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

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

• Papers retrieved: 19
• Snippets retrieved: 20

Relevant Papers

[1] 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: 63
• 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: 0.513) > 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.

[2] 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: 0.507) > 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: 0.449) > 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.

[3] Effects of Silymarin and Baicalein on Glycogen Storage in the Hepatocytes of Rat Models of Hepatic Injury

• Authors: Hongfei Yang, Didar Mehrabi Nasab, S. Athari
• Year: 2021
• Venue: Hepatitis Monthly
• URL: https://www.semanticscholar.org/paper/9cbe8774319f979fe8114a1b70779dfa16e2fc56
• DOI: 10.5812/HEPATMON.113114
• Citations: 4
• Summary: Baicalein and silymarin showed anti-inflammatory effects and could control inflammation and necrotic factors, but they did not affect hepatic glycogen storage.
• Evidence snippets:
• Snippet 1 (score: 0.503) > Hepatitis is the inflammation of the liver. Several factors can cause hepatitis, such as viral infections, fatty liver, glycogen deposition in high amounts, etc. Glycogen storage diseases (GSDs) are among the primary liver diseases that can lead to hepatitis. Carbohydrate-rich diets further contribute to glycogen accumulation and hyperinsulinism. A central function of hepatic glycogen, the storage form of glucose, is to regulate blood glucose and fasting homeostasis. > Glycogen storage diseases' pathophysiology is related to inborn errors of glycogen metabolism. Based on the deficient enzyme and affected tissue, there are at least 24 categories of GSDs (1,2). Glycogen storage diseases are characterized by deficiencies in the enzymes involved in glycogenesis and glycogenolysis. Among the various types of the disease, GSD type 0, I-IV, VI, IX, XI, XII, and XIV affect the liver. For example, GSD type I is characterized by glucose-6phosphate dehydrogenase (G6PD) deficiency, and patients with this type of GSD are unable to break glycogen into glucose because of having inadequate G6PD or its mediating transporter. Type III GSD is a metabolic problem caused by thee deficiency of the glycogen debranching enzyme, amylo-1,6-glucosidase, resulting in glycogen accumulation, hepatomegaly, and cardiomyopathy, and in turn, cardiac failure. Type XV presents with myocarditis and even evokes left ventricular arrhythmogenic cardiomyopathy (2-4). > G6PD and NADPH oxidase 4 (NOX4) play important roles in normal liver function. G6PD produces the NADPH used by NOX to produce superoxide. NOX increases reactive oxygen species (ROS), pro-inflammatory cytokines, and cellular damages and inhibits G6PD, which is more pronounced in G6PD deficiency and inactivity (5,6).

[4] 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: 0.492) > 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.

[5] 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: 0.478) > 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;

[6] 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: 0.466) > 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.

[7] 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: 0.464) > 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.

[8] Altered gut microbiota and microbial metabolism in children with hepatic glycogen storage disease: a case-control study

• Authors: Yizhong Wang, Honghong Liu, Fang Dong, Yongmei Xiao, Fangfei Xiao et al.
• Year: 2023
• Venue: Translational Pediatrics
• URL: https://www.semanticscholar.org/paper/39d1f265fe317e20a04144cb9ca582ca46f994f2
• DOI: 10.21037/tp-22-293
• PMID: 37181017
• PMCID: 10167392
• Citations: 6
• Summary: The hepatic GSD patients in this study presented with gut microbiota dysbiosis which correlated with altered BAs metabolism and fecal SCFAs changes, and the altered bacterial genera were correlated with the changes of both fecal BAs andSCFAs.
• Evidence snippets:
• Snippet 1 (score: 0.455) > Glycogen storage disease (GSD) is a group of hereditary metabolic disorders caused by the deficiency of enzymes involved in glycogen synthesis or glycolysis. The overall incidence of GSD is estimated at 1 in 20,000 to 43,000 live births (1). A total of 16 GSD TYPES (GSD 0-XV) have been reported according to the different enzyme deficiencies, affected tissue, and clinical symptoms (2). The majority of the GSD types are inherited in an autosomal recessive mode, with the exception of X-linked GSD type IXa (1). > Since glycogen is mainly stored in the liver and muscle, GSD may affect either the liver (hepatic GSD) or the muscles (muscle GSD), or both (1). Hypoglycemia and hepatomegaly are the major manifestations of hepatic GSD (3). In addition, hepatic GSD may present with several metabolic abnormalities, including hyperlipidemia, hyperlactatemia, and hyperuricemia (3,4). GSD I, GSD III, and GSD IX are the most common types, accounting for 80% of hepatic GSD cases, which result from glucose 6-phosphatase enzyme (G6PC), glycogen debranching enzyme (AGL), and phosphorylase kinase (PHKA2) deficiency, respectively (1). A variety of complications, such as delayed growth, osteoporosis, anemia, hepatocellular adenoma, and chronic kidney disease may occur in patients with GSD caused by long-term metabolic abnormalities (3,(5)(6)(7). The current standard therapies for hepatic GSD are nutritional intervention [e.g., uncooked cornstarch (UCCS)] and symptomatic supportive treatment (3,(5)(6)(7). > The human gut microbiota is an intricate microbial community consisting of trillions of microbes and millions of functional genes, which is significantly vital to human health. Its composition can be influenced by diet, lifestyle, medications, and genetics (8).

