Caso de curso letal de mutación homocigota del gen nuclear mitocondrial hidroxiisobutiril-CoA hidrolasa HIBCH / A lethal case due to nuclear mitochondrial gene 3-hydroxyisobutyryl-CoA hydrolase HIBCH mutation

Resumen Introducción: El síndrome de Leigh (SL) es una enfermedad neurodegenerativa infrecuente que afecta principalmente a lactantes y a escolares, ocasionada por una mutación en genes involucrados en la vía de la fosforilación oxidativa y cuyo déficit produce una disfunción en el metabolismo energético mitocondrial. Clínicamente, se caracteriza por un rápido deterioro neurológico, hallazgos típicos en neuroimagen y marcadores bioquímicos que orientan en su reconocimiento. En la mayoría de los pacientes tiene un curso progresivo y mortalidad temprana. Presentación del caso: Se presenta el caso de una lactante de 5 meses que presenta perdida de los hitos del desarrollo. Los paraclínicos mostraron lactoacidosis, en neuroimagen necrosis nucleobasal, y la secuenciación genómica completa puso en evidencia una mutación homocigota del gen nuclear mitocondrial de la enzima 3-hidroxiisobutiril-CoA hidrolasa HIBCH. La paciente evolucionó con epilepsia refractaria, movimientos anormales, síndrome de West, apneas y falleció a los 10 meses de vida por insuficiencia respiratoria aguda. Discusión: El SL es con frecuencia una enfermedad rápidamente progresiva, que puede ser causada por errores innatos del metabolismo como la mutación del gen de la enzima HIBCH. El diagnóstico confirmatorio se hace con secuenciación exómica o genómica masiva y su manejo consiste en el tratamiento de los síntomas, modificaciones nutricionales, cuidado paliativo y consejería genético-reproductiva. Conclusión: El SL por mutaciones en el gen HIBCH es una enfermedad neurodegenerativa con síntomas variables, que afecta el desarrollo motor e intelectual. El diagnóstico se basa en biología molecular. El tratamiento actual busca aliviar síntomas y ajustar la nutrición, evidenciando desafíos inherentes a errores innatos del metabolismo.

Abstract Introduction: Leigh's syndrome (LS) is a rare neurodegenerative disease affecting mostly infants and scholar age children, caused by mutations in oxidation phosphorylation pathway related genes and leading to a mitochondrial dysfunction. Clinically, it is characterized by rapid neurological deterioration, typical neuroimaging findings and biochemical markers that guide its recognition. In most patients it has a progressive course and early mortality. Case description: Here we show a 5-months-old infant with developmental milestones regression. Lac-toacidosis was evident in labs, neuroimages had nucleobasal necrosis and whole genomic sequencing found a homozygous mutation in 3-hydroxyisobutyryl-CoA hydrolase HIBCH mitochondrial nuclear gene. The patient developed refractory epilepsy, abnormal movements, West'syndrome, apneas and death overcomes at 10-month of life by acute respiratory failure. Discussion: LS is often a rapidly progressive disease, which can be caused by inborn errors of metabolism such as mutation of the HIBCH enzyme gene. Confirmatory diagnosis is made with exome or massive genomic sequencing and its management consists of treatment of symptoms, nutritional modifications, palliative care and genetic-reproductive counseling. Conclusion: LS due to mutations in the HIBCH gene is a neurodegenerative disease with variable symptoms, affecting motor and intellectual development. Diagnosis is based on molecular biology. Current treatment seeks to alleviate symptoms and adjust nutrition, evidencing challenges inherent to inborn errors of metabolism.

Neonatal-onset primary mitochondrial disease caused by nuclear gene mutations: a report of 4 cases / 中国新生儿科杂志

