晚发型甲基丙二酸尿症cblC型家系快速诊断、治疗与随诊
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摘要
目的总结晚发型甲基丙二酸尿症cblC型两家系4例患儿临床表型、治疗原则及预后,探讨其病理生理学机制。方法与结果采用外显子组测序技术快速诊断晚发型甲基丙二酸尿症cblC型两家系。家系1姊妹存在MMACHC基因外显子4 c.482G> A(p.Arg161Gln)和c.615C> A(p.Tyr205X)复合杂合突变,分别来自其父母。先证者主要表现为智力减退、下肢痉挛性运动障碍伴癫发作;其妹则呈现以轴索损害为主的四肢周围神经病变和视神经萎缩,而智力减退症状相对较轻。家系2兄妹存在MMACHC基因外显子4 c.440_441del(p.Gly147fs)和c.482G>A(p.Arg161Gln)复合杂合突变,分别来自其父母。先证者表现为智力减退、精神行为异常和双下肢无力伴锥体束征,呈髓鞘和轴索混合性损害的周围神经病变;其妹症状相似但发病年龄较早。采用维生素B12、叶酸、左卡尼汀等药物联合治疗6个月患儿智力水平明显提高、癫发作得以控制,但均遗留不同程度双下肢运动障碍。结论晚发型甲基丙二酸尿症cblC型临床表现复杂多样,可广泛累及大脑皮质、锥体束、锥体外系、周围神经等,目标区域捕获联合第二代测序技术可以快速明确诊断,早期诊断、积极治疗对改善患者预后至关重要。
Objective To summarize phenotype, treatment principles and prognosis of 4 patients from 2 pedigrees with late-onset methylmalonic aciduria(MMA) and homocystinuria cobalamin C(cblC)type, so as to explore the pathophysiological mechanism of this disease.Methods and Results Exome sequencing was applied to rapidly diagnose 2 pedigrees of late-onset MMA and homocystinuria cblC type.The MMACHC gene mutations of the sisters in pedigree 1 were exon 4 c.482 G > A(p.Arg161 Gln) and c.615 C > A(p.Tyr205 X). Their parents carried the gene mutation respectively. The proband presented intelligence deterioration, spastic motor dysfunction of lower limbs and epilepsy. The younger sister presented axonal peripheral neuropathy and optic nerve atrophy, while the mental retardation was mild. For the brother and sister in pedigree 2, c.440_441 del(p.Gly147 fs) and c.482 G > A(p.Arg161 Gln) in exon 4 of MMACHC gene were identified which came from their parents respectively. The proband presented mental retardation and behavior disorder, weakness of lower limbs with pyramidal sign, and myelinated and axonal mixed peripheral neuropathy. His younger sister had similar symptoms and suffered earlier. After treated by vitamin B12, folic acid and levocarnitine for 6 months, all patients showed intelligence improved and seizures controlled, while still suffered from different degrees of dyskinesia of lower limbs.Conclusions The clinical symptoms of late-onset MMA and homocystinuria cblC type are complex and variable.Cerebral cortex, pyramidal system, extrapyramidal system and peripheral nerve could be widely involved.Target region gene capture combined with next-generation sequencing technology can be used to diagnose the disease rapidly, and early diagnosis and treatment are crucial to improve the prognosis.
Objective To summarize phenotype, treatment principles and prognosis of 4 patients from 2 pedigrees with late-onset methylmalonic aciduria(MMA) and homocystinuria cobalamin C(cblC)type, so as to explore the pathophysiological mechanism of this disease.Methods and Results Exome sequencing was applied to rapidly diagnose 2 pedigrees of late-onset MMA and homocystinuria cblC type.The MMACHC gene mutations of the sisters in pedigree 1 were exon 4 c.482 G > A(p.Arg161 Gln) and c.615 C > A(p.Tyr205 X). Their parents carried the gene mutation respectively. The proband presented intelligence deterioration, spastic motor dysfunction of lower limbs and epilepsy. The younger sister presented axonal peripheral neuropathy and optic nerve atrophy, while the mental retardation was mild. For the brother and sister in pedigree 2, c.440_441 del(p.Gly147 fs) and c.482 G > A(p.Arg161 Gln) in exon 4 of MMACHC gene were identified which came from their parents respectively. The proband presented mental retardation and behavior disorder, weakness of lower limbs with pyramidal sign, and myelinated and axonal mixed peripheral neuropathy. His younger sister had similar symptoms and suffered earlier. After treated by vitamin B12, folic acid and levocarnitine for 6 months, all patients showed intelligence improved and seizures controlled, while still suffered from different degrees of dyskinesia of lower limbs.Conclusions The clinical symptoms of late-onset MMA and homocystinuria cblC type are complex and variable.Cerebral cortex, pyramidal system, extrapyramidal system and peripheral nerve could be widely involved.Target region gene capture combined with next-generation sequencing technology can be used to diagnose the disease rapidly, and early diagnosis and treatment are crucial to improve the prognosis.
