Abstract
Fabry disease (FD) is a progressive multisystemic lysosomal storage disease. Early diagnosis by newborn screening (NBS) may allow for timely treatment, thus preventing future irreversible organ damage. We present the results of 5.5 years of NBS for FD by α-galactosidase A activity and globotriaosylsphingosine (lyso-Gb3) assays in dried blood spot through a multiplexed MS/MS assay. Furthermore, we report our experience with long-term follow-up of positive subjects. We screened more than 170,000 newborns and 22 males were confirmed to have a GLA gene variant, with an incidence of 1:7879 newborns. All patients were diagnosed with a variant previously associated with the later-onset phenotype of FD or carried an unclassified variant (four patients) or the likely benign p.Ala143Thr variant. All were asymptomatic at the last visit. Although lyso-Gb3 is not considered a reliable second tier test for newborn screening, it can simplify the screening algorithm when its levels are elevated at birth. After birth, plasma lyso-Gb3 is a useful marker for non-invasive monitoring of all positive patients. Our study is the largest reported to date in Europe, and presents data from long-term NBS for FD that reveals the current incidence of FD in northeastern Italy. Our follow-up data describe the early disease course and the trend of plasma lyso-Gb3 during early childhood.
Highlights
Fabry disease (FD, OMIM 301500) is an X-linked lysosomal disorder (LSD) caused by a deficiency of α-galactosidase A (α-GAL A) activity that results in the progressive accumulation of globotriaosylceramide (Gb3) and related glycosphingolipids, in cellular lysosomes and body fluids [1,2]
Diagnosis in affected males can be achieved by the α-GAL A enzyme activity assay on several sample matrix types and/or by molecular analysis [7,8]. α-GAL A enzyme activity levels may be normal in heterozygous females due to X-chromosome inactivation in blood cells, so that gene testing is necessary [1]
Lowα-GAL A activity was confirmed in 23 newborns (22 males and one female) at the second DBS and referred to our outpatient Clinical Unit for confirmatory testing
Summary
Fabry disease (FD, OMIM 301500) is an X-linked lysosomal disorder (LSD) caused by a deficiency of α-galactosidase A (α-GAL A) activity that results in the progressive accumulation of globotriaosylceramide (Gb3) and related glycosphingolipids, in cellular lysosomes and body fluids [1,2]. Biomolecules 2021, 11, 951 the later-onset phenotype of FD invariably present with cardiovascular involvement (hypertrophic cardiomyopathy with arrhythmias and conduction abnormalities), with very rare occurrences of renal (albuminuria, proteinuria) and cerebrovascular involvement [5]. Clinical manifestations vary from asymptomatic to the classic severe phenotype, largely depending on X-chromosome inactivation [6]. Diagnosis in affected males can be achieved by the α-GAL A enzyme activity assay on several sample matrix types (dried blood spot DBS, peripheral white blood cells or plasma) and/or by molecular analysis [7,8]. Α-GAL A enzyme activity levels may be normal in heterozygous females due to X-chromosome inactivation in blood cells, so that gene testing is necessary [1]. Intervention plays an important role in preventing irreversible damage due to disease progression [16]
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