Clinical、pathological And Genetic Analysis Of Lipid Storage Myopathy

Lipid storage myopathy( LSM) is due to abnormal lipid metabolism, especially the long chain fatty acid metabolism, causing the abnormal storage of lipid composition within the muscle cells, a group of genetic metabolic disease that lead to skeletal muscle lesions.LSM clinical type is more, each performance are similar, but belong to different clinical spectrums.There are four kinds of LSM that we know the genetics:primary carnitine deficiency(PCD),multiple acyl coenzyme A dehydrogenase deficiency(MADD),neutral lipid storage disease with myopathy(NLSDM), neutral lipid storage disease and ichthyosis(NLSDI).If give the treatment to some type of them,there will be a very good effect, for example, give the vitamin B2 to the riboflavin reactive MADD,carnitine replacement therapy to PCD.But the study found that the most of LSM in China is riboflavin reactive MADD(RR-MADD), and electron transfer flavoprotein dehydrogenase(ETFDH) defect is the main molecular pathologic basis of LSM in our country.Thus,understanding the clinical, pathological and genetic characteristics of LSM is particularly important.Multiple acyl coenzyme A dehydrogenase deficiency(MADD) is an autosomal recessive genetic disease.Its clinical manifestation is diversiform, can be divided into three subtypes,Ⅰ type for neonatal morbidity, congenital anomaly exists at the same time;Ⅱ type same as the onset of the neonatal period, but not associated with congenital anomaly;Ⅲ type Also called the late onset, diverse symptoms and relatively light.MADD is due to the electron transfer more flavoprotein(ETF) alpha and beta subgroups or electron transfer flavoprotein- ubiquinone oxidoreductase(ETF- QO)defects caused, the coding gene were ETFA, ETFB and ETFDH.There are many types of gene mutations were reported,it is not very clear that the association between genotype and phenotype.In order to improve the understanding of LSM and reduce the misdiagnosis rate,we analyse the clinical data of 3 cases LSM,as well as the characteristics of its pathological,biochemical, and genetic.At the second part,I analyse the published multiple acyl coenzyme A dehydrogenase deficiency(MADD) cases,and summarize the correlation between genotype and phenotype.Thus we not only understand the characteristic of the LSM disease more clearly,but also know the correlation between the genotype and phenotype of MADD.Part one The clinical, pathological, biochemical, and genetic analysis of 3 cases lipid storage myopathyObjective:To study the clinical, muscle pathology, urine organic acid and serum ester acyl carnitine, gene mutation of lipid storage myopathy(LSM).Methods:For three patients which received treatment in our hospital from 2013 to 2015,they were clinically suspected lipid storage myopathy, they were all done the skeletal muscle biopsy and frozen enzyme staining, and electron microscope examination for the case 1,three cases underwent urine organic acid and serum carnitine acid ester,three cases of patients and their families detected genetic testing. Analysis the clinical, pathological,biochemical and genetic characteristics.Results:3 cases were middle-aged women, the incidence of late,the course was chronic,mainly show proximal limb weakness, both involving the cervical and masticatory muscles, the case 1 and 2 also have vomiting,the case 2 have myalgia. It had been misdiagnosed as myasthenia gravis and polymyositis.The case 3 EMG shows myogenic damage, and the other two cases is normal. 3 cases of skeletal muscle pathology(H & E,GMT staining) seen scattered vacuoles in the cytoplasm of muscle fibers, the vacuoles dye red in ORO stain.The case 1 electron microscopy can see a lot of beaded arrangement of lipid droplets under the sarcolemma muscle fibers.The urine organic acid detection of case 1 is positive, the other two cases were negative;the serum acid esters carnitine detected of case 1 and 2 is positive,case 3 is negative. Case 1 was found gene mutations ETFDH c.185T> C, c.629A> G, case 2 have gene mutations of ETFDH c.770A> G, c.1691-3C> G, gene mutation of case 3 is ETFDH c.1313C> G, c.1390G> A mutation. Three cases were confirmed MADD by genetic testing.The riboflavin oral treatment is effective for 3 cases of patients.Conclusion:1, LSM manifested as episodic or fluctuating course more than other myopathies,and easily misdiagnosed as myasthenia gravis, polymyositis, etc., it is perceived to be improved. 2, Muscle pathology can see a large number of lipid droplets,thus can make the pathological diagnosis. 3, It can not be excluded MADD when the urine organic acids and serum carnitine detection were negative, genetic testing can confirm whether it is MADD. 4, For the majority of LSM, The riboflavin oral treatment is effective. 5,The majority of lipid storage myopathy is caused by ETFDH compound heterozygous mutations,and the clinical manifestation and gene mutation are significantly heterogeneity.Part two Analysis of the genotype and phenotype of 103 cases of multiple acyl coenzyme A dehydrogenase deficiencyObjective:Analysis the correlation between genotype and phenotype of multiple acyl coenzyme A dehydrogenase deficiency(MADD).Methods:We searched Pub Med search-service system in the relevant literature on MADD and its mutations, chosen for research purposes and the inclusion and exclusion criteria of the literature, the literature included a summary of the cases mutations and clinical data.The descriptive use medians and interquartile M(QR),the age analysis between different mutations using Mann-Whitney test and Kruskal-Wallis test. Comparison of different mutations appear a rate of clinical symptoms use continuity-corrected chi-square test,with a relative risk(odds ratio, OR) evaluate the strength of an association between mutations and symptoms.Results:We summary a total of 16 literatrues and 103 cases of MADD.The onset age between ETFA, ETFB, ETFDH three kinds of genes is statistically different, the onset age of ETFDH gene mutations is older when compared with ETF.We summary 23,11,68 numbers of ETFA, ETFB, ETFDH mutation, found six high-frequency mutations:ETFA c.797C> T, ETFDH c.389A> T, c.250G> A, c.770A> G, c.1227A> C, c.1367C> T.There was no significant difference in age between the high frequency sites and other sites. ETFDH c.250G> A mutation is a risk factor for cervical gravis; c.770A> G mutation is a risk factor for neck and chewing muscle weakness; c.1227A> C mutation is a risk factor for myalgia; c.1367C> T mutation is a protective factor for neck muscle weakness.Conclusion:There are some relationships between high frequency mutations and clinical symptoms of MADD,the characteristic of this disease can guide the emphasis of genetic testing, but the mechanism of the relevance needs further study.