Variants in the oxidoreductase PYROXD1 have recently been identified as a cause of an ultra-rare myopathy, with ~25 patients currently diagnosed worldwide. Our group initially described nine individuals with variants in PYROXD1 and a congenital onset myopathy with global muscle weakness, respiratory difficulties and nasopharyngeal speech. We now describe an expanding clinical phenotype for PYROXD1 myopathy including joint hypermobility, connective tissue involvement and myasthenic features.
PYROXD1 expression is essential for cell and animal life, but its exact function remains unclear. Our studies are focused on determining the cellular role of PYROXD1, which is ubiquitously expressed, but appears to have a specialised role in nerve and muscle cells.
We have created an inducible PYROXD1 knock out mouse line to study the acute loss of PYROXD1 protein, and a mouse line bearing the recurrent N155S patient variant to more accurately model the human myopathy. Agnostic proteomics revealed that acute loss of PYROXD1 has a significant effect on multiple components of the mitochondrial respiratory chain complex. Our studies are now focused on determining the phenotype of the N155S mouse model and whether it is a good model for evaluating the efficacy of any future therapeutic interventions.