Neutral lipid storage disease with myopathy(NLSDM)is a rare autosomal recessive disorder,due to an enzymatic error of lipid metabolism.Patients present always with skeletal muscle myopathy and variable cardiac and hep...Neutral lipid storage disease with myopathy(NLSDM)is a rare autosomal recessive disorder,due to an enzymatic error of lipid metabolism.Patients present always with skeletal muscle myopathy and variable cardiac and hepatic involvement.NLSDM is caused by mutations in the PNPLA2 gene,which encodes the adipose triglyceride lipase(ATGL).Here we report the molecular characterization and clinical findings of two NLSDM siblings carrying the novel c.187t1G>C homozygous PNPLA2 mutation,localized in the splice site of intron 2.Molecular analyses revealed that neither aberrant PNPLA2 mRNA isoforms,nor ATGL mutated protein were detectable in patient’s cells.Clinically,both patients presented early onset muscle weakness,in particular of proximal upper limb muscles.In almost 15 years,muscle damage affected also distal upper limbs.This is a NLSDM family,displaying a severe PNPLA2 mutation in two siblings with clinical presentation characterized by an early onset,but a slowly evolution of severe myopathy.展开更多
Background:Abnormally activated mechanistic target of rapamycin(mTOR)pathway has been reported in several model animals with inherited metabolic myopathies(IMMs).However,the profiles of mTOR pathway in skeletal muscle...Background:Abnormally activated mechanistic target of rapamycin(mTOR)pathway has been reported in several model animals with inherited metabolic myopathies(IMMs).However,the profiles of mTOR pathway in skeletal muscles from patients are still unknown.This study aimed to analyze the activity of mTOR pathway in IMMs muscles.Methods:We collected muscle samples from 25 patients with mitochondrial myopathy(MM),lipid storage disease(LSD)or Pompe disease(PD).To evaluate the activity of mTOR pathway in muscle specimens,phosphorylation of S6 ribosomal protein(p-S6)and p70S6 kinase(p-p70S6K)were analyzed by Western blotting and immunohistochemistry.Results:Western blotting results showed that p-p70S6K/p70S6K in muscles from LSD and MM was up-regulated when compared with normal controls(NC)(NC vs.LSD,U=2.000,P=0.024;NC vs.MM:U=6.000,P=0.043).Likewise,p-S6/S6 was also upregulated in muscles from all three subgroups of IMMs(NC vs.LSD,U=0.000,P=0.006;NC vs.PD,[7=0.000,P=0.006;NC vs.MM,U=1.000,P=0.007).Immunohistochemical study revealed that p-S6 was mainly expressed in fibers with metabolic defect.In MM muscles,most p-S6 positive fibers showed cytochrome C oxidase(COX)deficiency(U=5.000,P=0.001).In LSD and PD muscles,p-S6 was mainly overexpressed in fibers with intramuscular vacuoles containing lipid droplets(17=0.000,P=0.002)or basophilic materials(U=0.000,P=0.002).Conclusion:The mTOR pathway might be activated in myofibers with various metabolic defects,which might provide evidence for mTOR inhibition therapy in human IMMs.展开更多
基金grant GGP14066 from Telethon Foundationthe patient for their kind cooperation,to the EuroBioBank and the Telethon Network of Genetic Biobanks(GTB12001F)for providing biological samples and to professor Francesco Mauri for his scientific assistance。
文摘Neutral lipid storage disease with myopathy(NLSDM)is a rare autosomal recessive disorder,due to an enzymatic error of lipid metabolism.Patients present always with skeletal muscle myopathy and variable cardiac and hepatic involvement.NLSDM is caused by mutations in the PNPLA2 gene,which encodes the adipose triglyceride lipase(ATGL).Here we report the molecular characterization and clinical findings of two NLSDM siblings carrying the novel c.187t1G>C homozygous PNPLA2 mutation,localized in the splice site of intron 2.Molecular analyses revealed that neither aberrant PNPLA2 mRNA isoforms,nor ATGL mutated protein were detectable in patient’s cells.Clinically,both patients presented early onset muscle weakness,in particular of proximal upper limb muscles.In almost 15 years,muscle damage affected also distal upper limbs.This is a NLSDM family,displaying a severe PNPLA2 mutation in two siblings with clinical presentation characterized by an early onset,but a slowly evolution of severe myopathy.
文摘Background:Abnormally activated mechanistic target of rapamycin(mTOR)pathway has been reported in several model animals with inherited metabolic myopathies(IMMs).However,the profiles of mTOR pathway in skeletal muscles from patients are still unknown.This study aimed to analyze the activity of mTOR pathway in IMMs muscles.Methods:We collected muscle samples from 25 patients with mitochondrial myopathy(MM),lipid storage disease(LSD)or Pompe disease(PD).To evaluate the activity of mTOR pathway in muscle specimens,phosphorylation of S6 ribosomal protein(p-S6)and p70S6 kinase(p-p70S6K)were analyzed by Western blotting and immunohistochemistry.Results:Western blotting results showed that p-p70S6K/p70S6K in muscles from LSD and MM was up-regulated when compared with normal controls(NC)(NC vs.LSD,U=2.000,P=0.024;NC vs.MM:U=6.000,P=0.043).Likewise,p-S6/S6 was also upregulated in muscles from all three subgroups of IMMs(NC vs.LSD,U=0.000,P=0.006;NC vs.PD,[7=0.000,P=0.006;NC vs.MM,U=1.000,P=0.007).Immunohistochemical study revealed that p-S6 was mainly expressed in fibers with metabolic defect.In MM muscles,most p-S6 positive fibers showed cytochrome C oxidase(COX)deficiency(U=5.000,P=0.001).In LSD and PD muscles,p-S6 was mainly overexpressed in fibers with intramuscular vacuoles containing lipid droplets(17=0.000,P=0.002)or basophilic materials(U=0.000,P=0.002).Conclusion:The mTOR pathway might be activated in myofibers with various metabolic defects,which might provide evidence for mTOR inhibition therapy in human IMMs.
