Population Carrier Rates of Pathogenic ARSA Gene Mutations: Is Metachromatic Leukodystrophy Underdiagnosed?

Agnieszka Ługowska,Grażyna Broda,Paweł Krajewski,Rafał Płoski,Joanna Ponińska,Bob Lightowlers

doi:10.1371/journal.pone.0020218

Agnieszka Ługowska, Grażyna Broda + Show 4 more

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https://doi.org/10.1371/journal.pone.0020218

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Abstract

BackgroundMetachromatic leukodystrophy (MLD) is a severe neurometabolic disease caused mainly by deficiency of arylsulfatase A encoded by the ARSA gene. Based on epidemiological surveys the incidence of MLD per 100 000 live births varied from 0.6 to 2.5. Our purpose was to estimate the birth prevalence of MLD in Poland by determining population frequency of the common pathogenic ARSA gene mutations and to compare this estimate with epidemiological data.MethodologyWe studied two independently ascertained cohorts from the Polish background population (N∼3000 each) and determined carrier rates of common ARSA gene mutations: c.459+1G>A, p.P426L, p.I179S (cohort 1) and c.459+1G>A, p.I179S (cohort 2).Principal FindingsTaking into account ARSA gene mutation distribution among 60 Polish patients, the expected MLD birth prevalence in the general population (assuming no selection against homozygous fetuses) was estimated as 4.0/100 000 and 4.1/100 000, respectively for the 1st and the 2nd cohort with a pooled estimate of 4.1/100 000 (CI: 1.8–9.4) which was higher than the estimate of 0.38 per 100 000 live births based on diagnosed cases. The p.I179S mutation was relatively more prevalent among controls than patients (OR = 3.6, P = 0.0082, for a comparison of p.I179S frequency relative to c.459+1G>A between controls vs. patients).Conclusions/SignificanceThe observed discrepancy between the measured incidence of metachromatic leukodystrophy and the predicted carriage rates suggests that MLD is substantially underdiagnosed in the Polish population. The underdiagnosis rate may be particularly high among patients with p.I179S mutation whose disease is characterized mainly by psychotic symptoms.

Highlights

Metachromatic leukodystrophy (MLD; OMIM 250100) is a severe demyelinating disease inherited in an autosomal recessive fashion
MLD is caused by deficient activity of lysosomal hydrolase arylsulfatase A (ARSA; EC 3.1.6.8) which leads to sulfatide storage
Screening population cohort 1 During the initial screening performed among subjects undergoing paternity testing results were obtained for 3 320, 3 467, and 3 159 samples, respectively for mutations c.459+1G.A, p.P426L, and p.I179S

Summary

Introduction

Metachromatic leukodystrophy (MLD; OMIM 250100) is a severe demyelinating disease inherited in an autosomal recessive fashion. The overall incidence of MLD varies from 1 in 40 000 to 1 in 170 000 in different populations [1] most likely reflecting different pathogenic mutation carriage rates as well as differences in the diagnosis rate. Based on this data it can be assumed that carrier frequency for MLD varies from ,1:100 to 1:130 implying that among ,3500 individuals from the general population 17–35 persons should be MLD carriers. Metachromatic leukodystrophy (MLD) is a severe neurometabolic disease caused mainly by deficiency of arylsulfatase A encoded by the ARSA gene. Our purpose was to estimate the birth prevalence of MLD in Poland by determining population frequency of the common pathogenic ARSA gene mutations and to compare this estimate with epidemiological data

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