About Fabry Disease

Fabry disease is a progressive disorder of glycosphingolipid metabolism caused by a deficiency or absence of lysosomal α-galactosidase A activity due to mutations in the GLA gene, located on the x-chromosome.

Lack of sufficient α-galactosidase A activity leads to progressive accumulation of the glycosphingolipids globotriaosylceramide (denoted Gl3 or Gb3) and globotriaosylsphingosine (lyso-Gl3 or lyso-Gb3) within lysosomes in a variety of cells types, including vascular endothelium, podocytes, arterial smooth muscle cells, and cardiomyocytes.1,2 Fabry patients are typically classified as Classic or Late-onset (Non-classic) where classic males primarily present in childhood/adolescence with neuropathic pain, angiokeratomas, corneal opacities, hypohidrosis and GI disturbances that progresses to chronic kidney disease, cardiomyopathy, cardiovascular disease, arrhythmias, and stroke/TIA.

Late-onset patients present with variable age of onset and manifestations, and may not have multiple organ involvement. Female Fabry patients have a wide spectrum of disease manifestations from asymptomatic to a severe phenotype similar to classic.7

Males typically exhibit symptoms earlier than females but all patients typically experience a diagnostic delay due to the non-specific disease symptoms that overlap with other diseases7.

Disease presentation is heterogeneous, but the following symptoms may prompt further examination: pain, gastrointestinal symptoms (postprandial abdominal pain, diarrhea, nausea, vomiting), hypohidrosis or anhidrosis, angiokeratomas on the skin, corneal changes, chronic fatigue, and difficulty gaining weight.1

Diagnosis of Fabry disease involves assay of α-galactosidase A activity in males, followed by GLA sequencing. For females, GLA sequencing is the appropriate first test as enzyme activity can be normal. In addition, current evidence suggests globotriaosylsphingosine (denoted Lyso-Gl3 or Lyso-Gb3) can be useful in the diagnostic process. Lyso-Gl3 is significantly increased in classic male and classic female Fabry patients; elevated but less so in non-classic males and may be mildly elevated or normal in non-classic female Fabry patients.6


The reported incidence of Fabry disease has been estimated at 1 in 117,0001; United States incidence estimates based on newborn screening vary from 1 in 1500 males (Missouri) to 1 in 7800 males (Washington state).2


Fabry Disease follows an X-linked inheritance pattern, but 70% of heterozygous females manifest symptoms of varying degrees.7

Program Eligibility

The Roadmap2Rare Diagnostic Program consists of α-galactosidase A enzyme assay with reflex to GLA sequencing if deficient in males, GLA sequencing in females, and quantitation of lyso-Gl3 for both males and females. This program is for individual patients suspected of having Fabry disease via:

  1. Symptoms consistent with Fabry disease
  2. Presumptive positive newborn screen for Fabry disease
  3. Family history of Fabry disease or individuals with symptoms consistent with Fabry disease

About the Test

Testing Algorithm:

  • Males: α-galactosidase A enzyme activity assay, if deficient, will reflex to GLA sequencing and lyso-Gl3.
  • Females:  GLA gene sequencing; samples demonstrating one pathogenic or likely-pathogenic variant, or one variant of uncertain significance will reflex to lyso-Gl3.
  • *LysoGl3 testing via the Roadmap2Rare Diagnostic Program is for diagnostic purposes only – for ongoing monitoring at PerkinElmer please click here. For more information about sponsored LysoGl3 monitoring offered by Sanofi, please click here.
Order Testing
  1. Germain DP. Fabry disease. Orphanet J Rare Dis. 2010;5(30):1-49.
  2. Schiffmann R, Hughes DA, Linthorst GE, et al. Screening, diagnosis, and management of patients with Fabry disease: conclusions from “Kidney Disease: Improving Global Outcomes” (KDIGO) Controversies Conference. Kidney Int. 2017;91:284-293.
  3. 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.
  4. Ortiz A et al. Fabrydisease revisited: Management and treatment recommendations for adult patients. Mol Genet Metab. 2018 Apr;123(4):416-427. doi: 10.1016/j.ymgme.2018.02.014. Epub 2018 Feb 28. Review. PMID: 29530533
  5. Matern, D. Gavrilov, D. Oglesbee, K. Raymond, P. Rinaldo, S. Tortorelli, Newborn screening for lysosomal storage disorders, Semin. Perinatol. 39 (2015) 206–216.
  6. Smid BE, et al. Plasma globotriaosylsphingosine in relation to phenotypes of Fabry disease J Med Genet 2015;52:262–268
  7. Wilcox W et al Females with Fabry disease frequently have major organ involvement: Lessons from the Fabry Registry Molecular Genetics and Metabolism 93 (2008) 112–128.

*Specimen Requirements, Methodology, Turn-Around-Times (TATs), Ordering Instructions (Placing Your Order, Collecting a Specimen, Results), Other Conditions in the Roadmap2Rare Diagnostic Program