptoms is lower in patients with disorders-Ataxia can be a feature of several of a higher number of CAG repeats (anticipa- the mitochondrial disorders, especially the on September 27, 2021 by guest. Protected copyright. tion). MERRF and MELAS syndromes, and the Dentatorubral-pallidoluysian atrophy (DRPLA) rare syndrome termed NARP.34 The presence is a rare autosomal dominant neurodegenera- of retinitis pigmentosa should raise the index tive disorder, usually classified under the of suspicion for NARP, which is sometimes ataxias. The disorder can be associated with due to a point mutation at bp8993 resulting myoclonus, , dementia, and seizures. in substitution of arginine for leucine in Juvenile and adult onsets are reported.94 subsequence 6 of the mitochondrial The disorder may be misdiagnosed as H+ATPase. Patients with this disorder may Huntington's disease.48 The molecular defect have seizures, muscle weakness, mental retar- is an expanded CAG repeat on the gene dation and long tract signs with symptoms located on chromosome 12p and can be diag- beginning from infancy to late adulthood. nosed by molecular analysis.4950 Another disorder that may present with MOTOR NEURON DISEASE ataxia is Cerebrotendinous xanthomatosis. This Most patients with suspected amyotrophic condition is suspected in a patient who has lateral sclerosis (ALS) have no known tendon xanthomas, often in the Achilles biochemical defect. Kennedy's syndrome tendons.95 The diagnosis is confirmed by (spinal bulbar muscular atrophy) may clini- showing raised concentrations of cholestanol cally resemble the bulbar form of ALS, (dihydrocholesterol) in blood or tissue.96 This though progression is usually slow. A genetics Diagnosis ofinherited metabolic disorders affecting the nervous system 467 J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp.59.5.460 on 1 November 1995. Downloaded from laboratory can confirm this diagnosis by Other metabolic causes ofdystonia determining the presence of an expanded Adult onset of can occur in GM, CAG repeat on the X chromosome (table 4). gangliosidosis."2 The disorder is autosomal About 20% of cases of familial ALS have recessive and is diagnosed by showing been discovered to have one of several muta- pronounced reduction of activity of the tions of the gene on chromosome 21 that enzyme f)-galactosidase which can be codes for the Cu/Zn binding superoxide measured in leucocytes. Progressive dopa dysmutase enzyme (SOD).101'12 responsive dystonia has been recently reported In patients with mutations in this gene, the to be associated with mutations in a gene on concentration and specific activity of Cu/Zn chromosome 14q22.1-22.2 which codes for SOD are reduced in erythrocytes by about the enzyme GTP cyclohydrolase 1.114 50%"13; however, these changes do not corre- late with disease severity. Detection of the Other movement disorders Cu/Zn SOD mutation requires DNA analysis Choreic movements are characteristic of of a blood sample by a genetics laboratory Huntington's disease, which is discussed in studying this disorder. the section on dementia. Another disorder in which chorea can occur is ataxia-telangiecta- MOVEMENT DISORDERS (TABLE 6) sia, discussed in the section on ataxias. Wilson's disease Patients with Wilson's disease can develop STROKE symptoms of hepatic or neurological dysfunc- Metabolic causes of stroke are rare, but must tion. Symptoms that may bring a patient to a be considered in children and young adults neurologist include involuntary movements presenting with an acute ischaemic event. (, dystonia, chorea, spasms), and Disorders to consider include MELAS behavioural and personality changes. syndrome, homocystinuria, sulphite oxidase Psychiatric symptoms account for a high deficiency, and Fabry's disease. MELAS proportion of presenting complaints.64 A syndrome can be associated with stroke-like Kayser-Fleischer ring may be seen on exami- episodes in young adults."5 Diagnosis may be nation of the cornea. difficult (see section on mitochondrial disor- Wilson's disease is commonly but not ders) and requires strong suspicion and invariably associated with reduction in serum communication with a genetics laboratory ceruloplasmin concentrations (normal range specialising in mitochondrial disorders. 