Objective:To study the clinical manifestations and genetic characteristics of neonatal-onset primary mitochondrial disease (PMD) caused by nuclear gene mutations.Methods:From May 2020 to March 2022, the clinical data, genetic results and follow-up information of neonates with PMD admitted to the Department of Neonatology of our two hospitals were retrospectively analyzed.Results:A total of 4 patients were enrolled, all with hyperlactatemia and metabolic acidosis. In case 1, the fetal cranial MRI showed agenesis of corpus callosum. In case 2, echocardiography after birth indicated hypertrophic cardiomyopathy. Whole exome sequencing found the following mutations: EARS2 nuclear gene c.1294C>T and c.971G>T variants, COA6 nuclear gene c.411_412insAAAG variant, ACAD9 nuclear gene c.1278+1G>A and c.895A>T variants, FOXRED1 nuclear gene c.1054C>T and c.3dup variants. Mitochondrial second-generation sequencing and multiplex ligation-dependent probe amplification showed no abnormalities. Cases 1 and 3 died during the neonatal period. Case 2 died at 2-year-and-2-month of age. Case 4 was followed up to 1 year of age with developmental delay.Conclusions:The main phenotypes of neonatal-onset PMD caused by nuclear gene mutations are hyperlactatemia, refractory metabolic acidosis and cardiomyopathy, which have a poor prognosis. Proactive genetic tests are helpful for early diagnosis.

Mitochondrial transplantation as a promising therapy for mitochondrial diseases

Mitochondrial diseases are a group of inherited or acquired metabolic disorders caused by mitochondrial dysfunction which may affect almost all the organs in the body and present at any age. However, no satisfactory therapeutic strategies have been available for mitochondrial diseases so far. Mitochondrial transplantation is a burgeoning approach for treatment of mitochondrial diseases by recovery of dysfunctional mitochondria in defective cells using isolated functional mitochondria. Many models of mitochondrial transplantation in cells, animals, and patients have proved effective via various routes of mitochondrial delivery. This review presents different techniques used in mitochondrial isolation and delivery, mechanisms of mitochondrial internalization and consequences of mitochondrial transplantation, along with challenges for clinical application. Despite some unknowns and challenges, mitochondrial transplantation would provide an innovative approach for mitochondrial medicine.

Mitochondrial complex Ⅰ deficiency due to NDUFAF5 gene mutations: report of 2 cases and literature review / 中华实用儿科临床杂志

Objective:To analyze the clinical features and genotypes of mitochondrial complex Ⅰ deficiency due to NDUFAF5 gene mutations.Methods:Clinical data of 2 cases with mitochondrial complex Ⅰ deficiency due to NDUFAF5 gene mutations admitted in the Department of Pediatrics, Peking University First Hospital from February 2015 to July 2018 were retrospectively reviewed and followed up.Reported cases of mitochondrial complex Ⅰ deficiency due to NDUFAF5 gene mutations were searched in online databases, including the PubMed, Wanfang, Chinese Journal Full-Text Database and VIP database from January 1975 to February 2020 with " NDUFAF5" as the key word.Through literature review, clinical features and genotypes of mitochondrial complex Ⅰ deficiency due to NDUFAF5 gene mutations were summarized.Results:Case 1 showed mentor and mental regression after infection at the age of 1 year and 4 months.The condition of case 1 remained stable at the age of 5 year and 6 months at the last follow-up.Brain magnetic resonance imaging (MRI) showed multiple lesions in the white matter of the frontal and parieto-occipital lobes, basal ganglia, thalamus, cerebellum, brain stem and corpus callosum.Case 2 showed rapidly bilateral visual impairment at the age of 7 years and 4 months.The patient′s vision moderately recovered at the age of 8 years and 8 months.Brain MRI showed midbrain, periaqueductal gray, medulla oblongata and putamen lesions.Spinal MRI showed continuous lesions in the cervical cord 1-4.Genetic test showed NDUFAF5 gene c. 764C>T (p.Ala255Val) and c. 508C>T (p.Arg170Trp), homozygous c. 836T>G (p.Met279Arg) mutations in case 1 and case 2 respectively.Through online searching, 6 reports involving 14 cases were retrieved.The most common clinical phenotype was Leigh syndrome.Two cases had disease onset during the neonatal period, and their disease progressed rapidly and died within 1 year old.Eleven cases had onset during the infantile period, and 72.7% (8/11 cases) of them had a normal development.The common initial symptoms were mental or motor regression, feeding difficulty and dystonia.Seventy-two point seven percent (8/11 cases) had acute/subacute onset after infection, showing paroxysmal deterioration, and died in infancy or childhood.One patient developed dystonia in childhood and visual impairment in adulthood.Conclusions:The onset age ranged from neonatal period to childhood in patients with NDUFAF5 gene mutations, and their clinical phenotypes vary a lot.The main clinical phenotype is Leigh syndrome.Disease onset during the infantile period is frequent, and mostly presents paroxysmal deterioration after infection, while disease onset in childhood is rare.

