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Lenz, D.* ; Stahl, M.* ; Seidl, E.* ; Schöndorf, D.* ; Brennenstuhl, H.* ; Gesenhues, F.* ; Heinzmann, T.* ; Longerich, T.* ; Mendes, M.I.* ; Prokisch, H. ; Salomons, G.S.* ; Schön, C.* ; Smith, D.E.C.* ; Sommerburg, O.* ; Wagner, M. ; Westhoff, J.H.* ; Reiter, K.* ; Staufner, C.* ; Griese, M.*

Rescue of respiratory failure in pulmonary alveolar proteinosis due to pathogenic MARS1 variants.

Pediatr. Pulmonol. 55, 3057-3066 (2020)
Verlagsversion Forschungsdaten DOI PMC
Open Access Hybrid
Creative Commons Lizenzvertrag
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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Publikationstyp Artikel: Journalartikel
Dokumenttyp Wissenschaftlicher Artikel
Schlagwörter Interstitial Lung And Liver Disease ; Mars1 ; Methionine ; Pulmonary Alveolar Proteinosis ; Whole Lung Lavage; Mutations; Disease; Onset
Sprache englisch
Veröffentlichungsjahr 2020
HGF-Berichtsjahr 2020
ISSN (print) / ISBN 8755-6863
e-ISSN 1099-0496
Zeitschrift Pediatric Pulmonology
Quellenangaben Band: 55, Heft: 11, Seiten: 3057-3066 Artikelnummer: , Supplement: ,
Verlag Wiley
Verlagsort 111 River St, Hoboken 07030-5774, Nj Usa
Begutachtungsstatus Peer reviewed
Institut(e) Institute of Human Genetics (IHG)
Institute of Neurogenomics (ING)
POF Topic(s) 30501 - Systemic Analysis of Genetic and Environmental Factors that Impact Health
30205 - Bioengineering and Digital Health
Forschungsfeld(er) Genetics and Epidemiology
PSP-Element(e) G-500700-001
G-503200-001
Förderungen Dietmar Hopp Stiftung
DOI 10.1002/ppul.25031
WOS ID WOS:000566577400001
Scopus ID 85090311851
PubMed ID 32833345
Erfassungsdatum 2020-10-20
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