Chapter 139

## Abstract

Abstract

1. Schindler disease is a recently recognized autosomal recessive disorder caused by the deficient activity of α-N-acetylgalactosaminidase, a lysosomal hydrolase previously known as α-galactosidase B. The enzymatic defect results in the accumulation of sialylated and asialoglycopeptides, as well as glycosphingolipids and oligosaccharides with α-N-acetylgalactosaminyl residues.

2. The disease is clinically heterogeneous; three major phenotypes have been identified. Type I disease is an infantile-onset neuroaxonal dystrophy. The disease has been described in three related infants, two sibs, and a distant cousin. It is characterized by normal development for the first 8 to 15 months of life, followed by a rapid neurodegenerative course resulting in severe psychomotor retardation, cortical blindness, myoclonus, seizures, and a decorticate state by 3 to 4 years of age. Type II disease is an adult-onset disorder characterized by angiokeratoma corporis diffusum and mild intellectual impairment. To date, three affected adults in two unrelated consanguineous families have been identified. Type III disease, described in two sibs and an unrelated child, is an intermediate and variable form with manifestations ranging from seizures and moderate psychomotor retardation in infancy to a milder autistic presentation with speech and language delay, and marked behavioral difficulties in early childhood.

3. Morphologic examination of a cortical brain biopsy from a type I patient revealed abundant “spheroids” in terminal and preterminal axons, the characteristic pathology of a neuroaxonal dystrophy. The type I patients had no histologic evidence of lysosomal pathology, whereas the type II patients had prominent cytoplasmic vacuoles in granulocytes, monocytes, and lymphocytes. Ultrastructural examination of skin from the type II patients revealed numerous cytoplasmic vacuoles containing amorphous or filamentous material in endothelial cells of blood and lymphatic vessels, sweat gland cells, and axons. In contrast, only peripheral blood cells have been examined in type III disease and no vacuolation was observed by electron microscopy.

4. Diagnosis of affected homozygotes and heterozygous carriers can be made by determination of the α-N-acetylgalactosaminidase activity in various sources. Affected individuals have abnormal urinary oligosaccharide and glycopeptide profiles. Prenatal diagnosis is feasible by demonstration of the enzymatic defect in chorionic villi or cultured amniocytes.

5. The α-N-acetylgalactosaminidase gene has been localized to the chromosomal region 22q13.1→13.2. The full-length cDNA and the entire 14-kb gene encoding α-N-acetylgalactosaminidase have been isolated and sequenced. Comparison of the human α-N-acetylgalactosaminidase and α-galactosidase A genes revealed remarkable homology of their predicted amino acid sequences and positions of their intron-exon junctions, which suggests that they evolved by duplication and divergence from a common ancestral gene. Characterization of the mutations in the α-N-acetylgalactosaminidase gene causing the three subtypes revealed a nonsense (E193X) and several missense mutations (S160C, E325K, R329W, and E367K). Transient expression of the type I E325K and the type II R329W alleles revealed that both mutant enzyme subunits were synthesized, but were unstable, the E325K glycopeptide having a shorter half-life. Consistent with this finding, no enzyme protein was immunologically detectable in cultured fibroblasts from either the type I or type II probands who were homoallelic for these mutations.

6. The murine α-N-acetylgalactosaminidase gene is highly homologous to the human sequence and was used to produce knockout mice which have α-N-acetylgalactosaminidase deficiency, and which pathologically have lysosomal accumlation of substrates with α-N-acetylgalactosaminyl residues in neural and visceral tissues with the notable occurrence of “spheroids” in the spinal cord which resemble those seen in Seitelberger disease.

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