Females with the GLA mutation, once thought to be asymptomatic carriers, may in fact develop disease manifestations ranging from mild to severe.
Deegan PB, et al. Natural history of Fabry disease in females in the Fabry Outcome Survey. J Med Genet 2006;43:347–52.
MacDermot KD, Holmes A, Miners AH. Anderson-Fabry disease: clinical manifestations and impact of disease in a cohort of 60 obligate carrier females. J Med Genet 2001;38:769–75.
3. Wang RY, et al. Heterozygous Fabry women are not just carriers, but have a significant burden of disease and impaired quality of life. Genet Med 2007;9:34–45.
Eng CM, et al. Fabry disease: baseline medical characteristics of a cohort of 1765 males and females in the Fabry Registry. J Inherit Metab Dis 2007;30:184–92.
Analysis of the baseline medical characteristics of a cohort of 1765 males and females in the Fabry Registry showed that the median age of symptom onset was 13 years in females, compared with age of onset of 9 years in males. Eng CM, et al. Fabry disease: baseline medical characteristics of a cohort of 1765 males and females in the Fabry Registry. J Inherit Metab Dis 2007;30:184–92.
In females, neurological pain was the most common presenting symptom reported in 41% of patients, with a median age of onset of 10 years. Other symptoms had an age of onset of 12–32 years, compared with age of onset of 8–20 years in males.
X-inactivation in females
The variable expression of symptoms in females is thought to be influenced by X-inactivation, a phenomenon in which one of two haploid sets of X-linked genes in each cell is inactivated and has no phenotypic expression. Analysis has shown that X-inactivation is an important factor in determining the severity and clinical involvement in heterozygous females, and that there is a statistically significant difference between symptom severity scores of patients with balanced and skewed X-inactivation patterns. Dobrovolny R, et al. Relationship between X-inactivation and clinical involvement in Fabry heterozygotes. Eleven novel mutations in the α-galactosidase A gene in the Czech and Slovak population. J Mol Med. 2005;83(8):647-654. The pattern of inactivation may differ from one organ to another, so that a female patient may experience severe symptoms in some organs, while remaining symptom-free in others.