OVERVIEW OF LYSOSOMAL STORAGE DISORDERS
- Lysosomes: Membrane‐bound cytoplasmic organelles containing enzymes for degrading sphingolipids, mucopolysaccharides, and glycoproteins.
- Enzyme deficiencies → accumulation of partially degraded substrate → cell distension → disruption of cellular function.
- Clinical presentation depends on the site(s) and extent of abnormal substrate accumulation.
- Categories:
- Sphingolipidoses (focus of this summary)
- Mucopolysaccharidoses (e.g., Hurler syndrome)
- Glycoproteinoses (e.g., sialidosis, mannosidosis)
- Mucolipidoses (disorders of lysosomal enzyme transport)
- Lysosomal membrane transport disorders (e.g., sialic acid storage disease, cystinosis)
Sphingolipidoses include:
- Tay‐Sachs disease
- Niemann‐Pick disease
- Gaucher disease
- Metachromatic leukodystrophy
- Fabry disease
- GM1 gangliosidosis
- Krabbe disease
- Multiple sulfatase deficiency
SPHINGOLIPIDS AND CERAMIDE
- Sphingolipids: Contain sphingosine (18‐carbon amino alcohol synthesized from palmitic acid and serine).
- A long‐chain fatty acid bound in peptide linkage to sphingosine → forms ceramide.
- Sphingolipids differ by the polar group linked to the C‐1 hydroxyl of the ceramide moiety.
- Some are concentrated in nervous tissue:
- Gangliosides (in ganglion cells)
- Cerebrosides and cerebroside sulfatides (in myelin)
- Sphingomyelin (the phosphorylcholine ester of ceramide) is found in almost every cell type.
TAY‐SACHS DISEASE
- Cause: Deficiency of lysosomal enzyme β‐hexosaminidase A (Hex A) → accumulation of gangliosides.
- Inheritance: Autosomal recessive; carrier frequency ~1 in 25 among Ashkenazi Jews; disease incidence ~1 in 3600 in this population.
- Onset: Usually by 6 months of age; progressive neurologic deficits (e.g., hypotonia, hyperreflexia, weakness, spasticity, seizures, blindness, loss of motor function).
- Pathology:
- Destructive swelling of ganglion cells
- Widespread gliosis → cranial enlargement
- Cherry‐red spots on the macula
- Course: Rapidly progressive; typical life expectancy 2‐5 years.
- Testing: DNA mutation analysis; enzyme assays for leukocyte Hex A activity.
NIEMANN‐PICK DISEASE (NPD)
- General: Sphingomyelin‐cholesterol lipidosis; rare autosomal recessive disorders; 3 main clinical forms (type A, B, C).
NPD Type A and B
- Cause: Mutations in the gene encoding sphingomyelin phosphodiesterase‐1 → deficiency of acid sphingomyelinase activity.
- Type A:
- Complete absence of acid sphingomyelinase
- Early onset, hepatosplenomegaly by 3 months
- Respiratory failure, neurologic dysfunction
- Death by 2–3 years of age
- Macular cherry‐red spots often present by 1 year
- Lipid‐laden foam cells in tissues
- Type B:
- Partial acid sphingomyelinase deficiency (~5% normal)
- Later onset than type A
- Hepatosplenomegaly, thrombocytopenia in early childhood
- Delayed skeletal maturation, short stature, interstitial lung disease, macular cherry‐red spots
- Absent or late neurologic involvement
- Diagnosis: Biochemical testing for acid sphingomyelinase; molecular genetic testing.
NPD Type C
- Cause: Mutations in NPC1 or NPC2 genes (key in intracellular cholesterol transport).
- Presentation: Any age; cerebellar ataxia, impaired vertical gaze, cognitive issues, dysphagia, hepatosplenomegaly.
- Mechanism: Lipid accumulation + neuronal degeneration.
- Diagnosis: Biochemical tests on cultured fibroblasts; molecular genetic testing.
GAUCHER DISEASE (GD)
- Cause: Deficiency of glucocerebrosidase (autosomal recessive), due to mutations in the gene encoding this enzyme.
- Accumulation: Glucocerebrosides in macrophages → “Gaucher cells” (wrinkled tissue paper appearance).
- Prevalence: Most common lysosomal storage disorder (1 in 75,000).
Clinical Types
- Type 1 (Chronic Adult Form):
- ~90% of cases
- More frequent in Ashkenazi Jews
- Age of onset: 1 year to adulthood
- Key features: Massive splenomegaly, hepatomegaly, bone disease (osteoporosis, avascular necrosis, bone pain), thrombocytopenia
- Erlenmeyer flask deformity (distal femur)
- Pingueculae on the conjunctiva
- Neurologic involvement absent
- Type 2 (Acute Neuronopathic):
- Rarest
- Fatal by age 2 years
- Onset in first year with rapid neurologic deterioration (oculomotor problems, hypertonia, rigidity, seizures)
- Type 3 (Chronic Neuronopathic):
- Later onset than type 2
- Less severe neurologic involvement than type 2
- Diagnosis: DNA mutation analysis; leukocyte glucocerebrosidase enzyme assay.
METACHROMATIC LEUKODYSTROPHY (MLD)
- Cause: Deficiency of arylsulfatase A (autosomal recessive), leading to defective desulfation of cerebroside sulfate.
- Key feature: Sulfate accumulation → demyelination in CNS + peripheral nerves.
- Forms:
- Late infantile (onset 6 months–2 years): ataxia, hypotonia, regression of motor skills, optic atrophy
- Juvenile
- Adult
- Visceral involvement: Less prominent than CNS involvement.
- Ancillary findings: EMG shows decreased nerve conduction velocity; CSF with high protein.
- Diagnosis: Enzyme assay for arylsulfatase A in leukocytes.
FABRY DISEASE
- Cause: Deficiency of α‐galactosidase A → accumulation of globotriaosylceramide (Gb3).
- Inheritance: X‐linked recessive.
- Tissue involvement: Vascular endothelium, glomeruli, distal renal tubules.
- Clinical:
- Typically starts in adolescence or early adulthood.
- Neuropathic pain in extremities
- Diffuse angiokeratomas (especially in periumbilical/groin areas)
- Corneal opacities (cornea verticillata)
- Hypohidrosis/anhidrosis
- Cardiovascular disease (CAD, strokes, peripheral disease)
- Renal failure (proteinuria, edema)
- Diagnosis: Low leukocyte α‐galactosidase A activity; molecular genetic testing.