Secondary manifestations of mitochondrial disorders

Secondary manifestations of mitochondrial disorders 线粒体病的继发表现 first-author †E-mail:fifigs1@yahoo.de †E-mail:fifigs1@yahoo.de fifigs1@yahoo.de Krankenanstalt Rudolfstiftung, Messerli Institute, Vienna, Austria Krankenanstalt Rudolfstiftung, Messerli Institute, Vienna, Austria Mitochondrial disorders (MIDs) are a heterogeneous group of genetic metabolic diseases due to mutations in the mitochondrial DNA (mtDNA) or in the nuclear DNA (nDNA) (Rahman and Rahman, 2018 2018 ). Some affected genes encode proteins with various functions, or structural RNAs such as transfer RNAs (tRNAs) and ribosomal RNAs (rRNAs). MIDs may also be caused by mutations in non-coding regions (e.g., D-loop of mtDNA) (Rahman and Rahman, 2018 2018 ). Proteins involved in MIDs include enzymes, assembling factors, transport proteins, signaling proteins, pore proteins, and fusion/fission proteins (Gorman et al., 2016 2016 ). The pathways most frequently affected by mutations in “mitochondrial genes” are the respiratory chain and the oxidative phosphorylation. Dysfunction of many other pathways (e.g., β-oxidation, pyruvate-dehydrogenase complex, and heme synthesis) may also manifest as MIDs (Hu et al., 2019 2019 ). The estimated prevalence of MIDs is at least 1:5000 (Ng and Turnbull, 2016 2016 ). 线粒体病(MID)是由线粒体DNA(mtDNA)或核DNA(nDNA)基因突变引起的一组异质性遗传代谢疾病.由于其广泛的遗传异质性,MID具有多种表型.有时,受MID影响的器官可能会因另一器官、组织、系统的继发性疾病而变得复杂.继发性并发症可通过动脉、神经或内分泌信号从原发部位传播.动脉受MID影响可能会导致动脉高压、缺血、出血或动脉瘤形成.癫痫发作可能与创伤性脑损伤、Takotsubo综合征或癫痫猝死(SUDEP)有关.垂体腺瘤可能引起皮质功能减退、动脉低血压、性腺功能减退或身材矮小.糖尿病或甲状旁腺功能减退可能与神经病变、动脉低血压、低钙血症或视野缺损有关.肾脏受累可引起动脉高压.肝脏或免疫细胞受累可能会导致感染.MID的继发性表现可能会严重影响治疗管理、疾病轨迹和患者预后,因此需要仔细评估. Mitochondrial disorder nDNA Multiple mtDNA deletions Phenotype Multisystem involvement 线粒体疾病(MID) 核DNA(nDNA) 多重由线粒体DNA缺失 表型 多系统参与 Mitochondrial disorders (MIDs) are a heterogeneous group of genetic metabolic diseases due to mutations in the mitochondrial DNA (mtDNA) or in the nuclear DNA (nDNA) (Rahman and Rahman, 2018 2018 ). Some affected genes encode proteins with various functions, or structural RNAs such as transfer RNAs (tRNAs) and ribosomal RNAs (rRNAs). MIDs may also be caused by mutations in non-coding regions (e.g., D-loop of mtDNA) (Rahman and Rahman, 2018 2018 ). Proteins involved in MIDs include enzymes, assembling factors, transport proteins, signaling proteins, pore proteins, and fusion/fission proteins (Gorman et al., 2016 2016 ). The pathways most frequently affected by mutations in “mitochondrial genes” are the respiratory chain and the oxidative phosphorylation. Dysfunction of many other pathways (e.g., β-oxidation, pyruvate-dehydrogenase complex, and heme synthesis) may also manifest as MIDs (Hu et al., 2019 2019 ). The estimated prevalence of MIDs is at least 1:5000 (Ng and Turnbull, 2016 2016 ). Because of the strong genetic heterogeneity and highly variable pathogenetic background of MIDs, a myriad of phenotypes ensue, which can vary even with a single mutation (phenotypic heterogeneity) (Finsterer, 2018 2018 ). Phenotypic heterogeneity of MIDs results from the broad genetic background of these disorders, which is further complicated by the unique characteristics of mitochondrial genetics (e.g., heteroplasmy, copy number variation, threshold effect, and mitotic segregation) (Rahman, 2020 2020 ). MIDs may manifest in any organ or tissue, but more frequently affect those with high energy demand (Rahman, 2020 2020 ). These organs include brain, eyes, ears, endocrine organs, heart, intestines, kidneys, muscle, and nerves (Finsterer, 2012 2012 ). Rarely, MIDs manifest in lungs, immune system, skin, bones, arteries, or bone marrow (Finsterer, 2012 2012 ). MIDs either manifest as a syndrome, defined as a collection of characteristic symptoms (syndromic MIDs), or non-syndrome (Finsterer, 2012 2012 ). Mitochondrial syndromes are frequently expressed as acronyms, of which over 50 are currently known. The best known syndromic MIDs are MELAS (mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes), MERRF (myoclonus epilepsy with ragged-red fibers), LHON (Leber hereditary optic