HUMAN ALPHA-N-ACETYLGALACTOSAMINIDASE (ALPHA-NAGA) DEFICIENCY - NEW MUTATIONS AND THE PARADOX BETWEEN GENOTYPE AND PHENOTYPE

Up to now eight patients with alpha-NAGA deficiency have been describe d. This includes the newly identified patient reported here who died u nexpectedly aged 1 1/2 years of hypoxia during convulsions; necropsy w as not performed. Three patients have been genotyped previously and he re we report the mutations in the other five patients, including two n ew mutations (S160C and E193X). The newly identified patient is consan guineous with the first patients reported with alpha-NAGA deficiency a nd neuroaxonal dystrophy and they all had the alpha-NAGA genotype E325 K/E325K. Clinical heterogeneity among patients with alpha-NAGA deficie ncy is extreme. Two affected sibs, homozygotes for E325K, are severely affected and have the signs and symptoms of infantile neuroaxonal dys trophy, but prominent vacuolisation is lacking. The mildly affected pa tients (two families, three patients) at the opposite end of the clini cal spectrum have clear vacuolisation and angiokeratoma but no overt n eurological manifestations. Two of them are homozygous for the stop mu tation E193X, leading to complete loss of alpha-NAGA protein. These ob servations are difficult to reconcile with a simple genotype-phenotype correlation and we suggest that factors or genes other than alpha-NAG A contribute to the clinical heterogeneity of the eight patients with alpha-NAGA deficiency. At the metabolic level, the patients with alpha -NAGA deficiency are similar. The major abnormal urinary oligosacchari des are sialylglycopeptides of the O linked type. Our enzymatic studie s indicated that these compounds are not the primary lysosomal storage products.