The clinical maze of mitochondrial neurology

Abstract

Mitochondrial diseases involve the respiratory chain, which is under the dual control of nuclear and mitochondrial DNA (mtDNA). The complexity of mitochondrial genetics provides one explanation for the clinical heterogeneity of mitochondrial diseases, but our understanding of disease pathogenesis remains limited. Classification of Mendelian mitochondrial encephalomyopathies has been laborious, but whole-exome sequencing studies have revealed unexpected molecular aetiologies for both typical and atypical mitochondrial disease phenotypes. Mendelian mitochondrial defects can affect five components of mitochondrial biology: subunits of respiratory chain complexes (direct hits); mitochondrial assembly proteins; mtDNA translation; phospholipid composition of the inner mitochondrial membrane; or mitochondrial dynamics. A sixth category—defects of mtDNA maintenance—combines features of Mendelian and mitochondrial genetics. Genetic defects in mitochondrial dynamics are especially important in neurology as they cause optic atrophy, hereditary spastic paraplegia, and Charcot–Marie–Tooth disease. Therapy is inadequate and mostly palliative, but promising new avenues are being identified. Here, we review current knowledge on the genetics and pathogenesis of the six categories of mitochondrial disorders outlined above, focusing on their salient clinical manifestations and highlighting novel clinical entities. An outline of diagnostic clues for the various forms of mitochondrial disease, as well as potential therapeutic strategies, is also discussed.

Leukoencephalopathy due to Complex II Deficiency and Bi-Allelic SDHB Mutations: Further Cases and Implications for Genetic Counselling

“…Oxidative phosphorylation is the primary mechanism of ATP production in eukaryotic cells, utilizing the five transmembrane complexes (complex I-V), which constitute the respiratory chain (RC) in the inner mitochondrial membrane. The RC consists of at least 90 protein subunits encoded by nuclear and mitochondrial genes (DiMauro et al 2013). Clinically, deficiency of the RC with onset in childhood is associated with a variable spectrum of manifestations, including Leigh syndrome, mitochondrial encephalomyopathy with multisystem involvement, and leukoencephalopathy (Goldstein et al 2013).…”

Mitochondrial quality control: Cell-type-dependent responses to pathological mutant mitochondrial DNA

“…Mutations in the mtDNA are responsible for a wide range of diseases. 12 The most common point mutation is an adenine to guanine transition at nucleotide position 3243 (m3243G), in the MT-TL1 gene (mitochondrially encoded tRNA leucine 1 (UUA/G)), responsible for several clinical phenotypes, including syndromes characterized by mitochondrial encephalomyopathy, lactic acidosis, and strokelike episodes (MELAS), cardiomyopathy, and maternally inherited diabetes and deafness (MIDD). 13,14 Human cells have thousands of copies of mtDNA and individuals with pathogenetic mtDNA mutations often carry a mixture of mutated and wild-type (WT) mtDNAs in their cells, a situation referred to as heteroplasmy.…”

Glucocorticoids for mitochondrial disorders

“…Although there is no causal treatment of mitochondrial disorders (MIDs) yet available, (1) treatment strategies to enhance respiratory chain (RC) functions, eliminate noxious compounds, shift the heteroplasmy rate, alter mitochondrial dynamics, transfer cytoplasm, or treat genes are increasingly applied.…”