核黄素反应性脂质沉积性肌病临床特征与基因突变分析:两家系三例报告并文献复习
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摘要
目的分析核黄素反应性脂质沉积性肌病临床特征和基因型,以实现早期诊断与治疗。方法与结果两家系3例核黄素反应性脂质沉积性肌病患者主要表现为进行性呼吸肌、四肢近端肌无力,肌电图呈肌源性损害,油红O染色肌纤维内可见脂肪滴沉积。3例患者均存在电子转移黄素蛋白脱氢酶(ETFDH)基因突变,分别为c.250G>A(Ala84Thr)纯合突变和c.250G>A(Ala84Thr)、c.524G>A(Arg175His)复合杂合突变。维生素B2治疗后症状明显改善,1例治疗10个月后呼吸肌和四肢近端肌无力症状完全消失,恢复正常运动功能;1例治疗2个月后行走、跑步如常,颈部肌肉恢复至正常状态;1例治疗2个月后可参加剧烈运动且无疲劳感。结论核黄素反应性脂质沉积性肌病虽然以四肢近端和躯干肌无力,以及运动不耐受为主要表现,但也需注意少数以呼吸肌无力为首发症状的病例,避免漏诊和误诊。维生素B2单药治疗效果极佳,症状可明显好转或痊愈。因此,临床疑似核黄素反应性脂质沉积性肌病患者可尝试维生素B2诊断性治疗。
ObjectiveThe clinical manifestation and electron transfer flavoprotein dehydrogenase(ETFDH) gene mutation of riboflavin-responsive lipid storage myopathy were analyzed for early diagnosisand treatment.MethodsClinical material, ETFDH gene mutation and the motor function before and aftervitamin B2treatment in 3 patients from 2 predigrees were collected from August 2012 to March 2013 in ourhospital.ResultsCase 1 was 16-year-old female. The chief complaint was difficulty of breathing andexpectorating for over 3 years. Clinical symptoms included progressive respiratory muscle and proximallimb muscle weakness and worsen by fever, cardiac involvement, myopathic electromyography(EMG)changes and deposition of lipid droplets in muscle fiber by oil red O staining. Case 2 and Case 3 werebrothers, the chief complaint of whom was fatigue after exercise for more than 1 year and 1 month,respectively. Clinical symptoms included significantly weakness of lower limbs and neck muscles afterexercise and myopathic EMG changes. All 3 patients from two predigrees presented ETFDH gene mutation[c.250G > A(Ala84Thr) homozygous mutations and c.250G > A(Ala84Thr) and c.524G > A(Arg175His)compound heterozygous mutations, respectively]. They all had a dramatic response to vitamin B2treatmentwith muscle strength and motor function recovering to normal. The symptoms of Case 1 were completelydisappeared with vitamin B2treatment for over 10 months, including respiratory muscle and proximal limbmuscle weakness, and the motor function of her limbs returned to normal, characterized by completing over10 squat-stand in 1 min. Case 2 could walk and run as ordinary people, raise his head without difficultyand play basketball about 2 h without fatigue after vitamin B2treatment for over 2 months. Case 3 couldparticipate in any kind of strenuous exercise without fatigue after vitamin B2treatment for over 2 months.ConclusionsRiboflavin-responsive lipid storage myopathy is mainly characterized by proximal limb andtrunk muscle weakness and intolerance of movement, however, rare cases with first symptom of respiratorymuscle weakness should also be concerned. In addition, it is a treatable genetic disease. The patientscould be cured or significantly improved with vitamin B2monotherapy. So vitamin B2exploratory treatmentshould be given when the patients are suspected of riboflavin-responsive lipid storage myopathy.
