Mitochondrial encephalopathy, lactic acidosis and stroke-like episodes / myoclonus epilepsy with ragged-red fibers /Leigh overlap syndrome caused by mitochondrial DNA 8344A>G mutation / 北京大学学报(医学版)

OBJECTIVE@#Mitochondrial deoxyribonucleic acid (mtDNA) 8344 A>G (m.8344A>G) mutation is the common mutation associated with mitochondrial myoclonus epilepsy with ragged-red fibers (MERRF) syndrome. Herein we report a rare case with mitochondrial encephalopathy, lactic acidosis and stroke-like episodes/MERRF/Leigh (MELAS/MERRF/Leigh) overlap syndrome caused by m.8344A>G mutation.@*METHODS@#The clinical and imaging data of the patient were collected and an open muscle biopsy was carried out. We further employed molecular genetic analyses to detect mtDNA mutation in the proband and his mother. And then a clinical and neuroimaging follow-up was performed.@*RESULTS@#This patient was a 25-year-old male, who developed exercise intolerance since the age of 6. At age 10, he suffered from acute episodes of hemianopia, and cranial magnetic resonance imaging (MRI) showed occipital stroke-like lesions and cranial magnetic resonance spectroscopy (MRS) revealed a lactate peak corresponding to the lesion. After that the patient presented slowly progressive psychomotor decline. He had myoclonic seizures and cerebellar ataxia since the age of 12. At age 21, he was admitted to our hospital because of confusion and cranial MRI revealed symmetrical lesions in bilateral posterior putamen, thalami and midbrain. Then repeated MRI showed progression of original lesions and new frontal multiple stroke-like lesions. Symptomatic and rehabilitation treatment relieved his condition. Follow-up cranial MRI at age 24 showed the lesions in basal ganglia and thalami diminished, and the midbrain lesions even completely vanished. Muscle pathology indicated the presence of numerous scattered ragged-red fibers (RRF), suggestive of a mitochondrial disorder. Polymerase chain reaction-restricted fragment length polymorphism (PCR-RFLP) detected the m.8344A>G mutation of the MT-TK gene encoding mitochondrial transfer RNA for lysine in the patient's blood. Next generation sequencing (NGS) of the whole mitochondrial genome identified that the proportion of m.8344A>G was 90%, and no other mtDNA mutation was detected. Sanger sequencing further identified this mutation both in the proband and his mother's blood, although the mutation load was much lower in his mother's blood with approximately 10% heteroplasmy.@*CONCLUSION@#The present study is the first to describe a patient with m.8344A>G mutation in association with the MELAS/MERRF/Leigh overlap syndrome, which expands the phenotypic spectrum of the m.8344A>G mutation.

A Case of MELAS Syndrome Presenting with Type 1 Diabetes Mellitus / 대한내과학회지

Mitochondrial encephalopathy, lactic acidosis, and stroke-like episodes (MELAS) syndrome presents with various clinical features, including seizures, stroke-like episodes, encephalopathy, myopathy, cardiac involvement, and diabetes. However, due to its clinical heterogeneity, the diagnosis of MELAS syndrome is complex and difficult. The present report describes an 18-year-old male who was diagnosed with MELAS syndrome following the onset of type 1 diabetes. The patient had suffered from ataxia, mental retardation, and recurrent headaches for several years; following hospitalization for loss of consciousness, he was treated for cerebellar atrophy and Wolf-Parkinson-White (WPW) syndrome. Although the patient had no history of lactic acidosis, the recent onset of type 1 diabetes and his medical history of encephalopathy and WPW syndrome suggested MELAS syndrome. The diagnosis of MELAS syndrome was confirmed by molecular genetic testing, which revealed a point mutation (A3243G) in the patient's mitochondrial DNA.

