Faculty Bibliography

A 32-year-old man with mannosidosis had a gait disorder develop that was associated with communicating hydrocephalus. The gait disorder improved with ventriculoperitoneal shunting, but proximal muscle weakness remained. Biopsy specimens of muscle and nerve disclosed typical lysosomal inclusions in both tissues, as well as selective loss of unmyelinated axons

Many of the known gene defects result in inborn errors of metabolism that produce irreversible damage to the central nervous system. A variety of new clinical, morphologic, biochemical, and genetic techniques are being used to characterize these disorders more precisely. At the Shriver Center, the different genotypes of GM2-gangliosidosis are distinguished according to the ability of cells in culture to metabolize radioactively-labeled GM2-ganglioside. Large-scale screening for carriers of the trait for Tay-Sachs disease, the most common of the GM2-gangliosidoses, has dramatically reduced the incidence of this disease. Current efforts to isolate the genes for the alpha and beta chains of hexosaminidase A will lay the groundwork for better understanding of the molecular defects in these diseases and offers hope for a possible treatment

This study presents the case of a patient who had jejunal diverticulosis with perforation and abscess formation as a complication of Fabry's disease. Light microscopy disclosed glycolipid deposition in the neurons and nerve fibers of the intestinal nerve plexuses and smooth muscle. Silver stains of the myenteric plexus in the involved segment of the bowel showed enlarged, granular argyrophobic neurons and a marked decrease in the number of argyrophilic neurons, with those remaining being enlarged and distorted by the cytoplasmic glycolipid accumulation. These abnormalities of the myenteric plexus suggest that jejunal diverticulosis may be the result of a variety of disorders of the smooth muscle or myenteric plexus, or both. We propose that jejunal diverticulosis in our patient was a consequence of uncoordinated smooth muscle activity resulting from Fabry's involvement of myenteric plexus neurons, with mucosal protrusion through the smooth muscle

Low arylsulfatase A levels are reported in two siblings, one with a neurologic disability not typical for metachromatic leukodystrophy, the other a healthy 18-year-old female with a normal developmental history. In both individuals, arylsulfatase A levels in white blood cells were 7-8% of control values. Cultured fibroblasts gave low values (8-10% of normal) for both cerebroside sulfatase and arylsulfatase A activities. Other family members had enzyme levels consistent with heterozygote or normal status. Cerebroside sulfate loading tests of cultured fibroblasts in 199-CO2 media were normal for all family members who were tested. In MEM-HEPES media, however, cells from the two arylsulfatase A deficient siblings showed attenuated sulfolipid catabolism. Additional clinical and laboratory studies on these individuals failed to demonstrate any features suggestive of metachromatic leukodystrophy, i.e., normal nerve conduction velocities, normal sural nerve biopsy results, and normal urinary sulfatide excretion. It is concluded that the neurologic abnormalities in the one sibling are not the result of the low enzyme activity and that both individuals represent examples of pseudo arylsulfatase A deficiency (arylsulfatase A deficiency without metachromatic leukodystrophy). These results thus call into question the ability of the high-sensitivity cerebroside sulfate loading test as carried out in MEM-HEPES media to differentiate pathologically significant defects i.e., metachromatic leukodystrophy from benign 'pseudo-deficiencies.'