Schindler disease: An inherited neuroaxonal dystrophy due to α‐ N ‐acetylgalactosaminidase deficiency

Summary The clinical, pathological and biochemical features of a neuroaxonal dystrophy resulting from the deficient activity of lysosomal α‐ N ‐acetylgalactosaminidase are described. This neurodegenerative disorder was recognized in two brothers who had the typical clinical manifestations and neuropathological lesions observed in patients with Seitelberger disease, the infantile form of neuroaxonal dystrophy. Axonal ‘spheroids’ were observed histologically in the grey matter, and ultrastructural examination revealed the characteristic formations in dystrophic axons in the myenteric plexus and neocortex. Using a newly synthesized fluorogenic substrate, 4‐methylumbelliferyl‐ α ‐ N ‐acetylgalactosaminide, the markedly deficient activity of α ‐ N ‐acetylgalactosaminidase was demonstrated in the affected brothers while their consanguineous parents had intermediate activities, consistent with the autosomal recessive transmission of this disease. No detectable α ‐ N ‐acetylgalactosaminidase was seen in immunoblots using monospecific rabbit antihuman α ‐ N ‐acetylgalactosaminidase antibodies. Abnormally increased amounts of urinary glycopeptides were observed by high resolution thin layer chromatography. Analytical studies identified four of the accumulating urinary compounds, the blood group A trisaccharide GalNAc α 1 → 3(Fuc α 1 → 2)Gal and three O ‐linked glycopeptides, GalNAc α 1 → O ‐serine and ‐threonine, NeuNAc α 2 → 3Gal β 1 → 3(NeuNAc α 2 → 6)GalNAc α 1 → O ‐serine and ‐threonine, and NeuNAc α 2 → 3Gal β 1 → 4GlcNAc β 1 → 6(NeuNAc α 2 → 3Gal β 1 → 3)GalNAc α 1 → O ‐serine and ‐threonine. Of eight unrelated patients diagnosed as having infantile neuraxonal dystrophy by pathological studies, none had deficient α ‐ N ‐acetylgalactosaminidase activity, emphasizing the biochemical heterogeneity underlying this diagnostic entity. These findings document the first delineation of a metabolic defect in an inherited neuroaxonal dystrophy and suggest that the axonal pathology in this disorder, and perhaps in the other neuroaxonal dystrophies, results from abnormal glycoprotein metabolism involving O ‐linked glycopeptides.