Diagnosis of a child with mitochondrial myopathy and cerebellar atrophy with ataxia due to compound heterozygous variants of MSTO1 gene / 中华医学遗传学杂志

OBJECTIVE@#To explore the genetic basis for a child with myopathy and cerebellar atrophy with ataxia.@*METHODS@#Clinical examinations and laboratory testing were carried out for the patient. The proband and the parents' genomic DNA was extracted from peripheral blood samples and subjected to trio whole-exome sequencing. Candidate variant was validated by Sanger sequencing.@*RESULTS@#The 1-year-and-8-month-old boy manifested motor developmental delay, ataxia, hypomyotonia, increased serum creatine kinase. Cranial MRI showed cerebellar atrophy with progressive aggravation. Genetic testing revealed that the patient has harbored compound heterozygous variants of the MSTO1 gene, namely c.13delG (p.Ala5ProfsTer68) and c.971C>T (p.Thr324Ile), which were respectively inherited from his mother and father. The former was unreported previously and was predicted to be likely pathogenic, whilst the latter has been reported previously and was predicted to be of uncertain significance.@*CONCLUSION@#The compound heterozygous c.13delG (p.Ala5ProfsTer68) and c.971C>T (p.Thr324Ile) variants probably underlay the disease in the proband. Above finding has enriched the spectrum of MSTO1 gene variants underlying mitochondrial myopathy and cerebellar atrophy with ataxia.

Effect of one-time high load exercise on skeletal muscle injury in rats of different genders: oxidative stress and mitochondrial responses

Purpose: To evaluate the impact of one-time high load exercise on skeletal muscle injury and analysis its mechanism in different genders. Methods: Twenty-four male and 24 female rats were divided randomly into four groups respectively: control, 0 h, 6 h, and 24 h after exercise. The activities of creatine kinase (CK), lactate dehydrogenase (LDH), and myohemoglobin (MYO) in serum, the expression level of oxidative stress markers, mitochondrial respiratory chain complex enzyme, and the apoptosis related protein in quadriceps were detected. Results: The results showed that the activities of CK, LDH and MYO in serum increased immediately after exercise and restored faster in female rats. More obvious structural disorder and apoptosis in male rats were showed. Malondialdehyde (MDA) and superoxide dismutase (SOD) were increased while catalase (CAT) and glutathione (GSH) were decreased in male rats. SOD, CAT and GSH were increased in female rats. Mitochondrial complex enzyme activity was decreased in males and increased in females. Conclusions: The skeletal muscle injury in both genders of rat could be induced by one-time high load exercise due to the mitochondrial respiratory enzyme dysfunction and oxidative stress, which was relatively mild and recovered quicker in female rats.

Miopatia mitocondrial e deficiência auditiva neurossensorial: estudo de caso / Mitochondrial myopathy and sensorineural hearing loss: case study

Resumo A miopatia mitocondrial é causada pela ausência e/ou insuficiência de uma enzina quaternária, L-carnitina, responsável por transportar ácidos graxos livres para a parte interna da mitocôndria. A função da mitocôndria é produzir energia, contribuindo para o bom funcionamento das células. A Lipidose Muscular é uma doença que provoca anomalias em enzimas que metabolizam gordura e por consequência causa acúmulo de toxinas de subprodutos com gordura nos tecidos. O objetivo deste trabalho é apresentar o estudo de caso da paciente B.D., 37 anos, diagnosticada com Lipidose Muscular aos seis anos, com deficiência de L-Carnitina e relatar o acompanhamento fonoaudiológico realizado em um serviço de saúde auditiva. A abertura de prontuário da paciente foi realizada em 05/03/1989. Foi prescrito pelo neurologista o uso contínuo de 2g/dia de L-carnitina. A mãe relatou que B.D. apresentava dificuldades em ouvir, pois era muito desatenta, o que foi mais evidente quando começou a frequentar a escola. Em 1988, a paciente foi diagnosticada com perda auditiva neurossensorial de grau moderado bilateral e começou a fazer uso de aparelhos de amplificação sonora individual retroauriculares em 1989. O desempenho escolar e comunicação melhoraram. Em 1998, passou a utilizar aparelhos tipo micro canal, o que a favoreceu esteticamente, promoveu melhora da localização sonora e maior ganho em altas frequências. Os limiares de audibilidade apresentaram uma leve piora e a paciente atualmente é pós-graduada e trabalha em uma grande instituição financeira. Conclui-se que o diagnostico neurológico e a intervenção fonoaudiológica precoces possibilitaram o adequado desenvolvimento de linguagem da paciente.

