• Information
  1. Overview
  2. Tay-Sachs Disease
  3. Gaucher Disease
  4. Fabry Disease
  5. Krabbe Disease
  6. Mucopolysaccharidosis I
  7. Pompe Disease
  8. Cystinosis
  9. Niemann-Pick Disease
  10. Acid-Lipase Deficiency
  11. Metachromatic Leukodystrophy
  12. Globoid-Cell Leukodystrophy
  13. Danon Disease

A. Overview
[Figure] "Sphingolipid Storage Diseases"

1. Variety of enzymatic deficiencies
2. Leads to accumation of various substances in lysosomes
3. Symptoms are variable, but most diseases have (severe) neurologic involvement
4. Majority of the diseases are autosomal recessive (AR)
5. Glycogen Storage Diseases discussed separately
6. Note that all individuals probably carry 5-7 lethal AR mutations

B. Tay-Sachs Disease

1. One of the more common inborn metabolic errors
   1. Homozygous ~1:3000
   2. Heterozygous 1:21 in Ashkenazi Jews
   3. AR inheritance
2. Deficiency in hexosaminidase A with accumulation of GM2 ganglioside
3. Mental retardation, blindness, seizures are major symptoms
4. Cherry red spot on retina
5. Invariably fatal at present time

C. Gaucher Disease [1,2,3]

1. Biochemical Disease Name: glucosylceramide lipidosis
2. Estimated ~25,000 cases worldwide
3. May begin throughout life; more comon in Ashkenazi Jews
4. Classified into three types based on nature of CNS involvement
   1. Type 1: most common, non-neuronopathic; previously referred to as "adult" type
   2. Type 2: infantile, severe CNS involvement in infants with early death
   3. Type 3: onset of mild CNS involvement as adolescents, slow progression
5. Genetics
   1. Gene identified as encoding ß-glucocerebrosidase
   2. AR inheritance with various mutations in gene on chromosome 1q2.1
   3. Carrier rate 1:14-18 in Ashkenazi Jews [4]
   4. More than 80 mutations have identified but 7 account for majority of cases
6. Symptoms
   1. Hepatosplenomegaly is most prominant
   2. Hepatosplenomegaly often causes thrombocytopenia, portal hypertension
   3. Bone pain and bone crises also occur
   4. Hepatosplenomegaly with bone pain or crisis is specific to Gaucher's Disease
   5. Mental retardation, spacticity, flaccidity
   6. Pulmonary disease uncommon - Gaucher cells in lungs; pulmonary hypertension
7. Diagnosis
   1. Assay for ß-Glucocerebrosidase deficiency is definitive method
   2. Can also demonstrate glucosylceramide accumulation
   3. Gaucer cells are present on bone biopsy: these are histiocytes with fibrillar cytoplasm
   4. Mutation analysis may be helpful in predicting progression of disease
8. Serial monitoring to document rate and progression of disease is critical [6]
   1. Thorough history and physical every 6-12 months
   2. Monitoring also varies with use of enzyme replacement therapy
9. Enzyme Replacement Therapy [7]
   1. Enzyme replacement is very effective in preventing complications
   2. Recombinant ß-Glucocerebrosidase (Alglucerase; Ceridase®) is standard of care
   3. Aglucerase prevents progression of disease and normalizes many parameters
10. N-butyldeoxynojirimycin [8]
    1. Inhibits ceramide-specific glucosyltransferase
    2. Glucosyltransferase initiates the formation of glucocerebroside
    3. N-butyldeoxynojirimycin has shown some activity in early studies

