A case of overlap myoclonic epilepsy with ragged-red fibers-Leigh syndrome associated with mitochondrial DNA 8344A>G mutation / 中华神经科杂志

Overlap myoclonic epilepsy with ragged-red fibers (MERRF)-Leigh syndrome is a rare mitochondrial encephalomyopathy. A case of MERRF-Leigh syndrome associated with mitochondrial DNA 8344A>G (m.8344A>G) mutation was reported in this article. The patient has suffered from the disease since 15-year old with myoclonus, exercise intolerance, ataxia, limb weakness, dysphasia, dyspnea, blurred vision and hearing loss. Magnetic resonance imaging revealed lesions on right thalamus, bilateral medulla and lumbar spinal cord and atrophy of cervical spinal cord. Electromyography showed predominantly axonal damage of both sensory nerve and motor nerve. Histochemical analyses revealed ragged red fibers, ragged blue fibers, succinate dehydrogenase-stronghly reactive vessels and decreased cytochrome oxidase activity. Gene tests demonstrated a high level of m.8344A>G mutation and m. 14484T>C mutation. MERRF-Leigh overlap syndrome with m.8344A>G mutation was rare. Bulbar paralysis following myoclonus is the main clinical symptom.

Myoclonus epilepsy with ragged-red fibers:a case report and literature review / 北京大学学报(医学版)

SUMMARY To demonstrate the clinical manifestation, diagnosis and treatment of myoclonus epilepsy with ragged-red-fibers ( MERRF) , a case of MERRF was presented with review of the literature. A 4-year-7-month-old girl was diagnosed with MERRF. She had tremor, fatigue and developmental delay for more than 2 years. Laboratory tests showed that the serum and urine lactic acid and pyruvic acid increased significantly. Electroencephalogram showed diffuse and focal spike slow wave and slow wave in right central and parietal regions. Electromyogram showed neurological damage. Gene mutational analysis showed mtDNA 8344 A>G mutation. The mutational rate was 78%. Mitochondrial disease MERRF syndrome was diagnosed. Cocktails therapy with vitamins B1, B6, B12, L-carnitine, and coenzyme Q10 was administra-ted to the patient. MERRF is a rare disease. The diagnosis can be made by gene mutational analysis. Cocktail therapy may slow down the deterioration of the disease. Gene therapy is still experimental.

Identification of causative mutations in patients with Leigh syndrome and MERRF by mitochondrial DNA-targeted next-generation sequencing

PURPOSE: Mitochondrial diseases are clinically and genetically heterogeneous disorders, which make their exact diagnosis and classification difficult. The purpose of this study was to identify pathogenic mitochondrial DNA (mtDNA) mutations in 2 Korean families with myoclonic epilepsy with ragged-red fibers (MERRF) and Leigh syndrome, respectively. MATERIALS AND METHODS: Whole mtDNAs were sequenced by the method of mtDNA-targeted next-generation sequencing (NGS). RESULTS: Two causative mtDNA mutations were identified from the NGS data. An m.8344A>G mutation in the tRNA-Lys gene (MT-TK ) was detected in a MERRF patient (family ID: MT132), and an m.9176T>C (p.Leu217Pro) mutation in the mitochondrial ATP6 gene (MT-ATP6) was detected in a Leigh syndrome patient (family ID: MT130). Both mutations, which have been reported several times before in affected individuals, were not found in the control samples. CONCLUSION: This study suggests that mtDNA-targeted NGS will be helpful for the molecular diagnosis of genetically heterogeneous mitochondrial diseases with complex phenotypes.

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.

Mutational analysis of whole mitochondrial DNA in patients with MELAS and MERRF diseases

Mitochondrial diseases are clinically and genetically heterogeneous disorders, which make the exact diagnosis and classification difficult. The purpose of this study was to identify pathogenic mtDNA mutations in 61 Korean unrelated families (or isolated patients) with MELAS or MERRF. In particular, the mtDNA sequences were completely determined for 49 patients. From the mutational analysis of mtDNA obtained from blood, 5 confirmed pathogenic mutations were identified in 17 families, and 4 unreported pathogenically suspected mutations were identified in 4 families. The m.3243A>G in the tRNA(Leu(UUR)) was predominantly observed in 10 MELAS families, and followed by m.8344A>G in the tRNA(Lys) of 4 MERRF families. Most pathogenic mutations showed heteroplasmy, and the rates were considerably different within the familial members. Patients with a higher rate of mutations showed a tendency of having more severe clinical phenotypes, but not in all cases. This study will be helpful for the molecular diagnosis of mitochondrial diseases, as well as establishment of mtDNA database in Koreans.

Clinical Spectrum and Prognostic Factors of Acute Necrotizing Encephalopathy in Children

This study was conducted to investigate the etiology, the clinical characteristics and prognosis of acute necrotizing encephalopathy (ANE) in Korean children. Six children (1 yr to 7 yr) patients with ANE were enrolled. They were diagnosed by clinical and radiological characteristics and their clinical data were retrospectively analyzed. In a search of clinically plausible causes, brain MRI in all patients, mitochondrial DNA studies for mitochondrial encephalomyopathy, lactic acidosis, and strokelike episodes (MELAS) and myoclonus epilepsy and ragged red fibers (MERRF) in four patients, and genomic typing on HLA DRB/HLA DQB genes in three patients were performed. All had precedent illnesses and the main initial symptoms included mental change (83%), seizures (50%), and focal deficits (50%). MRI revealed increased T2 signal density in the bilateral thalami and/or the brainstem in all patients. Mitochodrial DNA studies for MELAS and MERRF were negative in those children and HLA-DRB1*1401, HLA-DRB3*0202, and HLA-DQB1*0502 seemed to be significant. A high dose steroid was given to all patients, which seemed to be partly effective except for 2 patients. In conclusion, ANE is relatively rare, but can result in serious neurological complication in children. Early detection and appropriate treatment may lead to a better neurological outcome.