Abstract Mitochondrial myopathy is caused by the absence and/or insufficiency of L-carnitine, a quaternary enzyme responsible for transporting free fatty acids into the mitochondria. The primary function of the mitochondria is to produce energy, contributing to proper cell functioning. Muscular lipidosis causes abnormalities in enzymes that metabolize fat, resulting in the accumulation of harmful amounts of fats in tissues. The aim of this study was to present the case study of patient B.D., a 37-year-old woman diagnosed with muscular lipidosis with L-carnitine deficiency at 6 years old, and describe the speech-language follow-up performed at a hearing care clinic. The first entry in the patient's medical chart was on 03/05/1989, with continuous use of 2g/day of L-carnitine prescribed by a neurologist. The mother reported that B.D. had difficulty hearing and was inattentive, which became more evident when she started school. In 1988 the patient was diagnosed with moderate bilateral sensorineural hearing loss and began using behind-the-ear (BTE) hearing aids in 1989, after which her academic performance and communication improved. In 1998 she switched to Completely in Canal (CIC) hearing aids, which are more discreet, provided better sound localization and greater high frequency gain, although her hearing thresholds worsened slightly. She completed her graduate studies and currently works at a large financial institution. It was concluded that early neurological diagnosis and speech-language intervention enabled adequate language development in the patient.

Neumopatía crónica secundaria al trastorno de la deglución en un paciente con miopatía mitocondrial / Chronic pneumopathy secondary to swallowing disorder in a patient with mitochondrial myopathy

RESUMEN Introducción: la enfermedad pulmonar crónica secundaria a la disfagia es una complicación frecuente en los pacientes con enfermedades neuromusculares. Las miopatías mitocondriales son un conjunto de enfermedades que pueden conducir a daño pulmonar progresivo, secundario al síndrome aspirativo crónico. Caso clínico: niño de 7 años con signos clínicos y radiológicos de enfermedad pulmonar crónica; además, con desnutrición crónica, debilidad muscular, disfonía y oculoparesia externa crónica multiplanar. Su padre tuvo síntomas similares desde la infancia y requirió alimentación con dieta espesa por trastorno de la deglución. Se confirma en el paciente la presencia de disfagia como la causa de la neumopatía crónica y se sospecha miopatía congénita hereditaria. En consecuencia, se realiza el diagnóstico de enfermedad mitocondrial con oculoparesia externa crónica, mediante la secuenciación del gen polimerasa gamma del ADN mitocondrial (POLG). Conclusiones: en los pacientes con neumopatía crónica se deben considerar las enfermedades neuromusculares en el diagnóstico diferencial. La miopatía mitocondrial con oculoparesia externa crónica progresiva, se asocia con trastorno de la deglución hasta en un 50 % de los casos. El diagnóstico temprano es importante para retardar el deterioro de la función pulmonar.

SUMMARY Introduction: Chronic lung disease secondary to dysphagia is a frequent complication in patients with neuromuscular diseases. Mitochondrial myopathies could lead to progressive lung damage due to chronic aspiration syndrome. Clinical case: Seven-year-old male with clinical and radiological signs of chronic lung disease, as well as low weight, weakness, dysphonia and multiplanar external oculoparesis. His father had similar symptoms during infancy and needed thickened liquid diet due to swallowing disorder. Dysphagia was confirmed as the cause of chronic lung disease and, therefore, hereditary congenital myopathy was suspected. Mitochondrial disease with chronic external oculoparesis was confirmed by molecular sequencing of the mitochondrial DNA gamma polymerase gene (POLG). Conclusion: Neuromuscular disorders may cause chronic lung disease. Mitochondrial myopathy with progressive chronic external oculoparesis is associated with swallowing disorder in 50 % of the cases. Early diagnosis is important to slow decline in lung function.

