Fabry Disease
Fabry Disease is an X-linked recessive lysosomal storage disorder caused by deficiency of the enzyme alpha-galactosidase A. Due to X-linked recessive inheritance, affected males are more common and more easily recognized than females.
PrintFabry Disease is an X-linked recessive lysosomal storage disorder caused by deficiency of the enzyme alpha-galactosidase A. Due to X-linked recessive inheritance, affected males are more common and more easily recognized than females.
Estimates of Fabry Disease incidence in males (approximately 1/40,000) and in the general population are likely low due to late and variable disease presentation. Early initiation of enzyme replacement therapy is recommended for all males and for females with significant disease.
Enzyme activity measurement in plasma, leukocytes, or cultured fibroblasts can establish the diagnosis for Fabry Disease in males but not all females, as some carriers’ results may be in the normal range. The Ambry Test: Fabry Disease can detect mutations in approximately 99% of affected males and carrier females, including asymptomatic at-risk women who may benefit from early diagnosis.
Fabry disease is an X-linked recessive lysosomal storage disorder caused by deficiency of the enzyme alpha-galactosidase A (α-Gal A). Accumulation of lipids (particularly GL-3) in the vascular endothelium and visceral tissues leads to symptoms in multiple organs. Classic disease results from enzyme activity of less than 1% of normal and results in childhood or adolescent onset of the following: chronic, intermittent pain in the extremities with episodes of intense pain and fever; angiokeratomas; opacities of the cornea and lens; intolerance to heat, cold, and exercise; insufficient sweating; and gastrointestinal disturbance with pain, diarrhea, and vomiting. Disease progression through adulthood can bring kidney dysfunction with proteinuria and hypertension preceding end-stage renal disease, cardiac dysfunction including left ventricular hypertrophy, stroke or other cerebrovascular complications, and airway obstruction. Patients with residual α-Gal A enzyme activity may present with cardiac or renal variant disease in which cardinal signs are absent and only one organ system is significantly affected.1
Due to X-linked recessive inheritance, affected males are more common and more easily recognized than females. The phenotype in carrier females is typically milder with later onset of cardiac or renal symptoms and normal lifespan, though it ranges from asymptomatic to classic. Estimates of disease incidence in males (approximately 1/40,000) and in the general population are likely low due to late and variable disease presentation.2 Fabry disease occurs in all racial groups.1
Management includes pain control, coronary bypass or pacemaker, and dialysis or renal transplant. Early initiation of enzyme replacement therapy is recommended for all males and for females with significant disease.
Enzyme activity measurement in plasma, leukocytes, or cultured fibroblasts can establish the diagnosis in males but not all females, as some carriers’ results may be in the normal range. Gene sequencing can detect mutations in approximately 99% of affected males and carrier females, including asymptomatic at-risk women who may benefit from early diagnosis. Indications are:
- confirmation of diagnosis in symptomatic males
- mutation identification to facilitate prenatal diagnosis and family carrier testing
- determination of carrier status in symptomatic or at-risk female
The Ambry Test: Fabry Disease is performed by PCR-based double-stranded automated sequencing in the sense and antisense directions for exons 1-7 of the GLA gene, at least 20 bases into the 5’ and 3’ ends of all the introns, and for a known mutation in the intronic region IVS4+919. Specific mutation analysis for known family mutations in GLA is also available.
The Ambry Test: Fabry Disease detects about 98% of known GLA mutations; large deletions and gross rearrangements are not reliably detected (analytical sensitivity). Such deletions and rearrangements occur at a low frequency in the patient population, so about 99% of affected patients and carriers have mutations detectable by the Ambry Test (clinical sensitivity).
Blood: Collect 3-5 cc from adult or 2 cc minimum from child into EDTA purple-top tube (first choice) or ACD yellow-top tube (second choice). Store at room temperature or refrigerate. Ship at room temperature.
Blood Spot: Call for availability.
Saliva: Collect 2 ml into Oragene™ DNA Self Collection container. Store and ship at room temperature.
DNA: Minimum DNA Amount of 5μg of DNA at a concentration of ~100ng/μl in 50μl TE (10mM Tris-Cl pH 8.0, 1mM EDTA); preferred 20μg. Store frozen and ship on ice or dry ice.
Prenatal: Prenatal testing is available. Please call an Ambry Genetic Counselor to discuss your case.
| Technique | Days |
|---|---|
| GLA Gene Sequence Analysis | 20-42 |
1. Reviewed in Desnick RJ et al. Fabry disease, an under-recognized multisystemic disorder: expert recommendations for diagnosis, management, and enzyme replacement therapy. Ann Intern Med. 2003;138:338-346. [PMID: 12585833]
2. Spada M et al. High incidence of later-onset fabry disease revealed by newborn screening. Am J Hum Genet. 2006;79:31-40. [PMID: 16773563]