Outer retinal tubulation and inner retinal pseudocysts in a patient with maternally inherited diabetes and deafness evaluated with optical coherence tomography angiogram

A 47-year-old lady (index case) with diabetes and deafness showed multiple oval circumferential areas of perifoveal atrophy in both eyes. Autofluorescence revealed areas of hypoautofluorescence. Optical coherence tomography (OCT) showed depression of inner retinal surface, inner retinal hyporeflective spaces (pseudocysts), disorganization/thinning of outer retina, outer retinal tubulation, loss of external limiting membrane, ellipsoid and interdigitation zone, and thinning of the retinal pigment epithelium and choriocapillaris. The patient was evaluated using OCT angiogram. Retinal lesions of her mother (68-year-old) were very obvious on autofluorescence imaging. The result of A3243G mutation in MTTL1 gene was positive in the index case confirming the diagnosis of maternally inherited diabetes and deafness (MIDD).

Lennox-Gastaut Syndrome in Mitochondrial Disease

PURPOSE: Previous studies have shown that neurologic symptoms are dominant in patients with mitochondrial diseases, and most of these patients have seizure-related disorders. The epileptic classification of these patients as Lennox-Gastaut syndrome (LGS) is as high as 25%. This study aimed to investigate the clinical manifestations, diagnoses, treatments, and epilepsy in LGS, which is associated with mitochondrial disease. MATERIALS AND METHODS: A retrospective study was conducted on 372 patients who were diagnosed with mitochondrial disease between 2006 and 2016. Of these 372 patients, 40 patients diagnosed with LGS were selected, and they were classified into two groups based on the history of West syndrome. Patient characteristics were reviewed, and associations between clinical factors and outcomes after the treatment were analyzed. RESULTS: The proportion of individuals with mitochondrial disease with LGS with a history of West syndrome was 32.5%. Among the patients with mitochondrial disease with LGS, neonatal seizure (p=0.029), seizure as the first symptom (p=0.018), and generalized paroxysmal fast activity frequency on electroencephalogram (p=0.018) in the group with a history of West syndrome were statistically significantly high. The first symptom onset (0.6±0.4 yrs vs. 1.6±0.9 yrs, p=0.003) and first seizure onset (0.9±0.7 yrs vs. 3.9±3.1 yrs, p < 0.001) were significantly faster in patients with a history of West syndrome. CONCLUSION: Close monitoring of the medical condition and early intervention might improve the prognosis of individuals with mitochondrial disease with LGS and a history of West syndrome.

Hypertrophic cardiomyopathy associated with mitochondrial disease in children / 中国实用儿科杂志

Mitochondrial disease is a heterogeneous group of hereditary diseases caused by the defects in the mitochondrial respiratory chain and abnormal cellular energy metabolism.Heart is one of the most common organs involved,and hypertrophic cardiomyopathy is the most common and important type of cardiac involvement in mitochondrial disease. Hypertrophic cardiomyopathy in the patients with mitochondrial disease with childhood onset is more common than those with adulthood onset. Mortality in children with cardiac involvement caused by mitochondrial disease is significantly higher than that in children without cardiac involvement,so the early diagnosis and treatment is very important. But the early diagnosis is still difficult due to the complexity of clinical manifestations of mitochondrial disease. There is no specific treatment for mitochondrial disease and its associated hypertrophic cardiomyopathy,so supportive therapy is still the main treatment.