25-45 mg/dl). Total serum copper concentra- Homocystinuria is much more common tions may not be raised. "Free" serum copper than sulphite oxidase deficiency. Both disorders can be calculated by subtracting from the may be suspected by the presence of ectopia total copper (gg/dl), that amount bound to lentis. Chronic homocysteine infusions in ceruloplasmin (multiply by 3 the cerulo- baboons produce sustained endothelial cell plasmin concentration (in mg/dl) to obtain loss and result in accelerated atherosclero- the bound copper in ,ug/dl). The free copper sis.116 It has been suggested that moderate concentration should be <10-15 jg/dl. homocysteinaemia in otherwise normal Laboratory standards are variable, however, subjects may be a risk factor for athero- so it is recommended that a 24 hour urinary sclerotic stroke."17 The disorder is due to an

copper be obtained. In Wilson's disease inborn error of cystathionine synthase. http://jnnp.bmj.com/ copper excretion is >100 gg/24 h (normal Urinary amino acid screen will detect raised <30 gg/24 h). concentrations of homocystine. Sulphite In an asymptomatic patient at risk for oxidase deficiency can be associated with Wilson's disease, liver biopsy may be neces- stroke-like episodes in infancy and child- sary to detect increased copper content in the hood."8 Amino acid screening of the urine liver (patients with Wilson's disease have must be done carefully and on fresh urine, >200 gsg/g wet weight). and should show the presence of S-sulphocysteine.ll9 S-sulphocysteine and on September 27, 2021 by guest. Protected copyright. sulphite are also detectable in plasma.'20 infarction in children, and adult onset chorea and dementia have been reported in 122 Table 6 Metabolic disorders associated with involuntary movements propionic acidaemia."'2 Disease Type of movement Associatedfeatures Diagnostic test Fabry's disease Huntington's disease Chorea Dementia Molecular analysis for This X linked lysosomal storage disease is Dystonia (juvenile) CAG repeat expansion associated with accumulation of trihexose Wilson's disease Tremor, dystonia Hepatic insufficiency Ceruloplasmin, serum to chorea Kayser-Fleischer ring and urine copper ceramide due deficiency in the enzyme Dentatorubral Chorea Ataxia, myoclonus, Molecular analysis for ceramide trihexoside a-galactosidase (table pallidoluysian atrophy dementia CAG repeat expansion 3). At an early age, patients develop pinpoint (DRPLA) skin lesions, especially on the abdomen. GM, gangliosidosis Dystonia, Gait disturbance Leucocyte lysosomal Choreoathetosis acid fi-galactosidase Trihexose ceramide accumulates in blood activity vessel walls, in kidney, and in myocardium. Dopa responsive Dystonia Levodopa Research laboratory Death is usually due to renal or failure. dystonia responsiveness for GTP cyclohydrolase mutation Patients have been reported to develop Ataxia-telangiectasia Choreoathetosis Ataxia, auricular, Decreased a-fetoprotein, episodic stroke-like symptoms and . and conjunctival immunoglobulin Small infarcts have been found in cerebral telangiectases abnormalities hemispheres, associated with proliferative 468 Swanson J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp.59.5.460 on 1 November 1995. Downloaded from changes in vessel intima and media, presum- GM, gangliosidosis: immunohistochemical and ultra- structural findings in an autopsy case. Neurology 1994; ably due to glycolipid deposition.123 44:2376-82. 