Pharmacological approaches for treating glycogen storage disorders involving polyglucosan body accumulation

2017 ◽  
Vol 5 (12) ◽  
pp. 977-982
Author(s):  
Or Kakhlon
Keyword(s):  
Glycogen Storage ◽  
Polyglucosan Body ◽  
Storage Disorders

scholarly journals A new drug candidates for glycogen storage disorders enhances glycogen catabolism: Lessons from Adult Polyglucosan Body Disease models

2021 ◽  
Author(s):  
Hilla Vaknin ◽  
Kumudesh Mishra ◽  
Jeevitha D’Souza ◽  
Monzer Marisat ◽  
Uri Sprecher ◽  
...  
Keyword(s):  
Ex Vivo ◽  
Glycogen Storage ◽  
Cellular Level ◽  
Mitochondrial Activity ◽  
Atp Production ◽  
Drug Candidates ◽  
Polyglucosan Body ◽  
Adult Polyglucosan Body Disease ◽  
Storage Disorders

AbstractThis work employs Adult Polyglucosan Body Disease (APBD) models to explore the efficacy and mechanism of action of 144DG11, a new polyglucosan-reducing lead compound discovered by a high-throughput screen (HTS). APBD is an adult onset glycogen storage disorder (GSD) manifesting as a debilitating progressive axonopathic leukodystrophy. APBD is caused by glycogen branching enzyme (GBE) deficiency leading to poorly branched and insoluble glycogen inclusions, which precipitate as neuropathogenic polyglucosans (PG). 144DG11 led to prolonged survival and improved motor parameters in a GBE knockin (Gbeys/ys) APBD mouse model. Histopathologically, 144DG11 reduced PG and glycogen levels in brain, liver, heart, and peripheral nerve. Indirect calorimetry experiments revealed that 144DG11 increases carbohydrate burn at the expense of fat burn, suggesting metabolic mobilization of pathogenic PG. These results were also reflected at the cellular level by increased glycolytic, mitochondrial and total ATP production. Mechanistically, we show that the molecular target of 144DG11 is the lysosomal membrane protein LAMP1, whose interaction with the compound, similar to LAMP1 knockdown, enhanced autolysosomal degradation of glycogen and lysosomal acidification. Enhanced mitochondrial activity and lysosomal modifications were also the most pronounced effects of 144DG11 in APBD patient fibroblasts as discovered by image-based multiparametric phenotyping analysis and corroborated by proteomics. In summary, this work presents a broad mechanistic and target-based characterization of 144DG11 in in vivo and cell models of the prototypical GSD APBD. This investigation warrants development of 144DG11 into a safe and efficacious GSD therapy.One Sentence SummaryA new compound, demonstrated to ameliorate APBD in vivo and ex vivo by autophagic catabolism of glycogen, may potentially become a universal drug for glycogen storage disorders.

Glycogen Storage Disorders

2016 ◽  
Author(s):  
David Cassiman ◽  
Pascal Laforêt ◽  
Fanny Mochel
Keyword(s):  
Axonal Neuropathy ◽  
Glycogen Storage ◽  
Exercise Intolerance ◽  
Polyglucosan Body ◽  
Major Energy Source ◽  
Cns Effects ◽  
The Brain ◽  
Adult Polyglucosan Body Disease ◽  
Storage Disorders ◽  
Gsd Ii

Glucose is the body’s major energy source, and carbohydrate serves as fuel—particularly during high-intensity exercise that requires rapid energy release. A deficiency of any of the enzymes involved in the catabolism of glycogen to glucose may cause symptoms, with hypoglycemia and exercise intolerance as the most common presentations. Glycogen storage disorders (GSD) affect muscle, liver, and brain. The most common GSDs affecting muscle are GSD II (Pompe disease) and GSD V (McArdle disease). GSDs affecting mainly the liver are GSD I, III, IV, VI, IX, XI. Most liver-GSDs present during infancy, with symptoms of hypoglycemia, impressive hepatomegaly, and retarded growth. Adult presentations have been reported for GSD Ia, III, IV, and IX.Adult polyglucosan body disease (APBD) is the main GSD affecting primarily the brain and mainly characterized by spastic paraplegia, axonal neuropathy and leukodystrophy. APBD is a subtype of GSD IV and is due to a deficiency of glycogen branching enzyme (GBE). Besides GSD IV, other GSDs have been reported to have CNS effects in some patients—notably GSD II and GSD III.

