Successful Lung Transplantation for Genetic Pulmonary Alveolar Proteinosis Caused by Methionyl-TRNA Synthetase (MARS) Mutation: 2 Cases.

Among the rare genetic causes of pulmonary alveolar proteinosis (PAP), some have been evidenced to be linked to methionyl-tRNA synthetase (MARS) mutation. Lung transplantation (LTx) can be offer in case of secondary PAP, but it is admitted that underlying genetic PAP should be ruled out to prevent the recurrence of the disease. Nevertheless, recent investigations have evidenced the defective methionyl-tRNA synthetase (MetRS) activity in MARS-related PAP, and further, its correction with methionine supplementation. Because of significant clinical and imaging pulmonary improvement under methionine supplementation in non-transplanted affected patients, LTx was proposed to 2 patients with life-threatening end-stage MARS-related PAP, associated to an anticipated methionine supplementation following LTx. CASE 1 A 21 years old female underwent a bilateral-LTx in July 2019 for an end-stage PAP. A bridge to Tx had to be performed with ECMO. CASE 2 A 32 years old female underwent a bilateral-LTx in June 2021 for an end-stage PAP associated lung fibrosis, despite methionine supplementation started in December 2019. For both: (i) Diagnosis of a biallelic missense mutation in MARS was performed previously; (ii) Post-operative course was uneventful, with satisfactory graft function at 1095 POD and 455 POD, respectively; (ii) Methionine supplementation was administered each day post-LTx without side effects, (iii) At last follow-up, no PAP recurrence was observed in CT-scan (Figure), and patients had stable lung function. Our 2 LTx cases suggest the feasibility of LTx in MARS-related PAP under methionine supplementation. It suggests that the correction of MetRS activity under methionine supplementation allows functioning alveolar macrophage (AM) in a scenario of replacement of AM from donor by recipient origin. Nevertheless, other scenarios involving inflammatory or cholesterol homeostasis pathways cannot be ruled out. [ABSTRACT FROM AUTHOR]