13 Kolodny EH. Metachromatic leukodystrophy and multi- ple sulfatase deficiency: lipidosis. In: Rosenberg RN, Prusiner SB, DiMauro S et al, eds. The Summary molecular and genetic basis of neurological disease. Boston: Butterworth-Heinemann, 1993:497-503. Knowledge of the molecular causes for 14 Kolodny EH. The GM2 Gangliosidoses. In: Rosenberg genetic diseases that affect the nervous system RN, Prusiner SB, DiMauro S et al, eds. The molecular and genetic basis of neurological disease. Boston: is rapidly expanding. Especially striking has Butterworth-Heinemann, 1993:531-40. been the finding in several autosomal domi- 15 Navon R, Argov Z, Frisch A. Hexosaminidase A defi- ciency in adults. AmJ Hum Genet 1986;24:179-96. nant neurodegenerative disorders that unsta- 16 Yoshida IC, Oshima A, Sakuraba H, et al. GM, ble expansions of trinucleotide repeats are gangliosidosis in adults: clinical and molecular analysis of 16 Japanese patients. Ann Neurol 1992;31:328-32. responsible for the and that 17 Nishimoto J, Nanba E, Inui K, et al. GMl-gangliosidosis the length of the repeat can be correlated with (genetic ,B-galactosidase deficiency): identification of four mutations in different clinical phenotypes among the age of onset and the severity of symp- Japanese patients. Am J Hum Genet 1991;49:566-72. toms. Phenotypic heterogeneity in many 18 Leinekugal P, Michel S, Conzelmann E, Sandhoff C. Quantitative correlation between the residual activity disorders associated with enzyme deficiencies of ,B-hexosaminidase A and arylsulfatase A and the can often be linked to the amount of residual severity of the resulting lysosomal storage disease. Hum Genet 1992;88:513-23. enzyme activity occurring with different gene 19 Goldman JE, Katz D, Rapin I, et al. Chronic G.\,- mutations. gangliosidosis presenting as dystonia: I. clinical and pathological features. Ann Neurol 1981;9:465-75. Making a specific diagnosis of a neurologi- 20 Neufeld EF, Lim TW, Shapiro LJ. Inherited disorders of cal disorder associated with deter- lysosomal metabolism. Ann Rev Biochem 1975;44: genetically 357-76. mined metabolic defects requires access to a 21 Matalon R, Kaul R, Michals K. The mucopolysacchari- laboratory that can assist in arranging for doses and the mucolipidoses. In: Rosenberg RN, Prusiner SB, DiMauro S et al, eds. The molecular and appropriate testing to be carried out. In some genetic basis of neurological disease, Boston: Butterworth- disorders such as the aminoacidurias diagnos- Heinemann, 1993:401-9. 22 Moser HW, Moser AE, Singh I, O'Neill BP. tic metabolic studies can be performed in Adrenoleukodystrophy: survey of 303 cases: biochem- clinical laboratories. In istry, diagnosis and . Ann Neurol 1984;16: hospital chemistry 628-41. others, such as the lysosomal storage diseases, 23 Moser HW. Peroxisomal disorders. In: Rosenberg RN, a that carries out Prusiner SB, DiMauro S, et al, eds. The molecular laboratory special lipid and genetic basis of neurological disease. Boston: analyses and white blood cell enzyme assays Butterworth-Heinemann, 1993:351-87. will be necessary. DNA mutational analyses 24 Mosser J, Douar AM, Sarde CO, et al. Putative X-linked adrenoleukodystrophy gene shows unexpected homol- are becoming commercially available for diag- ogy with ABC transporter. Nature 1993;361:726-30. many disorders such as mitochondrial 25 van Geel BM, Assies J, Weverling GJ, Barth PG. nosing Predominance of the adrenomyeloneuropathy pheno- diseases and those conditions associated with type of X-linked adrenoleukodystrophy in the It be Netherlands: A survey of 30 kindreds. Neurology 1994; expanded trinucleotide repeats. may 44:2343-6. necessary