Pleuroparenchymal fibroelastosis in a monogenic mitochondrial DNA depletion syndrome.

DGUOK

Deoxyguanosine kinase (DGUOK) deficiency with mitochondrial DNA depletion; mitochondrial abnormalities and a nuclear DNA damage response signature in aberrant basaloid epithelial cells

Bi-allelic DGUOK variants cause a mitochondrial DNA depletion syndrome mainly affecting infants, with severe hepatic and neurological disease, and no pulmonary phenotype had been reported. This study describes nine patients aged 5-36 years, all carrying bi-allelic pathogenic DGUOK variants, including an unreported intronic alteration in seven, presenting with pleuroparenchymal fibroelastosis (PPFE) with progressive dyspnoea, weight loss and, in some, pneumothorax. Chest CT and lung biopsies showed PPFE features, and single-nucleus RNA sequencing of lung tissue from four children identified aberrant basaloid cells at the fibrotic edge with a nuclear DNA damage response signature. Ultrastructural analysis confirmed mitochondrial abnormalities in alveolar type 2 and aberrant basaloid cells.

Synthesis written by Geno'X. For the full original abstract, please refer to the source publication.

The clinical message is clear: in unexplained PPFE in a child or young adult, DGUOK deficiency and other hereditary mitochondrial disorders should be considered. The intronic alteration shared by seven patients deserves attention, as it can escape exon-centred filtering; the abstract gives neither its position nor evidence of its effect. Quantifying mitochondrial DNA from genome sequencing data is an interesting methodological contribution.

Analysis by Dr Thibaut Benquey