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Neurological manifestations in adult patients with the m.3243A>G variant in mitochondrial DNA
Kari Majamaa1,2, Mikko Kärppä1,2, Jukka S Moilanen3,4
1Research Unit of Clinical Medicine, Neurology, University of Oulu, Oulu, Finland.
Background:
The m.3243A>G variant in mitochondrial DNA (mtDNA) is the most common cause of the MELAS (Mitochondrial encephalopathy, lactic acidosis and stroke-like episodes) syndrome usually commencing in childhood or adolescence. In adults, the variant presents with versatile and mostly neurological phenotypes, but MELAS may not be common.
Objective:
To examine the frequency of phenotypes in adults with m.3243A>G in a population-based cohort and in a meta-analysis of reported case series.
Methods:
We clinically examined 51 adult patients with m.3243A>G to determine the frequency of phenotypes and to analyse the contribution of variant heteroplasmy, age, sex and mtDNA haplogroup to the phenotypes. The frequencies of neurological features were also assessed in a meta-analysis on 25 published case series reporting 1314 patients.
Results:
Sensorineural hearing impairment (HI), cognitive impairment and myopathy were the most common manifestations, whereas stroke-like episodes were infrequent. Variant heteroplasmy and age were only modest predictors of the phenotypes, although heteroplasmy correlated significantly with disability and Kaplan-Meier analysis showed progression of phenotypes with age. Male sex predicted more severe disability, whereas haplogroup UK was associated with no significant disability. Meta-analysis revealed substantial heterogeneity of phenotype frequencies and preferential inclusion of the MELAS phenotype.
Discussion:
In adult patients with m.3243A>G sensorineural HI, cognitive impairment and myopathy are common manifestations with lifetime prevalences approaching unity. Stroke-like episodes are rare. Variant heteroplasmy, age, sex and mtDNA haplogroup contribute to the severity of the disease. Meta-analysis provided a solid estimate of the various neurological symptoms in adults with m.3243A>G.
Insights
The common m.3243A>G mitochondrial DNA variant causes varied adult symptoms, with hearing loss, cognitive decline, and myopathy being frequent. Stroke-like episodes are rare, but severity is influenced by heteroplasmy, age, and sex.
Area of Science:
- Genetics
- Neurology
- Mitochondrial Diseases
Background:
- The m.3243A>G variant in mitochondrial DNA (mtDNA) is a primary cause of MELAS syndrome.
- In adults, this variant presents with diverse neurological symptoms, often without the classic MELAS phenotype.
Purpose of the Study:
- To determine the frequency of clinical phenotypes in adults with the m.3243A>G mtDNA variant.
- To analyze factors influencing phenotype presentation, including heteroplasmy, age, sex, and mtDNA haplogroup.
Main Methods:
- Clinical examination of 51 adult patients with the m.3243A>G variant.
- Meta-analysis of 25 published case series (1314 patients) to assess neurological feature frequencies.
Main Results:
- Sensorineural hearing impairment, cognitive impairment, and myopathy were the most prevalent manifestations.
- Stroke-like episodes were infrequent; heteroplasmy and age modestly predicted phenotypes, with progression over time.
- Male sex correlated with increased disability, while haplogroup UK showed no significant association.
Conclusions:
- Adults with m.3243A>G commonly exhibit sensorineural hearing loss, cognitive impairment, and myopathy, with stroke-like episodes being rare.
- Mitochondrial DNA heteroplasmy, age, sex, and haplogroup significantly contribute to disease severity and phenotype expression.
- Meta-analysis offers a reliable estimation of neurological symptoms in adults carrying the m.3243A>G variant.
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