title: Genotypic characterization of Brazilian patients with infantile and juvenile forms of metachromatic leukodystrophy.
abstract: Metachromatic leukodystrophy (MLD) is a lysosomal storage disorder inherited as an autosomal recessive trait. MLD is caused by the deficiency of arylsulfatase A (ARSA), a lysosomal enzyme that catalyzes the first step in the degradation of sulfated glycolipids, which are essential components of the myelin sheet. Notably, between 7% and 15% of healthy individuals show in vitro deficiency of ARSA, a condition called ARSA pseudodeficiency (ARSA-PD). To date, 151 ARSA-MLD mutations have been reported in the gene encoding ARSA (ARSA), among which IVS2+1G>A and P426L occur at high frequencies in most of the studied populations. The aim of this work was to identify ARSA mutant alleles in a cohort of 27 unrelated Brazilian MLD patients. The most frequent ARSA-MLD mutation, IVS2+1G>A, and the ARSA-PD polymorphisms, N350S and 1524+95A>G, were detected using real-time PCR, while the remaining mutations were detected using direct sequencing of ARSA. In concordance with previous reports, IVS2+1G>A and P426L were the most common ARSA-MLD mutations in our cohort of MLD patients, found at frequencies of 0.05 and 0.08, respectively. Interestingly, two mutations previously reported as rare, 103_110del8 and 1190_1191insC, were found at higher frequencies in our cohort of MLD patients, 0.08 and 0.06, respectively. Additionally, 11 other rare ARSA-MLD mutations were found at lower frequencies in our cohort of MLD patients. To our knowledge, this is the first systematic genotypic characterization of MLD patients from Latin America. This work highlights the genetic heterogeneity of MLD, and supports genotype-phenotype associations, which become more important as specific treatments are being developed for this devastating disorder.
authors.affiliation: Laboratório de Identificação Genética, Centro de Pesquisa Experimental, Hospital de Clínicas de Porto Alegre, Ramiro Barcelos, 2350, Porto Alegre, RS 90035-903, Brazil; Departamento de Genética, Universidade Federal do Rio Grande do Sul, Bento Gonçalves, 9500, Porto Alegre, RS 91500-970, Brazil.; Serviço de Genética Médica, Hospital de Clínicas de Porto Alegre, Ramiro Barcelos, 2350, Porto Alegre, RS 90035-903, Brazil; Moved to Department of Anthropology, University of California at Berkeley, 232 Kroeber Hall, Berkeley, CA 94720, USA.
authors.forename: M Y F
authors.initials: MY
authors.lastname: Virgens
authors.affiliation: Laboratório de Identificação Genética, Centro de Pesquisa Experimental, Hospital de Clínicas de Porto Alegre, Ramiro Barcelos, 2350, Porto Alegre, RS 90035-903, Brazil; Serviço de Genética Médica, Hospital de Clínicas de Porto Alegre, Ramiro Barcelos, 2350, Porto Alegre, RS 90035-903, Brazil; Programa de Pós-Graduação em Biologia Celular e Molecular, Universidade Federal do Rio Grande do Sul, Bento Gonçalves, 9500, Porto Alegre, RS 91501-970, Brazil.
authors.forename: M
authors.initials: M
authors.lastname: Siebert
authors.affiliation: Laboratório de Identificação Genética, Centro de Pesquisa Experimental, Hospital de Clínicas de Porto Alegre, Ramiro Barcelos, 2350, Porto Alegre, RS 90035-903, Brazil; Serviço de Genética Médica, Hospital de Clínicas de Porto Alegre, Ramiro Barcelos, 2350, Porto Alegre, RS 90035-903, Brazil; Programa de Pós-Graduação em Ciências Biológicas: Bioquímica, Universidade Federal do Rio Grande do Sul, Ramiro Barcelos, 2600, Porto Alegre, RS 90035-003, Brazil.
authors.forename: H
authors.initials: H
authors.lastname: Bock
authors.affiliation: Serviço de Genética Médica, Hospital de Clínicas de Porto Alegre, Ramiro Barcelos, 2350, Porto Alegre, RS 90035-903, Brazil.
authors.forename: M
authors.initials: M
authors.lastname: Burin
authors.affiliation: Laboratório de Identificação Genética, Centro de Pesquisa Experimental, Hospital de Clínicas de Porto Alegre, Ramiro Barcelos, 2350, Porto Alegre, RS 90035-903, Brazil; Departamento de Genética, Universidade Federal do Rio Grande do Sul, Bento Gonçalves, 9500, Porto Alegre, RS 91500-970, Brazil.; Serviço de Genética Médica, Hospital de Clínicas de Porto Alegre, Ramiro Barcelos, 2350, Porto Alegre, RS 90035-903, Brazil.
authors.forename: R
authors.initials: R
authors.lastname: Giugliani
authors.affiliation: Laboratório de Identificação Genética, Centro de Pesquisa Experimental, Hospital de Clínicas de Porto Alegre, Ramiro Barcelos, 2350, Porto Alegre, RS 90035-903, Brazil; Departamento de Genética, Universidade Federal do Rio Grande do Sul, Bento Gonçalves, 9500, Porto Alegre, RS 91500-970, Brazil.; Serviço de Genética Médica, Hospital de Clínicas de Porto Alegre, Ramiro Barcelos, 2350, Porto Alegre, RS 90035-903, Brazil; Programa de Pós-Graduação em Biologia Celular e Molecular, Universidade Federal do Rio Grande do Sul, Bento Gonçalves, 9500, Porto Alegre, RS 91501-970, Brazil; Programa de Pós-Graduação em Ciências Biológicas: Bioquímica, Universidade Federal do Rio Grande do Sul, Ramiro Barcelos, 2600, Porto Alegre, RS 90035-003, Brazil; Departamento de Bioquímica, Universidade Federal do Rio Grande do Sul, Ramiro Barcelos, 2600, Porto Alegre, RS 90035-003, Brazil. Electronic address: mlpereira@hcpa.edu.br.
authors.forename: M L
authors.initials: ML
authors.lastname: Saraiva-Pereira
mesh_terms: D001938:Brazil; D002553:Cerebroside-Sulfatase / Q000235:genetics; D002648:Child; D002675:Child, Preschool; D005260:Female; D005787:Gene Frequency; D056726:Genetic Association Studies; D005838:Genotype; D006801:Humans; D007223:Infant; D007966:Leukodystrophy, Metachromatic / Q000235:genetics*; D008297:Male; D020641:Polymorphism, Single Nucleotide; D017422:Sequence Analysis, DNA
chemical_list: D002553:Cerebroside-Sulfatase
keywords: ARSA pseudodeficiency; Arylsulfatase A; Metachromatic leukodystrophy; Neurodegeneration; Sulfatides