原发性肉碱缺乏症与猝死两家系分析

目的：探讨两个原发性肉碱缺乏症家系的临床特点及基因突变位点的检测，分析其中3例患儿的猝死原因。方法回顾性分析两个原发性肉碱缺乏症家系的临床资料，分别对两个家系的先证者行血氨、血乳酸、肝酶、心肌酶测定，血酰基肉碱分析和尿有机酸分析，提示原发性肉碱缺乏症可能，进一步对两家系成员行SLC22A5基因测序分析。结果两个家系先证者游离肉碱及多种酰基肉碱明显低下，死亡患儿在发病前均有发热、呕吐、嗜睡等表现。家系Ⅰ的先证者为c.760C>T( p. R254X)纯合突变，家庭其他成员均为c.760C>T杂合子。患儿死于严重心律失常及心肌病。尸体解剖病理提示部分心肌纤维断裂或呈波浪状排列、肝细胞弥漫性脂肪变性、部分肺泡腔可见中性粒细胞浸润。家系Ⅱ中2例死亡患儿疑似“病毒性心肌炎”。先证者并未发病，但已出现轻微心肌肥厚、血氨增高等，经左卡尼汀治疗后各项指标恢复正常，存在c.760C>T和c.844dupC(p. R282fs)两个杂合突变，分别遗传自父母。结论原发性肉碱缺乏症患儿，在疾病的缓解期无特殊表现，发病急且病情迅速恶化，甚至死亡。家系Ⅰ先证者因全身肉碱缺乏而发生心源性猝死。 c.760C>T纯合突变、c.760C>T和c.844dupC复合杂合突变可能分别是家系Ⅰ和家系Ⅱ发病的分子基础。早期诊断、规范治疗是决定远期预后的关键。

Analysis of primary carnitine deficiency with sudden death in two pedigrees

Objective Primary carnitine deficiency( PCD) is an autosomal recessive disorder of fatty acid oxidation due to mutations in SLC22A5 gene,which encodes organic cation transporter 2(OCTN2). De-fects of the OCTN2 prevent tissues from accumulating carnitine,resulting in renal carnitine wasting and low plasma carnitine. PCD is a potentially deadly disease. In the present article,we discussed clinical manifestation and gene mutations in two primary carnitine deficiency families,and analyzed the causes of sudden death in three cases. Methods We retrospectively analyzed clinical data of two PCD families. Probands from both families received test of serum ammonia,lactic acid,hepatic and myocardial enzymes. The results indicated probability of PCD. Further sequencing of the SLC22A5 gene was performed in diseased children and family members. Results Probands from both families showed a significant decrease in free carnitine and several acyl carnitine. Fever,vomiting,drowsiness and other manifestations were found in three death children before the onset of disease. Proband from the first family had a c. 760C>T(p. R254X) homozygous mutation,other family members were c. 760C>T heterozygous. Proband from the first family died of severe arrhythmia and cardiomyopathy. The autopsy showed broken or wavy arrangement of the part of myocardial fibers and dif-fused fatty degeneration of hepatocytes,with infiltration of neutrophils in some of the alveolar. Proband from the second family were heterozygous of two mutations:c. 760C>T and c. 844dupC (p. R282fs),inherited from parents. He was asymptomatic when was diagnosed but there had been a slight myocardial hypertrophy and increased blood ammonia. However,the indicators returned to normal following L-carnitine supplementa-tion. Two died cases were suspected “viral myocarditis” in the second family. Conclusion The PCD chil-dren often show no symptom in quiescent stage of the disease. However,the disease can be triggered by com-mon cold or diarrhea,aggravate rapidly and even result in sudden death. Proband from the first family had oc-curred sudden cardiac death caused by systemic carnitine deficiency. The homozygous c. 760C> T mutation, and the heterozygous c. 760C> T combined with c. 844dupC mutations might be the pathogenesis basis of family Ⅰ and family Ⅱ,respectively. Early diagnosis and treatment is the key to long-term prognosis.