ObjectiveThe clinical manifestation and electron transfer flavoprotein dehydrogenase(ETFDH) gene mutation of riboflavin-responsive lipid storage myopathy were analyzed for early diagnosisand treatment.MethodsClinical material, ETFDH gene mutation and the motor function before and aftervitamin B2treatment in 3 patients from 2 predigrees were collected from August 2012 to March 2013 in ourhospital.ResultsCase 1 was 16-year-old female. The chief complaint was difficulty of breathing andexpectorating for over 3 years. Clinical symptoms included progressive respiratory muscle and proximallimb muscle weakness and worsen by fever, cardiac involvement, myopathic electromyography(EMG)changes and deposition of lipid droplets in muscle fiber by oil red O staining. Case 2 and Case 3 werebrothers, the chief complaint of whom was fatigue after exercise for more than 1 year and 1 month,respectively. Clinical symptoms included significantly weakness of lower limbs and neck muscles afterexercise and myopathic EMG changes. All 3 patients from two predigrees presented ETFDH gene mutation[c.250G > A(Ala84Thr) homozygous mutations and c.250G > A(Ala84Thr) and c.524G > A(Arg175His)compound heterozygous mutations, respectively]. They all had a dramatic response to vitamin B2treatmentwith muscle strength and motor function recovering to normal. The symptoms of Case 1 were completelydisappeared with vitamin B2treatment for over 10 months, including respiratory muscle and proximal limbmuscle weakness, and the motor function of her limbs returned to normal, characterized by completing over10 squat-stand in 1 min. Case 2 could walk and run as ordinary people, raise his head without difficultyand play basketball about 2 h without fatigue after vitamin B2treatment for over 2 months. Case 3 couldparticipate in any kind of strenuous exercise without fatigue after vitamin B2treatment for over 2 months.ConclusionsRiboflavin-responsive lipid storage myopathy is mainly characterized by proximal limb andtrunk muscle weakness and intolerance of movement, however, rare cases with first symptom of respiratorymuscle weakness should also be concerned. In addition, it is a treatable genetic disease. The patientscould be cured or significantly improved with vitamin B2monotherapy. So vitamin B2exploratory treatmentshould be given when the patients are suspected of riboflavin-responsive lipid storage myopathy.
引文
[1]Xing YZ,Qiu WJ.Progresses of diagnosis and therapy in multipleacyl-CoA dehydrogenase deficiency.Guo Ji Er Ke Xue Za Zhi,2010,37:518-521.[邢雅智,邱文娟.多种酰基辅酶A脱氢酶缺乏症的诊治进展.国际儿科学杂志,2010,37:518-521.]
[2]Liang WC,Ohkuma A,Hayashi YK,López LC,Hirano M,NonakaI,Noguchi S,Chen LH,Jong YJ,Nishino I.ETFDH mutations,CoQ10 levels,and respiratory chain activities in patients withriboflavin-responsive multiple acyl-CoA dehydrogenase deficiency.Neuromuscul Disord,2009,19:212-216.
[3]Carroll JE,Shumate JB,Brooke MH,Hagberg JM.Riboflavin-responsive lipid myopathy and carnitine deficiency.Neurology,1981,31:1557-1559.
[4]Wang Y,Zhao DH,Hong DJ,Wang ZX,Yuan Y.Hot spotmutations in electron transfer flavoprotein dehydrogenase geneof riboflavin responsive lipid storage myopathy in 20 Chinesefamilies.Zhonghua Shen Jing Ke Za Zhi,2011,44:309-313.[王韵,赵丹华,洪道俊,王朝霞,袁云.核黄素反应性脂质沉积性肌病20个家系的电子转移黄素蛋白脱氢酶基因存在热点突变.中华神经科杂志,2011,44:309-313.]
[5]Wang QZ,Yan CZ,Wu JL,Liu SP,Gao SQ,Li W,Li DN.Clinical and pathological characteristics of riboflavin-reactivelipid storage myopathy.Lin Chuang Shen Jing Bing Xue Za Zhi,2005,18:357-359.[王勤周,焉传祝,吴金玲,刘淑萍,高素琴,李伟,李大年.核黄素反应性脂质沉积性肌病的临床和病理特征.临床神经病学杂志,2005,18:357-359.]
[6]Liang Y,Liu L,Wei H,Luo XP,Wang MT.Late-onsetriboflavin-responsive multiple acyl-CoA dehydrogenasedeficiency(glutaric aciduria typeⅡ).Zhonghua Er Ke Za Zhi,2003,41:916-920.[梁雁,刘丽,魏虹,罗小平,王慕逖.维生素B2治疗有效的晚发型戊二酸尿症Ⅱ型.中华儿科杂志,2003,41:916-920.]