Activated mTOR signaling pathway in myofibers with inherited metabolic defect might be an evidence for mTOR inhibition therapies / 中华医学杂志(英文版)

BACKGROUND@#Abnormally activated mechanistic target of rapamycin (mTOR) pathway has been reported in several model animals with inherited metabolic myopathies (IMMs). However, the profiles of mTOR pathway in skeletal muscles from patients are still unknown. This study aimed to analyze the activity of mTOR pathway in IMMs muscles.@*METHODS@#We collected muscle samples from 25 patients with mitochondrial myopathy (MM), lipid storage disease (LSD) or Pompe disease (PD). To evaluate the activity of mTOR pathway in muscle specimens, phosphorylation of S6 ribosomal protein (p-S6) and p70S6 kinase (p-p70S6K) were analyzed by Western blotting and immunohistochemistry.@*RESULTS@#Western blotting results showed that p-p70S6K/p70S6K in muscles from LSD and MM was up-regulated when compared with normal controls (NC) (NC vs. LSD, U = 2.000, P = 0.024; NC vs. MM: U = 6.000, P = 0.043). Likewise, p-S6/S6 was also up-regulated in muscles from all three subgroups of IMMs (NC vs. LSD, U = 0.000, P = 0.006; NC vs. PD, U = 0.000, P = 0.006; NC vs. MM, U = 1.000, P = 0.007). Immunohistochemical study revealed that p-S6 was mainly expressed in fibers with metabolic defect. In MM muscles, most p-S6 positive fibers showed cytochrome C oxidase (COX) deficiency (U = 5.000, P = 0.001). In LSD and PD muscles, p-S6 was mainly overexpressed in fibers with intramuscular vacuoles containing lipid droplets (U = 0.000, P = 0.002) or basophilic materials (U = 0.000, P = 0.002).@*CONCLUSION@#The mTOR pathway might be activated in myofibers with various metabolic defects, which might provide evidence for mTOR inhibition therapy in human IMMs.

Nicotinamide riboside regulates inflammation and mitochondrial markers in AML12 hepatocytes

BACKGROUND/OBJECTIVES: The NAD+ precursor nicotinamide riboside (NR) is a type of vitamin B3 found in cow's milk and yeast-containing food products such as beer. Recent studies suggested that NR prevents hearing loss, high-fat diet-induced obesity, Alzheimer's disease, and mitochondrial myopathy. The objective of this study was to investigate the effects of NR on inflammation and mitochondrial biogenesis in AML12 mouse hepatocytes. MATERIALS/METHODS: A subset of hepatocytes was treated with palmitic acid (PA; 250 µM) for 48 h to induce hepatocyte steatosis. The hepatocytes were treated with NR (10 µM and 10 mM) for 24 h with and without PA. The cell viability and the levels of sirtuins, inflammatory markers, and mitochondrial markers were analyzed. RESULTS: Cytotoxicity of NR was examined by PrestoBlue assay. Exposure to NR had no effect on cell viability or morphology. Gene expression of sirtuin 1 (Sirt1) and Sirt3 was significantly upregulated by NR in PA-treated hepatocytes. However, Sirt1 activities were increased in hepatocytes treated with low-dose NR. Hepatic pro-inflammatory markers including tumor necrosis factor-alpha and interleukin-6 were decreased in NR-treated cells. NR upregulated anti-inflammatory molecule adiponectin, and, tended to down-regulate hepatokine fetuin-A in PA-treated hepatocytes, suggesting its inverse regulation on these cytokines. NR increased levels of mitochondrial markers including peroxisome proliferator-activated receptor γ coactivator-1α, carnitine palmitoyltransferase 1, uncoupling protein 2, transcription factor A, mitochondrial and mitochondrial DNA in PA-treated hepatocytes. CONCLUSIONS: These data demonstrated that NR attenuated hepatic inflammation and increased levels of mitochondrial markers in hepatocytes.

