Ultrastructural and clinical findings of mitochondrial encephalomyopathy:report of 27 cases / 中华病理学杂志

Objective@#To investigate the ultrastructural features of muscle in patients with mitochondrial encephalomyopathy for its diagnosis and differential diagnosis.@*Methods@#The clinical data of 27 mitochondrial encephalomyopathy patients who underwent left or right biceps brachii muscle biopsy at Department of Neurosurgery, Beijing Tiantan Hospital, Capital Medical University from July 2006 to August 2017 were analyzed retrospectively. The muscle biopsy specimens were examined underlight microscope and transmission electron microscope.@*Results@#There were 27 patients (17 males, 10 females) with an age range of 12 to 62 years (mean 29 years). The age of onset ranged from 3 to 38 years. The course of disease ranged from 1 month to 24 years. Twenty-two cases presented with lactic acidosis and stroke-like episodes (MELAS) syndrome, four with myoclonic epilepsy with ragged red fibers (MERRF) syndrome, and one with chronic progressive paralysis of extraocular muscle (CPEO) syndrome. Skeletal muscle biopsy showed abundant ragged red fibers and strongly SDH-reactive vessel. Genetic studies showed 17 of 22 cases of MELAS syndrome had A3243G mutation, and the other 5 cases had no abnormality. A8344G mutation was found in 3 of 4 cases of MERRF syndrome. No single or multiple mtDNA mutations were found in the single case of CPEO. Transmission electron microscopy of all 27 cases showed diffuse proliferation of mitochondria between the myofibrils and beneath the sarcolemma, with increased spacing between muscle cells. Seven cases showed numerous glycogen and four showed subsarcolemmal lipid droplets, 13 cases showed unusual mitochondrial morphology, including mitochondrial electron-dense substances and paracrystal line inclusions ("parking lot" change)in eight cases.@*Conclusions@#Transmission electron microscopy shows significant differences in ultrastructural pathological changes among different patients with mitochondrial encephalomyopathy. Some patients with mild clinical symptoms have increased mitochondrial number, increased metabolism of glycogen and lipid droplets, while others with severe clinical symptoms have abnormal mitochondrial morphology. Typical crystalloid inclusions are found in mitochondria, which are of great value in the diagnosis of this disease.

A case of middle-aged mitochondrial encephalomyopathy with multiple cerebrovascular stenosis / 中国脑血管病杂志

A case of middle-age-onset mitochondrial encephalomyopathy,lactic acidosis and stroke-like episodes (MELAS) type mitochondrial myopathy was retrospectively analyzed, and clinical features and diagnostic criteria of MELAS with multiple cerebrovascular stenosis in the middle-aged were summarized. The patient was a middle-aged woman who suffered from repeated headaches and limb convulsions and admitted by Xuanwu Hospital Capital Medical University. She had various risk factors of atherosclerosis. Related examination revealed multiple intracranial vascular stenosis. The lesions could be caused by the stenotic vessels. Therefore, the first diagnosis was ' acute cerebral infarction' after admission. But the clinical symptoms were characterized by ' relapse-remission'. The patient also suffered from headaches, seizures, and cognitive decline. There was past history of ' neurological deafness' and hearing loss in both ears. Magnetic resonance imaging (MRI) showed that ischemic lesions were distributed in the cortex. So further examinations were conducted. She was diagnosed as MELAS-type mitochondrial myopathy by head MR, magnetic resonance spectroscopy (MRS) and genetic examination. Neurotrophic factors, mitochondria-protection,anti-epilepsy,and relief therapy were given. The genetics and clinical manifestations of MELAS-type of mitochondrial myopathy are broadly heterogeneous. For middle-age-onset patients who have various atherosclerotic risk factors and stroke-like symptoms, doctors should be cautious about the mitochondrial disease by dynamically observing patient's clinical symptoms and head MRI, and perform pathology and gene mutation examination for comprehensive analysis. Only in this way,can we timely consider the possibility of mitochondrial encephalomyopathy and correctly make diagnosis as early as possible.

