Glycogen storage diseases (GSDs) result from the deficiency of enzymes involved in glycogen synthesis and breakdown into glucose. Mutations in the gene PHKA2 encoding phosphorylase kinase regulatory subunit alpha 2 have been linked to GSD type IXa. We describe a family with two adult brothers with neonatal hepatosplenomegaly and later onset of hearing loss, cognitive impairment, and cerebellar involvement. Whole-exome sequencing was performed on both subjects and revealed a shared hemizygous missense variant (c.A1561G; p.T521A) in exon 15 of PHKA2. The phenotype broadens the clinical and magnetic resonance imaging spectrum of GSD type IXa to include later onset neurological manifestations.

Background: Previous reports suggest that although a diagnostic muscle biopsycan confirm the presence of Pompe disease, the absence of a definitivebiopsy result does not rule out the diagnosis. Methods: In this study, we reviewed patients with a limb-girdle syndrome whodemonstrated nonspecific abnormalities of muscle, without evidence of theclassical changes of acid maltase deficiency. These patients were rescreenedfor Pompe disease using dried blood spot (DBS) testing. Results: Twenty-seven patients provided blood samples for the DBS test. Fourpatients underwent subsequent genetic testing. Genetic analysis demonstratedthat one patient tested positive for Pompe disease and one patient had onecopy of a pathogenic variant. Conclusions: In conclusion, the ability of a diagnostic muscle biopsy todefinitively rule out the presence of Pompe disease is limited. There is arole for a screening DBS in all patients presenting with a limb-girdlesyndrome without a clear diagnosis.