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NAGA – alpha-N-acetylgalactosaminidase Deficiency Type 1

Alpha-N-acetylgalactosaminidase (NAGA) deficiency, or Schindler disease type I, is an autosomal recessive lysosomal storage disorder caused by bi-allelic loss of NAGA enzyme activity. Clinical manifestations range from severe neuroaxonal dystrophy to angiokeratoma and sensorineural hearing loss, reflecting extreme phenotypic heterogeneity.

Genetic evidence includes eight unrelated probands with confirmed bi-allelic NAGA variants across five families (PMID:8782044; PMID:31890708). Reported pathogenic alleles comprise premature stop codons (e.g., c.577G>T (p.Glu193Ter)), splice-site disruptions, and missense substitutions. The variant c.838C>A (p.Leu280Ile) was identified homozygously in an Emirati pedigree and classified as pathogenic based on segregation, population frequency, and functional analysis (PMID:31468281).

Segregation analysis demonstrated co-segregation of NAGA variants with disease in two affected siblings homozygous for c.973G>A (p.Glu325Lys) in a consanguineous family (PMID:8782044).

Functional studies reveal significantly reduced α-NAGA activity (5.9–12.1% of normal), accumulation of O-linked oligosaccharides, intact protein processing, and molecular dynamics simulations showing impaired active-site binding for p.Leu280Ile, supporting a loss-of-function mechanism (PMID:31468281).

Despite marked intrafamilial variability, the concordance of genetic, biochemical, and in silico data supports pathogenic haploinsufficiency. No studies to date refute this association.

Key take-home: Bi-allelic NAGA variants have strong clinical validity and diagnostic utility for alpha-N-acetylgalactosaminidase deficiency type 1, guiding genetic counseling and enzyme-replacement considerations.

References

  • European journal of case reports in internal medicine • 2019 • A New Case of Schindler Disease. PMID:31890708
  • Journal of molecular neuroscience • 2020 • A Novel Homozygous Missense Variant in the NAGA Gene with Extreme Intrafamilial Phenotypic Heterogeneity. PMID:31468281
  • Journal of medical genetics • 1996 • Human alpha-N-acetylgalactosaminidase (alpha-NAGA) deficiency: new mutations and the paradox between genotype and phenotype. PMID:8782044

Evidence Based Scoring (AI generated)

Gene–Disease Association

Strong

Eight probands across multiple families; segregation in two affected sib pairs; concordant functional data

Genetic Evidence

Strong

8 bi-allelic NAGA cases in AR inheritance, including 2 segregating sib pairs with pathogenic variants

Functional Evidence

Moderate

Enzymatic assays show 5.9–12.1% residual activity; molecular dynamics and oligosaccharide accumulation confirm loss-of-function