PHKA1-associated phosphorylase kinase deficiency: a monogenic disorder of exercise intolerance and myalgia.

Muscle phosphorylase kinase deficiency results from X-linked pathogenic variants in PHKA1, leading to glycogen storage disease (GSD) type IXα1 (also known as GSD IXd). As part of an international collaboration, we describe 14 previously unreported cases (12 males, 2 females; ClinicalTrials.gov NCT04454216, registered 2020-07-01). We compared our cohort to 18 cases previously reported and to an additional 16 cases identified through the National Institutes of Health All of Us Research Program. The clinical presentations highlight the predominance of myopathic symptoms on exertion and emphasize the variability in age of onset. Examination of muscle biopsies revealed glycogen accumulation and an increase in lipid droplets indicative of mitochondrial dysfunction and mitophagy. We encourage clinicians to maintain a high level of suspicion even in the setting of normal blood creatine kinase levels. Comprehensive longitudinal natural history studies remain necessary to improve disease detection, inform management guidelines, and provide a foundation for therapeutic development.