Diagnóstico clínico y bioquímico del síndrome de leigh en cinco pacientes colombianos / Clinical and biochemical diagnosis of leigh syndrome in five colombian patients / Diagnóstico clínico e bioquímico da síndrome de leigh em cinco pacientes colombianos

Resumen El síndrome de Leigh (SL) es una enfermedad neurodegenerativa, descrita como una encefalomielopatía necrotizante subaguda, y es una de las enfermedades de origen mitocondrial más frecuentes. El SL es causado por el déficit en la producción de energía, originada en defectos en los genes que codifican alguno de los complejos mitocondriales; el gen afectado puede ser de codificación tanto nuclear como mitocondrial, lo que explica que se encuentren diferentes mecanismos de herencia, incluyendo autosómica recesiva y herencia materna, lo que, a su vez, hace más difícil su diagnóstico molecular. Clínicamente se presenta con regresión del desarrollo cognitivo y pérdida de habilidades motoras con trastorno de movimiento, de rápida progresión. El diagnóstico se basa en la demostración bioquímica de la elevación del ácido láctico y de la relación lactato/piruvato, así como hallazgos en las neuroimágenes por resonancia magnética que muestran lesiones focales, bilaterales y simétricas en ganglios basales o tallo cerebral asociadas a leucoencefalopatía y atrofia cerebral. Se reportan cinco casos con diagnóstico clínico y bioquímico del SL que ejemplifican la variabilidad clínica y gravedad encontrada en este grupo de pacientes.

Summary Leigh syndrome (LS) is a neurodegenerative disease, described as a subacute necrotizing encephalomyelopathy and is one of the most frequent diseases of mitochondrial origin. LS is caused by a deficit in the energy production due to defects in the genes that encode some of the mitochondrial complexes. The affected gene can be due to either nuclear and/or mitochondrial coding, which explains why there are different ways of inheriting the disease, including autosomal recessive and maternal inheritance, which makes its molecular diagnosis even more difficult. Clinically, LS is characterized by regression in cognitive development and motor abilities, as well as movement disorders of rapid progression. Its diagnosis is based on the biochemical demonstration of an increase in lactic acid and lactate / pyruvate ratio, as well as magnetic resonance neuroimaging findings showing focal, bilateral and symmetric lesions in basal ganglia or brainstem associated with leukoencephalopathy and cerebral atrophy. Five cases are reported with clinical and biochemical diagnosis of LS that exemplify the clinical variability and severity found in this group of patients.

Resumo A síndrome de Leigh (SL) é uma doença neurodegenerativa, descrita como uma encefalomielopatia necrotizante subaguda e é uma das doenças de origem mitocondrial mais frequente. A SL é causada pelo déficit na produção de energia originada em defeitos nos genes que codificam algum dos complexos mitocondriais; o gene afetado pode ser de codificação tanto nuclear como mitocondrial, o que explica que se encontrem diferentes mecanismos de herança, incluindo autossômica recessiva e herança materna, o que torna mais difícil seu diagnóstico molecular. Clinicamente se apresenta com regressão do desenvolvimento do desenvolvimento cognitivo e perda de habilidades motoras com transtorno de movimento, de rápida progressão. O diagnóstico se baseia na demonstração bioquímica da elevação do ácido láctico e da relação lactato/piruvato, assim como descobertas nas neuro imagens por ressonância magnética que mostram lesões focais, bilaterais e simétricas em gânglios basais ou talo cerebral associadas a leucoencefalopatia e atrofia cerebral. Reportam-se cinco casos com diagnóstico clínico e bioquímico da SL que exemplificam a variabilidade clínica e gravidade encontrada neste grupo de pacientes.

Application and prospect of mitotherapy in mitochondria-related diseases / 中国药理学通报

Mitochondria is an important organelle in mammalian cells with multiple functions,such as ener-gy production and cell homeostasis maintaining. It is known that hundreds of diseases are associated with mi-tochondrial defects. The studies show that the exoge-nous mitochondria can directly enter mammalian cells in vitro, and they also can quickly transform into ani-mal tissues by local or intravenous injection. Current-ly, it has raised a new therapeutic strategy for mito-chondrial diseases, called mitotherapy, which trans-plants exogenous functional mitochondria into mito-chondria-defective cells. The mitochondria in recipient cells play their own roles, including energy produc-tion,maintaining free radical balance,and cell viabili-ty recovery. Since there is no effective method for mito-chondria-related diseases up to now, the mitotherapy will provide a new approach for the prevention and treatment of these diseases.

