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Clinical spectrum of the MELAS mutation in a large pedigree
M S Damian1, P Seibel, H Reichmann
1Department of Neurology, University of Giessen, Germany.
Introduction:
MELAS is most often due to an mentally transmitted A-G transition mutation of mitochondrial DNA (mtDNA) at position 3243. In this study we report on the clinical spectrum associated with the mutation in the largest family reported so far.
Patients And Methods:
In a family with three MELAS cases we identified 47 persons at risk for the mutation; sufficient data was available on 29. Mitochondrial disease was diagnosed in two of 9 deceased numbers (posthumous molecular analysis in one); 27 surviving family members underwent examination and 25 a molecular analysis of mt DNA from lymphoblasts. Then had a muscle biopsy and two were later autopsied.
Results:
All 26 cases investigated by molecular analysis showed the mutation at position 3243. The 18 symptomatic patients without stroke-like episodes had sensorineural hearing loss in 15 cases, diabetes in 6, nephropathy in 7, mild myopathy in 4, cardiomyopathy in 2, cerebellar disease in 4 and mental retardation in 2 cases. Eight carriers were asymptomatic. Autopsy showed > 80% mutant mt DNA in all tissues except blood (20%) examined in a MELAS patients, but < 20 mutant mt DNA in all tissues except lever (40%) and kidney (70%) in a patient with hepatopathy, renal failure and diabetes. Histologic and biochemical studies of muscle biopsy were often non-informative.
Conclusions:
The mutation of mt DNA at position 3243 causes a multisystem disorder with a variable phenotype due to heteroplasmy. Most carriers are oligosymptomatic with hearing loss and a variety of neurological and internal medical symptoms. Diabetes, cardiomyopathy and renal disease, which is newly reported here for this mutation, are frequent. The blood test is a reliable screening tool in affected families, but is of prognostic value only combined with examination of other tissues.
Insights
The A-G transition mutation at mtDNA position 3243 causes MELAS, a multisystem disorder. This study details the variable clinical spectrum in the largest reported family, highlighting frequent diabetes, cardiomyopathy, and renal disease.
Area of Science:
- Genetics
- Mitochondrial Biology
- Neurology
Background:
- Mitochondrial Encephalopathy, Lactic Acidosis, and Stroke-like episodes (MELAS) is typically caused by an A-G transition mutation in mitochondrial DNA (mtDNA) at position 3243.
- This study investigates the clinical manifestations of this mutation in the largest family documented to date.
Purpose of the Study:
- To delineate the full clinical spectrum of the mtDNA 3243 mutation.
- To analyze genotype-phenotype correlations in a large family cohort.
Main Methods:
- Identified 47 at-risk individuals in a family with three MELAS cases; data analyzed for 29.
- Conducted molecular analysis of mtDNA from lymphoblasts in 25 surviving family members.
- Performed clinical examinations, muscle biopsies, and autopsies on affected individuals.
Main Results:
- The mtDNA 3243 mutation was confirmed in all 26 molecularly analyzed cases.
- Symptomatic patients exhibited sensorineural hearing loss (15/18), diabetes (6/18), nephropathy (7/18), myopathy (4/18), cardiomyopathy (2/18), cerebellar disease (4/18), and mental retardation (2/18).
- Autopsy revealed high mutant mtDNA loads (>80%) in most tissues of MELAS patients, with varying levels in other affected family members.
Conclusions:
- The mtDNA 3243 mutation results in a multisystem disorder with variable phenotypes due to heteroplasmy.
- Oligosymptomatic carriers frequently present with hearing loss and diverse neurological and internal medical symptoms.
- Newly reported manifestations include diabetes, cardiomyopathy, and renal disease; blood tests are useful for screening but require tissue analysis for prognostic value.