to contact individual research labo- 26 Moser HW, Moser AB, Smith KD, et al. Adreno- ratories when confronted with a disorder that leukodystrophy: phenotypic variability and implica- tions for therapy. J Inherit Metab Dis 1992;15:645-64. has been newly discovered or that is very rare. 27 Farrell DF, Hamilton SR, Knauss TA, et al. X-linked A of labo- adrenoleukodystrophy: adult cerebral variant. computerised directory specialised Neurology 1993;43:1518-22. ratories that perform disease specific testing 28 Kennedy CR, Allen JT, Fensom AH, Steinberg SJ, for genetic disorders should be useful in Wilson R. X-linked adrenoleukodystrophy with non- diagnostic plasma very long chain fatty acids. J Neurol choosing the appropriate diagnostic or Neurosurg Psychiatry 1994;57:759-61. 29 Vorgerd M, Fuchs S, Tegenthoff M, Malin J-P. A

research http://jnnp.bmj.com/ laboratory. missense point mutation (Ser515Phe) in the adrenoleukodystrophy gene in a family with adreno- myeloneuropathy: a clinical, biochemical, and genetic 1 Beaudet AL, Scriver CR, Sly WS, et al. Genetics and study. J7 Neurol Neurosurg Psychiatry 1995;58:229-3 1. of variant human phenotypes. In: Scriver 30 Crimmins D, Morris JGL, Walker GL, et al. Mitochon- CR, Beaudet AL, Sly WS, Valle D, eds. The metabolic drial encephalomyopathy: variable clinical expression basis of inherited disease. 6th ed. New York: McGraw- within a single kindred. _7 Neurol Neurosurg Psychiatry Hill, 1989:3-53. 1993;56:900-5. 2 Harding AE. The DNA laboratory and neurological 31 DeVivo DC. The expanding clinical spectrum of mito- practice. J Neurol Neurosurg Psychiatry 1993;56: chondrial diseases. Brain Dev 1993;15:1-22. 229-33. 32 Fryer A, Appleton R, Sweeney MG, et al. Mitochondrial 3 Bird TD, Farrell DF. Genetics and neurology. In: DNA 8993 (NARP) mutation presenting within a on September 27, 2021 by guest. Protected copyright. Swanson PD, ed. in neurology, heterogeneous phenotype including "". Philadelphia: JB Lippincott, 1984:345-77. Arch Dis Child 1994;71:419-22. 4 Dubourg 0, Durr A, Cancel G, et al. Analysis of the 33 Lestienne P, Bataille N. Mitochondrial DNA alterations SCAl CAG repeat in a large number of families with and genetic diseases: a review. Biomed Pharmacother dominant ataxia: clinical and molecular correlations. 1994;48:199-214. Ann Neurol 1995;37:176-80. 34 Holt IJ, Harding AE, Petty RKH, Morgan-Hughes JA. A 5 Nyhan WL, Haas R. Inborn errors of amino acid meta- new associated with mitochon- bolism and transport. In: Rosenberg RN, Prusiner SB, drial DNA heteroplasmy. Am .7 Hum Genet 1990;46: DiMauro S, et al, eds. The molecular and genetic basis of 428-33. neurological disease, Boston; Butterworth-Heinemann, 35 Lodi R, Montagna P, Iotti S, et al. Brain and muscle 1993:145-65. energy metabolism studied in vivo by 31P magnetic 6 Cox RP, Chuang DT. Maple syrup urine disease: clinical resonance imaging in NARP syndrome. _7 Neurol and molecular genetic considerations. In: Rosenberg Neurosurg Psychiatry 1994;57: 1492-6. RN, Prusiner SB, DiMauro S et al, eds. The molecular 36 Zeviani M, Taroni F. Mitochondrial diseases. Bailliere's and genetic basis of neurological disease. Boston: clinical neurology 1994;3:315-34. Butterworth-Heinemann, 1993:189-207. 37 Santorelli FM, Shanske S, Jain K, et al. A T -. C muta- 7 de Duve C, Pressman BC, Gianetto R, et al. Tissue frac- tion at nt8993 of mitochondrial DNA in a child with tionation studies. 6. Intracellular distribution patterns . Neurology 1994;44:972-4. of enzymes in rat-liver tissue. Biochem J 1955;60: 38 Tatuch Y, Christodonlon J, Feigenbaum A, et al. 604-17. Heteroplasmic mtDNA mutation (T -+ G) at 8993 can 8 Hers HG. Inborn lysosomal diseases. cause Leigh disease when the percentage of abnormal 1965;48:625-33. mtDNA is high. AmJHum Genet 1992;50:852-8. 