引文
[1]Liu Y,Liu YP,Zhang Y,Song JQ,Zheng H,Dong H,Ma YY,Wu TF,Wang Q,Li XY,Ding Y,Li DX,Jin Y,Li MQ,Wang ZX,Yuan Y,Li HX,Qin J,Yang YL.Heterogeneous phenotypes,genotypes,treatment and prevention of 1003patients with methylmalonic acidemia in the mainland of China[J].Zhonghua Er Ke Za Zhi,2018,56:414-420.[刘怡,刘玉鹏,张尧,宋金青,郑宏,董慧,马艳艳,吴桐菲,王峤,李溪远,丁圆,李东晓,金颖,李梦秋,王朝霞,袁云,李海霞,秦炯,杨艳玲.中国1003例甲基丙二酸血症的复杂临床表型、基因型及防治情况分析[J].中华儿科杂志,2018,56:414-420.]
[2]Ren GF,Zhang HZ,Wang D.The clinical characteristics and the pathogenic gene mutations in two infants with methylmalonie aciduria[J].Zhongguo Dang Dai Yi Yao,2016,23:104-106[.任广芳,张豪正,王东.2例甲基丙二酸尿症患儿的临床和致病基因突变研究[J].中国当代医药,2016,23:104-106.]
[3]Yang Y,Sun F,Song J,Hasegawa Y,Yamaguchi S,Zhang Y,Jiang Y,Qin J,Wu X.Clinical and biochemical studies on Chinese patients with methylmalonic aciduria[J].J Child Neurol,2006,21:1020-1024.
[4]Liu MY,Yang YL,Chang YC,Chiang SH,Lin SP,Han LS,Qi Y,Hsiao KJ,Liu TT.Mutation spectrum of MMACHC in Chinese patients with combined methylmalonic aciduria and homocystinuria[J].J Hum Genet,2010,55:621-626.
[5]Martinelli D,Deodato F,Dionisi-Vici C.Cobalamin C defect:natural history,pathophysiology and treatment[J].J Inherit Metab Dis,2011,34:127-135.
[6]Huemer M,Diodato D,Schwahn B,Schiff M,Bandeira A,Benoist JF,Burlina A,Cerone R,Couce ML,Garcia-Cazorla A,la Marca G,Pasquini E,Vilarinho L,Weisfeld-Adams JD,Ko?ich V,Blom H,Baumgartner MR,Dionisi-Vici C.Guidelines for diagnosis and management of the cobalaminrelated remethylation disorders cblC,cblD,cblE,cblF,cblG,cblJ and MTHFR deficiency[J].J Inherit Metab Dis,2017,40:21-48.
[7]Oberholzer VG,Levin B,Burgess EA,Young WF.Methylmalonie aciduria:an inborn errors of metabolism leading to chronic metabolic acidosis[J].Arch Dis Child,1967,42:492-504.
[8]Lerner-Ellis JP,Tirone JC,Pawelek PD,DoréC,Atkinson JL,Watkins D,Morel CF,Fujiwara TM,Moras E,Hosack AR,Dunbar GV,Antonicka H,Forgetta V,Dobson CM,Leclerc D,Gravel RA,Shoubridge EA,Coulton JW,Lepage P,Rommens JM,Morgan K,Rosenblatt DS.Identification of the gene responsible for methylmalonic aciduria and homocystinuria,cblC type[J].Nat Genet,2006,38:93-100.
