[Frontiers in Bioscience E4, 1706-1716, January 1, 2012]

Mitochondrial DNA related cardiomyopathies

Shamayel Mohammed1,2, Wesam Bahitham1, Alicia Chan3, Brian Chiu 1, Fiona Bamforth 1, Consolato Sergi1-4

1Department of Lab. Medicine and Pathology, University of Alberta, Edmonton, Alberta, Canada, 2Department of Lab. Medicine and Pathology, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia,3Stollery Children's Hospital, University of Alberta, Edmonton, Alberta, Canada,4 Institute of Pathology, Medical University of Innsbruck, Innsbruck, Austria

TABLE OF CONTENTS

1. Abstract
2. Introduction
3. Oxidative phosphorylation (OXPHOS) and mtDNA
4. Genetically defined mtDNA defects
4.1. Large scale rearrangements of mtDNA
4.2. Point mutations (PM) of mtDNA
4.2.1. PM in the tRNA Leu(UUR) gene
4.2.1.1. Mutation A3243G
4.2.1.2. Mutation A3260G
4.2.1.3. Mutation C3303T
4.2.2. PM in the tRNALeu(CUN) gene
4.2.2.1. Mutation T12297C
4.2.3. PM in the tRNAIle gene
4.2.3.1. Mutation A4317
4.2.3.2. Mutation A4269G
4.2.3.3. Mutation A4295G
4.2.3.4. Mutation A4300G
4.2.4. PM in the tRNALys gene
4.2.4.1. Mutation A8344G
4.2.4.2. Mutation G8363A
4.2.5. PM in the 12S rRNA gene
4.2.5.1. Mutation in A1555G
4.2.6. PM in polypeptide-encoding mtDNA
4.2.6.1. Mutations encoding the ND5 subunit of the respiratory chain complex I and mutations in the mt-ATP6 gene
4.2.6.1.1. Leigh syndrome
4.2.6.1.2. Mutation in the overlapping region of mitochondrial ATPase 6 and ATPase 8 genes
4.2.7. PM in the mitochondrial ND1 gene
4.2.7.1. Mutation G3337A
4.3. mtDNA lesions transmitted in a Mendelian manner
4.3.1. Multiple familial mtDNA deletions
4.3.2. mtDNA depletion syndrome
5. Diagnostic modalities and consideration
5.1. Clinical assessment and laboratory findings
5.2. Muscle biopsy: histochemistry, enzymology, electron microscopy, and genetic analysis
5.3. Myocardial morphological findings
5.4. Genetic based diagnosis
6. Treatment
7. Conclusion
8. Acknowledgements
9. References

1. ABSTRACT

Cardiomyopathies are a heterogeneous group of diseases characterized by impaired heart muscle function. Over the last few years, interest in mitochondrial cardiomyopathies has been galvanized by a number of significant molecular biology discoveries. There is overwhelming evidence that genetic factors play a pivotal role in the pathogenesis of primary cardiomyopathies. Mitochondrial cardiomyopathy is a cardiomyopathy in which the clinical and pathological phenotype result from mitochondrial diseases due to pathogenic mutation in both mitochondrial and/or nuclear genes causing defects in the oxidative phosphorylation system (OXPHOS) in cardiac muscle. We review and provide an update of the current concepts, molecular genetics, clinical features, pathology, diagnostic modalities, and latest therapeutic options in mitochondrial cardiomyopathies specifically caused by mutations in the mitochondrial DNA (mtDNA).