title: Allele copy number and underlying pathology are associated with subclinical severity in equine type 1 polysaccharide storage myopathy (PSSM1).
abstract: Equine type 1 polysaccharide storage myopathy (PSSM1), a common glycogenosis associated with an R309H founder mutation in the glycogen synthase 1 gene (GYS1), shares pathological features with several human myopathies. In common with related human disorders, the pathogenesis remains unclear in particular, the marked phenotypic variability between affected animals. Given that affected animals accumulate glycogen and alpha-crystalline polysaccharide within their muscles, it is possible that physical disruption associated with the presence of this material could exacerbate the phenotype. The aim of this study was to compare the histopathological changes in horses with PSSM1, and specifically, to investigate the hypothesis that the severity of underlying pathology, (e.g. vacuolation and inclusion formation) would (1) be higher in homozygotes than heterozygotes and (2) correlate with clinical severity. Resting and post-exercise plasma creatine kinase (CK) and aspartate aminotransferase (AST) enzyme activity measurements and muscle pathology were assessed in matched cohorts of PSSM1 homozygotes, heterozygotes or control horses. Median (interquartile range (IR)) resting CK activities were 364 (332-764) U/L for homozygotes, 301 (222-377) U/L for heterozygotes and 260 (216-320) U/L for controls, and mean (+/- SD) AST activity for homozygotes were 502 (+/116) U/L, for heterozygotes, 357 (+/-92) U/L and for controls, 311 (+/-64) U/L and were significantly different between groups (P = 0.04 and P = 0.01 respectively). Resting plasma AST activity was significantly associated with the severity of subsarcolemmal vacuolation (rho = 0.816; P = 0.01) and cytoplasmic inclusions (rho = 0.766; P = 0.01). There were fewer type 2× and more type 2a muscle fibres in PSSM1-affected horses. Our results indicate that PSSM1 has incomplete dominance. Furthermore, the association between plasma muscle enzyme activity and severity of underlying pathology suggests that physical disruption of myofibres may contribute to the myopathic phenotype. This work provides insight into PSSM1 pathogenesis and has implications for related human glycogenoses.
authors.affiliation: Comparative Neuromuscular Diseases Laboratory, The Royal Veterinary College, London, United Kingdom.
authors.forename: Rosie J
authors.initials: RJ
authors.lastname: Naylor
authors.forename: Leanda
authors.initials: L
authors.lastname: Livesey
authors.forename: John
authors.initials: J
authors.lastname: Schumacher
authors.forename: Nicole
authors.initials: N
authors.lastname: Henke
authors.forename: Claire
authors.initials: C
authors.lastname: Massey
authors.forename: Kenny V
authors.initials: KV
authors.lastname: Brock
authors.forename: Marta
authors.initials: M
authors.lastname: Fernandez-Fuente
authors.forename: Richard J
authors.initials: RJ
authors.lastname: Piercy
mesh_terms: D000483:Alleles; D000818:Animals; D001706:Biopsy; D018628:Gene Dosage; D006734:Horse Diseases / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D006736:Horses; D007150:Immunohistochemistry; D009135:Muscular Diseases / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D011134:Polysaccharides / Q000378:metabolism*
chemical_list: D011134:Polysaccharides