About Fabry disease
Fabry disease pathophysiology and natural history
Fabry disease is a rare, X-linked lysosomal storage disorder (LSD) caused by mutations in the GLA gene coding for the enzyme α-galactosidase A (α-Gal A).1
The figure below summarises the underlying mechanism of Fabry disease.
Fabry disease is caused by mutations or variations in the GLA gene
These mutations can lead to absence or defiency of an enzyme named
α-galactosidase A (α-Gal A)
When α-Gal A is absent or deficient, its substrates, including globotriaosylceramide (GL–3) and globotriaosylsphingosine (lyso-Gb3), accumulate in cells
This leads to cell damage within affected parts of the patient’s body, and causes the various pathologies seen in Fabry disease
Adapted from Germain 2010.2
The range of clinical presentations in Fabry disease has traditionally been described in terms of various phenotypes. However, it is important to keep in mind that the current classification system oversimplifies the true range of phenotypes that exist in Fabry disease.
Fabry disease subtypes
Fabry disease is categorised as ‘classic’ or ‘late-onset’ based on the symptoms experienced, when symptoms appear, and the level of α-Gal A activity.1
In addition, there is a further recognised category for Fabry disease in females, characterised by their unique profile and variable manifestations.
Click on each heading to learn more about the main subtypes of Fabry disease.
- α-Gal A activity usually completely absent
- GL-3 accumulates in most body tissues resulting in cellular abnormalities and organ dysfunction
- Symptoms usually have early onset (3–10 years; males affected earlier than females)
- Occurs with full spectrum of symptoms:
- Symptoms are progressive and span several major organ systems, especially the heart, kidneys and nervous system
- Significant organ damage typically develops after 20 years of age
- Residual α-Gal A activity is present (2–20% of normal)
- GL-3 accumulates at lower levels and more slowly than in the classic subtype which leads to symptoms of broad severity
- Symptoms usually present in the fourth to sixth decades of life but are still progressive and severe
- Adult-onset cardiac and renal variants are more prevalent than classic disease
- α-Gal A levels range from deficient to normal levels
- Symptoms tend to occur at a later age than in males (around 12 years)
- Females are not just carriers of a defective GLA gene
- There is a more variable disease course compared to males
- Females generally have a more drawn-out course of disease
Adapted from Wanner 2007.6
Natural history
Fabry disease is a progressive disorder. If left untreated, it can lead to life-threatening cardiovascular or cerebrovascular complications, end-stage kidney disease (ESKD) and early death.2
The life expectancy of patients with Fabry disease is significantly shorter than that of the general population. Lifespan may be shortened to approximately 50 years in untreated males and to approximately 70 years in untreated females, representing a 20- and 10-year reduction, respectively.2,7
For more detailed information on pathophysiology relating to specific organ systems, please view the pages on Nephrology, Cardiology and Neuropsychology and ophthalmology.
Leading causes of death in Fabry disease
The most common cause of death among both sexes is cardiovascular disease, often in patients who had previously received renal replacement therapy.8
Cardiovascular disease 53.6% and 50% of male and female deaths, respectively
Cerebrovascular complications 12.5% of male deaths
Renal disease 10.7% of male deaths
Adapted from Waldek et al 2009.8
NP-NN-UKI-00051024
October 2024
- National Organization for Rare Disorders (NORD). Fabry Disease. 2019. Available at . Accessed July 2022.
- Germain DP. Fabry disease. Orphanet J Rare Dis. 2010;5:30.
- El-Abassi R, Singhal D & England JD. Fabry’s disease. J Neurol Sci. 2014;344:5–19.
- Sivley MD. Fabry disease: a review of ophthalmic and systemic manifestations. Optometry and Vision Science. 2013;90:e63–e78.
- Deegan PB, Baehner AF, Barba Romero M-A, et al. Natural history of Fabry disease in females in the Fabry Outcome Survey. J Med Genet. 2006;43:347–352.
- Wanner C. Fabry disease model: a rational approach to the management of Fabry disease. Clin Ther. 2007;29.
- Mehta A, Beck M, Eyskens F, et al. Fabry disease: a review of current management strategies. Q J Med. 2010;103:641-59.
- Waldek S, Patel MR, Banikazemi M, et al. Life expectancy and cause of death in males and females with Fabry disease: findings from the Fabry Registry. Genet Med. 2009;11:790–796.
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About Fabry
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Prevalence of Fabry disease
