The genetics and pathology of mitochondrial disease.

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mitochondrial disease 36 endocrinologydiseases
lactic acidosis 3 endocrinologydiseases
leukodystrophy 2 endocrinologydiseases

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lactic acidosis 6068 devastating syndromic neurological condition whose predominant features, i.e. mitochondrial encephalopathy, lactic acidosis , and stroke‐like episodes, give rise to the acronym. Clinical symptoms can present in child or adulthood,
lactic acidosis 15134 five assembly/ancillary factors 48, with presentations including developmental delay, encephalopathy, lactic acidosis , liver dysfunction, renal tubulopathy, and muscle weakness 48, 49.Isolated complex IV deficiencyCytochrome
lactic acidosis 17291 phenotypes. The most common defects involve TMEM70, including a Roma TMEM70 founder mutation causing lactic acidosis and cardiomyopathy 58, although encephalopathy and cataracts have been reported in other populations
leukodystrophy 12581 acidosis is a common feature, although it is often present with other symptoms, such as cardiomyopathy or leukodystrophy . Mutations have been identified in 19 of the 37 structural subunits, and in 10 of 14 identified assembly
leukodystrophy 13890 predominantly affecting either the central nervous system (CNS) or heart (hypertrophic cardiomyopathy, leukodystrophy , Leigh syndrome, and encephalopathy) 43, whereas heterozygous mutations are associated with cancer susceptibility,
mitochondrial disease 61 Title: The Journal of PathologyThe genetics and pathology of mitochondrial disease Alternative Title: Mitochondrial genetic diseaseAlternative Title: CL Alston et alDavid T BonthronWilliam
mitochondrial disease 1180 with symptoms affecting a single organ or tissue, or multisystem involvement. There is no cure for mitochondrial disease for the vast majority of mitochondrial disease patients, and a genetic diagnosis is therefore crucial
mitochondrial disease 1227 tissue, or multisystem involvement. There is no cure for mitochondrial disease for the vast majority of mitochondrial disease patients, and a genetic diagnosis is therefore crucial for genetic counselling and recurrence risk calculation,
mitochondrial disease 1627 the diagnosis of clinically affected patients; mutations in >250 genes have now been shown to cause mitochondrial disease , and the biochemical, histochemical, immunocytochemical and neuropathological characterization of these
mitochondrial disease 1914 and novel diagnostic techniques. This review focuses on the current genetic landscape associated with mitochondrial disease , before focusing on advances in studying associated mitochondrial pathology in two, clinically relevant
mitochondrial disease 3553 condition or a secondary, age‐associated effect attributable to somatic mutation 6.The umbrella term ‘ mitochondrial disease ’ refers to a clinically heterogeneous group of primary mitochondrial disorders in which the tissues
mitochondrial disease 4410 in recent years 10, i.e. the molecular genetics, muscle pathology and neuropathology associated with mitochondrial disease , highlighting the range of new techniques that are improving the diagnosis of patients with suspected
mitochondrial disease 4534 highlighting the range of new techniques that are improving the diagnosis of patients with suspected mitochondrial disease , with the aim of providing options to families at risk of an otherwise incurable condition.The genetics
mitochondrial disease 4663 the aim of providing options to families at risk of an otherwise incurable condition.The genetics of mitochondrial disease Mitochondrial disease caused by mtDNAUnlike nuclear DNA, which is diploid and follows Mendelian laws
mitochondrial disease 8402 and point mutations represent primary mtDNA defects, but secondary defects are other common causes of mitochondrial disease . Defective mtDNA maintenance, transcription, or protein translation, or a defective ancillary process
mitochondrial disease 9317 encoding a structural subunit of complex II 25, and there has been monumental progress in the discovery of mitochondrial disease candidate genes since then. New proteomic and transcriptomic approaches are being applied to models
mitochondrial disease 10510 nuclear gene defects are overrepresented in paediatric cases 31.In this review, we delineate the nuclear mitochondrial disease genes into those that cause isolated and those that cause multiple respiratory chain complex deficiencies,
mitochondrial disease 13628 (transferring electrons from FADH2 to reduce ubiquinone to ubiquinol). Complex II deficiency is rare (2–8% of mitochondrial disease cases 41, 42), with <50 patients having been reported. Biallelic mutations have been associated with
mitochondrial disease 14193 initially believed to have distinct genotype–phenotype relationships (SDHA and SDHAF1 being linked to mitochondrial disease , and SDHB/SDHC/SDHD/SDHAF2 being linked with cancer susceptibility), it is emerging that there is phenotypic
mitochondrial disease 18612 mitochondrial genes have now been reported in association with multiple respiratory chain defects and clinical mitochondrial disease 29. The genetic diagnostic pathway for these disorders is complex, and WES is often the most successful
