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Glycogen Storage Disease Type VII

Asta Literature Retrieval: Pathophysiology and clinical mechanisms of Glycogen Storage Disease Type VII. Core disease mechanisms, molecular and...

2026-05-11
Asta MONDO:0009295 Model: Asta Scientific Corpus Retrieval 18 citations

Asta Literature Retrieval: Pathophysiology and clinical mechanisms of Glycogen Storage Disease Type VII. Core disease mechanisms, molecular and...

This report is retrieval-only and is generated directly from Asta results.

  • Papers retrieved: 18
  • Snippets retrieved: 20

Relevant Papers

[1] Proteomic investigations of adult polyglucosan body disease: insights into the pathobiology of a neurodegenerative disorder

  • Authors: Joseph R. Abraham, F. M. Allen, J. Barnard, Daniela Schlatzer, Marvin R. Natowicz
  • Year: 2023
  • Venue: Frontiers in Neurology
  • URL: https://www.semanticscholar.org/paper/ed095bd45be8b002bf7a4ab7109e96db7e95e7ae
  • DOI: 10.3389/fneur.2023.1261125
  • PMID: 38033781
  • PMCID: 10683643
  • Summary: The findings suggest that proteomic analysis of GBE1 mutant lymphoblasts can be leveraged as part of the screening for pharmaceutical agents for the treatment of APBD.
  • Evidence snippets:
  • Snippet 1 (score: 0.500) > GBE1 is a glycogen branching enzyme that catalyzes the transfer of alpha-1,4-linked glucosyl units to an alpha-1,6 position on the same or adjacent glycogen chain. Branching of glycogen chains is important for the synthesis of structurally normal glycogen. The absence or a critical insufficiency of GBE1 activity results in the accumulation of structurally abnormal, poorly soluble glycogen and one of the clinical forms of autosomal recessive glycogen storage disease type IV (1). > Adult polyglucosan body disease (APBD) represents the "mildest" known clinical form of GSD IV although it is, nevertheless, a neurodegenerative condition associated with significant and progressive central and peripheral nervous system sequelae (2,3). The molecular basis of the underlying disease process in APBD is inadequately understood. Here, we sought to leverage proteomic methodology to obtain additional insights regarding the molecular basis of APBD pathogenesis. Using an unbiased label-free LC-MS/MS approach we identified 531 lymphoblast proteins that were significantly differentially expressed between APBD subjects and controls and multiple metabolic pathways and protein-protein interaction networks that were markedly differentially expressed between APBD and controls. > Determination of the primary pathogenetic mechanism(s) in APBP presents significant challenges. Elucidation of the pathophysiology is complex for several reasons. First, there are varying glycogen biosynthetic and degradative capacities in different cell types, including within the central nervous system (CNS). Related to this and illustrating the complexity, recent studies reveal molecular heterogeneity of soluble and insoluble glycogen in GBE1-deficient cells and demonstrate that different cell types can produce distinct types of polyglucosan bodies and that there can be variation of the storage product even within a specific cell type (21)(22)(23). Second, there is evidence of varied cytological sensitivity to the accumulation of polyglucosan bodies across different cell types and tissues.

[2] Glycogen storage diseases: An update

  • Authors: E. Gümüş, Hasan Özen
  • Year: 2023
  • Venue: World Journal of Gastroenterology
  • URL: https://www.semanticscholar.org/paper/8e6ccdf404ea7fdbba736bcbda06bd27f80f996d
  • DOI: 10.3748/wjg.v29.i25.3932
  • PMID: 37476587
  • PMCID: 10354582
  • Citations: 64
  • Influential citations: 3
  • Summary: This review provides general characteristics of all types of GSDs with a focus on those with liver involvement, with a focus on those with liver involvement.
  • Evidence snippets:
  • Snippet 1 (score: 0.474) > Glycogen storage diseases (GSDs), also referred to as glycogenoses, are inherited metabolic disorders of glycogen metabolism caused by deficiency of enzymes or transporters involved in the synthesis or degradation of glycogen leading to aberrant storage and/or utilization. The overall estimated GSD incidence is 1 case per 20000-43000 live births. There are over 20 types of GSD including the subtypes. This heterogeneous group of rare diseases represents inborn errors of carbohydrate metabolism and are classified based on the deficient enzyme and affected tissues. GSDs primarily affect liver or muscle or both as glycogen is particularly abundant in these tissues. However, besides liver and skeletal muscle, depending on the affected enzyme and its expression in various tissues, multiorgan involvement including heart, kidney and/or brain may be seen. Although GSDs share similar clinical features to some extent, there is a wide spectrum of clinical phenotypes. Currently, the goal of treatment is to maintain glucose homeostasis by dietary management and the use of uncooked cornstarch. In addition to nutritional interventions, pharmacological treatment, physical and supportive therapies, enzyme replacement therapy (ERT) and organ transplantation are other treatment approaches for both disease manifestations and long-term complications. The lack of a specific therapy for GSDs has prompted efforts to develop new treatment strategies like gene therapy. Since early diagnosis and aggressive treatment are related to better prognosis, physicians should be aware of these conditions and include GSDs in the differential diagnosis of patients with relevant manifestations including fasting hypoglycemia, hepatomegaly, hypertransaminasemia, hyperlipidemia, exercise intolerance, muscle cramps/pain, rhabdomyolysis, and muscle weakness. Here, we aim to provide a comprehensive review of GSDs. This review provides general characteristics of all types of GSDs with a focus on those with liver involvement.