9 Brady RO. Biochemical genetics in neurology. Arch 39 La Spada AR, Paulson HL, Fishbeck KH. Trinucleotide Neurol 1976;33:145-51. repeat expansion in neurological diseases. Ann Neurol 10 Kolodny EH. Current concepts in genetics. Lysosomal 1 994;36:8 14-22. storage diseases. New EnglJ Med 1976;294: 1217-20. 40 La Spada, Wilson EM, Lubahn DB, Harding AE, 11 Suzuki K. Enzymatic diagnosis of . Fischbeck KH. Androgen receptor gene mutations in Methods in enzymology 1987;138:727-62. X-linked spinal and bulbar muscular atrophy. Nature 12 Yoshida K, Ikeda S, Kawaguchi K, Yanagisawa N. Adult 199 1;352:77-9. Diagnosis ofinherited metabolic disorders affecting the nervous system 469 J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp.59.5.460 on 1 November 1995. Downloaded from 41 Plassart E, Fontaine B. Genes with triplet repeats: a new resolution of the Sherman paradox. Cell 1992;67: class of mutations causing neurological diseases. 1047-58. Biomed Pharmacother 1994;48: 191-7. 72 Menkes JH. Textbook of child neurology, 5th ed. 42 Stevanin G, Le Guem E, Ravise N, et al. A third locus Baltimore: Williams and Wilkins, 1995. for autosomal cerebellar ataxia (ADCA) type 1 maps 73 Goate A, Chartier Harlin MC, Mullan M, et al. to chromosome 14q26.3qter: evidence for the exis- Segregation of missense mutations in amyloid precur- tence of a fourth locus. Am J Hum Genet 1994;521: sor protein gene with familial Alzheimer's disease. 11-20. Nature 1991;349:704-6. 43 Willems PJ. Dynamic mutations hit double figures. 74 Hardy J. Alzheimer's disease. Molecular genetics. J Fla Nature Genetics 1994;8:213-5. MedAssoc 1994;91:759-61. 44 Kawaguchi Y, Okamoto T, Taniwaki M, et al. CAG 75 Schellenberg GD, Bird T, Wijsman E et al. Genetic link- expansions in a novel gene for Machado-Joseph disease age evidence for a familial Alzheimer's disease locus on at chromosome 14q32. 1. Nature Genetics 1994;8: chromosome 14. Science 1992;258:668-71. 221-7. 76 Kremer B, Goldberg P, Andrew SE et al. A worldwide 45 Ranum LPW, Chung M, Banfi S, et al. Molecular and study of the Huntington's disease mutation. The sensi- clinical correlations in spinocerebellar ataxia 1 (SCA1): tivity and specificity of measuring CAG repeats. N Engl evidence for familial effects on the age of onset. Am Jf JfMed 1994;330:1401-6. Hum Genet 1994;55:244-52. 77 Saito Y, Ando T, Doyu M, et al. An adult case of classi- 46 Giunti P, Sweeney MG, Spadaro M, et al. The trinu- cal Pelizaeus-Merzbacher disease-magnetic resonance cleotide repeat expansion on chromosome 6p (SCA 1) images and neuropathological findings. Rinsho in autosomal dominant cerebellar ataxias. Brain 1994; Shinkeigaku. Clinical Neurology 1993;33: 187-93. 227:645-9. 78 Pham-Dinh D, Boespflug-Tanguy 0, Mimault C, et al. 47 Duryao M, Ambrose C, Myers R et al. Trinucleotide Pelizaeus-Merzbacher disease: a frameshift deletion/ repeat length instability and age of onset in insertion event in the myelin proteolipid gene. Human Huntington's disease. Nature Genetics 1993;4:387-92. Molecular Genetics 1993;2:465-7. 48 Potter NT, Meyer MA, Zimmerman AW. Molecular 79 Boespflug-Tanguy 0, Mimault C, Melki J, et al. Genetic and clinical findings in a family with denta- homogeneity of Pelizaeus-Merzbacher disease: tight torubral-pallidoluysian atrophy. Ann Neurol 1995:37: linkage to the proteolipoprotein locus in 16 affected 273-7. families. Am J Hum Genet 1994;55:461-7. 