Abstract
PurposePlasma globotriaosylsphingosine (lyso-Gb3) is a promising secondary screening biomarker for Fabry disease. Here, we examined its applicability as a primary screening biomarker for classic and late-onset Fabry disease in males and females. MethodsBetween 1 July 2014 and 31 December 2015, we screened 2,360 patients (1,324 males) referred from 169 Japanese specialty clinics (cardiology, nephrology, neurology, and pediatrics), based on clinical symptoms suggestive of Fabry disease. We used the plasma lyso-Gb3 concentration, α-galactosidase A (α-Gal A) activity, and analysis of the α-Gal A gene (GLA) for primary and secondary screens, respectively. ResultsOf 8 males with elevated lyso-Gb3 levels (≥2.0 ng ml–1) and low α-Gal A activity (≤4.0 nmol h–1 ml–1), 7 presented a GLA mutation (2 classic and 5 late-onset). Of 15 females with elevated lyso-Gb3, 7 displayed low α-Gal A activity (5 with GLA mutations; 4 classic and 1 late-onset) and 8 exhibited normal α-Gal A activity (1 with a classic GLA mutation and 3 with genetic variants of uncertain significance). ConclusionPlasma lyso-Gb3 is a potential primary screening biomarker for classic and late-onset Fabry disease probands.
Highlights
Fabry disease (FD) is an X-linked lysosomal storage disorder that results from a deficiency in the activity of α-galactosidase A (α-Gal A).[1]
We found that the plasma lyso-Gb3 screening was effective for selecting candidates for genetic counseling and testing, revealing unrecognized FD cases, and reducing the number of unnecessary gene analyses.[14]
Lyso-Gb3 and α-Gal A screening This study had four steps: (i) patients were screened for FD by measuring the concentration of plasma lyso-Gb3 (≥2.0 ng ml–1: positive) and plasma α-Gal A activity; (ii) patients with elevated lyso-Gb3 or low α-Gal A activity were informed that they may have FD; (iii) with the consent of the patient, the FD diagnosis was confirmed by genetic testing using GLA; and (iv) a familial diagnosis was confirmed by screening other family members based on the lyso-Gb3 concentration, α-Gal A activity, and GLA analysis when indicated
Summary
Fabry disease (FD) is an X-linked lysosomal storage disorder that results from a deficiency in the activity of α-galactosidase A (α-Gal A).[1] The α-Gal A deficiency causes systemic lysosomal accumulation of glycolipids, predominantly globotriaosylceramide (Gb3), in the vascular endothelium and other tissues. Morbidity and mortality from FD—caused by renal failure, cardiac disease, and early-onset stroke—increase with age. Cardiac deaths account for most FD-related deaths in females and males.[2] FD can be classified as classic or late-onset.[3] Late-onset FD lacks classic early manifestations, such as acroparesthesia, clustered angiokeratoma, cornea verticillata, and hypo-anhidrosis, and exhibits exclusively renal, cardiac, and cerebral impairments. Recognizing late-onset FD is difficult, and undiagnosed patients with lateonset FD may outnumber those with classic FD.[4]
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