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Home Understanding Fabry Disease The Genotype-Phenotype Relationship

The Genotype-Phenotype Relationship

Fabry disease is experienced differently by each patient

With more than 1000 known mutations of the GLA gene, there is no single genotypic anomaly that causes Fabry disease,1 and manifestations of the disease can differ significantly from individual to individual.2,3 In one study, the functional effects of 3 different mutations that cause Fabry disease were studied. Each mutation can present in a unique way.4

Michael*

Age of Diagnosis

42

Genotype

c.155G>A,
p.C52Y

Phenotype

Prior to diagnosis, Michael experienced acroparesthesia, hypohidrosis, and recurrent abdominal pain. Since being diagnosed, he has presented with multiple brain lesions and has experienced loss of mobility and cardiac disease.

Anne*

Age of Diagnosis

49

Genotype

c.548G>C,
p.G183A

Phenotype

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.

George*

Age of Diagnosis

20

Genotype

c.647A>G,
p.Y216C

Phenotype

Prior to diagnosis, George experienced diffuse angiokeratoma, acroparesthesia, pain, and limb edema. George has also presented with cardiac involvement.

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

Even when family members share an identical mutation, their disease presentation may be completely different.2,5,6 One study examined the effects of a W226X mutation in 2 male relatives, showing that although both individuals had an identical mutation, each experienced a unique presentation.5

Bill*

Age of Diagnosis

18

Genotype

W226X

Phenotype

Bill was diagnosed with Fabry disease after being evaluated due to severe growth retardation, skeletal dysplasia, and delayed puberty.†

Marc*

Age of Diagnosis

11

Genotype

W226X

Phenotype

Marc was diagnosed with Fabry disease after being referred for evaluation due to a family history of Fabry disease. He experienced acroparesthesia, hypohidrosis, and discomfort. He was previously diagnosed with celiac disease.

*Represent real examples from peer-reviewed literature; not actual patient names or images.
†Clinical presentation is not typical of Fabry disease.

Our understanding of the genotype/phenotype relationship continues to grow. For example, evidence suggests that certain genotypes can result in classic or non-classic (later-onset) phenotype.7,8 In addition, select genotypes have been described as renal or cardiac subtypes (or variants) of disease.9 However, the current knowledge of genotype/phenotype relationship is based on limited data and further studies on the natural history of the disease are required.

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References:

  1. 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.
  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. Mehta A, Beck M, Eyskens F, et al. Fabry disease: a review of current management strategies. QJM. 2010;103(9):641-659.
  4. 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.
  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. Militaru S, Adam R, Dorobantu L, et al. Rare presentation and wide intrafamilial variability of Fabry disease: A case report and review of the literature. Anatol J Cardiol. 2019;22(3):154-158.
  7. El-Abassi R, Singhal D, England JD. Fabry’s disease. J Neurol Sci. 2014;344(1-2):5-19.
  8. Desnick RJ. Enzyme replacement and enhancement therapies for lysosomal disease. J Inherit Metab Dis. 2004;27(3):385-410.
  9. Germain DP. Fabry disease. Orphanet J Rare Dis. 2010;5:30.