Our objective in this review article is to present a clinical case of a patient with antisynthetase syndrome (ASyS) and provide an overview of the pathogenesis, classification criteria, antibody profiles, clinical features, and current knowledge of treatment options, focusing on interstitial lung disease (ILD). ASyS is an uncommon autoimmune disease with a heterogenous clinical presentation characterized by the presence of autoantibodies against an aminoacyl-tRNA synthetase and manifested by myositis, fever, inflammatory arthritis, Raynaud\'s phenomenon, mechanics hands, and ILD. ASyS-associated ILD (ASyS-ILD) is the most serious complication of ASyS, which may evolve to rapidly progressive ILD; therefore, it often requires thorough clinical and radiologic evaluation including recognition of a specific clinical phenotype associated with the antisynthetase antibodies (ASAbs) to guide therapeutic interventions.

Aminoacyl-tRNA synthetases (ARSs) aminoacylate tRNA molecules with their cognate amino acid, enabling information transmission and providing substrates for protein biosynthesis. They also take part in nontranslational functions, mediated by the presence of other proteins domains. Mutations in ARS genes have been described as responsive to numerous factors, including neurological, autoimmune, and oncological. Variants of the ARS genes, both in heterozygosity and homozygosity, have been reported to be responsible for different pathological pictures in humankind. We present the case of a patient referred in infancy for failure to thrive and acquired microcephaly (head circumference: -5 SD). During follow-up we highlighted: dysphagia (which became increasingly severe until it became incompatible with oral feeding, with gastrostomy implantation, resulting in resolution of feeding difficulties), strabismus, hypotonia. NCV (Nerve Conduction Velocity) showed four limbs neuropathy, neurophysiological examination performed at 2 years of age mainly sensory and demyelinating. Exome sequencing (ES) was performed, detecting two novel compound heterozygous variants in the NARS1 gene (OMIM *108410): NM_004539:c.[662 A > G]; [1155dup], p.[(Asn221Ser)]; [(Arg386Thrfs*19)], inherited from mother and father respectively. In this article, we would like to focus on the presence of progressive dysphagia and severe neurodevelopmental disorder, associated with two novel variants in the NARS1 gene.

BACKGROUND: Hypomyelinating leukodystrophy-9 (HLD-9) is caused by biallelic pathogenic variants in RARS1, which codes for the cytoplasmic tRNA synthetase for arginine (ArgRS). This study aims to evaluate the clinical, neuroradiological, and genetic characteristics of patients with RARS1-related disease and determine probable genotype-phenotype relationships.
METHODS: We identified three patients with RARS1 homozygous pathogenic variants. Furthermore, we performed a comprehensive review of the literature.
RESULTS: Homozygous variants of RARS1 (c.2T>C (p.Met1Thr)) were identified in three patients with HLD-9. Clinical symptoms were severe in all patients. Following the literature review, thirty HLD-9 cases from eight studies were found. The 33 patients\' main symptoms were hypomyelination, language delay, and intellectual disability or developmental delay. The mean age of onset for HLD9 in the group of 33 patients with a known age of onset was 5.8 months (SD = 8.1). The interquartile range of age of onset was 0-10 months. Of the 25 variants identified, c.5A>G (p.Asp2Gly) was identified in 11 patients.
CONCLUSIONS: Pathogenic variants in RARS1 decrease ArgRS activity and cause a wide range of symptoms, from severe, early onset epileptic encephalopathy with brain atrophy to a mild condition with relatively maintained myelination. These symptoms include the classic hypomyelination presentation with nystagmus and spasticity. Furthermore, the pathogenicity of the variation c.2T>C (p.Met1Thr) has been shown.

暂无摘要。

Aminoacyl-tRNA synthetases (ARSs) are indispensable enzymes for protein biosynthesis in cells. The phenylalanyl-tRNA synthetase (FARS1) located in cytoplasm which consists of two FARS alpha subunits (FARSA) and two FARS beta subunits (FARSB). Autosomal recessive inheritance of pathogenic variants of FARSA or FARSB can result in defective FARS1 which are characterized by interstitial lung disease, liver disease, brain abnormalities, facial dysmorphism and growth restriction.
Exome sequencing was used to detect the candidate variants. The in silico prediction and expressional level analysis were performed to evaluate the pathogenicity of the variations. Additionally, we presented the patient\'s detailed clinical information and compared the clinical feature with other previously reported patients with FARSA-deficiency.
We identified compound heterozygous rare missense variants (c.1172 T > C/ p.Leu391Pro and c.1211G > A/ p.Arg404His) in FARSA gene in a Chinese male patient. The protein structure prediction and the analysis of levels of FARSA and FARSB subunits indicated both variants pathogenic. Clinical feature review indicated inflammatory symptoms in young infants may be an additional key feature. Thyroid dysfunction should be considered as a phenotype with variable penetrance.
Our results expanded the current phenotypic and genetic spectrum of FARSA-deficiency.