Myocardial Layer-Specific Strain Analysis in Children with Mitochondrial Disease

PURPOSE: Children with mitochondrial disease (MD) have clinical phenotypes that are more severe than those found in adults. In this study, we assessed cardiac function in children with MD using conventional and advanced echocardiographic measurements, explored any unique patterns present, and investigated the development of early cardiomyopathy (CMP). MATERIALS AND METHODS: We retrospectively reviewed the medical records of 33 children with MD. All patients underwent transthoracic echocardiography with conventional and advanced myocardial analysis. We compared all data between patients and an age-matched healthy control group. RESULTS: Conventional echocardiographic diastolic measurements of mitral E, E/A, and tissue Doppler E′ were significantly lower and E/E′ was significantly higher in children with MD, compared with the measurements from the control group. There was no significant difference in longitudinal and radial strain between the groups. Circumferential strain in the endocardium (p=0.161), middle myocardium (p=0.008), and epicardium (p=0.042) were lower in patients, compared to the values in controls. Circumferential strain was correlated with E′ (p 0.60). CONCLUSION: In children with MD, myocardial circumferential strain may develop early in all three layers, even with normally preserved longitudinal and radial strain. This may be an early diagnostic indicator with which to predict CMP in this patient population.

Age-Based Characteristics of West Syndrome in Patients with Mitochondrial Disease / 대한소아신경학회지

PURPOSE: West syndrome is a severe form of age-specific epilepsy that typically affects infants younger than 2 years of age with mitochondrial disease. We aimed to examine age-specific characteristics of the syndrome in these patients. METHODS: We retrospectively analyzed 54 patients with West syndrome diagnosed with mitochondrial disease between March 2006 and March 2016. We compared treatment strategies and diagnostic and clinical variables between patients with early-onset ( < 6 months of age) and late-onset (≥6 months of age) seizures. RESULTS: Seizure was the first symptom in 30 (90.9%) and 13 (65%) patients of the early-onset and late-onset groups, respectively (P=0.046). Delayed development was observed in 3 (9.1%) and 7 (35%) patients of the early-onset and late-onset groups, respectively (P=0.023). Lactate levels were normal in 17 patients (55%) of the early-onset group and 5 (25%) of the late-onset group (P=0.036), while initial brain magnetic resonance imaging (MRI) findings were normal in 23 (67.6%) and 8 (40%) patients of the early-onset and late-onset groups, respectively. Final MRI findings were abnormal in 32 patients (94.1%) of the early-onset group and 18 (90%) of the late-onset group (P=0.036). Although ketogenic diets reduced seizure frequency in both groups, the difference was not significant. CONCLUSION: There is no significant difference in epilepsy-related variables when patients are divided based on a cut-off age of 6 months. However, differences in the first symptom at onset and MRI findings were observed. Although lactate levels were not of significant diagnostic value in the early-onset group, they may be in the late-onset group.

Five Chinese patients with mitochondrial diseases caused by POLG gene mutations / 中华神经科杂志

Objective To report the clinical features, myopathological changes, and gene mutations in five Chinese patients with mitochondrial diseases caused by POLG gene mutations. Methods Clinical materials of five unrelated patients who were referred to Department of Neurology, Peking University First Hospital from April 2012 to January 2018, carrying POLG gene mutations, were retrospectively analyzed. Muscle/nerve biopsies and targeted second-generation gene sequencing were performed on the patients. Results Among the five patients, three were male and two were female. Two cases were dominant inheritance and three were sporadic or recessive inheritance. The ages of onset were from 15 to 40 years with disease course of one to 26 years. One of them showed atypical SANDO (sensory ataxic neuropathy, dysarthria, and ophthalmoparesis) syndrome accompanied by cardiac preexcitation syndrome. There were two cases with autosomal dominant and one case with recessive progressive external ophthalmoplegia plus syndrome. One case presented with cognitive delay and sensory neuropathy. The pathological changes of mitochondrial myopathy were observed in all four patients with muscle involvement. Sural nerve biopsy in the patient with cognitive delay and sensory ataxia revealed chronic axonal pathological changes. POLG gene mutations were found in all five patients by targeted next generation sequencing, including single heterozygous mutations in two dominant inherited patients (c. 914 G＞A and c. 2864A＞G, respectively), and compound heterozygous POLG gene mutations in the other three sporadic/recessive inherited patients (c. 2591 A＞G/c. 1790 G＞A, c. 924G＞T/c. 3002delG and c. 1613A＞T/c. 1612 G＞T, respectively). There were six novel mutations not reported before, i.e., c.914G＞A(p.S305N), c.924G＞T(p.Q308H), c.1613A＞T(p.E538V), c.1612G＞T(p.E538*), c.1790 G＞A(p.R597Q) and c.3002delG. Conclusions POLG gene mutations can lead to different clinical spectrums. Progressive external ophthalmoplegia, limb weakness and axonal sensory neuropathy are common presentations in this group of patients with POLG gene related mitochondrial neuromuscular diseases. Novel mutations found in this study expand the mutational spectrum of POLG gene.