Histochemical and Molecular Genetic Study of MELAS and MERRF in Korean Patients

Mitochondrial myopathy, encephalopathy, lactic acidosis and stroke-like episode (MELAS) and myoclonic epilepsy and raggedred fibers (MERRF) are rare disorders caused by point mutation of the tRNA gene of the mitochondrial genome. To understand the pathogenetic mechanism of MELAS and MERRF, we studied four patients. Serially sectioned frozen muscle specimens with a battery of histochemical stains were reviewed under light microscope and ultrastructural changes were observed under electron microscope. The polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) analysis was performed and the tRNA genes were sequenced to confirm mutations. In two patients with MELAS, strongly succinyl dehydrogenase positive blood vessels (SSVs) and many cytochrome oxidase (COX) positive raggedred fibers (RRFs) were observed, and A3243G mutations were found from the muscle samples. In two patients with MERRF, neither SSV nor COX positive RRFs were seen and A8344G mutations were found from both muscle and blood samples. In the two MERRF families, the identical mutation was observed among family members. The failure to detect the mutation in blood samples of the MELAS suggests a low mutant load in blood cells. The histochemical methods including COX stain are useful for the confirmation and differentiation of mitochondrial diseases. Also, molecular biological study using muscle sample seems essential for the confirmation of the mtDNA mutation.

Molecular Genetic Diagnosis in Korean Patients with Myoclonic Epilepsy with Ragged Red Fiber (MERRF) Syndrome

PURPOSE: Myoclonic epilepsy with ragged red fiber (MERRF) syndrome is a disease of the mitochondrial encephalomyopathies, characterized by progressive myoclonus (action), epilepsy, cerebellar ataxia, intention tremor, muscle weakness, progressive dementia, sensorineural hearing loss and optic atrophy. Its inheritance is maternally inherited mitochondrial mutation, and its pathologic finding is characterized by ragged red fibers (RRF). Biochemically its defects are diverse. This study was undertaken to investigate the pattern of mitochondrial mutation and characterize the clinical features in Korean patients with MERRF. METHODS: We collected 3 clinically suspected MERRF patients from 2 Korean families who have progressive myoclonus, epilepsy, cerebellar ataxia, intention tremor, muscle weakness, progressive dementia etc. We reviewed their clinical findings, electrophysiologic studies, radiologic findings and pathologic findings, retrospectively. Of the 2 patients (case 1 and case 3) who had undergone muscle biopsy, case 1 showed RRF in modified Gomori trichrome staining, increased mitochondrial number and abnormal inclusion body in EM. To examine the pattern of mitochondrial mutation of these patients, molecular study was carried out in 3 patients, 2 mothers, 2 fathers, and 4 siblings. Their genomic DNAs were isolated from peripheral leukocytes, subsequent PCR-direct nucleotide sequencing and Ban II digestion were followed. RESULTS: All mutations in our cases were A to G point mutations in the tRNALys gene at position 8344. CONCLUSION: We confirmed clinically suspected MERRF patients as MERRF and their mothers and siblings as carriers, on the basis of molecular genetic analysis. This study suggests that the molecular genetic analysis can be utilized to diagnose MERRF patients easily and confirm carriers, especially at the presymptomatic stage before the characteristic pathologic changes appear.

Molecular Genetic Diagnosis in Korean Patients with Myoclonic Epilepsy with Ragged Red Fiber (MERRF) Syndrome

PURPOSE: Myoclonic epilepsy with ragged red fiber (MERRF) syndrome is a disease of the mitochondrial encephalomyopathies, characterized by progressive myoclonus (action), epilepsy, cerebellar ataxia, intention tremor, muscle weakness, progressive dementia, sensorineural hearing loss and optic atrophy. Its inheritance is maternally inherited mitochondrial mutation, and its pathologic finding is characterized by ragged red fibers (RRF). Biochemically its defects are diverse. This study was undertaken to investigate the pattern of mitochondrial mutation and characterize the clinical features in Korean patients with MERRF. METHODS: We collected 3 clinically suspected MERRF patients from 2 Korean families who have progressive myoclonus, epilepsy, cerebellar ataxia, intention tremor, muscle weakness, progressive dementia etc. We reviewed their clinical findings, electrophysiologic studies, radiologic findings and pathologic findings, retrospectively. Of the 2 patients (case 1 and case 3) who had undergone muscle biopsy, case 1 showed RRF in modified Gomori trichrome staining, increased mitochondrial number and abnormal inclusion body in EM. To examine the pattern of mitochondrial mutation of these patients, molecular study was carried out in 3 patients, 2 mothers, 2 fathers, and 4 siblings. Their genomic DNAs were isolated from peripheral leukocytes, subsequent PCR-direct nucleotide sequencing and Ban II digestion were followed. RESULTS: All mutations in our cases were A to G point mutations in the tRNALys gene at position 8344. CONCLUSION: We confirmed clinically suspected MERRF patients as MERRF and their mothers and siblings as carriers, on the basis of molecular genetic analysis. This study suggests that the molecular genetic analysis can be utilized to diagnose MERRF patients easily and confirm carriers, especially at the presymptomatic stage before the characteristic pathologic changes appear.