Background Pleuroparenchymal fibroelastosis (PPFE) is a rare, fibrotic lung disease with poor prognosis, usually affecting adults which most commonly occurs idiopathically. Biallelic pathogenic variants in DGUOK cause mitochondrial DNA (mtDNA) depletion syndrome, predominantly affecting infants with severe hepatic and neurological symptoms. Detailed description of pulmonary manifestations with late-onset presentation have not been reported.

Methods We describe nine patients with PPFE and DGUOK-associated mitochondriopathy. Clinical, radiological, histopathological, and genetic data were systematically collected from all patients. Functional studies, single nucleus RNA sequencing (snRNAseq), immunofluorescence staining, transmission electron microscopy and respiratory chain enzyme activity assays were conducted on patient-derived fibroblasts, muscle or lung tissues. mtDNA content quantification was performed on whole genome sequencing (WGS) data.

Results All patients (ages 5–36) presented with progressive dyspnea, weight loss and some with spontaneous pneumothoraces. Chest computed tomography and lung biopsies showed features of PPFE. Biallelic pathogenic DGUOK variants were identified in all patients, seven of them carry an unreported intronic variant leading to mtDNA depletion. snRNAseq of lung tissue from four pediatric patients identified Aberrant Basaloid cells and intermediate cells as their precursor localized at the fibrotic edge. Mitochondrial alterations were identified by electron microscopy.

Conclusion PPFE in children and young adults is associated with DGUOK-related mitochondriopathy. For the first time, we demonstrate Aberrant Basaloid cells in pediatric fibrotic lung tissue. Since pulmonary involvement may be underrecognized or misinterpreted and the clinical presentation may not always be typical of a mitochondriopathy, we recommend genetic testing in all patients with PPFE of unknown origin.

JCS reports reports consulting fees and honoraria from Boehringer Ingelheim, Merck/MSD, GSK, AOP Health, and Vicore Pharma; support for meetings from Boehringer Ingelheim; and he has IP on basal cell-targeted therapies in IPF. PM reports personal honoraria for a lecture from Boehringer Ingelheim, Germany. AH reports consulting fees from Alexion, BMS, Galapagos, Johnson & Johnson, Kyverna, Merck Serono, and Sanofi; honoraria for lectures or other educational activities from AbbVie, Medscape, Merck Serono, Pfizer, Roche, and Sanofi; and participation on boards for Kyverna, BMS, and Alexion and engagements with in DGN (German Society of Neurology), DMSG (German Multiple Sclerosis Society), and DGKN (German Society for Clinical Neurophysiology. MG reports institutional funding from the Deutsche Forschungsgemeinschaft and Boehringer Ingelheim, Germany, and participation on Advisory board for Boehringer Ingelheim (InpedILD study), with receipt of honoraria. TH reports a grant from the Peter-Max-Mueller Stiftung; speaking fees from ARGENX and Alexion; and travel support from Merck (Charcot Meeting). JR reports honoraria from Boehringer Ingelheim, AstraZeneca, and CSL Behring. KP provided support for Sanger sequencing of cDNA. NS reports consulting fees and honoraria for lectures from Boehringer Ingelheim and Infectopharm, participation on Advisory board for Boehringer Ingelheim (InpedILD study); and serves as President of the German-speaking Society for Pediatric Pneumology (GPP). NJ reports honoraria from Orphalan and Sanofi; travel support from ESPGHAN and ELITA; advisory board memberships in ELITA and ERN Rare Liver; and engagements with Hepatology Committee ESPGHAN, RARE Liver ERN, ERN Transplantchild, and ELTR/ELITA. DR reports grants/contracts from RACOON-RESCUE and RACOON-INCLUDED, funded by the Federal Ministry of Research, Technology, and Space. BS reports institutional funding and research collaboration with GlaxoSmithKline; consulting fees from Boehringer Ingelheim, AstraZeneca, and GlaxoSmithKline; honoraria for lectures from Boehringer Ingelheim, AstraZeneca, and GlaxoSmithKline; and travel support from Boehringer Ingelheim. All other authors report no conflicts of interest.

JCS is supported by the Else Kroener-Fresenius-Stiftung (2023_EKCS.18) and the German Center for Lung Research (FKZ 82DZL002C1 & FKZ 82DZLT82C1). PM is supported by the Clinician Scientist Program TITUS, funded by Hannover Medical School and the Biomedical Research in Endstage and Obstructive Lung Disease Hannover (BREATH, member of the German Center for Lung Research).

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