Genetic Mutations Play a Specific Role in Fabry Disease1

Fabry is an X-linked disease caused by mutations in the alpha-galactosidase A (GLA) gene, which encodes the alpha-galactosidase-A (α-Gal A) enzyme.2,3 These mutations can cause the absence or deficiency of functional α-Gal A, which breaks down globotriaosylceramide (GL-3), plasma globotriaosylsphingosine (lyso-Gb3), and other disease substrates in healthy individuals.4,5 When α-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.4,5 This substrate build-up of GL-3, lyso-Gb3, and other disease substrates can lead to irreversible organ damage.5,6

Fabry is uniquely experienced among patients, with high variability in disease manifestation and progression.7 Due to this high degree of phenotypic heterogeneity, Fabry presentation can differ even from one person to another within families that have the same genetic mutation.7

When treating a disorder with the varied range of pathology and severity seen in Fabry, and the potential to be highly disruptive for patients, it is important to tailor management strategies specifically to each patient’s needs.5

Managing Fabry requires a multidisciplinary approach to treatment over time, that is best started early in the disease process to help deter permanent tissue or organ damage.7 Personalized symptom management and preemptive measures may also include lifestyle modifications and prophylactic medications.5,7

Mutation Types in the GLA Gene

Establishing a clear relationship between genotype and phenotype when diagnosing Fabry disease is challenging. With more than 900 known mutations of the GLA gene, there is no single genotypic cause of Fabry.4,8

It is important, however, to recognize that there are a variety of mutations that can give rise to Fabry disease, such as missense mutations, splicing mutations, small deletions and insertions, and large deletions.5

Approximately 60% of the GLA mutations known to cause Fabry disease are missense mutations.9 Missense mutations are those in which the mutation of a single nucleotide causes the introduction of an incorrect amino acid into a protein. In Fabry, these point mutations cause structural changes that significantly affect the function and stability of the α-Gal A enzyme.4,5 Alternatively, some mutations can cause the complete absence of α-Gal A, or result in the production of a nonfunctional enzyme.4,5 Mutations that result in improper protein folding or reduce the stability of α-Gal A often lead to enzyme degradation in the endoplasmic reticulum prior to normal transport to the lysosome.5 When α-Gal A is absent or deficient, GL-3, lyso-Gb3, and other disease substrates can accumulate, leading to cell damage within organs that causes the various pathologies seen in Fabry disease.4,5 This build-up of GL-3, lyso-Gb3, and other disease substrates can lead to irreversible organ damage.4-6

GLA Gene Mutations in Heterozygous Females

Unlike many X-linked disorders, female heterozygotes are not only “carriers” of mutations that cause Fabry, but often experience typical disease manifestations.10,11 The biological basis for this is not fully understood. However, it is thought that the natural process of random X-chromosome inactivation (lyonization) results in the expression of the wild-type GLA gene in some cells and the mutated GLA gene in others, leading to the expression of the disease phenotype.11,12

Consequently, females display a less predictable pattern of disease manifestations than is typically seen in males, but females can still develop severe disease manifestations, such as cardiac, renal, and stroke complications that are also seen in males.13

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Learn more about the genotype-phenotype relationship in Fabry

Review studies

  1. Branton MH, Schiffmann R, Sabnis SG, et al. Natural history of Fabry renal disease: influence of alpha-galactosidase A activity and genetic mutations on clinical course. Medicine (Baltimore). 2002;81(2):122-138.
  2. 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.
  3. GLA galactosidase alpha [Homo sapiens (human)]. NCBI website. Accessed December 9, 2015.
  4. Tuttolomondo A et al. Oncotarget. 2017. 29;8(37):61415-61424.
  5. Germain DP. Fabry disease. Orphanet J Rare Dis. 2010;5:30. doi:10.1186/1750-1172-5-30.
  6. Namdar M, Gebhard C, Studiger R, et al. Globotriaosylsphingosine accumulation and not alpha-galactosidase-A deficiency causes endothelial dysfunction in Fabry disease. PLoS One. 2012;7(4):e36373. doi:10.1371/journal.pone.0036373.
  7. Eng CM, Germain DP, Banikazemi M, et al. Fabry disease: guidelines for the evaluation and management of multi-organ system involvement. Genet Med. 2006;8(9):539-548.
  8. Bichet DG, Germain DP, Giugliani R, et al. Migalastat reduces left ventricular mass index in Fabry patients naïve to ERT and previously treated with ERT. Poster presented at: American Society of Human Genetics Annual Meeting; October 2015; Baltimore, MD.
  9. 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.
  10. Mehta A, Ricci R, Widmer U, et al. Fabry disease defined: baseline clinical manifestations of 366 patients in the Fabry Outcome Survey. Eur J Clin Invest. 2004;34:236-242.
  11. Mehta A, Beck M, Eyskens F, et al. Fabry disease: a review of current management strategies. Q J Med. 2010;103(9):641-659.
  12. Lyon MF. X-chromosome inactivation and human genetic disease. Acta Paediatr Suppl. 2002;91:107-112.
  13. Guffon N. Clinical presentation in female patients with Fabry disease. J Med Genet. 2003;40(4):e38.
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