Clinical,Pathological And Genetic Analysis Of M.3243A>G Related Mitochondrial Diseases

Mitochondrial disease is a disease that due to mitochondrial DNA and nuclear DNA mutation or deletion which may lead to abnormal mitochondrial respiratory ch-ainassociated protein oxidation and then result in multiple organ dysfunction syndro-me by impeding the ATP synthesis,and it is also known as mitochondria respirato-ry chain disorders.According to the clinical manifestations it can be divided into different subtypes: 1.mitochondrial encephalopathy: Leigh disease;Alpers syndrome;mitochondrial spinocerebellar ataxia with epilepticsyndrome.2.Mitochondrial Encepha-lomyopathy:Mitochondrial Encephalomyopathy,Lactic Acidosis and Stroke-like episo-des(MELAS);Myoclonic Epilepsy and Ragged Red Fibres(MERRF);Kearns-Sayrs syndrome(KSS);ochondrialneuro-gastrointestinal-encephalomyopathy(MNGIE).3.mitochondrial neuropathy: Leber hereditary optic neuropathy;neurogenic muscular atrophy a-taxiapigmented retinal lesions syndrome;Sensory ataxia associated with extraocular-muscle palsy.4.Mitochondrial myopathy: Chronic Progressive External Ophthalmoplegia(CPEO);Limb girdle mitochondrial myopathy.Mitochondrial DNA mutation types including base mutations,insertions,deletion,mtDNA copy number mutations,m.3243A>G is most common mitochondrial DNA mutations which can can lead to a series of clinical symptoms from mild to lethal.It is usually maternally inherited,but occasionally mutations.This paper will analysi s clinical,pathological and genetic features of the 6 patients with m3243A>G mutat i-on related mitochondrial that admitted in our hospital.And we wanted to solve th e problems:(1)reveal the relationship between phenotype and genotype;(2)determi ne the gene's molecular diagnostic possibilities based on clinical symptoms and auxi lia-ry examination.And we summarize the literature and statistical analysis,then con clu-ded that the distribution of mutations of mitochondrial disease symptoms.Part one The clinical,pathological,and genetic analysis of 6 cases m.3243A>G related mitochondrial disease Objective:Investigate the clinical,pathological,blood lactate acid,muscle pathology,imaging and genetic features of m.3243A>G related mitochondrial diseases.Methods:We collected data from 6 patients with m.3243A>G associated mitochondrial disease in our hospital.Cases 1,2 and 6 was conducted skeletal muscle biopsy and frozen enzyme histochemical staining and blood lactate detection,then case 1,2,3,5 and 6 have a head MRI,and MRS was performed in four of them,case 1 and 5 also had family verification.And we analyzed The clinical,pathological and genetic characteristics.The survival time was estimated by Kaplan-Meier method.Results:There were 6 patients,and the ratio of male to female was 1:2.the onset age was ranged from 10 to 52 years old which didn't follow the normal distribution.And median was 33.5years(age,20.5).The peak age range of patients was 31-40.The first symptom:3 case of mental disorders(3/6),3 cases decreased visual acuity(3/6),3 cases of dizziness(3/6),2 cases of seizure(2/6),2 cases of nausea and vomiting(2/6),1 case of headache(1/6),and 1 case of memory loss(1/6).Family history: 3 of the patients had a family history.The mother of case 1 was short stature and hearing loss.The mother of case 3 showed a short stature.In daughter of case 5,seizures and decreased exercise tolerance.Clinical symptoms: neurological symptoms:4 cases of epilepsy(4/6),4 cases of hearing loss(4/6),4 cases of abnormal behavi-or(4/6),3 cases of headache(3/6),3 cases of dementia(3/6),exercise intolerance in 3 cases(3/6),visual acuity decreased by 2 cases(2/6),partial blindness in 1 cases(1/6),stroke like episodes in 1 cases(1/6).Non neurological symptoms: 5 cases of short stature(5/6),4 cases of gastrointestinal symptoms(4/6),3 cases of diabetes(3/6).MRI results:5 cases of patients was conducted cranial MRI examination,and 4 of them had MRS examination.They all had abnormal signals in the brain,and elevated lactate peak.Muscle pathology: 3 patients underwent muscle pathology,RRFs(1/3),SSVs(1/3),and normal(1/3).Genetic examination: 6 patients were detected by gene,the mutation rate was range from 20% to 67%.And Median(four digit spacing)was 25.00% years(20.80%).6 patients were