Submission Details

PYROXD1 was first reported in relation to autosomal recessive myofibrillar myopathy 8 in 2016 (O'Grady GL, et al., 2016, PMID: 27745833). At least 7 unique variants (including missense, frameshift, and intronic) have been reported in humans. Evidence supporting this gene-disease relationship includes case-level data and experimental data. Variants in this gene have been reported in at least 12 probands in four publications (PMIDs: 27745833, 31455395, 30345904, 30515627). Variants in this gene segregated with disease in six additional family members. This gene-disease relationship is supported by a Zebrafish knockdown model which is rescued by expression of human PYROXD1 (PMID: 27745833). Of note, this gene has been implicated in 12 families to date with a progressive course of disease and a predominant involvement of upper and lower limb muscles, however some exhibit a LGMD-like phenotype with childhood or adulthood disease onset while others are affected at birth, or in infancy, and manifest a more severe and complex clinical picture including scoliosis, nasal speech, joint hypermobility, contractures, rigid spine, pectus excavatum, and anomalies of the feet and hands. Overall and in view of the histological characteristics on biopsies as cores, central nuclei, and sarcoplasmic aggregates, PYROXD1-related myopathy can be considered as mixture of core myopathy, centronuclear myopathy, and myofibrillar myopathy which here have all been lumped into one disease entity. In summary, PYROXD1 is definitively associated with autosomal recessive myofibrillar myopathy 8.