Lysosomal Storage Disorders

1. INTRODUCTION AND DEFINITION

• Definition: A heterogeneous group of >50 inherited metabolic disorders characterized by the accumulation of macromolecules (lipids, glycoproteins, mucopolysaccharides) within lysosomes due to specific enzyme, transporter, or activator protein defects.
• Pathophysiology:
  • "Garbage Disposal" Failure: Lysosomes fail to degrade substrates.
  • Storage: Substrates accumulate, causing lysosomal hypertrophy and cellular dysfunction.
  • Consequences: Disrupted autophagy, mitochondrial dysfunction, inflammation, and apoptosis leading to multi-organ damage.
• Epidemiology: Combined incidence ~1 in 5,000 live births.
• Inheritance:
  • Most are Autosomal Recessive.
  • X-Linked Recessive: Hunter Syndrome (MPS II), Fabry Disease, Danon Disease.

2. CLASSIFICATION (BASED ON ACCUMULATED SUBSTRATE)

3. CLINICAL APPROACH AND PRESENTATION

Presentation varies by age of onset and severity.

A. Phenotypic Patterns

1. Dysmorphic / Somatic Pattern (MPS-like):
   • Coarse facies, macroglossia, stiff joints, hepatosplenomegaly.
   • Examples: MPS, Mucolipidoses, Mannosidosis, Sialidosis.
2. Neurologic / Neurodegenerative Pattern:
   • Progressive regression, seizures, ataxia, spasticity.
   • Examples: Tay-Sachs, Krabbe, Metachromatic Leukodystrophy (MLD), Sanfilippo (MPS III).
3. Visceral / Organomegaly Pattern:
   • Hepatosplenomegaly without marked dysmorphism.
   • Examples: Gaucher (Type 1), Niemann-Pick B, Wolman disease.

B. "Clinical Clues" (Buzzwords)

• Cherry-Red Spot: Tay-Sachs, Sandhoff, Niemann-Pick A, Sialidosis, Farber.
• Corneal Clouding: MPS I (Hurler), MPS VI (Maroteaux-Lamy), GM1 Gangliosidosis. (Clear in Hunter & Sanfilippo).
• Angiokeratomas: Fabry Disease, Fucosidosis, Sialidosis.
• Dysostosis Multiplex: MPS, Mucolipidoses.
• Gibbus Deformity: MPS I (Hurler), MPS IV (Morquio).
• Acroparesthesia (Pain): Fabry Disease.
• Hydrops Fetalis: MPS VII (Sly), Gaucher (severe), Sialidosis, Niemann-Pick C.

4. DIAGNOSTIC EVALUATION

Step 1: Screening Tests

• Urine:
  • GAGs (Dermatan/Heparan Sulfate): Positive in MPS.
  • Oligosaccharides: Positive in Mannosidosis, Fucosidosis, Pompe.
• Blood Smear:
  • Vacuolated Lymphocytes: Pompe, Niemann-Pick A, Batten disease, Mannosidosis.
• Radiology (Skeletal Survey):
  • Look for Dysostosis Multiplex (Ovoid vertebrae, spatulate ribs, proximal pointing metacarpals).

Step 2: Confirmatory Testing (Gold Standard)

• Enzyme Assay:
  • Measured in leukocytes, plasma, or dried blood spots (DBS).
  • Demonstration of deficient activity (<5-10%) of the specific lysosomal enzyme.
  • Example: Beta-glucosidase deficiency = Gaucher; Hexosaminidase A = Tay-Sachs.
• Biomarkers (Monitoring):
  • Chitotriosidase: Markedly elevated in Gaucher and Niemann-Pick.
  • Lyso-Gb1 / Lyso-SM-509: Sensitive for Gaucher/Niemann-Pick.

Step 3: Molecular Genetics

• Next-Generation Sequencing (NGS):
  • Single gene (if diagnosis clear).
  • LSD Gene Panels: Preferred for overlapping phenotypes.
  • Whole Exome Sequencing (WES) for difficult cases.

5. SPECIFIC IMPORTANT DISORDERS (SUMMARY)

A. Gaucher Disease (Most Common LSD)

• Defect: Acid Beta-Glucosidase (GBA).
• Features: Hepatosplenomegaly, Pancytopenia, Bone pain (Erlenmeyer flask deformity).
• Types: Type 1 (Non-neuronopathic), Type 2 (Acute infantile), Type 3 (Chronic neuronopathic).
• Tx: ERT + SRT.

B. Niemann-Pick Disease

• Type A/B (ASMD): Acid Sphingomyelinase deficiency. HSM, Cherry-red spot (A), Lung disease (B).
• Type C: Cholesterol trafficking defect. Ataxia, Vertical Supranuclear Gaze Palsy (VSGP).

C. Pompe Disease (GSD II)

• Defect: Acid Alpha-Glucosidase (GAA).
• Features: Floppy infant, Macroglossia, Massive Cardiomegaly (Infantile); Limb-girdle weakness (Late-onset).
• Tx: ERT.

D. Tay-Sachs Disease (GM2 Gangliosidosis)

• Defect: Hexosaminidase A (HEXA).
• Features: Hyperacusis (startle), Cherry-red spot, Macrocephaly, Neurodegeneration. NO organomegaly.

E. Fabry Disease

• Defect: Alpha-Galactosidase A (GLA). X-Linked.
• Features: Acroparesthesia (burning pain), Angiokeratomas, Hypohidrosis, Renal failure, Stroke.
• Tx: ERT + Chaperone.

F. Metachromatic Leukodystrophy (MLD)

• Defect: Arylsulfatase A.
• Features: Gait disturbance, spasticity, regression, gallbladder accumulation. MRI: "Tigroid" pattern of demyelination.

6. MANAGEMENT

Moving from supportive care to disease-modifying therapies.

A. Enzyme Replacement Therapy (ERT)

Recombinant enzymes given IV (weekly/biweekly). Effective for visceral symptoms; generally does not cross Blood-Brain Barrier (BBB).

• Gaucher: Imiglucerase, Velaglucerase.
• Fabry: Agalsidase alfa/beta.
• Pompe: Alglucosidase alfa.
• MPS I: Laronidase.
• MPS II: Idursulfase.
• MPS IV: Elosulfase alfa.
• MPS VI: Galsulfase.
• Acid Sphingomyelinase Deficiency (Niemann-Pick B): Olipudase alfa.
• Batten Disease (CLN2): Cerliponase alfa (Intraventricular).

B. Substrate Reduction Therapy (SRT)

Oral small molecules that inhibit substrate synthesis.

• Gaucher: Eliglustat, Miglustat.
• Niemann-Pick C: Miglustat (stabilizes neurological progression).

C. Chaperone Therapy

Small molecules that stabilize misfolded enzymes (amenable mutations only).

• Fabry: Migalastat.

D. Hematopoietic Stem Cell Transplantation (HSCT)

• Donor cells provide enzyme source.
• Standard of Care: MPS I (Hurler) if <2 years (preserves cognition).
• Effective: X-linked Adrenoleukodystrophy (early cerebral).
• Variable/Ineffective: Sanfilippo, Hunter, severe Gaucher.

E. Supportive Care

• Physical therapy for contractures.
• VP shunt for hydrocephalus.
• Management of seizures and feeding.

7. PROGNOSIS

• Untreated: Most infantile forms are fatal in the first decade due to neurodegeneration or cardiorespiratory failure.
• Treated: Life expectancy significantly improved with ERT/HSCT (e.g., Gaucher Type 1 patients live near-normal lives).
• Key determinant: Presence and severity of Central Nervous System involvement (hardest to treat).