Severe neonatal-onset PYROXD1-related myopathy with a novel homozygous missense variant: expanding the phenotypic...

PYROXD1-related myopathy is a rare genetic disorder with variable age of onset, ranging from the neonatal period to late adulthood. We report a male infant presenting with congenital hypotonia, progressive severe weakness, respiratory insufficiency, stridor, and ophthalmoplegia. Muscle biopsy revealed fibre size variation, internalized nuclei, and myofibrillary changes with sarcoplasmic disorganization. Genetic testing identified a novel homozygous missense variant in the PYROXD1 gene (NM_024854.5:c.1498G>A, p.Asp500Asn), located at the C-terminal end, affecting the final amino acid before the stop codon. Yeast complementation assays show that transfected yeast express comparable levels of both wild-type and Asp500Asn PYROXD1. However, the Asp500Asn variant cannot protect redox-sensitive cells from oxidative stress as wild-type PYROXD1, indicating functional impairment. This case identifies likely pathogenicity of a novel p. Asp500Asn PYROXD1 missense substitution and highlights new features, including vocal cord paralysis and ophthalmoplegia, thereby expanding the known phenotype of neonatal-onset PYROXD1-related myopathy caused by this variant.