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Understanding Fabry Disease

Fabry disease is a progressive, multisystemic, X-linked lysosomal disorder
affecting both males and females.1,2

Fabry disease is caused by mutations in the galactosidase alpha gene (GLA), which encodes the alpha-galactosidase A (alpha-Gal A) enzyme.1,2 These mutations can cause the absence or deficiency of functional alpha-Gal A, which breaks down globotriaosylceramide (GL-3), plasma globotriaosylsphingosine (lyso-Gb3), and other disease substrates in healthy individuals.3,4 When alpha-Gal A is absent or deficient, GL-3, lyso-Gb3, and other disease substrates accumulate, leading to cell damage within affected parts of the individual’s body and causing the various pathologies seen in Fabry disease.3,4 This substrate build-up of GL-3, lyso-Gb3, and other disease substrates can lead to irreversible organ damage.3,4

In addition to the symptoms caused by GL-3 and lyso-Gb3 accumulation, activation of other pathways triggering inflammation may also contribute to the disease process and may be a driver of fibrosis and end organ damage.3,5-7

As a progressive, multisystemic disease, Fabry disease can1:

  • Have a devastating impact on people’s lives
  • Have a wide spectrum of symptoms
  • Present differently in each affected individual
  • Be a significant burden regardless of presentation

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 MOTHER3

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 FATHER3

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 disease to their sons, but will always transmit the disease to their daughters3
  • Females with Fabry disease have a 50% chance of transmitting the disease to their sons and daughters3
The actual incidence of Fabry disease may be much higher.

Fabry disease has historically been estimated to occur in 1 in 40,000 to 60,000 live births.1 There were an estimated 16,688 cases of Fabry disease in 2017 spanning the United States, Germany, Spain, Italy, France, the United Kingdom, and Japan.8 The number of cases in those countries is estimated to continue to rise.8 However, newborn screenings suggest that Fabry disease may be much more common than these estimates.9

On average, each Fabry disease diagnosis leads to the diagnosis of 5 additional family members.10

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References:

  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. Mehta A, Beck M, Eyskens F, et al. Fabry disease: a review of current management strategies. QJM. 2010;103(9):641-659.
  3. Germain DP. Fabry disease. Orphanet J Rare Dis. 2010;5:30.
  4. Tuttolomondo A, Simonetta I, Duro G, et al. Inter-familial and intra-familial phenotypic variability in three Sicilian families with Anderson-Fabry disease. Oncotarget. 2017;8(37):61415-61424.
  5. Akhtar MM, Elliott PM. Anderson-Fabry disease in heart failure. Biophys Rev. 2018;10(4):1107-1119.
  6. Anastasakis A, Papatheodorou E, Steriotis AK. Fabry disease and cardiovascular involvement. Curr Pharm Des. 2013;19(33):5997-6008.
  7. Rozenfeld P, Feriozzi S. Contribution of inflammatory pathways to Fabry disease pathogenesis. Mol Genet Metab. 2017;122(3):19-27.
  8. DelveInsight. Fabry Disease – Market, Epidemiology and Market Forecast 2028: Report and Perspectives. January 2019.
  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. Laney, 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.