Diagnostic and Confirmatory Testing

Diagnosis of Fabry disease should be made on the basis of clinical presentation and family history, enzymatic testing, and DNA analysis. In some cases, it might be needed to also include organ histology, biomarkers and check for  storage material. Hopkin RJ, et al. Characterization of Fabry disease in 352 pediatric patients in the Fabry Registry. Pediatr Res. 2008;64:550-5.
Eng CM, et al. Fabry disease: Baseline medical characteristics of a cohort of 1765 men and women in the Fabry Registry. J Inherit Metab Dis. 2007;30:184-92.
Smid BE, et al. Plasma globotriaosylsphingosine in relation to phenotypes of Fabry disease. J Med Genet. 2015 Apr;52(4):262-8.

Fabry disease in male patients can be confirmed by: Laney DA, et al. Fabry disease practice guidelines: recommendations of the national society of genetic counselors. J Genet Counsel 2013;22(5):555-64.

  • α-GAL enzyme activity assay: may be performed in plasma, leukocytes, cultured skin fibroblasts or dried blood spot. Residual enzyme activity is typically <5% in males with  Fabry disease. Arends M, et al. Retrospective study of long-term outcomes of enzyme replacement therapy in Fabry disease: Analysis of prognostic factors. PLoS One. 2017 Aug 1;12(8).
  • DNA analysis: presence of a Fabry GLA mutation. Please refer to ‘Genetics and Epidemiology’ for more information regarding the wide variety of mutations.

The diagnosis of Fabry disease in female patients can be more challenging. Although females with a mutation on the GLA gene may be asymptomatic or present with mild clinical manifestations, definitive identification of heterozygotes is important. Females may develop disease manifestations ranging from mild to severe. Wilcox WR, Oliveira JP, Hopkin RJ, et al. Women with Fabry disease frequently have major organ involvement: lessons from the Fabry Registry. Mol Genet Metab 2008;93:112-28.  Because females with Fabry disease can have α-GAL activity in the low-normal range, confirmation of Fabry disease in females is via identification of a disease-causing mutation in the GLA gene. Laney DA, et al. Fabry disease practice guidelines: recommendations of the national society of genetic counselors. J Genet Counsel 2013;22(5):555-64. and biomarker measures such as  Lyso-GL3. Smid BE, et al. Plasma globotriaosylsphingosine in relation to phenotypes of Fabry disease. J Med Genet. 2015 Apr;52(4):262-8.
Laney DA, et al. Fabry disease practice guidelines: recommendations of the national society of genetic counselors. J Genet Counsel 2013;22(5):555-64.

Patients with a known familial history of Fabry disease should be tested by a confirmatory method regardless of symptomology.

Prenatal diagnosis

Prenatal diagnosis is possible via amniocentesis or chronic villus sampling. Laney DA, et al. Fabry disease practice guidelines: recommendations of the national society of genetic counselors. J Genet Counsel 2013;22(5):555-64. Preimplantation genetic diagnosis for families with a known familial mutation may also be available via assisted reproduction centers.