Fabry disease

🧬 Fabry disease is a rare X-linked lysosomal storage disorder caused by deficiency of the enzyme α-galactosidase A. This leads to pathological accumulation of globotriaosylceramide (GL-3 or Gb3) in multiple organs. The result is a multi-systemic disease with dermatological, renal, neurological, ocular, and cardiovascular involvement. Without treatment, progressive organ failure shortens life expectancy.

📖 About

• Inherited in an X-linked recessive manner. Males are usually more severely affected, but heterozygous females can also show symptoms due to random X-inactivation (lyonisation).
• Incidence: ~1 in 40,000 males 👶, though newborn screening suggests higher prevalence of late-onset variants.
• One of the few lysosomal storage diseases for which enzyme replacement therapy (ERT) is available.
• Classic Fabry disease often presents in childhood; late-onset forms may present only with cardiac or renal disease in adulthood.

🧬 Aetiology & Pathophysiology

• Mutations in the GLA gene (Xq22.1) → deficiency of α-galactosidase A enzyme.
• Accumulation of GL-3 in lysosomes of vascular endothelial cells, smooth muscle, renal epithelial cells, and cardiac myocytes → progressive cellular dysfunction.
• Vascular GL-3 deposition → impaired blood flow, inflammation, and fibrosis → multi-organ complications (stroke, cardiomyopathy, renal failure).
• Blood group B individuals may be more severely affected since α-GAL A also helps break down B antigens.

🌈 Clinical Features

• Skin 🟤: Angiokeratomas (tiny, dark red-purple skin lesions), classically in a "bathing trunk" distribution (between knees and umbilicus).
• Neurological ⚡: Pain crises (acroparaesthesiae) with burning pain in hands/feet, especially in childhood; risk of early strokes (often posterior circulation).
• Renal 💧: Proteinuria, polyuria, progressive CKD; may progress to ESRD. Fanconi-like tubular dysfunction possible.
• Cardiac ❤️: LVH, arrhythmias, heart failure, valvular disease → major cause of death in late-onset forms.
• Ocular 👁️: Cornea verticillata (whorled corneal deposits), lens opacities, vascular tortuosity.
• Other: Hypohidrosis (↓ sweating), heat intolerance, lymphoedema, osteoporosis, GI symptoms (diarrhoea, abdominal pain).

Fabry disease: GL-3 accumulation causes systemic involvement

🔍 Investigations

• Enzyme Assay 🧪: Low α-galactosidase A activity in leukocytes, plasma, or dried blood spot confirms diagnosis in males.
• Genetic Testing 🧬: Identifies GLA mutation; crucial for confirming carrier status in females.
• Urine Analysis: Proteinuria + elevated GL-3.
• MRI Brain 🧠: May show white matter lesions and pulvinar sign (posterior thalamic calcification).
• Cardiac Work-up: ECG/echo for LVH, arrhythmias; cardiac MRI can show late gadolinium enhancement (fibrosis).
• Renal Biopsy: Zebra bodies on EM; reserved for atypical cases.
• Ophthalmology 👁️: Slit-lamp reveals cornea verticillata.
• Prenatal Diagnosis: Enzyme assay in amniocytes or chorionic villus sampling.

💊 Management

• Enzyme Replacement Therapy (ERT) 💉: Recombinant α-galactosidase A (agalsidase alfa or beta) slows GL-3 accumulation and organ damage.
• Chaperone Therapy 💊: Migalastat stabilises certain mutant enzymes (only in amenable mutations).
• Renal Care 💧: ACE inhibitors/ARBs for proteinuria, dialysis or renal transplantation for ESRD.
• Cardiac Care ❤️: Arrhythmia monitoring, pacemakers, heart failure therapy, cardiac MRI surveillance.
• Pain Control ⚡: Neuropathic agents (gabapentin, carbamazepine, TCAs).
• Supportive: Physical therapy, psychological support, patient education, and genetic counselling for families.

📌 Clinical Pearls

• Classic male Fabry = angiokeratomas + neuropathic pain + corneal verticillata + renal dysfunction.
• Females can be anything from asymptomatic carriers to as severe as males.
• Always consider in young patients with stroke (esp. posterior circulation, LVH, proteinuria).
• ERT works best when started before irreversible organ damage has occurred.

📚 References

• Fabry Disease and Early Stroke – Hindawi
• Orphanet: Fabry Disease
• UpToDate – Fabry Disease