mitochondrial disease 18763 pathway for these disorders is complex, and WES is often the most successful strategy 68.Non‐OXPHOS mitochondrial disease Not all mitochondrial disease patients have evidence of respiratory chain enzyme dysfunction, but have
mitochondrial disease 18792 complex, and WES is often the most successful strategy 68.Non‐OXPHOS mitochondrial diseaseNot all mitochondrial disease patients have evidence of respiratory chain enzyme dysfunction, but have other evidence of mitochondrial
mitochondrial disease 18905 disease patients have evidence of respiratory chain enzyme dysfunction, but have other evidence of mitochondrial disease , such as elevated lactate levels, suggestive magnetic resonance imgaing brain changes, and multisystem
mitochondrial disease 19217 aconitase/ACO269) or cofactor transport (e.g. thiamine transporter/SLC19A370).Molecular genetic analysis of mitochondrial disease In the absence of effective treatments, provision of a firm genetic diagnosis facilitates genetic counselling
mitochondrial disease 19495 and their families. Given the small size of the mtDNA genome, this is often sequenced in suspected mitochondrial disease patients to exclude a primary mtDNA defect before nuclear genes are scrutinized. NGS‐based testing
mitochondrial disease 20884 complicated by genetic heterogeneity 75.Figure 2NGS strategies employed in the genetic diagnosis of mitochondrial disease . (A) WGS analyses all coding and non‐coding regions of the genome. (B) WES targets only the coding
mitochondrial disease 22912 strategy for identifying novel disease candidate genes 26.Investigating muscle pathology associated with mitochondrial disease As discussed above, the laboratory investigation of suspected mitochondrial disease is complex, and algorithms
mitochondrial disease 22995 associated with mitochondrial diseaseAs discussed above, the laboratory investigation of suspected mitochondrial disease is complex, and algorithms employ a multidisciplinary approach using clinical and functional studies
mitochondrial disease 29113 assay with biopsies from patients showing a range of mtDNA‐related and nuclear genetic diagnoses of mitochondrial disease . The assay also shows promise as a powerful tool with which to investigate the mitochondrial pathological
mitochondrial disease 29372 other myopathies (e.g. myofibrillar myopathies 90), to investigate molecular disease mechanisms and mitochondrial disease progression, as well as providing an extremely sensitive outcome measure in clinical therapeutic intervention
mitochondrial disease 29616 (e.g. pharmacological agents or exercise) aimed at improving muscle oxidative capacity in patients with mitochondrial disease .PATH-4809-FIG-0004-cNeuropathology associated with mitochondrial diseaseNeurological symptoms are particularly
mitochondrial disease 29689 capacity in patients with mitochondrial disease.PATH-4809-FIG-0004-cNeuropathology associated with mitochondrial disease Neurological symptoms are particularly common, and may be devastating in patients with mitochondrial
mitochondrial disease 29797 mitochondrial diseaseNeurological symptoms are particularly common, and may be devastating in patients with mitochondrial disease , including sensorineural deafness, cerebellar ataxia, peripheral neuropathy, dementia, and epilepsy
mitochondrial disease 30060 neuropathological studies have documented the characteristic features of neurodegeneration in patients with mitochondrial disease , and these have spurred the development of novel tools with which to understand the mechanisms underlying
mitochondrial disease 30339 mechanisms of neurodegenerationUpon neuropathological investigation, the brains from patients with mitochondrial disease often show atrophy, cortical lesions, evidence of neuronal cell loss, and mitochondrial OXPHOS abnormalities
mitochondrial disease 32591 the brain.Figure 5Neuropathological changes associated with stroke‐like episodes in patients with mitochondrial disease . (A) Extensive cortical necrosis affecting the occipital, temporal and parietal lobes in a brain from
mitochondrial disease 33433 recessive POLG mutations. Scale bar: 10 µm.PATH-4809-FIG-0005-cThe cerebellum is frequently involved in mitochondrial disease , with many patients developing cerebellar ataxia. Neuropathologically, the cerebellum reveals signs
mitochondrial disease 36609 of the neuronal networks 113. This will enable a greater understanding of neuronal vulnerability in mitochondrial disease 114. The recent development of induced pluripotent stem cell technology allows the cellular transfection
mitochondrial disease 37435 specific disease mechanisms 117, 118, 119.Challenges for the futureDeveloping an effective treatment for mitochondrial disease is an enormous challenge that is dependent on the integration of clinical understanding of disease progression,
mitochondrial disease 37633 understanding of disease progression, molecular genetic mechanisms, and neuropathological features in mitochondrial disease . Patient‐based clinical, molecular genetic and histopathology studies can then inform the development
mitochondrial disease 37883 model systems to determine mechanisms and treatment to ultimately improve the lives of patients with mitochondrial disease .Author contributions statementAll authors contributed to the drafting of the manuscript and its critical

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