[9] 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: 0.455) > 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.

[10] 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: 0.448) > 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

[11] 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: 85
• 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: 0.438) > 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.

[12] Omics-Based Approaches for the Characterization of Pompe Disease Metabolic Phenotypes

• Authors: Nuria Gómez-Cebrián, Elena Gras-Colomer, J. L. Poveda Andrés, A. Pineda-Lucena, L. Puchades-Carrasco
• Year: 2023
• Venue: Biology
• URL: https://www.semanticscholar.org/paper/1ba7b13c5b85a99fc7a38c2111db38ade8f2fb8f
• DOI: 10.3390/biology12091159
• PMID: 37759559
• PMCID: 10525434
• Citations: 5
• Summary: The metabolic alterations reported to be significantly altered in Pompe disease patients in recent years are described to be a discovery tool for investigating disease-induced modifications in the complete metabolic profile, including large numbers of metabolites that are simultaneously analyzed, enabling the identification of novel potential biomarkers associated with these conditions.
• Evidence snippets:
• Snippet 1 (score: 0.437) > Simple Summary Pompe disease is produced by an enzymatic deficiency that leads to aberrant accumulation of glycogen in in multiple tissues, mainly muscle, causing progressive heart, respiratory and motor failure. Dysregulations observed in these patients are derived from glycogen accumulation but also to different secondary abnormalities. The characterization of the metabolic profile associated with this disease is a valuable approach to gain a larger view of all the metabolic dysregulations caused by the disease, and its potential correlation with clinical progression and response to therapies. This article describes the metabolic alterations reported to be significantly altered in Pompe disease patients in recent years. From a clinical perspective, this information could contribute to guide in the diagnosis, evaluation of disease severity, treatment decision and monitoring of Pompe disease patients. Abstract Lysosomal storage disorders (LSDs) constitute a large group of rare, multisystemic, inherited disorders of metabolism, characterized by defects in lysosomal enzymes, accessory proteins, membrane transporters or trafficking proteins. Pompe disease (PD) is produced by mutations in the acid alpha-glucosidase (GAA) lysosomal enzyme. This enzymatic deficiency leads to the aberrant accumulation of glycogen in the lysosome. The onset of symptoms, including a variety of neurological and multiple-organ pathologies, can range from birth to adulthood, and disease severity can vary between individuals. Although very significant advances related to the development of new treatments, and also to the improvement of newborn screening programs and tools for a more accurate diagnosis and follow-up of patients, have occurred over recent years, there exists an unmet need for further understanding the molecular mechanisms underlying the progression of the disease. Also, the reason why currently available treatments lose effectiveness over time in some patients is not completely understood. In this scenario, characterization of the metabolic phenotype is a valuable approach to gain insights into the global impact of lysosomal dysfunction, and its potential correlation with clinical progression and response to therapies. These approaches represent a discovery tool for investigating disease-induced modifications in the complete metabolic profile, including large numbers of metabolites that are simultaneously analyzed, enabling the identification of novel potential biomarkers associated with these conditions. This review aims to highlight the most relevant findings of recently published omics

[13] Pombiliti and Opfolda: shaping the future of adult late-onset pompe disease: an editorial

