|Title||Biochemical-clinical correlation in patients with different loads of the mitochondrial DNA T8993G mutation.|
|Publication Type||Journal Article|
|Year of Publication||2002|
|Authors||Carelli, V, Baracca, A, Barogi, S, Pallotti, F, Valentino, MLucia, Montagna, P, Zeviani, M, Pini, A, Lenaz, G, Baruzzi, A, Solaini, G|
|Date Published||2002 Feb|
|Keywords||Adenosine Triphosphate, Ataxia, Blood Platelets, DNA Mutational Analysis, DNA, Mitochondrial, Female, Gene Expression Regulation, Humans, Hydrolysis, Leigh Disease, Male, Nervous System Diseases, Phenotype, Retinitis Pigmentosa|
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.
|Alternate Journal||Arch. Neurol.|