ABSTRACT
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.
Subject(s)
Carbohydrate Metabolism, Inborn Errors/diagnosis , Lysosomal Storage Diseases, Nervous System/diagnosis , N-Acetylneuraminic Acid/genetics , Adult , Alleles , Carbohydrate Metabolism, Inborn Errors/genetics , Carbohydrate Metabolism, Inborn Errors/metabolism , Chorionic Villi Sampling , Chromosome Mapping , DNA/analysis , DNA Mutational Analysis , Female , Finland , Genetic Linkage , Haplotypes , Humans , Lysosomal Storage Diseases, Nervous System/genetics , Lysosomal Storage Diseases, Nervous System/metabolism , Male , Microsatellite Repeats , Mutation, Missense , N-Acetylneuraminic Acid/metabolism , Pedigree , Polymerase Chain Reaction , PregnancyABSTRACT
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.
