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In two unrelated families, biallelic missense variants in NAGA cause alpha-N-acetylgalactosaminidase deficiency (MONDO:0017779). The first family harbored compound heterozygous variants c.479C>G (p.Ser160Cys) and c.973G>A (p.Glu325Lys) in an 11-month-old girl presenting with generalized-onset seizures without angiokeratoma; enzymatic assays showed profound α-NAGA deficiency in plasma, leukocytes, and fibroblasts, while heterozygous parents and a clinically healthy brother exhibited intermediate or deficient enzyme levels, indicating segregation in one additional relative (1 family, 1 relative) (PMID:8071745). The second family carried a homozygous c.838C>A (p.Leu280Ile) variant in a 5-year-old with microcephaly and severe neurological features; two homozygous relatives (sister and cousin) displayed reduced enzyme activity and abnormal oligosacchariduria, consistent with biochemical disease despite phenotypic heterogeneity (1 family, 2 relatives) (PMID:31468281).
Inheritance is autosomal recessive. A total of 3 missense variants have been reported across 2 probands, with segregation in 3 affected relatives. Variants are exclusively missense, and no recurrent or founder alleles have been described. The predominant clinical feature is generalized-onset seizure (HP:0002197), sometimes accompanied by microcephaly and oligosacchariduria.
Mechanistic studies demonstrate markedly reduced α-NAGA activity to 5.9% and 12.1% of normal in the proband and sister, respectively (PMID:31468281), alongside intracellular N-acetylgalactosamine accumulation detected by Helix pomatia lectin in patient fibroblasts (PMID:8071745). Molecular dynamics predict impaired substrate binding, supporting a loss-of-function mechanism.
No conflicting reports have been identified. Additional rare variants and long-term follow-up studies may strengthen the phenotypic spectrum. Key take-home: NAGA biallelic missense variants lead to autosomal recessive alpha-N-acetylgalactosaminidase deficiency, with biochemical assays and functional analyses critical for diagnosis and management.
Gene–Disease AssociationLimited2 probands with biallelic NAGA variants, segregation in 3 relatives, consistent biochemical phenotype Genetic EvidenceLimitedIdentification of 3 pathogenic missense variants in 2 unrelated families with limited segregation data Functional EvidenceModerateReduced α-NAGA activity assays, lectin staining confirming storage, and molecular dynamics supporting impact on enzyme function |