The Glycogen Storage Disorders

2020 ◽  
Vol 41 (1) ◽  
pp. 41-44 ◽  
Author(s):  
Robert W. Marion ◽  
Esma Paljevic
Keyword(s):  
Glycogen Storage ◽  
Storage Disorders

Molecular Characterization of a Novel Endonuclease (Xib) and Possible Involvement in Lysosomal Glycogen Storage Disorders

1999 ◽  
Vol 66 (2) ◽  
pp. 123-130 ◽  
Author(s):  
Giulia Malferrari ◽  
Umberto Mazza ◽  
Cristina Tresoldi ◽  
Ermanna Rovida ◽  
Maia Nissim ◽  
...  
Keyword(s):  
Molecular Characterization ◽  
Glycogen Storage ◽  
Storage Disorders

Liver histology in children with glycogen storage disorders type VI and IX

2021 ◽  
Vol 53 (1) ◽  
pp. 86-93
Author(s):  
Irene Degrassi ◽  
Maesha Deheragoda ◽  
David Creegen ◽  
Helen Mundy ◽  
Ahlam Mustafa ◽  
...  
Keyword(s):  
Glycogen Storage ◽  
Liver Histology ◽  
Storage Disorders

scholarly journals A new UHPLC-MS/MS method for the screening of urinary oligosaccharides expands the detection of storage disorders

2021 ◽  
Vol 16 (1) ◽  
Author(s):  
Michela Semeraro ◽  
Elisa Sacchetti ◽  
Federica Deodato ◽  
Turgay Coşkun ◽  
Incilay Lay ◽  
...  
Keyword(s):  
Pompe Disease ◽  
Internal Standard ◽  
Glycogen Storage ◽  
The Novel ◽  
Inherited Disorders ◽  
Danon Disease ◽  
Mucolipidosis Ii ◽  
Set Up ◽  
Urinary Oligosaccharides ◽  
Storage Disorders

Abstract Background Oligosaccharidoses are storage disorders due to enzymatic defects involved in the breakdown of the oligosaccharidic component of glycosylated proteins. The defect cause the accumulation of oligosaccharides (OS) and, depending on the lacking enzyme, results in characteristic profiles which are helpful for the diagnosis. We developed a new tandem mass spectrometry method for the screening of urinary OS which was applied to identify a large panel of storage disorders. Methods The method was set-up in urine and dried urine spots (DUS). Samples were analysed, without derivatization and using maltoheptaose as internal standard, by UHPLC-MS/MS with MRM acquisition of target OS transitions, including Glc4, the biomarker of Pompe disease. The chromatographic run was < 30 min. Samples from patients with known storage disorders were used for clinical validation. Results The method allowed to confirm the diagnosis of oligosaccharidoses (sialidosis, α-/β-mannosidosis, fucosidosis, aspartylglucosaminuria) and of GM1 and GM2 (Sandhoff type) gangliosidosis, by detecting specific OS profiles. In other storage disorders (mucolipidosis II and III, mucopolysaccharidosis type IVB) the analyisis revealed abnormal OS excretion with non-specific profiles. Besides Pompe disease, the tetrasaccharide Glc4 was increased also in disorders of autophagy (Vici syndrome, Yunis-Varon syndrome, and Danon disease) presenting cardiomuscular involvement with glycogen storage. Overall, results showed a clear separation between patients and controls, both in urine and in DUS. Conclusion This new UHPLC/MS-MS method, which is suitable for rapid and easy screening of OS in urine and DUS, expands the detection of storage disorders from oligosaccharidoses to other diseases, including the novel category of inherited disorders of autophagy.

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