DGUOK-associated mitochondrial disease linked to early-onset pleuroparenchymal fibroelastosis in nine patients

Pleuroparenchymal fibroelastosis (PPFE) is a rare fibrotic lung disease that mainly affects adults and is often idiopathic. An observational case series in the European Respiratory Journal describes nine patients with PPFE and DGUOK-associated mitochondrial disease. Biallelic pathogenic variants in DGUOK typically cause mitochondrial DNA depletion syndrome with severe hepatic and neurological disease in infancy. Investigators systematically collected clinical, imaging, histopathological and genetic data and performed functional and molecular analyses of patient-derived tissues.

The patients were aged 5–36 years, and all carried biallelic pathogenic DGUOK variants; seven had a previously unreported intronic alteration. All presented with progressive dyspnea and weight loss, and some experienced pneumothoraces. Computed tomography and lung biopsies showed features of PPFE. Single-nucleus RNA sequencing of lung tissue from four pediatric patients identified aberrant basaloid cells at the fibrotic edge and a nuclear DNA damage response signature. Ultrastructural analysis demonstrated mitochondrial abnormalities in alveolar type 2 and aberrant basaloid cells.

The findings support a possible contribution of mitochondrial dysfunction to early-onset PPFE. The authors suggest considering DGUOK deficiency and other hereditary mitochondrial disorders in children and young adults with PPFE of unknown origin. This small descriptive series does not establish the frequency of these disorders among patients with PPFE or inform treatment effectiveness. Only the abstract was available for assessment.