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Fabry Disease

Summary

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  • X-linked lysosomal storage disorder caused by deficiency of α-galactosidase A enzyme
  • Progressive accumulation of glycosphingolipids in various tissues and organs
  • Characterised by neuropathic pain, angiokeratomas, renal and cardiac dysfunction

Pathophysiology

  • Mutation in GLA gene on X chromosome (Xq22)
  • Deficiency of α-galactosidase A enzyme leads to:
    • Accumulation of globotriaosylceramide (Gb3) in lysosomes
    • Progressive damage to vascular endothelium, kidneys, heart, and nervous system
  • Multisystemic involvement due to widespread glycosphingolipid deposition

Demographics

  • Incidence: 1:40,000 to 1:117,000 live births
  • X-linked inheritance pattern:
    • Males more severely affected
    • Females can be carriers or have variable disease expression
  • Onset:
    • Classic form: childhood or adolescence
    • Late-onset variants: adulthood

Diagnosis

  • Clinical presentation:
    • Acroparesthesias and neuropathic pain
    • Angiokeratomas
    • Corneal opacities (cornea verticillata)
    • Hypohidrosis or anhidrosis
    • Proteinuria and progressive renal failure
    • Left ventricular hypertrophy and arrhythmias
  • Laboratory tests:
    • Decreased α-galactosidase A enzyme activity in plasma or leukocytes
    • Elevated plasma and urinary Gb3 levels
  • Genetic testing:
    • GLA gene sequencing to confirm diagnosis and identify specific mutation

Imaging

  • Cerebral MRI:
    • White matter lesions
    • Dolichoectasia of basilar artery
    • Increased signal intensity in pulvinar on T1-weighted images ("pulvinar sign")
  • Cardiac imaging:
    • Echocardiography: Left ventricular hypertrophy, valvular abnormalities
    • Cardiac MRI: Late gadolinium enhancement in basal inferolateral wall
  • Renal imaging:
    • Ultrasound: Increased echogenicity, cysts, and reduced corticomedullary differentiation
    • MRI: T1 and T2 shortening due to lipid accumulation

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  • 30-year-old patient with history of Fabry disease presented with left sided weakness.
  • There was an acute infarct in the rigth corona radiata as well as many old small vessel deep lacunar infarcts and larger vessel infarcts in both cerebral hemispheres.
  • Vessel wall imaging showed eccentric enhancement of the vertebrobasilar system without dolichoectasia.

Treatment

  • Enzyme replacement therapy (ERT):
    • Agalsidase alfa or agalsidase beta
    • Intravenous infusion every two weeks
    • Slows disease progression and improves quality of life
  • Chaperone therapy:
    • Migalastat for amenable GLA mutations
  • Supportive care:
    • Pain management
    • ACE inhibitors or ARBs for proteinuria
    • Anticoagulation for stroke prevention
    • Cardiac medications for arrhythmias and heart failure
  • Renal replacement therapy:
    • Dialysis or kidney transplantation for end-stage renal disease
  • Genetic counseling for affected individuals and family members

Differential diagnosis

Differential diagnosis Differentiating feature
CADASIL Similar small vessel disease white matter pattern with anterior temporal lobe predominance; NOTCH3 mutation; no pulvinar T1 hyperintensity or dolichoectasia
Multiple sclerosis Periventricular ovoid lesions (Dawson's fingers); calloso-septal interface; no T1 pulvinar hyperintensity; no vertebrobasilar dolichoectasia
Hypertensive microangiopathy Deep white matter and basal ganglia hyperintensities; associated with hypertension; no pulvinar sign and no dolichoectasia
Mitochondrial disease (MELAS) Basal ganglia and thalamic signal changes; stroke-like lesions not conforming to vascular territories; lactate peak on MR spectroscopy
Cerebral amyloid angiopathy Lobar microhaemorrhages with posterior predominance; cortical superficial siderosis; typically older patients; no pulvinar sign