Tay-Sachs Disease: Ultrastructural Studies on Cultured Fibroblasts

Abstract

SummaryThe knowledge that the biochemical lesion associated with Tay-Sachs disease is demonstrable in many tissues, and in particular in cultured fibroblasts, suggested that ultrastructural lesions might also accompany hexosaminidase A deficiency in cultured fibroblasts. Electron microscopic studies on six human skin fibroblast lines and four amniotic fluid fibroblast lines, biochemically confumed to be deficient in hexosaminidase A, showed characteristic cvtoplasmic inclusions not observed in any normal lines studied. u p i o 60 of these abnormal cytoplasm^ inclusions were observed in full cell cross sections in all affected lines examined. SpeculationElectron microscopy of cultured fibroblasts deficient in hexosaminidase A may have value in the understanding of the cellular processes which led to Tay-Sachs disease. Ultrastructural examination may also prove to be of value in the prenatal diagnosis of the disease and possible enzyme replacement therapy Tay-Sachs disease, also termed Gm, gangliosidosis type I, is an autosomal recessive condition which is found predominantly among decendants of Ashkenazie Jews (1 1). The frequency of carriers in these populations is approximately 1 in 30 and the frequency of affected individuals approximately 1 in 4000 live births in this ethnic group (16). Individuals affected with TaySachs disease usually die by 5 years of age.The biochemical abnormality in this disease has been determined to be a marked deficiency in the enzyme hexosaminidase A which, because of the altered metabolic activity, leads to the accumulation of ganglioside Gm, in numerous tissues of the affected individual (13). The accumulation of ganglioside Gm, has also been detected in cultured cells (2). Biochemical assay of the activity of hexosaminidase A has been determined in liver, brain, skin, kidney, leukocytes, serum, cultured fibroblasts, and amniotic fluid cells (6, 13). In addition, electron microscopic examination of neuronal cells from children affected with Tay-Sachs disease has shown the presence of numerous membraneous cytoplasmic bodies which are composed of concentrically arranged membranes, closely packed together (16). Some investigators consider these inclusions to be characteristic for the disease (12). The bodies measure between 0.5 and 2.0 p m in diameter and have been demonstrated to be the site of acid phosphatase activity, indicating their probable lysosomal origin (17). Chemical analysis demonstrates that they contain large quantities of ganglioside Gm, (15).The knowledge that the biochemical lesion associated with Tay-Sachs disease is demonstrable in many tissues and, in particular, in cultured fibroblasts, suggested that ultrastructural lesions might also accompany hexosaminidase A deficiency in cultured fibroblasts. To investigate this possibility, an electron microscopic examination was made of cultured cells known to be deficient in hexosaminidase A .We have demonstrated that cultured fibroblasts derived from individuals affected with Tay-Sachs disease have distinct morphologic ...

Differential activities of glycolipid glycosyltransferases in Tay-Sachs disease: studies in cultured cells from cerebrum.

“…It is classified as GM2-gangliosidosis type I because of its neuronal accumulation of GM2 ganglioside (1-3) and its asialo derivative (4), gangliotriaosylceramide (GgOsesCer). Since the publication by Klenk in 1939, it has been reported repeatedly that TSD is a clinically (5), morphologically (6,7), and genetically (8) well-defined entity, but its exact biochemical cause is evidently very complex. It has been observed that cultured skin fibroblast cells from TSD patients lack 3-D-hexosaminidase A (9), but these cultured cells do not accumulate GM2 ganglioside.…”