Clinical Characteristics of the GLA N215S Variant and Implications for the Diagnosis and Management of Nonclassic Fabry Disease.

Abstract

Our understanding of Fabry disease continues to evolve since its first description as a dermatologic disorder over a century ago, and the more we learn, the more it becomes clear that this complex disorder defies simple categorizations. A progressive inborn error of lysosomal glycosphingolipid metabolism caused by disruption of the X-linked GLA gene, Fabry disease exhibits a wide spectrum of severity and clinical findings. The phenotype that is most likely to be recognized clinically is the well-described classic form that manifests in boys or young men with neuropathic pain and paresthesia, angiokeratomas, hypohydrosis or anhydrosis, corneal verticillata, hypertrophic cardiomyopathy, renal failure, and cerebrovascular strokes.1 However, the diagnosis remains challenging in people with nonclassic presentations, such as female heterozygotes, who may have a milder course or later onset but are still at risk for life-threatening complications of the disease, and cases of variant Fabry, where clinical involvement is largely confined to a single organ. For example, cardiac variant Fabry can mimic sarcomeric hypertrophic cardiomyopathy.1 These diagnostic challenges are of particular concern to providers who are likely to encounter nonclassic presentations, such as those working in cardiology clinics. Fabry disease-specific treatments, such as enzyme replacement therapy or chaperone treatment, can only be initiated after an accurate diagnosis is established, and the efficacy of treatment may be limited in those with advanced disease.2 See Article by Oder et al In this issue, Oder et al3 describe a cohort of patients who were referred for evaluation of apparently isolated hypertrophic cardiomyopathy but who on further workup and genetic testing were diagnosed with nonclassic Fabry disease. This article describes 26 patients (13 men and 13 women) with the N215S (c.644A>G, p.Asn215Ser) variant in the GLA gene. The N215S variant is a common cause of Fabry, occurring in 4.8% of people in …