SLC17A5 – Salla disease

Salla disease is an autosomal recessive lysosomal storage disorder characterized by impaired export of free sialic acid due to biallelic mutations in SLC17A5, encoding the sialic acid transporter sialin. Patients typically present in infancy with hypotonia, ataxia, moderate intellectual disability, and hypomyelination on MRI. The locus was mapped to chromosome 6q14-q15 by linkage in Finnish families, and SLC17A5 was identified as the causative gene in 1999 (PMID:10581036).

Genetic evidence includes a Finnish founder missense variant, c.115C>T (p.Arg39Cys), identified homozygously in five unrelated patients with classic Salla disease (PMID:10581036) and observed in 91% of Finnish alleles in a cohort of 80 patients (PMID:10947946). Over 20 additional pathogenic alleles—including nonsense, frameshift, splice, and in-frame deletions—have been reported in compound heterozygosity with R39C or other variants in non-Finnish patients, confirming allelism with the severe infantile form ISSD.

The variant spectrum comprises missense (e.g., p.Arg39Cys), loss-of-function (e.g., c.1039C>T (p.Gln347Ter)), splice site (e.g., c.1111+1G>A), and small in-frame deletions (e.g., c.802_816del (p.Ser268_Asn272del)). The founder R39C allele demonstrates a strong genotype–phenotype correlation with milder, later-onset disease, whereas null alleles or compound heterozygosity with severe variants drive earlier onset and more rapid progression.

Clinical phenotype includes onset within the first year of life, developmental delay, truncal hypotonia, spastic-ataxic syndrome, moderate intellectual disability (HP:0002342), and cerebral hypomyelination (HP:0003429). MRI shows diffuse dysmyelination without visceral involvement, distinguishing it from ISSD. Repeated biochemical assays of urine free sialic acid and targeted genetic testing enable reliable diagnosis across ethnicities.

Functional studies using plasma-membrane redirected constructs and proteoliposomes demonstrate that the p.Arg39Cys mutant slows but does not abolish H+/sialic acid co-transport, consistent with residual activity in Salla disease (PMID:15510212). In contrast, mutations associated with ISSD abolish transport or cause mislocalization to the ER/Golgi, correlating with phenotype severity (PMID:15516337).

Collectively, there is definitive evidence for SLC17A5 in Salla disease based on extensive segregation, large patient cohorts, and concordant functional data. Genetic testing for c.115C>T (p.Arg39Cys) and comprehensive SLC17A5 sequencing is clinically indicated for early diagnosis and family counseling. Key take-home: SLC17A5 mutation analysis provides a robust molecular diagnosis for Salla disease and informs prognosis and management.

References

• Nature Genetics • 1999 • A new gene, encoding an anion transporter, is mutated in sialic acid storage diseases. PMID:10581036
• American Journal of Human Genetics • 2000 • The spectrum of SLC17A5-gene mutations resulting in free sialic acid-storage diseases indicates some genotype-phenotype correlation. PMID:10947946
• 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

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