肉碱-酰基肉碱转位酶缺乏症三例并文献复习

Three cases of carnitine-acylcarnitine transposase deficiency and literature review

目的探讨肉碱-酰基肉碱转位酶缺乏症(carnitine-acylcarnitine translocase deficiency,CACTD)患儿的临床特征、生化结果及基因突变特点。方法选择2017年广州市妇女儿童医疗中心新生儿科诊治的3例CACTD患儿,对其临床特征、生化结果及基因突变特点进行回顾性分析。以"新生儿"、"婴儿"、"肉碱-酰基肉碱转位酶缺乏症"、"肉碱-酰基肉碱转位酶"和"carnitine-acylcarnitine translocase deficiency"、"SLC25A20"为检索词,分别对中国知网、万方数据库、生物医学文献数据库(PubMed)、美国国家生物技术中心及Embase生物医学全文数据库自建库至2018年4月收录的文献进行检索,总结CACTD患儿的临床资料、生化代谢指标、基因突变特点、治疗方法和预后。结果 3例患儿中男2例,女1例,均为足月儿,生后无窒息。母亲孕期无异常,父母非近亲婚配。生后15~20 h均以反应差、严重低血糖起病;血氨、肝酶、肌酸激酶及其同工酶明显升高,二羧基酸尿阳性,血游离肉碱水平降低,长链酰基肉碱水平增高;2例血酮体水平明显降低;3例患儿心电图均显示房室传导阻滞、室性心动过速,给予反复电复律、利多卡因、胺碘酮治疗;2例给予精氨酸降血氨、补充左卡尼汀、低脂+中链脂肪酸配方奶喂养。2例分别于生后3 d和8 d死于心肺衰竭;1例治疗后病情明显改善家长签字出院。基因测序回报:病例2为SLC25A20基因c.199-10T>G和IVS7-9_16ins复合杂合突变,其中IVS7-9_16ins杂合突变可能是一种新发致病突变;病例3为SLC25A20基因c.199-10T>G纯合突变,父母为该突变携带者。共纳入17篇文献,包括50例CACTD患儿,其中男31例,女19例。患儿均以低血糖,尤其是低酮性低血糖、高氨血症,肝酶及肌酸激酶升高,血游离肉碱水平明显降低,长链酰基肉碱水平明显升高,二羧基酸尿,伴心律失常、心肌病为临床特征。Sanger直接测序检测等位基因100条,突变种类为40种;纯合突变23例,复合杂合突变27例;c.199-10T>G位点突变频次最高,为22次;其他突变类型均不超过6次。生后1周内起病44例(88.0%,44/50);死亡30例,存货13例,未知7例,病死率69.8%(30/43),其中生后1周内死亡14例。结论 CACTD的早期识别、早期诊断、快速治疗是关键。基因分析是目前明确诊断最可靠的方法。c.199-10T>G突变是存在于亚洲人群中最常见的致病突变类型,低酮性低血糖是早期线索;有先证者的家庭再次妊娠时需做产前诊断。

Objective To study the clinical features, biochemical characteristics and gene mutations of patients with carnitine-acylcarnitine translocase deficiency (CACTD). Method The clinical data, biochemical markers and gene mutations of three cases with CACTD admitted our hospital in 2017 were retrospectively analyzed. The related literatures were searched from China national knowledge infrastructure, wanfang database, PubMed, national center for biotechnology information and Embase using keywords "neonate","infant","carnitine-acylcarnitine deficiency","carnitine-acylcarnitine translocase", and SLC25A20"(up to April 2018). Result (1) Three cases (2 boys and 1 girl) with CACTD were full-term infants without asphyxia after birth. The mothers had no abnormal pregnancy, and the parents had no consanguinity. All the patients had poor response and severely hypoglycemia 15~20 hours after birth. Hyperammonemia, elevated liver enzymes and creatine kinase, severe dicarboxylic aciduria, significantly increased level of long-chain acylcarnitine, and significantly decreased concentration of free carnitine were observed in all 3 patients. Significantly decreased serum ketone body was observed in 2 cases. All of them had recurrent atrioventricular block and ventricular tachycardia requiring repeated electrocardioversion, lidocaine, and amiodarone treatment. Arginine, carnitine and special formula with low fat and high medium-chain-triglyceride were given to two infants. Two infants died of cardiorespiratory failure at 3-day and 8-day of life, respectively. The other infant′s clinical condition improved significantly.However, he was discharged from our NICU at the request of his parents. Gene analysis revealed that compound heterozygous mutations c.199-10T>G and IVS7-9_16 ins (a possible novel mutation) were detected in the SLC25A20 gene of case 2. Homozygous mutation c.199-10T>G was identified in the SLC25A20 gene of case 3 whose parents both carried this mutation.(2) A total of 17 articles and 50 cases were retrieved and analyzed. A total of 40 mutations were found in the SLC25A20 gene. Homozygous mutations were found in 23 cases, and compound heterozygous mutations were found in 27 cases. The mutation of c.199-10T>G was the most common mutation and occurred 22 times in the patients from Asia population. Other mutations were found less than 6 times. The review showed that the most common clinical features included hypoketotic hypoglycemia, hyperammonemia, elevated liver enzymes and creatine kinase, remarkable dicarboxylic aciduria, significantly increased level of long-chain acylcarnitine, significantly decreased free carnitine, arrhythmia and cardiomyopathy. Mostly, the onset of symptoms was within 1 week after birth (88%, 44/50). The mortality was 69.8%(30/43). Most patients died within the first year of their life.Conclusion Early recognition, early diagnosis and prompt treatment are crucial for CACTD patients. Gene analysis is a reliable diagnostic method. The mutation of c.199-10T>G is the most common SLC25A20 mutation reported in Asia population. Hypoketotic hypoglycemia is an early sign of this disease. Families with a proband need prenatal diagnosis during the second pregnancy.