[9]Wu LY,An H,Liu J,Li JY,Han Y,Zhou AH,Wang F,Jia JP.Manic-depressive psychosis as the initial symptom in adult siblings with late-onset combined methylmalonic aciduria and homocystinemia,cobalamin C type[J].Chin Med J(Engl),2017,130:492-494.
[10]Wang SJ,Yan CZ,Liu YM,Zhao YY.Late-onset cobalamin Cdeficiency Chinese sibling patients with neuropsychiatric presentations[J].Metab Brain Dis,2018,33:829-835.
[11]Hu S,Mei SY,Liu N,Kong X.Molecular genetic characterization of cblC defects in 126 pedigrees and prenatal genetic diagnosis of pedigrees with combined methylmalonic aciduria and homocystinuria[J].BMC Med Genet,2018,19:154.
[12]Wang J,Li EZ,Wang LW,Yang SH,Hu T,Wang ZL,Zhou Q.Application of gene capture technology combined with next generation sequencing technology on methylmalonic academia[J].Zhonghua Shi Yong Er Ke Lin Chuang Za Zhi,2014,29:1548-1551[.王珺,李尔珍,王立文,杨圣海,胡涛,王志龙,周巧.基因捕获联合高通量测序技术在甲基丙二酸血症诊断中的应用[J].中华实用儿科临床杂志,2014,29:1548-1551.]
[13]Roze E,Gervais D,Demeret S,Ogier de Baulny H,Zittoun J,Benoist JF,Said G,Pierrot-Deseilligny C,Bolgert F.Neuropsychiatric disturbances in presumed late-onset cobalamin C disease[J].Arch Neurol,2003,60:1457-1462.
[14]Lei RY,Liu YR,Ji YF,Ma XR,Wang JT,Cui HW,Wang Z,Wang CE,Zhang BA.Clinical features and gene analysis of three cases of late-onset methylmalonic aciduria,cblC type[J].Zhonghua Shen Jing Ke Za Zhi,2014,47:101-106[.雷如意,刘艳茹,籍炀飞,马兴荣,王景涛,崔红卫,王震,王长娥,张博爱.晚发型甲基丙二酸尿症cblC型三例临床特点和基因分析[J].中华神经科杂志,2014,47:101-106.]
[15]Huemer M,Scholl-Bürgi S,Hadaya K,Kern I,Beer R,Seppi K,Fowler B,Baumgartner MR,Karall D.Three new cases of lateonset cblC defect and review of the literature illustrating when to consider inborn errors metabolism beyond infancy[J].Orphanet J Rare Dis,2014,9:161.Carrillo-Carrasco N,Chandler RJ,Venditti CP.Combined
[16]Carrillo-Carrasco N,Chandler RJ,Venditti CP.Combined methylmalonic acidemia and homocystinuria,cblC type.Ⅰ:clinical presentations,diagnosis and management[J].J Inherit Metab Dis,2012,35:91-102.
[17]Ouyang M,Liu L,Liang P,Cheng HB,Wang Y,Liu GQ,Liu XY,Fan N.Clinical and molecular analysis of cobalamin Ctype methylmalonic aciduria with homocystinuria in a Chinese family[J].Zhonghua Shi Yan Yan Ke Za Zhi,2014,32:723-727[.欧阳明,刘璐,梁平,成洪波,王云,刘桂琴,刘旭阳,樊宁.甲基丙二酸尿症合并同型半胱氨酸血症cblC型家系的临床与分子遗传学研究[J].中华实验眼科杂志,2014,32:723-727.]
[18]Wang ZX,Zhang W,Yang YL,Yuan Y.Clinical and radiological features of the late-onset methylmalonic aciduria:a review of three cases[J].Zhonghua Shen Jing Ke Za Zhi,2004,37:327-330[.王朝霞,张巍,杨艳玲,袁云.迟发型甲基丙二酸尿症三例临床和影像学分析[J].中华神经科杂志,2004,37:327-330.]
