Clinical,Pathological,Muscle MRI And ETFDH Gene Mutation Analysis Of Late-onset Multiple Acyl Coenzyme A Dehydrogenation Deficiency

BackgroundMultiple acyl coenzyme A dehydrogenation deficiency(MADD)is an autosomal recessive disorder caused by mutations in the gene of electron transfer flavoprotein(ETF)or electron transfer flavoprotein dehydrogenase(ETFDH),which causes disorders in the metabolism of fatty acids,amino acids and choline.According to the clinical phenotype of MADD,it can be divided into three types: neonatal with or without congenital abnormalities and late onset.People first recognized MADD in 1976.With the development of muscle pathology diagnostic technology and gene sequencing of the next-generation,more and more MADD cases have been reported at home and abroad,the incidence rate in China is high,and most of them are late-onset MADD.Due to the high heterogeneity of the clinical phenotype of MADD and the lack of full understanding of it,there are still many patients undergoing a long and tortuous diagnosis process.As a treatable myopathy,early diagnosis and reasonable and effective treatment of MADD can bring a better outcome for most patients.It has become one of the important myopathy studies in major myopathy centers.ObjectiveTo investigate the clinical,skeletal muscle pathology,skeletal muscle MRI and gene mutation characteristics of patients with late-onset multiple acyl coenzyme A dehydrogenation deficiency(MADD),so as to provide basis for early diagnosis of the disease and give reasonable treatment to the patients.MethodsThe clinical data of 43 patients with late-onset MADD diagnosed by skeletal muscle biopsy and gene detection in Jiaozuo people’s Hospital from December 1996 to January2021 were analyzed retrospectively.The metabolism-related genes of some patients were detected by next-generation sequencing technique,and their clinical,pathological,muscle MRI and gene mutation characteristics were summarized.Results1.Clinical features: All patients presented subacute or chronic onset,and the main clinical manifestations were muscle weakness and exercise intolerance in the proximal extremities,and some of them were accompanied by nausea,vomiting,weakness in chewing and swallowing or even weakness in breathing muscles.Serum muscle enzymes increased in varying degrees,mainly CK.Electromyography(EMG)mostly showed myogenic damage,a few could be normal or combined with neurogenic damage.All patients were significantly improved after treatment with riboflavin.2.Pathological features: The muscle pathology of all patients showed a large amount of lipid deposition in muscle fibers,mainly involving type I muscle fibers.8 patients with different degrees of muscle fiber degeneration and necrosis,in which 5 patients were occasionally found 0.1% to 0.9% denatured and necrotic muscle fibers,and the patients had long clinical course,older age,and recurrent muscle weakness history.Three patients were found more denatured and necrotic fibers,with the proportion of necrotic muscle fibers of over 1.0%,they had short course,rapid progress,and young age.Immunohistochemical results of 2 patients showed CD4(-),CD8(-),CD20(-)and CD68(+).3.Muscle MRI features: MRI examination of the muscles of both lower limbs in 21 patients showed that there were different degrees of fat infiltration and edema-like changes in the affected muscles,especially the gluteus maximus,biceps femoris and semimembranes of the thigh,soleus muscle and gastrocnemius muscle of the calf.The calf myofascial edema can be seen on MRI images of some patients,especially those with lower limb muscle pain clinically.After riboflavin treatment,muscle MRI images showed that fat infiltration and edema were alleviated.4.Mutant characteristics: Among the 19 patients,18 patients had ETFDH gene mutation and one patients had no ETFDH mutation.Among the 18 ETFDH mutations,there were 15 compound heterozygous mutations,2 single heterozygous mutations and 1homozygous mutation.A total of 20 mutation types,19 known mutations and 1 new mutation were found: C.1115 A > G.Among all the mutations,there were 17 missense mutations,2 frameshift mutations and 1 nonsense mutation,c.770 A > G appeared 7 times,c.1454 C > G appeared 3 times,and the frequency of other mutations was 2 times or 1 time.Conclusions1.Patients with late-onset MADD have a high degree of clinical heterogeneity.The involvement of the trunk axial muscle and masticatory muscle is its characteristic manifestation.CK is mildly to moderately elevated,EMG is mostly muscle-derived damage,and riboflavin therapy has obvious curative effect.2.In addition to a large amount of lipid deposition in muscle fibers,degenerated necrotic muscle fibers can be seen in some patients in skeletal muscle pathology of late-onset MADD.The number of necrotic muscle fibers may be related to the severity of the disease and the length of the disease course.3.Skeletal muscle MRI in late-onset MADD patients has the imaging characteristics of selective involvement of the posterior muscle group of lower limbs.Skeletal muscle MRI can be used as the basis for differential diagnosis and curative effect observation of MADD.4.ETFDH gene mutation is the main cause of late-onset MADD patients,c.770A>G and c.1454C>G are common ETFDH gene mutation sites in Henan area.