NEU1 – Sialidosis

Sialidosis is an autosomal recessive lysosomal storage disorder caused by biallelic mutations in NEU1, encoding lysosomal alpha-neuraminidase 1. Clinical forms range from the severe, early-onset type II with hydrops fetalis and dysmorphism to the milder, late-onset type I characterized by myoclonus, cerebellar ataxia and macular cherry-red spots.

Genetically, sialidosis exhibits recessive inheritance with over 100 unrelated probands documented across more than 20 publications since 1997 ([PMID:9054950]). In a recent cohort of 31 patients from 23 unrelated families, the homozygous c.544A>G (p.Ser182Gly) variant recurred at a founder frequency in East Asian populations, with segregation confirmed in multiple sibships ([PMID:39482827]).

The NEU1 variant spectrum includes missense substitutions (e.g., c.544A>G (p.Ser182Gly)), nonsense mutations (e.g., c.45G>A (p.Trp15Ter)), splice-site defects (c.1021+1G>C), small indels and rare frameshifts, all resulting in absent or reduced enzymatic activity. Recurrent alleles such as p.Gly227Arg and p.Gly328Ser have been reported in distinct ethnic groups, indicating both private and population-specific founder mutations ([PMID:10767332], [PMID:9054950]).

Functional assays demonstrate that pathogenic NEU1 variants disrupt glycosidase activity, impair lysosomal multienzyme complex formation and lead to intralysosomal substrate accumulation. Structural modeling of missense mutations clustered on the sialidase surface revealed destabilization of key interaction interfaces with cathepsin A and beta-galactosidase ([PMID:10767332]).

In vivo, a mouse model expressing the V54M NEU1 variant recapitulated features of type I sialidosis and showed that co-delivery of PPCA via AAV vector increased NEU1 activity and ameliorated disease manifestations, supporting chaperone-mediated gene therapy as a therapeutic strategy ([PMID:23770387]).

Collectively, robust genetic, biochemical and animal model data substantiate a Definitive gene–disease relationship between NEU1 and sialidosis. Routine NEU1 variant screening in patients with myoclonus or ataxia—even in the absence of cherry-red spots—facilitates early diagnosis and informs carrier detection, reproductive counseling and emerging gene therapy approaches.

References

• Nature Genetics • 1997 • Cloning, expression and chromosomal mapping of human lysosomal sialidase and characterization of mutations in sialidosis. PMID:9054950
• Human Molecular Genetics • 2000 • Characterization of the sialidase molecular defects in sialidosis patients suggests the structural organization of the lysosomal multienzyme complex. PMID:10767332
• Biochimica et Biophysica Acta • 2013 • Chaperone-mediated gene therapy with recombinant AAV-PPCA in a new mouse model of type I sialidosis. PMID:23770387
• Annals of Clinical and Translational Neurology • 2024 • Progressive myoclonic ataxia as an initial symptom of typical type I sialidosis with NEU1 mutation. PMID:39482827

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