[3] Starch Binding Domain-containing Protein 1/Genethonin 1 Is a Novel Participant in Glycogen Metabolism*

  • Authors: Sixin Jiang, Brigitte L. Heller, V. Tagliabracci, L. Zhai, José M. Irimia et al.
  • Year: 2010
  • Venue: The Journal of Biological Chemistry
  • URL: https://www.semanticscholar.org/paper/1bf15d9d6a5f79afbceaa7ac743b242253e27e17
  • DOI: 10.1074/jbc.M110.150839
  • PMID: 20810658
  • Citations: 84
  • Influential citations: 2
  • Summary: It is concluded that Stbd1 is involved in glycogen metabolism by binding to glycogen and anchoring it to membranes, thereby affecting its cellular localization and its intracellular trafficking to lysosomes.
  • Evidence snippets:
  • Snippet 1 (score: 0.472) > Glycogen is a branched storage polymer of glucose that serves as an energy reserve in many cell types, with liver and skeletal muscle housing the largest deposits in mammals (1)(2)(3). Glycogen metabolism and its regulation have been studied for decades, with most focus on its cytosolic synthesis and degradation in relation to mechanisms of enzyme regulation, intracellular energy metabolism, and whole body glucose homeostasis. Glycogen biosynthesis is initiated by a specialized self-glucosylating protein, called glycogenin, followed by bulk synthesis mediated by glycogen synthase and the branching enzyme. Regulated breakdown of glycogen, to fuel contractile activity in muscle or to generate free glucose in the liver for blood glucose homeostasis, is mediated by glycogen phosphor-ylase and debranching enzyme. Although glycogen metabolism is usually considered cytosolic, electron microscopy studies generally place glycogen in relative proximity to membranous structures, like the endoplasmic reticulum in liver (4) or the sarcoplasmic reticulum in muscle (5). In several disease states and some genetically modified mouse models, aberrant glycogen metabolism results in the accumulation of abnormal glycogen deposits. Glycogen is also transported to lysosomes where it is directly hydrolyzed to glucose by a lysosomal ␣-glucosidase (acid maltase) (6). Although probably not the major degradative mechanism under normal circumstances, the significance of this pathway is emphasized by the symptoms of patients with Pompe disease in which the ␣-glycosidase gene is mutated (7)(8)(9). The severity of the phenotype varies with the degree of impairment of glycosidase activity, in the worst cases leading to death within the 1st year after birth. In the disease, undegraded glycogen accumulates in the lysosomes, resulting in potentially fatal tissue damage. > The molecular mechanism by which glycogen is transferred to the lysosome is poorly understood but could involve an autophagy-like pathway.

[4] Mitochondrial Dysfunction in Glycogen Storage Disorders (GSDs)

  • Authors: Kumudesh Mishra, O. Kakhlon
  • Year: 2024
  • Venue: Biomolecules
  • URL: https://www.semanticscholar.org/paper/beabb5e517ed40ea3f0c149e40bdc2bf857a591f
  • DOI: 10.3390/biom14091096
  • PMID: 39334863
  • PMCID: 11430448
  • Citations: 7
  • Influential citations: 1
  • Summary: The intertwining of mitochondrial dysfunction and GSDs underscores the complexity of these disorders and has significant clinical implications, and potential strategies include antioxidants to mitigate oxidative stress, compounds that enhance mitochondrial biogenesis, and gene therapy to correct the underlying mitochondrial enzyme deficiencies.
  • Evidence snippets:
  • Snippet 1 (score: 0.469) > Mitochondrial dysfunction in glycogen storage disorders (GSDs) represents a critical aspect of these metabolic diseases, underscoring the complex interplay between cellular energy management and glycogen metabolism. GSDs, characterized by deficiencies in enzymes involved in glycogen synthesis or degradation, lead to the accumulation or improper utilization of glycogen in tissues such as the liver and muscle. This metabolic dysregulation often results in impaired energy production within mitochondria. Studies have shown that mitochondrial dysfunction in GSDs manifests through various mechanisms including altered mitochondrial biogenesis, disturbed ROS activity, increased oxidative stress, and impaired OXPHOS. These anomalies resulted in impaired structure and function of the mitochondria and contributed to clinical symptoms such as muscle weakness, exercise intolerance, and hepatic dysfunction, which are very common in GSDs. Furthermore, the intricate relationship between mitochondrial function and glycogen metabolism suggests that targeting mitochondrial pathways could offer therapeutic potential for managing GSDs. Advancements in molecular biology and genetics have provided deeper insights into the mitochondrial disturbances in GSDs, highlighting the need for comprehensive diagnostic and therapeutic strategies that address both glycogen metabolism and mitochondrial health. Interventions aiming to restore mitochondrial function, such as antioxidant therapy, gene therapy, and enzyme replacement therapy, hold promise but require further research and clinical validation. In conclusion, mitochondrial dysfunction plays a pivotal role in the pathophysiology of glycogen storage disorders, significantly influencing disease outcomes and patient quality of life. A multidisciplinary approach that integrates metabolic, genetic, and mitochondrial-targeted therapies is essential for developing effective treatments for GSDs, ultimately aiming to improve clinical outcomes and enhance the well-being of affected individuals.
  • Snippet 2 (score: 0.442) > Glycogen storage disorders (GSDs) are a group of inherited metabolic disorders characterized by defects in enzymes involved in glycogen metabolism. Deficiencies in enzymes responsible for glycogen breakdown and synthesis can impair mitochondrial function. For instance, in GSD type II (Pompe disease), acid alpha-glucosidase deficiency leads to lysosomal glycogen accumulation, which secondarily impacts mitochondrial function through dysfunctional mitophagy, which disrupts mitochondrial quality control, generating oxidative stress. In GSD type III (Cori disease), the lack of the debranching enzyme causes glycogen accumulation and affects mitochondrial dynamics and biogenesis by disrupting the integrity of muscle fibers. Malfunctional glycogen metabolism can disrupt various cascades, thus causing mitochondrial and cell metabolic dysfunction through various mechanisms. These dysfunctions include altered mitochondrial morphology, impaired oxidative phosphorylation, increased production of reactive oxygen species (ROS), and defective mitophagy. The oxidative burden typical of GSDs compromises mitochondrial integrity and exacerbates the metabolic derangements observed in GSDs. The intertwining of mitochondrial dysfunction and GSDs underscores the complexity of these disorders and has significant clinical implications. GSD patients often present with multisystem manifestations, including hepatomegaly, hypoglycemia, and muscle weakness, which can be exacerbated by mitochondrial impairment. Moreover, mitochondrial dysfunction may contribute to the progression of GSD-related complications, such as cardiomyopathy and neurocognitive deficits. Targeting mitochondrial dysfunction thus represents a promising therapeutic avenue in GSDs. Potential strategies include antioxidants to mitigate oxidative stress, compounds that enhance mitochondrial biogenesis, and gene therapy to correct the underlying mitochondrial enzyme deficiencies. Mitochondrial dysfunction plays a critical role in the pathophysiology of GSDs. Recognizing and addressing this aspect can lead to more comprehensive and effective treatments, improving the quality of life of GSD patients. This review aims to elaborate on the intricate relationship between mitochondrial dysfunction and various types of GSDs. The review presents challenges and treatment options for several GSDs.

