Pulmonary alveolar proteinosis related to mutations in the methionine tRNA synthetase (MARS1) gene is a severe, early-onset disease that results in death before the age of 2 years in one-third of patients. It is associated with a liver disease, growth failure and systemic inflammation. As methionine supplementation in yeast models restored normal enzymatic activity of the synthetase, we studied the tolerance, safety and efficacy of daily oral methionine supplementation in patients with severe and early disease.

Four patients received methionine supplementation and were followed for respiratory, hepatic, growth and inflammation-related outcomes. Their course was compared to those of historical controls. Reactive oxygen species production by patient monocytes before and after methionine supplementation was also studied.

Methionine supplementation was associated with respiratory improvement, clearance of the extracellular lipoproteinaceous material and discontinuation of whole-lung lavage in all patients. The three patients who required oxygen or noninvasive ventilation could be weaned off within 60 days. In addition, liver dysfunction, inflammation and growth delay improved or resolved. At a cellular level, methionine supplementation normalised the production of reactive oxygen species by peripheral monocytes.

Methionine supplementation was associated with important improvements in children with pulmonary alveolar proteinosis related to mutations in the MARS1 gene. This study paves the way for similar strategies for other tRNA synthetase deficiencies.

与蛋氨酸 tRNA 合成酶 ( MARS1 ) 基因突变相关的肺泡蛋白沉积症是一种严重的早发性疾病，三分之一的患者会在 2 岁前死亡。它与肝脏疾病、生长障碍和全身炎症有关。由于酵母模型中补充蛋氨酸恢复了合成酶的正常酶活性，我们研究了严重和早期疾病患者每日口服蛋氨酸补充的耐受性、安全性和有效性。

四名患者接受了蛋氨酸补充剂，并对其呼吸、肝脏、生长和炎症相关结果进行了随访。他们的课程与历史对照的课程进行了比较。还研究了补充蛋氨酸前后患者单核细胞产生的活性氧。

在所有患者中，补充蛋氨酸与呼吸改善、细胞外脂蛋白物质的清除和全肺灌洗的中断有关。三名需要吸氧或无创通气的患者可在 60 天内断奶。此外，肝功能障碍、炎症和生长迟缓得到改善或解决。在细胞水平上，补充蛋氨酸使外周单核细胞产生的活性氧物质正常化。

补充蛋氨酸与MARS1基因突变相关的肺泡蛋白沉积症儿童的重要改善有关。这项研究为其他 tRNA 合成酶缺陷的类似策略铺平了道路。