伴中枢神经系统损害的晚发型MMA的临床特征及其家系成员突变基因分析

Clinical features and gene mutation analysis of one family with late-onset methylmalonic acidemia with central nervous system damage

目的分析晚发型甲基丙二酸血症(MMA)的临床特征及其家系成员基因突变情况。方法回顾性分析1例晚发型MMA患者病历资料,并对其一级亲属进行家系调查,同时采集外周静脉血,提取基因组DNA进行全外显子组测序,通过生物信息学方法筛选致病性变异,利用Sanger测序进行验证及来源分析。结果先证者,男,27岁。因“反复精神行为异常2年,行走不稳1个月,发作性意识不清、肢体抽搐8 d”收入院。主要临床表现为反复精神行为异常,行走不稳,发作性意识不清,肢体抽搐,四肢腱反射亢进,双侧踝阵挛+,双侧病理征+,共济运动不稳不准。发病初期即存在肾功能损害。血液检查示同型半胱氨酸明显升高,肌酐、尿素氮升高;血液酰基肉碱谱分析示丙酰肉碱及丙酰肉碱/乙酰肉碱升高,尿液有机酸分析示甲基丙二酸明显升高。脑脊液蛋白轻度升高。颅脑MRI检查示双侧小脑半球异常信号。根据体格检查、实验室检查和影像学检查,临床诊断为伴中枢神经系统损害的晚发型MMA。经先证者及其家属同意,对先证者一级亲属进行家系调查。该家系两代3人,均为山东省原住居民,汉族,仅发现1例MMA患者(先证者)。该家系成员突变基因分析显示,先证者同时存在MMACHC基因第4外显子c.658_660delAAG(Lys220del)和c.482G→A(Arg161Gln)位点杂合突变;先证者父亲存在MMACHC基因第4外显子c.482G→A(Arg161Gln)位点杂合突变,母亲存在MMACHC基因第4外显子c.658_660delAAG(Lys220del)位点杂合突变。结论该例晚发型MMA患者主要临床特征为精神行为异常、癫痫发作、锥体束和小脑损害体征,伴高同型半胱氨酸血症和肾功能损害,其发病是由于MMACHC基因第4外显子c.658_660delAAG(Lys220del)和c.482G→A(Arg161Gln)位点杂合突变所致。

Objective To investigate the clinical features and gene mutations of a pedigree with late-onset methylmalonic acidemia(MMA).Methods A patient with late-onset MMA was selected.The medical records of the patient were analyzed retrospectively and his first-degree relatives were investigated.Meanwhile,whole exome sequencing was used to screen the pathogenic variation through bioinformatics analysis,and Sanger sequencing was used for verification and source analysis.Results The proband was a 27-year-old man.He was admitted to the hospital because of repeated mental and behavior abnormalities for 2 years,walking instability for 1 month,episodic unconsciousness and limb twitch for 8 days.The clinical manifestations were repeated mental and behavior abnormalities,walking instability,episodic unconsciousness,limb twitch,increased tendon reflex in all four limbs,positive bilateral ankle clonus,positive bilateral Babinski sign and mutual aid movement unstable and inaccurate.Renal impairment was present at the beginning of the disease.Blood tests showed significantly elevated serum homocysteine,and increased serum creatinine and urea nitrogen.Blood acylcarnitine profiling showed elevated blood propionylcarnitine(C3)concentration as well as an elevated propionylcarnitine-acetylcarnitine(C3/C2)ratio;urine organic acid analysis showed increased levels of methylmalonic acid.There was mildly elevated protein in the cerebrospinal fluid(CSF).Magnetic resonance imaging(MRI)of the brain showed abnormal signals in bilateral cerebellar hemispheres.Based on physical examination,laboratory examination and imaging,the patient was diagnosed with late-onset MMA with central nervous system damage.With the consent of the proband and his family members,the first-degree relatives of the proband were investigated.The family with a total of two generations of three people were permanent residents in Shandong Province,and of Han nationality;only one case was MMA patient(the proband).The disease gene mutation analysis showed that the proband had complex heterozygous mutations in exon 4 of MMACHC gene c.658_660delAAG(Lys220del)and c.482G→A(Arg161Gln).The father of the proband had heterozygous mutation in exon 4 of MMAHC gene c.482G→A(Arg161Gln).The mother of the proband had heterozygous mutation in exon 4 of MMAHC gene c.658_660delAAG(Lys220del).Conclusion The main clinical features of this patient with late-onset MMA were mental and behavior abnormalities,seizures,signs of pyramidal tract and cerebellar impairment,accompanied by hyperhomocysteine and renal impairment,which was caused by the complex heterozygous mutations in exon 4 of MMACHC gene c.658_660delAAG(Lys220del)and c.482G→A(Arg161Gln).