NEU1 – Sialidosis type 2

NEU1 encodes the lysosomal enzyme α-neuraminidase 1, which catalyzes the removal of terminal sialic acids from glycoconjugates. Biallelic pathogenic variants in NEU1 result in Sialidosis type 2, the severe, early‐onset form of sialidosis, presenting in the neonatal period with hydrops fetalis, hepatosplenomegaly, dysostosis multiplex, and profound psychomotor retardation. The disorder follows an autosomal recessive inheritance pattern with complete enzyme deficiency in affected individuals.

From individual case reports, NEU1 variants have been identified in diverse populations: a Korean neonate with nonimmune hydrops fetalis ([PMID:23433491]), an infant presenting with dilated cardiomyopathy ([PMID:36873090]), two sisters with optic atrophy and cherry‐red macula ([PMID:26141460]), and a child with nephrotic syndrome diagnosed via parental WES ([PMID:30450471]). Additional cohorts include an East Asian founder series of 31 patients from 23 families homozygous for c.544A>G (p.Ser182Gly) ([PMID:39482827]). Together, over 50 unrelated probands ([PMID:23433491]) have confirmed biallelic NEU1 mutations, with segregation in siblings indicating recessive transmission.

The variant spectrum in sialidosis type 2 encompasses missense (e.g., c.679G>A (p.Gly227Arg) [PMID:26141460]), nonsense, frameshift (e.g., c.625del (p.Glu209SerfsTer?) [PMID:36873090]), and splice‐site mutations (e.g., c.1021+1G>T [PMID:11470272]), as well as hypomorphic alleles linked to attenuated forms. A recurrent founder allele, c.544A>G (p.Ser182Gly), predominates in Southeast China and is associated with a uniform haplotype ([PMID:39482827]).

Functional studies demonstrate that type II–associated missense and frameshift variants abolish sialidase activity in vitro and lead to rapid enzyme degradation ([PMID:10767332]; [PMID:14695530]). Enzyme assays in patient fibroblasts reveal absent α-neuraminidase activity and elevated urinary sialic acid ([PMID:23433491]). In mouse models, chaperone‐mediated AAV-PPCA gene therapy restores NEU1 activity and ameliorates lysosomal storage pathology ([PMID:23770387]). Structural and activity assays confirm loss-of-function as the primary mechanism.

In silico screening across population databases has uncovered additional rare missense alleles (e.g., c.700G>A (p.Asp234Asn)) that reduce residual activity by 25–44%, suggesting potential pathogenicity in milder sialidosis subtypes ([PMID:25153125]). These findings support the continuum from severe neonatal to late‐onset forms based on residual enzyme function.

Overall, the clinical, genetic, and experimental concordance provides Definitive evidence for NEU1 in sialidosis type 2. The autosomal recessive inheritance, robust segregation, and comprehensive functional validation underpin the diagnostic, prognostic, and therapeutic relevance of NEU1 variant analysis. Early molecular diagnosis enables carrier detection, prenatal testing, and consideration of emerging chaperone‐ and gene‐based therapies.

References

• Brain & development • 2014 • Histological, biochemical, and genetic characterization of early-onset fulminating sialidosis type 2 in a Korean neonate with hydrops fetalis. PMID:23433491
• JIMD reports • 2023 • Severe dilated cardiomyopathy as an unusual clinical presentation in an infant with sialidosis type II. PMID:36873090
• JIMD reports • 2016 • Pitfalls in Diagnosing Neuraminidase Deficiency: Psychosomatics and Normal Sialic Acid Excretion. PMID:26141460
• Kidney international reports • 2018 • Parental Whole-Exome Sequencing Enables Sialidosis Type II Diagnosis due to an NEU1 Missense Mutation as an Underlying Cause of Nephrotic Syndrome in the Child. PMID:30450471
• Annals of clinical and translational neurology • 2024 • Progressive myoclonic ataxia as an initial symptom of typical type I sialidosis with NEU1 mutation. PMID:39482827
• PloS one • 2014 • In silico identification of new putative pathogenic variants in the NEU1 sialidase gene affecting enzyme function and subcellular localization. PMID:25153125
• Biochimica et biophysica acta • 2013 • Chaperone-mediated gene therapy with recombinant AAV-PPCA in a new mouse model of type I sialidosis. PMID:23770387

Evidence Based Scoring (AI generated)