• Authors: Rumaisa Riaz, Ajeet Singh, Laiba Shakeel, L. Fatima, Aymar Akilimali
• Year: 2024
• Venue: Annals of Medicine and Surgery
• URL: https://www.semanticscholar.org/paper/695a697954d561f4a8a82f670d77213385ec973f
• DOI: 10.1097/MS9.0000000000002483
• PMID: 39359790
• PMCID: 11444574
• Summary: ,
• Evidence snippets:
• Snippet 1 (score: 0.432) > Pompe disease (PD) is an autosomal recessive condition arising from mutations in the acid alpha-glucosidase gene (GAA) located on chromosome 17, encoding the lysosomal GAA enzyme, which is responsible for the conversion of glycogen into glucose, a critical energy source for muscle function. This enzyme deficiency, whether partial or total, leads to an abnormal buildup of glycogen, serving as the underlying cause of Pompe's disease [1] . This mechanism by which glycogen builds up is shown in Fig. 1. Glycogen is an intracellular polymer consisting of glucose residues joined in linear chains by α 1→4 bonds and branches joined at branch sites by α 1→6 bonds [3] . Glycogen accumulation occurs in lysosomes across various tissues, with skeletal and cardiac muscles primarily affected, resulting in clinical symptoms. The condition manifests with diverse signs, ranging from hypertrophic cardiomyopathy and hypotonia in infancy to a gradual skeletal muscle myopathy in adults. Muscle structure and strength decline due to progressive lysosomal enlargement, rupture, cytoplasmic glycogen accumulation, and myofibril displacement. Recent research underscores multiple pathogenic mechanisms, including autophagy, oxidative stress, mitochondrial abnormalities, and calcium homeostasis, contributing to tissue damage in Pompe disease and similar lysosomal storage disorders. Non-contractile substances, such as glycogen-filled lysosomes, cytoplasmic glycogen pools, autophagic remnants, and lipofuscin, disrupt the contractile machinery, ultimately causing muscle injury and reduced performance [1] . Although this condition manifests as a single disease continuum, two distinct phenotypes are widely accepted. The early onset, the infantile form, is marked by a profound or near complete deficiency of GAA. Symptoms emerge within the initial months of life, presenting as feeding difficulties, poor weight gain, dyspnea, muscle weakness, an enlarged heart, floppiness, and head lag. In the absence of prompt and appropriate treatment, many infants affected by this form do not survive beyond their first year, succumbing to cardiac or respiratory complications.

[14] 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: 8
• 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: 0.430) > 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

[15] 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: 37
• 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.

[16] Transcriptional profiling of Hutchinson-Gilford progeria patients identifies primary target pathways of progerin

• Authors: Sandra Vidak, Sohyoung Kim, Tom Misteli
• Year: 2026
• Venue: Nucleus
• URL: https://www.semanticscholar.org/paper/4bd99b0875508364d8672b6da5a50d024d485a53
• DOI: 10.1080/19491034.2025.2611484
• PMID: 41489464
• PMCID: 12773485
• Summary: To probe the clinical relevance of previously implicated cellular pathways and to address the extent of gene expression heterogeneity between patients, transcriptomic analysis of a comprehensive set of HGPS patients finds misexpression of several cellular pathways, including multiple signaling pathways, the UPR and mesodermal cell fate specification.
• Evidence snippets:
• Snippet 1 (score: 0.424) > Oxidative stress represents another key pathogenic mechanism in HGPS, as impaired NRF2 activity or increased reactive oxygen species (ROS) levels are sufficient to recapitulate HGPSassociated phenotypes [17,32,60]. Collectively, these findings underscore the multifactorial nature of HGPS pathogenesis, implicating interconnected signaling cascades involved in inflammation, oxidative stress, proteostasis, and vascular remodeling. Reassuringly, our findings indicate that many of the major pathways that have been described to contribute to HGPS phenotypes in mouse and cellular disease models are also misregulated in progeria patients, and targeting these pathways may provide therapeutic avenues to mitigate disease severity and improve outcomes in HGPS. > Although individuals with HGPS typically exhibit a characteristic set of clinical features, such as craniofacial abnormalities, growth retardation, and cardiovascular complications, there is notable variability in the age of onset, severity, and progression of symptoms between patients [7,9]. At the cellular level, HGPS is associated with several hallmark abnormalities, including nuclear envelope defects, decreased expression of several nuclear proteins and epigenetic marks, mitochondrial dysfunction, and increased cellular senescence [1,11,30,31,61]. These cellular phenotypes also exhibit considerable variation between patients, possibly contributing to differences in clinical outcomes. Our results indicate that even though some degree of transcriptional heterogeneity between the individual patients exists, the majority of patients exhibit misregulation of a set of shared pathways, suggesting that these pathways are universal driver mechanisms in HGPS. Further work is needed to understand the molecular and genetic factors that underlie inter-individual variability in disease expression and progression. > A limitation of pathway analysis of HGPS patient samples is to distinguish the pathways which are directly targeted by the disease-causing progerin protein and the emergence of adaptive secondary response pathways during progression of the disease in patients during their lifetime. The same caveat applies to the use of cell-based models used in the study of HGPS disease mechanisms.

