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Biochemical-Clinical Correlation in Patients With Different Loads of the Mitochondrial DNA T8993G Mutation
Valerio Carelli, MD, PhD;
Alessandra Baracca, PhD;
Silvia Barogi, PhD;
Francesco Pallotti, MD, PhD;
Maria Lucia Valentino, MD;
Pasquale Montagna, MD;
Massimo Zeviani, MD;
Antonella Pini, MD;
Giorgio Lenaz, MD;
Agostino Baruzzi, MD;
Giancarlo Solaini, PhD
Arch Neurol. 2002;59:264-270.
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.
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).
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