treated with antioxidant and complementary metabolic coenzyme support,the effective rate was 3/6.Conclusion:1.The clinical phenotype of m.3243A>G associated mitochondrial disease differented a lot,short stature,epilepsy,hearing loss,mental and behavioral abnormalities,gastrointestinal symptoms are often symptoms,and 3 or more than 3 symptoms at the same patient can be considered m.3243A>G gene screening.2.The presence of RRFs and SSVs in muscle pathology and brain MRI showed inconsistent abnormal signal with vascular distribution and MRS had a peak of lactic acid can provide higher diagnostic value.However the results of gene detection should be considered in order to avoid misdiagnosis and missed diagnosis.3.Patients with the disease should be screened for multiple systems,including heart,hearing,vision,blood glucose levels and complications of diabetes,then take early intervention to improve the quality of life of patients.Part 2 Literature analysis of m.3243A>G mutations associat ed mitochondrial disease of genotype and clinical phenotype Objective:Investigate the distribution characteristics of m.3243A>G gene mutations associated with mitochondrial diseases,and to analyze the subgroups according to race.At the same time,the difference between hearing loss and diabetes mellitus,abnormal cardiac function,stroke-like attack and exercise intolerance and the incidence of eyelid droop and cardiac dysfunction were statistically analyzed.And predict the survival time.Methods:We used R3.1.1 software for Meta analysis.First of all,the incidence of each clinical performance was transformed to Freeman-Tukey double sine.and then the sample size was used as the weight to calculate the combined value,and finally we get the combined incidence and 95%CI.Homogeneity test(Q test)was used for heterogeneity test(test level was ?=0.1),and I2 was used to determine the size of heterogeneity.If P ?0.10 and I2 ?50%,it was suggested the homogeneity between the results,so we used a fixed effects model for Meta analysis.On the contrary,there isheterogeneity between the results of the study,random effects model for Meta analysis.The level of Meta analysis was ? =0.05.Analysis of the correlation between the incidence of symptoms reported in the literature were analyzed by chi square test,the significance level alpha was set to 0.05.Because the theoretical value was of T>5,we used Pearson chi square test.The difference of P<0.05 was statistically significant.The survival time was estimated by Kaplan-Meier method.Results:A total of 710 cases were included in the study,from a total of 8 cases.Meta analysis results: Hearing loss exercise 53.95% [95%CI(47.76,60.02),P<0.0001],Exe-rcise intolerance 48.64%[95%CI(34.39,63.12),P<0.0001],headache 44.97%[95%CI(27.18,64.15),P<0.0001],epilepsy 42.32%[95%CI(21.52,66.25),P<0.0001],blood gluco-se increased 33.78%[95%CI(25.94,42.64),P<0.0001],decreased intelligence 32.94%[95%CI(15.44,56.910,P<0.0001],short stature 30.62%[95%CI(16.64,49.39),P<0.0001],stroke like episodes 29.10%[95%CI(20.21%,39.94),P<0.0001],gastrointestinal sympt-oms 27.23%[95%CI(16.16,42.09),P<0.0001],cardiac dysfunction 26.24%[95%CI(20.17,33.37),P<0.0001],decreased visual 25.74[95%CI(13.01,44.55),P<0.0001],ptosis 21.09%[95%CI(14.87,29.01),P<0.0001],mental and behavioral abnormalities 13.00%[95%CI(7.80,20.88),P<0.0001].Subgroup analysis suggested racial differences.There was no significant difference in the incidence of hearing loss,with diabetes mellitus,stroke like episodes and cardiac dysfunction.There were significant differences in hearing loss and exercise intolerance,ptosisand cardiac dysfunction.The prognosis o-f the disease is poor,median survival time is only 9(1.3-10)years,the main caus-e of poor outcome include early onset age,epilepsy(84.6%)and abnormal cardiac f-unction(15%).Conclusion:1.m.3243A>G associated mitochondrial disease had a wide spectrum of clinical manifestations,including the nervous system,cardiovascular system,endocrine system and digestive system,different clinical phenotypes are different occured,and there is a racial gap,which can provide reference for the selection of clinical gene detection.2.Hearing loss is a sign of multiple system involvement,if happen,multiple screening should be taken.3.The average survival time is poor.