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

Abstract

Two new individuals with α-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 α-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 α-NAGA deficiency presenting as infantile neuroaxonal dystrophy. Thus, at the age of 7 years the same genotype of α-NAGA may present as a 'non-disease' (present healthy case) and can be associated with the vegetative state (the first two patients described with α-NAGA deficiency). The clinical heterogeneity among the 11 known individuals with α-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 α-NAGA contribute to the clinical heterogeneity of the 11 patients with α-NAGA deficiency.