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

TLDR

The m.3243A>G mtDNA mutation, present in about 1 in 400 people, is the most common pathogenic mutation and is linked to MELAS, MIDD, and PEO, yet many carriers exhibit phenotypes that do not fit these classical syndromes. The study aims to develop screening and management guidelines for individuals with confirmed m.3243A>G mutations. Researchers characterized the phenotypic spectrum in 129 patients from 83 unrelated families enrolled in the UK Mitochondrial Disease Patient Cohort Study. Among the cohort, 10% had classical MELAS, 30% MIDD, 6% MELAS/MIDD, 2% MELAS/CPEO, 5% MIDD/CPEO, 6% PEO with other features, 3% isolated hearing loss, 28% displayed mixed features not matching classical syndromes, and 9% were asymptomatic.

Abstract

<h3>Background</h3> Population-based studies suggest the m.3243A&gt;G mutation in <i>MTTL1</i> is the most common disease-causing mtDNA mutation, with a carrier rate of 1 in 400 people. The m.3243A&gt;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. <h3>Methods</h3> We have defined the phenotypic spectrum associated with the m.3243A&gt;G mtDNA mutation in 129 patients, from 83 unrelated families, recruited to the Mitochondrial Disease Patient Cohort Study UK. <h3>Results</h3> 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&gt;G mutation. 9% of individuals harbouring the mutation were clinically asymptomatic. <h3>Conclusion</h3> Following this study we propose guidelines for screening and for the management of confirmed cases.