Fabry disease is an X-linked, multi-systemic, genetic disorder of glycosphingolipid metabolism.
Clinical manifestations are due to absence / deficiency of lysosomal α-Galactosidase A activity,
the result of pathogenic mutations in GLA.1
Fabry disease patients are typically classified as “classic” or “non-classic”, often referred to as “late-onset”:
- Classic males primarily present in childhood or adolescence with neuropathic pain, angiokeratomas, corneal opacities, hypohidrosis, and GI disturbances. In adulthood, patients with classic disease are at risk for kidney failure, cardiomyopathy, cardiovascular disease, arrhythmias, and stroke/TIA.2
- Organ damage often begins without overt symptoms, particularly in females, and may become irreversible and potentially life-threatening3,4
- Non-classic patients present with variable age of onset and manifestations, most commonly seen in the 4th to 7th decades and may be initially limited to single-organ involvement.2
- Phenotypic heterogeneity and overlap with more common conditions can make predicting genotype:phenotype correlations challenging.2
Female Fabry patients have a wide spectrum of disease manifestations from asymptomatic to a severe phenotype similar to classic males.1
- 70–100% of females heterozygous for pathogenic Fabry disease mutations develop symptoms; they are not “carriers”.1, 5-6
As an X-linked disease, the genetic defect that causes Fabry disease can be transmitted by both males and females1, 7-8
- Sons with a pathogenic GLA mutation are affected
- Daughters with a pathogenic GLA mutation can have variable clinical severity, ranging from asymptomatic to severe disease due to X-inactivation
1. Germain DP. Orphanet J Rare Dis 2010;5:30; 2. Ortiz A, et al. Mol Genet Metab. 2018;123:416-427. 3. Moura LA, et al. ASN Kidney Week 2017; Abstract SA-PO628;
4. Niemann M, et al. JACC Cardiovasc Imaging 2011; 4:592-601; 5.Wang RY, et al. Genet Med 2007;9:34–45; 6. Dobyns WB. Acta Paediatr 2006;95(Suppl):11–15.
7. Desnick RJ, et al. α-Galactosidase A Deficiency: Fabry Disease. In: Valle D, et al; eds. New York, NY. McGraw Hill, 2001; 8. Echeverria L, et al. Clin Genet 2016;89:44