REVIEW AND PERSPECTIVES Update on polyglucosan storage diseases Giovanna Cenacchi 1 & V. Papa 1 & R. Costa 1 & V. Pegoraro 2 & R. Marozzo 2 & M. Fanin 3 & C. Angelini 4 Received: 12 June 2019 /Revised: 18 July 2019 /Accepted: 22 July 2019 # Springer-Verlag GmbH Germany, part of Springer Nature 2019 Abstract An abnormal structural form of glycogen (with less branching points or amylopectin-like polysaccharide) called polyglucosan (PG) may accumulate in various tissues such as striated and smooth muscles, brain, nerve, liver and skin, and cause a group of nine different genetic disorders manifesting with a variety of clinical phenotypes that affect mainly the nervous system (Lafora disease, adult PG body disease), the heart (glycogen storage disease type XV, hypertrophic cardiomyopathy type 6, PG body myopathy type 1) and the skeletal muscle (glycogen storage disease type IV, glycogen storage disease type VII, PG body myopathy type 2), depending on the organs which are mostly affected by the PG aggregates. The pathological feature of PG storage in tissues is a hallmark of these disorders. Whole-genome sequencing has allowed to obtain a diagnosis in a large number of patients with a previously unrecognized disorder. We describe the clinical, pathological and molecular features of these genetic disorders, for many of which the pathological mechanisms underlying the corresponding mutant gene have been investigated and, at least in part, understood. Keywords Polyglucosan . Polyglucosan storage . Glycogenin-1 . Lafora . Glycogen storage Glycogen is the storage form of glucose in the cells, and it is essential for energy supply and glucose homeostasis. It is a highly branched polymer of glucose molecules connected by α-1,4-glucosidic linkages, and branched by α-1,6-glucosidic linkages (Fig. 1). De novo biosynthesis of glycogen requires the initiator protein called “glycogenin” (EC 2.4.1.186), a glycosyl- transferase that catalyzes the formation of a glucose polymer using uridine-diphosphate (UDP)-glucose as donor [1, 2]. An un-glycosylated dimer of apo-glycogenin-1 is auto- glycosylated by an initial glucose-1-O-tyrosine linkage formed with the hydroxyl group of tyrosine-195 residue [3, 4], followed by addition of 8–13 glucose molecules by several α-1,4-glucosidic linkages (Fig. 1 ). This glycogenin- oligosaccharide molecule constitutes the primer for the reac- tions of elongation [at the non-reducing end by glycogen syn- thase (EC 2.4.1.11)], and branching [by glycogen branching enzyme (EC 2.4.1.18)]. Each glycogen granule (β-particle) contains approximately 55,000 glucose residues with numer- ous non-reducing ends for rapid access to glucose. A glycogen molecule is soluble because its glucose chains are short (13 units), each chain is a branch of another, and the whole molecule has a spherical structure [4]. An abnormal quantity or quality of glycogen accumulating in tissues causes a group of disorders called “glycogen storage diseases (GSDs)”, which were among the earliest inborn er- rors of metabolism for which specific enzyme deficiencies were identified. Research on GSDs has identified enzyme deficiencies and their underlying gene mutations for nearly all steps of the pathways of glycogen and glycolysis metabo- lism (“primary GSDs”) (Table 1), but GSDs can also be caused by mutations in proteins which have an indirect impact on glycogen metabolism (e.g. regulatory proteins), leading to “secondary GSDs” [5]. In GSDs, an increased quantity of glycogen is most fre- quently found, but rare defects of glycogen synthesis may lead to reduced glycogen level. Conversely, an abnormal quality of * Giovanna Cenacchi giovanna.cenacchi@unibo.it 1 Department of Biomedical and Neuromotor Sciences, “Alma Mater” University of Bologna, Via Massarenti 9, 40138 Bologna, Italy 2 Neurobiology Laboratory, Fondazione San Camillo Hospital IRCCS, Lido Venice, Italy 3 Department of Neurosciences, University of Padova, Padova, Italy 4 Neuromuscular Department, Fondazione San Camillo Hospital IRCCS, Lido Venice, Italy Virchows Archiv https://doi.org/10.1007/s00428-019-02633-6