Variants in the enzyme PYROXD1 cause a myopathy characterized by generalized muscle weakness, feeding and respiratory difficulties and nasal speech. PYROXD1 myopathy is ultra-rare with ~20 patients currently diagnosed world-wide; age of presentation and clinical severity varies from severe congenital onset to milder adult onset. The phenotypic spectrum continues to expand with new patient diagnoses and further patients are likely to be identified as PYROXD1 screening is increasingly included in diagnostic genomic services.
PYROXD1 is an oxidoreductase of unknown function that belongs to a family of enzymes known to maintain cellular redox homeostasis and keep other enzymes and signalling proteins in their active, reduced state. We are focused on identifying the pathway in which PYROXD1 acts by defining its substrate(s). Essential for cell and animal life, we propose that PYROXD1 has a non-redundant reductase activity for which no other enzyme can compensate.
We have shown that PYROXD1 is expressed ubiquitously at low levels, although patients develop a predominantly skeletal muscle phenotype. Using two mouse models – an acute conditional knock out and a model of a recurrent patient variant – we are performing agnostic omics-based screens to determine the impact of loss of PYROXD1 activity. Due to pathological and clinical similarities, we are also exploring functional links between PYROXD1 myopathy and other myopathies, such as that caused by variants in SEPN1.
Our ultimate goal is to explore therapeutic options for patients with PYROXD1 myopathy; understanding the disease mechanism will facilitate this.