Rivastigmine prevents injury induced by ischemia and reperfusion in rat liver

Abstract Purpose: To evaluate whether pre-treatment with rivastigmine is able to attenuate the I/R induced lesions in rat liver. Methods: SHAM animals or those submitted to I/R, non-treated or pre-treated with rivastigminine (2mg/kg) either 50 or 15 minutes before ischemia, were used. After I/R protocol, these animals were killed and their livers were harvested to measurement of the mitochondrial swelling as well as the malondialdehyde (MDA), nitrite and nitrate tissue concentration. Blood was also harvested for serum aspartate aminotransferase (AST) and alanine aminotransferase (ALT) determinations. Results: I/R promoted a significant increase of mitochondrial swelling in the studied animals. This increase of mitochondrial swelling was partially prevented by rivastigmine, but only if administered 50 minutes before ischemia. No significant modification of MDA, nitrite or nitrate tissue concentrations was observed in consequence of I/R, followed or not by rivastigmine treatments. In addition, I/R elevated both AST and ALT. These elevations of serum enzymes were not reversed by the different rivastigmine treatments. Conclusions: Rivastigmine administered 50 minutes before ischemia attenuates I/R-induced mitochondrial swelling, that indicates liver injury. This protective effect may be related to a greater stimulation of α7nAChR present in the Kupffer cells by the non-methabolized ACh, leading to an attenuation of I/R-induced inflammation.

Clevudine Induced Mitochondrial Myopathy

Clevudine was approved as an antiviral agent for hepatitis B virus, which showed marked, rapid inhibition of virus replication without significant toxicity. However, several studies have reported myopathy associated with clevudine therapy. Also, we experienced seven patients who suffered from myopathy during clevudine therapy. To characterize clevudine-induced myopathy, we collected previously reported cases of clevudine myopathy and analyzed all the cases including our cases. We searched electronic databases that were published in English or Korean using PubMed and KoreaMed. Ninety-five cases with clevudine myopathy, including our seven cases, were selected and analyzed for the demographic data, clinical features, and pathologic findings. The 95 patients with clevudine-induced myopathy comprised 52 women and 43 men aged 48.9 years (27–76 years). The patients received clevudine therapy for about 14.2 months (5–24 months) before the development of symptoms. Weakness mainly involved proximal extremities, especially in the lower extremities, and bulbar and neck weakness were observed in some cases (13.7%). Creatine kinase was elevated in the majority of patients (97.9%). Myopathic patterns on electromyography were observed in most patients examined (98.1%). Muscle biopsy presented patterns compatible with mitochondrial myopathy in the majority (90.2%). The weakness usually improved within about 3 months after the discontinuation of clevudine. Though clevudine has been known to be safe in a 6-month clinical trial, longer clevudine therapy for about 14 months may cause reversible mitochondrial myopathy. Careful clinical attention should be paid to patients with long-term clevudine therapy.

The Newcastle Pediatric Mitochondrial Disease Scale: translation and cultural adaptation for use in Brazil / Escala Pediátrica de Doença Mitocondrial de Newcastle: tradução e adaptação cultural para uso no Brasil

ABSTRACT Objective The aim of this study was to translate and adapt the Newcastle Paediatric Mitochondrial Disease Scale (NPMDS) to Portuguese for use in Brazil. Methods The scale was applied in 20 pediatric patients with mitochondrial disease, in three groups: myopathy (n = 4); Leigh syndrome (n = 8); and encephalomyopathy (n = 8). Scores were obtained for the various dimensions of the NPMDS, and comparisons were drawn between the groups. Results There was a statistically significant difference between the myopathy group and the Leigh syndrome group (p = 0.0085), as well as between the myopathy and encephalomyopathy groups (p = 0.01). Conclusions The translation of the NPMDS, and its adaptation to the socioeconomic and cultural conditions in Brazil, make the NPMDS score useful as an additional parameter in the evaluation and monitoring of pediatric patients with MD in Brazil.

