Mitochondrial DNA from genotype to phenotype related to Maternally inherited syndromes

Mitochondrial DNA (mtDNA) mutations cause maternally inherited diseases; the symptoms appear in late childhood or adulthood. The pathogenicity of the mtDNA differs among individuals within the same family due to the difference between mitochondrial phenotype and genotype modulated by heteroplasmy, which refers to the presence of both mutated and normal mtDNA within the cell.
Monoploidy and the lack of compensation alleles lead to a higher risk of mtDNA mutations than nuclear DNA. Point mutation and large-scale deletion disrupt mitochondrial function, such as oxidative phosphorylation, leading to syndromes like MELAS, Leigh syndrome, and Kearns-Sayre syndrome. They also underlined that heteroplasmy influences the severity of symptoms in offspring, often leaving mothers asymptomatic.
This study aims to determine the pathogenic role of mtDNA mutations, their contributions to maternally inherited syndromes, and their implications for genetic counseling and premarital testing. For this purpose, mtDNA mutations associated with maternally inherited syndromes are underlined, focusing on their impact on mitochondrial function and the phenotypic expression influenced by heteroplasmy. We collected data from existing research and databases, including MITOMAP.
Due to mitochondria's heteroplasmic nature, even if the mother is asymptomatic, premarital carrier testing and genetic counseling for mtDNA mutations should be considered necessary to ascertain the mother's genotype and identify thirteen disorders the offspring may inherit. However, the heterogeneity resulting from heteroplasmy and non-Mendelian inheritance patterns makes it challenging to predict the manifestation of a disease. More studies are required to enhance mtDNA disease diagnostic and therapeutic strategies.