Symptoms in the late-onset phenotype usually are not identified until age 30 or later and may be limited to a single organ, usually the heart or kidneys (late-onset cardiac variant or late-onset renal variant).¹ The first sign of Fabry disease may be heart disease or kidney failure.⁴

Some genetic variants in GLA, referred to as VUS, may be detected during screening but have an unclear relationship with clinical disease.³ Some individuals with these variants will have signs and symptoms consistent with Fabry disease, while others may be asymptomatic.^5-8 Alpha-Gal A enzyme activity levels may be lower than in individuals without a GLA variant.⁹ In patients with VUS, clinical, biochemical, or histopathological evidence may be required to confirm Fabry disease.^3,8 In addition, a family history of Fabry disease can predict pathogenicity for a GLA VUS.^3,8 Consultation with a genetics professional is advised in cases of VUS.³  

Females with Fabry were once referred to as “carriers,” but this is now known to be inappropriate.¹ Fabry disease presentations and severity are especially variable in females, who may present with symptoms from mild to severe, with end organ damage similar to those in males with the classic phenotype.¹ Females with Fabry disease are subject to cardiac, renal, and cerebrovascular complications of the disorder, and untreated females have a life expectancy 10 years fewer than those without Fabry disease.¹

Lyonization, in which one copy of the X chromosome in each cell is randomly inactivated in females, contributes to this variability.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.^3,10