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Updated: May 27, 2026
Genotyping Single Nucleotide Polymorphisms in the Mitochondrial Genome by Pyrosequencing
Published on: February 10, 2023
Natural history of MELAS associated with mitochondrial DNA m.3243A>G genotype
P Kaufmann1, K Engelstad, Y Wei
1The Neurological Institute, Columbia University, 710 W. 168th Street, New York, NY 10032, USA. pk88@columbia.edu
Objective:
To describe the natural history of clinical and laboratory features associated with the m.3243A>G mitochondrial DNA point mutation. Natural history data are needed to obtain prognostic information and for clinical trial planning.
Methods:
We included 85 matrilineal relatives from 35 families with at least 2 visits in this prospective cohort study. Thirty-one were fully symptomatic with mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS), and 54 were carrier relatives. Evaluations included standardized questionnaires (medical history and daily living functioning), physical examination, neuropsychological testing, and a battery of imaging and laboratory tests. We evaluated changes in clinical and laboratory features over time and survival. Outcomes are reported over a follow-up period of up to 10.6 years (mean 3.8 ± 2.2 years for patients and 5.5 ± 3.0 for carrier relatives).
Results:
Neurologic examination, neuropsychological testing, and daily living scores significantly declined in all patients with MELAS, whereas no significant deterioration occurred in carrier relatives. Cerebral MRI scores declined significantly in patients with MELAS. Magnetic resonance spectroscopy estimates of lactate in the lateral ventricles increased over time, and high lactate was associated with increased mortality. Symptom onset in childhood often was associated with worse outcome. Patients with MELAS had a greater death rate than carrier relatives.
Conclusions:
Patients with MELAS carrying the m.3243A>G mutation show a measurable decline in clinical and imaging outcomes. It is hoped that these data will be helpful in anticipating the disease course and in planning clinical trials for MELAS.
Insights
The m.3243A>G mitochondrial DNA mutation causes progressive decline in patients with MELAS, affecting neurological function and imaging. Carrier relatives showed no significant deterioration, highlighting disease-specific progression.
Area of Science:
- Genetics
- Neurology
- Mitochondrial Diseases
Background:
- The m.3243A>G mitochondrial DNA point mutation is associated with MELAS (mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes).
- Understanding the natural history of this mutation is crucial for prognostic information and clinical trial design.
Purpose of the Study:
- To describe the natural history of clinical and laboratory features in individuals with the m.3243A>G mitochondrial DNA mutation.
- To evaluate disease progression and survival in symptomatic MELAS patients and asymptomatic carrier relatives.
Main Methods:
- Prospective cohort study of 85 matrilineal relatives from 35 families.
- Evaluations included standardized questionnaires, physical examinations, neuropsychological testing, imaging, and laboratory tests over a mean follow-up of 3.8-5.5 years.
- Comparison of clinical and laboratory features, imaging scores, and survival between MELAS patients and carrier relatives.
Main Results:
- Symptomatic MELAS patients showed significant declines in neurological examination, neuropsychological testing, and daily living scores.
- Cerebral MRI scores declined, and elevated lactate levels (measured by magnetic resonance spectroscopy) correlated with increased mortality.
- Early symptom onset in childhood was linked to poorer outcomes, and MELAS patients had a higher mortality rate than carriers.
Conclusions:
- Patients with MELAS carrying the m.3243A>G mutation experience a measurable decline in clinical and imaging outcomes.
- These findings aid in anticipating disease course and planning future clinical trials for MELAS.
- The study differentiates disease progression between affected individuals and asymptomatic carriers.
