To Study The Diagnostic Sensitive Indicators Of Common Genetic Metabolic Myopathy Based On Clinical And Muscle Pathology

Metabolic myopathy refers to the hereditary neuromuscular diseases caused by a group of gene defects.Most of them are chronic and insidious,with diverse clinical manifestations and distinct prognoses.Some are completely cured and some are fatal at any time.According to the different defects of metabolic sub-stances,metabolic myopathy can be divided into three main categories of neuro-myopathy,namely mitochondrial myopathy or mitochondrial encephalomyopathy,lipid deposition myopathy and glycogen accumulation disease.Each type is di-vided into different subtypes according to different gene and enzyme deletion types,and the clinical manifestations of different subtypes are very similar.Metabolic myopathy is difficult to be known by clinicians due to its low clinical specificity and difficult diagnosis.Mitochondrial myopathy and mitochondrial encephalomyopathy are a group of multi-system diseases mainly involving brain and muscle system caused by mi-tochondrial DNA（mt DNA）or nuclear DNA（n DNA）defects.Clinically,the ones that are mainly damaged skeletal muscle are called"mitochondrial myopathy",while those that damage central nervous system are called"mitochondrial enceph-alomyopathy".The most common clinical,The most well-studied is mitochondrial myopathy encephalopathy with lactic acidosis and stroke-like episodes（MELAS）syndrome,Untreated patients with this form have a high fatality rate.Lipid storage myopathy（LSM）refers to genetic metabolic myopathy of lipid metabolism disor-der caused by the defect of the oxidation process of long chain fatty acids in muscle.Among them,Multiple acyl-Co A dehydrogenateion-deficiency（MADD）is the most common and most visited subtype in China,and MADD is A treatable myopathy with excellent clinical efficacy after treatment by riboflavin（vitamin B2）.glycogen accumulation disease（GSD）is a rare genetic metabolic disease caused by glycogen synthesis and catabolism abnormalities in tissues,glycogen accumulation disease type II is also called Pompe disease（PD）,is the most serious clinical type.Late-onset Pompe disease（LOPD）is the most common type of PD.However,recently there is specific enzyme replacement therapy,the activity of acid A-αglucosidase（GAA）in patients is significantly reduced,without treat-ment,the disease develops rapidly,and eventually will lead to the death of patients due to respiratory failure.Metabolic myopathy,as a kind of myopathy that can accumulate multiple systems,is often missed and misdiagnosed due to its similar clinical symptoms and the relative specificity of its diagnosis by clinicians,which seriously affects the treatment and prognosis of patients and leads to serious ad-verse consequences.ObjectiveTo explore the clinical manifestations,imaging,neuroelectrophysiology,la-boratory examination,muscle pathology,gene and other characteristics of common genetic metabolic myopathy,and to study the diagnostic sensitive indicators of common genetic metabolic myopathy based on clinical and muscle pathology.MethodForty patients with metabolic myopathy,including 19 patients with MELAS syndrome,16 patients with MADD,and 5 patients with LOPD,who were diag-nosed by muscle pathology or genetic testing in outpatient and inpatient settings from August 2020 to February 2023 at the Affiliated Hospital of the Institute of Neurology,Anhui University of Traditional Chinese Medicine were selected,and all patients met their diagnostic criteria^[2-5].The clinical data of the enrolled pa-tients were collected by face-to-face history taking,telephone follow-up,and case review,including general information（including gender,age of onset,disease du-ration,family history,etc.）,clinical symptoms and signs（including first symptoms,common clinical manifestations,and physical examination）,muscle pathological findings,imaging findings,neurophysiological findings,laboratory test results,and molecular biological findings.Finally,all measurement data were analyzed,and SPSS25.0 software was applied for statistical processing.The measurement data conforming to normal distribution were expressed as mean±standard devia-tion（（?）