Gene Sequencing Can Inform Fabry Diagnosis and Management

Genotype alone does not determine disease progression in Fabry disease—the etiology is complex, and there is great variability in the manifestation and progression of disease.1 People with Fabry disease may experience severe symptoms, or seemingly none at all, with a variety of clinical presentations in between.2 But even when disease presentation is asymptomatic or mild, the accumulation of disease substrates (including globotriaosylceramide [GL-3] and plasma globotriaosylsphingosine [lyso-Gb3]) can contribute to long-term damage of organs and tissues.2-4 If there is suspicion of Fabry disease, gene sequencing is generally recommended.5-7

Identification of the genetic mutation specific to an individual with Fabry may provide insight into the unique nature of his or her disease.5-7 For instance, some mutations have been associated with the cardiac and renal variants of Fabry disease.8,9

Gene sequencing is the only valid tool to diagnose Fabry disease in heterozygous females because in these women, enzyme activity can appear normal.10 With diverse expression of the mutated α-galactosidase A (GLA) gene, females display a less predictable pattern of disease manifestations than is typically seen in males.11 Consequently, this may mean increased time to diagnosis.11

For families affected by Fabry, targeted mutational analysis can be used to diagnose at-risk individuals who may not yet exhibit the phenotypic characteristics of the disease.12

For a fully informed diagnosis, genetic sequencing is advisable for both males and females.5-7 In addition, gene sequencing may lead to a more personalized approach to treatment and disease management.5-7,13 Supportive care is important, and managing Fabry requires a multidisciplinary approach.

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  1. 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.
  2. Germain DP. Fabry disease. Orphanet J Rare Dis. 2010;5:30.
  3. 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.
  4. Data on file. Amicus Therapeutics, Inc.
  5. 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.
  6. Desnick RJ, Ioannou YA, Eng CM. α-galactosidase A deficiency: Fabry disease. In: Valle D, ed. The Metabolic and Molecular Bases of Inherited Disease. New York, NY: McGraw Hill, 2001:3733-3774.
  7. Anderson LJ, Wyatt KM, Henley W, et al. Long-term effectiveness of enzyme replacement therapy in Fabry disease: results from the NCS-LSD cohort study. J Inherit Metab Dis. 2014;37(6):969-978.
  8. Mehta A, Widmer U. Natural history of Fabry disease. In: Mehta A, Beck M, Sunder-Plassmann G, eds. Fabry Disease: Perspectives from 5 Years of FOS. Oxford, England: Oxford PharmaGenesis; 2006: Chapter 19. https://www.ncbi.nlm.nih.gov/books/NBK11572/. Accessed April 24, 2017.
  9. Ishii S, Nakao S, Minamikawa-Tachino R, Desnick RJ, Fan J-Q. Alternative splicing in the α-galactosidase a gene: increased exon inclusion results in the Fabry cardiac phenotype. Am J Hum Genet. 2002; 70:994-1002.
  10. Lukas J, Giese A-K, Markoff A, et al. Functional characterisation of alpha-galactosidase A mutations as a basis for a new classification system in Fabry disease. PLoS Genet. doi:10.1371/journal.pgen.1003632.
  11. Guffon N. Clinical presentation in female patients with Fabry disease. J Med Genet. 2003;40(4):e38.
  12. Yousef Z, Elliott PM, Cecchi F, et al. Left ventricular hypertrophy in Fabry disease: a practical approach to diagnosis. Eur Heart J. 2013;34(11):802-808.
  13. Biegstraaten M, Arngrímsson R, Barbey F, et al. Recommendations for initiation and cessation of enzyme replacement therapy in patients with Fabry disease: the European Fabry Working Group consensus document. Orphanet J Rare Dis. 2015;10:36. doi:10.1186/s13023-015-0253-6.
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