<scp><i>GBE1</i></scp>‐related disorders: Adult polyglucosan body disease and its neuromuscular phenotypes

Souza, Paulo Victor Sgobbi de; Badia, Bruno Mattos Lombardi; Farias, Igor Braga; Pinto, Wladimir Bocca Vieira de Rezende; Oliveira, Acary Souza Bullé; Akman, Hasan O.; DiMauro, Salvatore

doi:10.1002/jimd.12325

Cited by 23 publications

(22 citation statements)

References 48 publications

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“…The formation of polyglucosan bodies in inherited diseases has been attributed to faulty glycogen synthesis and the production of elongated glucan chains with lack of branching leading to insoluble molecules and aggregation. This may be caused by an imbalance of the enzymatic activities of glycogen related proteins, for instance, due to hypomorphic mutations in GBE1 encoding branching enzyme, 38,39 or overexpression of glycogen synthase 40,41 . In Lafora disease, a central quality control mechanism, prohibiting extensive glucan chain elongation in glycogen, is disabled by mutations of either laforin or malin 9 …”

Section: Discussionmentioning

confidence: 99%

Proteomic characterisation of polyglucosan bodies in skeletal muscle in RBCK1 deficiency

Thomsen

Malfatti

Jovanović

et al. 2021

Neuropathology Appl Neurobio

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Aims Several neurodegenerative and neuromuscular disorders are characterised by storage of polyglucosan, consisting of proteins and amylopectin‐like polysaccharides, which are less branched than in normal glycogen. Such diseases include Lafora disease, branching enzyme deficiency, glycogenin‐1 deficiency, polyglucosan body myopathy type 1 (PGBM1) due to RBCK1 deficiency and others. The protein composition of polyglucosan bodies is largely unknown. Methods We combined quantitative mass spectrometry, immunohistochemical and western blot analyses to identify the principal protein components of polyglucosan bodies in PGBM1. Histologically stained tissue sections of skeletal muscle from four patients were used to isolate polyglucosan deposits and control regions by laser microdissection. Prior to mass spectrometry, samples were labelled with tandem mass tags that enable quantitative comparison and multiplexed analysis of dissected samples. To study the distribution and expression of the accumulated proteins, immunohistochemical and western blot analyses were performed. Results Accumulated proteins were mainly components of glycogen metabolism and protein quality control pathways. The majority of fibres showed depletion of glycogen and redistribution of key enzymes of glycogen metabolism to the polyglucosan bodies. The polyglucosan bodies also showed accumulation of proteins involved in the ubiquitin‐proteasome and autophagocytosis systems and protein chaperones. Conclusions The sequestration of key enzymes of glycogen metabolism to the polyglucosan bodies may explain the glycogen depletion in the fibres and muscle function impairment. The accumulation of components of the protein quality control systems and other proteins frequently found in protein aggregate disorders indicates that protein aggregation may be an essential part of the pathobiology of polyglucosan storage.

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Section: Discussionmentioning

confidence: 99%

Proteomic characterisation of polyglucosan bodies in skeletal muscle in RBCK1 deficiency

Thomsen

Malfatti

Jovanović

et al. 2021

Neuropathology Appl Neurobio

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“…The observation of periodic acid-Schiff-positive polyglucosan bodies on skin or peripheral nerve biopsy is pathognomonic. 6 However, the most common initial sign of APBD is urinary incontinence, which is not reported in this patient.…”

Section: Sectionmentioning

confidence: 64%

Clinical Reasoning: A 50-Year-Old Man With Progressive Limb Weakness and Slurred Speech

et al. 2022

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“…Brain glycogen in APBD and LD consists of normal water-soluble glycogen and precipitated and aggregated glycogen (polyglucosans, PBs) [ 36 – 38 ]. The soluble portion degrades at room temperature, while the insoluble does not.…”

Section: Resultsmentioning

confidence: 99%

AAV-Mediated Artificial miRNA Reduces Pathogenic Polyglucosan Bodies and Neuroinflammation in Adult Polyglucosan Body and Lafora Disease Mouse Models

et al. 2022

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Adult polyglucosan body disease (APBD) and Lafora disease (LD) are autosomal recessive glycogen storage neurological disorders. APBD is caused by mutations in the glycogen branching enzyme (GBE1) gene and is characterized by progressive upper and lower motor neuron dysfunction and premature death. LD is a fatal progressive myoclonus epilepsy caused by loss of function mutations in the EPM2A or EPM2B gene. These clinically distinct neurogenetic diseases share a common pathology. This consists of time-dependent formation, precipitation, and accumulation of an abnormal form of glycogen (polyglucosan) into gradually enlarging inclusions, polyglucosan bodies (PBs) in ever-increasing numbers of neurons and astrocytes. The growth and spread of PBs are followed by astrogliosis, microgliosis, and neurodegeneration. The key defect in polyglucosans is that their glucan branches are longer than those of normal glycogen, which prevents them from remaining in solution. Since the lengths of glycogen branches are determined by the enzyme glycogen synthase, we hypothesized that downregulating this enzyme could prevent or hinder the generation of the pathogenic PBs. Here, we pursued an adeno-associated virus vector (AAV) mediated RNA-interference (RNAi) strategy. This approach resulted in approximately 15% reduction of glycogen synthase mRNA and an approximately 40% reduction of PBs across the brain in the APBD and both LD mouse models. This was accompanied by improvements in early neuroinflammatory markers of disease. This work represents proof of principle toward developing a single lifetime dose therapy for two fatal neurological diseases: APBD and LD. The approach is likely applicable to other severe and common diseases of glycogen storage.

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GBE1‐related disorders: Adult polyglucosan body disease and its neuromuscular phenotypes

Cited by 23 publications

References 48 publications

Proteomic characterisation of polyglucosan bodies in skeletal muscle in RBCK1 deficiency

Proteomic characterisation of polyglucosan bodies in skeletal muscle in RBCK1 deficiency

Clinical Reasoning: A 50-Year-Old Man With Progressive Limb Weakness and Slurred Speech

AAV-Mediated Artificial miRNA Reduces Pathogenic Polyglucosan Bodies and Neuroinflammation in Adult Polyglucosan Body and Lafora Disease Mouse Models

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