河北省石家庄市新生儿短链酰基辅酶A脱氢酶缺乏症筛查及基因突变分析

Screening and gene mutation analysis of neonates with short-chain acyl-coenzyme A dehydrogenase deficiency in Shijiazhuang city of Hebei province

目的了解短链酰基辅酶A脱氢酶缺乏症(short-chain acyl-coenzyme A dehydrogenase deficiency,SCADD)在河北省石家庄市新生儿中的患病率和临床特征,以及酰基辅酶A脱氢酶(acylcoenzyme A dehydrogenase,ACADS)基因突变情况。方法2014年1月至2021年12月,河北省石家庄市共分娩185683例活产新生儿,行串联质谱筛查,检测丁酰基肉碱(butylcarnitine,C4)、C4/乙酰基肉碱(acetylcarnitine,C2)、C4/丙酰基肉碱(propionylcarnitine,C3)。筛查阳性患儿进一步行基因检测,Sanger测序进行验证。185683例活产新生儿中,纳入118502例出生胎龄信息准确完整的新生儿,分为早产儿组(5597例)、足月儿组(112369例)、过期产儿组(536例),比较3组间C4、C4/C2及C4/C3水平。统计学方法采用单因素方差分析、t检验和Pearson相关性分析。结果185683例新生儿中,确诊4例SCADD患儿,患病率为1/46421。基因检测到ACADS基因2例复合杂合突变、1例纯合突变及1例杂合突变;发现了4种突变位点,分别为:c.625 G>A、c.1031A>G、c.1157 G>A和c.1130 C>T,均为已知突变。4例患儿初筛C4水平为0.65~0.84μmol/L。随访4例确诊患儿的生长发育情况,未出现临床表现。早产儿、足月儿、过期产儿组的C4分别为(0.192±0.073)、(0.168±0.058)、(0.158±0.052)μmol/L(F=447.700,P<0.001);C4/C2分别为0.0115±0.0047、0.0106±0.0040、0.0104±0.0038(F=110.200,P<0.001);C4/C3分别为0.1175±0.0714、0.1161±0.0563、0.1180±0.0593(F=2.481,P=0.084)。早产儿C4、C4/C2水平均高于足月儿(P值均<0.001);过期产儿C4水平低于足月儿(P<0.001)。出生胎龄与C4水平、C4/C2值均呈负相关(r值分别为-0.119与-0.036,P值均<0.001)。结论串联质谱联合基因测序技术可及早确诊SCADD患儿。河北省石家庄市新生儿的SCADD患病率为1/46421;检测到4种ACADS基因已知突变位点。

Objective To investigate the prevalence and clinical characteristics of short-chain acylcoenzyme A dehydrogenase deficiency(SCADD)and the gene mutation of acyl-coenzyme A dehydrogenase(ACADS)in Shijiazhuang city of Hebei province.Method From January 2014 to December 2021,a total of 185683 neonates in Shijiazhuang city of Hebei province were screened by tandem mass spectrometry to detect butylcarnitine(C4),C4/acetylcarnitine(C2),C4/propionyl carnitine(C3).The positive children were further tested for gene detection and verified by Sanger sequencing.Among 185683 neonates,118502 neonates with accurate and complete birth age information were divided into premature neonates group(n=5597),term neonates group(n=112369)and post term neonates group(n=536),and compared by the level of C4,C4/C2 and C4/C3.One-way ANOVA test,t-test and Pearson correlation analysis were performed for statistical analysis.Result Four children with SCADD were diagnosed in 185683 neonates,with a prevalence of 1/46421.Two cases with complex heterozygous mutations,one case with homozygous mutation and one case with heterozygous mutation of ACADS gene were found.Four mutation sites were found,c.625 G>A,c.1031A>G,c.1157 G>A and c.1130 C>T,all of which were known mutations.The C4 level of the four children in initial screening was 0.65-0.84μmol/L.No clinical symptoms appeared during the follow-up period of the four children.The C4 levels in premature,term and post term neonates were(0.192±0.073),(0.168±0.058)and(0.158±0.052)μmol/L,respectively(F=447.700,P<0.001).The values of C4/C2 were 0.0115±0.0047,0.0106±0.0040 and 0.0104±0.0038(F=110.200,P<0.001).The values of C4/C3 were 0.1175±0.0714,0.1161±0.0563 and 0.1180±0.0593(F=2.481,P=0.084).The levels of C4 and C4/C2 in premature neonates were higher than those in term neonates(all P<0.001);the level of C4 in post term neonates was lower than that in term neonates(P<0.001).The gestational age at birth was negatively correlated with C4 level and C4/C2 value(r=-0.119 and-0.036,all P<0.001).Conclusion Tandem mass spectrometry combined with gene sequencing technology can confirm the diagnosis of children with SCADD in time.The prevalence of SCADD in Shijiazhuang city of Hebei province is 1/46421;and four known mutation sites of ACADS gene were detected.