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Biochemical-clinical correlation in patients with different loads of the mitochondrial DNA T8993G mutation.

Authors: Carelli, Valerio  Baracca, Alessandra  Barogi, Silvia  Pallotti, Francesco  Valentino, Maria Lucia  Montagna, Pasquale  Zeviani, Massimo  Pini, Antonella  Lenaz, Giorgio  Baruzzi, Agostino  Solaini, Giancarlo 
Citation: Carelli V, etal., Arch Neurol. 2002 Feb;59(2):264-70.
Pubmed: (View Article at PubMed) PMID:11843698

OBJECTIVE: To investigate the correlation between biochemical and clinical phenotype in 6 patients from 3 unrelated families with different mutation loads (heteroplasmy) of the T8993G mitochondrial DNA mutation associated with neuropathy, ataxia, and retinitis pigmentosa-Leigh syndrome.
METHODS: We studied adenosine triphosphate (ATP) synthase activity (synthesis and hydrolysis) in platelet-derived submitochondrial particles and assessed mutant loads both in platelets used for biochemical analysis and in other available tissues. Biochemical and molecular results were correlated with clinical features.
RESULTS: The rate of ATP hydrolysis was normal, but ATP synthesis was severely impaired (30% to 4% of residual activity) in patients harboring 34% to 90% mutant mitochondrial DNA, without any evidence of a threshold for the expression of this defect. There was little variation in heteroplasmy among tissues from each patient, but wider variability was detected in 2 mothers. Correlation of heteroplasmy and clinical and biochemical features suggested that ATP synthesis is defective at mutant loads as low as 34% and is extremely reduced at mutant loads above 80% when the phenotype is neuropathy, ataxia, and retinitis pigmentosa-Leigh syndrome.
CONCLUSIONS: This study indicates a close relationship between tissue heteroplasmy, expression of the biochemical defect in platelets, and clinical involvement. The biochemical defect was greater than previously reported, and we found no evidence of a biochemical threshold. The uniform distribution of high mutant loads among our patients' tissues suggests a differential tissue-specific reliance on mitochondrial ATP synthesis.


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RGD Object Information
RGD ID: 13825442
Created: 2018-12-05
Species: All species
Last Modified: 2018-12-05
Status: ACTIVE


RGD is funded by grant HL64541 from the National Heart, Lung, and Blood Institute on behalf of the NIH.