Newborn Screening for Fabry Disease in Northeastern Italy: Results of Five Years of Experience

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.

Challenging the traditional approach for interpreting genetic variants: Lessons from Fabry disease

“…Previous prevalence 5,6 Revised prevalence 7,8 Absolute prevalence 7,8 Newborn males 5,7 0.03% 5 0.014% 7 1 in 6883 7 Adult males simultaneously determined for quality control. Alpha-Gal A deficiency is expressed in micromole/L/h.…”

“…Revised interpretation of GLA variants, previously inaptly classified "pathogenic," has decreased the estimates of FD prevalence (Table 1). [5][6][7][8] Over 1000 GLA variants have been reported, [9][10][11][12] most of them private, including some variants of unknown significance (VUS). 13 Furthermore, the non-specificity of FD symptoms presents a challenge for physicians attempting to interpret the clinical relevance of a VUS.…”

“…Revised interpretation of GLA variants, previously inaptly classified “pathogenic,” has decreased the estimates of FD prevalence (Table 1 ). 5 , 6 , 7 , 8 …”

The Benefits of Family Screening in Rare Diseases: Genetic Testing Reveals 165 New Cases of Fabry Disease among At-Risk Family Members of 83 Index Patients

“…However, the number of relatives potentially at risk of Fabry disease per proband was relatively low in our study (median: 7), and so our results are not surprising. Family genetic testing was significantly more effective (49.8%) than screening programs in newborns [ 36 ] or patients with end-stage renal disease [ 18 , 19 , 20 , 21 , 22 , 23 , 24 , 25 , 26 , 37 , 38 ], unexplained left ventricular hypertrophy [ 27 , 28 , 29 , 30 , 39 ], or stroke [ 31 ], which are costly and often have a diagnostic yield below 1% [ 32 ]. It is noteworthy that almost 20% of patients newly diagnosed with Fabry disease in this study were under the age of 18, and around 40% of patients were still asymptomatic.…”

Lysosomal Storage Disorders: Molecular Basis and Therapeutic Approaches

“…The author proposes the use of these new detected terminal degradation products of rhGAA in the serum as biomarkers for follow-up and treatment protocols [7]. Gragnaniello and collaborators presented their long-term experience on a wide newborn screening for Fabry disease and proposed lyso-Gb3 as a useful biomarker for diagnostic and follow-up protocols [8]. Kok and colleagues collected an exhaustive overview of Fabry disease pathogenesis and treatment, considering the role of neutralizing antibodies against recombinant enzymes, which are responsible for the relapse in plasma lysoGb3 levels after several years of ERT in affected patients.…”