49 Nagafuchi S, Yanagisawa H, Sato K, et al. Dentatorubral 80 Strautnieks S, Rutland P, Winter RM, et al. Pelizaeus- and pallidoluysian atrophy expansion of an unstable Merzbacher disease: detection of mutations THR"'8 - CAG trinucleotide on chromosome 12p. Nature Pro and Leu223 -. Pro in the proteolipid protein gene, Genetics 1994;6: 14-8. and prenatal diagnosis. Am J Hum Genet 1992;51: 50 Nagafuchi S, Yanagisawa H, Ohsaki E, et al. Structure 871-8. and expression of the gene responsible for the triplet 81 Matalon R, Michals K, Sebasta D, et al. Aspartoacyclase repeat disorder, dentatorubral and pallidoluysian atro- deficiency and N-acetylaspartic aciduria in patients phy (DRPLA). Nature Genetics 1994;8:177-82. with . Am J Med Genet 1988;29: 51 Menkes JH, Alter M, Steigleder GK et al. A sex-linked 463-71. recessive disorder with growth retardation, peculiar 82 Gardiner RM. Genetic analysis of . _J hair, and focal cerebral and cerebellar degeneration. Inherit Metab Dis 1993;16:787-90. 1962;29;764-79. 83 Mitchison HM, Taschner PE, O'Rawe AM et al. Genetic 52 Menkes JH. Kinky : twenty-five years later. mapping of the Batten disease locus (CLN3) to the Brain Dev 1988;lO:77-9. interval D16S288-D16S383 by analysis of haplotypes 53 Danks DM, Campbell PE, Stevens BJ et al. Menkes' and allelic association. Genomics 1994;22:465-8. kinky hair syndrome: an inherited defect in copper 84 Ferrer I, Arbizu T, Pena J, Serra JP. A Golgi and ultra- absorption with widespread effects. Pediatrics 1972;50: structural study of a dominant form of Kufs' disease. J 188-201. Neurol 1980;222:183-90. 54 Gunn TR, Macfarlane S, Phillips LI. Difficulties in the 85 Martin J-J. Adult type of neuronal ceroid-lipofuscinosis. neonatal diagnosis of Menkes' kinky hair syndrome- Jl Inherit Metab Dis 1993;16:237-40. trichopoliodystrophy. Clinical Pediatr 1984;23:514-6. 86 Rosenberg RN. Autosomal dominant cerebellar pheno- 55 Tonnesen T, Horn N. Prenatal and postnatal diagnosis types: the genotype has settled the issue. Neurology of , an inherited disorder of copper 1995;45: 1-5. metabolism. J7 Inherit Metab Dis 1989;12 (suppll): 87 Savitsky K, Bar-Shira A, Gilad S, et al. A single ataxia 207-14. telangiectasia gene with a product similar to PI-3 56 Tumer Z, Tonnesen T, Bohmann J, et al. First trimester kinase. Science 1995;268:1749-53. prenatal diagnosis of Menkes disease by DNA analysis. 88 Serizawa M, Sakamoto M, Hirabayashi K, et al. JfMed Genet 1994;31:615-7. Histological and radiobiological study of adult cases 57 Bull PC, Cox DW. Wilson disease and Menkes disease: with ataxia telangiectasia. Rinsho Shinkeigaku. Clin new handles on heavy-metal transport. Trends Genet Neurol 1994;34:38-42. 1994;10:246-52. 89 Boder E. Ataxia-telangiectasia. In: Gomez MR, ed. 58 Tanzi RE, Petrukhin K, Chernov I et al. The Wilson Neurocutaneous diseases. A practical approach, Boston: disease gene is a copper transporting ATPase with Butterworths, 1987:95-117. homology to the Menkes disease gene. Nature Genetics 90 Gardner K, Alderson K, Galster B, et al. Autosomal

1993;5:344-50. dominant spinocerebellar ataxia: clinical description of http://jnnp.bmj.com/ 59 Yamaguchi Y, Heiny ME, Gitlin JD. Isolation and a distinct hereditary ataxia and genetic localization to characterization of a human liver cDNA as a candidate chromosome 16 (SCA4) in a Utah kindred. Neurology gene for Wilson disease. Biochem Biophys Res Commun 1994;921S. 1993;197:271-7. 91 Benomar A, Le Guern E, Dure A. Autosomal dominant 60 Thomas GR, Forbes JR, Roberts EA. The Wilson cerebellar ataxia with retinal degeneration (ADCA type disease gene: spectrum of mutations and their conse- II) is genetically different from ADCA type 1. Ann quences. Nature Genetics 1995;9:210-7. Neurol 1994;35:439-44. 61 Czaja MJ, Weiner FR, Schwarzenberg FJ, et al. 92 Ranum LPW, Schut LJ, Lundgren JK, et al. Molecular studies of ceruloplasmin deficiency in Spinocerebellar ataxia type 5 in a family descended Wilson's disease. J Clin Invest 1987;80: 1200-4. from the grandparents of President Lincoln maps to 62 Walshe JM. Diagnosis and treatment of presymptomatic . Nature Genetics

