| Project/Area Number |
10670735
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| Research Category |
Grant-in-Aid for Scientific Research (C)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
Pediatrics
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| Research Institution | University of Tokushima |
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Principal Investigator |
ETSUO Naito Dept. of Pediatrics, School of Medicine, Univ. of Tokushima, Assistant Professor, 医学部, 講師 (30227706)
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| Co-Investigator(Kenkyū-buntansha) |
KURODA Yasuhiro Dept. of Pediatrics, School of Medicine, Univ. of Tokushima, Professor, 医学部, 教授 (20035471)
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| Project Period (FY) |
1998 – 2000
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| Project Status |
Completed (Fiscal Year 2000)
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| Budget Amount *help |
¥3,100,000 (Direct Cost: ¥3,100,000)
Fiscal Year 2000: ¥900,000 (Direct Cost: ¥900,000)
Fiscal Year 1999: ¥800,000 (Direct Cost: ¥800,000)
Fiscal Year 1998: ¥1,400,000 (Direct Cost: ¥1,400,000)
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| Keywords | Leigh syndrome / Lactic acidomia / Mitochondrial disease |
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| Research Abstract |
We analyzed the biochemical and molecular defects in cultured lymphoblastoid cells obtained from 52 Japanese patients with Leigh syndrome, and these defects were determined in 26 patients (50%). Pyruvate dehydrogenase complex (PDHC) deficiency was detected in five patients, cytochrome c oxidase (complex IV, COX) deficiency in four patients, NADH-cytochrome c reductase (complex I) deficiency in four patients, and a point mutation of mitochondrial DNA in 13 patients (A8344G in one, T8993C in two, and T8993G in ten). These findings suggest that cultured lymphoblastoid cells are useful for elucidating the etiology of Leigh syndrome.
The most striking finding in our study was the higher incidence of thiamine-responsive PDHC deficiency in PDHC deficiency with Leigh syndrome. In four of five patients with PDHC deficiency, PDHC showed a reduced affinity for thiamine pyrophosphate. Treatment with high doses of thiamine resulted in a reduction in lactate and clinical improvement in these four patients, suggesting that some patients with Leigh syndrome may have a thiamine-responsive PDHC deficiency and high doses of thiamine may be useful at an early stage of neurologic abnormalities in patients with this type of PDHC deficiency.
We analyzed the SURF-1 gene in three patients with COX deficincy. Three novel mutations of the SURF-1 gene were identified. All mutations predicted loss of function of the SURF-1 protein ; in both patients' cells COX activity was decreased to less than 20% of the control mean. These results indicate that cultured lymphoblastoid cells are useful for elucidating the etiology of Leigh syndrome, and that loss of function of the SURF-1 gene product can be responsible for Leigh syndrome associated with severe COX deficiency in Japanese patients.
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