Myotonic dystrophy type 1(DM1) is a spliceopathy related to the mis-splicing of several genes caused by sequestration of nuclear transcriptional RNA-binding factors from non-coding CUG repeats of DMPK pre-mRNAs. Dysre...Myotonic dystrophy type 1(DM1) is a spliceopathy related to the mis-splicing of several genes caused by sequestration of nuclear transcriptional RNA-binding factors from non-coding CUG repeats of DMPK pre-mRNAs. Dysregulation of ryanodine receptor 1(RYR1), sarcoplasmatic/endoplasmatic Ca^2+-ATPase(SERCA) and α1 S subunit of voltage-gated Ca^2+ channels(Cav1.1) is related to Ca^2+ homeostasis and excitation-contraction coupling impairment. Though no pharmacological treatment for DM1 exists, aberrant splicing correction represents one major therapeutic target for this disease. Resveratrol(RES, 3,5,4′-trihydroxy-trans-stilbene) is a promising pharmacological tools for DM1 treatment for its ability to directly bind the DNA and RNA influencing gene expression and alternative splicing. Herein, we analyzed the therapeutic effects of RES in DM1 myotubes in a pilot study including cultured myotubes from two DM1 patients and two healthy controls. Our results indicated that RES treatment corrected the aberrant splicing of RYR1, and this event appeared associated with restoring of depolarization-induced Ca^2+ release from RYR1 dependent on the electro-mechanical coupling between RYR1 and Cav1.1. Interestingly, immunoblotting studies showed that RES treatment was associated with a reduction in the levels of CUGBP Elav-like family member 1, while RYR1, Cav1.1 and SERCA1 protein levels were unchanged. Finally, RES treatment did not induce any major changes either in the amount of ribonuclear foci or sequestration of muscleblind-like splicing regulator 1. Overall, the results of this pilot study would support RES as an attractive compound for future clinical trials in DM1. Ethical approval was obtained from the Ethical Committee of IRCCS Fondazione Policlinico Universitario A. Gemelli, Rome, Italy(rs9879/14) on May 20, 2014.展开更多
Myotonic dystrophy type 1, also known as Steinert＇s disease, is an autosomal dominant disorder with multisystemic clinical features affecting the skeletal and cardiac muscles, the eyes, and the endocrine system. Thia...Myotonic dystrophy type 1, also known as Steinert＇s disease, is an autosomal dominant disorder with multisystemic clinical features affecting the skeletal and cardiac muscles, the eyes, and the endocrine system. Thiamine （vitamin B1） is a cofactor of fundamental enzymes involved in the energetic cell me- tabolism; recent studies described its role in oxidative stress, protein processing, peroxisomal function, and gene expression. Thiamine deficiency is critical mainly in the central and peripheral nervous system, as well as in the muscular cells. Our aim was to investigate the potential therapeutical effects of long-term treatment with thiamine in myotonic dystrophy type 1 in an observational open-label pilot study. We de- scribed two patients with myotonic dystrophy type 1 treated with intramuscular thiamine 100 mg twice a week for 12 or 11 months. We evaluated the patients using the grading of muscle strength according to Medical Research Council （MRC）, the Muscular Impairment Rating Scale （MIRS）, and the Modified Barthel index. High-dose thiamine treatment was well tolerated and effective in improving the motor symptomatology, particularly the muscle strength evaluated with the MRC scale, and the patients＇ activi- ties of daily living using the Modified Barthel Index. At the end of treatment, the MRC score was 5 in the proximal muscles and 2-4 in the distal muscles （the MRG score before the treatment was 3-4 and 1-3, re- spectively）. The MIRS grade improved by 25% compared to baseline for both patients. In patient #1, the Modified Barthel Index improved by 44%, and in patient #2 by 29%. These findings suggest that clinical outcomes are improved by long-term thiamine treatment.展开更多
BACKGROUND Myotonic dystrophy type 1(DM1)is a genetic neuromuscular disease involving multiple systems,especially the cardiopulmonary system.The clinical phenotype of DM1 patients is highly variable,which limits early...BACKGROUND Myotonic dystrophy type 1(DM1)is a genetic neuromuscular disease involving multiple systems,especially the cardiopulmonary system.The clinical phenotype of DM1 patients is highly variable,which limits early diagnosis and treatment.In the present study,we reported a 35-year-old female DM1 patient with dyspnea as the primary onset clinical manifestation,analyzed her family's medical history,and reviewed related literature.CASE SUMMARY A 35-year-old woman was admitted to the hospital with dyspnea of 1 mo duration,and sleep apnea for 3 d.Her respiratory pattern and effort were normal,but limb muscle tension was low.Investigation into the patient's medical history revealed that she might have hereditary neuromuscular disease.Electromyography showed that her myotonia