Disease Progression

Accumulation of α-galactosidase A substrates over time triggers a cascade of events leading to secondary disease processes. Progressive damage to vital organ systems leads to significant renal, cardiac and cerebrovascular complications.

The primary pathological process in Fabry disease is the storage of GL3. This may begin as early as in the foetal stage of development.1

Accumulation of GL3 over time triggers a cascade of events leading to secondary disease processes.1 Progressive damage to vital organ systems with advancing age leads to significant renal, cardiac and cerebrovascular complications after the age of 20 years in classically affected patients.2

Renal Disease

Proteinuria can begin in the second to third decades of life. It worsens with age and is associated with renal disease progression in classically affected males and females.3,4 Gradual deterioration of renal function and development of azotemia usually occur in the third to fifth decades of life.3 Fibrosis, sclerosis, and tubular atrophy portends end-stage renal disease that generally occurs in the fourth to fifth decade of life in males.3 Without chronic haemodialysis or renal transplantation, end-stage renal failure usually results in death.4

Cardiac Disease

Ventricular hypertrophy, arrhythmia, angina and dyspnoea occur in 40-60% of classically affected patients. Diastolic dysfunction and concentric left ventricular hypertrophy (LVH) are key features of Fabry disease. Other cardiac manifestations include right ventricular hypertrophy, angina, myocardial infarction and mild mitral valve insufficiency. Progression of cardiac disease with age is characterised by myocardial fibrosis which develops with both intersticial and replacement fibrosis. In the end stages of cardiac disease, transmural replacement fibrosis gradually leads to congestive heart failure. Malignant arrhythmias are also a cause of death.3

Cerebrovascular Disease

Signs and symptoms of cerebrovascular involvement include headache, vertigo and dizziness, transient ischemic attacks, ischemic strokes and more rarely vascular dementia.3,5 Intracerebral haemorrhage, subarachnoid hemorrhage, microbleeds, cerebral venous thrombosis and cervical carotid dissection can also occur presenting as white matter lesions on MRI.5

References

  1. 1.Wanner C. (2007) Fabry disease model: a rational approach to the management of Fabry disease. Clin Ther 29 Suppl A: S2-5.
  2. 2.El-Abassi R, Singhal D, England JD. (2014) Fabry's disease. J Neurol Sci 344(1-2): 5-19.
  3. 3.Germain DP. (2010) Fabry disease. Orphanet J Rare Dis 5: 30.
  1. 4.Schiffmann R, Warnock DG, Banikazemi M, et al. (2009) Fabry disease: progression of nephropathy, and prevalence of cardiac and cerebrovascular events before enzyme replacement therapy. Nephrol Dial Transplant 24(7): 2102-2111.
  2. 5.Kolodny E, Fellgiebel A, Hilz MJ, et al. (2015) Cerebrovascular involvement in Fabry disease: current status of knowledge. Stroke 46(1): 302-313.