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

Abstract

Two new individuals with a-NAGA deficiency are presented. The index patient, 3 years old, has congenital cataract, slight motor retardation and secondary demyelinisation. Screening of his sibs revealed an a-NAGA deficiency in his 7-year-old healthy brother who had no clinical or neurological symptoms. Both sibs are homozygous for the E325K mutation, the same genotype that was found in the most severe form of a-NAGA deficiency presenting as infantile neuroaxonal dystrophy. Thus, at the age of 7 years the same genotype of a-NAGA may present as a`non-disease' (present healthy case) and can be associated with the vegetative state (the first two patients described with a-NAGA deficiency). The clinical heterogeneity among the 11 known individuals with a-NAGA deficiency is extreme, with a`non-disease' (two cases) and infantile neuroaxonal dystrophy (two cases) at the opposite sides of the clinical spectrum. The broad spectrum is completed by a very heterogeneous group of patients with various degrees of epilepsy/behavioural difficulties/psychomotor retardation (four patients) and a mild phenotype in adults without overt neurological manifestations who have angiokeratoma and clear vacuolisation in various cell types (three cases). These observations are difficult to reconcile with a straightforward genotype-phenotype correlation and suggest that factors or genes other than a-NAGA contribute to the clinical heterogeneity of the 11 patients with a-NAGA deficiency.

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.…”

“…Up to now, 12 patients from eight families with a-NAGA deficiency have been reported, and this disease is known as a clinically heterogeneous disorder (Bakker et al 2001;Kodama et al 2001). In 1987, two German brothers with a-NAGA deficiency were first described (van Diggelen et al 1987).…”

“…So, the E325K mutation had been thought to be associated with a severe phenotype with an infantile neuroaxonal dystrophy. However, Bakker et al (2001) recently reported two Moroccan sibs with a-NAGA deficiency. They are homozygous for E325K alleles.…”

Defects in degradation of blood group A and B glycosphingolipids in Schindler and Fabry diseases

“…Meanwhile, 11 patients with NAGA deficiency have been diagnosed worldwide. Their clinical pictures are extremely heterogeneous, including two severe infantile cases with neuroaxonal dystrophy and a mild adult type of the disease (10), but also two individuals without overt clinical symptoms (11). In other lysosomal storage diseases, such as metachromatic leukodystrophy or the G M2 gangliosidoses, the mild, protracted, late-onset forms could be correlated with small but discernible residual activities of the affected enzyme, sufficient to maintain a still-considerable degradation rate of the substrate and thus to retard the storage process (14).…”

“…␣-NAGA deficiency is characterized by remarkable clinical heterogeneity (type I, severe infantile; type II, mild adult; type III, intermediate form) (10), and patients without overt clinical symptoms have been also reported (11). In many lysosomal storage diseases, such a variation could largely be explained by differences in the residual activities of the affected enzyme (12), although in some cases, such as ␣-l-Iduronidase deficiency [mucopolysaccharidosis (MPS) I, Hurler/Scheie syndromes], the differences are minute and are difficult to detect with standard enzyme assays (13).…”