potentials were visible in the resting state of the examined muscles,with decreased motor unit potential time limit and amplitude.Genetic testing for DM1 revealed that the cytosine-thymine-guanine(CTG)repeat number of the DMPK gene exceeded 50,while cytosine-CTG expansion in intron 1 of ZNF9 gene was<30 repeats.The patient was diagnosed with DM1.CONCLUSION DM1 is a genetic neuromuscular disease involving multiple systems,and the clinical phenotype in DM1 is extremely variable.Some patients with DM1 may be presented at the respiratory department because of dyspnea,which should be cautioned by the pulmonologists.There may be no obvious or specific symptoms in the early stage of disease,and clinicians should improve their understanding of DM1 and make an early diagnosis,which will improve patients’quality of life.展开更多
Myotonic dystrophy （DM） is a chronic, slowly progressing, highly variable, inherited multisystemic disease, which includes two main types： DM type 1 （DM1） and DM type 2 （DM2）. Both DM 1 and DM2 are autosomal do...Myotonic dystrophy （DM） is a chronic, slowly progressing, highly variable, inherited multisystemic disease, which includes two main types： DM type 1 （DM1） and DM type 2 （DM2）. Both DM 1 and DM2 are autosomal dominantly inherited disorder. DM1, also called Steinert disease, is characterized by myotonia, muscle weakness, muscular dystrophy, endocrinopathy, cataract, cardiac conduction defect, central nervous system （CNS） dysfunction, and so on.展开更多
Myotonic dystrophy type 1 (DM1),or Steiner’s disease,is an autosomal dominant disorder caused by the expansion of unstable trinucleotide repeats (CTG) in the 3’ untranslated region of the myotonic dystrophy protein ...Myotonic dystrophy type 1 (DM1),or Steiner’s disease,is an autosomal dominant disorder caused by the expansion of unstable trinucleotide repeats (CTG) in the 3’ untranslated region of the myotonic dystrophy protein kinase gene (DMPK) (Brook et al.,1992;Mahadevan et al.,1992).The number of CTG repeats observed in normal individuals is in a range of 5-34,while the individuals with 35-49 CTG repeats are usually asymptomatic but at risk of展开更多
Myotonic dystrophy type 1 （DM1） is the most common disease causing muscle weakness and atrophy in adults. The prevalence of DM1 in China is not clear. DM1 is an autosomal dominant genetic disorder associated with th...Myotonic dystrophy type 1 （DM1） is the most common disease causing muscle weakness and atrophy in adults. The prevalence of DM1 in China is not clear. DM1 is an autosomal dominant genetic disorder associated with the cytosine-thynline-guanine （CTG） repeat expansion in 3＇untranslated region in dystrophia myotonica-protein kinase （DMPK） gene on chromosome 19q 13.3. In DM 1, CTG pathological repeat numbers are more than 50. The size of CTG repeat expansion is associated with the time of clinical phenotypes onset and severity The coexistence of DMI and syrlngomyelia is rare. Here, we report DM1 coexisting with syringonlyelia in a Chinese male patient.展开更多
基金supported by grants from UniversitàCattolica and Italian Ministry of Scientific Research(grant number D1-2016 to GS)
文摘Myotonic dystrophy type 1(DM1) is a spliceopathy related to the mis-splicing of several genes caused by sequestration of nuclear transcriptional RNA-binding factors from non-coding CUG repeats of DMPK pre-mRNAs. Dysregulation of ryanodine receptor 1(RYR1), sarcoplasmatic/endoplasmatic Ca^2+-ATPase(SERCA) and α1 S subunit of voltage-gated Ca^2+ channels(Cav1.1) is related to Ca^2+ homeostasis and excitation-contraction coupling impairment. Though no pharmacological treatment for DM1 exists, aberrant splicing correction represents one major therapeutic target for this disease. Resveratrol(RES, 3,5,4′-trihydroxy-trans-stilbene) is a promising pharmacological tools for DM1 treatment for its ability to directly bind the DNA and RNA influencing gene expression and alternative splicing. Herein, we analyzed the therapeutic effects of RES in DM1 myotubes in a pilot study including cultured myotubes from two DM1 patients and two healthy controls. Our results indicated that RES treatment corrected the aberrant splicing of RYR1, and this event appeared associated with restoring of depolarization-induced Ca^2+ release from RYR1 dependent on the electro-mechanical coupling between RYR1 and Cav1.1. Interestingly, immunoblotting studies showed that RES treatment was associated with a reduction in the levels of CUGBP Elav-like family member 1, while RYR1, Cav1.1 and SERCA1 protein levels were unchanged. Finally, RES treatment did not induce any major changes either in the amount of ribonuclear foci or sequestration of muscleblind-like splicing regulator 1. Overall, the results of this pilot study would support RES as an attractive compound for future clinical trials in DM1. Ethical approval was obtained from the Ethical Committee of IRCCS Fondazione Policlinico Universitario A. Gemelli, Rome, Italy(rs9879/14) on May 20, 2014.