±s）,and those not conforming to normal distribution were expressed as me-dian and interquartile spacing.Results1.Clinical symptoms and Signs:Among the 19 patients with MELAS syndrome,there were 7 males and 12females.Epilepsy（6/19）and headache（6/19）were the main initial symptoms in the patients with MELAS syndrome.The common clinical symptoms and signs in the course of the disease were apoplexy like seizures（19 cases）,headache（19cases）,epileptic seizures（15 cases）,etc.Of the 16 patients with MADD,11 were male and 5 were female,and the most common initial symptom was weakness of the lower extremities（9 cases）,fol-lowed by neck drooping and mastication difficulties（4 cases）.The main symptoms are neck droop,laborious chewing,squat standing difficulty,etc.The most com-mon positive symptoms are neck extensor weakness and exercise intolerance.Among the 5 patients with LOPD,there were 3 males and 2 females.The most common initial symptoms were dyspnea（3/5）and weakness of both lower limbs（2/5）.The most common clinical symptoms during the course of the disease were difficulty in squatting and standing up,difficulty in raising head,dyspnea,etc.The common positive signs were mainly paravertebral muscle atrophy of different de-grees.2.Muscle pathology:The muscle pathological characteristics of the 19 patients with MELAS syn-drome were as follows:15 patients showed RRF by MGT staining,while all pa-tients showed strongly SDEH-reactive blood vessels（SSV）by SDH staining.The pathological characteristics of 16 patients with MADD were as follows:HE staining showed different muscle fiber sizes and a large number of vacuolar fibers in all patients.NADH staining showed that all vacuolar fibers in 16 patients were mainly type I fibers.ORO staining showed that the number of lipid droplets in 16 patients increased to varying degrees,that is,3 patients had a slight increase,11 patients had a moderate increase,and 2 patients had a significant increase.The muscle pathological results of 5 LOPD patients were as follows:HE stain-ing showed different muscle fiber sizes in all patients,and a large number of vac-uoles in and around muscle fibers.PAS staining showed significantly increased glycogen content.3.Imaging examination:The main features of brain MRI in 19 patients with MELAS syndrome were abnormal signals in the cerebral hemisphere cortex,mainly located in the temporal lobe,parietal lobe and occipital lobe.The abnormal signals were long T1 and long T2 signals,high DWI and FLAIR sequence signals,and abnormal Lac peaks in MRS.Muscle MRI of 5 LOPD patients showed mixed signals of thigh,calf and glu-teal muscles,and diffuse atrophy of different degrees.Neck muscle mass volume decreased and signal increased.4.Neuroelectrophysiology:Eleven of the 19 patients with MELAS syndrome underwent electromyogra-phy,and 5 showed myogenic lesions.Electroencephalogram（EEG）examination was performed in 11 patients,and the result was abnormal EEG.All 16 MADD patients underwent electromyography,and the results showed myogenic injury in 10 patients and neurogenic injury in 6 patients.All 5 LOPD patients underwent electromyographic examination,and the re-sults showed myogenic injury.5.Laboratory examination:Blood lactic acid exercise test was performed in 6 of 19 patients with MELAS syndrome,and the results were positive.Quiescent lactic acid was measured in 16patients,and 11 patients had varying degrees of quiescent lactic acid.Creatine kinase was measured in all patients,including 12 patients with varying degrees of elevated creatine kinase values.Serum creatine kinase levels were slightly elevated in 12 of the 16 MADD patients,normal in 4 patients,and elevated levels of pyruvate,3-hydroxybutyric acid,acetoacetic acid,and acetyl glycol were found in 11 of the 16 patients and no abnormalities were found in 2 patients.The levels of creatine kinase,alanine aminotransferase and aspartate ami-notransferase increased in 5 LOPD patients.GAA enzyme activity decreased sig-nificantly in 5 LOPD patients,ranging from 3%to 30%.6.Molecular Biological Characteristics:The results of peripheral blood gene in 19 patients with MELAS syndrome showed 3243A>.G mutation.The results of peripheral blood gene in 16 patients with MADD showed3243A>.G mutation.The main mutation site of 5 LOPD patients was c.784G>.A p.E262k c.2297A>G P Y766c.Conclusion1.Clinically,the possibility of MELAS syndrome should be highly suspected in patients with young-onset stroke accompanied by headache,epilepsy and other symptoms.Selective injury to the cervical extensor should consider the possibility of MADD.Selective injury to cervical flexors and paraspinal muscles,early and heavy involvement of respiratory muscles,and the possibility of LOPD should be considered.2.The possibility of metabolic myopathy should be considered if creatine ki-nase is slightly elevated;the possibility of MELAS syndrome should be highly suspected if brain MRI is abnormal in the temporal,parietal and occipital lobes with lactic acid peaks.MRI of MADD and LOPD showed no specific findings.3.The muscle pathology of MELAS syndrome is characterized by RRF,SSV and RBF,and SSV is the specific pathological manifestation of MELAS syndrome.The typical manifestation of MADD muscle pathology was an increase in the num-ber of lipid droplets in type I muscle fibers.The typical manifestations of LOPD muscle pathology are a large number of vacuoles in the muscle fibers,an increase in the content of basophilic substances and glycogen.