For US healthcare professionals only
Home Resources

INHERITANCE

Fabry disease demonstrates X-linked inheritance1

Because the gene implicated in Fabry disease, GLA, is found on the X chromosome, Fabry disease can be passed down by either parent.2 However, unlike some X-linked diseases, females with Fabry disease are not “carriers.” Instead, they have highly variable symptoms that can range from mild to severe.1
X-linked inheritance of Fabry disease2
An image X-linked disease inherited from the father
Because males have only one X chromosome, the variant gene will be passed to all daughters, but no sons.2
An image X-linked disease inherited from the mother
Because females have two X chromosomes, both daughters and sons have a 50% chance of receiving the variant gene.2

Variability in presentation is extensive1,3,4

The symptoms of Fabry disease vary in both type and severity according to the causative GLA variant and other factors.3,5,6 Among the factors that may have the potential to alter the impact of a given genetic variant are the presence of other GLA variants, the genetic background of the patient, concomitant diseases, environmental modifiers, polymorphisms of other genes, and modifiers of lysosomal pH.3,7 Clinical presentation may vary even in members of the same family with the same GLA variant.3,7

Clinical presentation of Fabry disease may vary even among members of the same family.3,7,8

This variability is one of the factors, along with the nonspecificity and breadth of symptoms and rarity of the disease, that frequently makes reaching a diagnosis of Fabry disease challenging and often delayed.1,9-13
Lyonization as a contributor to variability in females
Lyonization, in which one copy of the X chromosome in each cell is randomly inactivated in females, further contributes to the variability in severity and presentation seen in females.1 Females may exhibit more or less severe symptoms if inactivation is skewed such that the wild-type or variant gene is inactivated more often.3,14
Learn to recognize signs and symptoms of Fabry disease

GLA, galactosidase alpha gene.

References: 1. Germain DP. Fabry disease. Orphanet J Rare Dis. 2010;5:30. 2. ThinkGenetic Foundation. Fabry disease. Accessed April 27, 2025. https://thinkgenetic.org/diseases/fabry-disease 3. Ortiz A, Germain DP, Desnick RJ, et al. Fabry disease revisited: management and treatment recommendations for adult patients. Mol Genet Metab. 2018;123(4):416-427. 4. El-Abassi R, Singhal D, England JD. Fabry’s disease. J Neurol Sci. 2014;344(1-2):5-19. 5. Filoni C, Caciotti A, Carraresi L, et al. Functional studies of new GLA gene mutations leading to conformational Fabry disease. Biochim Biophys Acta. 2010;1802(2):247-252. 6. Gal A. Molecular genetics of Fabry disease and genotype-phenotype correlation. In: Elstein D, Altarescu G, Beck M, eds. Fabry Disease. Springer Science and Business Media; 2010:3-19. 7. Tuttolomondo A, Simonetta I, Duro G, et al. Inter-familial and intra-familial phenotypic variability in three Sicilian families with Anderson-Fabry disease. Oncotarget. 2017;8(37):61415-61424. 8. Knol IE, Ausems MGEM, Lindhout D, et al. Different phenotypic expression in relatives with Fabry disease caused by a W226X mutation. Am J Med Genet. 1999;82(5):436-439. 9. Hoffmann B, Mayatepek E. Fabry disease—often seen, rarely diagnosed. Dtsch Arztebl Int. 2009;106(26):440-447. 10. Marchesoni CL, Roa N, Pardal AM, et al. Misdiagnosis in Fabry disease. J Pediatr. 2010;156(5):828-831. 11. Pieroni M, Namdar M, Olivotto I, Desnick RJ. Anderson-Fabry disease management: role of the cardiologist. Eur Heart J. 2024;45(16):1395-1409. 12. Reisin R, Perrin A, García-Pavía P. Time delays in the diagnosis and treatment of Fabry disease. Int J Clin Pract. 2017;71(1):e12914. 13. Wilcox WR, Oliveira JP, Hopkin RJ, et al. Females with Fabry disease frequently have major organ involvement: lessons from the Fabry Registry. Mol Genet Metab. 2008;93(2):112-128. 14. Echevarria L, Benistan K, Toussaint A, et al. X-chromosome inactivation in female patients with Fabry disease. Clin Genet. 2016;89(1):44-54.