The Clinical Differentiation And Possible Pathogenesis Of Neutral Lipid Storage Disease With Myopathy And Riboflavin Responsive Lipid Storage Myopathy

Objectives:Neutral lipid storage disease with myopathy(NLSDM)is a rare autosomal recessive genetic disease caused by mutations in the patatin-like phospholipase domain-containing protein 2(PNPLA2)gene,which casuses lipid metabolism disorders.Riboflavin responsive multiple Acyl-Co A dehydrogenation deficiency(RR-MADD)is also an autosomal recessive disease,mainly caused by mutations in the electron transfer flavoprotein dehydrogenase(ETFDH)gene.The Pathological examination of muscle biopsy showed that these two types of lipid storage myopathy in patients with muscle fibers,which were filled with a mass of lipid droplets.The difference was that NLSDM in most patients with muscle fibers,which were filled with amount of various sizes lipid vacuoles,some patients had rimmed vacuoles.And in most patients of RR-MADD,there were lots of lipid vacuoles in muscle fibers,which were accompanied by muscle fiber necrosis and degeneration.These pathological changes indicate that the pathogenesis of these two diseases is different.Therefore,it is necessary to summarize the clinical manifestations and pathological features of these two lipid metabolism disorders,which researched further into possible pathogenesis.So we report the clinical manifestations,pathological features of 8 patients with RR-MADD and 4 patients with NLSDM in Jiangxi,and explore the possible pathogenesis.Material and methods:The clinical data of 12 cases in the First Affiliated Hospital of Nanchang University from April 2011 to April 2013 with lipid storage myopathy confirmed by muscle biopsy,frozen enzyme histochemical staining and gene examination,who were collected.Analysis of clinical and pathological data were performed in 8 patients with RR-MADD and 4 patients with NLSDM.The expression of autophagy and apoptosis related proteins were detected by immuno-fluorescence assay.Results:1.In 8 patients with RR-MADD,seven patients were sporadic while one had positive family history.They were both in the adult onset,whose major clinical manifestations were characteristic of proximal limb weakness,exercise intolerance and muscle soreness.2 cases had vomiting after eating and 2 cases had limb paraesthesia,sensory ataxia.All patients were dramatically responsive to riboflavin treatment.4 patients with NLSDM were sporadic and in the adult onset.The major symptoms were asymmetric proximal limb weakness,accompanied by heart involvement.There is no specific therapeutic drugs at present.2.In 8 patients with RR-MADD,muscle biopsy showed that a large number of lipid droplets were deposited in muscle fibers,mainly in the type I muscle fibers.2 cases had many muscle fibers necrosis.In 4 patients with NLSDM,there were lots of lipid droplets deposition in muscle fibers.These muscle fibers had different numbers of rimmed vacuoles,accompanied with hypertrophy atrophy and tissue hyperplasia.3.In 8 patients with RR-MADD,immunofluorescence showed that muscle fibers were found the expression of apoptosis-inducing protein(Bax?Caspase-3),and the anti-apoptotic protein(Bcl-2)was no significant change.In 4 patients with NLSDM,immunofluorescence showed that muscle fibers were found autophagy protein(P62?LC3)gather high signal,and the apoptotic protein(Bax?Caspase-3)were no obvious aggregation.Conclusions:1.In RR-MADD and NLSDM,the clinical manifestations of these two types of lipid storage myopathy had great differences.In RR-MADD,the main clinical manifestations were symmetric proximal limb weakness,fluctuation and fatigue of myasthenia symptoms,accompanied by gastrointestinal or peripheral nerve symptoms.In NLSDM,the main clinical manifestations were asymmetric limb and trunk weakness,asymptomatic fluctuations,and accompanied by myocardial or diabetes.2.In RR-MADD and NLSDM,the pathological changes in the middle and late stages of the disease had some differences.In RR-MADD,the pathology of muscle fibers were necrosis and degeneration.In NLSDM,the pathology of muscle fibers were atrophy and hypertrophy,as well as the change of rimmed vacuoles.3.In NLSDM,autophagy pathway was obviously activated in pathological changes of muscle fibers.In RR-MADD,apoptotic pathway was significantly activated in pathological changes of muscle fibers.