1994;8:280-4. on September 27, 2021 by guest. Protected copyright. Wilson's disease. Lancet 1988;ii:435-7. 93 Harding AE. The clinical features and classification of 63 Walshe JM. Wilson's disease: yesterday, today, and the late onset autosomal dominant cerebellar ataxias. tomorrow. Mov Dis 1988;3:10-29. Brain 1982;105:1-28. 64 Walshe JM, Yealland M. Wilson's disease: the problem 94 Smith JK, Gonda VE, Malamud N. Unusual form of of delayed diagnosis. Jf Neurol Neurosurg Psychiatry cerebellar ataxia. Combined dentato-rubral and 1992;55:692-6. pallido-luysian degeneration. Neurology 1958;8:205-9. 65 Gibbs K, Walshe JM. A study of the coeruloplasmin 95 Schimschock JR, Alvord EC, Swanson PD. Cerebro- concentrations found in 75 patients with Wilson's tendinous xanthomatosis: clinical and pathological disease, their kinships and various control groups. studies. Arch Neurol 1968;18:688-98. QuartJ Med 1979;48:447-63. 96 Menkes JH, Schimschock JR, Swanson PD. Cerebro- 66 Neri G, Chiurazzi P, Arena JF, Lubs HA. XLMR genes: tendinous xanthomatosis: the storage of cholestanol update 1994.AmJ Med Genet 1994;51:542-9. within the nervous system. Arch Neurol 1968;19:47-53. 67 Jacobs PA, Glover TW, Mayer M, et al. X-linked mental 97 Bferginer VM, Salen G, Shefer S. Long-term treatment of retardation: a study of 7 families. Am J Med Genet cerebrotendinous xanthomatosis with chenodeoxy- 1980;7:471-89. cholic acid. New EnglJMed 1984;311:1649-52. 68 Turner G, Brookwell R, Daniel A, et al. Heterozygous 98 Leitersdorf E, Reshef A, Meiner V, et al. Frameshift and expression of X-linked mental retardation and X- splice-junction mutations in the sterol 27-hydroxylase chromosome marker fra(X) (q27). N EnglJ Med 1980; gene cause cerebrotendinous xanthomatosis in Jews of 303:662-4. Moroccan origin. J Clin Invest 1993;91:2488-96. 69 Nielson KB. Diagnosis of the fragile X syndrome: 99 Kim K-S, Kubota S, Kuriyama M, et al. Identification clinical findings in 27 males with the fragile site at of new mutations in sterol 27-hydroxylase gene Xq28. J'ournal of Mental Deficiency Research 1983:27: in Japanese patients with cerebrotendinous 211-26. xanthomatosis (CTX). J7 Lipid Research 1994;35: 70 Verkerk AJMH, Pieretti M, Sutcliffe JS, et al. 1031-9. Identification of a gene (FMR-1) containing CGG 100 Nakashima N, Sakai Y, Sakai H, etal. A point mutation repeat coincident with a breakpoint cluster region in the bile acid biosynthetic enzyme sterol 27-hydroxy- exhibiting length variation in fragile X syndrome. Cell lase in a family with cerebrotendinous xanthomatosis. J' 1991;65:905-14. Lipid Research 1994;35:663-8. 71 Fu Y-H, Kuhl DPA, Pizzuti A. Variation of the CGG 101 Meiner V, Meiner Z, Reshef A, etal. Cerebrotendinous repeat at the fragile X site results in genetic instability: xanthomatosis: molecular diagnosis enables presymp- 470 Swanson J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp.59.5.460 on 1 November 1995. Downloaded from tomatic detection of a treatable disease. Neurology gene: a possible new subtype of familial ALS. 1994;44:288-90. Neurological Sciences 1994;126:77-83. 102 Harding AE, Matthews S, Jones S, et al. Spinocerebellar 113 Bowling AC, Barkowski EE, McKenna YD, et al. degeneration associated with a selective defect of vita- dismutase concentration min E absorption. Superoxide and activity in NEnglJMed 1985;313:32-5. familial amyotrophic lateral sclerosis. .7 Neurochem 103 Stumpf DA, Sokol R, Bettis D, et al. Friedreich's 1995;64:2366-9. disease: V. Variant form with and 114 Ichinose H, Ohye T, Takahashi E, et al. Hereditary normal fat absorption. Neurology 1987;37:68-74. progressive dystonia with marked diurnal fluctuation 104 Ben Hamida M, Belal S, Sirugo G, et al. Friedreich's caused by mutations in the GTP cyclohydrolase 1 ataxia phenotype not linked to chromosome 9 and Nature Genetics associated