Manifesting heterozygotes in McArdle disease: a myth or a reality—role of statins

Abstract

McArdle disease is an autosomal recessive condition caused by deficiency of the PYGM gene-encoded muscle isoform of glycogen phosphorylase. Some cases of "manifesting" heterozygotes or carriers (i.e., patients who show some McArdle-like symptoms or signs despite being carriers of only one mutated PYGM allele) have been reported in the literature but there is controversy, with misdiagnosis being a possibility. The purpose of our study was to determine if there are actually "manifesting" heterozygotes of McArdle disease and, if existing, whether statin treatment can trigger such condition. Eighty-one relatives of McArdle patients (among a total of 16 different families) were studied. We determined whether they were carriers of PYGM mutations and also collected information on exercise tests (second wind and modified Wingate anaerobic test) and statin intake. We found 50 carriers and 31 non-carriers of PYGM mutations. Although we found existence of heterozygotes manifesting some exercise-related muscle problems such as exacerbated myalgia or weakness, they only accounted for 14% of the carriers and muscle symptoms were milder than those commonly reported in patients. Further, no carrier (whether reporting symptoms or not) showed the second wind phenomenon or a flat blood lactate response to maximal-intensity exercise, both of which are hallmarks of McArdle disease. On the other hand, statin myotoxicity was not associated with muscle symptom onset.

Clinical practice guidelines for glycogen storage disease V & VII (McArdle disease and Tarui disease) from an international study group

“…Some cases of 'manifesting' heterozygotes or carriersindividuals who show some symptoms characteristic of GSD V despite being carriers of only one pathogenic variant in the PYGM genehave been reported, [80][81][82][83][84][85][86] but there is controversy, with misdiagnosis being a possibility. In a recent study, 50 GSD V carriers were assessed to see whether any were actually 'manifesting' heterozygotes of GSD V [87]. Only 14% of carriers manifested some activity-related muscle problems (for example, exacerbated myalgia or weakness), and when present muscle symptoms were milder than those commonly reported in patients.…”

Defect in degradation of glycogenin‐exposed residual glycogen in lysosomes is the fundamental pathomechanism of Pompe disease

“…There are two pathways for glycogen degradation (Figure 1A), and deficiencies of glycogen debranching enzyme and glycogen phosphorylase in cytoplasmic pathway result in GSD III and GSD V, respectively [41][42][43]. Histological analysis revealed glycogen with α-amylase resistance was absent in muscle sections from patients with GSD III or GSD V, and staining for glycogenin was negative (Figure 5A,B).…”