Allele Copy Number and Underlying Pathology Are Associated with Subclinical Severity in Equine Type 1 Polysaccharide Storage Myopathy (PSSM1)

PLOS ONE, Dec 2019

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.

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Allele Copy Number and Underlying Pathology Are Associated with Subclinical Severity in Equine Type 1 Polysaccharide Storage Myopathy (PSSM1)

et al. (2012) Allele Copy Number and Underlying Pathology Are Associated with Subclinical Severity in Equine Type 1 Polysaccharide Storage Myopathy (PSSM1). PLoS ONE 7(7): e42317. doi:10.1371/journal.pone.0042317 Allele Copy Number and Underlying Pathology Are Associated with Subclinical Severity in Equine Type 1 Polysaccharide Storage Myopathy (PSSM1) Rosie J. Naylor 0 Leanda Livesey 0 John Schumacher 0 Nicole Henke 0 Claire Massey 0 Kenny V. Brock 0 Marta Fernandez-Fuente 0 Richard J. Piercy 0 Mel B. Feany, Brigham and Women's Hospital, Harvard Medical School, United States of America 0 1 Comparative Neuromuscular Diseases Laboratory, The Royal Veterinary College , London , United Kingdom , 2 Auburn University , Auburn, Alabama , United States of America 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 (+/2 SD) AST activity for homozygotes were 502 (+/116) U/L, for heterozygotes, 357 (+/292) U/L and for controls, 311 (+/264) 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 26 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. - There are eleven glycogen storage myopathies recognized in humans, associated with the excessive accumulation of glycogen and/or amylopectin-like polyglucosan bodies within skeletal muscle fibres [1]. In addition, reports exist of other human cases with similar pathological features, where genetic causes are suspected, but unknown [2]. To date, the pathophysiology of many of these glycogenoses remains poorly understood. Patients may develop muscle cramps, weakness, exercise intolerance and rhabdomyolysis [3], but it remains unclear the degree to which these signs are associated with the physical disruption of muscle fibre ultrastructure by the accumulations of glycogen or polyglucosan [4], or with other disease mechanisms, such as diminished energy supply [5,6,7]. Type 1 equine polysaccharide storage myopathy (PSSM1) in horses is associated with a variety of clinical signs, including intermittent exertional rhabdomyolysis, muscle fasciculations, muscle atrophy, gait abnormalities and paresis [8]. PSSM1 was first described in detail by Valberg and colleagues in 1992 [9] and is associated with an autosomal dominant, missense, gain of function mutation (R309H) in the skeletal muscle glycogen synthase gene (GYS1) [10]. Suspected to be the result of an ancestral founder, the identical mutation is found in many different horse breeds worldwide, with some breeds, for example Percheron and Belgian Draft horses, having a particularly high disease prevalence [10,11,12]. As with some of the known human glycogenoses [13,14,15,16], affected horses accumulate excessive glycogen and abnormal alpha-crystalline polysaccharide inclusions within skeletal muscle fibres, often in sub-sarcolemmal vacuoles or cytoplasmic inclusions [17,18]. Consequently, study of this equine disease may provide important information regarding the pathogenesis of related human disorders, perhaps prompting novel treatment or management strategies. In PSSM1-affected horses, pathological changes are most prominent in muscles with a high proportion of glycolytic (type 26) fibres [1 (...truncated)


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Rosie J. Naylor, Leanda Livesey, John Schumacher, Nicole Henke, Claire Massey, Kenny V. Brock, Marta Fernandez-Fuente, Richard J. Piercy. Allele Copy Number and Underlying Pathology Are Associated with Subclinical Severity in Equine Type 1 Polysaccharide Storage Myopathy (PSSM1), PLOS ONE, 2012, 7, DOI: 10.1371/journal.pone.0042317