[19]Richard E,Jorge-Finnigan A,Garcia-Villoria J,Merinero B,Desviat LR,Gort L,Briones P,Leal F,Pérez-CerdáC,Ribes A,Ugarte M,Pérez B;MMACHC Working Group.Genetic and cellular studies of oxidative stress in methylmalonic aciduria(MMA)cobalamin deficiency type C(cblC)with homocystinuria(MMACHC[)J].Hum Muta,2009,30:1558-1566.
[20]Papatheodorou L,Weiss N.Vascular oxidant stress and inflammation in hyperhomocysteinamia[J].Antioxid Redox Signal,2007,9:1941-1958.
[21]Liu YR,Ji YF,Wang YL,Zhang BA,Fang GY,Wang JT,Sun GF,Lu H.Clinical analysis of late-onset methylmalonic acidaemia and homocystinuria,cblC type with a neuropsychiatric presentation[J].J Neurol Neurosurg Psychiatry,2015,86:472-475.
[22]Malfatti CR,Perry ML,Schweigert ID,Muller AP,Paquetti L,Rigo FK,Fighera MR,Garrido-Sanabria ER,Mello CF.Convulsions induced by methylmalonic acid are associated with glutamic acid decarboxylase inhibition in rats:a role for GABAin the seizures presented by methylmalonic academic patients[J]?Neuroscience,2007,146:1879-1887.
[23]Yu W,Liu XJ,Zhang ZC.Effect of hyperhomocysteinemia on structure and function of peripheral nerve in rats[J].Zhongguo Shen Jing Jing Shen Ji Bing Za Zhi,2009,35:581-585[.于伟,刘学军,张哲成.高同型半胱氨酸血症对大鼠周围神经结构和功能的影响[J].中国神经精神疾病杂志,2009,35:581-585.]
[24]Foese DS,Zhang J,Healy S.Mechanism of vitamin B12:responsiveness in cblC methylmalonie aeiduria with homocystinuria[J].Mol Genet Metab,2009,98:338-343.
[25]Zhao YY,Yan CZ,Qi FY,Wang SJ,Li W,Zhao XH,Wang CL,Liu YM.Characteristics of clinical manifestations and molecular genetics of late-onset cobalamin C deficiency[J].Zhonghua Shen Jing Ke Za Zhi,2018,51:863-870[.赵玉英,焉传祝,亓法英,王胜军,李伟,赵秀鹤,王翠兰,刘艺鸣.晚发型钴胺素C缺陷病临床及分子遗传学特点分析[J].中华神经科杂志,2018,51:863-870.]
[26]Huang Z,Han LS,Ye J,Qiu WJ,Zhang HW,Gao XL,Wang Y,Ji WJ,Li XY,Gu XF.Outcomes of patients with combined methylmalonic acidemia and homocystinuria after treatment[J].Zhonghua Er Ke Za Zhi,2013,51:194-198[.黄倬,韩连书,叶军,邱文娟,张惠文,高晓岚,王瑜,季文君,李晓燕,顾学范.甲基丙二酸血症合并同型半胱氨酸尿症患者治疗效果分析[J].中华儿科杂志,2013,51:194-198.]2019-05-08
[2]Ren GF,Zhang HZ,Wang D.The clinical characteristics and the pathogenic gene mutations in two infants with methylmalonie aciduria[J].Zhongguo Dang Dai Yi Yao,2016,23:104-106[.任广芳,张豪正,王东.2例甲基丙二酸尿症患儿的临床和致病基因突变研究[J].中国当代医药,2016,23:104-106.]
[3]Yang Y,Sun F,Song J,Hasegawa Y,Yamaguchi S,Zhang Y,Jiang Y,Qin J,Wu X.Clinical and biochemical studies on Chinese patients with methylmalonic aciduria[J].J Child Neurol,2006,21:1020-1024.
[4]Liu MY,Yang YL,Chang YC,Chiang SH,Lin SP,Han LS,Qi Y,Hsiao KJ,Liu TT.Mutation spectrum of MMACHC in Chinese patients with combined methylmalonic aciduria and homocystinuria[J].J Hum Genet,2010,55:621-626.
[5]Martinelli D,Deodato F,Dionisi-Vici C.Cobalamin C defect:natural history,pathophysiology and treatment[J].J Inherit Metab Dis,2011,34:127-135.
