Biochemical-clinical correlation in patients with different loads of the mitochondrial DNA T8993G mutation.
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.
Carelli
Valerio
V
Istituto di Clinica Neurologica, Universita' di Bologna, Via U Foscolo 7, 40123 Bologna, Italy. carelli@neuro.unibo.it
Baracca
Alessandra
A
Barogi
Silvia
S
Pallotti
Francesco
F
Valentino
Maria Lucia
ML
Montagna
Pasquale
P
Zeviani
Massimo
M
Pini
Antonella
A
Lenaz
Giorgio
G
Baruzzi
Agostino
A
Solaini
Giancarlo
G
D000255:Adenosine Triphosphate / Q000096:biosynthesis* / Q000378:metabolism; D001259:Ataxia / Q000235:genetics* / Q000473:pathology; D001792:Blood Platelets; D004252:DNA Mutational Analysis; D004272:DNA, Mitochondrial / Q000235:genetics*; D005260:Female; D005786:Gene Expression Regulation; D006801:Humans; D006868:Hydrolysis; D007888:Leigh Disease / Q000235:genetics* / Q000473:pathology; D008297:Male; D009422:Nervous System Diseases / Q000235:genetics / Q000473:pathology; D010641:Phenotype; D012174:Retinitis Pigmentosa / Q000235:genetics* / Q000473:pathology
D004272:DNA, Mitochondrial; D000255:Adenosine Triphosphate