38 Disorders of Sphingolipid Metabolism Marie-Thérèse Vanier 38.1 Gaucher Disease – 481 38.2 Niemann-Pick Disease Type A and B – 482 38.3 GM1-Gangliosidosis – 484 38.4 GM2-Gangliosidoses – 485 38.5 Krabbe Disease – 486 38.6 Metachromatic Leukodystrophy – 487 38.7 Fabry Disease – 489 38.8 Farber Disease – 490 38.9 Prosaposin Deficiency – 490 38.10 Niemann-Pick Disease Type C – 491 References – 492 480 Chapter 38 · Disorders of Sphingolipid Metabolism Sphingolipid Structure and Metabolism The common lipophilic moiety of all sphingolipids is compartments. Glycosphingolipids are formed in the ceramide (. Fig. 38.1), in which a long-chain sphingoid Golgi apparatus by sequential addition of monosaccha- base (such as sphingosine) is attached by an amide link- rides to ceramide, catalysed by specific glycosyltrans- age to a long-chain or very long-chain fatty acid. In ferases. Sphingolipids are then transported and inserted glycosphingolipids, the carbohydrate moiety is linked in the plasma membrane where they play a structural to the primary alcohol group of the sphingoid base. and functional role. For degradation (. Fig. 38.1), after Neuraminic acid-containing glycosphingolipids are transport by the endosomal pathway to the lysosome, named gangliosides. The hydrophilic portion of sphin- they are hydrolysed stepwise by specific sphingohydro- gomyelin is phosphorylcholine. Synthesis and degrada- lases, some of which may need co-factors called sphin- tion of sphingolipids take place in different cellular golipid activator proteins for their in vivo action. X . Fig. 38.1. Sphingolipid structure and degradation. Glc, glu- ceramide; GM1, GM1 ganglioside; GM2, GM2 ganglioside; ASA, cose; Gal, galactose; GalNAc, galactosamine; NeuAc, N-acetyl- aryl sulfatase A; GALC, galactocerebrosidase; MLD, metachromatic neura minic acid; LacCer, lactosylceramide; GlcCer, glucosylce- leukodystrophy; sap, saposin. Enzyme defects are indicated by ramide; GalCer, galactosylceramide; Gb3, globotriaosylceramide; solid bars across the arrows Gb4, globotetraosylceramide (globoside); diGalCer, galabiosyl- 481 38 38.1 · Gaucher Disease Leukopenia is less frequent. Children may show delayed Sphingolipidoses are a subgroup of lysosomal storage growth and menarche. Subcapsular splenic infarctions may disorders in which sphingolipids accumulate in one or cause attacks of acute abdominal pain and medullary in- several organs as the result of a primary deficiency in farction of long bones, excruciating pain often referred to enzymes or activator proteins involved in their degra- as bone crises. Essentially in adult patients, bone involve- dative pathway. Traditionally, this subgroup also in- ment represents a major cause of morbidity. Aseptic necro- cludes Niemann-Pick disease type C, characterized by sis of the femoral head and spontaneous fractures due to impaired cellular trafficking of several lipids. With the osteopenia are other common complications. Lung involve- exception of Fabry disease, which is X-linked recessive, ment with diffuse infiltration may occur. In adults, pul- sphingolipidoses have an autosomal recessive inheri- monary hypertension has been described in rare, usually tance. The clinical presentation and course of the classi- splenectomized, patients. An association of Gaucher di- cal forms of the various diseases are often characteris- sease with parkinsonism has been reported [4]. tic. With the help of relevant procedures (imaging, neu- rophysiology, ophthalmologic examination…), careful Type II (Acute neuronopathic Gaucher disease). Classi- examination of the patient and perusal of the disease cally, patients present early in infancy with brainstem history (especially age and type of first symptom) dysfunction (horizontal gaze palsy, convergent squint, should lead to a provisional diagnosis and oriented bio- dysphagia), visceromegaly, retroflexion of the neck, pro- chemical tests. Late-onset forms are often more diffi- nounced spasticity, failure to thrive and cachexia. The cult to recognize, and foetal presentations have also downhill clinical course is rapid and few of these patients been overlooked in the past. No overall screening pro- survive beyond the age of 2 years. This form has been sub- cedure is yet available to date. In most sphingolipidoses, categorized as type IIB [5]. Type IIA refers to patients with the diagnosis is made by demonstration of the enzym- strabismus, paucity of facial movements but less or no sign atic defect, generally expressed in most cells, organs or of pyramidal involvement, irritability or cognitive impair- even serum (leukocytes represent the most widely used ment and a slower course (they may survive up to 5 years), enzyme source). In specific diseases, more complex bio- who fill the gap between