The UK MRC Mitochondrial Disease Patient Cohort Study: clinical phenotypes associated with the m.3243A>G mutation—implications for diagnosis and management

• Published in: Journal of neurology, neurosurgery and psychiatry Vol. 84; no. 8; pp. 936 - 938
• Main Authors: Nesbitt, Victoria, Pitceathly, Robert D S, Turnbull, Doug M, Taylor, Robert W, Sweeney, Mary G, Mudanohwo, Ese E, Rahman, Shamima, Hanna, Michael G, McFarland, Robert
• Format: Journal Article
• Language: English
• Published: England BMJ Publishing Group Ltd 01.08.2013; BMJ Publishing Group LTD
• Subjects: Adolescent; Adult; Aged; Cardiomyopathies - epidemiology; Cardiomyopathies - etiology; Cardiomyopathies - genetics; Cardiomyopathy; Child; Child, Preschool; Clinical Neurology; Cohort Studies; Diabetes; Diabetes Complications - epidemiology; Diabetes Complications - genetics; Diabetes Mellitus; Diabetes Mellitus - epidemiology; Diabetes Mellitus - genetics; Disease; Epidemiology; Epilepsy; Family medical history; Female; Genotype & phenotype; Hearing Loss, Sensorineural - epidemiology; Hearing Loss, Sensorineural - etiology; Humans; Infant; Male; MELAS Syndrome - epidemiology; MELAS Syndrome - genetics; Middle Aged; Mitochondrial Diseases - diagnosis; Mitochondrial Diseases - genetics; Mitochondrial Diseases - therapy; Mitochondrial Disorders; Mitochondrial DNA; Mitochondrial Encephalomyopathies - epidemiology; Mitochondrial Encephalomyopathies - etiology; Mitochondrial Encephalomyopathies - genetics; Mutation; Mutation - genetics; Neuromuscular diseases; Studies; Surveillance; United Kingdom - epidemiology; Young Adult; Clinical Neurology; Diabetes Mellitus; Epidemiology; Epilepsy; Mitochondrial Disorders
• ISSN: 0022-3050; 1468-330X; 1468-330X
• DOI: 10.1136/jnnp-2012-303528

Background Population-based studies suggest the m.3243A>G mutation in MTTL1 is the most common disease-causing mtDNA mutation, with a carrier rate of 1 in 400 people. The m.3243A>G mutation is associated with several clinical syndromes including mitochondrial encephalopathy lactic acidosis and stroke-like episodes (MELAS), maternally inherited deafness and diabetes (MIDD) and progressive external ophthalmoplegia (PEO). Many patients affected by this mutation exhibit a clinical phenotype that does not fall within accepted criteria for the currently recognised classical mitochondrial syndromes. Methods We have defined the phenotypic spectrum associated with the m.3243A>G mtDNA mutation in 129 patients, from 83 unrelated families, recruited to the Mitochondrial Disease Patient Cohort Study UK. Results 10% of patients exhibited a classical MELAS phenotype, 30% had MIDD, 6% MELAS/MIDD, 2% MELAS/chronic PEO (CPEO) and 5% MIDD/CPEO overlap syndromes. 6% had PEO and other features of mitochondrial disease not consistent with another recognised syndrome. Isolated sensorineural hearing loss occurred in 3%. 28% of patients demonstrated a panoply of clinical features, which were not consistent with any of the classical syndromes associated with the m.3243A>G mutation. 9% of individuals harbouring the mutation were clinically asymptomatic. Conclusion Following this study we propose guidelines for screening and for the management of confirmed cases.