RESUMO Objetivo O objetivo do presente estudo foi realizar a tradução e adaptação da escala NPMDS para a população brasileira. Métodos A escala foi aplicada em 20 crianças e adolescentes com doença mitocondrial (DM) divididos em três grupos: miopatia (n=4), síndrome de Leigh (n=8) e encefalomiopatia (n=8). Obteve-se os escores separados das dimensões da escala NPMDS, foram realizadas comparações entre os escores da NPMDS nos diferentes grupos. Conclusão A tradução da escala NPMDS e sua adequação as condições socioeconômicas e culturais de nossa população tornam este instrumento um parâmetro adicional na avaliação e acompanhamento de pacientes pediátricos com DM.

MELAS en el Perú: reporte de caso / MELAS in Peru: case report

El síndrome de MELAS es una rara citopatía mitocondrial de difícil diagnóstico. Reportamos el caso de una niña de 10 años, que ingresó al Instituto Nacional de Ciencias Neurológicas de Lima, Perú, quien presentó episodios bruscos similares a accidentes cerebrovasculares y crisis epilépticas. Los estudios de neuroimágenes mostraron infartos y el examen genético fue positivo para MELAS identificando la mutación más frecuente A3243G...

MELAS syndrome is a rare mitochondrial cytopathy difficult to diagnose. We report the case of a 10 year old girl who was admitted to the National Institute of Neurological Sciences of Lima - Peru, who presented sudden stroke like episodes and seizures. Neuroimaging studies showed infarction and genetic testing was positive for identifying the most common MELAS mutation (A3243)...

Effect of L-carnitine on exercise performance in patients with mitochondrial myopathy

Exercise intolerance due to impaired oxidative metabolism is a prominent symptom in patients with mitochondrial myopathy (MM), but it is still uncertain whether L-carnitine supplementation is beneficial for patients with MM. The aim of our study was to investigate the effects of L-carnitine on exercise performance in MM. Twelve MM subjects (mean age±SD=35.4±10.8 years) with chronic progressive external ophthalmoplegia (CPEO) were first compared to 10 healthy controls (mean age±SD=29±7.8 years) before they were randomly assigned to receive L-carnitine supplementation (3 g/daily) or placebo in a double-blind crossover design. Clinical status, body composition, respiratory function tests, peripheral muscle strength (isokinetic and isometric torque) and cardiopulmonary exercise tests (incremental to peak exercise and at 70% of maximal), constant work rate (CWR) exercise test, to the limit of tolerance [Tlim]) were assessed after 2 months of L-carnitine/placebo administration. Patients with MM presented with lower mean height, total body weight, fat-free mass, and peripheral muscle strength compared to controls in the pre-test evaluation. After L-carnitine supplementation, the patients with MM significantly improved their Tlim (14±1.9 vs 11±1.4 min) and oxygen consumption ( V ˙ O 2 ) at CWR exercise, both at isotime (1151±115 vs 1049±104 mL/min) and at Tlim (1223±114 vs 1060±108 mL/min). These results indicate that L-carnitine supplementation may improve aerobic capacity and exercise tolerance during high-intensity CWRs in MM patients with CPEO.

Obstetric anesthesia considerations in Kearns-Sayre syndrome: a case report / 대한마취과학회지

Kearns-Sayre syndrome (KSS) is a rare mitochondrial myopathy that usually develops before 20 years of age. It demonstrates multisystemic involvement with a triad of cardinal features: progressive ophthalmoplegia, pigmentary retinopathy, and cardiac conduction abnormalities. In addition, patients might have cerebellar ataxia, a high content of protein in the cerebrospinal fluid, proximal myopathy, multiple endocrinopathies, and renal tubular acidosis. We herein report the successful obstetric analgesic and anesthetic management of a 28-year-old parturient patient with KSS who required labor analgesia and proceeded to deliver by cesarean section. We extrapolate that regional analgesia/anesthesia might be beneficial for reducing the metabolic demands associated with the stress and pain of labor in patients with KSS. Efficient postoperative analgesia should be provided to decrease oxygen requirements.