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.

MR diagnosis of mitochondrial encephalomyopathy / 中国介入影像与治疗学

Objective To analyze MRI findings of the mitochondrial encephalopathy, in order to improve the understanding of this disease. Methods MR findings of 5 patients of clinically proved mitochondrial encephalopathy were retrospectively analyzed. Results Brain parenchymal lesions in all patients were low intensity on T1WI and high signal intensity on T2WI. One patient had bilateral globus pallidus involvement, while involvement of gray matter and white matter were observed in 4 patients. Three patients had enlargement of supratentorial ventricles, 2 patients had cerebellar atrophy and 1 patient had bilateral basal galia calcification. Conclusion MRI can show the intracranial lesions in patients with mitochondrial encephalomyopathy clearly, but accurate diagnosis should depend on clinical data.

Síndrome de Leigh: relato de caso / Leigh syndrome: case report

Os autores descrevem pela primeira vez no país um caso de criança do sexo feminino, com 10 anos de idade, atendida no ambulatório de Oftalmologia do Hospital Universitário Clementino Fraga Filho - UFRJ, portadora da síndrome de Leigh, que faz parte de um grupo de enfermidades metabólicas conhecidas como encefalomiopatias mitocondriais. É doença hereditária transmitida por diferentes modos de herança: mitocondrial, autossômica recessiva e recessiva ligada ao X. O início das manifestações clínicas é variado, ocorrendo em geral, dentro dos primeiros dois anos de vida, com evolução insidiosa, progressiva e com períodos de exacerbações. O diagnóstico é difícil pelo pleomorfismo de sua apresentação, sendo baseado nos achados clínicos e estudos complementares relacionados à deficiência na produção mitocondrial de ATP e da citocromo C oxidase. Como não há tratamento específico, este é baseado em medidas paliativas, portanto a identificação desta síndrome é importante como diagnóstico correto permitindo condutas adequadas à melhor qualidade de vida de seus portadores.

The authors describe for the first time in the Country a case of a 10-year-old female child, assisted at the Ophthalmology Clinic of the Hospital Universitário Clementino Fraga Filho UFRJ, with Leigh's syndrome that is part of a metabolic disease group known as mitochondrial encephalomyopathies. It is an hereditary disease transmitted by a different mode of inheritance: mitochondrial, X-linked recessive and autosomal recessive. The beginning of clinical manifestations is varied and occurs usually in the first two years of life, with progressive and insidious evolution and exacerbation periods. Diagnosis is difficult because pleomorphic presentation, based on clinical findings and complementary study related to mitochondrial production of ATP and cytochrome c oxidase deficiencies. Considering that there is no specific treatment, this is based on a palliative procedure. So, the identification of this syndrome is very important to keep it under control, since its evolution is progressive.

Auxiliary diagnosis of aerobic forearm exercise in mitochondriai myopathy and encephalopathy / 中华神经科杂志

Objective To investigate blood gas analysis and lactic acid evaluation in aerobic forearm exercise and the significance of aerobic forearm exercise for the auxiliary diagnosis of mitochondrial myopathy and encephalopathy patients.Methods Forty-two patients with mitochondrial myopathy and encephalopathy patients, 40 healthy control, and 40 patients control were studied.They performed a protocol under aerobic exercise conditions, consisting of intermittent forearm exercise for 4 minutes at 40% of intented maximal voluntary contraction force.Blood samples were collected to monitor blood gas and plasma lactate before, during arid after exercise.Results During exercise venous PO_2(mm Hg, 1 mm Hg=0.133 kPa)decreased in mitochondrial myopathy and encephalopathy patients from 41.2?12.6 to 39.5?16.2, whereas PO_2 fell from 50.5?14.4 to 30.8?13.1 in healthy control and from 50.1?7.9 to 44.3?35.5 in patient control.Venous PO_2 decreased much more in healthy control group than the other 2 groups(F= 6.34,P

