Alpha-N-acetylgalactosaminidase (alpha-NAGA) deficiency (Schindler/Kanzaki 
disease) is a clinically and pathologically heterogeneous genetic disease with a 
wide spectrum including an early onset neuroaxonal dystrophy (Schindler disease) 
and late onset angiokeratoma corporis diffusum (Kanzaki disease). In alpha-NAGA 
deficiency, there are discrepancies between the genotype and phenotype, and also 
between urinary excretion products (sialyl glycoconjugates) and a theoretical 
accumulated material (Tn-antigen; Gal NAcalpha1-O-Ser/Thr) resulting from a 
defect in alpha-NAGA. As for the former issue, previously reported genetic, 
biochemical and pathological data raise the question whether or not E325K 
mutation found in Schindler disease patients really leads to the severe 
phenotype of alpha-NAGA deficiency. The latter issue leads to the question of 
whether alpha-NAGA deficiency is associated with the basic pathogenesis of this 
disease. To clarify the pathogenesis of this disease, we performed structural 
and immunocytochemical studies. The structure of human alpha-NAGA deduced on 
homology modeling is composed of two domains, domain I, including the active 
site, and domain II. R329W/Q, identified in patients with Kanzaki disease have 
been deduced to cause drastic changes at the interface between domains I and II. 
The structural change caused by E325K found in patients with Schindler disease 
is localized on the N-terminal side of the tenth beta-strand in domain II and is 
smaller than those caused by R329W/Q. Immunocytochemical analysis revealed that 
the main lysosomal accumulated material in cultured fibroblasts from patients 
with Kanzaki disease is Tn-antigen. These data suggest that a prototype of 
alpha-NAGA deficiency in Kanzaki disease and factors other than the defect of 
alpha-NAGA may contribute to severe neurological disorders, and Kanzaki disease 
is thought to be caused by a single enzyme deficiency.