[5] Crosstalk between Glycogen-Selective Autophagy, Autophagy and Apoptosis as a Road towards Modifier Gene Discovery and New Therapeutic Strategies for Glycogen Storage Diseases

  • Authors: M. Andjelkovic, A. Skakic, M. Ugrin, Vesna Spasovski, K. Klaassen et al.
  • Year: 2022
  • Venue: Life
  • URL: https://www.semanticscholar.org/paper/c55c145d3e454d95810e25b543ae6872c5d3f858
  • DOI: 10.3390/life12091396
  • PMID: 36143432
  • PMCID: 9504455
  • Citations: 6
  • Summary: The discovery of modifier genes related to glycogen-selective autophagy and Autophagy will start a new chapter in understanding of GSDs and enable the usage of autophagic-inducing drugs for the treatment of this group of rare-disease patients.
  • Evidence snippets:
  • Snippet 1 (score: 0.468) > Glycogen storage diseases (GSDs) are rare metabolic monogenic disorders characterized by an excessive accumulation of glycogen in the cell. However, monogenic disorders are not simple regarding genotype–phenotype correlation. Genes outside the major disease-causing locus could have modulatory effect on GSDs, and thus explain the genotype–phenotype inconsistencies observed in these patients. Nowadays, when the sequencing of all clinically relevant genes, whole human exomes, and even whole human genomes is fast, easily available and affordable, we have a scientific obligation to holistically analyze data and draw smarter connections between genotype and phenotype. Recently, the importance of glycogen-selective autophagy for the pathophysiology of disorders of glycogen metabolism have been described. Therefore, in this manuscript, we review the potential role of genes involved in glycogen-selective autophagy as modifiers of GSDs. Given the small number of genes associated with glycogen-selective autophagy, we also include genes, transcription factors, and non-coding RNAs involved in autophagy. A cross-link with apoptosis is addressed. All these genes could be analyzed in GSD patients with unusual discrepancies between genotype and phenotype in order to discover genetic variants potentially modifying their phenotype. The discovery of modifier genes related to glycogen-selective autophagy and autophagy will start a new chapter in understanding of GSDs and enable the usage of autophagy-inducing drugs for the treatment of this group of rare-disease patients.

[6] Carnitine is a pharmacological allosteric chaperone of the human lysosomal α-glucosidase

  • Authors: R. Iacono, Nadia Minopoli, M. Ferrara, Antonietta Tarallo, C. Damiano et al.
  • Year: 2021
  • Venue: Journal of Enzyme Inhibition and Medicinal Chemistry
  • URL: https://www.semanticscholar.org/paper/2af839ec28eeba06b63c58294f5a3ddd43ea7867
  • DOI: 10.1080/14756366.2021.1975694
  • PMID: 34565280
  • PMCID: 8477953
  • Citations: 9
  • Influential citations: 1
  • Summary: These drugs stabilise the enzyme at pH and temperature without inhibiting the activity and acted synergistically with active-site directed pharmacological chaperones, enhancing by 4-fold the acid α-glucosidase activity in fibroblasts from three Pompe patients with added rhGAA.
  • Evidence snippets:
  • Snippet 1 (score: 0.444) > Glycogen storage disease type 2, or Pompe disease (PD, OMIM 232300) is an inborn metabolic disorder caused by the functional deficiency of the acid lysosomal a-glucosidase (GAA, acid maltase, E.C. 3.2.1.20), the enzyme hydrolysing a-1,4 and a-1,6-glucosidic bonds in glycogen and belonging to family GH31 of the carbohydrate-active enzyme (CAZy) classification (www.cazy.org 1 ). GAA deficiency results in glycogen accumulation in lysosomes and in secondary cellular damage, with mechanisms not fully understood [2][3][4][5] . In PD, muscles are particularly vulnerable to glycogen storage, and disease manifestations are predominantly related to the involvement of cardiac and skeletal muscles. However, central nervous system involvement is emerging as part of the clinical spectrum in infantile-onset patients 6 . > It is assumed that to obtain positive therapeutic effects it is enough that the enzymatic activity of GAA is rescued at about 10% of the wild type, meaning that a relatively small increase in activity can mitigate the clinical course 2 . Therapeutic strategies include the supply of wild type enzymes, such as enzyme replacement therapy (ERT), gene therapy, or small-molecule drugs able to adjust cellular networks controlling protein synthesis, folding, trafficking, aggregation, and degradation, thus facilitating the escape of mutated proteins from the endoplasmic reticulum-associated degradation (ERAD) machinery [7][8][9][10] . > Since 2006, enzyme replacement therapy (ERT) with recombinant human a-glucosidase has been approved and is currently considered the standard of care for the treatment of PD, improving survival by stabilising the disease course 6,[11][12][13] . However, limitations are also known, in fact, despite treatment, some patients experience little clinical benefit or show signs of disease progression 14 . Several factors concur in limiting the therapeutic success of ERT, including the age at the start of treatment 15,16 , the immunological status of patients 17 , the insufficient targeting of the enzyme to

[7] Glycogen-autophagy: Molecular machinery and cellular mechanisms of glycophagy

