Sialuria

Sialuria (also known as French-type sialuria or sialic acid storage disease, French type) is an extremely rare inborn error of sialic acid metabolism caused by gain-of-function mutations in the GNE gene, which encodes the rate-limiting enzyme UDP-N-acetylglucosamine 2-epimerase/N-acetylmannosamine kinase in the sialic acid biosynthesis pathway. Normally, free sialic acid (N-acetylneuraminic acid) exerts feedback inhibition on this enzyme; in sialuria, mutations in the allosteric site abolish this feedback control, leading to massive overproduction and accumulation of free sialic acid in the cytoplasm of cells throughout the body. This results in excessive urinary excretion of free (unconjugated) sialic acid. Clinical features are variable but typically present in early childhood and may include mild to moderate developmental delay, coarse facial features, hepatomegaly, and mildly impaired cognitive development. Some patients exhibit recurrent upper respiratory infections and mild hypotonia. Importantly, sialuria is clinically distinct from Salla disease and infantile free sialic acid storage disease (ISSD), which involve defective lysosomal transport of sialic acid rather than overproduction. The clinical course of sialuria tends to be milder than these lysosomal sialic acid storage disorders. There is currently no specific or curative treatment for sialuria. Management is supportive and symptomatic, focusing on developmental therapies, monitoring of organ involvement, and management of recurrent infections. Fewer than 20 cases have been reported worldwide, making it one of the rarest metabolic disorders known. Diagnosis is established by demonstrating markedly elevated free sialic acid in urine with normal or near-normal levels of bound sialic acid, and confirmed by molecular analysis of the GNE gene.

Common questions about Sialuria