Clinical And Whole Genetic Analysis Of Mitochondrial Encephalomyopathy

Mitochondrial encephalomyopathy,the type of hereditary metabolic disease,is due to mitochondrial DNA(mt DNA)or nuclear DNA(n DNA)defects leading to mitochondrial structure and function disorder,that is,primary mitochondrial disease.Current definite syndromes include MELAS,KSS,CPEO,LS and other syndromes.The diagnosis of mitochondrial disease need to be combined with its clinical manifestations,family history,laboratory tests,imaging data,muscle histochemical staining,mitochondrial respiratory chain enzyme activity,mt DNA or n DNA detection and other informations.Each method has some limitations in the evaluation of mitochondrial function,and needs comprehensive analysis of various information systems.Leigh syndrome,also known as subacute necrotizing cerebrospinal myopia,is a progressive neurodegenerative disease associated with mitochondrial oxidative phosphorylation deficiency.The main victims are infants and preschool children.Its primary clinical symptoms are exercise retardation,mental retardation,progressive cognitive dysfunction,dyskinesia,dystonia,ataxia,brain stem dysfunction.It is divided into early-onset LS and late-onset LS.LS can not be clearly separated from the age temporarily.In this paper,we analyzed the clinical data of four cases of mitochondrial encephalomyopathy in our hospital,and performed the skeletal muscle biopsy and mitochondrial whole genetic analysis,and confirmed the value of whole genetic analysis in the diagnosis of this disease.By summarizing A meta-analysis of published Leigh syndrome(LS)cases,we summarized the incidence of clinical symptoms and respiratory chain enzyme complex gene mutation,and the correlation between age of onset and type of gene mutation.Part one The clinical,pathological and genetic analysis of 4cases Mitochondrial encephalomyopathyclinicalObjective:To analyze the clinical data of four patients with suspected mitochondrial disease,patients have been carried out skeletal muscle biopsy and mitochondrial whole genetic analysis.we want to clarify the value of whole genetic analysis in the diagnosis of this disease.Methods:Four patients with suspected mitochondrial disease were all done the skeletal muscle biopsy and frozen enzyme histochemical staining.The mt DNA and n DNA were detected by Sanger sequencing,next generation sequencing,MLPA,CNV and the whole genetic analysis.Results:1,The four patients involved in skeletal muscle were different degrees of muscle weakness and exercise intoleranc.Their symptoms were fluctuating and aggravated.The damage in nervous system showed mental retardation,epilepsy and so on.Other system performance are kidney Failure,metabolic acidosis,decreased vision and neurological deafness.Although the CK of patients were normal or slightly increased,the value below1000U/L.Two patients were positive in lactate exercise test.In the other two patients,the blood lactic acid increased.2,Two patients' cranial MRS showed impaired lactate peaks in the damaged site.3,Muscle biopsy revealed that three patients had 10%-80% RRFs on the GMT staining.COX staining indicated that the enzyme activity was partially absent.One patient had no specific RRFs in muscle biopsy,but he was diagnosed as mitochondrial encephalopathy with clinical manifestations,imaging and genetic testing.4,Mitochondrial genome analysis found that one patient was a large fragment deletion of the mitochondrial cytochrome B gene,two patients were point mutation of michondrial nuclear gene,one patient did not find a clear pathogenicity mutation.Conclusion:1,The genotype and clinical phenotype of mitochondrial encephalomyopathy were highly heterogeneous.2,Clinical manifestations,imaging,muscle biopsy and genetic testing are important evidences for the diagnosis of mitochondrial encephalopathy.Part two Analysis of the clinical manifestations and gene mutation of 385 patients with Leigh syndromeObjective:By summarizing A meta-analysis of published Leigh syndrome(LS)cases,we summarized the incidence of clinical symptoms and respiratory chain enzyme complex gene mutation,and the correlation between age of onset and type of gene mutation.Methods:R2.15.3 software was used for Meta analysis.Firstly,the incidence rate of each clinical symptom has a logit transform,then the merging rate is calculated with the weight of sample size.Finally the "incidence rate" and its 95% CI are obtained.Homogeneity Test was used to examine the heterogeneity(the standard is ?=0.1),and then we used the I2 to judge the size of heterogeneity.If P<0.10 and I2 >50%,it is suggested that there is heterogeneity between the results of this study,using random effects model for Meta analysis.On the contrary,the fixed effect model was used for Meta analysis.Publication bias was assessed by Eggers' test.Finally,the sensitivity analysis was carried out by calculating the merging rate after excluding the lowest quality literatures.The level of Meta analysis is ?=0.05.The age analysis of different gene mutations was analyzed by Mann-Whitney test and Kruskal-Wallis test.The Pearson card test was used to analyze the difference between the common clinical symptoms,and there was statistically significant difference in P<0.05.Results:We summary a total of 5 literatures and 385 cases of LS.The Meta analysis of the clinical symptom merging rate was lactic acid value increased 62%,growth retardation60%,muscle tension decreased 47%,epilepsy 33%,impaired ocular muscle and respiratory function 28%,muscle weakness 27%,feeding difficulty 26%,ataxia 20%.The incidence of different clinical symptoms was statistically significant,and the increase of lactic acid value may be the earliest manifestation.It should be noticed early diagnosis and early detection.The mt DNA and n DNA genes were statistically significant,and mt DNA gene mutations were larger than n DNA mutations.The age of onset of gene mutation in n DNA patients was statistically significant.The age of PDHA1 gene was late,and the age of SLC19A3 gene was the earliest.The results of Meta analysis of respiratory chain enzyme complex gene mutation suggest that complex type I 34%,complex IV 20%,complex I + IV 15%,complex V 9%.Conclusion:The clinical manifestations of LS are various.Elevated lactate may be the earliest manifestation.The age of onset is related to the type of gene mutation.Respiratory chain enzyme complex gene mutation is the most common cause of LS,which is a common mutation of the complex I gene.