Metachromatic leukodystrophy genotypes in The Netherlands reveal novel pathogenic ARSA variants in non-Caucasian patients

Shanice Beerepoot,Marjo S Van Der Knaap,Silvy J.M Van Dooren,Edwin H Jacobs,Gajja S Salomons,Nicole I Wolf,Jaap Jan Boelens,André B.P Van Kuilenburg

doi:10.1007/s10048-020-00621-6

Abstract

Metachromatic leukodystrophy (MLD) is an autosomal recessively inherited sulfatide storage disease caused by deficient activity of the lysosomal enzyme arylsulfatase A (ASA). Genetic analysis of the ARSA gene is important in MLD diagnosis and screening of family members. In addition, more information on genotype prevalence will help interpreting MLD population differences between countries. In this study, we identified 31 different ARSA variants in the patient cohort (n = 67) of the Dutch expertise center for MLD. The most frequently found variant, c.1283C > T, p.(Pro428Leu), was present in 43 (64%) patients and resulted in a high prevalence of the juvenile MLD type (58%) in The Netherlands. Furthermore, we observed in five out of six patients with a non-Caucasian ethnic background previously unreported pathogenic ARSA variants. In total, we report ten novel variants including four missense, two nonsense, and two frameshift variants and one in-frame indel, which were all predicted to be disease causing in silico. In addition, one silent variant was found, c.1200C > T, that most likely resulted in erroneous exonic splicing, including partial skipping of exon 7. The c.1200C > T variant was inherited in cis with the pseudodeficiency allele c.1055A > G, p.(Asn352Ser) + ∗96A > G. With this study we provide a genetic base of the unique MLD phenotype distribution in The Netherlands. In addition, our study demonstrated the importance of genetic analysis in MLD diagnosis and the increased likelihood of unreported, pathogenic ARSA variants in patients with non-Caucasian ethnic backgrounds.

Highlights

Metachromatic leukodystrophy (MLD, OMIM #250100) is an autosomal recessively inherited sulfatide storage disease caused by deficient activity of the lysosomal enzyme arylsulfatase A (ASA)
We considered MLD to be confirmed when at least two different tests were compatible with the diagnosis: homozygosity or compound heterozygosity for two pathogenic ARSA variants, increased urinary sulfatide excretion and/or decreased ASA activity within the range of MLD patients analyzed according to the Baum assay or modified Baum assay either at 0 or 4 °C depending on the laboratory [10,11,12], or when genetic testing of an affected sibling identified the same pathogenic ARSA variants as the index patient
We observed that in The Netherlands the juvenile type is much more common (58% of all patients). We showed that this is due to the high frequency of the c.1283C > T, p.(Pro428Leu) missense variant in Dutch MLD patients, a pathogenic ARSA variant that affects the stability of the ASA octamer by lowering the acidic pH [19]

Summary

Introduction

Metachromatic leukodystrophy (MLD, OMIM #250100) is an autosomal recessively inherited sulfatide storage disease caused by deficient activity of the lysosomal enzyme arylsulfatase A (ASA). The disease is characterized by progressive central and peripheral demyelination, resulting in severe neurological deterioration. The most prominent signs and symptoms are ataxia, André B.P. van Kuilenburg and Nicole I. Extended author information available on the last page of the article

Methods

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Conclusion