with gene. 1994;8:236-41. selective autosomal recessive vitamin E 115 Lertrit P, Noer AS, Jean-Francis MJB, et al. A new deficiency in two inbred Tunisian families. Neurology disease related mutation for mitochondrial encephalo- 1993;43:2179-83. myopathy, lactic acidosis and stroke-like episodes 105 Ben Hamida C, Doerflinger N, Belal S, et al. syndrome affecting the ND4 subunit of complex I. Am Localization of Friedreich ataxia phenotype with selec- Hum Genet 1992;52:457-68. tive vitamin E deficiency to chromosome 8q by 116 Harker LA, Ross R, Slichter SJ, Scott CR. Homocystine- homozygosity mapping. Nature Genetics 1993;5:195-200. induced arteriosclerosis. The role of endothelial cell 106 Ouahchi K, Arita M, Kayden H, et al. Ataxia with injury and platelet response in its genesis. Y Clin Invest isolated vitamin E deficiency is caused by mutations in 1976;58:731-41. the a-tocopherol transfer protein. Nature Genetics 1995; 117 Brattstrom LE, Hardebo JE, Hultberg BC. Moderate 9:141-5. homocysteinemia-a possible risk factor for arterioscle- 107 Kayden HJ. The neurologic syndrome of vitamin E defi- rotic . Stroke 1984;15:1012-6. ciency: a significant cause of ataxia. Neurology 1993; 118 Riela AR, Roach S. Etiology of stroke in children. T Child 43:2167-9. Neurol 1993;8:201-20. 108 Sharp D, Blinderman L, Combs KA et al. Cloning and 119 Mudd SH, Irreverre F, Laster L. Sulfite oxidase defi- gene defects in microsomal triglyceride transfer protein ciency in man: demonstration of the enzymatic defect. associated with abetalipoproteinemia. Nature 1993; Science 1967;156: 1599-602. 365:65-9. 120 Shih VE, Abroms IF, Johnson JL, et al. Sulfite oxidase 109 DiDonato S. Can we avoid AVED? Nature Genetics deficiency. Biochemical and clinical investigations of a 1995;9: 106-7. hereditary in sulfur metabolism. 110 Rosen DR, Siddique T, Patterson D, et al. Mutations in New EnglJ Med 1977;297:1022-8. Cu/Zn superoxide dismutase gene are associated with 121 Haas RH, Marsden DL, Capistrano-Estrada S, familial amyotrophic lateral sclerosis. Nature 1993; Hamilton R et al. Acute basal infarction in 362:59-62. ganglia . _7 Child Neurol 1995;10: 18-22. 111 Deng H-X, Hentati A, Tainer JA. Amyotrophic lateral 122 Sesthi KD, Ray R, Roesel RA. Adult-onset chorea and sclerosis and structural defects in Cu,Zn superoxide dementia with propionic acidemia. Neurology 1989; dismutase. Science 1993;261: 1047-51. 39:1343-5. 112 Aoki M, Ogasawara M, Matsubara Y, et al. Familial 123 Christensen Lou HO, Reske-Nielson E. The central amyotrophic lateral sclerosis (ALS) in Japan associated nervous system in Fabry's disease. Arch Neurol with H46R mutation in Cu/Zn superoxide dismutase 25:351-9. 1971;

NEUROLOGICAL STAMP

.. Rosa w-@e3igw-m W '?t %j >-97 ' w -'= §'~~~ U Ai0 'V J canina (dog rose) .'g;@ .t ..0

The Roman naturalist Pliny attributed the name dog rose to a belief that the plant's root could cure the bite of a

mad dog. It is not clear if the dogs were rabid. The use of v. w IN http://jnnp.bmj.com/ the dog rose in prescriptions dates back to Hippocrates but precisely what for is unclear. As a medicinal plant it came into full bloom in the second world war. When 'V~~~~~~~~~~~~~~~~1. Britain was unable to import fresh citrus fruits the government organised the gathering of dog rose fruits, or hips, which were known to be a rich rource of vitamin C. A'#4W'~~~~~~~~~~~~~~~~~~~~~~5~~~~~~a*~ ~ ~~f Processed into syrup the rose hips helped to prevent

-7 on September 27, 2021 by guest. Protected copyright. scurvy and, today, the plant is valued as a rich source of &t- vitamin C. d. ji fM>f i. The dog rose is illustrated as part of a commemorative set issued for the International Congress of LX Pharmacology held in Prague in 1971 (Stanley Gibbons 1980, Scott 1773). L F HAAS i1..hSipo