• Fabry disease (FD) is a rare inherited lysosomal storage disorder that can cause severe damage to multiple organs, particularly the kidneys and heart
    • first described by Anderson and Fabry in 1898 as angiokeratoma corporis diffusum (also known as Anderson-Fabry disease)
  • FD is caused by mutations in the α-galactosidase A (α-Gal-A) gene located on the X chromosome   
    • > 400 known mutations of the GLA gene cause a complete or partial defect in the lysosomal enzyme alpha-galactosidase (α-Gal-A), which is responsible for the cleavage of glycosphingolipids
    • its substrate, mainly globotriaosylceramide (Gb3), cannot be degraded by other pathways and accumulates in lysosomes;  thereby affecting cellular functions and causing organ complications
    • women have a 50% chance of passing the gene to their children
    • men with Fabry disease pass the defective gene to all their daughters; sons are healthy
  • cells mainly affected
    • vascular endothelium and vascular smooth muscle cells
    • kidney cells
    • myocardial cells
    • nerve cells
  • phenotype is variable, depending on the gene defect and residual enzyme activity; the severe form may be seen in both males and heterozygous females
    • male patients
      • disability is more pronounced and manifests earlier  (males are hemizygous, and the disease has a high penetrance in them ⇒  classic phenotype)
      •  late-onset forms have also been reported, depending on the degree of individual enzymatic compromise
    • female patients
      • variable expression (asymptomatic to severe) due to the random inactivation of one of the X chromosomes (the female body is thus a mosaic of cells in which either the healthy or the diseased X chromosome is active)
      • unlike other X-linked diseases such as hemophilia, the population of cells expressing the healthy chromosome is unable to correct the metabolic defect in cells where the chromosome carrying the gene mutation is active
  • the disease can become severe and fatal with advanced brain, renal, or cardiac involvement
  • early diagnosis and enzyme replacement therapy (ERT) reduce morbidity and mortality (without treatment, patients die after age 40)

Stroke is most commonly caused by:

  • dolichoectasia
  • cardioembolism
  • arteriolopathy

Clinical presentation

Neurologic symptoms

  • acroparesthesia – pain, tingling, and burning in the hands and feet – one of the first symptoms
    • mostly neuropathic pain provoked by heat, exertion, and stress and due to the involvement of nociceptive nerve fibers
  • autonomic dysfunction
    • GIT disorders associated with impaired bowel motility (frequent diarrhea, feeling of early satiety)
    • decreased heart rate variability
    • hypo-/anhidrosis (damage to sweat cells and autonomic nervous system)
  • recurrent headache
  • vestibulocochlear system impairment
    • vertigo and hearing loss
  • vascular disease (usually beginning in the 3rd decade)
    • stroke (prevalence of Fabry disease in young men with cryptogenic stroke is reported < 1%)
      • lacunar infarcts
      • infarcts with a predilection for the posterior circulation due to dolichoectasia
      • infarcts due to cardioembolism
    • ischemic leukoencephalopathy due to a progressive arteriolopathy (initially asymptomatic, later development of cognitive deficits)

Renal symptoms

  • from the 2nd decade, a progressive course occurs due to glomerular and tubular cell damage
  • microalbuminuria and then proteinuria appear first
  • especially in males, the disease progresses with a gradual decline in glomerular filtration to renal failure with the need for dialysis therapy or renal transplantation, usually in the 4th decade
    • the fate of the transplanted kidney in Fabry disease is good
  • the diagnosis is often made by a renal biopsy performed for proteinuria
    • with conventional fixation of the biopsy material, lipid inclusions in the cells may not be visible
    • the classic electron microscopic image shows zebrafish-like bodies of accumulated Gb3

Cardiologic disorders

  • cardiac involvement is very complex – pathological changes are evident not only in endothelial cells of arterioles and capillaries but also in smooth muscle cells
  • reduced coronary reserve, endothelial dysfunction, cardiomyopathy, and myocardial fibrosis ⇒ cardiac failure
  • arrhythmias
    • conduction disturbances in the form of fascicular block or AV block of varying degrees
    • these patients require pacemaker implantation
    • atrial flutter and fibrillation ⇒ cardioembolism

Skin and eye symptoms

  • angiokeratoma   (Resende de Jesus, 2018)    Angiokeratoma  Angiokeratoma 
    • papular red spots about 1 mm in size protruding above the surface
    • preferentially located in the lower abdomen, genitalia, buttocks, flanks, and extensor surfaces of the upper limbs, less on mucous membranes and other parts of the body
    • onset in childhood, progressive over some time
  • angiectasia – small, slightly raised, purple-red dilated blood vessels. The number and size of the lesions increase with age
  • lymphedema
  • cornea verticillata – the corneal hyperdensities  Cornea verticillata  Cornea verticillata
    • can be observed with a slit lamp as whitish streaks

Diagnostic evaluation

Clinical presentation

  • “cryptogenic” stroke in young age + nephropathy + neuropathy with acroparesthesia + cardiopathy + skin (angiokeratoma) and eye lesions (cornea verticillata)

Imaging methods

  • brain MRI
    • leukoencephalopathy with T2 hyperintensities (nonspecific for Fabry disease)
    • pulvinar sign – increased signal on T1 (calcifications) [Takanashi, 2003]
    • lacunar infarcts
    • microbleeds on GRE
    • basilar dolichoectasia (frequent but nonspecific sign)   Basilar artery dolichoectasia (CTA)
    • some MRI changes may resolve with early specific treatment
  • TTE
  • renal imaging
    • nonspecific findings with increased echogenicity and thinned renal cortex
    • multiple renal cysts (typically small, uniform in size, located beneath the capsule)

Laboratory test

Content available only for logged-in subscribers (registration will be available soon)


Specific therapy

Enzyme replacement therapy
  • enzyme replacement therapy (ERT) is fully indicated in patients with stroke  (AHA/ASA 2011 I/B)
    • stroke risk remains high despite ERT
    • it is unclear whether ERT reduces the risk of recurrent stroke
  • two recombinant agents are available – agalsidase α and β
    • agalsidase β (FABRAZYME)
    • agalsidase α (REPLAGAL)
    • intravenous infusion over 120-180 min at a dose of 1mg/kg every 14 days
  • treatment is effective if initiated before the development of irreversible organ damage
    • a number of studies have shown a reduction in pain intensity, improvement in quality of life, stabilization of renal function, and slowing of the progression of myocardial hypertrophy
    • late initiation of treatment may prevent the progression of left ventricular hypertrophy but does not prevent renal failure
Content available only for logged-in subscribers (registration will be available soon)

Symptomatic therapy

  • stroke prevention – antiplatelets/anticoagulants
  • treatment of pain and acroparesthesia (phenytoin, carbamazepine, gabapentin, pregabalin)
  • nephroprotective treatment
    • ACE-I, AT receptor blockers (sartans)
    • spironolactone
  • treatment of GIT disorders
    • prokinetics
    • pancreatic lipase
    • H2 blockers
  • cardiological treatment
    • antiarrhythmic drugs, cardioverter implantation
    • treatment of CAD
    • treatment of atrial fibrillation
      heart transplantation
  • measures to minimize triggers of painful attacks (prompt treatment of fever and infections, adequate physical activity, use of air conditioning, maintaining adequate hydration, etc.)

You cannot copy content of this page

Send this to a friend
you may find this topic useful:

Fabry disease