The Clinical, Pathological And Molecular Studies Of A Mitochondrial Encephalomyopathy Family

Background:Mitochondrial encephalopathy (ME), is a group of multi-system involvement disorders caused by structural and(or) functional dysfunction of mitochondria, which mainly involves central nervous system and skeletal muscles. These diseases are not as rare as commonly believed; their estimated prevalence of10to15cases per100,000persons is similar to that of better known neurologic diseases, such as amyotrophic lateral sclerosis and the muscular dystrophies. According to the clinical manifestation, it can be classified into:(1)chronic progressive external ophthalmoplegia (CPEO);(2) Mitochondrial myopathy, encephalopathy, lactic acidosis and stroke like episodes(MELAS);(3) Myoclonus epilepsy associated with ragged red fiber (MERRF);(4) Kearns-Sayre syndrome (KSS), etc. CPEO and KSS mainly caused by mtDNA deletion, while the mtDNA point mutation is often the etiology of MELAS and MERRF patients. The diagnosis should based on clinical features, laboratory examinations, photographic methods and muscle biopsy. Gene analysis is needed for definite diagnosis. There is currently no effective way to treat this diseases. Pharmacologic interventions are aimed at palliation of symptoms, postponing progression and improvement of quality of life. The gene therapy and stem cell treatment are promising approaches.Objective:We analyze the clinical features of three ME patients from a family, and to investigate the possible mutations in the mtDNA. Object and Methods:We collected clinical data of a patient in neurological department of Qilu hospital in June,2011, who were diagnosed MELAS and MERRF overlap syndrome based on the characteristics that were onset of epileptic attack, myoclonus, stroke-like episodes and cerebellar ataxia. Clinical manifestations, laboratory examinations photographic methods and muscle biopsy were analyzed, and then we analyzed the possible mutation in the patient and her families.Results:1.III, female,17years old, at the age of14years had her first epileptic attack. Clinical manifestation include:myoclonus, cerebellar ataxia, EEG showed:showed single and paroxysmal spike/spike and slow wave complexes, most evident on the frontotemporal region,which roughly conform the diagnosis of MERRF. The patient also had recurrent stroke-like attack:recurrent magraine-like headaches with nausea and vomiting, homonymous hemianopia, hemiparesis, hemihypesthesia and increased resting blood lactate, brain CT showed bilateral and symmetric calcifications of the basal ganglia, stroke-like lesions located on the right occipito-parieto-temporal lobe prominent in the cortical areas on the brain MRI, which all corresponding to the diagnosis of MELAS.Ⅰ1, female,46years old, she was normal except for a slight figure.Ⅱ2, female,6month old, she developed normal until now.2. A muscle biopsy was performed on the left biceps brachii of Ⅱ1, H&E showed a moderate variation in fibre size. Nemerous RRFs was observed with modified Gomori trichrome stain(approximately10%);many COX deficiency fibre;SSV were scattered on SDH stain; many blue fibre were observer on S/C stain, which corresponding to the classical changes of mitochondrial encephalopathy.3. A mt.3291T>C point mutation were found in the blood of Ⅰ1and Ⅱ1.Though the PCR-RFLP,we identified the mt.3291T>C mutation in the muscle of III,the urinary sediment of Ⅰ1and the oral mucosa of112. Conclusions:Clinical manifestations of the proband, involving outstanding symptoms, combined with laboratory examinations, photographic methods and muscle biopsy, corresponding with the characteristics of MELAS and MERRF overlap syndrome reported previously, so the clinical diagnosis is MELAS and MERRF overlap syndrome.We found the mt.3291T>C mutation in three members of the family. mt.3291T>C is a rare mutation,which had been reported in four cases previously. Combing with the former reports, we think the mt.3291T>C is a pathogenic mutation.Currently, mt.3291T>C mutation had never been reported to been related with MELAS and MERRF overlap syndrome, our case is the first report that MELAS and MERRF overlap syndrome due to mt.3291T>C mutation.Altogether three members in this family were found to be the carrier of mt.3291T>C mutation, the clinical manifestation ranging from asymptomatic carrier to the severe MELAS and MERRF overlap syndrome. Combining our case with former reported cases, we think that mt.3291T>C mutation is associate with a wide spectrum of phenotypes.