Polyglucosan storage myopathies

Hedberg‐Oldfors, Carola; Oldfors, Anders

doi:10.1016/j.mam.2015.08.006

Cited by 64 publications

(73 citation statements)

References 82 publications

(93 reference statements)

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“…The accumulated glycogen is partly alpha-amylase resistant and has a partly filamentous structure compatible with amylopectin-like material or polyglucosan. This type of storage in muscle is not unique for glycogenin-1 deficiency but is also found in deficiency of branching enzyme, phosphofructokinase and RBCK1 and in Lafora disease among others (Hedberg-Oldfors and Oldfors 2015). Therefore, multiple different gene mutations result in this type of abnormal storage.…”

Section: Discussionmentioning

confidence: 91%

“…Muscle GSD XV that is caused by variants in GYG1 belongs to a group of disorders of glycogen metabolism with storage of polyglucosan in muscle and other tissues (Hedberg-Oldfors and Oldfors 2015). Several human genes are known to be associated with polyglucosan storage in muscle including GYG1 , GBE1 , RBCK1 ( HOIL-1 ), PFKM , EPM2A , EPM2B ( NHLRC1 ), PRDM8 and PRKAG2 .…”

Section: Discussionmentioning

confidence: 99%

“…There are two types of muscle glycogenoses, those with defective degradation of normal glycogen (such as GSD II, III, V, VII, IX) and those with defective synthesis of glycogen (GSD 0, IV, XV) (DiMauro and Spiegel 2011; Oldfors and DiMauro 2013; Hedberg-Oldfors and Oldfors 2015). …”

Section: Introductionmentioning

confidence: 99%

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Cardiomyopathy as presenting sign of glycogenin‐1 deficiency—report of three cases and review of the literature

Hedberg‐Oldfors

Glamuzina

Ruygrok

et al. 2016

J of Inher Metab Disea

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We describe a new type of cardiomyopathy caused by a mutation in the glycogenin-1 gene (GYG1). Three unrelated male patients aged 34 to 52 years with cardiomyopathy and abnormal glycogen storage on endomyocardial biopsy were homozygous for the missense mutation p.Asp102His in GYG1. The mutated glycogenin-1 protein was expressed in cardiac tissue but had lost its ability to autoglucosylate as demonstrated by an in vitro assay and western blot analysis. It was therefore unable to form the primer for normal glycogen synthesis. Two of the patients showed similar patterns of heart dilatation, reduced ejection fraction and extensive late gadolinium enhancement on cardiac magnetic resonance imaging. These two patients were severely affected, necessitating cardiac transplantation. The cardiomyocyte storage material was characterized by large inclusions of periodic acid and Schiff positive material that was partly resistant to alpha-amylase treatment consistent with polyglucosan. The storage material had, unlike normal glycogen, a partly fibrillar structure by electron microscopy. None of the patients showed signs or symptoms of muscle weakness but a skeletal muscle biopsy in one case revealed muscle fibres with abnormal glycogen storage. Glycogenin-1 deficiency is known as a rare cause of skeletal muscle glycogen storage disease, usually without cardiomyopathy. We demonstrate that it may also be the cause of severe cardiomyopathy and cardiac failure without skeletal muscle weakness. GYG1 should be included in cardiomyopathy gene panels.Electronic supplementary materialThe online version of this article (doi:10.1007/s10545-016-9978-1) contains supplementary material, which is available to authorized users.

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Section: Discussionmentioning

confidence: 91%

Section: Discussionmentioning

confidence: 99%

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Cardiomyopathy as presenting sign of glycogenin‐1 deficiency—report of three cases and review of the literature

Hedberg‐Oldfors

Glamuzina

Ruygrok

et al. 2016

J of Inher Metab Disea

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“…However, our results suggest that therapeutic modification of AMPK activity might be ineffective in mutant animals, as increased GS phosphorylation does not reduce the mutant enzyme's hyperactivity; instead, efforts aimed at direct enzyme inhibition might be more effective. Finally, dysregulation of GS or other related enzymes should be considered in humans and animals with glycogen storage diseases of unknown origin, particularly when a dominant mode of inheritance is identified; indeed, this common equine disease represents a large animal model for evaluation of treatments aimed at reducing polyglucosan formation in skeletal muscle [33], a feature of a number of important, but comparatively rare, human myopathic disorders.…”

Section: Discussionmentioning

confidence: 99%

“…Furthermore, it could prompt investigation of specific treatments for this common equine myopathy or for other related glycogenoses in humans [33]. In this work, we investigate the enzyme's regulation in silico via computational modelling and through biochemical analysis in vitro of whole muscle extracts and via recombinant expressed enzyme kinetics.…”

Section: Introductionmentioning

confidence: 99%

A highly prevalent equine glycogen storage disease is explained by constitutive activation of a mutant glycogen synthase

