Overview

• Most prevalent lysosomal storage disorder.
• Elevated incidence in Ashkenazi Jews (6% carrier frequency).
• Autosomal recessive inborn error of metabolism.
• Caused by mutations in the GBA1 gene, leading to deficient glucocerebrosidase activity.
• Characterized by toxic accumulation of glucocerebroside lipids in multiple organs.

Clinical Manifestations

1. Hepatosplenomegaly:
   • Enlarged liver and spleen.
2. Hematologic:
   • Pancytopenia (anemia, thrombocytopenia, leukopenia).
   • Risk of bleeding and infections.
3. Skeletal:
   • Osteoporosis, bone crises, avascular necrosis, pathological fractures.
   • Erlenmeyer flask deformity.
4. Metabolic:
   • Abnormal body weight, insulin resistance, lipid metabolism issues.
5. Neurological (types 2 and 3):
   • Seizures, intellectual disability, myoclonus, ocular apraxia.

Etiology

• Mutation in GBA1 gene → Deficient glucocerebrosidase → Lipid accumulation.
• Lysosomal storage disorder (like Tay-Sachs and Fabry disease).
• Variability in phenotype even among individuals with the same mutation.

Types of Gaucher Disease

1. Type 1:
   • Non-neuropathic, variable severity.
   • May have a normal lifespan with treatment.
2. Type 2:
   • Acute neuropathic, severe, onset in infancy.
   • Poor prognosis; usually fatal in early childhood.
3. Type 3:
   • Chronic neuropathic, milder than type 2.
   • Variable prognosis; neurological involvement common.
4. Perinatal Lethal:
   • Most severe; complications start before birth.
   • Fatal in infancy.
5. Cardiovascular:
   • Rare; glucocerebroside deposits in cardiovascular structures.

Diagnosis

• Laboratory:
  • Low glucocerebrosidase activity in leukocytes (<15% normal activity).
  • Elevated chitotriosidase (except in 10% of individuals deficient in this enzyme).
  • Molecular testing for mutations.
• Imaging:
  • MRI, radiography for skeletal involvement.
  • Ultrasound for organomegaly.
  • DXA for bone density.
• Histopathology:
  • Wrinkled tissue-paper macrophages in bone marrow.
• Avoid invasive tests like bone marrow or liver biopsy unless necessary.

Treatment

1. Enzyme Replacement Therapy (ERT):
   • Intravenous infusion of deficient enzyme (e.g., Cerezyme, VPRIV).
   • Effective for non-CNS symptoms (hepatosplenomegaly, bone issues).
   • Ineffective for CNS due to blood-brain barrier.
2. Substrate Reduction Therapy (SRT):
   • Oral drugs (e.g., eliglustat, miglustat).
   • Reduces substrate levels.
   • Eliglustat: For Type 1; does not cross the blood-brain barrier.
   • Miglustat: May benefit CNS involvement.
3. Hematopoietic Stem Cell Transplantation:
   • Rarely used; high-risk but effective for Type 3.
4. Splenectomy:
   • Last resort for severe thrombocytopenia or abdominal pain.
5. Emerging Therapies:
   • Gene therapy and gene editing.

Complications

• Skeletal:
  • Chronic pain, fractures, impaired mobility.
• Hematologic:
  • Bleeding, fatigue, infections.
• Pulmonary:
  • Interstitial lung disease.
• Neurological:
  • Cognitive and motor impairments (types 2 and 3).

Prognosis

• Type 1: Near-normal lifespan with treatment.
• Type 2: Poor, fatal in early childhood.
• Type 3: Variable, reduced life expectancy.
• Perinatal Lethal: Fatal in infancy.
• Cardiovascular: Prognosis depends on cardiac care and severity.

Interprofessional Team Approach

• Team Members:
  • Physicians, nurses, pharmacists, genetic counselors, physical therapists.
• Roles:
  • Diagnosis, treatment, patient education, psychological support.
• Goals:
  • Comprehensive care addressing medical, psychological, and social needs.
  • Regular monitoring and coordinated care.

Patient Education

• Focus on genetic counseling for high-risk groups (e.g., Ashkenazi Jews).
• Importance of early diagnosis and adherence to treatment.
• Awareness of increased Parkinson's disease risk in Gaucher patients and carriers.

Key Takeaways

• Early recognition and treatment are critical.
• Multidisciplinary care improves patient outcomes.
• ERT and SRT are cornerstone therapies.
• Genetic counseling and family screening are essential.