G
            <sub>M2</sub>
            ‐gangliosidosis with total hexosaminidase deficiency

Suzuki, Yôichi; Jacob, Jerry; Kutty, Karthiyanee; Suzuki, Kiminori

doi:10.1212/wnl.21.4.313

Cited by 87 publications

(16 citation statements)

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“…Our results indicate that previous reports of the elevation of GM3 in TS brain samples (25)(26)(27)(28)(29), based primarily on TLC analysis, may instead be due to the presence of tauro-GM2, because the TLC mobility of tauro-GM2 is very close to that of GM3 (see Fig. 2B).…”

Section: Immunological Detection Of the Presence Of Tauro-gm2 Insupporting

confidence: 67%

“…Because the TLC mobilities of these two fast moving GSLs were very close to those of GM3 (see Fig. 1A), and the level of GM3 had been reported to be also elevated in TS brains (25)(26)(27)(28)(29), we initially regarded them as a doublet of GM3. However, clostridial sialidase (Sigma) converted only about 30% of these fast moving bands to lactosylceramide, indicating that these bands contained a UC other than GM3.…”

Section: Detection and Isolation Of A Uc From A Variant B Ts Brainmentioning

confidence: 99%

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Presence of an Unusual GM2 Derivative, Taurine-conjugated GM2, in Tay-Sachs Brain

Maskos

Chou

et al. 2003

Journal of Biological Chemistry

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Tay-Sachs disease (TSD) is a classical glycosphingolipid (GSL) storage disease. Although the genetic and biochemical bases for a massive cerebral accumulation of ganglioside GM2 in TSD have been well established, the mechanism for the neural dysfunction in TSD remains elusive. Upon analysis of GSLs from a variant B TS brain, we have detected a novel GSL that has not been previously revealed. We have isolated this GSL in pure form. Using NMR spectroscopy, mass spectrometry, and chemical synthesis, the structure of this unusual GSL was established to be a taurine-conjugated GM2 (tauro-GM2) in which the carboxyl group of Nacetylneuraminic acid was amidated by taurine. Using a rabbit anti-tauro-GM2 serum, we also detected the presence of tauro-GM2 in three other small brain samples from one variant B and two variant O TSD patients. On the other hand, tauro-GM2 was not found in three normal human brain samples. The presence of tauro-GM2 in TS brains, but not in normal brains, indicates the possible association of this unusual GM2 derivative with the pathogenesis of TSD. Our findings point to taurine conjugation as a heretofore unelucidated mechanism for TS brain to cope with water-insoluble GM2. Tay-Sachs disease (TSD)1 is a classical inborn lysosomal glycosphingolipid (GSL) storage disease characterized by massive cerebral accumulation of ganglioside GM2 due to the deficiency of either ␤-hexosaminidase A or GM2-activator protein (1). Although the genetic mutations and biochemical basis of TSD have been well established (1, 2), the mechanism that leads to the neuropathological manifestations in TSD is still not fully understood (1). Based on the premise that GSLs specifically found in TS brain are associated with the pathogenesis of TSD, we carried out studies of GSLs in brain samples from patients with TSD. This report describes the detection and structural elucidation of a novel GM2 derivative in TS brain samples. By using NMR spectroscopy, mass spectrometry, and chemical synthesis, the structure of this GM2 derivative isolated from a 75-g variant B TS brain sample was established to be tauro-GM2 in which the carboxyl group of Neu5Ac is amidated by taurine. We have also raised a rabbit anti-tauro-GM2 serum and immunologically detected the presence of tauro-GM2 in additional small brain samples (1-2 g) from one variant B and two variant O TSD patients. Under the same conditions, we did not detect the presence of tauro-GM2 in three normal human brain samples. EXPERIMENTAL PROCEDURES Isolation of an Unknown Compound (UC) from a Variant B TS BrainSample-Crude GSL extract was prepared from the brain sample (75 g) of a variant B TS patient as described (3). The GSL extract was dissolved in 70 ml of chloroform/methanol/water (30/60/8, v/v/v) and applied onto a Q-Sepharose column (2.5 ϫ 75 cm) that had been equilibrated with the same solvent. After washing the column with the same solvent, the gangliosides were eluted with a linear gradient of sodium acetate (4). The flow rate was 1.0 ml/min, and 7-ml fractions were collec...

