Late Breaking Abstract - DGUOK dysfunction as a monogenetic cause of pleuroparenchymal fibroelastosis with onset in childhood.

<bold>Introduction:</bold> Pleuroparenchymal fibroelastosis (PPFE) is a rare, progressive lung disease with poor prognosis, usually affecting adults and often considered idiopathic. Biallelic pathogenic variants in DGUOK cause mitochondrial DNA depletion syndromes with muscle and liver involvement. Primary pulmonary manifestations have not been described. <bold>Methods:</bold> Clinical, radiological, histopathological and genetic analysis, as well as vitro analysis on patient-derived fibroblast were performed in three DGUOK-deficient adolescents with confirmed PPFE in the absence of liver disease. <bold>Results:</bold> PPFE with chronic secondary sponateous pneumothoraces and failure to thrive was confirmed at the age of 14, 15 and 16 years by Chest-CT and histopathological examination of lung biopsies. Treatment with methylprednisolone and nintedanib was ineffective in all 3 patients. One patient required lung transplantation due to end stage lung disease at age 17. All carried the same homozygous pathogenic intronic DGUOK variant causing aberrant splicing and mitochondrial DNA depletion. Treatment of fibroblasts with antisense oligonucleotides (ASO) could restore the pathogenic effect of this variant. The effect of nucleoside supplementation in these fibroblasts is currently under investigation. <bold>Conclusion:</bold> These are the first reported cases of a monogenetic, inherited form of PPFE with onset in childhood. As PPFE might be underdiagnosed in DGUOK deficient patients, pulmonary work up is imperative. Furthermore, genetic testing should be performed in all patients with PPFE of unknown origin. ASO-treatment or nucleoside supplementation may be an effective treatment option and should be evaluated in clinical trials.