neuropathy), CPEO (chronic progressive external ophthalmoplegia), NARP (neuropathy, ataxia and retinitis pigmentosa), KSS (Kearns-Sayre syndrome), and LBSL (leukoencephalopathy with brain stem and spinal cord involvement and lactate elevation) (Finsterer, 2012 2012 ). MIDs are diagnosed based on the individual and family history, clinical exam, muscle biopsy, immunohistological analysis, biochemical studies, polarography, cybrid studies, and genetic tests. Primary manifestations of MIDs in organs may lead to secondary disorders in an organ/tissue/system that are not primarily affected (Fig. 1 1 ). Recognizing secondary complications is crucial as they may strongly influence the clinical presentation and outcome of an MID. Moreover, these secondary diseases should be recognized as they are usually more accessible to treatment than the primary metabolic defects. Secondary diseases may originate from any organ at a variable frequency, but most frequently involve heart, arteries, and brain (Fig. 1 1 ). Secondary complications may be transmitted to another organ via arteries, nerves, or endocrine signaling. Cardiac involvement in MIDs is most frequently associated with complications in the brain. Primary mitochondrial arterial hypertension (Lin et al., 2019 2019 ) may lead to ischemic stroke or intracerebral bleeding (ICB), headache, atherosclerosis (ASCL), vertigo, or aneurysm formation. Heart failure caused by cardiomyopathy (Mima et al., 2011 2011 ) may lead to ischemic stroke (due to intra-cardiac thrombus formation), vertigo, or syncope (due to arterial hypotension). Atrial fibrillation (Malfatti et al., 2013 2013 ) may be associated with cardio-embolic events, vertigo, or syncope (Fig. 1 1 ). Ventricular arrhythmias may lead to arterial hypotension, vertigo, or syncope (Fig. 1 1 ). Involvement of the arteries (Finsterer and Zarrouk-Mahjoub, 2016 2016 ) may lead to arterial hypertension or ischemia due to dissection and consequent occlusion of an artery, or to aneurysm formation and consequent spontaneous rupture and bleeding (Kalashnikova et al., 2010 2010 ; Sun et al., 2018 2018 ). Rupture of intracerebral aneurysms may lead to subarachnoid bleeding. Spontaneous rupture of the aorta may lead to shock or even death (Tay et al., 2006 2006 ). Moreover, involvement of the central nervous system (CNS) may cause severe complications in other organs (Fig. 1 1 ). Seizures may lead to multiple CNS manifestations: traumas, including traumatic brain injury during falls (Rahman, 2019 2019 ); syncope, confusion, or psychosis; Takotsubo syndrome or sudden unexplained death in epilepsy (SUDEP) (Nandal et al., 2019 2019 ); and severe ventricular arrhythmias (Kennedy et al., 2016 2016 ). Pituitary adenoma (macro-adenoma) (Varanasi et al., 1999 1999 ) may be associated with arterial hypotension or visual field defects. AF: atrial fibrillation; AHT: arterial hypertension; ASCL: atherosclerosis; HF: heart failure; ICB: intracerebral bleeding; VA: ventricular arrhythmia; SAB: subarachnoid bleeding; SUDEP: sudden unexplained death in epilepsy; Endocr. o.: endocrine organs Every endocrine organ can be affected in an MID. Diabetes, hyperthyroidism, or hypothyroidism that occurs in an MID may be associated with encephalopathy (Finsterer et al., 2019 2019 ). Pituitary adenoma may be associated with hypocorticism, arterial hypotension, hypogonadism, or short stature. Hypoparathyroidism may be complicated by neuropathy, encephalopathy, or visual impairment (Kytövuori et al., 2016 2016 ). Diabetes may be responsible for ASCL. Hypoaldosteronism may be associated with hyponatremia or arterial hypotension. Involvement of the kidneys (Emma and Salviati, 2017 2017 ) may lead to arterial hypertension. Liver involvement may lead to lactic acidosis or hepatic encephalopathy. If the cellular immune system is affected by the MID, recurrent infectious disease may occur (Galassi et al., 2017 2017 ). In conclusion, the broad spectrum of MID phenotypes is further complicated by secondary manifestations in organs that are not primarily affected. 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