Update on polyglucosan storage diseases

Shared and Distinctive Ultrastructural Abnormalities Expressed by Megakaryocytes in Bone Marrow and Spleen From Patients With Myelofibrosis

“…Further support for this hypothesis comes from a re-analyses of the expression signature of MF BM (33) that identified modest fold changes above threshold in the expression of several genes of the glycogen pathway, four of which (PHKA2, PHKB, and PYGL down-regulated whereas PRDM8 upregulated) mutated in inherited disorders associated with increased glycogen storage (38)(39)(40)(41)(42)(43)(44) (Table S2, Figure S3). Upregulation of PRDM8 expression is particularly intriguing because gain of function mutations of this gene are associated with the neurodegenerative Lafora disease (30,41) which is characterized by the presence in the neurons of specific polyglucosan-rich glycosomes, defined Lafora body, similar in morphology to some of the glycosomes identified by us in the malignant megakaryocytes from MF BM. In conclusion, the expression signature and the TEM observations support the hypothesis that the glycogen pathway in megakaryocytes from MF BM is skewed toward the formation of acid-insoluble glycosomes, making the energy of the cells exquisitely depend on lipid consumption and reducing the lipid pool devoted to membrane biosynthesis.…”

“…The electron density and the morphological features of these structures are similar to that of the glycogen droplets present in muscle and liver cells ( 34 ). In some cases, these granules are so heavily electron-dense to resemble glycogen granules containing acid-insoluble polyglucosan formed in Lafora disease ( 30 ) ( Figures 5 and S2 ). By contrast, these structures are observed in only 5–7% of megakaryocytes from the patients’ spleen and are seldom detected in cells from BM of HC ( Figure 5 ).…”

“…These granules are turned by phosphorylation into heavy electron-dense acid-insoluble polyglucosan granules which, on the basis of their electron density, are defined as intermediate or mature glycosomes. In the case of glycogen storage diseases, acid-insoluble polyglucosan molecules accumulate in the cytoplasm either as large isolated granules or as packed glycosomes (the bodies found in Lafora disease) ( 30 ). Mitochondria are recognized as round (cross section) or rod (longitudinal section) structures surrounded by a double membrane system with the inner membrane presenting regular invagination defined crests ( 31 ).…”

“…Granules were identified as circular bodies surrounded by a single membrane enclosing electron-dense material. Polyglucosan granules and glycosomes were identified based on published TEM criteria ( Figure S2) (28)(29)(30). Glycosomes are formed by granuli of progressively increased electron density orderly enclosing circular areas of the cytoplasm that is not surrounded by membranes.…”

Metastasis of Uveal Melanoma with Monosomy-3 Is Associated with a Less Glycogenetic Gene Expression Profile and the Dysregulation of Glycogen Storage

“…We were also not able to determine whether the formation of aberrant glycogen fibers and their possible exocytosis [ 66 ] contributed to the extracellular vasculogenic mimicry patterns, which are usually visualized by a normal PAS staining without amylase pretreatment. Abnormal glycogen fibers with a less branched structure are indeed the hallmarks of several glycogen storage disorders and induce pathogenesis by accumulating as polyglucosan bodies that are more resistant to amylase digestion [ 67 , 68 ]. Remarkably, the extracellular polyglucosan bodies can exhibit a tendency to congregate in the vicinity of blood vessels [ 69 , 70 ] possibly as an attempt to facilitate their disposal from the affected tissues.…”