Clinical, biochemical, and molecular diagnosis of a free sialic acid storage disease patient of moderate severity

Abstract

The allelic autosomal recessive lysosomal storage disorders Salla disease and infantile free sialic acid storage disease (ISSD) result from mutations in SLC17A5. This gene codes for sialin, a lysosomal membrane protein that transports the charged sugar, N-acetylneuraminic acid (sialic acid), out of lysosomes. ISSD has a severe phenotype with infantile onset, while the Finnish variant, Salla disease, has a milder phenotype with later onset. Both disorders cause developmental delay, and ISSD is generally fatal in early childhood. We describe a 30-month old non-Finnish, Caucasian child with global developmental delay of postnatal onset, language, and motor skills stagnant at a 3-4 month level, hypotonia, and mild but progressive coarsening of facial features. Urinary excretion of free sialic acid was elevated 4.5 times above control. EM of a skin biopsy revealed enlarged secondary lysosomes consistent with oligosaccharide storage. Free sialic acid in Wbroblasts was 3.8 § 0.9 nmol/mg protein (concurrent normal controls, 0.5 § 0.1); diVerential centrifugation indicated a lysosomal location. Genomic analysis revealed compound heterozygosity for two new SLC17A5 mutations. This child's clinical manifestations of a lysosomal free sialic acid storage disease are consistent with her sialin mutations and biochemical Wndings. The diVerential diagnosis of postnatal developmental delay should include free sialic acid storage disorders such as ISSD and Salla disease. Published by Elsevier Inc.

Identification of a vesicular aspartate transporter

“…Mutations in the sialin gene are known to cause two distinct diseases, infantile sialic acid storage disease (ISSD), an early fatal disorder with many features characteristic of a lysosomal disorder and Salla disease, a neurological disorder in which the affected persons have a near-normal life expectancy (25)(26)(27)(28)(29)(30). However, why different sialin mutations cause different diseases is less understood.…”

G328E and G409E sialin missense mutations similarly impair transport activity, but differentially affect trafficking

“…While one individual presented with congenital ascites and died shortly after birth, others were noted to have a milder phenotype with survival to at least several years of age. The G409E mutation has been identified in a compound heterozygous individual with a phenotype intermediate in severity between ISSD and Salla disease [7]. The second mutation **To whom correspondence should be addressed Phone: 650-724-4179, Fax: 650-498-6262, email: rjreimer@stanford.edu.…”

Crystal structure of 8,9-O-isopropylidine-Neu5Ac-methylester-methylketoside, C16H27NO9

“…One of the most interesting properties of sialic acid is its structural diversity, and over 40 kinds of derivatives of N-acetylneuraminic acid (Neu5Ac) arek nown [1,2]. It has been well known that these derivatives of N-acetylneuraminic acid must play an improtant part in various biological processes [3].Inrecentyears,N-acetylneuraminicacid as anti-influenzadrugs andasadetection regent of influenzavirushas attracted much attention [4,5].…”

“…All Hatoms on Catoms were generated geometrically andrefined as riding atomswith d(C-H) =0.96-0.98 Å, and U iso (H) =1.2 U eq (C) for Catoms of CH 2 and CH groups and U iso (H) =1.5 U eq (C) for Catoms of CH 3 groups. This is also true for the hydrogen atom of hydroxyl groups.…”