  • Authors: P. Koutsifeli, U. Varma, L. Daniels, M. Annandale, Xun Li et al.
  • Year: 2022
  • Venue: The Journal of Biological Chemistry
  • URL: https://www.semanticscholar.org/paper/c878ff436fe40c3560df83bbec7b50eee4ed93c7
  • DOI: 10.1016/j.jbc.2022.102093
  • PMID: 35654138
  • PMCID: 9249846
  • Citations: 56
  • Influential citations: 2
  • Summary: Current evidence of glycophagy involvement in homeostatic cellular metabolic processes and of molecular mediators participating in glycogen-selective autophagy flux is reviewed.
  • Evidence snippets:
  • Snippet 1 (score: 0.443) > Autophagy is an essential cellular process involving degradation of superfluous or defective macromolecules and organelles as a form of homeostatic recycling. Initially proposed to be a “bulk” degradation pathway, a more nuanced appreciation of selective autophagy pathways has developed in the literature in recent years. As a glycogen-selective autophagy process, “glycophagy” is emerging as a key metabolic route of transport and delivery of glycolytic fuel substrate. Study of glycophagy is at an early stage. Enhanced understanding of this major noncanonical pathway of glycogen flux will provide important opportunities for new insights into cellular energy metabolism. In addition, glycogen metabolic mishandling is centrally involved in the pathophysiology of several metabolic diseases in a wide range of tissues, including the liver, skeletal muscle, cardiac muscle, and brain. Thus, advances in this exciting new field are of broad multidisciplinary interest relevant to many cell types and metabolic states. Here, we review the current evidence of glycophagy involvement in homeostatic cellular metabolic processes and of molecular mediators participating in glycophagy flux. We integrate information from a variety of settings including cell lines, primary cell culture systems, ex vivo tissue preparations, genetic disease models, and clinical glycogen disease states.
  • Snippet 2 (score: 0.433) > Autophagy is an essential cellular process involving degradation of superfluous or defective macromolecules and organelles as a form of homeostatic recycling. Initially proposed to be a "bulk" degradation pathway, a more nuanced appreciation of selective autophagy pathways has developed in the literature in recent years. As a glycogen-selective autophagy process, "glycophagy" is emerging as a key metabolic route of transport and delivery of glycolytic fuel substrate. Study of glycophagy is at an early stage. Enhanced understanding of this major noncanonical pathway of glycogen flux will provide important opportunities for new insights into cellular energy metabolism. In addition, glycogen metabolic mishandling is centrally involved in the pathophysiology of several metabolic diseases in a wide range of tissues, including the liver, skeletal muscle, cardiac muscle, and brain. Thus, advances in this exciting new field are of broad multidisciplinary interest relevant to many cell types and metabolic states. Here, we review the current evidence of glycophagy involvement in homeostatic cellular metabolic processes and of molecular mediators participating in glycophagy flux. We integrate information from a variety of settings including cell lines, primary cell culture systems, ex vivo tissue preparations, genetic disease models, and clinical glycogen disease states. > Glycogen is a hexose sugar polymer central to systemic and cellular metabolic homeostasis. Cytosolic regulated metabolism of glycogen has been extensively studied. Recently a noncanonical pathway of glycogenolysis involving a selective autophagy pathway trafficking glycogen to the lysosome has received attention. Macroautophagy (from the Greek "selfeating") is an essential cellular process that describes the packaging of cytoplasmic materials into autophagosomes for trafficking to lysosomes for degradation (1). Autophagy was initially conceptualized as a nonselective "bulk" degradation process. More recently the notion of selective autophagy has emerged, with specific protein mediators targeting organelles and macromolecules for destruction (2,3). The molecular mechanisms of autophagy involve coordination of several protein complexes and vesicle fusion events (

[8] PRKAG2 Variant, Motor Neuron Disease, and Parkinsonism: Fortuitous Association or a Potentially Underestimated Pathophysiological Mechanism?

  • Authors: Marco Orsini, W. B. Pinto, Paulo Sgobbi, A. S. B. Oliveira
  • Year: 2024
  • Venue: Muscles
  • URL: https://www.semanticscholar.org/paper/25f89e5a21a44526251c8bdc6858b066f1db303c
  • DOI: 10.3390/muscles3030021
  • PMID: 40757593
  • PMCID: 12225452
  • Summary: Clinicians must be aware of the possibility of PRKAG2 variants in complex clinical scenarios associating cardiac arrhythmia, preexcitation syndromes, hypertrophic cardiomyopathy, motor neuron disease, and parkinsonism.
  • Evidence snippets:
  • Snippet 1 (score: 0.439) > There is, however, current evidence demonstrating the expression of the PRKAG2 gene (ENSG00000106617.13) in different locations of the central nervous system, most significantly in the basal ganglia in the nucleus accumbens, putamen, and caudate, although it also occurs in other regions (the Human Protein Atlas) [23]. Likewise, the AMPK protein is currently implicated in the pathophysiology of different processes related to neurological diseases, especially in pathways related to mammalian target of rapamycin (mTOR) and in the regulation of autophagy mechanisms, modulating short-term metabolism cellular enzymes in the cholesterol and fatty acid biosynthesis pathways, and pathways related to mitochondrial biogenesis through the peroxisome proliferator-activated receptor (PPAR) and PPAR coactivator-1 alpha (PGC1alpha) [24]. In a similar clinical context, in adult polyglucosan body disease (APBD), due to variants in the GBE1 gene, neuropathy, dysautonomia, parkinsonism, cognitive decline, and leukoencephalopathy can be observed in varying degrees in affected adult individuals [25]. Compound heterozygous or homozygous variants in the GBE1 gene have been also associated with myopathic, hepatic, and cardiomyopathic involvement seen in glycogen storage disease type IV (Andersen disease) [25]. > Genetic variants in several genes related to inherited metabolic diseases, such as Gaucher disease, and heterozygous polymorphisms, such as in the GBA gene, have been previously identified as risk factors for the occurrence of parkinsonism and even MND. In these contexts, these variants usually represent additional risk factors and not specific monogenic pathophysiological mechanisms that occur along with the clinical neurological presentation. The contribution role of variants in the GBA gene within the neurodegenerative process due to endolysosomal dysfunction in MND/ALS has been established [26,27].

