Deficiency of acyl-CoA synthetase 5 is associated with a severe and treatable failure to thrive of neonatal onset
Deficiency of acyl-CoA synthetase 5 is associated with a severe and treatable failure to thrive of neonatal onset
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DOI：
10.1111/cge.13883
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发表时间：
2020-11-25
影响因子：
3.5
通讯作者：
Al-Maawali, Almundher
中科院分区：
文献类型：
--
作者：
Al-Thihli, Khalid;Afting, Cassian;Al-Maawali, Almundher
发育不良（FTT）导致显著的发病率，通常没有明确的病因。一个大的血缘家庭的六个人在新生儿期出现反复呕吐和腹泻，导致严重的FTT。标准诊断检查未确定病因。同源性作图和全外显子组测序鉴定了在受影响个体中共享的长链脂肪酰辅酶A合成酶5（ACSL 5）的新遗传变体的纯合性（NM_203379.1：c.1358C>A：p.（Thr453Lys））。通过桑格测序证实常染色体隐性遗传基因型-表型分离。通过免疫荧光、蛋白质印迹和酶测定对ACSL 5变体进行的体外功能分析表明，Thr 453 Lys是一种功能丧失突变，没有任何剩余活性。ACSL 5属于脂质代谢所需的必需酶家族，已知其在小鼠肠道中发挥主要活性。基于ACSL 5在肠道长链脂肪酸代谢中的功能和胃肠病学症状，受影响的个体接受全肠外营养或限制长链甘油三酯的中链甘油三酯配方治疗。患者反应良好，随访表明仅在生命早期需要治疗。
Failure to thrive (FTT) causes significant morbidity, often without clear etiologies. Six individuals of a large consanguineous family presented in the neonatal period with recurrent vomiting and diarrhea, leading to severe FTT. Standard diagnostic work up did not ascertain an etiology. Autozygosity mapping and whole exome sequencing identified homozygosity for a novel genetic variant of the long chain fatty acyl-CoA synthetase 5 (ACSL5) shared among the affected individuals (NM_203379.1:c.1358C>A:p.(Thr453Lys)). Autosomal recessive genotype-phenotype segregation was confirmed by Sanger sequencing. Functional in vitro analysis of the ACSL5 variant by immunofluorescence, western blotting and enzyme assay suggested that Thr453Lys is a loss-of-function mutation without any remaining activity. ACSL5 belongs to an essential enzyme family required for lipid metabolism and is known to contribute the major activity in the mouse intestine. Based on the function of ACSL5 in intestinal long chain fatty acid metabolism and the gastroenterological symptoms, affected individuals were treated with total parenteral nutrition or medium-chain triglyceride-based formula restricted in long-chain triglycerides. The patients responded well and follow up suggests that treatment is only required during early life.