Edoardo Malfatti, MD Pascal Laforêt, MD, PhD Claude Jardel, PhD Tanya Stojkovic, MD Anthony Behin, MD Bruno Eymard, MD, PhD Anne Lombès, MD, PhD Amria Benmalek, MD Henri-Marc Bécane, MD Nawal Berber, PhD Christophe Meune, MD, PhD Denis Duboc, MD, PhD Karim Wahbi, MD Correspondence to Dr. Wahbi: karim.wahbi@psl.aphp.fr Supplemental data at www.neurology.org Supplemental Data High risk of severe cardiac adverse events in patients with mitochondrial m.3243A.G mutation ABSTRACT Objectives: To determine the long-term incidence of cardiac life-threatening complications and death in patients with the m.3243A.G mutation, and to identify cardiac prognostic factors. Methods: We retrospectively included patients carrying the m.3243A.G mutation who were admitted to the Neuromuscular Disease Clinic of Pitié Salpêtrière Hospital between January 1992 and December 2010. We collected information relative to their yearly neurologic and car- diac investigations, their mutation load in blood, urine, and muscle at initial admission, and the occurrence of cardiac life-threatening adverse events and death during follow-up. Results: Forty-one patients (median age 5 47 years [36–55 years], men 5 13) were included, of whom 38 had clinical manifestations of mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS) and 3 were asymptomatic. One patient had a personal history of cardiac transplantation. Cardiac investigations displayed left ventricular hypertrophy, left ven- tricular dysfunction, or both abnormalities in 18 patients, along with Wolff-Parkinson-White syn- drome in 7, conduction system disease in 4, and atrial fibrillation in 1. Over a median 5-year (3–9 years) follow-up period, 11 patients died, including 3 due to heart failure; 7 had life-threatening adverse events, including 6 hospitalizations for severe heart failure and 1 resuscitated cardiac arrest. By multivariate analysis, left ventricular hypertrophy was the only parameter indepen- dently associated with occurrence of cardiac adverse events. Conclusion: Patients with the m.3243A.G mutation have a high incidence of cardiac death and life-threatening adverse events. Left ventricular hypertrophy was the only parameter indepen- dently associated with occurrence of these events. Neurology â 2013;80:100–105 GLOSSARY DGGE 5 denaturing gradient gel electrophoresis; LV 5 left ventricular; m.3243A>G 5 A-to-G transition at nucleotide 3243; MELAS 5 mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes. Mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS) is a maternally inherited disorder characterized by progressive encephalopathy punctuated by episodes of focal brain injury. 1 The A-to-G transition at nucleotide 3243 (m.3243A.G) in MT-TL1, a mitochondrial leucine transfer RNA gene, is the most common mutation underlying MELAS. 2–6 Variation in the mutation load from patient to patient and heteroplasmy account at least partly for its phenotypic variability. 7–9 MELAS is associated with a reduced life expectancy mainly because of brain involvement, with possible occurrence of life-threatening complications such as stroke-like episodes or status epilepti- cus. 10,11 Among other manifestations of this multisystemic disease, cardiac involvement is one of the most frequently reported and may include hypertrophic cardiomyopathy, ventricular systolic dysfunction, and Wolff-Parkinson-White syndrome. 12–19 However, the impact of heart disease on From the AP-HP, Pitié-Salpêtrière Hospital (E.M., P.L., T.S., A.B., B.E., A.B., H.-M.B., N.B. K.W.), Reference Center for Muscle Diseases Paris- Est, Myology Institute, Paris, France; Department of Neurological, Neurosurgical, and Behavioral Sciences (E.M.), University of Siena, Italy; AP- HP, Biochemistry Department (C.J.), Pitié-Salpêtrière Hospital, Paris; AP-HP, Cochin Hospital (C.M., D.D.), Department of Cardiology, Paris Descartes University, Paris; INSERM (A.L.), UMRS 975 Cochin Hospital, APHP, Paris; Paris-Descartes (C.M., D.D.), Sorbonne Paris Cité University, Paris; and Pierre et Marie Curie–Paris 6 University (K.W.), Myology Institute, Pitié-Salpêtrière Hospital, Paris, France. Go to Neurology.org for full disclosures. Funding information and disclosures deemed relevant by the authors, if any, are provided at the end of the article. 100 © 2012 American Academy of Neurology ª 2012 American Academy of Neurology. Unauthorized reproduction of this article is prohibited.