[9] Characterization of a canine model of glycogen storage disease type IIIa

  • Authors: Haiqing Yi, B. Thurberg, S. Curtis, S. Austin, J. Fyfe et al.
  • Year: 2012
  • Venue: Disease Models & Mechanisms
  • URL: https://www.semanticscholar.org/paper/fc1ed8f05e79692376f8e95062bbc4e774e6209f
  • DOI: 10.1242/dmm.009712
  • PMID: 22736456
  • PMCID: 3484863
  • Citations: 37
  • Influential citations: 2
  • Summary: In conclusion, the CCR dogs are an accurate model of GSD IIIa that will improve the understanding of the disease progression and allow opportunities to investigate treatment interventions.
  • Evidence snippets:
  • Snippet 1 (score: 0.437) > GSD III is one of the most common glycogen storage diseases. Currently, disease progression and pathology are not well characterized. Other than symptomatic management, no therapy is available for this condition . There is an urgent need for an animal model to study disease progression and to develop effective therapies that are definitive or targeted and relevant to human treatment modalities. In the past decade, canine models have emerged as a powerful tool for studying hereditary diseases and for the development of new therapeutic approaches. For example, a canine model of GSD I has been established and successfully used for studying disease pathophysiology, long-term complications, and development of gene therapy (Kishnani et al., 2001;Koeberl et al., 2008). The naturally occurring GDE frameshift mutation in CCR was first identified in 2007 (Gregory et al., 2007). The initial study of two affected dogs confirmed glycogen accumulation in liver and muscle and both dogs showed similar clinical signs to those of the human disease (Gregory et al., 2007). A breeding colony was established to obtain a larger cohort of affected dogs with the aim of understanding pathophysiological disease progression and developing novel therapies. The current study was designed to investigate in detail the natural history of the disease in this canine model. > Hypoglycemia and hyperlipidemia are dominant features in patients with GSD III in infancy and childhood (Hershkovitz et al., 1999;Geberhiwot et al., 2007;Bernier et al., 2008;

[10] Changes in Serum Proteomic Profiles at Different Stages of Pregnancy Toxemia in Goats

  • Authors: M. Uzti̇mür, C. N. Ünal, Gurler Akpinar
  • Year: 2025
  • Venue: Journal of Veterinary Internal Medicine
  • URL: https://www.semanticscholar.org/paper/4b9c488b5dbd65d7b26fd2ad9aed70e8c4b59942
  • DOI: 10.1111/jvim.70139
  • PMID: 40492724
  • PMCID: 12150350
  • Summary: Understanding the serum proteome profiles of goats with pregnancy toxemia might help identify the proteomes and pathways responsible for the development of this disease and improve diagnosis and treatment.
  • Evidence snippets:
  • Snippet 1 (score: 0.435) > The pathophysiology and progression of this disease are not fully understood. > Traditional biomedical research has focused on the analysis of single genes, proteins, metabolites, or metabolic pathways in diseases. This molecular reductionist approach is based on the assumption that identifying genetic variations and molecular components will lead to new treatments for diseases [13][14][15][16]. However, many diseases are complex and multifactorial, and in order to determine the phenotype of such diseases, it is necessary to understand the changes that occur in more than one gene, pathway, protein, or metabolite at the cellular, tissue, and organismal levels [17][18][19]. Therefore, in recent years, proteomics, as one field of multi-omics technologies, has helped in evaluating the complex pathogenetic mechanisms of different diseases from a broad perspective and has made substantial contributions [20,21]. In veterinary medicine, proteomic analysis of metabolic diseases such as ketosis [16], hypocalcemia [22], and fatty liver [23] in dairy cows has contributed valuable insights for the definition of new pathophysiological pathways and new diagnosis and treatment protocols for these diseases. The proteomic approach can contribute importantly to a broad and detailed understanding of the changes that occur at the organismal level associated with the increase in BHBA concentration in goats with pregnancy toxemia. Our aim was to evaluate the serum protein profiles of goats with SPT or CPT using proteomic techniques to determine the proteomic profiles of these animals and to identify the relevant pathophysiological mechanisms.

[11] Distribution of Exonic Variants in Glycogen Synthesis and Catabolism Genes in Late Onset Pompe Disease (LOPD)

  • Authors: P. de Filippi, E. Errichiello, A. Toscano, T. Mongini, M. Moggio et al.
  • Year: 2023
  • Venue: Current Issues in Molecular Biology
  • URL: https://www.semanticscholar.org/paper/c4ddac50dc1a3af8588a413eecf1a5e01aae11ac
  • DOI: 10.3390/cimb45040186
  • PMID: 37185710
  • PMCID: 10136686
  • Citations: 5
  • Summary: It appears that the current clinical scores used in LOPD do not describe muscle impairment with enough qualitative/quantitative details to correlate it with genes that, even with a slightly reduced function due to genetic variants, impact the phenotype.
  • Evidence snippets:
  • Snippet 1 (score: 0.433) > Pompe disease (PD) is a monogenic autosomal recessive disorder caused by biallelic pathogenic variants of the GAA gene encoding lysosomal alpha-glucosidase; its loss causes glycogen storage in lysosomes, mainly in the muscular tissue. The genotype–phenotype correlation has been extensively discussed, and caution is recommended when interpreting the clinical significance of any mutation in a single patient. As there is no evidence that environmental factors can modulate the phenotype, the observed clinical variability in PD suggests that genetic variants other than pathogenic GAA mutations influence the mechanisms of muscle damage/repair and the overall clinical picture. Genes encoding proteins involved in glycogen synthesis and catabolism may represent excellent candidates as phenotypic modifiers of PD. The genes analyzed for glycogen synthesis included UGP2, glycogenin (GYG1-muscle, GYG2, and other tissues), glycogen synthase (GYS1-muscle and GYS2-liver), GBE1, EPM2A, NHLRC1, GSK3A, and GSK3B. The only enzyme involved in glycogen catabolism in lysosomes is α-glucosidase, which is encoded by GAA, while two cytoplasmic enzymes, phosphorylase (PYGB-brain, PGL-liver, and PYGM-muscle) and glycogen debranching (AGL) are needed to obtain glucose 1-phosphate or free glucose. Here, we report the potentially relevant variants in genes related to glycogen synthesis and catabolism, identified by whole exome sequencing in a group of 30 patients with late-onset Pompe disease (LOPD). In our exploratory analysis, we observed a reduced number of variants in the genes expressed in muscles versus the genes expressed in other tissues, but we did not find a single variant that strongly affected the phenotype. From our work, it also appears that the current clinical scores used in LOPD do not describe muscle impairment with enough qualitative/quantitative details to correlate it with genes that, even with a slightly reduced function due to genetic variants, impact

