Gaucher's Disease

1. DEFINITION

Definition: The most common Lysosomal Storage Disorder (LSD) characterized by the accumulation of glucosylceramide in the reticuloendothelial system due to specific enzyme deficiency.
Epidemiology: Pan-ethnic; Type 1 has a high predilection for the Ashkenazi Jewish population (carrier frequency ~1/18).

Inheritance: Autosomal Recessive.
Enzyme Defect: Deficiency of Acid $β$ -Glucosidase (Glucocerebrosidase).
Gene: GBA gene located on chromosome 1q21.
Pathophysiology:
- Defective enzyme leads to accumulation of undegraded substrate (Glucosylceramide) within the lysosomes of macrophages.
- Engorged macrophages are termed "Gaucher Cells".
- Accumulation occurs primarily in the spleen, liver, bone marrow, and (in some types) the central nervous system.
Genotype-Phenotype Correlation:
- N370S (p.Asn370Ser): Associated with Type 1 (non-neuronopathic); neuroprotective.
- L444P (p.Leu444Pro): Associated with Type 2 and 3 (neuronopathic forms).

Onset: Variable (childhood to adulthood). Accounts for 99% of cases.
CNS: No primary neurologic involvement.
Visceral: Massive Splenomegaly (can be huge) and Hepatomegaly.
Hematologic: Hypersplenism leading to anemia (fatigue) and thrombocytopenia (bruising/bleeding).
Skeletal:
- Bone pain and "Bone crises" (pseudo-osteomyelitis).
- Erlenmeyer Flask Deformity: Flaring of distal femoral metaphyses (classic radiologic sign).
- Pathologic fractures, osteopenia, avascular necrosis of femoral head.
Growth: Growth retardation/short stature in untreated children.

Onset: Infancy (<6 months).
Neurologic: Rapidly progressive neurodegeneration.
- Bulbar signs: Poor suck/swallow, aspiration.
- Laryngospasm: Stridor (characteristic feature).
- Hypertonia, opisthotonos, strabismus.
Visceral: Hepatosplenomegaly.
Prognosis: Death usually by 2–3 years of age due to respiratory compromise.

Onset: Childhood/Adolescence. Predilection for Swedish (Norrbottnian) population.
Neurologic: Intermediate severity.
- Oculomotor Apraxia: Horizontal supranuclear gaze palsy (hallmark).
- Progressive myoclonus, ataxia, dementia (Type 3a).
- Isolated gaze palsy with visceral disease (Type 3b).
Visceral: Significant hepatosplenomegaly and skeletal involvement.

Enzyme Assay (Gold Standard): Demonstration of deficient Acid $β$ -Glucosidase activity in peripheral leukocytes or cultured skin fibroblasts.
Molecular Genetics: GBA gene mutation analysis. Essential for carrier detection and genetic counseling.
Bone Marrow Aspiration/Biopsy:
- Gaucher Cells: Large (20–100 $μ$ m) macrophages with eccentric nuclei and "wrinkled tissue paper" or "crumpled silk" appearance of cytoplasm.
- Note: Rarely required for diagnosis now due to enzyme/DNA testing; may be incidental finding.
Biomarkers:
- Chitotriosidase: Markedly elevated (monitor for treatment response).
- Angiotensin Converting Enzyme (ACE), Ferritin, TRAP (Tartrate-resistant acid phosphatase).
Imaging:
- X-ray/MRI: To detect Erlenmeyer flask deformity, medullary infarction, and osteonecrosis.

Drug: Recombinant acid $β$ -glucosidase (e.g., Imiglucerase, Velaglucerase).
Indications: Standard of care for Type 1 and Type 3 (visceral symptoms).
Efficacy: Reverses hematologic and visceral pathology; improves bone density. Does not cross blood-brain barrier (ineffective for CNS symptoms).

Mechanism: Inhibits Glucosylceramide Synthase to reduce substrate production.
Drugs:
- Eliglustat: Oral first-line for adults.
- Miglustat: Used if ERT is unsuitable; crosses blood-brain barrier but has limited CNS efficacy.

Hematologic: Blood products for severe cytopenias (rarely needed with ERT).
Skeletal: Analgesics for bone pain; orthopedic management for fractures/necrosis. Bisphosphonates for osteopenia.
Splenectomy: Generally avoided now; reserved for massive splenomegaly causing mechanical compromise or severe hypersplenism refractory to ERT.