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Original Contribution
February 2002

Biochemical-Clinical Correlation in Patients With Different Loads of the Mitochondrial DNA T8993G Mutation

Author Affiliations

From the Istituto di Clinica Neurologica (Drs Carelli, Valentino, Montagna, and Baruzzi) and Dipartimento di Biochimica (Drs Baracca and Lenaz), Universita' di Bologna, Bologna, Italy; Doheny Eye Institute, University of Southern California, Los Angeles (Dr Carelli); Scuola Superiore di Studi Universitari e di Perfezionamento S. Anna, Pisa, Italy (Drs Barogi and Solaini); College of Physicians and Surgeons, Columbia University, New York, NY (Dr Pallotti); Istituto Nazionale Neurologico "C. Besta," Milano, Italy (Dr Zeviani); and Ospedale Maggiore, Bologna (Dr Pini).

Arch Neurol. 2002;59(2):264-270. doi:10.1001/archneur.59.2.264

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.