D. Fabry Disease [9,10,11]

1. X-Linked (chr Xp22) recessive disorder
2. Occurs in ~1:55,000 male births
3. alpha-Galactosidase A Deficiency
   1. Leads to accumulation of globotriaosylceramide in white blood cells or skin fibroblasts
   2. Galabiosylceramide and blood group B and AB related glycosphingolipids also accumulate
   3. Endothelial dysfunction occurs with consequent vascular events
   4. Death usually occurs by 6th decade
4. Symptoms
   1. Painful peripheral neuropathy
   2. Corneal dystrophy
   3. Cataracts
   4. Thrombosis
   5. Angiokeratomas
   6. Telangiectasias on hands (especially ventral region)
   7. Cardiac: sinus bradycardia, short PR interval, ventricular hypertrophy
   8. Hemizygous form may be associated with left ventricular hypertrophy
5. Stroke [5]
   1. Female carriers have increased risk of stroke
   2. Amongst patients with cryptogenic stroke, ~1% have Fabry disease
   3. Increased risk of stroke in young persons with Fabry disease
6. Diagnosis
   1. Demonstration of marked deficiency of alpha-galactosidase A
   2. Elevated serum glycosphingolipid levels
7. Treatment with alpha-galactosidase replacement therapy recommended:
   1. All males
   2. Any females with substantial disease manifestations
   3. Replacement should be started as early as possible
   4. Do not coadminister with chloroquine, amiodarone, benoquin or gentamicin
8. alpha-galactosidase A Replacement Therapy [9,23]
   1. Dosage 0.2mg/kg intravenously (IV) every other week
   2. Body weight increases and cardiac conduction improve
   3. Plasma glycosphingolipid levels reduced ~50%
9. alpha-galactosidase A Replacement (agalsidase beta, Fabrazyme®) [12,13]
   1. Dosage 1mg/kg IV every other week for 20 weeks (11 doses)
   2. Serum globotriaosylceramide clearance improved dramatically
   3. Markedly reduces deposition of globotriaosylceramide from (renal) endothelium
   4. Improved histopathology in kidney, heart and skin tissue pathology
   5. Improved composite endpoint of organ dysfunction and death in severe disease [22]
   6. Quality of life improved with treatment
   7. Cost $75,000-$180,000 per year
10. Galactose infusions improve cardiac function in cardiac-variant Fabry Disease [14]

E. Krabbe Disease

1. Galactosylceramide ß-Galactosidase Deficiency
2. Accumulation of Galactoscerebrosides; increased glactoscerebroside / Sulfatide ratio
3. Infantile and late onset forms, AR inheritance
4. Mental Retardation and Leukodystrophy (white matter breakdown)
5. Optic Atrophy
6. Blood Cell Transplantation [15]
   1. Transplant with unrelated donor umbilical cord blood cells
   2. 100% engraftment in 25 patients with Krabbe Disease
   3. In 11 patients <44 days old (asymptomatic) provided for 100% survival after 3 years
   4. In 14 patients 142-352 days old (symptomatic), 43% survival at 3.4 years

F. Mucopolysaccharidosis I

1. Deficiency of alpha-L-iluronidase
   1. Iluronidase cleaves terminal alpha-L-iduronic acid residues from GAGs
   2. These glycosaminoglycans (GAGs) include heparan sulfate and dermatan sulfate
   3. Deficiency blocks degration of these GAGs, which accumulate in lysosomes
2. Three Syndromes
   1. Hurler's Syndrome - severe deficiency
   2. Hurler-Scheie's Syndrome - intermediate deficiency
   3. Scheie's Syndrome - mild deficiency
3. Hurterl's Syndrome
   1. Progressive developmental delay and cognitive dysfunction
   2. Corneal clouding
   3. Airway obstruction
   4. Cardiac disease
   5. Hepatosplenomegaly
   6. Severe joint restriction
   7. Death by age of 10 years in most patients
4. Treatment [16]
   1. Recombinant alpha-iluronidase reduces lysosomal storage
   2. Treatment improves sytemic but probably non CNS symptoms of disease
   3. Non-neutralizing antibodies to ilururonidase can develop
   4. Laronidase (human alpha-L-iduronidase, Aldurazyme®) FDA approved
   5. Cord blood transplantation with 1-3 HLA mismatches is likely superior to bone marrow transplantation and can improve cognitive and systemic disease [17]
   6. Cord blood transplant does not require total body irradiation and did not result in chronic graft-versus host disease (GVHD) [17]

