具有c.199-10T>G纯合突变的肉碱-酰基肉碱转位酶缺乏症一例报告及文献复习

Carnitine-acylcarnitine translocase deficiency with homozygous mutation of c.199-10T>G: a case report and literature review

目的探讨具有c.199-10T>G纯合突变的肉碱-酰基肉碱转位酶缺乏症(carnitine-acylcarnitine translocase deficiency, CACTD)的临床特征及SLC25A20基因突变特点。方法(1)病例回顾:回顾性分析2017年9月广州市妇女儿童医疗中心收治的1例具有c.199-10T>G纯合突变的CACTD患儿的临床资料、基因突变特点、诊治经过和结局。(2)文献检索:以"CACT""SLC25A20"或"肉碱-酰基肉碱转位酶"为检索词,分别在中国知网、万方数据库、美国国家生物技术中心和PubMed数据库检索建库至2018年4月的相关文献。分析所获文献,以总结分析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(1)病例回顾:本例患儿为男性,外院足月阴道分娩出生,因生后15 h出现呻吟、青紫,微量血糖0.8 mmol/L,于生后2 d 5 h转入本院新生儿重症监护病房。该患儿有一兄,生后50 d因类似症状死亡,病因未明确。患儿血氨、肝酶、肌酸激酶均明显升高;血氨基酸分析提示肝损伤;尿气相层析-质谱技术分析结果提示大量二羧基酸尿;血游离肉碱含量极低;长链酰基肉碱含量明显增高、血酮体水平极低;心电图显示房室传导阻滞、室性心动过速。给予反复电复律、利多卡因、胺碘酮等治疗心律失常;精氨酸降血氨;以及补充左卡尼汀、中链脂肪酸配方奶喂养等措施后,患儿病情明显改善,生后29 d家长要求出院。出院后2周,又因"小儿腹泻病"再次住院,给予对症支持治疗后,腹泻好转,于生后45 d,家长再次要求出院。出院后失访。(2)SLC25A20基因分析:分析显示该患儿为c.199-10T>G纯合突变,父母为该突变的携带者。(3)文献检索:共获得32篇相关英文文献,共报道CACTD 50例,共测序检测等位基因100条;突变共40种,具有c.199-10T>G突变的患儿13例(包括纯合突变9例和复合杂合突变4例),突变频率为22/100。13例患儿均在生后72 h内(25 min^52 h)起病,均有低血糖,尤其是低酮性低血糖、高氨血症、肝酶及肌酸激酶升高、血游离肉碱含量明显降低、长链酰基肉碱含量明显升高、二羧基酸尿、心律失常、心肌病为常见的临床表现,12例中的11例死亡(另1例未交代结局)。结论c.199-10T>G是存在于亚洲人群中的常见致病突变类型,临床表现严重,结局不良。对于婴儿猝死及新生儿早期出现的无法解释的突发的临床状况恶化均需排查"遗传代谢病"(包括CACTD)的可能。

Objective To investigate the clinical features of carnitine-acylcarnitine translocase deficiency (CACTD) with c.199-10T>G homozygous mutation and the characteristics of SLC25A20 gene mutation. Methods This study retrospectively analyzed the clinical data, biochemical and genetic features, treatment and outcome of a boy with CACTD with c.199-10T>G homozygous mutation, who admitted to Guangzhou Women and Children's Medical Center in September 2017. Pertinent articles were retrieved from China National Knowledge Infrastructure (CNKI), Wanfang Database, National Center for Biotechnology Information and PubMed from the establishment of these databases to April 2018 using key words including CACT, SLC25A20 and carnitine-acylcarnitine translocase. Clinical information of all affected cases in the retrieved publications was analyzed. Results (1) The full-term boy born vaginally at a local hospital was transferred to neonatal intensive care unit (NICU) of Guangzhou Women and Children's Medical Center at 2 days and 5 hours due to groaning, cyanosis and severe hypoglycemia (0.8 mmol/L) at 15 h after birth. His elder brother with similar symptoms died of unknown reason at 50 days of age. In this case, ammonemia, liver enzyme and creatine kinase were significantly elevated, amino acid analysis suggested liver damage, and high amounts of dicarboxylic aciduria, low free carnitine, markedly increased long-chain acylcarnitine and hypoketotic hypoglycemia were also observed. His electrocardiogram showed atrioventricular block and ventricular tachycardia. After a series of treatments, including repeated electrical cardioversion, lidocaine and amiodarone for arrhythmia, arginine for blood ammonia level reduction, formula supplement containing L-carnitine and medium-chain fatty acid, the patient whose conditions had significantly improved and was discharged at the request of his parents at 29 days old. Two weeks later, he was re-admitted due to diarrhea, and discharged two days later when he was 45 days old. He was lost to follow up since then.(2) A homozygous mutation of c.199-10T>G was detected in this boy in SLC25A20 gene, which was also carried by his parents.(3) Thirty-two publications in English were retrieved, involving 50 cases of CACTD and 100 sequenced alleles. A total of 40 mutations in SLC25A20 gene were found so far, and c.199-10T>G was the most common mutation with a frequency of 22/100. It was identified in 13 patients, including nine homozygous mutations and four compound heterozygous mutations. Symptoms presented within 72 h after birth (25 min-52 h) in all the 13 infants, such as hypoketotic hypoglycemia, hyperammonemia, elevated liver enzyme and creatine kinase, significantly decreased free carnitine level, markedly increased level of long-chain acylcarnitine, dicarboxylic aciduria, arrhythmia and cardiomyopathy. The mortality rate of CACTD was 11/12 (the outcome of one case was not reported). Conclusions c.199-10T>G is the most common SLC25A20 gene mutation reported in Asia population with severe phenotypes and poor outcomes. Early diagnosis and timely treatment of CACTD are crucial. Inborn metabolic diseases such as CACTD should be considered if unexplainable exacerbation of clinical signs in neonatal period, or sudden infant death occurs.