早发型极长链酰基辅酶A脱氢酶缺乏症3例临床及遗传学分析

doi:10.12372/jcp.2023.22e0453

摘要/Abstract

摘要：

目的探索早发型极长链酰基辅酶A脱氢酶缺乏症(VLCADD)的临床与遗传特征，提高对该疾病的认识。方法回顾性分析2017年9月至2020年4月在上海交通大学医学院附属新华医院新生儿监护室诊治的3例早发型VLCADD患儿的基因型、临床表型及其预后情况。结果 3例经分子诊断的早发型VLCADD患儿中男2例，女1例，均无阳性家族史。3例患儿均在新生儿期以代谢危象或消化道症状起病。新生儿筛查2例C14:1增高，1例未行筛查。3例患儿均存在ACADVL基因变异，都为复合杂合子，变异来自父母，其中c.1615C>T、c.231-232insAATG未见报道。1例患儿生后母乳喂养，2日龄呼吸心跳骤停；另2例患儿因新生儿筛查异常，诊断后立即开始富含中链三酰甘油的特殊奶粉喂养，分别于3月龄、4月龄发生猝死。结论早发型VLCADD为新生儿期、婴儿期潜在猝死性疾病之一，尽管积极开展早期诊断与治疗，但总体预后仍不佳，因此对先证者家系进行产前诊断、避免患儿出生至关重要。

关键词: 脂肪酸β氧化代谢障碍, 极长链酰基辅酶A脱氢酶缺乏症, 早发型, 婴儿猝死, ACADVL基因

Abstract:

Objective To explore the clinical features and genetic characteristics for early onset very long chain acyl-coenzyme A dehydrogenase deficiency (VLCADD) and to improve the understanding of this disease. Methods The genotypes, clinical phenotypes and prognosis of 3 neonates with early-onset VLCADD diagnosed and treated in the neonatal intensive care unit of Xinhua Hospital, Shanghai Jiao Tong University School of Medicine from September 2017 to April 2020 were retrospectively analyzed. Results Three children (2 boys and 1 girl) with early onset VLCADD were diagnosed by molecular method, and none of them had a positive family history. All three patients presented with metabolic crisis or digestive tract symptoms during the neonatal period. Two children were found to have increased C14:1 during the neonatal screening, and 1 case was not screened. All three children had ACADVL gene variations, which were complex heterozygotes, and the variations were from parents, among which c.1615C > T and c.231-232insAATG were not reported. One patient was breastfed after birth and had respiratory and cardiac arrest at 2 days of age. The other two children were fed special milk powder rich in medium-chain triacylglycerol immediately after the diagnosis due to abnormalities found in the neonatal screening, and sudden death occurred at 3 and 4 months of age, respectively. Conclusions Early onset VLCADD is one of the potential sudden death diseases in neonatal period and infancy. The prognosis is still poor despite early diagnosis and treatment. Therefore, prenatal diagnosis of fetuses from families with previous birth of VLCADD is an effective way to avoid the birth of early onset VLCADD children.

Key words: fatty acid β oxidative metabolism disorder, very long chain acyl-coenzyme A dehydrogenase deficiency, early onset, sudden infant death, ACADVL gene

李艳君, 张永红, 陈妍, 邱文娟, 韩连书, 朱天闻. 早发型极长链酰基辅酶A脱氢酶缺乏症3例临床及遗传学分析[J]. 临床儿科杂志, 2023, 41(5): 381-386.

LI Yanjun, ZHANG Yonghong, CHEN Yan, QIU Wenjun, HAN Lianshu, ZHU Tianwen. Clinical and genetic analysis of early onset very long chain acyl-CoA dehydrogenase deficiency: a report of three cases[J]. Journal of Clinical Pediatrics, 2023, 41(5): 381-386.

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参考文献 23

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项目	例1	例2	例3
入院时间	2017年9月	2020年3月	2018年6月
性别	男	男	女
起病年龄	2天	生后	生后
起病表现	呼吸心跳骤停	反复腹胀	频繁吐奶
嗜睡	+	-	-
抽搐	-	-	-
青紫	+	+	+
肝脏增大	-	-	-
家族史	无	无	无
血氨（正常9~30）/μmol·L^-1	511.0	70	34
乳酸（正常0.7~2.1）/mmol·L^-1	10.7	1.7	1.4
GPT（正常21~72）/U·L^-1	78	71	45
GOT（正常17~59）/U·L^-1	463	159	79
血糖（正常3.6~6.1）/mmol·L^-1	1.0	2.0	4.5
CK（正常55~179）/U·L^-1	2 465	247	303
CK-MB（正常0~25）/U·L^-1	1 665.0	69.1	58.3
结局	2日龄死亡	3月龄死亡	4月龄死亡

患儿	C0	C2	C4	C6	C8	C12	C14	C14:1	C16:1	C18	C18:1
例1	32	6.32	0.12	0.06	0.14	0.11	1.82	2.82	0.58	1.35	1.78
例2	30	15.39	0.24	0.07	0.12	0.31	2.82	4.92	6.27	2.96	4.92
例3	37	13.39	0.11	0.06	0.07	0.13	0.69	2.90	1.48	1.20	1.94
正常参考	10~60	6~30	0.01~0.30	0.01~0.15	0.01~0.30	0.02~0.20	0.02~0.25	0.01~0.30	0.02~0.20	0.20~1.20	0.30~1.8

患儿	变异基因	变异状态	核苷酸	氨基酸	致病性	来源	变异类型	是否报道
例1	ACADVL	复合杂合	c.1280G>A c.1505T>A	p.W427X p.L502Q	致病意义不明	父母未验证父母未验证	无义变异错义变异	是是
例2	ACADVL	复合杂合	c.1615C>T c.1567G>A	p.R539X p.E523K	致病^1）可能致病	父亲母亲	无义变异错义变异	否是
例3	ACADVL	复合杂合	c.231-232insAATG c.878+1G>C	p.F78Nfs*27 —	致病^2）致病	父亲母亲	移码变异剪切变异	否是