Abstract
BackgroundSialic acid storage diseases are neurodegenerative disorders characterized by accumulation of sialic acid in the lysosome. These disorders are caused by mutations in SLC17A5, the gene encoding sialin, a sialic acid transporter located in the lysosomal membrane. The most common form of sialic acid storage disease is the slowly progressive Salla disease, presenting with hypotonia, ataxia, epilepsy, nystagmus and findings of cerebral and cerebellar atrophy. Hypomyelination and corpus callosum hypoplasia are typical as well. We report a 16 year-old boy with an atypically mild clinical phenotype of sialic acid storage disease characterized by psychomotor retardation and a mixture of spasticity and rigidity but no ataxia, and only weak features of hypomyelination and thinning of corpus callosum on MRI of the brain.ResultsThe thiobarbituric acid method showed elevated levels of free sialic acid in urine and fibroblasts, indicating sialic acid storage disease. Initial Sanger sequencing of SLC17A5 coding regions did not show any pathogenic variants, although exon 9 could not be sequenced. Whole exome sequencing followed by RNA and genomic DNA analysis identified a homozygous 6040 bp insertion in intron 9 of SLC17A5 corresponding to a long interspersed element-1 retrotransposon (KF425758.1). This insertion adds two splice sites, both resulting in a frameshift which in turn creates a premature stop codon 4 bp into intron 9.ConclusionsThis study describes a novel pathogenic variant in SLC17A5, namely an intronic transposal insertion, in a patient with mild biochemical and clinical phenotypes. The presence of a small fraction of normal transcript may explain the mild phenotype. This case illustrates the importance of including lysosomal sialic acid storage disease in the differential diagnosis of developmental delay with postnatal onset and hypomyelination, as well as intronic regions in the genetic investigation of inborn errors of metabolism.
Highlights
Sialic acid storage diseases are neurodegenerative disorders characterized by accumulation of sialic acid in the lysosome
Sanger sequencing of the coding regions of SLC17A5 In the first attempt to find pathogenic variants in the SLC17A5 gene, Sanger sequencing of the coding regions was performed not showing any pathogenic variants, exon 9 could not be sequenced
Whole exome sequencing Using our semi-automated bioinformatics approach [11], 20 candidate genes affected by rare variants predicted to affect protein function and segregating according to Mendelian inheritance models were identified
Summary
Sialic acid storage diseases are neurodegenerative disorders characterized by accumulation of sialic acid in the lysosome. The most common form of sialic acid storage disease is the slowly progressive Salla disease, presenting with hypotonia, ataxia, epilepsy, nystagmus and findings of cerebral and cerebellar atrophy. Sialic acid storage diseases (SASDs) are autosomal recessive neurodegenerative disorders that are characterized by an excessive storage of sialic acid in the lysosomes caused by defective transport by the sialin protein. Common symptoms are intellectual developmental disorder, muscular hypotonia, failure to thrive as well as coarse features, seizures, bone malformations, hepatosplenomegaly, and cardiomegaly in some patients. This condition is associated with non-immune hydrops fetalis. The clinical progression is slow, and patients can live throughout adulthood
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