文摘Myotonic dystrophy type 1, also known as Steinert＇s disease, is an autosomal dominant disorder with multisystemic clinical features affecting the skeletal and cardiac muscles, the eyes, and the endocrine system. Thiamine （vitamin B1） is a cofactor of fundamental enzymes involved in the energetic cell me- tabolism; recent studies described its role in oxidative stress, protein processing, peroxisomal function, and gene expression. Thiamine deficiency is critical mainly in the central and peripheral nervous system, as well as in the muscular cells. Our aim was to investigate the potential therapeutical effects of long-term treatment with thiamine in myotonic dystrophy type 1 in an observational open-label pilot study. We de- scribed two patients with myotonic dystrophy type 1 treated with intramuscular thiamine 100 mg twice a week for 12 or 11 months. We evaluated the patients using the grading of muscle strength according to Medical Research Council （MRC）, the Muscular Impairment Rating Scale （MIRS）, and the Modified Barthel index. High-dose thiamine treatment was well tolerated and effective in improving the motor symptomatology, particularly the muscle strength evaluated with the MRC scale, and the patients＇ activi- ties of daily living using the Modified Barthel Index. At the end of treatment, the MRC score was 5 in the proximal muscles and 2-4 in the distal muscles （the MRG score before the treatment was 3-4 and 1-3, re- spectively）. The MIRS grade improved by 25% compared to baseline for both patients. In patient #1, the Modified Barthel Index improved by 44%, and in patient #2 by 29%. These findings suggest that clinical outcomes are improved by long-term thiamine treatment.
文摘BACKGROUND Myotonic dystrophy type 1(DM1)is a genetic neuromuscular disease involving multiple systems,especially the cardiopulmonary system.The clinical phenotype of DM1 patients is highly variable,which limits early diagnosis and treatment.In the present study,we reported a 35-year-old female DM1 patient with dyspnea as the primary onset clinical manifestation,analyzed her family's medical history,and reviewed related literature.CASE SUMMARY A 35-year-old woman was admitted to the hospital with dyspnea of 1 mo duration,and sleep apnea for 3 d.Her respiratory pattern and effort were normal,but limb muscle tension was low.Investigation into the patient's medical history revealed that she might have hereditary neuromuscular disease.Electromyography showed that her myotonia potentials were visible in the resting state of the examined muscles,with decreased motor unit potential time limit and amplitude.Genetic testing for DM1 revealed that the cytosine-thymine-guanine(CTG)repeat number of the DMPK gene exceeded 50,while cytosine-CTG expansion in intron 1 of ZNF9 gene was<30 repeats.The patient was diagnosed with DM1.CONCLUSION DM1 is a genetic neuromuscular disease involving multiple systems,and the clinical phenotype in DM1 is extremely variable.Some patients with DM1 may be presented at the respiratory department because of dyspnea,which should be cautioned by the pulmonologists.There may be no obvious or specific symptoms in the early stage of disease,and clinicians should improve their understanding of DM1 and make an early diagnosis,which will improve patients’quality of life.
文摘Myotonic dystrophy （DM） is a chronic, slowly progressing, highly variable, inherited multisystemic disease, which includes two main types： DM type 1 （DM1） and DM type 2 （DM2）. Both DM 1 and DM2 are autosomal dominantly inherited disorder. DM1, also called Steinert disease, is characterized by myotonia, muscle weakness, muscular dystrophy, endocrinopathy, cataract, cardiac conduction defect, central nervous system （CNS） dysfunction, and so on.
基金supported by the National Basic Research Program of China(2010CB529601 and 2013CB945404)to B.L.Wuthe Fudan Young Teacher Funding to Y.An,the higher Education Research Project of Gansu Province(2015B-094)to X.LanShanghai Children’s Hospital Funding(2016YMS001)to X.Lan
文摘Myotonic dystrophy type 1 (DM1),or Steiner’s disease,is an autosomal dominant disorder caused by the expansion of unstable trinucleotide repeats (CTG) in the 3’ untranslated region of the myotonic dystrophy protein kinase gene (DMPK) (Brook et al.,1992;Mahadevan et al.,1992).The number of CTG repeats observed in normal individuals is in a range of 5-34,while the individuals with 35-49 CTG repeats are usually asymptomatic but at risk of
文摘Myotonic dystrophy type 1 （DM1） is the most common disease causing muscle weakness and atrophy in adults. The prevalence of DM1 in China is not clear. DM1 is an autosomal dominant genetic disorder associated with the cytosine-thynline-guanine （CTG） repeat expansion in 3＇untranslated region in dystrophia myotonica-protein kinase （DMPK） gene on chromosome 19q 13.3. In DM 1, CTG pathological repeat numbers are more than 50. The size of CTG repeat expansion is associated with the time of clinical phenotypes onset and severity The coexistence of DMI and syrlngomyelia is rare. Here, we report DM1 coexisting with syringonlyelia in a Chinese male patient.
