Makindo Medical Notes

Glucocerebroside can collect in the spleen, liver, kidneys, lungs, brain, and bone marrow, leading to progressive multi-system disease. 🧬

📖 About

• Most frequent of the lysosomal storage diseases.
• Caused by low levels of glucocerebrosidase in leucocytes.
• Most common in individuals of Ashkenazi Jewish descent.
• Symptoms can appear at any age (childhood → adulthood).

🧪 Aetiology

• Inherited autosomal recessive disorder (mutations in the GBA gene).
• Deficiency of the lysosomal enzyme glucocerebrosidase → accumulation of glucocerebroside in macrophages.
• Gaucher cells = lipid-laden macrophages with a "wrinkled tissue paper" cytoplasm, found in liver, spleen, and bone marrow.

🧾 Types

• Type 1 (Non-neuronopathic): Most common form. No CNS involvement. Features: hepatosplenomegaly, anaemia, thrombocytopenia, lung disease, and bone abnormalities (pain, fractures, arthritis).
• Type 2 (Acute neuronopathic): Severe CNS involvement with seizures, brainstem dysfunction, rapid neurodegeneration → often fatal in infancy.
• Type 3 (Chronic neuronopathic): Similar CNS features but slower progression than type 2. Onset in childhood/adolescence.
• Perinatal lethal: Presents with hydrops fetalis, severe hepatosplenomegaly, and ichthyosis. Neonates usually survive only days.
• Cardiovascular type: Calcification of heart valves (esp. aortic and mitral), bone disease, and mild splenomegaly.

🩺 Clinical Features

• Hepatosplenomegaly: Due to Gaucher cell accumulation.
• Thrombocytopenia & Petechiae: Hypersplenism → low platelets.
• Anaemia & Fatigue: Bone marrow infiltration + nutritional deficiencies (B12, folate, iron).
• Bone disease: Bone pain, "bone crises," infarction, avascular necrosis (AVN), osteopenia/osteoporosis.
• Neurological features: Brainstem dysfunction, seizures (mainly in Types 2 and 3).

🧠 Differentials

• Other lysosomal storage disorders (e.g., Niemann-Pick disease, Tay-Sachs).
• Hepatosplenomegaly causes (leukaemia, lymphoma, myelofibrosis, chronic infections).
• Bone pain differentials: sickle cell disease, osteomyelitis, malignancy.

🔬 Investigations

• Bloods: FBC (anaemia, thrombocytopenia), B12/folate/iron levels.
• Abnormal lipid profile (low HDL, altered LDL).
• Enzyme assay: Low glucocerebrosidase activity in leukocytes or fibroblasts.
• Raised biomarkers: chitotriosidase, tartrate-resistant acid phosphatase.
• Bone marrow: Gaucher cells visible.
• Genetic testing: Confirms GBA mutations.

💊 Management

• Enzyme replacement therapy (ERT): IV glucocerebrosidase (improves systemic but not CNS disease).
• Substrate reduction therapy: Miglustat (inhibits glucosylceramide synthase) for mild/moderate Type 1 disease.
• Supportive care: Osteoporosis treatment (bisphosphonates, calcium, vitamin D).
• Splenectomy: Used historically; now less common with ERT.
• Bone marrow transplantation: Potentially curative but high-risk, rarely used today.

📚 References

• GeneReviews: Gaucher Disease
• NHS – Gaucher’s Disease