SLC17A5 – Infantile Free Sialic Acid Storage Disease

Free sialic acid storage disease, infantile form (ISSD) is a severe autosomal recessive lysosomal storage disorder characterized by accumulation of free sialic acid in lysosomes, profound hypotonia, cerebellar atrophy, visceromegaly, and early-onset neurodegeneration. The disorder is allelic to Salla disease, sharing pathogenic variants in the SLC17A5 gene encoding the lysosomal sialic acid transporter, sialin.

Genetic evidence for SLC17A5 in ISSD was first established by linkage to chromosome 6q14-q15 in Finnish families, followed by identification of a homozygous p.Arg39Cys variant in Salla disease patients and six distinct mutations in six unrelated ISSD probands (PMID:10581036). Subsequent studies described two Italian siblings with severe Salla-like disease harboring a 15-bp deletion (c.802_816del (p.Ser268_Asn272del)) previously seen in French-Canadian ISSD cases (PMID:12121352).

The variant spectrum in ISSD includes predominantly loss-of-function alleles: nonsense (e.g., c.1039C>T (p.Gln347Ter)), frameshift (e.g., c.575del (p.Pro192fs)), splice-site (e.g., c.1111+1G>A), and in-frame deletions (e.g., c.802_816del (p.Ser268_Asn272del)), as well as rare missense changes that abolish transporter activity. No founder effect has been reported outside the Finnish Salla p.Arg39Cys change.

Segregation of pathogenic alleles has been demonstrated in multiplex families, including sib-pair concordance in Italian kindreds (n=2) and linkage-defined Finnish pedigrees, supporting autosomal recessive inheritance and co-segregation of biallelic SLC17A5 variants with disease.

Functional assays in heterologous systems show that ISSD-associated mutations abolish H+-driven sialic acid transport and impair lysosomal targeting, whereas Salla disease variants retain residual transport activity, correlating with phenotypic severity (PMID:15510212; PMID:15516337; PMID:12359136). Cellular localization studies confirm enhanced retention of mutant sialin in the Golgi and endoplasmic reticulum compartments in ISSD alleles.

In sum, there is strong and reproducible evidence that biallelic loss-of-function variants in SLC17A5 cause ISSD via a loss-of-function (haploinsufficiency) mechanism. Diagnostic sequencing of SLC17A5 is clinically indicated in infants with unexplained hypotonia, ataxia, visceromegaly, and hypomyelination. Key take-home: ISSD is a genetically and functionally validated autosomal recessive disorder of lysosomal sialic acid transport with critical implications for early diagnosis and potential gene-based therapies.

References

• Nature Genetics • 1999 • A new gene, encoding an anion transporter, is mutated in sialic acid storage diseases. PMID:10581036
• Clinical Genetics • 2002 • An Italian severe Salla disease variant associated with a SLC17A5 mutation earlier described in infantile sialic acid storage disease. PMID:12121352
• The EMBO Journal • 2004 • Functional characterization of wild-type and mutant human sialin. PMID:15510212
• The Journal of Biological Chemistry • 2005 • Varied mechanisms underlie the free sialic acid storage disorders. PMID:15516337
• Molecular Genetics and Metabolism • 2002 • Unraveling the molecular pathogenesis of free sialic acid storage disorders: altered targeting of mutant sialin. PMID:12359136

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