Construction of model for cardiomyocyte disease MERRF using patient-derived iPSC / 临床检验杂志

Objective To obtain myoclonic epilepsy with ragged-red fibers (MERRF)-specific cardiomyocytes by the differentiation in vitro of inducing pluripotent stem cells (iPSC) derived from a MERRF patient and evaluate the application of the prepared cardiomyocytes in construction of MERRF syndrome model.Methods The patient-derived iPSCs and H9 embryonic stem (ES) cells,the control cell line,were unidirectionally differentiated into cardiomyocytes n in vitro.The obtained cardiomyocytes were identified and validated by detecting the presence of cardiomyocyte-specific markers using immunofluorescence staining and RT-PCR.The beating frequencies were recorded to compare the functional evaluation for the two groups of cardiomyocyte.Results Both the patient-derived iPSC and H9 ES cells were differentiated into cardiomyocytes successfully.The average beating frequencies of MERRF-induced cardiomyocytes (iCMs) were 13,24,15 and 18 times/min on the day 10,13,15 and 16 during the cell differentiation process.The average beating frequencies of H9-iCMs were 80,96,120 and 120 times/min,respectively.The beating ability of iPSC-differentiated cardiomyocytes was significantly lower than that of corresponding control (all P ＜ 0.05).Conclusion The patient-derived iPSCs may differentiated into cardiomyocytes.Based on the functional evaluation for these cardiomyocytes,the model for MERRF syndrome with mitochondrial mutations was generated and characterized in vitro.

Overview of Approaches to Mitochondrial Disease Therapy

Abstract Mitochondrial respiratory chain diseases are the most prevalent group of inherited neurometabolic disorders and are clinically, biochemically, and genetically heterogeneous. They may present at any stage of life and often manifest with severe multisystem disease, although single organ involvement is characteristic of some conditions such as Leber hereditary optic neuropathy. As a result of these complexities, the diagnostic pathway is often challenging, so too is further advice, guidance, and therapy following diagnosis. Difficulties also occur with regard to genetic counseling, prognostic assessment, and treatment; there is still no cure or even agreed standards of treatment available for these debilitating diseases. Limited therapeutic options and a lack of curative treatment have led to physicians prescribing individual "trials of therapy" for which no evidence-based recommendations are available. However, new therapeutic options are the focus of active molecular genetic, biochemical, and clinical research, and some medicinal compounds have achieved international governmental approval. In this chapter, we summarize these advances and provide a broad overview of the treatment and novel approaches to preventing transmission of mitochondrial disease.

A case of SUCLG1-related infantile encephalomyopathy mitochondrial DNA depletion syndrome / 临床儿科杂志

