Hoytema van Konijnenburg Eva M M, Rohof Joline, Kok Gautam, van Hasselt Peter M, van Karnebeek Clara D, Muffels Irena J J, Fuchs Sabine A
Department of Metabolic Diseases, Wilhelmina Children's Hospital University Medical Centre Utrecht, the Netherlands.
On Behalf of United for Metabolic Diseases, Amsterdam, the Netherlands.
J Inherit Metab Dis. 2025 Mar;48(2):e70017. doi: 10.1002/jimd.70017.
Aminoacyl-transfer RNA (tRNA) synthetases (ARSs) are key enzymes for protein translation. The number of identified patients with recessive ARS1 deficiencies is rapidly increasing. Initially, only supportive care was available, but in recent years beneficial effects of targeted amino acid supplementation have been described. To allow early treatment and prevention of symptoms, rapid recognition is necessary, as well as insight into the natural history to evaluate treatment effects. We performed a scoping literature search for clinical characteristics and treatment effects of patients with ARS1 deficiencies. Symptoms were matched to Human Phenotype Ontology terms. We identified 438 patients with 20 different ARS1 deficiencies. Overall mortality was 22%. Neurological symptoms were most prevalent across all ARS1 deficiencies (in 87% of patients), including neurodevelopmental disorder (79%), microcephaly (50%) and seizures (46%). Growth issues and ophthalmological symptoms were also prevalent in many ARS1 deficiencies. Two distinct phenotypical clusters were seen: one with multisystemic disease including liver- and lung disease and another with a predominantly neurological phenotype. Supplementation with cognate amino acids was described in 21 patients, with beneficial effects (e.g., improvements in growth, development, liver and lung disease) in the majority. Treatment did not alleviate the most severe phenotypes. Specific symptoms relate to (a cluster of) specific ARS1 deficiencies; the mechanism is not yet understood. Multi-organ involvement should trigger inclusion of ARS1 genes in the diagnostic work-up. Treatment with cognate amino acids is promising, but it remains challenging to distinguish treatment effects from natural history. Synopsis: Treatment with cognate amino acids in ARS1 deficiencies is promising, but it remains challenging to distinguish treatment effects from natural history.
氨酰基转移核糖核酸（tRNA）合成酶（ARSs）是蛋白质翻译的关键酶。已确诊的隐性ARS1缺陷患者数量正在迅速增加。最初，只有支持性治疗方法，但近年来已描述了靶向氨基酸补充的有益效果。为了实现早期治疗和症状预防，快速识别以及深入了解疾病自然史以评估治疗效果是必要的。我们对ARS1缺陷患者的临床特征和治疗效果进行了一项范围综述性文献检索。将症状与人类表型本体术语进行匹配。我们确定了438例患有20种不同ARS1缺陷的患者。总体死亡率为22%。在所有ARS1缺陷类型中，神经症状最为普遍（87%的患者出现），包括神经发育障碍（79%）、小头畸形（50%）和癫痫发作（46%）。生长问题和眼科症状在许多ARS1缺陷类型中也很常见。观察到两个不同的表型集群：一个是多系统疾病，包括肝脏和肺部疾病，另一个主要是神经表型。21例患者接受了同源氨基酸补充治疗，大多数患者有有益效果（如生长、发育、肝脏和肺部疾病改善）。治疗并未缓解最严重的表型。特定症状与特定的ARS1缺陷（一组）相关；其机制尚不清楚。多器官受累应促使在诊断检查中纳入ARS1基因检测。同源氨基酸治疗前景良好，但区分治疗效果与疾病自然史仍具有挑战性。综述：ARS1缺陷的同源氨基酸治疗前景良好，但区分治疗效果与疾病自然史仍具有挑战性。