[7]Wen B,Dai T,Li W,Zhao Y,Liu S,Zhang C,Li H,Wu J,LiD,Yan C.Riboflavin-responsive lipid-storage myopathy causedby ETFDH gene mutations.J Neurol Neurosurg Psychiatry,2010,81:231-236.
[8]Olsen RK,Olpin SE,Andresen BS,Miedzybrodzka ZH,Pourfarzam M,Merinero B,Frerman FE,Beresford MW,DeanJC,Cornelius N,Andersen O,Oldfors A,Holme E,GregersenN,Turnbull DM,Morris AA.ETFDH mutations as a majorcause of riboflavin-responsive multiple acyl-CoAdehydrogenation deficiency.Brain,2007,130:2045-2054.
[9]Law LK,Tang NL,Hui J,Fung SL,Ruiter J,Wanders RJ,FokTF,Lam CW.Novel mutations in ETFDH gene in Chinesepatients with riboflavin-responsive multiple acyl-CoAdehydrogenase deficiency.Clin Chim Acta,2009,404:95-99.
[10]Yotsumoto Y,Hasegawa Y,Fukuda S,Kobayashi H,Endo M,Fukao T,Yamaguchi S.Clinical and molecular investigations ofJapanese cases of glutaric acidemia type 2.Mol Genet Metab,2008,94:61-67.
[11]Wang ZQ,Chen XJ,Murong SX,Wang N,Wu ZY.Molecularanalysis of 51 unrelated pedigrees with late-onset multiple acyl-CoA dehydrogenation deficiency(MADD)in southern Chinaconfirmed the most common ETFDH mutation and high carrierfrequency of c.250G-A.J Mol Med(Berl),2011,89:569-576.
[12]Dong WJ,Chen WJ,Wang N.Lipid storage myopathy.Zhongguo Xian Dai Shen Jing Ji Bing Za Zhi,2008,8:109-111.[董碗娟,陈万金,王柠.脂质沉积性肌病.中国现代神经疾病杂志,2008,8:109-111.]
[13]Olsen RK,Andresen BS,Christensen E,Bross P,Skovby F,Gregersen N.Clear relationship between ETF/ETFDH genotypeand phenotype in patients with multiple acyl-CoAdehydrogenation deficiency.Hum Mutat,2003,22:12-23.
[14]Lan MY,Fu MH,Liu YF,Huang CC,Chang YY,Liu JS,PengCH,Chen SS.High frequency of ETFDH c.250G>A mutation inTaiwanese patients with late-onset lipid storage myopathy.ClinGenet,2010,78:565-569.
[15]Wang ZQ,Wang N,Wu ZY.Hotspot c.250G>A mutations in electron transfer flavoprotein dehydrogenase gene of late-onsetmultiple acyl-CoA dehydrogenation deficiency(MADD)inSouthern China.Zhonghua Shen Jing Ke Za Zhi,2011,44:368.[王志强,王柠,吴志英.中国南方晚发型多种酰基辅酶A脱氢酶缺陷的电子转移黄素蛋白脱氢酶基因存在高频热点突变c.250G>A.中华神经科杂志,2011,44:368.]
[2]Liang WC,Ohkuma A,Hayashi YK,López LC,Hirano M,NonakaI,Noguchi S,Chen LH,Jong YJ,Nishino I.ETFDH mutations,CoQ10 levels,and respiratory chain activities in patients withriboflavin-responsive multiple acyl-CoA dehydrogenase deficiency.Neuromuscul Disord,2009,19:212-216.
[3]Carroll JE,Shumate JB,Brooke MH,Hagberg JM.Riboflavin-responsive lipid myopathy and carnitine deficiency.Neurology,1981,31:1557-1559.
[4]Wang Y,Zhao DH,Hong DJ,Wang ZX,Yuan Y.Hot spotmutations in electron transfer flavoprotein dehydrogenase geneof riboflavin responsive lipid storage myopathy in 20 Chinesefamilies.Zhonghua Shen Jing Ke Za Zhi,2011,44:309-313.[王韵,赵丹华,洪道俊,王朝霞,袁云.核黄素反应性脂质沉积性肌病20个家系的电子转移黄素蛋白脱氢酶基因存在热点突变.中华神经科杂志,2011,44:309-313.]