[17] The ties that bind: functional clusters in limb-girdle muscular dystrophy

• Authors: E. Barton, C. A. Pacak, Whitney L. Stoppel, P. Kang
• Year: 2020
• Venue: Skeletal Muscle
• URL: https://www.semanticscholar.org/paper/653422e1a9dc9cc7f16758b10f3f203155bc68c9
• DOI: 10.1186/s13395-020-00240-7
• PMID: 32727611
• PMCID: 7389686
• Citations: 24
• Summary: A deeper understanding of these disease pathways could yield a new generation of precision therapies that would each be expected to treat a broader range of LGMD patients than a single subtype, thus expanding the scope of the molecular medicines that may be developed for this complex array of muscular dystrophies.
• Evidence snippets:
• Snippet 1 (score: 0.424) > Pyridine nucleotide-disulfide reductase [55] Many of the protein functions listed require further confirmation or are disputed these methodologies. Those patients with moderate disease phenotypes regardless of the underlying causative gene mutation would likely fall into a category where there may be interest in testing a pharmacological treatment (that could be halted) but reduced interest in a more permanent experimental strategy. For all of the above-mentioned reasons, the identification of unifying therapeutic targets applicable to multiple subtypes of > LGMDs is highly desirable. > To identify such targets, we should first consider the question: What binds all of these LGMDs together? The two core phenotypic features are progressive proximal muscle weakness, along with characteristic signs of muscle fiber destruction on biopsy, referred to as "dystrophic" features. Nuances in clinical presentation have helped to distinguish some of the LGMDs, such as the frequent occurrence of difficulty walking on tiptoes in LGMD R2 (LGMD2B), caused by dysferlin deficiency. However, heterogeneity associated with variable ages of onset and ranges of severity makes it generally difficult to distinguish and diagnose LGMD subtypes based on clinical presentation alone. A change in perspective is in order to aid in understanding disease pathways responsible for clinical features even when the genetic mutation is unknown. Further, given the large number of genespecific LGMD subtypes, it could very well be that several major disease mechanisms may be shared across the family of diseases. Yet despite careful studies that have collectively determined the cellular localization of most proteins associated with LGMD (Fig. 1), there is limited knowledge of potentially unifying molecular disease mechanisms. We assert that the identification of functional clusters of these proteins, grouped by such common mechanisms, will streamline our understanding of the disease processes and identify therapeutic targets relevant to individuals in multiple disease subgroups, including individuals whose pathogenic mutations have not been found. By extension, this approach may serve as a tool to not only find common mechanisms, but may also help to distinguish LGMD subtypes that do not share similar functional patterns, and afford further refinement of potential treatments.

[18] The ties that bind: functional clusters in limb-girdle muscular dystrophy

• Authors: E. Barton, C. A. Pacak, Whitney L. Stoppel, Peter B. Kang
• Year: 2020
• Venue: Skeletal Muscle
• URL: https://www.semanticscholar.org/paper/3493c658bb8716d789a05ddf292162832e064e47
• DOI: 10.1186/s13395-020-00240-7
• Summary: A deeper understanding of these disease pathways could yield a new generation of precision therapies that would each be expected to treat a broader range of LGMD patients than a single subtype, thus expanding the scope of the molecular medicines that may be developed for this complex array of muscular dystrophies.
• Evidence snippets:
• Snippet 1 (score: 0.424) > Pyridine nucleotide-disulfide reductase [55] Many of the protein functions listed require further confirmation or are disputed these methodologies. Those patients with moderate disease phenotypes regardless of the underlying causative gene mutation would likely fall into a category where there may be interest in testing a pharmacological treatment (that could be halted) but reduced interest in a more permanent experimental strategy. For all of the above-mentioned reasons, the identification of unifying therapeutic targets applicable to multiple subtypes of > LGMDs is highly desirable. > To identify such targets, we should first consider the question: What binds all of these LGMDs together? The two core phenotypic features are progressive proximal muscle weakness, along with characteristic signs of muscle fiber destruction on biopsy, referred to as "dystrophic" features. Nuances in clinical presentation have helped to distinguish some of the LGMDs, such as the frequent occurrence of difficulty walking on tiptoes in LGMD R2 (LGMD2B), caused by dysferlin deficiency. However, heterogeneity associated with variable ages of onset and ranges of severity makes it generally difficult to distinguish and diagnose LGMD subtypes based on clinical presentation alone. A change in perspective is in order to aid in understanding disease pathways responsible for clinical features even when the genetic mutation is unknown. Further, given the large number of genespecific LGMD subtypes, it could very well be that several major disease mechanisms may be shared across the family of diseases. Yet despite careful studies that have collectively determined the cellular localization of most proteins associated with LGMD (Fig. 1), there is limited knowledge of potentially unifying molecular disease mechanisms. We assert that the identification of functional clusters of these proteins, grouped by such common mechanisms, will streamline our understanding of the disease processes and identify therapeutic targets relevant to individuals in multiple disease subgroups, including individuals whose pathogenic mutations have not been found. By extension, this approach may serve as a tool to not only find common mechanisms, but may also help to distinguish LGMD subtypes that do not share similar functional patterns, and afford further refinement of potential treatments.

[19] 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: 55
• 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: 0.420) > 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 (

Notes

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