[6]Huemer M,Diodato D,Schwahn B,Schiff M,Bandeira A,Benoist JF,Burlina A,Cerone R,Couce ML,Garcia-Cazorla A,la Marca G,Pasquini E,Vilarinho L,Weisfeld-Adams JD,Ko?ich V,Blom H,Baumgartner MR,Dionisi-Vici C.Guidelines for diagnosis and management of the cobalaminrelated remethylation disorders cblC,cblD,cblE,cblF,cblG,cblJ and MTHFR deficiency[J].J Inherit Metab Dis,2017,40:21-48.
[7]Oberholzer VG,Levin B,Burgess EA,Young WF.Methylmalonie aciduria:an inborn errors of metabolism leading to chronic metabolic acidosis[J].Arch Dis Child,1967,42:492-504.
[8]Lerner-Ellis JP,Tirone JC,Pawelek PD,DoréC,Atkinson JL,Watkins D,Morel CF,Fujiwara TM,Moras E,Hosack AR,Dunbar GV,Antonicka H,Forgetta V,Dobson CM,Leclerc D,Gravel RA,Shoubridge EA,Coulton JW,Lepage P,Rommens JM,Morgan K,Rosenblatt DS.Identification of the gene responsible for methylmalonic aciduria and homocystinuria,cblC type[J].Nat Genet,2006,38:93-100.
[9]Wu LY,An H,Liu J,Li JY,Han Y,Zhou AH,Wang F,Jia JP.Manic-depressive psychosis as the initial symptom in adult siblings with late-onset combined methylmalonic aciduria and homocystinemia,cobalamin C type[J].Chin Med J(Engl),2017,130:492-494.
[10]Wang SJ,Yan CZ,Liu YM,Zhao YY.Late-onset cobalamin Cdeficiency Chinese sibling patients with neuropsychiatric presentations[J].Metab Brain Dis,2018,33:829-835.
[11]Hu S,Mei SY,Liu N,Kong X.Molecular genetic characterization of cblC defects in 126 pedigrees and prenatal genetic diagnosis of pedigrees with combined methylmalonic aciduria and homocystinuria[J].BMC Med Genet,2018,19:154.
[12]Wang J,Li EZ,Wang LW,Yang SH,Hu T,Wang ZL,Zhou Q.Application of gene capture technology combined with next generation sequencing technology on methylmalonic academia[J].Zhonghua Shi Yong Er Ke Lin Chuang Za Zhi,2014,29:1548-1551[.王珺,李尔珍,王立文,杨圣海,胡涛,王志龙,周巧.基因捕获联合高通量测序技术在甲基丙二酸血症诊断中的应用[J].中华实用儿科临床杂志,2014,29:1548-1551.]
[13]Roze E,Gervais D,Demeret S,Ogier de Baulny H,Zittoun J,Benoist JF,Said G,Pierrot-Deseilligny C,Bolgert F.Neuropsychiatric disturbances in presumed late-onset cobalamin C disease[J].Arch Neurol,2003,60:1457-1462.
[14]Lei RY,Liu YR,Ji YF,Ma XR,Wang JT,Cui HW,Wang Z,Wang CE,Zhang BA.Clinical features and gene analysis of three cases of late-onset methylmalonic aciduria,cblC type[J].Zhonghua Shen Jing Ke Za Zhi,2014,47:101-106[.雷如意,刘艳茹,籍炀飞,马兴荣,王景涛,崔红卫,王震,王长娥,张博爱.晚发型甲基丙二酸尿症cblC型三例临床特点和基因分析[J].中华神经科杂志,2014,47:101-106.]
[15]Huemer M,Scholl-Bürgi S,Hadaya K,Kern I,Beer R,Seppi K,Fowler B,Baumgartner MR,Karall D.Three new cases of lateonset cblC defect and review of the literature illustrating when to consider inborn errors metabolism beyond infancy[J].Orphanet J Rare Dis,2014,9:161.Carrillo-Carrasco N,Chandler RJ,Venditti CP.Combined
[16]Carrillo-Carrasco N,Chandler RJ,Venditti CP.Combined methylmalonic acidemia and homocystinuria,cblC type.Ⅰ:clinical presentations,diagnosis and management[J].J Inherit Metab Dis,2012,35:91-102.
