What Is Fabry Disease?

Fabry disease is an X-linked lysosomal storage disorder that can affect both males and females.1,2 Fabry is caused by mutations in the alpha-galactosidase A (GLA) gene, resulting in a deficiency or dysfunction of the α-galactosidase A (α-Gal A) enzyme.2

As a progressive, multisystemic disease, Fabry can have a devastating impact on people’s lives1,3 and has a wide spectrum of symptoms.1 Fabry disease may present differently in each affected individual, and it can prove to be a significant burden regardless of presentation.1

People with Fabry are generally categorized into 2 subtypes1: those with classic disease in whom symptoms tend to manifest during childhood or adolescence, and those with later-onset disease. The latter typically have healthy childhoods and may present with renal and/or cardiac disease as adults, anytime from their 20s to their 60s. Unfortunately, both subtypes can lead to organ failure and serious complications in adulthood and typically shorten lifespan.4 Heterozygous females can experience a variable presentation of Fabry disease, ranging from asymptomatic or mild symptoms to symptoms that are as severe as those experienced by male patients.1

The X-linked inheritance pattern of Fabry disease1

The orange X indicates an affected X chromosome

An individual with a gene mutation that causes Fabry disease
An individual without a gene mutation that causes Fabry disease

Inheritance through an affected mother5

There is a 50% chance that an affected mother with a heterozygous genotype will pass the defective gene to any of her children.

Inheritance through an affected father5

The daughter will inherit the defective gene from her father.
The son will not inherit the defective gene from his father.

Males with Fabry disease cannot transmit Fabry to their sons but will always transmit the disease to their daughters.6 Females with Fabry disease have a 50% chance of transmitting the disease to their sons and daughters.5

The image shows the x linked chromosome inheritance pattern for Fabry disease either through an affected mother or affected father. Males with Fabry disease cannot transmit Fabry to their sons, but will always transmit the disease to their daughters.5 Females with Fabry disease have a 50% chance of transmitting the disease to their sons and daughters.5

Epidemiological studies indicate an incidence of approximately 1 per 40,000 among males only and about 1 per 117,000 in the general population.6,7 The actual incidence of Fabry is thought to be much higher as suggested in newborn screening programs.8,9

Because signs and symptoms of Fabry disease are nonspecific and may be shared with other conditions, patients may be frequently misdiagnosed, and a diagnosis of Fabry disease may be delayed—especially in those who have no known family history of Fabry.5,10 Studies suggest that the average diagnostic delay in both men and women is approximately 15 years.5

Earlier genetic testing where there is a family history of Fabry disease, and screening newborns in general, could help to reduce this delay and potentially identify patients with Fabry disease before symptoms begin, so that disease management can be optimized and personalized over time.5

Genotype alone can’t always predict disease progression in Fabry, as the etiology is complex and there is high variability in disease manifestation and progression.5

Gene sequencing can be an important diagnostic tool and in many cases is recommended to confirm diagnosis of Fabry. In female patients, genetic testing is always a must, as near-normal levels of α-Gal enzyme are possible11 due to X-chromosome inactivation, which can mask the presence of Fabry disease.3

In some cases, gene sequencing can also provide valuable insight into the unique nature of a patient’s disease.7,11 For instance, Conversely, evidence suggests that certain genotypes are associated with the classic and later-onset disease phenotypes,12,13 and select genotypes have also been described as renal or cardiac subtypes (or variants) of Fabry disease.5 For these reasons, gene sequencing may be helpful in Fabry diagnosis and disease management.

There are more than 1000 known mutations of the GLA gene. No single genotypic anomaly causes Fabry,14 and phenotypic manifestations of the disease can differ significantly from individual to individual.5 Even when family members share an identical mutation, their disease presentation may be very different.1,15

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See how Fabry disease affects multiple organs

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Disease background brochure for healthcare professionals

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  1. Desnick RJ, Brady R, Barranger J, et al. Fabry disease, an under-recognized multisystemic disorder: expert recommendations for diagnosis, management, and enzyme replacement therapy. Ann Intern Med. 2003;138(4):338-346.
  2. Filoni C, Caciotti A, Carraresi L, et al. Functional studies of new GLA gene mutations leading to conformational Fabry disease. Biochim Biophys Acta. 2010;1802(2):247-252. doi:10.1016/j.bbadis.2009.11.003.
  3. Hoffmann B, Mayatepek E. Fabry disease-often seen, rarely diagnosed. Dtsch Arztebl Int. 2009;106(26):440-447.
  4. Fabry Disease. National Organization for Rare Disorders website. https://rarediseases.org/rare-diseases/fabry-disease. Accessed April 10, 2017.
  5. Germain DP. Fabry disease. Orphanet J Rare Dis. 2010;5:30. doi:10.1186/1750-1172-5-30.
  6. Meikle PJ, Hopwood JJ, Clague AE, Carey WF. Prevalence of lysosomal storage disorders. JAMA. 1999;281(3):249-254.
  7. Desnick RJ, Ioannou YA, Eng CM. Alpha-galactosidase A deficiency. In: Scriver CR, Beaudet AL, Sly WS, Valle D, eds. The Metabolic Basis of Inherited Disease. New York, NY: McGraw-Hill; 2001:3733-3774.
  8. Hwu WL, Chien YH, Lee NC, et al. Newborn screening for Fabry disease in Taiwan reveals a high incidence of the later onset GLA mutation c.936+919G>A (IVS4+919G>A). Hum Mutat. 2009;30(10):1397-1405.
  9. Spada M, Pagliardini S, Yasuda M, et al. High incidence of later-onset Fabry disease revealed by newborn screening. Am J Hum Genet. 2006;79(1):31-40.
  10. Lidove O, West ML, Pintos-Morell G, et al. Effects of enzyme replacement therapy in Fabry disease—a comprehensive review of the medical literature. Genet Med. 2010;12(11):668-679.
  11. Laney DA, Bennett RL, Clarke V, et al. Fabry disease practice guidelines: recommendations of the National Society of Genetic Counselors. J Genet Couns. 2013;22(5):555-564.
  12. Desnick RJ. Enzyme replacement and enhancement therapies for lysosomal diseases. J Inherit Metab Dis. 2004;27:385-410.
  13. El-Abassi R, Singhal D, England JD. Fabry’s disease. J Neurol Sci. 2014;344(1-2):5-19.
  14. Tuttolomondo A et al. Oncotarget. 2017. 29;8(37):61415-61424.
  15. Knol IE, Ausems MG, Lindhout D, et al. Different phenotypic expression in relatives with Fabry disease caused by a W226X mutation. Am J Med Genet. 1999;82(5):436-439.
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