A Diagnostic Conundrum: Atypical McArdle Disease Mimic With Heterozygous PYGM Mutation and Cytochrome C Oxidase (COX)-Negative Fibers

McArdle disease is inherited in an autosomal recessive pattern, with classical disease manifesting with biallelic pathogenic variants in the PYGM (myophosphorylase) gene. Here, we present a case of a 77-year-old man with a paraspinal myopathy and head drop with cytochrome c oxidase (COX)-negative fibers who is a heterozygous carrier of a pathogenic c.148C>T (p.Arg50*) nonsense variant in PYGM as identified on a comprehensive glycogen storage disease gene panel through Mayo Clinic Laboratories. Two findings complicate a confident diagnosis of classical McArdle disease. They are explicitly addressed: a single (heterozygous) pathogenic allele for an autosomal recessive disorder, and COX-negative fibers in the absence of frank glycogen accumulation on periodic acid-Schiff staining. The case is presented as suggestive of an atypical metabolic-mitochondrial phenotype, and we discuss the diagnostic limitations of a blood-based targeted gene panel, as well as further testing, including muscle RNA sequencing and tissue-specific mitochondrial DNA analysis, that could resolve a potentially undetected second variant or a tissue-restricted mitochondrial etiology.