3-羟基-3甲基戊二酰辅酶A裂解酶缺乏症临床特点及基因变异分析

Clinical and genetic analysis of children with 3-hydroxy-3-methyglutaryl-coenzyme A lyase deficiency

目的了解3-羟基-3甲基戊二酰辅酶A裂解酶缺乏症的临床特点及基因变异情况。方法分析6例3-羟基-3甲基戊二酰辅酶A裂解酶缺乏症患儿的临床资料及基因检测结果。结果6例患儿,男性3例,女性3例。1例家族史阳性。3例患儿当地医院行新生儿筛查提示该疾病,2例患儿为发病后临床诊断,1例患儿至今未发病。5例患儿发病年龄10天~5岁。初诊年龄为1个月~7岁,发病时均有不同程度的代谢危象、低血糖和高乳酸血症等表现。2例患儿死亡。血串联质谱显示3-羟基异戊酰肉碱升高,部分患儿伴有己二酰肉碱升高;尿有机酸分析提示3-羟基-3-甲基戊二酸显著升高,伴3-甲基戊烯二酸、3-羟基异戊酸等增高。4例患儿基因检测均发现HMGCL基因变异:2例c.122G>A(p.R41Q)纯合;1例c.697C>T(p.H233Y)纯合;1例c.145-2A>G和c.590G>A(p.C197Y)复合杂合。其中,c.697C>T(p.H 233Y)、c.145-2A>G和c.590G>A(p.C 197Y)变异均为首次报道,蛋白结构预测均为可能有害,ACMG评级为可能致病。另2例患儿未行基因检测。结论3-羟基-3甲基戊二酰辅酶A裂解酶缺乏症临床表型多样,结合血串联质谱、尿有机酸分析及基因诊断可确诊。对3-羟基-3甲基戊二酰辅酶A裂解酶缺乏症的筛查有助于早期确诊及合理治疗。

Objective To analyze the clinical characteristics and gene variation for children with 3-hydroxy-3-methyglutaryl-coenzyme A lyase deficiency(HMGCLD).Methods The clinical data and genetic sequencing results of children with HMGCLD were analyzed.Results There were 6 patients(3 boys and 3 girls).One patient had a positive family history.Neonatal screening in the local hospital indicated HMGCLD in 3 patients,2 patients were clinically diagnosed after the onset of the disease,and 1 patient remained disease-free.The onset age of 5 patients ranged from 10 days to 5 years and the age of first diagnosis ranged from 1 month to 7 years.There were metabolic crisis,hypoglycemia and hyperlactatemia in different degrees at the onset of the disease.Two patients died.Blood tandem mass spectrometry showed an increase in 3-hydroxyisovaleryl carnitine(C5-OH),and some of the children were accompanied by an increase in hexanedioyl carnitine(C 6DC).Urine organic acid analysis showed that 3-hydroxy-3-methylglutaric acid increased significantly,along with 3-methylpentene acid and 3-hydroxyisovaleric acid.The HMGCL gene variation was found in 4 patients.Two patients had a homozygous variation of c.122G>A(p.R41Q),1 patient had a homozygous variation of c.697C>T(p.H233Y)and 1 patient had a complex heterozygous variation of c.145-2A>G and c.590G>A(p.C197Y).Among them,c.697C>T(p.H 233Y),c.145-2A>G,and c.590G>A(p.C197Y)were all reported for the first time.Protein structure was predicted to be potentially harmful,and the grade of ACMG was likely pathogenic.The other two children did not undergo genetic testing.Conclusions The clinical phenotype of HMGCLD is diverse,which can be confirmed by combining blood tandem mass spectrometry,urine organic acid analysis and gene diagnosis.Screening of HMGCLD is helpful for early diagnosis and reasonable treatment.