GNE – Sialuria

Sialuria is a rare autosomal dominant inborn error of metabolism caused by heterozygous missense variants in GNE that disrupt allosteric feedback inhibition, leading to cytoplasmic accumulation and urinary excretion of free sialic acid. To date nine unrelated probands have been reported worldwide (PMID:29923088), with a three-generation family showing segregation in a mother-son-grandmother trio (PMID:27142465). Clinical features include global developmental delay (HP:0001263), prolonged neonatal jaundice (HP:0006579), and hepatomegaly (HP:0002240).

Functional assays in Lec3 Chinese hamster ovary cells lacking endogenous epimerase activity confirm that sialuria-associated variants (e.g., c.797G>A (p.Arg266Gln)) abolish feedback inhibition and are rescued by wild-type GNE expression (PMID:14561743). Preclinical gene transfer studies using the R266Q mutant further demonstrate increased UDP-GlcNAc 2-epimerase activity in GNE-deficient cells. Although early childhood morbidity is mild, long-term follow-up has raised concern that sialuria may predispose to intrahepatic cholangiocarcinoma in adulthood.

Key take-home: GNE-related sialuria is an autosomal dominant disorder with limited but consistent genetic and functional evidence supporting its clinical diagnosis and management.

References

• Molecular genetics and metabolism • 2016 • New observation of sialuria prompts detection of liver tumor in previously reported patient. PMID:27142465
• JIMD reports • 2019 • Sialuria: Ninth Patient Described Has a Novel Mutation in GNE. PMID:29923088
• The Journal of biological chemistry • 2003 • Lec3 Chinese hamster ovary mutants lack UDP-N-acetylglucosamine 2-epimerase activity because of mutations in the epimerase domain of the Gne gene. PMID:14561743

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