[17]Ouyang M,Liu L,Liang P,Cheng HB,Wang Y,Liu GQ,Liu XY,Fan N.Clinical and molecular analysis of cobalamin Ctype methylmalonic aciduria with homocystinuria in a Chinese family[J].Zhonghua Shi Yan Yan Ke Za Zhi,2014,32:723-727[.欧阳明,刘璐,梁平,成洪波,王云,刘桂琴,刘旭阳,樊宁.甲基丙二酸尿症合并同型半胱氨酸血症cblC型家系的临床与分子遗传学研究[J].中华实验眼科杂志,2014,32:723-727.]
[18]Wang ZX,Zhang W,Yang YL,Yuan Y.Clinical and radiological features of the late-onset methylmalonic aciduria:a review of three cases[J].Zhonghua Shen Jing Ke Za Zhi,2004,37:327-330[.王朝霞,张巍,杨艳玲,袁云.迟发型甲基丙二酸尿症三例临床和影像学分析[J].中华神经科杂志,2004,37:327-330.]
[19]Richard E,Jorge-Finnigan A,Garcia-Villoria J,Merinero B,Desviat LR,Gort L,Briones P,Leal F,Pérez-CerdáC,Ribes A,Ugarte M,Pérez B;MMACHC Working Group.Genetic and cellular studies of oxidative stress in methylmalonic aciduria(MMA)cobalamin deficiency type C(cblC)with homocystinuria(MMACHC[)J].Hum Muta,2009,30:1558-1566.
[20]Papatheodorou L,Weiss N.Vascular oxidant stress and inflammation in hyperhomocysteinamia[J].Antioxid Redox Signal,2007,9:1941-1958.
[21]Liu YR,Ji YF,Wang YL,Zhang BA,Fang GY,Wang JT,Sun GF,Lu H.Clinical analysis of late-onset methylmalonic acidaemia and homocystinuria,cblC type with a neuropsychiatric presentation[J].J Neurol Neurosurg Psychiatry,2015,86:472-475.
[22]Malfatti CR,Perry ML,Schweigert ID,Muller AP,Paquetti L,Rigo FK,Fighera MR,Garrido-Sanabria ER,Mello CF.Convulsions induced by methylmalonic acid are associated with glutamic acid decarboxylase inhibition in rats:a role for GABAin the seizures presented by methylmalonic academic patients[J]?Neuroscience,2007,146:1879-1887.
[23]Yu W,Liu XJ,Zhang ZC.Effect of hyperhomocysteinemia on structure and function of peripheral nerve in rats[J].Zhongguo Shen Jing Jing Shen Ji Bing Za Zhi,2009,35:581-585[.于伟,刘学军,张哲成.高同型半胱氨酸血症对大鼠周围神经结构和功能的影响[J].中国神经精神疾病杂志,2009,35:581-585.]
[24]Foese DS,Zhang J,Healy S.Mechanism of vitamin B12:responsiveness in cblC methylmalonie aeiduria with homocystinuria[J].Mol Genet Metab,2009,98:338-343.
[25]Zhao YY,Yan CZ,Qi FY,Wang SJ,Li W,Zhao XH,Wang CL,Liu YM.Characteristics of clinical manifestations and molecular genetics of late-onset cobalamin C deficiency[J].Zhonghua Shen Jing Ke Za Zhi,2018,51:863-870[.赵玉英,焉传祝,亓法英,王胜军,李伟,赵秀鹤,王翠兰,刘艺鸣.晚发型钴胺素C缺陷病临床及分子遗传学特点分析[J].中华神经科杂志,2018,51:863-870.]
[26]Huang Z,Han LS,Ye J,Qiu WJ,Zhang HW,Gao XL,Wang Y,Ji WJ,Li XY,Gu XF.Outcomes of patients with combined methylmalonic acidemia and homocystinuria after treatment[J].Zhonghua Er Ke Za Zhi,2013,51:194-198[.黄倬,韩连书,叶军,邱文娟,张惠文,高晓岚,王瑜,季文君,李晓燕,顾学范.甲基丙二酸血症合并同型半胱氨酸尿症患者治疗效果分析[J].中华儿科杂志,2013,51:194-198.]2019-05-08