[5]Wang QZ,Yan CZ,Wu JL,Liu SP,Gao SQ,Li W,Li DN.Clinical and pathological characteristics of riboflavin-reactivelipid storage myopathy.Lin Chuang Shen Jing Bing Xue Za Zhi,2005,18:357-359.[王勤周,焉传祝,吴金玲,刘淑萍,高素琴,李伟,李大年.核黄素反应性脂质沉积性肌病的临床和病理特征.临床神经病学杂志,2005,18:357-359.]
[6]Liang Y,Liu L,Wei H,Luo XP,Wang MT.Late-onsetriboflavin-responsive multiple acyl-CoA dehydrogenasedeficiency(glutaric aciduria typeⅡ).Zhonghua Er Ke Za Zhi,2003,41:916-920.[梁雁,刘丽,魏虹,罗小平,王慕逖.维生素B2治疗有效的晚发型戊二酸尿症Ⅱ型.中华儿科杂志,2003,41:916-920.]
[7]Wen B,Dai T,Li W,Zhao Y,Liu S,Zhang C,Li H,Wu J,LiD,Yan C.Riboflavin-responsive lipid-storage myopathy causedby ETFDH gene mutations.J Neurol Neurosurg Psychiatry,2010,81:231-236.
[8]Olsen RK,Olpin SE,Andresen BS,Miedzybrodzka ZH,Pourfarzam M,Merinero B,Frerman FE,Beresford MW,DeanJC,Cornelius N,Andersen O,Oldfors A,Holme E,GregersenN,Turnbull DM,Morris AA.ETFDH mutations as a majorcause of riboflavin-responsive multiple acyl-CoAdehydrogenation deficiency.Brain,2007,130:2045-2054.
[9]Law LK,Tang NL,Hui J,Fung SL,Ruiter J,Wanders RJ,FokTF,Lam CW.Novel mutations in ETFDH gene in Chinesepatients with riboflavin-responsive multiple acyl-CoAdehydrogenase deficiency.Clin Chim Acta,2009,404:95-99.
[10]Yotsumoto Y,Hasegawa Y,Fukuda S,Kobayashi H,Endo M,Fukao T,Yamaguchi S.Clinical and molecular investigations ofJapanese cases of glutaric acidemia type 2.Mol Genet Metab,2008,94:61-67.
[11]Wang ZQ,Chen XJ,Murong SX,Wang N,Wu ZY.Molecularanalysis of 51 unrelated pedigrees with late-onset multiple acyl-CoA dehydrogenation deficiency(MADD)in southern Chinaconfirmed the most common ETFDH mutation and high carrierfrequency of c.250G-A.J Mol Med(Berl),2011,89:569-576.
[12]Dong WJ,Chen WJ,Wang N.Lipid storage myopathy.Zhongguo Xian Dai Shen Jing Ji Bing Za Zhi,2008,8:109-111.[董碗娟,陈万金,王柠.脂质沉积性肌病.中国现代神经疾病杂志,2008,8:109-111.]
[13]Olsen RK,Andresen BS,Christensen E,Bross P,Skovby F,Gregersen N.Clear relationship between ETF/ETFDH genotypeand phenotype in patients with multiple acyl-CoAdehydrogenation deficiency.Hum Mutat,2003,22:12-23.
[14]Lan MY,Fu MH,Liu YF,Huang CC,Chang YY,Liu JS,PengCH,Chen SS.High frequency of ETFDH c.250G>A mutation inTaiwanese patients with late-onset lipid storage myopathy.ClinGenet,2010,78:565-569.
[15]Wang ZQ,Wang N,Wu ZY.Hotspot c.250G>A mutations in electron transfer flavoprotein dehydrogenase gene of late-onsetmultiple acyl-CoA dehydrogenation deficiency(MADD)inSouthern China.Zhonghua Shen Jing Ke Za Zhi,2011,44:368.[王志强,王柠,吴志英.中国南方晚发型多种酰基辅酶A脱氢酶缺陷的电子转移黄素蛋白脱氢酶基因存在高频热点突变c.250G>A.中华神经科杂志,2011,44:368.]