A Case of Mitochondrial Neurogastrointestinal Encephalomyopathy

Mitochondrial neurogastrointestinal encephalomyopahty (MNGIE) is a rare disorder and is clinically characterized by ophthalmoparesis, peripheral neuropathy, leukoencephalopathy, gastrointestinal symptoms with intestinal dysmotility, and histologically abnormal mitochondria in muscle. A 32-year-old female showed external ophthalmoparesis, bilateral ptosis, quadriparesis, and sensory change below both ankle joints. Level of serum lactic acid was highly increased. The brain MRI showed diffusely increased signal intensity in the centrum semiovale and white matter. Electron microscopic finding showed paracrystalline inclusions in mitochondria of a few muscle fibers. (J Korean Neurol Assoc 19(3):309~312, 2001)

Clinical features of mtDNA A3243G mutation in adult patients / 中华神经科杂志

Objective To analysis the clinical manifestations of mtDNA A3243G mutation in adulthood.Methods The clinical features were investigated in 36 cases (28 patients from 5 families with the mutation and 8 sporadic cases),in whom mtDNA A3243G mutation was confirmed genetically in 23 cases (15 cases from 5 mutation families and 8 sporadic cases).Cranium radiology was performed in 14 cases.Muscal biopsies were performed in l0 cases.Results Among 28 cases in the 5 family,there were 9 cases (32.1%) with stroke like episodes,17 cases (60.7%) with diabetic mellitus and 16 cases (57.1%) with deafness.Such symptoms usually combined with each other and rarely existed alone. Cardiomyopathy and renal failure were uncommon.In the 23 cases with mtDNA A3243G mutation,14 cases (61.0%) had mitochondria] myopathy,encephalopathy,lactic acidosis,and stroke-like episodes (MELAS),mostly presenting cognitive abnormalities,dysarthria or aphasia and headache,3 cases (13.0%) were asymptomatic carriers,2 cases (8.7%) had autonomic dysfunction,2 cases (8.7%) had diabetic mellitus with or without nerve deafness,1 case (4.3%) had diabetic mellitus with infertilitas and cardiomyopathy,respectively.Cranial radiological images revealed the changes more commonly in the temporal and occipital lobes and less frequently in the frontal lobes.Ragged red fibers were confirmed in 9 of 10 cases with muscle biopsies.The proportion of mutant mtDNA A3243C was not significantly different between MEALS (28.75%?13.69%) and non-MELAS (25.08%?11.54%).Conclusions mtDNA A3243G mutation mainly results in the lesions in the central nerve system,pancreatic island and acoustic nerve in adulthood.Heart and kidney are less frequently involved.Cognitive abnormalities,aphasia and headache are the major symptoms of adult MELAS.Families have with more than 1 patient with diabetic mellitus and deafness,indicating that the mutation is other than MELAS mutation.We should pay more attention to the non-MELAS symptoms in the families with mtDNA A3243G mutation.

Cytochrome C oxidase subunit 1 mutation result in mitochondrial encephaiomyopathy with lactic acidosis and stroke-like episodes / 中华神经科杂志

Objective To report a 33-year-old man with post-headache stroke-like episodes,with whom ischemic changes were found in basal ganglia and occipital-temporal lobe and muscle biopsy revealed abnormal mitochondrial structure and function without regular mutations detected in mtDNA.Methods Gene chip technique was used to detect the mutation of whole sequence of mtDNA,and direct sequencing technique was used to confirm the mutations.Results Three mutations were found.A new mutation in the mitochondrial cytochrome C oxidase subunit 1 (MTCO1),a T→C transition at nucleotide position 6253 resulted in conservative methionine transferring to threonine.His mother also held the mutation,which was not found in 98 control samples.So T6253C was considered the nosogenetic mutation.Conclusion This is the first time to report a mutation in MTCO1 responsible of MELAS.