Objective Mitochondrial DNA depletion syndrome is a rare autosomal recessive disorder characterized by complex genetic and clinical manifestations.This study aimed to investigate the clinical and laboratory features of a boy with mitochondrial encephalomyopathy caused by SUCLG1 mutation.Methods The clinical data and genetic test of a patient with mitochondrial DNA depletion syndrome were retrospectively analyzed.Result The proband presented with limb weakness at the 4th month after birth,and presented dystrophic appearance,muscular hypotonia,psychomotor retardation,failure to thrive,hearing impairment,scoliosis,thoracocyllosis and facial features at 9 months old.Laboratory tests showed blood lactic acid and pymvate increased,liver damage and abnormal myocardial enzymes.Plasma camitine ester profiling showed that amino acids decreased and C4-dicarboxylic-carnitine increased.Urinary organic acid analysis showed increased concentration of methylmalonic acid and its metabolites indicating methyl malonic aciduria.MRI showed bilateral T2 hyperintensities in bilateral caudate nuelei and lenticular and brain atrophy-like changes.Brainstem auditory evoked potential showed severe hearing loss.His development quotient was 35.Genetic sequencing of MUT,,MMAA,MMAB and other classic mitochondrial disease related genes of the proband revealed no mutation.Two heterozygous mutations,c.961C＞G and c.713T＞C,inherited from the phenotype of normal parents were detected in his SUCLG1 gene.The copy number of mitochondrial DNA was 244/cell in peripheral blood leukocytes,equivalent to 68.4％ of that in normal control.Conclusion In this study,an infant with muscular hypotonia,psychomotor retardation,deafness and slightly increased urine methyl malonic acid was diagnosed by genetic test.For patients with unexplained hypotonia,mental retardation,abnormal movements,hearing disorder together with increased blood pyruvic acid and lactic acid,mild methylmalonic acidemia and abnormal acylcarnitine,mitochondrial DNA depletion syndrome should be considered.Gene analysis is important for diagnosis and prenatal diagnosis of the next pregnancy.

Clinical Trials in Mitochondrial Disease: An Update on EPI-743 and RP103

Abstract Mitochondrial dysfunction results in the production of an abnormally high amount of reactive oxygen and nitrogen species, which results in redox imbalance and glutathione deficiency. Therapeutics such as EPI-743 (?-tocotrienol quinone) and RP103 (cysteamine bitartrate) have the theoretical potential to improve redox imbalance by increasing intracellular glutathione and are currently under investigation in multiple clinical trials. This review provides an update on the use of these compounds in clinical trials related to primary and secondary mitochondrial disorders. These clinical trials have not only provided hope to affected patients and their families and caregivers, but also will serve as important stepping stones for further studies as our understanding of mitochondrial disease pathogenesis continues to improve.

Epilepsy and Mitochondrial Dysfunction: A Single Center's Experience

Abstract Epilepsy is a common manifestation of mitochondrial disease. In a large cohort of children and adolescents with mitochondrial disease (n = 180), over 48% of patients developed seizures. The majority (68%) of patients were younger than 3 years and medically intractable (90%). The electroencephalographic pattern of multiregional epileptiform discharges over the left and right hemisphere with background slowing occurred in 62%. The epilepsy syndrome, infantile spasms, was seen in 17%. Polymerase ? mutations were the most common genetic etiology of seizures, representing Alpers-Huttenlocher syndrome (14%). The severity of disease in those patients with epilepsy was significant, as 13% of patients experienced early death. Simply the loss of energy production cannot explain the development of seizures or all patients with mitochondrial dysfunction would have epilepsy. Until the various aspects of mitochondrial physiology that are involved in proper brain development are understood, epilepsy and its treatment will remain unsatisfactory.

Use of Idebenone for the Treatment of Leber's Hereditary Optic Neuropathy

Abstract Leber's hereditary optic neuropathy (LHON) is one of the most frequent mitochondrial disorders. It is caused by mutations in genes of the mitochondrial DNA coding for subunits of the respiratory chain and leads to severe bilateral vision loss, from which spontaneous recovery is infrequent. Retinal ganglion cells show a selective vulnerability to mitochondrial dysfunction in LHON. Idebenone is the first medication approved for LHON. It is a short-chain benzoquinone, which is an analogue of coenzyme Q10, but with distinct properties and mechanisms of action. Idebenone is a potent antioxidant and inhibitor of lipid peroxidation. Importantly, it facilitates electron flux directly to complex III, bypassing the dysfunctional complex I of the mitochondrial respiratory chain, thereby increasing adenosine triphosphate (ATP) production. In the Rescue of Hereditary Optic Disease Outpatient Study (RHODOS) randomized placebo-controlled clinical trial, 85 patients with LHON were enrolled, in the first 5 years after symptom onset, and randomized to either idebenone 900 mg/d for 6 months or placebo. Idebenone was well tolerated, and although the prespecified primary end point (best recovery in visual acuity [VA]) did not reach statistical significance, all secondary end points (change in best VA, change of VA of best eye at baseline, and change of VA in all eyes) showed a trend toward visual recovery in favor of idebenone. An increasing body of evidence shows that idebenone is effective and safe for the treatment of patients with LHON, including a large retrospective open-label study, several case reports and case series, an expanded access program, and ongoing post-authorization clinical studies. Here, we review the literature on idebenone for the treatment of patients with LHON.

