Polyglucosan storage myopathies.

Polyglucosan is an amylopectin-like polysaccharide associated with defective glycogen metabolism and, unlike normal glycogen, it is to some extent resistant to α-amylase digestion. It also has a characteristic fibrillar appearance under the electron microscope. Polyglucosan may aggregate into dense inclusions known as polyglucosan bodies. Its accumulation can be found in various tissues to some degree in normal ageing, but it is also the hallmark of some diseases associated with defects in glycogen metabolism. These diseases frequently involve both skeletal and cardiac muscle tissue, causing myopathy with muscle weakness and wasting, and cardiomyopathy with arrhythmia, conduction block, and cardiac failure. Mutations in eight human genes are known to be associated with polyglucosan storage involving muscle, namely GYG1, GBE1, RBCK1 (HOIL-1), PFKM, EPM2A, EPM2B (NHLRC1), PRDM8, and PRKAG2. There is also a common equine polysaccharide storage myopathy belonging to this group of diseases involving the GYS1 gene. The pathogenic mechanisms that cause the abnormal glycogen accumulation appearing as polyglucosan have been studied in some of these diseases. In most cases the pathogenesis is largely unknown. In this review, we summarize the polyglucosan storage diseases from a clinical, morphological, and genetic standpoint. We also identify some important similarities and differences regarding the morphological appearance of polyglucosan accumulation and discuss pathogenic pathways.

Hedberg-Oldfors C ，Oldfors A 《-》

Proteomic profiling of polyglucosan bodies associated with glycogenin-1 deficiency in skeletal muscle.

Visuttijai K ，Hedberg-Oldfors C ，Costello DJ ，Bermingham N ，Oldfors A ... -  《-》

Development of polyglucosan inclusions in skeletal muscle.

Valentine BA ，Cooper BJ 《NEUROMUSCULAR DISORDERS》

Glycogen synthase downregulation rescues the amylopectinosis of murine RBCK1 deficiency.

Longer glucan chains tend to precipitate. Glycogen, by far the largest mammalian glucan and the largest molecule in the cytosol with up to 55 000 glucoses, does not, due to a highly regularly branched spherical structure that allows it to be perfused with cytosol. Aberrant construction of glycogen leads it to precipitate, accumulate into polyglucosan bodies that resemble plant starch amylopectin and cause disease. This pathology, amylopectinosis, is caused by mutations in a series of single genes whose functions are under active study toward understanding the mechanisms of proper glycogen construction. Concurrently, we are characterizing the physicochemical particularities of glycogen and polyglucosans associated with each gene. These genes include GBE1, EPM2A and EPM2B, which respectively encode the glycogen branching enzyme, the glycogen phosphatase laforin and the laforin-interacting E3 ubiquitin ligase malin, for which an unequivocal function is not yet known. Mutations in GBE1 cause a motor neuron disease (adult polyglucosan body disease), and mutations in EPM2A or EPM2B a fatal progressive myoclonus epilepsy (Lafora disease). RBCK1 deficiency causes an amylopectinosis with fatal skeletal and cardiac myopathy (polyglucosan body myopathy 1, OMIM# 615895). RBCK1 is a component of the linear ubiquitin chain assembly complex, with unique functions including generating linear ubiquitin chains and ubiquitinating hydroxyl (versus canonical amine) residues, including of glycogen. In a mouse model we now show (i) that the amylopectinosis of RBCK1 deficiency, like in adult polyglucosan body disease and Lafora disease, affects the brain; (ii) that RBCK1 deficiency glycogen, like in adult polyglucosan body disease and Lafora disease, has overlong branches; (iii) that unlike adult polyglucosan body disease but like Lafora disease, RBCK1 deficiency glycogen is hyperphosphorylated; and finally (iv) that unlike laforin-deficient Lafora disease but like malin-deficient Lafora disease, RBCK1 deficiency's glycogen hyperphosphorylation is limited to precipitated polyglucosans. In summary, the fundamental glycogen pathology of RBCK1 deficiency recapitulates that of malin-deficient Lafora disease. Additionally, we uncover sex and genetic background effects in RBCK1 deficiency on organ- and brain-region specific amylopectinoses, and in the brain on consequent neuroinflammation and behavioural deficits. Finally, we exploit the portion of the basic glycogen pathology that is common to adult polyglucosan body disease, both forms of Lafora disease and RBCK1 deficiency, namely overlong branches, to show that a unified approach based on downregulating glycogen synthase, the enzyme that elongates glycogen branches, can rescue all four diseases.

Nitschke S ，Sullivan MA ，Mitra S ，Marchioni CR ，Lee JPY ，Smith BH ，Ahonen S ，Wu J ，Chown EE ，Wang P ，Petković S ，Zhao X ，DiGiovanni LF ，Perri AM ，Israelian L ，Grossman TR ，Kordasiewicz H ，Vilaplana F ，Iwai K ，Nitschke F ，Minassian BA ... -  《-》

Polyglucosan myopathy and functional characterization of a novel GYG1 mutation.

Disorders of glycogen metabolism include rare hereditary muscle glycogen storage diseases with polyglucosan, which are characterized by storage of abnormally structured glycogen in muscle in addition to exercise intolerance or muscle weakness. In this study, we investigated the etiology and pathogenesis of a late-onset myopathy associated with glycogenin-1 deficiency. A family with two affected siblings, 64- and 66-year-olds, was studied. Clinical examination and whole-body MRI revealed weakness and wasting in the hip girdle and proximal leg muscles affecting ambulation in the brother. The sister had weakness and atrophy of hands and slight foot dorsiflexion difficulties. Muscle biopsy and whole-exome sequencing were performed in both cases to identify and characterize the pathogenesis including the functional effects of identified mutations. Both siblings demonstrated storage of glycogen that was partly resistant to alpha-amylase digestion. Both were heterozygous for two mutations in GYG1, one truncating 1-base deletion (c.484delG; p.Asp163Thrfs*5) and one novel missense mutation (c.403G>A; p.Gly135Arg). The mutations caused reduced expression of glycogenin-1 protein, and the missense mutation abolished the enzymatic function as analyzed by an in vitro autoglucosylation assay. We present functional evidence for the pathogenicity of a novel GYG1 missense mutation located in the substrate binding domain. Our results also demonstrate that glycogenin-1 deficiency may present with highly variable distribution of weakness and wasting also in the same family.

Hedberg-Oldfors C ，Mensch A ，Visuttijai K ，Stoltenburg G ，Stoevesandt D ，Kraya T ，Oldfors A ，Zierz S ... -  《-》