Analysis of mitochondrial DNA A3 243G point mutation in 9 cases with mitochondrial encephalomyopathy,lactic acidosis and stroke-like episodes / 中华神经科杂志

Objective To study the characteristics of molecular genetics concerning Chinese mitochondr ial encephalomyopathy,lactic acidosis and stroke-like episodes (MELAS). Methods A3243G and T3271C point mutations in the mtDNA of muscle and (or) blood cells were investigated in 9 patients with MELAS and some o f their maternal relatives from 7 families by using PCR-RFLP. Furthermore,mut ant mtDNA in the sample harboring mutation was quantitatively analysed. Results The mtDN A A3243G point mutation was unanimously identified in tissues of all patients an d 1 of their relatives. However,the T3271C point mutation was identi f ied in none of series in our study. The proportion of mtDNA A3243G was 46.8%～ 61. 0% in muscle (4 cases) as well as 26.8%～50.3% in blood (9 cases). In the 3 p atie nts with muscles and blood cells available,their mutant mtDNA proportion in mus cle is consistently higher than in blood cells. The study of leukocytes of some maternal relatives from 6 families showed that,while only 1 proband had a siste r harboring A3243G mutation and none of the mothers of another 3 probands or sib lings of the other 2 probands had the point mutation. However,the sons of 2 pr o bands had not only phenotype of MELAS,but also mtDNA A3243G point mutation in t heir blood. Conclusion mtDNA A3243G mutation highly exists in the series with M E LAS syndrome in our study and can be detected in various tissues,which is consi stent with reports abroad. However,most of our cases are sporadic rather than m aternal inherited. It is presumedly caused by a de novo mutation. Whether i t is due to ethnic difference or sporadic event needs to be investigated further.

The studies on clinical manifestations,histopathology and imaging of MELAS / 中华神经科杂志

Objective To investigate the clinical manifestions ,neuropathology and imaging in the patients with MELAS type of mitochondrial encephalomyopathy for exploring the diagnostic method of the disease. Methods Systemic study was performed on the clinical features,imaging of four MELAS patients. Muscle biopsy and 2 brain biopsies of 3 cases were examined. Results The main clinical features were characterized by intolerance to exercise,recurrent headache and vomit,focal or generalized seizures,dementia,stroke like episodes,sensorineural deafness, hypertrophic cardiomyopathy,endocrine dysfunction,short stature,lactic acidosis and so on. Electromyography showed myopathic damage. CT showed calcification in basal ganglia. CT showed multiple low density lesion primarily in gray matter of occipital,parietal and temporal cortex,which was expressed by the abnormal longer T 1 and T 2 weighted signals on MRI.Muscle biopsy showed red ragged fiber and abnormal mitochondria. Brain biopsy showed laminar necrosis of cortex,astrocytosis,diffused microvascular proliferation and calcification. Four cases were diagnosed as MELAS type.Conclusion According to clinical manifestations and neuroimage features,MELAS is possibly early defined in combination with muscle or/and brain biopsy.

Changes of enzyme histochemistry and ultrastructure in mitochondrial myopathy and encephalomyopathy / 中华神经科杂志

Objective To investigate the pathological features and clinical characteristics of primary mitochondrial myopathy and encephalomyopathy. Methods 11 cases of mitochondrial myopathy and encephalomyopathy were analyzed on clinical features, histochemical changes and ultrastructure observations of muscles. Results RRFs were found in all 11 cases by muscle staining of MGT under light microscope. 7 cases were only afflicated with muscle weakness, 4 cases also having impairment of central nervous system. The proportion of RRFs was 6.4% to 10.3%. We observed these cases under electronic microscope. In 9 cases,the ultrastructural alterations included subsarcolemmal accumulation of mitochondria,increases of the number,abnormal shape,disarrangement of cristae and paracrystaline inclusion bodies. In 2 cases the increase of mitochondrial number is only the alteration. Conclusions Typical RRF is valuable for diagnoses of mitochondrial myopathy and encephalomyopathy under light microscope. The accumulation of abnormal mitochondrials beneath sarcolemal,especially the paracrystaline inclusion bodies are significant in making a definite diagnosis of this disease under electronic microscope.