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Glycogen storage disease type V: a still under-recognized condition lacking definitive genotype-phenotype correlates

Pediatric Research (2024)Cite this article

Glycogen storage disease type V (GSDV, MIM #232600) is an autosomal recessive metabolic myopathy characterized by episodic exercise intolerance, cramps, and myalgias. GSDV is caused by biallelic pathogenic variants in the PYGM gene, encoding for a glycogen phosphorylase that breaks glucose from glycogen in the muscle. The common clinical picture is a mild, pure myopathy, yet a proportion of patients develop a more severe phenotype, characterized by fixed muscle weakness mainly involving proximal muscles (25% of patients), and episodes of myoglobinuria potentially leading to acute renal failure (40–50% of patients in different series).1,2

The common nonsense variant c.148C > T (p.Arg50*), either in homozygosity or compound heterozygosity, is detected in up to 60% of Caucasian patients.2 In this issue of Pediatric Research, Da Silva et al. retrospectively recruited 28 individuals with GDSV (including both adult and pediatric cases) from a single Center in Portugal; of them, 22 were diagnosed by genetic testing, and six by detection of enzyme deficiency on muscle biopsy.3 Of note, as many as 25% of these patients had fixed muscle weakness at the time of diagnosis, and the majority had a long history of persistently high creatine kinase levels (>1000 U/l) in-between attacks. Late diagnosis was common, even in patients experiencing more severe phenotypes, confirming the difficulties in reaching a timely diagnosis in rare diseases, especially those characterized by pure muscle phenotypes and episodic, rather than persistent, manifestations. In GSDV, such delay appears to be particularly prolonged (up to late adulthood), especially in those patients who never develop myoglobinuria or in those with lower CK between attacks. In the study by Silva et al., at the time of diagnosis, all patients reported the childhood onset of non-specific symptoms such as chronic fatigue, cramps, myalgias, but also the occurrence of unique manifestations that would deserve more attention, such as the pathognomonic “second wind” phenomenon.

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Funding

Research in the Valente Lab is supported by the Italian Ministry of Health (Ricerca Corrente 2023-2024).

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Authors and Affiliations

  1. Neuromuscular Unit, IRCCS Fondazione Mondino, Pavia, Italy

    Sabrina Ravaglia

  2. Neurogenetics Research Center, IRCCS Fondazione Mondino, Pavia, Italy

    Simone Gana & Enza Maria Valente

  3. Department of Molecular Medicine, University of Pavia, Pavia, Italy

    Enza Maria Valente

Authors
  1. Sabrina Ravaglia
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  2. Simone Gana
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Contributions

S.R.: drafting of the commentary; analysis and interpretation of literature data, with focus on clinical classification and scores; S.G., E.M.V.: revising the commentary critically, focusing on interpretation of genetic data, and genotype–phenotype correlations; E.M.V.: final approval of the version to be published.

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Correspondence to Sabrina Ravaglia.

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Ravaglia, S., Gana, S. & Valente, E.M. Glycogen storage disease type V: a still under-recognized condition lacking definitive genotype-phenotype correlates. Pediatr Res (2024). https://doi.org/10.1038/s41390-024-03149-9

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