Overview

• Fabry disease: X-linked lysosomal storage disorder caused by mutations in the GLA gene.
• Deficiency of alpha-galactosidase A leads to accumulation of globotriaosylceramide (GL3) in tissues.
• Results in multi-organ disease with variable onset (childhood to fifth decade).

Etiology

• Gene mutation: GLA gene on the X chromosome.
• Alpha-galactosidase A deficiency → GL3 accumulation.
• Types of mutations:
  • Classic Fabry disease: Multisystem involvement, severe course.
  • Late-onset variants: Predominantly cardiac manifestations.

Epidemiology

• Prevalence:
  • Classic phenotype: 1:22,000 to 1:40,000 males.
  • Atypical presentations: 1:1000 to 1:3000 males; 1:6000 to 1:40,000 females.
• Occurs in all racial and ethnic groups.

Pathophysiology

• GL3 accumulation:
  • Affects multiple tissues: kidney, heart, brain, skin, peripheral nervous system.
  • Vascular occlusion, ischemia, and infarction in major and microvascular systems.
• Progressive renal, cardiac, and cerebrovascular damage.

Clinical Presentation

1. Classic Male Presentation:
   • Onset: 5–10 years.
   • Neuropathic pain (acroparesthesias): Burning/tingling pain in hands and feet.
   • GI symptoms: Abdominal pain, diarrhea.
   • Skin: Angiokeratomas (purple, non-blanching lesions).
   • Renal: Progressive dysfunction, ESRD by ~47 years.
   • Cardiac: LVH, arrhythmias, myocardial fibrosis (onset ~4th decade).
   • Cerebrovascular: Stroke/TIA (~28.8 years).
   • Other: Hearing loss, cornea verticillata, obstructive lung disease, mood disorders.
2. Females:
   • Variable severity due to X-inactivation skewing.
   • Common symptoms: Neuropathic pain (43–77%), LVH (18–26%), cerebrovascular disease (4–25%), proteinuria (35–39%).

Diagnosis

• Enzyme assay: Deficient alpha-galactosidase activity (not reliable in females).
• Genetic testing: Confirms diagnosis, especially in females.
• Additional tests:
  • Elevated GL3 in plasma/urine for diagnosis and monitoring.
  • Imaging: MRI, echocardiogram, renal function tests.

Management

1. Enzyme Replacement Therapy (ERT):
   • Agalsidase beta (Fabrazyme®): FDA-approved in the U.S.
   • Agalsidase alfa (Replagal®): Available in other countries.
   • Improves symptoms but does not halt disease progression entirely.
   • Early initiation in symptomatic patients, recommended by 8–10 years for classic male children.
2. Adjunctive Therapies:
   • Acroparesthesias: Gabapentin, carbamazepine.
   • Renal disease: ACE inhibitors/ARBs for microalbuminuria.
   • TIA/Stroke: Aspirin or clopidogrel.
   • Lifestyle modifications: Avoid extreme temperatures; use cooling aids for hypohidrosis.
3. Alternative Therapy:
   • Migalastat (Galafold™): Oral chaperone therapy stabilizing the mutant enzyme.
   • Suitable for patients intolerant to ERT.
   • Requires further long-term studies to confirm efficacy.
4. Renal Transplantation:
   • For ESRD, with continued ERT post-transplant.

Prognosis

• Life expectancy significantly reduced in untreated males (~45.5 years).
• Most common causes of death: Renal failure, cardiac disease, stroke.
• Females generally have milder symptoms but can have significant disease burden.
• Early diagnosis and treatment improve quality of life.

Complications

• Renal: ESRD, proteinuria.
• Cardiac: LVH, arrhythmias, myocardial fibrosis.
• Neurological: TIA, stroke, neuropathic pain.
• Other: Hearing loss, corneal verticillata, angiokeratomas.

Interprofessional Collaboration

• Core Team:
  • Neurologists (stroke management).
  • Cardiologists (cardiac complications).
  • Nephrologists (renal disease).
  • Pharmacists (ERT, pain management).
  • Nurses and therapists (patient education, symptom management).
• Annual monitoring:
  • Renal function, proteinuria, cardiac imaging.
  • Screening of family members for genetic counseling.

Pearls

• Consider Fabry disease in young patients with stroke, proteinuria, or LVH.
• Symptomatic males and females should initiate ERT early.
• Continuous monitoring for progression and symptom management is essential.
• Comprehensive care improves outcomes and quality of life.