NEU1 – Sialidosis Type 1

NEU1, encoding lysosomal α-neuraminidase-1, is causally linked to autosomal recessive Sialidosis type 1. Patients typically present in adolescence with progressive action myoclonus, cerebellar ataxia, and macular cherry-red spots; brain MRI often shows no overt lesions despite abnormal cerebellar morphology (PMID:28138907; PMID:19473359). Biochemical confirmation relies on deficient neuraminidase activity in fibroblasts and elevated urinary bound sialic acid.

Genetic evidence comprises over 90 probands from 65 unrelated families worldwide harboring more than 40 distinct NEU1 mutations (PMID:39733340; PMID:19473359). All cases follow an autosomal recessive inheritance pattern, with segregation demonstrated in multiple consanguineous and familial pedigrees. The variant spectrum is dominated by missense substitutions, with fewer nonsense, frameshift, and splice-site alleles. Both compound heterozygosity and homozygosity for founder alleles have been documented.

A founder effect for c.544A>G (p.Ser182Gly) is evident in mainland Chinese and Taiwanese cohorts, representing 42.2% of familial alleles (PMID:39350194; PMID:39482827). Other recurrent variants include c.239C>T (p.Pro80Leu) in East Asians, c.649G>A (p.Val217Met) in Japanese patients, and c.880C>T (p.Arg294Cys) in Indian patients (PMID:39733340).

Functional assays and structural analyses confirm a loss-of-function mechanism. Patient-derived fibroblasts exhibit near-absent sialidase activity; three-dimensional modeling clusters pathogenic residues at the NEU1–PPCA interface (PMID:10767332; PMID:38600684). A NEU1 V54M knock-in mouse model recapitulates the mild ST-1 phenotype and is phenotypically rescued by AAV2/8-mediated PPCA delivery, highlighting therapeutic promise (PMID:23770387).

Given the robust genetic segregation in over 65 families and concordant functional data, the NEU1–sialidosis type 1 association is classified as Definitive. NEU1 molecular testing, including targeted screening for founder and recurrent alleles, is recommended for patients with juvenile myoclonus-ataxia syndromes regardless of ocular findings. Emerging PPCA-chaperone gene therapies warrant further clinical investigation.

References

• Journal of pediatric endocrinology & metabolism • 2025 • Sialidosis type 1 in a Turkish family: a case report and review of literatures. PMID:39733340
• European journal of neurology • 2009 • A longitudinal study of Taiwanese sialidosis type 1: an insight into the concept of cherry-red spot myoclonus syndrome. PMID:19473359
• Clinical genetics • 2012 • Lysosomal multienzymatic complex-related diseases: a genetic study among Portuguese patients. PMID:21214877
• Biochimica et biophysica acta • 2013 • Chaperone-mediated gene therapy with recombinant AAV-PPCA in a new mouse model of type I sialidosis. PMID:23770387
• Journal of movement disorders • 2024 • Clinical and Structural Characteristics of NEU1 Variants Causing Sialidosis Type 1. PMID:38600684

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