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MELAS: clinical features, biochemistry, and molecular genetics
E Ciafaloni1, E Ricci, S Shanske
1H. Houston Merritt Clinical Research Center for Muscular Dystrophy and Related Diseases, Columbia-Presbyterian Medical Center, New York, NY.
Annals of Neurology
|April 1, 1992
Summary
The mitochondrial transfer RNA(Leu(UUR)) gene mutation is highly prevalent in patients with mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS). This genetic marker was found in most MELAS patients and some relatives, with higher mutation loads in affected individuals.
Area of Science:
- Genetics
- Neurology
- Mitochondrial Biology
Background:
- Mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS) is a maternally inherited mitochondrial disorder.
- A specific heteroplasmic point mutation at nt 3,243 in the mitochondrial DNA transfer RNA(Leu(UUR)) gene has been associated with MELAS.
Purpose of the Study:
- To investigate the prevalence and correlation of the nt 3,243 transfer RNA(Leu(UUR)) gene mutation in patients with MELAS and their maternal relatives.
- To compare mutation loads in different tissues and their relationship with clinical presentation and biochemical defects.
Main Methods:
- Genotyping for the nt 3,243 mitochondrial DNA mutation in 23 MELAS patients, 25 maternal relatives, and 50 controls.
- Quantification of mutant genome proportion in muscle and blood tissues.
- Assessment of mitochondrial respiratory chain complex activities (I+III, II+III, IV) in muscle biopsies.
Main Results:
- The transfer RNA(Leu(UUR)) mutation was detected in 21/23 MELAS patients, 11/11 oligosymptomatic relatives, and 12/14 asymptomatic relatives, but only in 5/50 controls.
- Muscle mutant heteroplasmy levels (56-95%) were significantly higher in MELAS patients than in relatives.
- Mutation levels were lower in blood than muscle, and undetectable in 3/12 asymptomatic relatives.
- Decreased activities of mitochondrial respiratory chain complexes I+III, II+III, and IV were observed in mutation-positive muscle biopsies, but without clear correlation to mutation load.
Conclusions:
- The nt 3,243 transfer RNA(Leu(UUR)) gene mutation is a strong genetic marker for MELAS syndrome.
- Mutation load and tissue distribution (muscle vs. blood) influence clinical manifestation and penetrance.
- While the mutation affects mitochondrial respiratory chain function, the correlation between mutation percentage and biochemical defect severity is not straightforward.