Fabry Disease Testing

What is Fabry Disease?

Fabry disease is a rare and progressive lysosomal storage disorder with X-linked inheritance.1,2  Fabry is caused by mutations in the GLA gene which encodes the enzyme α-galactosidase A on the X chromosome.1,2  The deficiency of lysosomal α-galactosidase A activity leads to disordered glycosphingolipid metabolism. The result is an accumulation within the lysomes of GL3/GB3 (globotriaosylceramide) and Lyso-GL3/Lyso-GB3 (globotriaosylsphingosine) in a wide range of cell types, including nerve fibre cells, endothelium, vascular muscle cells, cardiomyocytes and podocytes.1,2

Fabry disease can be described as one of two phenotypes, classic phenotype and late-onset phenotype.3 Males affected with the classic phenotype of Fabry disease usually present with symptoms in childhood or adolescence.2,3 These symptoms may include corneal and lenticular opacities, angiokeratomas, hypohidrosis or anhidrosis, renal dysfunction progressing to end-stage kidney disease, neuropathic pain, gastrointestinal disorders, cardiac conduction disturbances, and cardiac and cerebrovascular disease (cardiomyopathy, TIA/stroke).2-4  

Patients with late-onset Fabry disease present later in life and are underdiagnosed.3 Age of onset may be variable and symptoms may differ, with fewer organs affected and slower disease progression compared to the classic phenotype of Fabry disease.3,4 Disease presentation is heterogeneous, and patients with late-onset Fabry disease often lack the early clinical features of the classic phenotype.5

Female patients with Fabry disease experience symptoms ranging from very mild to severe with a variety of presentations. Generally, male patients with this rare disease develop vital organ involvement earlier in the disease course than females.2,4 Diagnostic delays are common but are particularly common in female patients and may lead to complications that would otherwise be avoidable with early diagnosis.3

In males, Fabry disease diagnosis entails assay of α-galactosidase A enzyme activity with reflex GLA sequencing. In females, enzyme activity levels can be normal, therefore the primary test should be GLA sequencing2,4 More recently,  globotriaosylsphingosine (Lyso-GL3/Lyso-GB3) has been identified as a potential biomarker which may be useful in diagnostic interpretation.2  Lyso-GL3/GB3 is elevated in male and female patients with classic Fabry disease but to a lesser extent in females.2

What is the Incidence of Fabry Disease?

The incidence of classic Fabry disease has been estimated at 1:50,000 to 1:117,000 males; in the United States, the incidence was estimated at 1:2,913 to 1:3,277 individuals (Missouri) and at 1:6,000 to 1:9,000 males (Washington State).3

Fabry Disease Mode of Inheritance

Fabry disease is inherited in an X-linked manner. Heterozygous females may be as severely affected as males or asymptomatic throughout a normal life span.3

The Roadmap2Rare Diagnostic Program Eligibility

This rare disease testing program is designed for HCPs with eligible patients when there is clinical suspicion of Fabry disease, including family history. The program includes single disorder testing for Fabry (in males: α-galactosidase A enzyme activity with reflex to GLA sequencing and Lyso-GL3 analysis; in females: GLA sequencing with reflex to Lyso-GL3 analysis), familial variant sequencing, and a 60-gene Hypertrophic Cardiomyopathy Panel.

*Note: this diagnostic program is not appropriate for carrier testing.

What is the Fabry Disease Test?

For single disorder testing, the algorithm is as follows:

  1. GLA sequencing in females; if samples demonstrate one pathogenic or potentially pathogenic variant, subsequent Lyso-GL3* testing is performed
  2. α-galactosidase A enzyme activity assay in males; if enzyme levels are found to be deficient, subsequent GLA sequencing and Lyso-GL3* analysis is performed

*Testing of Lyso-GL3 through the Roadmap2Rare Diagnostic Program is only for the purposes of supporting diagnostic interpretation. If you require information regarding ongoing biomarker monitoring for diagnosed patients, please see the Rare Disease Specialty Testing Program


  1. Snit M, et al. Intractable Rare Dis Res. 2022;11(1):34–36.
  2. Germain DP. Orphanet J Rare Dis. 2010;5(30):1–49.
  3. Mehta A, Hughes DA. Fabry Disease. 2002 Aug 5 [Updated 2023 Mar 9]. In: Adam MP, et al. editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2023. Available from: https://www.ncbi.nlm.nih.gov/books/NBK1292/
  4. Ortiz A, et al. Mol Genet Metab. 2018;123(4):416–427.
  5. Schiffmann R, et al. Kidney Int. 2017;91:284–293.

The Roadmap2Rare Diagnostic Program is not intended to and should not interfere in any way with a clinician’s or patient’s independent judgment and freedom of choice in the testing and treatment options for these diseases. Clinicians and patients should always consider the full range of testing and treatment options and select those most appropriate for the individual patient. The identifying information of patients and clinicians is not shared with Sanofi Canada.