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:
    1. Sphingolipidoses (focus of this summary)
    2. Mucopolysaccharidoses (e.g., Hurler syndrome)
    3. Glycoproteinoses (e.g., sialidosis, mannosidosis)
    4. Mucolipidoses (disorders of lysosomal enzyme transport)
    5. 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

  1. 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
  2. Type 2 (Acute Neuronopathic):
    • Rarest
    • Fatal by age 2 years
    • Onset in first year with rapid neurologic deterioration (oculomotor problems, hypertonia, rigidity, seizures)
  3. 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.

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