Human alpha-N-acetylgalactosaminidase (alpha-NAGA) deficiency: new mutations and the paradox between genotype and phenotype.

Structural and immunocytochemical studies on α-N-acetylgalactosaminidase deficiency (Schindler/Kanzaki disease)

“…Our structural data are compatible with those of comparative studies including clinical, biochemical, pathological, and genetic analyses (Keulemans et al 1996;Bakker et al 2001), and the results support the suggestion of Keulemans et al (1996) and Bakker et al (2001) that a complete a-NAGA deficiency would cause late-onset angiokeratoma corporis diffusum (Kanzaki disease), and factors other than the defect of a-NAGA may contribute to the phenotypic expression in patients with an infantile neuroaxonal dystrophy (Schindler disease). The fact that patients other than the first German sibs with the combination of a-NAGA deficiency and neuroaxonal dystrophy have not been found would support this, although extensive research to find further patients has been performed.…”

“…Keulemans et al (1996) reported that the synthesis of precursor a-NAGA was normal, but mature a-NAGA was not detectable with the E325K mutation, and the a-NAGA activities in patients homozygous for E325K are relatively higher (0.6-1.7% of the normal control mean) than those in Spanish Kanzaki patients homozygous for E193X (0.2% of the normal control mean). We could not obtain clinical samples from patients with Schindler disease and the kinatic data are not available.…”

“…The first one is differences between the phenotype and genotype. Keulemans et al (1996) pointed out that vacuolization, the hallmark of lysosomal storage diseases, was observed in various cells from type II patients but not in ones from type I patients. A pathological finding in the latter cases was Ôspheroid degenerationÕ in axons, which does not indicate a lysosomal disease.…”

“…Furthermore, they found that type I patients have some residual a-NAGA activity, although the almost complete absence of a-NAGA activity was found in type II patients (Keulemans et al 1996). Two kinds of missense mutations (R329W and R329Q) and a nonsense mutation (E193X) were identified in Type II patients, each patient being homozygous for one of the mutations (Wang et al 1994;Kodama et al 2001;Keulemans et al 1996). The E193X mutation identified in Spanish patients represents a null mutation that should be associated with a severe phenotype.…”

Human α-N-acetylgalactosaminidase (α-NAGA) deficiency: no association with neuroaxonal dystrophy?

“…8,9 Mutation analysis of the a-NAGA gene revealed a paradox between genotype and phenotype. 10 At the most severe end of the clinical spectrum (infantile neuroaxonal dystrophy) a homozygous missense mutation E325K was found, with some residual a-NAGA activity. On the other hand, the Spanish patients with a rather mild, late onset disease were homozygous for the nonsense mutation E193X causing the complete absence of a-NAGAprotein.…”