Fabry disease in women: beyond the role of “carriers”

Abstract

Fabry disease (FD) is a rare X-linked lysosomal storage disease resulting from a deficiency of the lysosomal enzyme alpha-galactosidase A, caused by mutations in the GLA gene. This leads to the accumulation of glycosphingolipids, mainly globotriaosylceramide and its deacylated derivate globotriaosylsphingosine. Such non-metabolized substrates accumulate in cells and tissues throughout the body, resulting in significant morbidity, predominately in the kidneys, heart, and nervous system, and impaired quality of life. While FD was initially considered to predominantly affect men, women with this condition may manifest a wide array of clinical symptoms and, in some cases, a significant multi-systemic pathology similar to men. This has been mainly attributed to skewed X-chromosome inactivation, which causes different enzyme activity levels within tissues and organs. The diagnosis of FD in women is often delayed due to the initial non-specificity of presenting symptoms and the heterogeneity of clinical manifestations. The enzyme activities in the leukocytes of a significant number of women with this condition fall within the normal range. Therefore, genetic analysis for mutations in GLA has become the gold standard for the diagnosis of FD in women. Unlike men, the current criteria proposed to start specific treatment for women with this condition can underestimate the appropriate time to do so and impede women from obtaining the benefits of early initiation. In addition, there is some evidence that women with FD are still at risk of being undertreated, unlike male patients.

Highlights

Fabry disease is an X-linked lysosomal storage disease

Similar to men, women may manifest a wide array of clinical symptoms

In some cases, organ damage is as severe as that observed in men

Skewed lyonization of the X-chromosome may cause this clinical heterogeneity

Genetic analysis for GLA mutations is necessary for diagnosis in women

Current guidelines indicate that women may be at risk of undertreatment

Follow-up and treatment criteria for women may require revision

Keywords

Fabry disease / women / GLA gene / X-chromosome inactivation / diagnosis / clinical manifestations / follow-up / treatment

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