Fabry Disease Is Experienced Differently by Each Patient

With more than 900 known mutations of the GLA gene, there is no single genotypic anomaly that causes Fabry,1 and manifestations of the disease can differ significantly from individual to individual.2 In one study, the functional effects of 3 different mutations that cause Fabry disease were studied. Each patient can present in a unique way.3

Age at diagnosis Genotype Phenotype
Table image 42 c.155G>A, p.C52Y Prior to diagnosis, Michael experienced acroparaesthesia, hypohidrosis, and recurrent abdominal pain. Since being diagnosed, he has presented with multiple brain lesions and has experienced loss of mobility and cardiac disease.
Table image 49 c.548G>C, p.G183A Prior to diagnosis, Anne experienced mild hypertension and renal involvement. Anne has also presented with proteinuria (250 mg/h) and developed type 2 diabetes mellitus.
Table image 20 c.647A>G, p.Y216C Prior to diagnosis, George experienced diffuse angiokeratoma, acroparaesthesia, pain, and limb edema. George has also presented with cardiac involvement.

*Represent real examples from peer-reviewed literature; not actual patient names or images

Furthermore, even when family members share an identical mutation, their disease presentation may be completely different.4,5 One study examined the effects of a W226X mutation on 2 male relatives, showing that although both individuals had an identical mutation, each experienced a unique presentation.5

Age at diagnosis Genotype Phenotype
Table image 18 W226X Bill was diagnosed with Fabry disease after being evaluated due to severe growth retardation, skeletal dysplasia, and delayed puberty.
Table image 11 W226X Marc was diagnosed with Fabry disease after being referred for evaluation due to a family history of Fabry. He experienced acroparaesthesia, hypohidrosis, and discomfort. He was previously diagnosed with celiac disease.

*Represent real examples from peer-reviewed literature; not actual patient names or images

Our understanding of the genotype/phenotype relationship continues to grow. For example, evidence suggests that certain genotypes can result in classic or later-onset phenotype.6,7 In addition, select genotypes have been described as renal or cardiac subtypes (or variants) of disease.2 However, the current knowledge of genotype/phenotype relationship is based off of limited data and further studies on the natural history of the disease are required to determine if there are established genotype-phenotype correlations.

As such, gene sequencing can help to confirm a Fabry diagnosis as well as help guide the proactive management of some patients who might benefit from early lifestyle modifications and prophylactic medications.2,8,9

Benefits of α-Galactosidase A (GLA) Gene Sequencing

GLA gene sequencing to understand more about a patient’s mutation or mutations can help to identify affected family members, even before symptoms occur, and may lead to a more personalized approach to disease management.2,8,10-12 There is growing evidence that initiating certain treatments early in the disease process—before organ damage has ensued—may benefit clinical outcomes and reduce serious complications.9

Some mutations have been associated with the cardiac and renal variants of Fabry disease, in which patients often present later in life with specific organ symptoms.13,14 Knowledge of those mutations could conceivably help the healthcare provider to tailor recommendations for the individual patient around lifestyle management steps, medications, counseling, and preparation for other more serious events, such as dialysis and transplant.

Gene sequencing for select patients can also serve to advance the current body of knowledge around genotype/phenotype relationships in Fabry disease. Registries for Fabry disease collect genotype information and look at natural history and outcomes of patients with Fabry disease.

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  1. Tuttolomondo A et al. Oncotarget. 2017. 29;8(37):61415-61424.
  2. Germain DP. Fabry disease. Orphanet J Rare Dis. 2010;5:30. doi:10.1186/1750-1172-5-30.
  3. 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.
  4. 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.
  5. 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.
  6. Desnick RJ. Enzyme replacement and enhancement therapies for lysosomal diseases. J Inherit Metab Dis. 2004;27(3):385-410.
  7. El-Abassi R, Singhal D, England JD. Fabry’s disease. J Neurol Sci. 2014;344(1-2):5-19.
  8. 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.
  9. 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.
  10. 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.
  11. 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.
  12. 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.
  13. 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.
  14. 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.
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