Lysosomal alpha-N-acetylgalactosaminidase deficiency, the enzymatic defect in angiokeratoma corporis diffusum with glycopeptiduria.

Abstract

Recently a novel case of angiokeratoma corporis diffusum with glycoaminoaciduria was described in a 46-yr-old Japanese woman. Known causes of the cutaneous manifestation were eliminated by enzyme analyses, and further characterization of the accumulated urinary O-linked sialopeptides revealed identity to those excreted by patients with an infantile neuroaxonal dystrophy due to lysosomal a-N-acetylgalactosaminidase deficiency. Investigation of the a-N-acetylgalactosaminidase activity and protein in the proband revealed less than 2% of normal activity and the absence of detectable immunoreactive enzyme protein, findings comparable to those in the patients with infantile neuroaxonal dystrophy and a-N-acetylgalactosaminidase deficiency. In addition, the proband's unaffected offspring had half-normal levels of a-N-acetylgalactosaminidase activity, consistent with this enzymatic deficiency being the primary metabolic defect in this autosomal recessive trait. Ultrastructural examination of skin and blood cells from the adult proband revealed the presence of prominent lysosomal inclusions containing diffuse amorphous and filamentous material. In contrast, these morphologic findings were not observed in the nonneural tissues from patients with infantile neuroaxonal dystrophy and a-N-acetylgalactosaminidase deficiency. These studies document the occurrence of two forms of a-N-acetylgalactosaminidase deficiency and sialopeptiduria, a severe infantile-onset form of neuroaxonal dystrophy without angiokeratoma or visceral. lysosomal inclusions and an adult-onset form characterized by angiokeratoma, extensive lysosomal accumulation ofsialoglycopeptides and the absence ofdetectable neurologic involvement. (J. Clin. Invest. 1991. 87:707-711.)

The molecular lesion in the alpha-N-acetylgalactosaminidase gene that causes angiokeratoma corporis diffusum with glycopeptiduria.

“…The affected homozygote had levels of a-GalNAc activity that were < 1% of normal in various sources as assayed with the recently synthesized substrate, 4-methylumbelliferyl-a-Nacetylgalactosaminide (4MU-a-GalNAc) (2). Her children had intermediate levels of activity consistent with being obligate heterozygotes for this autosomal recessive disorder.…”

“…Angiokeratoma corporis diffusum with glycopeptiduria is a recently recognized inborn error of glycoprotein catabolism resulting from the deficient activity of the lysosomal glycohydrolase, a-N-acetylgalactosaminidase (E.C.3.2.1.49; a-Ga1NAc)1 (1)(2)(3). The enzymatic defect, inherited as an autosomal recessive trait, leads to the tissue accumulation and increased urinary excretion of glycopeptides and oligosaccharides containing a-N-acetylgalactosaminyl moieties.…”

Structural and immunocytochemical studies on α-N-acetylgalactosaminidase deficiency (Schindler/Kanzaki disease)

“…Thus, the substitutions are deduced to cause a significant influence to decrease the protein stability or to cause a folding defect. a-NAGA activities in clinical samples from the patients homozygous for these mutations are both very low (below 1% of the normal control mean) (Kanzaki et al 1991;Kodama et al 2001), and the kinetic data could not be obtained. However, R329 is far from the active site, and it is thought not to affect the kinetic character, including Km value.…”

“…However, R329 is far from the active site, and it is thought not to affect the kinetic character, including Km value. Indeed, Kanzaki et al performed immunoblotting analysis and found that no band representing the mature form of a-NAGA was detected in a patient with the R329W mutation (Kanzaki et al 1991).…”

“…They developed an early-onset severe progressive neurological disorder pathologically characterized by an infantile neuroaxonal dystrophy , and the disease was named Schindler disease. Then, a group of adult patients with angiokeratoma corporis diffusum and vacuolization in various cell types associated with a-NAGA deficiency and glycopeptiduria identical to those in Schindler disease was reported (Kanzaki et al 1989(Kanzaki et al , 1991(Kanzaki et al , 1993Chabas et al 1994;Kodama et al 2001), and the disease was named Kanzaki disease. Then, a-NAGA deficiency (Schindler/Kanzaki disease) was divided into three subtypes (types I-III) in a textbook (Desnick and Schindler, 2001).…”