原发性肉碱缺乏症的筛查、诊断、治疗及基因型研究

目的 分析新生儿及母源性原发性肉碱缺乏症(PCD)临床筛查、诊断、治疗及基因型,为PCD的临床诊治提供依据。方法 采用串联质谱法(MS/MS)对2009年1月1日—2018年12月31日在浙江省医疗机构出生后3 d的新生儿足跟血进行多种遗传代谢病筛查。游离肉碱(C0)低于本实验室切值的可疑患儿及其母亲同时召回确诊。结果 共筛查3 040 815例新生儿,血C0低于正常参考值(切值＜10μmol/L)者4 459例,确诊PCD 患儿121例(其中男55例,女66例);发病率为1/25 131。对确诊后随访资料完整的111例患儿分析显示:初筛C0值为(5.94±2.01)μmol/L、召回复查C0值为(5.70±1.99)μmol/L,差异无统计学意义(t=1.05,P>0.05)。左卡尼汀初始剂量为40～200mg/(kg·d),维持剂量时C0的水平为(24.94±10.26)μmol/L,显著高于治疗前C0水平(t=20.728,P<0.001)。母源性PCD 64例,发病率为1/47 513,C0平均为(3.31±1.79)μmol/L。111例PCD患儿共检出SLC22A5基因上42种变异,其中以c.1400C>G (p.S467C) 突变最为常见,约占33.33%(74/222);其次为c.51C>G(p.F17L)占14.73 %。93.75%的母源性PCD患者母亲进行基因检测(60/64),c.1400C>G (p.S467C) 突变约占35.83%(43/120)。除2例患儿不明原因死亡外,其他PCD患儿生长发育正常。结论 PCD可通过新生儿疾病筛查早期发现,但需排除母源性肉碱缺乏症。基因检测可明确诊断,SLC22A5 c.1400C>G (p.S467C) 变异是浙江省PCD患者最常见的突变类型。左卡尼汀治疗有效,但需要长期规范治疗与随访。

Study on screening,diagnosis,treatment and genotype in primary carnitine deficiency

Objective To investigate the clinical diagnose,treatment and genetical features of infant and maternal primary carnitine deficiency (PCD) in newborn screening,so as to provide basis for clinical diagnosis and treatment of PCD. Methods Heel prick blood samples of newborns were collected on 3 days after birth for the genetic metabolic diseases screening by tandem mass spectrometry (MS/MS) in Zhejiang from January 1st 2009 to December 31st 2018.The infants with lower free carnitine(C0) and their mothers were recalled for diagnosis. Results A total of 4 459 infants were detected with lower C0 compared with the cut-off value (10 mol/L),and eventually 121 subjects were diagnosed with PCD (55 males and 66 females) in 3 040 815 newborns screening program.The prevalence rate was 1/25 131.The results of 111 PCD patients with complete follow-up data after diagnosis showed the initial screening C0 value was (5.94±2.01) mol/L,the recalled C0 value was (5.70±1.99)mol/L,and the difference was not significant (t=1.05,P>0.05).After treatment with L-carnitine,the C0 level at maintenance dose was (24.94±10.26) mol/L,which was significantly higher than that of pre-treatment (t=20.728,P＜0.001).A total of 64 maternal PCD were identified with a prevalence of 1/47 513 and an average C0 level of (3.31±1.79) mol/L.Furthermore,111 PCD patients had homozygous or compound heterozygous mutations by the genetic analysis of SLC22A5 gene.Consequently,a total of 42 cases were identified with SLC22A5 variants,of which c.1400C>G (p.S467C) was the most common mutation with the allelic frequency of 33.33%(74/222),followed by c.51C>G(p.F17L)with a frequency of 14.73%.There were 93.75% mothers undergoing genetic testing (60/64),and the SLC22A5 c.1400C>G (p.S467C) mutation accounted for 35.83% (43/120).Except for 2 deaths due to unknown reasons,other PCD children showed normal growth and development. Conclusionss PCD can be detected early by newborn screening and diagnosed by genetic analysis,but maternal carnitine deficiency should be excluded.SLC22A5 c.1400C>G (p.S467C) is the most common mutation in PCD patients in Zhejiang province.The treatment of L-carnitine is effective,but long-term treatment and follow-up are warranted.