Obstetric anesthesia considerations in Kearns-Sayre syndrome: a case report / 대한마취과학회지

Kearns-Sayre syndrome (KSS) is a rare mitochondrial myopathy that usually develops before 20 years of age. It demonstrates multisystemic involvement with a triad of cardinal features: progressive ophthalmoplegia, pigmentary retinopathy, and cardiac conduction abnormalities. In addition, patients might have cerebellar ataxia, a high content of protein in the cerebrospinal fluid, proximal myopathy, multiple endocrinopathies, and renal tubular acidosis. We herein report the successful obstetric analgesic and anesthetic management of a 28-year-old parturient patient with KSS who required labor analgesia and proceeded to deliver by cesarean section. We extrapolate that regional analgesia/anesthesia might be beneficial for reducing the metabolic demands associated with the stress and pain of labor in patients with KSS. Efficient postoperative analgesia should be provided to decrease oxygen requirements.

Genetics of Mitochondrial Myopathies

Mitochondrion is an intracellular organelle with its own genome. Its function in cellular metabolism is indispensable that mitochondrial dysfunction gives rise to multisystemic failure. The manifestation is most prominent with tissues of high energy demand such as muscle and nerve. Mitochondrial myopathies occur not only by mutations in mitochondrial genome, but also by defects in nuclear genes or secondarily by toxic insult on mitochondrial replication. Currently curative treatment modality does not exist and symptomatic treatment remains mainstay. Administration of L-arginine holds great promise according to the recent reports. Advances in mitochondrial RNA import might enable a new therapeutic strategy.

A Case of Myopathy, Encephalopathy, Lactic Acidosis and Stroke-Like Episodes (MEALS) Syndrome with Intracardiac Thrombus

Myopathy, encephalopathy, lactic acidosis and stroke-like episodes (MELAS) is a multisystem clinical syndrome manifested by mitochondrial myopathy, encephalopathy, lactic acidosis and recurrent stroke-like episodes. A 27-year-old female with MELAS syndrome presented with cerebral infarction. Echocardiography revealed a thrombus attached to the apex of the hypertrophied left ventricle, with decreased systolic function. The embolism of the intracardiac thrombus might have been the cause of stroke. There should be more consideration given to the increased possibility of intracardiac thrombus formation when a MELAS patient with cardiac involvement is encountered.

Vascular Hyperemia and Crossed Cerebellar Diaschisis in MELAS Patient Presented as Stroke-Like Episode and Seizure

Mitochondrial encephalopathy, lactic acidosis, and stroke-like episodes (MELAS) is one of the mitochondrial disorders that can present as a stroke-like episode or seizure. Although the pathophysiology of MELAS remains inconclusive, the main possibilities are thus far thought to be mitochondrial cytopathy and angiopathy. This case report describes a 61-year-old woman diagnosed with MELAS who presented simultaneously with vascular hyperemia and crossed cerebellar diaschisis.

Vascular Hyperemia and Crossed Cerebellar Diaschisis in MELAS Patient Presented as Stroke-Like Episode and Seizure

Mitochondrial encephalopathy, lactic acidosis, and stroke-like episodes (MELAS) is one of the mitochondrial disorders that can present as a stroke-like episode or seizure. Although the pathophysiology of MELAS remains inconclusive, the main possibilities are thus far thought to be mitochondrial cytopathy and angiopathy. This case report describes a 61-year-old woman diagnosed with MELAS who presented simultaneously with vascular hyperemia and crossed cerebellar diaschisis.

Anesthetic Management of a Patient with Mitochondrial Myopathy Undergoing Orthopedic Surgery

Mitochondria myopathies consist of large heterogeneous groups of disorders resulting from primary dysfunction of the mitochondrial respiratory chain and causing muscle disease. These disorders involve the multiple organ system and appear to be extensive variability in clinical presentation. Therefore anesthetic management of patients with mitochondrial myopathies should begin with careful preoperative investigation and preparation. We report successful general anesthesia in a 22-year-old man with mitochondrial myopathy undergoing orthopedic surgery.