Clinical and molecular-genetic features and prognosis of mitochondrial encephalopathy in children / 临床儿科杂志

Objective To explore the clinical and molecular-genetic features and prognosis of mitochondrial encephalopathy in children. Methods A total of 11 patients diagnosed with mitochondrial encephalopathy were collected from 2008 to 2013 in Chinese PLA General Hospital, Department of Pediatrics. The clinical manifestations, laboratory tests, muscle pathology and mitochondrial gene sequencing in patients were analyzed and followed-up. Results The onset age of the patients ranged from 6 months to 12 years with the duration of disease from 2 months to 3 years. Of the 11 patients, 6 cases were diagnosed with mitochondrial myopathy, encephalopathy, lactic acidosis and stroke-like episodes (MELAS), 5 cases with mitochondrial disorder induced by mitochondrial respiratory chain enzyme deifciency. Main manifestations included convulsions, vomiting, headache, mental retardation, paralysis, etc. 10 patients had elevated lactate, and 7 patients had elevated pyruvate;6 cases showed increased slow wave in EEG background;Cranial MRI showed the damage involved in bilateral basal ganglia in 2 cases, temporal and occipital lobes in 3 cases, , multiple lesions in 2 cases, frontal and parietal occipital lobes in one patient and hypothalamus in one patient;3 patients were underwent MRA examination, 2 cases were normal, the other showed less shunts in contralateral left artery in the brain;3 cases who underwent MRS showed lactate peak. 2 cases of children underwent skeletal muscle biopsy, and one case showed abnormal mitochondria accumulation. Mitochondrial respiratory chain complex (I~V) defects test showed complex IV defects in 2 cases, complex V defects in 1 case, and combined defects of complex I+III in 2 case. 5 cases were found with mitochondrial DNA mutations in different sites of white blood cells including T8993G, T8993C, A3243G and 11,777 mutations. Conclusions Clinical manifestation of mitochondrial encephalopathy in children is strongly heterogeneous. Laboratory tests, brain imaging, gene mutation and respiratory chain enzyme examination can help to make early diagnosis and treatment. These diseases have poor prognosis.

Diffusion and Perfusion Characteristics of MELAS (Mitochondrial Myopathy, Encephalopathy, Lactic Acidosis, and Stroke-Like Episode) in Thirteen Patients

OBJECTIVE: We analyzed the diffusion and perfusion characteristics of acute MELAS (mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episode) lesions in a large series to investigate the controversial changes of the apparent diffusion coefficient (ADC) that were reported in prior studies. MATERIALS AND METHODS: We analyzed 44 newly appearing lesions during 28 stroke-like episodes in 13 patients with MELAS. We performed a visual assessment of the MR images including the ADC and perfusion maps, comparison of the ADC between the normal and abnormal areas, comparison of % ADC between the 44 MELAS lesions and the 30 acute ischemic infarcts. In addition, the patterns of evolution on follow-up MR images were analyzed. RESULTS: Decreased, increased, and normal ADCs were noted in 16 (36%), 16 (36%), and 12 (27%) lesions, respectively. The mean % ADC was 102 +/- 40.9% in the MELAS and 64 +/- 17.8% in the acute vascular infarcts (p < 0.001), while perfusion imaging demonstrated hyper-perfusion in six acute MELAS lesions. On follow-up images, resolution, progression, and tissue loss were noted in 10, 4, and 17 lesions, respectively. CONCLUSION: The cytotoxic edema gradually evolves following an acute stroke-like episode in patients with MELAS, and this may overlap with hyper-perfusion and vasogenic edema. The edematous swelling may be reversible or it may evolve to encephalomalacia, suggesting irreversible damage.

A study on the expression of anti-mitochondriai antibody in the brain of patients with MELAS syndrome / 中华内科杂志

Objective To investigate the pathological changes and pathogenesis of the MELAS syndrome (mitochondrial encephalopathy lactic acidosis strok-like episodes ) by using the method of immunohistochemical staining in the brain biopsy specimens with anti-mitochondrial antibody (AMA).Methods We performed immunohistochemical staining in 3 confirmed MELAS patients' paraffin-imbed brain biopsy specimens.Results Small vessel proliferation and the uneven thickness of the wall were found in the 3 MELAS patients.A lot of brown deposits was shown in the wall of small vessels and also noted in neurons.Conclusions The main pathological change in the MELAS brain biopsy immunohistochemical staining with AMA was the small vessel proliferation,indicating that abnormal mitochondria accumulated in the vascular smooth muscle,endothelial cell and neurons of the lesion sites.This finding was consistent with the electron microscopic discovery and valuable for the diagnosis of MELAS.