[12] First person – Sudipta Bar

  • Authors: First Person, Sudipta Bar
  • Year: 2018
  • Venue: Disease Models & Mechanisms
  • URL: https://www.semanticscholar.org/paper/4c5cb19ac22e19b76a915d7baf5a7c5cc08010b4
  • DOI: 10.1242/dmm.037754
  • PMCID: 6262813
  • Summary: Sudipta Bar conducted the research described in this article while studying a PhD in Dr Rupak Datta's lab at the Indian Institute of Science Education and Research Kolkata, Nadia, India, and is now a Post Doc in the lab of Prof. Pankaj Kapahi at Buck Institute for Research on Aging, Novato, USA, investigating the molecular basis of neurodegeneration and how neurodegenersation affects memory.
  • Evidence snippets:
  • Snippet 1 (score: 0.430) > Mucopolysaccharidosis type VII (MPS VII) is a rare, hereditary lysosomal storage disease mostly accompanied with behavioral abnormality, organ failure and premature death. MPS VII is known to be caused by mutation in the β-glucuronidase gene. The only treatment is enzyme replacement therapy, which is an expensive, invasive and lifelong treatment procedure. Deep insight about the disease progression is also vaguely known and one of the limitations is the availability of a more suitable and handier disease model organism to study this human disease in a lab animal. We generated a fruit fly model of this disease by deleting the β-glucuronidase gene from the fruit fly genome. The fly model shows many similar phenotypes as a human patient. For example, premature death, short lifespan, storage of lysosome in brain and neurodegeneration. We used this model to study the disease in detail and found a major abnormality in dopaminergic neurons and muscle. Dopaminergic neuronal loss and muscle degeneration in this fly explained the basis of the disease-associated movement disability. We found that these defects could be corrected by treatment with resveratrol, thus providing a therapeutic lead. This novel MPS VII model holds the key to deeper exploration of the disease mechanism and drug discovery. > What are the potential implications of these results for your field of research? > The new fruit fly model, along with available genetic tools, will become more powerful to study the mechanistic details of MPS VII. The fly can be used in large-scale screening of drugs; for example, we observed the rescue of the disease phenotypes upon treatment with the drug resveratrol. This protective effect of resveratrol can be studied further as a potential MPS VII disease management strategy. In addition, the flies show abnormality in lysosome-mediated recycling processes in the brain along with neurodegeneration, which makes the model ideal to study the roles of lysosomes in neurodegeneration. Since the phenotypes among different types of MPS disorders are similar, the observations made in our MPS VII model may potentially be relevant in terms of a broader understanding and management of other closely related MPS disorders.

[13] Significance of early diagnosis and treatment of adult late-onset Pompe disease on the effectiveness of enzyme replacement therapy in improving muscle strength and respiratory function: a case report

  • Authors: Moein Mir, Kianmehr Rouhani, Kiana Rouhani, M. Hassani, Mohammadrafi Damirchi et al.
  • Year: 2024
  • Venue: Journal of Medical Case Reports
  • URL: https://www.semanticscholar.org/paper/9e35ccd87927911c2446cfeab88ea2e1d65bb689
  • DOI: 10.1186/s13256-024-04837-0
  • PMID: 39375771
  • PMCID: 11459847
  • Summary: A case of a patient with Pompe disease diagnosed 20 years after the onset of clinical symptoms, which underscores the challenges and complexities involved in diagnosing and managing rare neuromuscular disorders like Pompe disease.
  • Evidence snippets:
  • Snippet 1 (score: 0.429) > Glycogen storage disease II, or Pompe disease (MIM 232300), is an autosomal recessive disorder caused by mutations in the GAA gene (MIM 606800), which encodes acid α-1,4-glucosidase, a lysosomal enzyme involved in the degradation of glycogen that results in glycogen storage, mainly in skeletal muscles but even in several other organs such as the central nervous system (CNS), heart, respiratory system, vessels, and so on. [1]. This degenerative process is sustained by the enlargement and rupture of glycogen-filled lysosomes; however, impaired autophagic flux is also present. The accumulation of glycogen results in cellular dysfunction and cell damage due to hypertrophy and lysosomal ruptures; additional factors such as impaired autophagy, disrupted lysosome signaling pathways, oxidative stress, and abnormal mitochondria also contribute to Pompe disease, causing alterations in muscle structure with the displacement of myofibrils [2][3][4]. > Two major distinctive clinical phenotypes are recognized on the basis of the age at which the symptoms appear and the presence or absence of cardiomyopathy: the most severe classic infantile-onset type (IOPD) includes patients with less than 1% of GAA activity who develop symptoms within the first year of life and, if left untreated, rarely survive beyond 18 months, and the milder late-onset type (LOPD) with higher enzyme activity that may become apparent in childhood, adolescence, or adulthood [5,6]. > As skeletal and respiratory muscle weakness progress, patients often require ambulatory and ventilation assistance. Respiratory failure is therefore a cause of significant morbidity and the most frequent cause of death. Alglucosidase alfa (Lumizyme ® /Myozyme ® , Sanofi Genzyme, Cambridge, MA, USA) is an enzyme replacement therapy (ERT) used for the treatment of Pompe disease that provides patients with exogenous recombinant human GAA [7].