The association of hypogonadism and cerebellar ataxia was first recognized in 1908 by Gordon Holmes. Since the seminal description, several heterogeneous phenotypes have been reported, differing for age at onset, associated features, and gonadotropins levels. In the last decade, the genetic bases of these disorders are being progressively uncovered. Here, we review the diseases associating ataxia and hypogonadism and the corresponding causative genes. In the first part of this study, we focus on clinical syndromes and genes (RNF216, STUB1, PNPLA6, AARS2, SIL1, SETX) predominantly associated with ataxia and hypogonadism as cardinal features. In the second part, we mention clinical syndromes and genes (POLR3A, CLPP, ERAL1, HARS, HSD17B4, LARS2, TWNK, POLG, ATM, WFS1, PMM2, FMR1) linked to complex phenotypes that include, among other features, ataxia and hypogonadism. We propose a diagnostic algorithm for patients with ataxia and hypogonadism, and we discuss the possible common etiopathogenetic mechanisms.

Translation of RNA to protein is a key feature of cellular life. The fidelity of this process mainly depends on the availability of correctly charged tRNAs. Different domains of tRNA synthetase (aaRS) maintain translation quality by ensuring the proper attachment of particular amino acid with respective tRNA, thus it establishes the rule of genetic code. However occasional errors by aaRS generate mischarged tRNAs, which can become lethal to the cells. Accurate protein synthesis necessitates hydrolysis of mischarged tRNAs. Various cis and trans-editing proteins are identified which recognize these mischarged products and correct them by hydrolysis. Trans-editing proteins are homologs of cis-editing domains of aaRS. The trans-editing proteins work in close association with aaRS, Ef-Tu, and ribosome to prevent global mistranslation and ensures correct charging of tRNA. In this review, we discuss the major trans-editing proteins and compared them with their cis-editing counterparts. We also discuss their structural features, biochemical activity and role in maintaining cellular protein homeostasis.

Aminoacyl-tRNA synthetases (aaRSs) are crucial for the correct assembly of amino acids to cognate tRNA to maintain the fidelity of proteosynthesis. AaRSs have become a hot target in antimicrobial research. Three aaRS inhibitors are already in clinical practice; antibacterial mupirocin inhibits the synthetic site of isoleucyl-tRNA synthetase, antifungal tavaborole inhibits the editing site of leucyl-tRNA synthetase, and antiprotozoal halofuginone inhibits proline-tRNA synthetase. According to the World Health Organization, tuberculosis globally remains the leading cause of death from a single infectious agent. The rising incidence of multidrug-resistant tuberculosis is alarming and urges the search for new antimycobacterial compounds, preferably with yet unexploited mechanism of action. In this literature review, we have covered the up-to-date state in the field of inhibitors of mycobacterial aaRSs. The most studied aaRS in mycobacteria is LeuRS with at least four structural types of inhibitors, followed by TyrRS and AspRS. Inhibitors of MetRS, LysRS, and PheRS were addressed in a single significant study each. In many cases, the enzyme inhibition activity translated into micromolar or submicromolar inhibition of growth of mycobacteria. The most promising aaRS inhibitor as an antimycobacterial compound is GSK656 (compound 8), the only aaRS inhibitor in clinical trials (Phase IIa) for systemic use against tuberculosis. GSK656 is orally available and shares the oxaborole tRNA-trapping mechanism of action with antifungal tavaborole.

