Cerebral metabolic abnormalities in A3243G mitochondrial DNA mutation carriers.
OBJECTIVE
To establish cerebral metabolic features associated with the A3243G mitochondrial DNA mutation with proton magnetic resonance spectroscopic imaging ((1)H MRSI) and to assess their potential as prognostic biomarkers.


METHODS
In this prospective cohort study, we investigated 135 clinically heterogeneous A3243G mutation carriers and 30 healthy volunteers (HVs) with (1)H MRSI. Mutation carriers included 45 patients with mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS); 11 participants who would develop the MELAS syndrome during follow-up (converters); and 79 participants who would not develop the MELAS syndrome during follow-up (nonconverters). The groups were compared with respect to MRSI metabolic indices of 1) anaerobic energy metabolism (lactate), 2) neuronal integrity (N-acetyl-l-aspartate [NAA]), 3) mitochondrial function (NAA; lactate), 4) cell energetics (total creatine), and 5) membrane biosynthesis and turnover (total choline [tCho]).


RESULTS
Consistent with prior studies, the patients with MELAS had higher lactate (p < 0.001) and lower NAA levels (p = 0.01) than HVs. Unexpectedly, converters showed higher NAA (p = 0.042), tCho (p = 0.004), and total creatine (p = 0.002), in addition to higher lactate levels (p = 0.032), compared with HVs. Compared with nonconverters, converters had higher tCho (p = 0.015). Clinically, converters and nonconverters did not differ at baseline. Lactate and tCho levels were reliable biomarkers for predicting the risk of individual mutation carriers to develop the MELAS phenotype.


CONCLUSIONS
(1)H MRSI assessment of cerebral metabolism in A3243G mutation carriers shows promise in identifying disease biomarkers as well as individuals at risk of developing the MELAS phenotype.
From the Department of Radiology (N.W., X.M., D.S.), Weill Cornell Medical College, New York; and Department of Neurology (P.K., K.M.E., V.H., S.D., D.D.V.), Columbia University College of Physicians and Surgeons, New York, NY.
Nora
N
Weiduschat
Petra
P
Kaufmann
Xiangling
X
Mao
Kristin Marie
KM
Engelstad
Veronica
V
Hinton
Salvatore
S
DiMauro
Darryl
D
De Vivo
Dikoma
D
Shungu
D000140:Acidosis, Lactic / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D000328:Adult; D000368:Aged; D001224:Aspartic Acid / Q000378:metabolism; D002540:Cerebral Cortex / Q000378:metabolism* / Q000473:pathology; D002794:Choline / Q000378:metabolism; D003401:Creatine / Q000378:metabolism; D004272:DNA, Mitochondrial / Q000235:genetics* / Q000378:metabolism; D005260:Female; D006801:Humans; D019344:Lactic Acid / Q000378:metabolism; D008137:Longitudinal Studies; D017241:MELAS Syndrome / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D008875:Middle Aged; D009154:Mutation; D011446:Prospective Studies
D004272:DNA, Mitochondrial; D001224:Aspartic Acid; D019344:Lactic Acid; D003401:Creatine; D002794:Choline