High-risk screening for Anderson-Fabry disease in patients with cardiac, renal, or neurological manifestations

Anderson-Fabry disease (AFD) is an X-linked lysosomal storage disorder caused by abnormalities in the alpha-galactosidase (Gal) A gene (GLA; MIM:300644). The reduced activity of the lysosomal enzyme, alpha-galactosidase A (alpha-Gal A) leads to classic early manifestations and vascular disease of the heart, kidneys, and brain. As a high-risk screening for symptomatic AFD using an enzymatic assay on dried blood spot samples, we enrolled 2325 individuals (803 females and 1522 males; median age: 66 years) with cardiac, renal, or neurological manifestations that met at least one of the following criteria: (a) family history of early-onset cardiovascular diseases; (b) typical classic manifestations, such as acroparesthesias, clustered angiokeratoma, cornea verticillata, and hypo-anhidrosis; (c) proteinuria; (d) receiving dialysis; (e) left ventricular hypertrophy on electrocardiography or echocardiography; or (f) history of stroke. Ninety-two patients displayed low alpha-Gal A activity. Four males and two females had different pathogenic GLA mutations (0.26%) including a novel mutation c.908-928de121. Four males (0.17%) harbored the GLA c.196G>C (p.E66Q) variant. This simple screening protocol using dried blood spot samples is useful for early diagnosis of AFD in high-risk and underdiagnosed patients suffering from various cardiac, renal, or neurological manifestations.