α-N-acetylgalactosaminidase Deficiency with Angiokeratoma Corporis Diffusum (Kanzaki Disease):

Discovery and Development Thereafter — 1986 through 2006 —

Abstract

A 48-year-old Japanese lady was examined in 1989. She was apparently healthy but showed numerous numbers of small petechiae-like angiokeratoma on her lower torso to upper thighs, axillae and beneath the breasts. Electron microscopic examination of the skin revealed largely dilated electron lucent lysosomes with fuzzy filamentous materials in vascular endothelial cells, fibroblasts, eccrine sweat gland cells and others. Urinary examination revealed unusual glycopeptides with GalNAc-Ser/Thr moieties. This disease was reported as a novel lysosomal storage disease with angiokeratoma corporis diffusum, crowned Kanzaki disease (MIM#104170). Soon, this disease was found to be caused by a deficit of α-N-acetylgalactosaminidase (α-NAGA, 4. 3. 2. 49) activity and a point mutation was found in the gene (R329W) encoding the enzyme. Another patient, 47-year-old Japanese woman, was found, and she also was apparently healthy, but had less angiokeratoma as compared to the first one. The gene mutation was found and the resultant mutant enzyme was R329Q. She excreted less amount of GalNAc-Ser in urine as compared to the first patient. These phenotypical differences between case 1 and 2 were estimated to be caused by the differences in the three-dimensional structures in mutated α-NAGAs (R329W v. s. R329Q). Schindler disease also shows α-NAGA deficiency but shows very severe central nervous symptoms before the age of one. Electron microscopically electron-dence material deposited in lysosomes in Schindler disease. Electron-dense material means that the substance are probably lipid- or lipoprotein-containg materials. This quiet contrasts to the findings in Kanzaki disease. These evidences suggest that Kanzaki disease is caused by a pure α-NAGA deficiency but Schindler disease is probably caused by together α-NAGA deficiency with some other factors.