Maile

Hingst

Mahalingan

et al. 2017

Biochimica et Biophysica Acta (BBA) - General Subjects

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Summary BACKGROUND Equine type 1 polysaccharide storage myopathy (PSSM1) is associated with a missense mutation (R309H) in the glycogen synthase (GYS1) gene, enhanced glycogen synthase (GS) activity and excessive glycogen and amylopectate inclusions in muscle. METHODS Equine muscle biochemical and recombinant enzyme kinetic assays in vitro and homology modelling in silico, were used to investigate the hypothesis that higher GS activity in affected horse muscle is caused by higher GS expression, dysregulation, or constitutive activation via a conformational change. RESULTS PSSM1-affected horse muscle had significantly higher glycogen content than control horse muscle despite no difference in GS expression. GS activity was significantly higher in muscle from homozygous mutants than from heterozygote and control horses, in the absence and presence of the allosteric regulator, glucose 6 phosphate (G6P). Muscle from homozygous mutant horses also had significantly increased GS phosphorylation at sites 2+2a and significantly higher AMPKα1 (an upstream kinase) expression than controls, likely reflecting a physiological attempt to reduce GS enzyme activity. Recombinant mutant GS was highly active with a considerably lower Km for UDP-glucose, in the presence and absence of G6P, when compared to wild type GS, and despite its phosphorylation. CONCLUSIONS Elevated activity of the mutant enzyme is associated with ineffective regulation via phosphorylation rendering it constitutively active. Modelling suggested that the mutation disrupts a salt bridge that normally stabilises the basal state, shifting the equilibrium to the enzyme's active state. GENERAL SIGNIFICANCE This study explains the gain of function pathogenesis in this highly prevalent polyglucosan myopathy.

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Glycogen Storage Diseases

Cox

2017

Encyclopedia of Life Sciences

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Glycogen is a dense repository of energy which is present mostly in animal tissues; with its highly arborised structure, the glycogen dendrimer is a source of readily accessible glucose units at low osmotic cost. Access to, and accretion of glycogen is subject to fine metabolic and hormonal regulation; indeed, glycogen biosynthesis is driven by high‐energy phosphate‐bond energy, requiring also the participation of several unique protein complexes. Seminal research by Carl and Gerty Cori into the pathophysiology of glycogen metabolism opened up scientific universe of hormonal signalling, phosphorylation control and second messengers. That the glycogen storage disorder, Pompe disease, proved to be an inborn error affecting lysosome function demonstrated the crucial importance of lysosomal autophagy in cellular housekeeping. The polyglucosan body diseases, characterised by insoluble starch‐like deposits, reveal the critical role of macromolecular remodelling for the symmetrical compaction of branched glycogen structures to ensure that safe storage in the cytoplasm is combined with rapid metabolic access. Inherited defects in proteins which regulate glycogen metabolism, those which enact glycogenolysis and glycogen synthesis cause pathological glycogen accumulation – or prevent its formation. Defects in glycolysis also have consequential metabolic effects on glycogen storage. Latterly, at least eight human loci which harbour mutations associated with polyglucosan and Lafora body disease have been reported in these clinically diverse, but fatal, multisystem disorders. The principal defects identify pathways responsible for the unique control of glycogen metabolism in neurons; other conditions point to coregulation of glycogen metabolism and control of immune and inflammatory responses. Glycogen is an essential macromolecule, the adaptive advantages of which come at a cost. Disorders affecting the dynamic metabolism, regulation and maintenance of this vital energy source offer unique insights into a vast interactive network of molecular cell physiology. Key Concepts Glycogen is an essential intracellular macromolecule; its highly branched but compacted polymeric structure facilitates the rapid availability of glucose units for metabolic utilisation. With ≈55 000 linked glucose units, mature glycogen is a highly ordered sphere with a low intrinsic osmotic burden (molecular mass ≈ 10 7 Da). Glycogen is near ubiquitous in cells including neurons; but it is most abundant in muscle tissue, including cardiac muscle, and in the liver. Skeletal muscle provides the greatest net repository of glycogen for short‐lived bursts of ATP generation but the concentration in liver tissue is several‐fold greater. Liver glycogen is principally used to maintain interprandial glucose homeostasis. Appropriate molecular compaction of its symmetrical, highly branched structure maintains the solubility of glycogen in the cytoplasm – it also promotes access of metabolic enzymes, including complex protein assemblies which regulate the supply of glucose energy from its breakdown. To maintain optimal functional integrity, the branched structure of glycogen is constitutively remodelled by autophagy in the lysosomal compartment. With a short half‐life, glycogen undergoes dynamic interactions; its synthesis and degradation are subject to fine metabolic control. Inborn errors of biosynthesis and catabolism, including disorders of glycolysis, not only affect the abundance and availability of metabolic glucose released from intracellular glycogen but can also lead to altered glycogen storage and its macromolecular structure. Defects in proteins that regulate glycogen metabolism and transport, as well as those which catalyse its biosynthesis and breakdown, cause pathological – or defective – accumulation of glycogen in diverse tissues. Failure to synthesise glycogen and defective glycogenolysis lead to complex metabolic disturbances characterised by interprandial hypoglycaemia; accumulation of aberrant glycogen structures has additional pathological effects due to cellular toxicity. Glycogen storage disorders reveal much about the physiological biochemistry of glycogen and regulatory processes in the dynamic control of energy metabolism – including the special case of neuronal tissue.

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Polyglucosan storage myopathies

Cited by 64 publications

References 82 publications

Cardiomyopathy as presenting sign of glycogenin‐1 deficiency—report of three cases and review of the literature

Cardiomyopathy as presenting sign of glycogenin‐1 deficiency—report of three cases and review of the literature

A highly prevalent equine glycogen storage disease is explained by constitutive activation of a mutant glycogen synthase

Glycogen Storage Diseases

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