Journal
PEDIATRIC PULMONOLOGY
Volume 55, Issue 11, Pages 3057-3066Publisher
WILEY
DOI: 10.1002/ppul.25031
Keywords
interstitial lung and liver disease; MARS1; methionine; pulmonary alveolar proteinosis; whole lung lavage
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Funding
- Dietmar Hopp Stiftung [23011235]
- GENOMIT [01GM1603]
- Deutsche Leberstiftung [S163/10052/2018]
- European Cooperation in Science and Technology [16125 ENTeR-chILD]
- Deutsche Forschungsgemeinschaft [GR 970/9-1]
- E-Rare-3 [01GM1702A]
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Background Pulmonary alveolar proteinosis (PAP) is a heterogeneous condition with more than 100 different underlying disorders that need to be differentiated to target therapeutic options, which are generally limited. Methods The clinical course of two brothers with pathogenic variants in the methionyl-tRNA synthetase (MARS)1gene was compared to previously published patients. Functional studies in patient-derived fibroblasts were performed and therapeutic options evaluated. Results The younger brother was diagnosed with PAP at the age of 1 year. Exome sequencing revealed the homozygousMARS1variant p.(Arg598Cys), leading to interstitial lung and liver disease (ILLD). At 2 years of age, following surgery hypoglycemia was detected, the pulmonary condition deteriorated, and the patient developed multiorgan failure. Six therapeutic whole lung lavages (WLL) were necessary to improve respiratory insufficiency. Methionine supplementation was started and a high protein diet ensured, leading to complete respiratory recovery. The older brother, homozygous for the sameMARS1variant, had a long-known distinct eating preference of methionine-rich food and showed a less severe clinical phenotype. Decreased aminoacylation activity confirmed the pathogenicity of p.(Arg598Cys) in vitro. In agreement with our review of currently published ILLD patients, the presence of hepatopathy, developmental delay, muscular hypotonia, and anemia support the multisystemic character of the disease. Conclusions Catabolic events can provoke a severe deterioration of the pulmonary situation in ILLD with a need for repetitive WLL. Although the precise role of oral methionine supplementation and high protein intake are unknown, we observed an apparent treatment benefit, which needs to be evaluated systematically in controlled trials.
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