致死型线粒体三功能蛋白缺乏症1例并文献复习

Lethal mitochondrial trifunctional protein deficiency:a case report and literature review

目的探讨致死型线粒体三功能蛋白缺乏症(mitochondrial trifunctional protein deficiency,MTPD)患儿的临床表型、诊治和基因特点。方法对桂林市妇幼保健院新生儿科收治的1例致死型MTPD患儿临床资料进行回顾性分析。以"线粒体三功能蛋白缺乏症"、"线粒体三功能蛋白"、"新生儿"、"婴儿"、"致死型"和"mitochondrial trifunctional protein deficiency"、"mitochondrial trifunctional protein"、"HADHA"、"HADHB"、"newborn"、"infant"、"lethal"为关键词,分别对中文科技期刊数据库、中国知网、万方数据、中华医学期刊全文数据库、中文生物医学期刊文献数据库、中国生物医学文献数据库、PubMed、Elsevier ScienceDirect、Embase、BIOSIS Previews等自建库至2023年7月收录的文献进行检索,总结致死型MTPD患儿的临床特征和基因变异特点。结果本例患儿男,胎龄33^(+3)周,生后9 d出现病情变化,以代谢性酸中毒、反复呼吸暂停、休克、心肌病、心力衰竭为主要表现,血串联质谱回报多种酰基肉碱增高,基因检测提示患儿HADHB基因存在母源性c.527C>G错义变异和新发c.1148C>T错义变异,确诊致死型MTPD,日龄12 d家属放弃抢救后患儿死亡。文献检索收集到相关文献13篇、共29例患儿资料,包括本例共30例。资料相对完整的16例患儿中,男10例,新生儿期起病15例,主要临床表现为心肌病、心肌酶谱异常、心力衰竭以及乳酸酸中毒或代谢性酸中毒;明确描述死亡时间的15例患儿中,3月龄内死亡14例;仅报道1例8岁时仍存活的患儿;29例通过基因检测确诊,HADHA基因变异10例,HADHB基因变异19例,1例通过病理检测及质谱分析确诊。结论MTPD是一种罕见的常染色体隐性遗传病,致死型MTPD发病时间早,新生儿期发病者可表现为严重酸中毒及心力衰竭,病死率高,应尽早对高度怀疑MTPD的患儿进行酰基肉碱及HADHB、HADHA基因检测,以助于早期基因诊断和干预治疗。

Objective To explore the clinical phenotype,diagnosis,treatment and genetic characteristics of infants with lethal mitochondrial trifunctional protein deficiency(MTPD).Methods The clinical data of one patient with lethal MTPD admitted to the neonatal department of Guilin Maternal and Child Health Hospital were retrospectively analyzed.Relevant literature published up to July 2023 were retrieved from the Chinese Science and Technology Journal database,CNKI,Wanfang Database,Chinese Medical Journal Full-text Database,Chinese Biomedical Journal Literature Database,China Biomedical Literature Database,PubMed,Elsevier ScienceDirect,Embase and BIOSIS Previews with the terms of"mitochondrial trifunctional protein deficiency","mitochondrial trifunctional protein","HADHA","HADHB","newborn","infant"and"lethal".Then the characteristics of clinical phenotypes and genetic variations about MTPD infants were summarized.Results This patient was a 33^(+3) week premature male infant who developed symptoms 9 d after birth.The main manifestations were metabolic acidosis,recurrent apnea,shock,cardiomyopathy and heart failure.Blood tandem mass spectrometry reported an increased levels of multiple acylcarnitines,and genetic testing indicated that the patient's HADHB gene had maternal c.527C>G missense mutation and de novo c.1148C>T missense mutation.The infant was diagnosed with lethal MTPD and died 12 d after birth after his family gave up the treatment.There were 29 cases in the total 13 publications that were retrieved.Together with this case,there were 30 cases involved.Among the 16 cases with relatively complete data,10 cases were male and 15 cases developed symptoms in neonatal period.The main clinical phenotypes were cardiomyopathy,abnormal myocardial enzyme spectrum,heart failure and lactic acidosis or metabolic acidosis.Among the 15 cases with clear age of death,14 died within 3 months of life.Of the reported patients,only one survived at 8 years of age.29 cases were confirmed through genetic test,10 infants had HADHA gene variations and 19 had HADHB gene variations.Only one patient was confirmed by pathological detection and mass spectrometry analysis.Conclusions MTPD is a rare autosomal recessive genetic disease.Lethal MTPD has an early onset with high mortality.Severe acidosis and heart failure are the most common symptoms in neonatal period.Early detection of acylcarnitine and HADHB,HADHA gene should be performed in highly suspected infants to help early genetic diagnosis and intervention.