type II and type III. chemical tests or/and a molecular genetics assessment may be necessary. The past 15 years have seen the era Foetal and lethal neonatal variants are reminiscent of the of specific therapies for non-neuronopathic Gaucher phenotype seen in the knock-out Gaucher mouse. Many disease and Fabry disease. But in spite of active research of these cases are associated with hydrops foetalis, some on animal models, knowledge on pathophysiology and have been described as »collodion babies« [6, 7]. progress toward therapy of the neurological forms in human patients remain to date limited. Type III (Subacute or chronic neuronopathic Gaucher di- sease) is heterogeneous. The most common form consists of severe systemic involvement and supranuclear saccadic horizontal gaze palsy, with or without developmental delay, 38.1 Gaucher Disease hearing impairment and other brainstem deficits [8]. The second most common phenotype shows a relatively mild 38.1.1 Clinical Presentation systemic disease but progressive myoclonic encephalo pathy, with seizures, dementia and death. There are also patients Historically, three clinical phenotypes are recognized, but the with severe systemic involvement and supranuclear gaze full disease spectrum is actually a continuum. All types are palsy who develop a progressive myoclonic encephalo pathy. panethnic but type 1 has a particularly high prevalence in the A particular presentation with cardiac involvement (heart Ashkenazi Jewish population (carrier frequency 1:13). valve and aortic calcification), supranuclear gaze palsy, mild hepatosplenomegaly and bone disease, has been associated Type I, defined by the lack of neurological symptoms, cons- with homozygocity for the D409H mutation. In neurological titutes 80-90% of all cases [1]. Most commonly diagnosed Gaucher disease, extrapyramidal involvement has also in adults, it can present at any age [2]. There is a wide va- been observed. Distinction between type II and type III, riability in the pattern and severity of the symptoms, from sometimes difficult, is however critical due to differences in extremely handicapping forms to asymptomatic in dividuals, prognosis and treatment. with most symptomatic patients having visceral, haemato- logical and (more frequently in adults) skeletal disease [3]. Children often show severe splenomegaly, generally associ- 38.1.2 Metabolic Derangement ated with hepatomegaly, but the degree of visceromegaly is highly variable, both in children and adults. This may lead The primary metabolic defect resides in a block of the lyso- to anemia, thrombocytopenia, and thus a bleeding tendency. somal degradation of glucosylceramide (glucocerebroside) 482 Chapter 38 · Disorders of Sphingolipid Metabolism and glucosylsphingosine. In the vast majority of cases this 38.1.5 Treatment and Prognosis is due to a deficiency of acid E-glucosidase (glucocerebro- sidase, glucosylceramidase). Exceedingly rare cases, pre- Two approaches are currently available for the specific treat- senting as type III [9] are due to a deficiency of the saposin ment of type I (and to some extent type 3) patients: enzyme (SAP) sap-C, required for the in vivo hydrolysis of glucosyl- replacement therapy (ERT) and substrate reduction therapy ceramide. Glucosylceramide (glucocerebroside) accumu- (SRT). Splenectomy enhances the risk of progression of the lates massively in liver and spleen of patients in all types. disease at other sites, especially bone and lung and can gen- Although elevated in cerebral gray matter of type II and erally be avoided by institution of ERT. Pregnancy is not type III patients, its concentration in brain remains low. contraindicated in untreated patients, although bleeding Pathophysiology of the disease is poorly understood [10]. may become critical before and after birth. There is now Glucosylsphingosine, a highly cytotoxic compound, Ca2+, a good experience of ERT throughout pregnancy [14]. En- and inflammatory responses seem to be involved. zyme therapy is conducted with slow infusions of a recom- binant enzyme modified to expose mannose groups (imi- glucerase), ensuring optimal uptake by macrophages. Dur- 38.1.3 Genetics ing the past 10 years more than 3000 patients have been treated worldwide, and this form of therapy has largely prov- The disease (except for sap-C deficiency) is caused by muta- en its safety and effectiveness. Guidelines have been pub- tions of the GBA (acid E-glucosidase) gene (1q21). N370S, lished [15–17]. The natural history of type I can be dramati- the most common mutation in Ashkenazim, is also very cally improved. ERT prevents progressive manifestations, frequent in Caucasian populations. Even as a genetic com- and ameliorates Gaucher disease-associated anemia, throm- pound with another