[14] Biomarkers in Lysosomal Storage Diseases

  • Authors: Joaquín Bobillo Lobato, Maria Jiménez Hidalgo, L. M. Jiménez Jiménez
  • Year: 2016
  • Venue: Diseases
  • URL: https://www.semanticscholar.org/paper/6a8bdc58db4d91dd2efe5adec28c651c2a2a41aa
  • DOI: 10.3390/diseases4040040
  • PMID: 28933418
  • PMCID: 5456325
  • Citations: 34
  • Influential citations: 1
  • Summary: The most promising biomarkers in major LSDs are summarized and discussed and why these are the most promising candidates for screening systems are discussed.
  • Evidence snippets:
  • Snippet 1 (score: 0.428) > Pompe disease (PD; OMIM 232300, with a prevalence at birth of 0.81/100,000 [12])-also known as glycogen storage disease type II, or acid maltase deficiency-is a lysosomal storage disorder in which mutations in the GAA cause deficiency of acid α-glucosidase enzyme (GAA; EC 3.2.1.20). This leads to the accumulation of glycogen in lysosomes of several tissues and cell types, particularly cardiac, skeletal, and smooth muscle cells [65]. Although glycogen breakdown also takes place outside the lysosome, interruption to lysosomal level affects several key processes, among which is autophagy, a critical survival mechanism in conditions of nutrient deprivation and cellular protein turnover [66]. > Cardiac pathology is a characteristic symptom of classic infantile Pompe disease-the most severe form. Usually, it presents in the first few months of life, and infants normally die within the first year. Late-onset forms of Pompe disease involve a wide age range (children, youth, and adults). This latter form initially presents hypotonia, muscle weakness, motor delay, and subsequent respiratory insufficiency [67,68]. The highly variable clinical presentation of the disease with respect to age of onset, disease severity, organ involvement, and clinical course is attributed to its allelic heterogeneity. In addition, it has been shown that there are polymorphisms which act as genotype modulators of PD that might determine the severity of final phenotype [69]. > Diagnosis of Pompe disease presents significant difficulties due to the rarity of the condition and the nonspecific nature of its phenotypic characteristics. Presentation in its infantile form is easily recognizable by its characteristic hypotonia, generalized weakness, and cardiomegaly. Patients with the adult form presentation develop less easily-identifiable symptoms that may be difficult to fit into the context of the disease. > Because it is a disease of accumulation in which the pathophysiological damage is progressive, a delay in diagnosis entails organic deterioration that may become increasingly severe and even irreversible [70].

[15] Metabolic Alterations in Inherited Cardiomyopathies

  • Authors: Claudia Sacchetto, V. Sequeira, E. Bertero, Jan Dudek, C. Maack et al.
  • Year: 2019
  • Venue: Journal of Clinical Medicine
  • URL: https://www.semanticscholar.org/paper/a51266219417743bebfd322375e424785d95e21c
  • DOI: 10.3390/jcm8122195
  • PMID: 31842377
  • PMCID: 6947282
  • Citations: 28
  • Influential citations: 2
  • Summary: A brief overview of the role of mitochondria in the energy metabolism in the heart is provided and focuses on metabolic abnormalities, mitochondrial dysfunction, and storage diseases associated with inherited cardiomyopathies.
  • Evidence snippets:
  • Snippet 1 (score: 0.428) > Also known as glycogen storage disease type II, Pompe disease is another storage disorder, leading to α-glucosidase (GAA) deficiency and subsequent intralysosomal build-up of glycogen in the affected tissues, including heart, skeletal muscle, and liver [219]. Pompe disease is inherited as an autosomal recessive trait and presents with a broad clinical spectrum that varies with respect to age and onset, rate of disease progression, and organ involvement [220]. Cardiac phenotypes include severe HCM or DCM with conduction abnormalities [221]. While the pathologic mechanisms of Pompe disease are not clear, more is known about Danon disease, an X-linked lysosomal disorder caused by mutations in the LAMP2 gene (lysosome-associated membrane protein 2) and associated with cardiomyopathies, including DCM and HCM [222,223]. Particularly, the first study performed on heart muscle from LAMP2-deficient mice showed accumulation of autophagic vesicles and glycogen deposits associated with reduced contractile function [224]. More recently, autophagy defects coupled with impaired mitochondrial clearance, also known as mitophagy, were reported by Hashem et al. in both human iPSC-derived cardiomyocytes carrying LAMP2 mutations and in LAMP2-deficient mice [225]. In these models, impaired mitochondrial respiratory capacity and abnormal gene expression of key mitochondrial pathways were observed, shedding light on pathological mechanisms of Danon disease, that might become potential targets for therapeutic intervention. > Fabry disease is a rare X-linked lysosomal storage disorder caused by a range of mutations in the gene encoding GLA, leading to α-galactosidase A deficiency [226]. It is characterized by accumulation of globotriaosylceramide (Gb3) in lysosomes within various tissues including the nervous system, kidneys, eyes, skin, and heart [227]. As a consequence of Gb3 accumulation, the activities of enzymes I, IV, and V of the respiratory chain are reduced, with subsequent reduction of levels of energy-rich phosphates [228].

[16] Cell Modeling and Rescue of a Novel Non-coding Genetic Cause of Glycogen Storage Disease IX