Objective: To investigate the clinical characteristics, treatment and prognosis of QARS1 gene related glutaminyl-tRNA synthetase deficiency. Methods: To summarize and analyze the clinical manifestations, imaging, laboratory examination, genetic variant characteristics and treatment of three patients from the Fujian Medical University Affiliated Union Hospital, the 900th Hospital of People\'s Liberation Army, the First Medical Center of People\'s Liberation Army General Hsopital carrying compound heterozygous variations in QARS1 gene with a long-term follow-up in China. A literature search was conducted using Wanfang, Weipu, China National Knowledge Infrastructure (CNKI) and Pubmed databases with the keywords \"QARS\", \"QARS1\" and \"glutaminyl-tRNA Synthetase\"(up to December 2019). Results: Case 1, a female 53 days of age, was admitted to the Fujian Medical University Affiliated Union Hospital for treatment because of the complaint of repetitive seizures for one month after birth and fever for one day. The seizure occurred within the first 2 hours of life with multiple forms and often had a status as persisted from hours to days. The seizures were resistant to many anti-epilepsy drugs (AED) and ketogenic diet but later controlled by clonazepam. However, she died at the age of seven years. Case 2 (younger brother of case 1), a one-hour-old boy, was hospitalized because of seizures after birth for 1 hour. Intrauterine growth retardation was discovered during late-pregnancy. The boy presented seizures and microcephaly immediately after birth, and his epilepsy was pharmacoresisitant. Case 3, an 8-month-old girl, was admitted due to recurrent convulsions for nearly two months. The girl had mild developmental retardation and hypotonia after birth. The infantile spasm was observed at her age of 6 months and disappeared under treatment with Vitamin B6, vigabatrin combined with adreno-cortico-tropic-hormone and magnesium sulfate. However, the seizure pattern turned to tonic seizures later. She was seizures free now with clobazam and zonisamide treatment. All of them manifested as a syndrome composed of severe global developmental retardation, progressive microcephaly, hypotonia from the very beginning, mild hypoproteinemia and diffuse brain atrophy. Genetic studies revealed compound heterozygous variations of QARS1 gene which were not reported previously. A review of the literature reported a total of 22 patients from 18 unrelated families all over the world. Except for 5 cases without epilepsy,all the patients shared very similar clinical manifestations as classic pentalogy. The recommended effective treatment for epilepsy has not been reported yet. Conclusions: Glutaminyl-tRNA synthetase deficiency caused by QARS1 gene variations manifested as a clinical syndrome\'s pentalogy, characterized by microcephaly, cerebral atrophy, intractable early-onset epileptic encephalopathy, global developmental retardation and severe muscle hypotonia.
目的： 探讨QRAS1基因异常导致谷氨酰胺tRNA合成酶缺陷综合征的特征、治疗及预后。 方法： 总结并分析福建医科大学附属协和医院、解放军联勤保障部队第九〇〇医院、解放军总医院第一临床医学中心3例长期随访QARS1基因复合杂合变异患儿的临床表现、影像学及实验室检查、基因变异特点及治疗情况。分别以“QARS”“QARS1”“谷氨酰胺tRNA合成酶”“Glutaminyl-tRNA synthetase”为检索词，在万方、维普、中国知网、PubMed数据库中检索建库至2019年12月已报道QRAS1基因变异家系病例并进行文献复习。 结果： 例1 女，53日龄，主因“生后反复抽搐1个月余，发热1 d”收入福建协和医院治疗，生后2 h内出现抽搐，形式多样，可持续达数小时至数天；癫痫早期多药难治，生酮饮食无效，后期氯硝西泮可显著缓解；7岁余死亡。例2（例1胞弟） 男，1小时龄，主因“生后抽搐1 h”入院，其母孕晚期发现宫内发育迟缓，患儿生后即抽搐并存在小头畸形，癫痫多药难治。例3 女，8月龄，主因“反复抽搐近2个月”就诊，生后表现为发育稍落后、肌张力低，6月龄时出现婴儿痉挛，维生素B6联合氨己烯酸、促肾上腺皮质激素、硫酸镁治疗后痉挛发作消失，但出现强直发作，现氯巴占、唑尼沙胺治疗，发作控制。3例患儿均存在严重全面发育落后、进行性加重的小头畸形、初始肌张力低下、轻度低蛋白血症、广泛性脑萎缩；均为QARS1基因复合杂合变异，变异位点均未见报道。文献检索未见国内报道，国外文献10篇，涉及18个家系22例病例，除5例无癫痫发作外，余临床均表现为经典五联征，文献无推荐有效抗癫痫治疗药物。 结论： QARS1基因异常导致谷氨酰胺tRNA合成酶缺陷可引起一组以小头畸形、脑萎缩、早发性难治性癫痫性脑病、全面性发育落后、严重肌张力低下的五联征临床症候群。.

Antisynthetase Syndrome (ASS) is a subset of idiopathic inflammatory myopathies characterised by specific clinical features such as interstitial lung disease (ILD), fever, myositis, Raynaud\'s phenomenon, cutaneous involvement and arthritis related to the presence of anti-aminoacyl-tRNA-synthetase (anti-ARS) autoantibodies. Moreover, Pulmonary arterial hypertension (PAH) is a life-threatening complication associated with connective tissue diseases mainly systemic sclerosis (SSc-PAH). It has been suggested that PAH can complicate ASS patients but little is known about the prevalence and risk factors to develop this complication. Here we report on two patients with ASS and PH. The first one represents a complete picture of ASS anti-Jo-1 positive, the second an amyophatic ASS anti-PL-12 positive. In one of our ASS-PAH patients, specific treatment lead to improvement of PAH. There are no specific recommendations on current guidelines regarding either PAH screening or treatment in ASS, but performing echocardiogram, ECG, pulmonary function test and prompt initiation of specific therapies seems to improve right heart catheterisation (RHC) parameters and survival.