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.
Key Points
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Few neurological disorders are as phenotypically heterogeneous and diagnostically challenging as mitochondrial encephalomyopathies
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The clinical heterogeneity of mitochondrial disorders can be explained by both the unique rules of mitochondrial genetics and the dependence of most mitochondrial functions on a wide variety of nuclear genes
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Despite advances in understanding the molecular aetiology of mitochondrial diseases, their pathogenesis is still largely unknown
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Through whole-exome or mito-exome sequencing, novel mutant genes and novel disease mechanisms of mitochondrial disease are being revealed
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Promising areas of investigation for neurological mitochondria-associated disorders include defects in lipid composition of the mitochondrial membrane and defects of the mitochondria-associated membrane
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The authors are supported by grants from the NIH (HD032062) and from the Marriott Mitochondrial Disorder Clinical Research Fund.
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S. DiMauro and V. Carelli researched data for the article. S. DiMauro wrote the article. All authors provided substantial contribution to discussion of content and to the review and/or editing of the manuscript before submission.
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DiMauro, S., Schon, E., Carelli, V. et al. The clinical maze of mitochondrial neurology. Nat Rev Neurol 9, 429–444 (2013). https://doi.org/10.1038/nrneurol.2013.126
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DOI: https://doi.org/10.1038/nrneurol.2013.126
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Human Genome Variation (2022)
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Genetic causes of acute encephalopathy in adults: beyond inherited metabolic and epileptic disorders
Neurological Sciences (2022)
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Megaconial congenital muscular dystrophy secondary to novel CHKB mutations resemble atypical Rett syndrome
Journal of Human Genetics (2021)
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Mutations in MT-ATP6 are a frequent cause of adult-onset spinocerebellar ataxia
Journal of Neurology (2021)