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Section: Immunological Detection Of the Presence Of Tauro-gm2 Insupporting

confidence: 67%

Section: Detection and Isolation Of A Uc From A Variant B Ts Brainmentioning

confidence: 99%

Presence of an Unusual GM2 Derivative, Taurine-conjugated GM2, in Tay-Sachs Brain

Maskos

Chou

et al. 2003

Journal of Biological Chemistry

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“…Chemical analysis of solid organ tissue was limited to the small sample of liver, precluding extensive study. Less than 25% of the increased dry weight of this sample could be accounted for by increased chloroform-methanol-extractable material; the other >75% may have been stored polysaccharide, as in liver in GM, gangliosidosis type I [48], and in brain in one reported case of lype 11 [39], particularly in view of our patient's increased urinary excretion of some polysaccharide component. However, this increase in dry weight must be interpreted cautiously; despite precautions, the sample may have become desiccated during storage.…”

Section: Enzyme Assaymentioning

confidence: 75%

A New Variant of Sandhoff's Disease

et al. 1974

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ExtractA 28-month-old Negro male with atypical Sandhoff's disease (GM2 gangliosidosis, type 2) is described. Clinical presentation closely resembled Sandhoff's disease. The appendiceal neuron cytoplasm was distended with periodic acid-Schiff (PAS)-positive material. Hepatic glycolipid N-acetylneuraminic acid was elevated 1.5-fold, chiefly because of increased GM2. Neutral glycolipid hexose was elevated twofold, mainly because of a component with globoside-like chromatographic properties. Unlike patients with Sandhops disease, the child had total 0-D-N-acetylhexosaminidase activity 20-24% of normal in serum and plasma and 7-1 1% of normal in leukocytes and cultured fibroblasts, but activity in liver (<2y0 of normal) was similar to that in Sandhoff's disease. In all tissues examined, >95% of the activity was heat denaturable, corresponding in electrophoretic mobility to the heat-denaturable component of normal tissues. The decrease in heat-denaturable activity with time and the pH optimum were similar in patient and control crude tissue preparations and partially purified preparations of plasma hexosaminidase A. In the child's mother, total hexosaminidase activity was approximately 50y0 of mean control values in serum, plasma, and leukocytes, and serum hexosaminidase A was relatively increased. This finding, together with the death of at least three other children in the kindred from an apparently phenotypically similar illness, indicates the inherited nature of the disorder. SpeculationAppreciable hexosaminidase activity in serum and plasma and its marked deficiency in liver suggest that the active form (or forms) in serum and plasma differ from those in solid tissues, and that the mutation in the case described has altered the hexosaminidases in a manner that virtually abolishes their activity in solid tissues but permits their partial activity in serum and plasma.

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“…Also, catabolism of GM2, peripherally, can also occur through the neuraminidase pathway and the combined activity of GM2 neuraminidase which is functioning and hexosaminidase B which is augmented in Tay-Sachs disease is sufficient to prevent the accumulation of a significant quantity of Tay-Sachs ganglioside in non-neural tissues. The absence of even hexosaminidase B in patients with the O-variant form of Tay-Sachs disease may be responsible for the even greater accumulation of GM2 in the brain of these infants compared with that in conventional cases of Tay-Sachs disease (26).…”

Section: Discussionmentioning

confidence: 95%

The metabolism of Tay-Sachs ganglioside: catabolic studies with lysosomal enzymes from normal and Tay-Sachs brain tissue

Tallman¹,

Johnson²,

Brady³

1972

J. Clin. Invest.

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G _M2 ‐gangliosidosis with total hexosaminidase deficiency

Cited by 87 publications

References 0 publications

Presence of an Unusual GM2 Derivative, Taurine-conjugated GM2, in Tay-Sachs Brain

Presence of an Unusual GM2 Derivative, Taurine-conjugated GM2, in Tay-Sachs Brain

A New Variant of Sandhoff's Disease

The metabolism of Tay-Sachs ganglioside: catabolic studies with lysosomal enzymes from normal and Tay-Sachs brain tissue

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G M2 ‐gangliosidosis with total hexosaminidase deficiency

Cited by 87 publications

References 0 publications

Presence of an Unusual GM2 Derivative, Taurine-conjugated GM2, in Tay-Sachs Brain

Presence of an Unusual GM2 Derivative, Taurine-conjugated GM2, in Tay-Sachs Brain

A New Variant of Sandhoff's Disease

The metabolism of Tay-Sachs ganglioside: catabolic studies with lysosomal enzymes from normal and Tay-Sachs brain tissue

Contact Info

Product

Resources

About

G _M2 ‐gangliosidosis with total hexosaminidase deficiency