Mitochondrial diseases with the main manifestations of cardiomyopathy and respiratory muscle damage / 中华实用儿科临床杂志

Objective The 3243A ＞ G mutation in mitochondrial DNA is a common cause of the classical mitochondrial diseases characterized by neuro-muscular disorders.This study reports a rare case with the main manifestations of mitochondrial disease in children of mitochondrial cardiomyopathy and respiratory muscle damage.Methods The clinical characteristics,diagnosis and treatment,biochemical,pathological and genetic features of a 10-year-old girl were studied.Results The girl was admitted because of heart failure and respiratory failure at the age of 10.Ragged red fibers in skeletal muscles had been noticed.On her mitochondrial gene,3243A ＞ G mutation,Leu tRNA (UUR),was detected.The mutation rate in the peripheral blood cells was 94％.After the treatment with a high dose of creatine phosphate sodium,coenzyme Q10 and L-carnitine with assisted ventilation,the patient improved rapidly.The child was followed up for 2 years without recurrence.Meanwhile the growth,development and daily life were normal.Conclusions Cardiac and respiratory muscle impairments that appeared at the same time as the first manifestations of the children's mitochondrial disease is not common,and it is rare to have cardiomyopathy based mitochondrial gene 3243A ＞ G mutation is seldom seen clinically.Skeletal muscle biopsy and genetic test is the key for accurate diagnosis.Improving mitochondrial metabolism and assisted ventilation appear to be helpful treatments.

Clinical phenotype and maternal mutation analysis of Leber hereditary optic neuropathy / 中华实验眼科杂志

Background Leber hereditary optic neuropathy (LHON) is a maternally inherited disease caused by mitochondrial DNA (mtDNA) mutation with the common mutation sites of m.3460 G＞A,m.11778 G＞A and m.14484 T＞C,and other mutation sites are rare.Understanding the mutation type of mtDNA in LHON patients has an important clinical significance.Objective This study was to analyze the clinical features of LHON and detect the mitochondrial mutation.Methods Twelve unrelated Chinese patients who was diagnosed as LHON were included in Peking University People's Hospital from 2010 to 2014.The visual acuity,perimetry,ocular segment,visual evoked potential,fundus were binocularly examined.The peripheral blood of 4 ml was collected from each patient and mtDNA was amplified and sequenced by using PCR.Three common genetic mutation sites for LHON and other mutation sites were determined and analyzed.This study protocol was approved by Ethic Committee of Peking University People's Hospital and complied with Helsinki Declaration.Written informed consent was obtained from each patient prior to any medical examination.Results Of the 12 patients,11 were male and 1 was female.The visual acuity of both eyes reduced simultaneously in 7 patients,and the visual acuity of left eye and the right eye first reduced in 3 patients and 1 patient,respectively.There was no significant correlation in the visual impairment between the left and right eyes (P＞0.05).In the near vision of the patients,J7 was invisible in 18 eyes,and J7 were obtained in 3 eyes,J6 were obtained in 2 eyes and J2 was obtained in 1 eye.In the distant vision of the patients,hand movement was obtained in 1 eye,light perception was obtained in 1 eye,0.01-0.1 were obtained in 18 eyes and 0.12-0.3 were obtained in 2 eyes.The visual field defect of nasal lateral was found in 7 eyes,visual field defect of temporal lateral was found in 3 eyes and the visual field defect of central was found in 8 eyes.mtDNA sequencing revealed that m.3460 G＞A mutation was seen in 3 patients,m.11778 G＞A mutation was seen in 5 patients and m.14484 T＞C mutation was seen in 2 patients.In addition,other 2 mutations were found in 2 patients,which were m.3497 C＞T and m.10663 T＞C mutations at the MT-ND1 and MT-ND4L genes,respectively.Conclusions LHON is more common in male.Visual impairment shows the varying degrees between both eyes of patients and appears to be severe in near vision.Central visual field defect is common in LHON patients.This study detects m.3497 C＞T and m.10663 T＞C mutation in Chinese LHON patients.