  • Authors: Apoorva K. Iyengar, Xue Zou, J. Dai, Rhodricia A. Francis, Alexias Safi et al.
  • Year: 2025
  • Venue: bioRxiv
  • URL: https://www.semanticscholar.org/paper/3b54dfdf82f86338dcfa434ff7dd5b33757ce2af
  • DOI: 10.1101/2025.05.14.654043
  • PMID: 40462889
  • PMCID: 12132531
  • Summary: A novel and robust pathway for detecting, validating, and reversing the impacts of novel non-coding causes of rare disease, including glycogen storage disease type IX γ2, is demonstrated.
  • Evidence snippets:
  • Snippet 1 (score: 0.426) > Determining the genetic variants that cause Mendelian disease is a crucial step in accurate diagnosis and consequently in patient care. A prolonged diagnostic odyssey is common and has lasting effects on the physical, psychological, and financial wellbeing of patients and their families (1,2). Understanding the genetic and molecular mechanisms underlying a patient's disease can inform prognosis, improve disease management, and may be required for insurance reimbursement and eligibility for clinical trials (3). Identifying novel causes of rare disease can also reveal new therapeutic targets for both rare and common disease. For those reasons, identifying additional genetic causes of rare disease is a profound opportunity for advancing precision medicine and improving healthcare (4)(5)(6)(7). > Glycogen storage diseases (GSDs) (incidence: 1:20,000-43,000 live births) provide an instrumental example of that diagnostic odyssey. GSDs are a group of mostly autosomal recessive disorders caused by genes involving glycogen synthesis and breakdown, typically in liver and muscle cells (8,9). These inborn errors of carbohydrate metabolism have high genetic and phenotypic heterogeneity with symptoms ranging from exercise intolerance to liver failure; however, most are progressive and in severe cases can cause metabolic crisis and irreversible organ damage if left untreated (10). Identifying genetic variants that cause GSDs can lead to accurate diagnosis prior to the onset of severe symptoms, allowing early nutrition and other medical interventions that can delay or prevent major organ damage. In contrast, delays in diagnosis can lead to much worse outcomes in the short term and over a lifetime (11)(12)(13). > One of the major challenges in identifying novel causes of rare diseases, including GSDs, is the identification of variants that disrupt mRNA splicing, which are thought to be involved in at least 10% of Mendelian disease cases (14)(15)(16)(17)(18). That challenge persists for several reasons. On one hand, whole-exome sequencing (WES) -commonly used for diagnosing genetic diseasetypically only identifies coding variants and non-coding variants at known splice sites that immediately flank exon boundaries.

[17] New therapeutic targets in rare genetic skeletal diseases

  • Authors: M. Briggs, Peter A. Bell, M. Wright, K. A. Pirog
  • Year: 2015
  • Venue: Expert Opinion on Orphan Drugs
  • URL: https://www.semanticscholar.org/paper/1363107f71ae6d2d60abca471cddf3da5d13644b
  • DOI: 10.1517/21678707.2015.1083853
  • PMID: 26635999
  • PMCID: 4643203
  • Citations: 38
  • Influential citations: 1
  • Summary: An overview of disease mechanisms that are shared amongst groups of different GSDs and potential therapeutic approaches that are under investigation are described to generate critical mass for the identification and validation of novel therapeutic targets and biomarkers.
  • Evidence snippets:
  • Snippet 1 (score: 0.425) > proteins of the cartilage ECM such as type II collagen [50]. However, emerging knowledge suggests that the primary genetic defect may be less important than the cells' response to the expression of the mutant gene product [107]. Moreover, the largely overlooked response of a cell (i.e. chondrocyte) to the abnormal extracellular environment is also important for disease progression as illustrated by several GSDs discussed in this review. > It is important that 'omics'-based approaches and technologies are systematically applied to the study of rare GSDs so that definitive reference profiles and disease signatures are generated for each phenotype. These can then be used in a Systems Biology approach to identify both common and dissimilar pathological signatures and disease mechanisms. This approach is entirely dependent upon relevant in vitro and in vivo models (and also novel 'disease-mechanism phenocopies' [107]) for testing new diagnostic and prognostic tools and for determining the molecular mechanisms that underpin the pathophysiology so that effective therapeutic treatments can be developed and validated. This approach will eventually lead to personalized treatments and care strategies centred on shared disease mechanisms with the use of relevant biomarkers to monitor the efficacy of treatment and disease progression. > It is vital that all relevant stakeholders are involved from the outset in defining the appropriate outcomes of any potential therapeutic regime. The perceptions of a successful therapy can differ widely between the clinical academic community and the relevant patient-support groups and it is vital that there is engagement on all these issues. > In summary, the identification of causative genes and mutations for GSDs over the last 20 years, coupled with the generation and in-depth analysis of a plethora of relevant cell and mouse models, has derived new knowledge on disease mechanisms and suggested potential therapeutic targets. The fast-evolving hypothesis that clinically disparate diseases can share common disease mechanisms is a powerful concept that will generate critical mass for the identification and validation of novel therapeutic targets and biomarkers.

[18] The molecular basis for Pompe disease revealed by the structure of human acid α-glucosidase

  • Authors: D. Deming, Karen L. Lee, T. McSherry, R. Wei, T. Edmunds et al.
  • Year: 2017
  • Venue: bioRxiv
  • URL: https://www.semanticscholar.org/paper/7ab7027ee067e8d00df8eab72c151eae1294d1e1
  • DOI: 10.1101/212837
  • Citations: 10
  • Influential citations: 1
  • Summary: Three structures of GAA complexes reveal the molecular basis for the hundreds of mutations that lead to Pompe disease and for pharmacological chaperoning in the protein, and reveals a surprising second sugar-binding site 34Å from the active site, suggesting a possible mechanism for processing of large glycogen substrates.
  • Evidence snippets:
  • Snippet 1 (score: 0.423) > Pompe disease results from a defect in human acid α-glucosidase (GAA), a lysosomal enzyme that cleaves terminal α1-4 and α1-6 glucose from glycogen. In Pompe disease (also known as Glycogen Storage Disorder type II), the accumulation of undegraded glycogen in lysosomes leads to cellular dysfunction, primarily in muscle and heart tissues. Pompe disease is an active candidate of clinical research, with pharmacological chaperone therapy tested and enzyme replacement therapy approved. Despite production of large amounts of recombinant GAA annually, the structure of GAA has not been reported until now. Here, we describe the first structure of GAA, at 1.7Å resolution. Three structures of GAA complexes reveal the molecular basis for the hundreds of mutations that lead to Pompe disease and for pharmacological chaperoning in the protein. The GAA structure reveals a surprising second sugar-binding site 34Å from the active site, suggesting a possible mechanism for processing of large glycogen substrates. Overall, the structure will assist in the design of next-generation treatments for Pompe disease.

Notes

  • This provider combines search_papers_by_relevance with snippet_search.
  • No synthesis or second-stage model call is performed.