TY - JOUR
T1 - Natural history of MELAS associated with mitochondrial DNA m.3243A>G genotype
AU - Kaufmann, Petra
AU - Engelstad, K.
AU - Wei, Y.
AU - Kulikova, R.
AU - Oskoui, M.
AU - Sproule, D. M.
AU - Battista, V.
AU - Koenigsberger, D. Y.
AU - Pascual, J. M.
AU - Shanske, S.
AU - Sano, M.
AU - Mao, X.
AU - Hirano, M.
AU - Shungu, D. C.
AU - DiMauro, S.
AU - De Vivo, D. C.
N1 - Funding Information:
Dr. Kaufmann conducted the work reported here while she was a full-time employee of Columbia University. This report is not related to her current work at NINDS. She has received consulting honoraria from the SMA Foundation; has received travel reimbursement to investigator meetings from the NIH, SMA Foundation, the MDA, Santhera Pharmaceuticals, and PTC Therapeutics, Inc.; serves on the editorial board of Neuromuscular Disorders ; has received research support from Santhera Pharmaceuticals, Penwest Pharmaceuticals Co., PTC Therapeutics, Inc., the NIH/NINDS, the US Department of Defense, and the SMA Foundation; and her spouse serves on the editorial board of Pediatric Pulmonology . K. Engelstad, Dr. Wei, and Dr. Kulikova report no disclosures. Dr. Oskoui has received fellowship support from the Canadian Institutes of Health Research. Dr. Sproule has received funding for travel from UCB; receives/has received research support from PTC Therapeutics, Inc., the NIH/NINDS Neurological Science Academic Development Award, the Spinal Muscular Atrophy Foundation, and the American Academy of Neurology Foundation; holds stock and stock options in Pfizer Inc; and his spouse is an employee of Pfizer Inc. V. Battista and D.Y. Koenigsberger report no disclosures. Dr. Pascual serves as an Associate Editor for Neuroscience Letters . Dr. Shanske reports no disclosures. Dr. Sano serves on a scientific advisory board for Medivation, Inc.; serves as a consultant for Bayer Schering Pharma, Bristol-Meyers Squibb, Elan Corporation, Genentech, Inc., Medivation, Inc., Medpace Inc., Pfizer Inc, Takeda Pharmaceutical Company Limited, and United Biosource Corporation; and receives research support from the NIH (NIA/NCRR). X. Mao reports no disclosures. Dr. Hirano serves on the scientific advisory board for Telethon Italy; has received funding for travel from the American College of Medical Genetics; serves as Nerve and Muscle editor of Current Neurology and Neuroscience Reports and served on the editorial board of the Journal of Neuromuscular Disorders ; has served on the speakers' bureau for Athena Diagnostics, Inc.; and has received research support from Santhera Pharmaceuticals, Edison Pharmaceuticals, Inc., the NIH, the Muscular Dystrophy Association USA, and the Marriott Mitochondrial Disorder Clinical Research Fund (MMDCRF). Dr. Shungu reports no disclosures. Dr. Di Mauro serves as Chairman, Scientific Advisory Committee, Telethon Italy; serves on the editorial boards of Muscle and Nerve, Neuromuscular Disorders , and Acta Myologica ; serves as a consultant for Athena Diagnostics, Inc.; and receives research support from the NIH/NICHD and the Marriott Mitochondrial Disorder Clinical Research Fund (MMDCRF). Dr. De Vivo serves on scientific advisory boards for the SMA Foundation, the Colleen Giblin Foundation, the Pediatric Neurotransmitter Disease Association, the International Reye Syndrome Foundation, and the Will Foundation; serves as a consultant for Isis Pharmaceuticals, Inc.; receives royalties from publishing The Molecular Basis and Genetic Basis of Neurologic and Psychiatric Disease, 4th edition (Lippincott Williams & Wilkins, 2008); receives research support from the NIH (NINDS, NICHD), the US Department of Defense, the SMA Foundation, the Colleen Giblin Foundation, the Will Foundation, and the Pediatric Neurotransmitter Disease Association; and has served as an expert witness in a medico-legal case.
PY - 2011/11/29
Y1 - 2011/11/29
N2 - Objective: To describe the natural history of clinical and laboratory features associated with the m.3243A>G mitochondrial DNA point mutation. Natural history data are needed to obtain prognostic information and for clinical trial planning. Methods: We included 85 matrilineal relatives from 35 families with at least 2 visits in this prospective cohort study. Thirty-one were fully symptomatic with mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS), and 54 were carrier relatives. Evaluations included standardized questionnaires (medical history and daily living functioning), physical examination, neuropsychological testing, and a battery of imaging and laboratory tests. We evaluated changes in clinical and laboratory features over time and survival. Outcomes are reported over a follow-up period of up to 10.6 years (mean 3.8 ± 2.2 years for patients and 5.5 ± 3.0 for carrier relatives). Results: Neurologic examination, neuropsychological testing, and daily living scores significantly declined in all patients with MELAS, whereas no significant deterioration occurred in carrier relatives. Cerebral MRI scores declined significantly in patients with MELAS. Magnetic resonance spectroscopy estimates of lactate in the lateral ventricles increased over time, and high lactate was associated with increased mortality. Symptom onset in childhood often was associated with worse outcome. Patients with MELAS had a greater death rate than carrier relatives. Conclusions: Patients with MELAS carrying the m.3243A>G mutation show a measurable decline in clinical and imaging outcomes. It is hoped that these data will be helpful in anticipating the disease course and in planning clinical trials for MELAS.
AB - Objective: To describe the natural history of clinical and laboratory features associated with the m.3243A>G mitochondrial DNA point mutation. Natural history data are needed to obtain prognostic information and for clinical trial planning. Methods: We included 85 matrilineal relatives from 35 families with at least 2 visits in this prospective cohort study. Thirty-one were fully symptomatic with mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS), and 54 were carrier relatives. Evaluations included standardized questionnaires (medical history and daily living functioning), physical examination, neuropsychological testing, and a battery of imaging and laboratory tests. We evaluated changes in clinical and laboratory features over time and survival. Outcomes are reported over a follow-up period of up to 10.6 years (mean 3.8 ± 2.2 years for patients and 5.5 ± 3.0 for carrier relatives). Results: Neurologic examination, neuropsychological testing, and daily living scores significantly declined in all patients with MELAS, whereas no significant deterioration occurred in carrier relatives. Cerebral MRI scores declined significantly in patients with MELAS. Magnetic resonance spectroscopy estimates of lactate in the lateral ventricles increased over time, and high lactate was associated with increased mortality. Symptom onset in childhood often was associated with worse outcome. Patients with MELAS had a greater death rate than carrier relatives. Conclusions: Patients with MELAS carrying the m.3243A>G mutation show a measurable decline in clinical and imaging outcomes. It is hoped that these data will be helpful in anticipating the disease course and in planning clinical trials for MELAS.
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U2 - 10.1212/WNL.0b013e31823a0c7f
DO - 10.1212/WNL.0b013e31823a0c7f
M3 - Review article
C2 - 22094475
AN - SCOPUS:82955225292
VL - 77
SP - 1965
EP - 1971
JO - Neurology
JF - Neurology
SN - 0028-3878
IS - 22
ER -