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


CONCLUSIONS
Following this study we propose guidelines for screening and for the management of confirmed cases.
Wellcome Trust Centre for Mitochondrial Research Group, Institute for Ageing and Health, Newcastle University, Newcastle upon Tyne, UK.
Victoria
V
Nesbitt
Robert D S
RD
Pitceathly
Doug M
DM
Turnbull
Robert W
RW
Taylor
Mary G
MG
Sweeney
Ese E
EE
Mudanohwo
Shamima
S
Rahman
Michael G
MG
Hanna
Robert
R
McFarland
D000293:Adolescent; D000328:Adult; D000368:Aged; D009202:Cardiomyopathies / Q000453:epidemiology / Q000209:etiology / Q000235:genetics; D002648:Child; D002675:Child, Preschool; D015331:Cohort Studies; D048909:Diabetes Complications / Q000453:epidemiology / Q000235:genetics; D003920:Diabetes Mellitus / Q000453:epidemiology / Q000235:genetics; D005260:Female; D006319:Hearing Loss, Sensorineural / Q000453:epidemiology / Q000209:etiology; D006801:Humans; D007223:Infant; D017241:MELAS Syndrome / Q000453:epidemiology / Q000235:genetics; D008297:Male; D008875:Middle Aged; D028361:Mitochondrial Diseases / Q000175:diagnosis / Q000235:genetics* / Q000628:therapy; D017237:Mitochondrial Encephalomyopathies / Q000453:epidemiology / Q000209:etiology / Q000235:genetics; D009154:Mutation / Q000235:genetics*; D006113:United Kingdom / Q000453:epidemiology; D055815:Young Adult
Clinical Neurology; Diabetes Mellitus; Epidemiology; Epilepsy; Mitochondrial Disorders