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Deficiency of acyl‐CoA synthetase 5 is associated with a severe and treatable failure to thrive of neonatal onset
Clinical Genetics ( IF 3.5 ) Pub Date : 2020-11-15 , DOI: 10.1111/cge.13883
Khalid Al-Thihli 1, 2 , Cassian Afting 3 , Nadia Al-Hashmi 4 , Mohammed Mohammed 4 , Svenja Sliwinski 3 , Naema Al Shibli 5 , Khoula Al-Said 4 , Ghalia Al-Kasbi 1 , Khalsa Al-Kharusi 2 , Uta Merle 3 , Joachim Füllekrug 3 , Almundher Al-Maawali 1, 2
Affiliation  

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.

中文翻译:

酰基辅酶A合成酶5的缺乏与新生儿发病严重且可治疗的发育不良有关

发育迟缓 (FTT) 会导致严重的发病率,通常没有明确的病因。一个大的近亲家庭的 6 个人在新生儿期出现反复呕吐和腹泻,导致严重的 FTT。标准诊断工作未确定病因。自合子映射和全外显子组测序确定了长链脂肪酰基辅酶 A 合成酶 5 ( ACSL5)的新型遗传变异的纯合子) 在受影响的个体之间共享 (NM_203379.1:c.1358C>A:p.(Thr453Lys))。Sanger 测序证实了常染色体隐性基因型-表型分离。通过免疫荧光、蛋白质印迹和酶测定对 ACSL5 变体进行的体外功能分析表明,Thr453Lys 是一种功能丧失突变,没有任何剩余活性。ACSL5 属于脂质代谢所需的必需酶家族,已知在小鼠肠道中发挥主要作用。基于 ACSL5 在肠道长链脂肪酸代谢中的功能和胃肠道症状,受影响的个体接受全胃肠外营养或以中链甘油三酯为基础的限制长链甘油三酯的配方治疗。
更新日期:2020-11-15
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