RESUMO
UNLABELLED: The first 23 patients diagnosed with Salla disease in Sweden are presented. A high incidence of the "Finnish" R39C mutation, together with genealogical data, indicates that a large proportion of the mutations are of Finnish origin. All patients had pathologically high levels of free sialic acid in urine and in fibroblasts. The clinical picture confirms what has already been reported from Finland, with early psychomotor retardation, ataxia and speech problems. One-third of the patients had epilepsy. CONCLUSIONS: Salla disease is more common in Sweden than supposed. A large proportion of the mutated alleles seem to be of Finnish origin. The clinical picture is the same as that reported from Finland.
Assuntos
Doença do Armazenamento de Ácido Siálico/epidemiologia , Feminino , Fibroblastos/química , Humanos , Masculino , Mutação , Ácido N-Acetilneuramínico/análise , Prevalência , Estudos Soroepidemiológicos , Doença do Armazenamento de Ácido Siálico/diagnóstico , Doença do Armazenamento de Ácido Siálico/genética , Suécia/epidemiologiaRESUMO
Sialic acid storage disorders, Salla disease (SD) and a severe infantile form of disease (ISSD), are recessively inherited allelic lysosomal storage disorders due to impaired egress of free sialic acid from lysosomes. Fourteen pregnancies at risk of adult-type free sialic acid storage disease, SD, were monitored by sialic acid assays, genetic linkage or mutation detection analyses using chorionic villus samples. Three affected and 12 unaffected fetuses were identified. The first studies were based on the sialic acid assays alone, but the location of the gene enabled the use of genetic linkage analysis and, more recently, the identification of the SLC17A5 gene and disease-causing mutations added yet another possibility for prenatal studies. A missense mutation 115C-->T (R39C) is present in 95% of all Finnish SD alleles, providing an easy and reliable means of diagnostic studies. Both molecular and biochemical (sialic acid assay) studies can be used for prenatal diagnosis of free sialic acid storage diseases.
Assuntos
Erros Inatos do Metabolismo dos Carboidratos/diagnóstico , Doenças por Armazenamento dos Lisossomos do Sistema Nervoso/diagnóstico , Ácido N-Acetilneuramínico/genética , Adulto , Alelos , Erros Inatos do Metabolismo dos Carboidratos/genética , Erros Inatos do Metabolismo dos Carboidratos/metabolismo , Amostra da Vilosidade Coriônica , Mapeamento Cromossômico , DNA/análise , Análise Mutacional de DNA , Feminino , Finlândia , Ligação Genética , Haplótipos , Humanos , Doenças por Armazenamento dos Lisossomos do Sistema Nervoso/genética , Doenças por Armazenamento dos Lisossomos do Sistema Nervoso/metabolismo , Masculino , Repetições de Microssatélites , Mutação de Sentido Incorreto , Ácido N-Acetilneuramínico/metabolismo , Linhagem , Reação em Cadeia da Polimerase , GravidezRESUMO
Lysosomal free sialic acid-storage diseases include the allelic disorders Salla disease (SD) and infantile sialic acid-storage disease (ISSD). The defective gene, SLC17A5, coding for the lysosomal free sialic acid transporter was recently isolated by positional cloning. In the present study, we have identified a large number of mutations in SLC17A5 in patients presenting with either Salla disease or the ISSD phenotype. We also report for the first time the exon-intron boundaries of SLC17A5. All Finnish patients with SD (n=80) had a missense mutation changing a highly conserved arginine to cysteine (R39C); 91% of them were homozygotes for this old founder mutation. The compound-heterozygote patients, with the founder mutation in only one allele, presented with a more severe phenotype than did the homozygote patients. The same R39C mutation was also found both in most of the Swedish patients with SD and in a heterozygous form in five patients from central Europe who presented with an unusually severe (intermediate) SD phenotype. Ten different mutations, including deletions, insertions, and missense and nonsense mutations, were identified in patients with the most severe ISSD phenotype, most of whom were compound heterozygotes. Our results indicate some genotype-phenotype correlation in free sialic acid-storage diseases, suggesting that the phenotype associated with the homozygote R39C mutation is milder than that associated with other mutations.
Assuntos
Doenças por Armazenamento dos Lisossomos/genética , Doenças por Armazenamento dos Lisossomos/metabolismo , Proteínas de Membrana Transportadoras/genética , Mutação/genética , Ácido N-Acetilneuramínico/metabolismo , Transportadores de Ânions Orgânicos , Simportadores , Idade de Início , Alelos , Substituição de Aminoácidos/genética , Sequência de Bases , Análise Mutacional de DNA , Éxons/genética , Finlândia/epidemiologia , Efeito Fundador , Frequência do Gene/genética , Testes Genéticos , Heterozigoto , Humanos , Lactente , Recém-Nascido , Íntrons/genética , Doenças por Armazenamento dos Lisossomos/epidemiologia , Doenças por Armazenamento dos Lisossomos/fisiopatologia , Proteínas de Membrana Transportadoras/química , Fenótipo , Reação em Cadeia da Polimerase , Conformação Proteica , RNA Mensageiro/análise , RNA Mensageiro/genética , Suécia/epidemiologiaRESUMO
Sialic acid storage diseases (SASD, MIM 269920) are autosomal recessive neurodegenerative disorders that may present as a severe infantile form (ISSD) or a slowly progressive adult form, which is prevalent in Finland (Salla disease). The main symptoms are hypotonia, cerebellar ataxia and mental retardation; visceromegaly and coarse features are also present in infantile cases. Progressive cerebellar atrophy and dysmyelination have been documented by magnetic resonance imaging (ref. 4). Enlarged lysosomes are seen on electron microscopic studies and patients excrete large amounts of free sialic acid in urine. A H+/anionic sugar symporter mechanism for sialic acid and glucuronic acid is impaired in lysosomal membranes from Salla and ISSD patients. The locus for Salla disease was assigned to a region of approximately 200 kb on chromosome 6q14-q15 in a linkage study using Finnish families. Salla disease and ISSD were further shown to be allelic disorders. A physical map with P1 and PAC clones was constructed to cover the 200-kb area flanked by the loci D6S280 and D6S1622, providing the basis for precise physical positioning of the gene. Here we describe a new gene, SLC17A5 (also known as AST), encoding a protein (sialin) with a predicted transport function that belongs to a family of anion/cation symporters (ACS). We found a homozygous SLC17A5 mutation (R39C) in five Finnish patients with Salla disease and six different SLC17A5 mutations in six ISSD patients of different ethnic origins. Our observations suggest that mutations in SLC17A5 are the primary cause of lysosomal sialic acid storage diseases.