G. Pompe Disease

1. Autosomal recessive, lysosomal alpha-glucosidase deficiency
2. Infantile - hypotonia, cardiomyopathy and cardiac failure, hyperglossia, fatal early
3. Juvenile - progressive skeletal muscle weakness
4. Adult - progressive muscle weakness, respiratory decline
5. Increased serum creatinine kinase
6. Recombinant alpha-glucosidase (from rabbit milk) [18]
   1. Dose is 15-40mg/kg intravenous once weekly
   2. Reverses cardiomyopathy in infantile form
   3. Generally well tolerated

H. Cystinosis [6]

1. Autosomal recessive disorder, ~1:150,000 live births (15 cases/year in USA)
2. Gene CTNS on chromosome 17p13
   1. Codes for protein cystinosin, 7 transmembrane protein
   2. Role in transport of cystine formed after protein degradation
   3. Cystinosis has defective cystine transport out of lysosomes into cytoplasm
3. Symptoms and Signs
   1. Renal Fanconi's Syndrome (95%) - age 6-12 months
   2. Hypothyroidism (50%) - age 5-10 years
   3. Photophobia (50%) - age 8-12 years
   4. Chronic Renal Failure (95%) - age 8-12 years
   5. Male hypogonadism (70%) - age 18-40 years
   6. Myopathy, retinal blindness, diabetes mellitus (5-20%) - age ~12-40 years
   7. Pulmonary dysfunction (100%) - age ~21-40 years
   8. CNS calcifications (15%) - age ~21-40 years
4. Pathology
   1. Cystine crystals in almost all cells and tissues
   2. Urinary crystals
   3. Diagnosis by measuring leukocyte cystine content
5. Treatment
   1. Identification and treatment early to prevent renal decline
   2. Supportive: replace fluid and solutes due to impaired renal tubular resorption
   3. Unrestrictive intake of salt and water essential
   4. Formal electrolyte replenishment
   5. Cysteamine (aminothiol) treatment leads to long term depletion of lysosomal cystine []
   6. Cysteamine improves growth, delays renal failure, reduces death rate
   7. Many patients survive to 3rd decade of life without renal transplantation

I. Niemann-Pick Disease

1. Forms of Disease
   1. Infantile and Late Onset Neuropathic Forms
   2. Visceral Form
2. Sphingomyelin Lipidosis
3. Types
   1. Types A and B: Acid Sphingomyelinase Deficiency
   2. Type C: defect in intracellular cholesterol processing [19]
4. Mental Retardation, Ataxia, Seizures
5. Liver and/or spleen enlargement; foam cells
6. Autosomal recessive - gene(s) not yet identified
7. Experimental stem cell (umbilical cord) transplantation may be effective

J. Acid-Lipase Deficiency

1. Infantile (Wolman's Disease) and Late Onset forms
2. Accumulation of cholesteryl ester and triglycerides; autosomal recessive
3. Hepatosplenomegaly; growth failure, mild mental retardation
4. Foam cells and vacuolated lymphocytes

K. Metachromatic Leukodystrophy

1. Arylsulfatase (Cerebroside Sulfatase) A Deficiency, AR inheritance
2. Symptoms may begin throughout life
3. Mental Retardation, Leukodystrophy, Psychosis, Dementia
4. Early Gait abnormalities, Optic Atrophy

L. Globoid-Cell Leukodystrophy [20]

1. Autosomal recessive disorder
   1. More common form begins in early infancy, progresses to death within 2 years
   2. Late-onset form beins in later childhood, and progresses to death over several years
2. Due to near or complete absence of galactocerbrosidase
3. Progressive loss of central and peripheral myelin
   1. Result is spasticfity, dementia and peripheral neuropathy
   2. Progression in all cases to chronic vegetative state and early death
4. Signs
   1. Progressive reduction in motor and sensory neuron conduction rates
   2. Increased cerebrospinal fluid protein levels
5. Allogeneic hematopoietic stem cell transplantation reverses and cures the disease

M. Danon Disease [21]

1. X-linked lysosome-associated membrane protein 2 (LAMP2) deficiency
2. Usually cause multisystem glycogen storage disease
3. May also cause primary cardiomyopathy

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