RARE DISEASE
Glycogen storage disease type IV
Glycogen storage disease type IV
Glycogen storage disease type IV
Synonyms: Amylopectinosis, Andersen disease, GSD due to glycogen branching enzyme deficiency, GSD type 4, GSD type IV, Glycogen storage disease type 4, Glycogen storage disease type IV, Glycogenosis due to glycogen branching enzyme deficiency, Glycogenosis type 4, Glycogenosis type IV
Synonyms: Amylopectinosis, Andersen disease, GSD due to glycogen branching enzyme deficiency, GSD type 4, GSD type IV, Glycogen storage disease type 4, Glycogen storage disease type IV, Glycogenosis due to glycogen branching enzyme deficiency, Glycogenosis type 4, Glycogenosis type IV
Synonyms: Amylopectinosis, Andersen disease, GSD due to glycogen branching enzyme deficiency, GSD type 4, GSD type IV, Glycogen storage disease type 4, Glycogen storage disease type IV, Glycogenosis due to glycogen branching enzyme deficiency, Glycogenosis type 4, Glycogenosis type IV
Drug discovery
2
drugs
With orphan designations
Overview
Glycogen storage disease type IV (GSD IV), or Andersen disease, is a rare autosomal recessive disorder caused by GBE1 gene mutations, leading to deficient glycogen branching enzyme activity. This results in abnormal glycogen (polyglucosan) accumulation, primarily affecting the liver, heart, and neuromuscular systems. Clinical heterogeneity ranges from lethal perinatal forms to adult-onset presentations (e.g., adult polyglucosan body disease [APBD]) [1][8][17]. Diagnosis involves enzymatic assays, genetic testing, and histopathology [1][5].
Population
Prevalence: ~1 in 600,000–800,000 individuals [8]; accounts for ~3% of all glycogen storage disorders [1].
Affects all ages, with severe hepatic/neuromuscular forms often presenting in infancy [1][8].
Autosomal recessive inheritance; carrier frequency elevated in Ashkenazi Jewish populations (APBD) [5][17].
Burden
Therapies
Symptomatic management: Hypoglycemia control (frequent feeds, cornstarch), cardiac/respiratory support, and physical therapy [3][7][17].
Liver transplantation: Considered for progressive hepatic failure without cardiac involvement [1][8].
Experimental approaches: Pharmacologic chaperones (e.g., peptide Leu-Thr-Lys-Glu) and enzyme replacement therapy under investigation [5][17].
Categories: rare cardiac diseases, rare genetic diseases, rare hepatic diseases, rare inborn errors of metabolism, rare neurological diseases, rare transplant-related disorders
Research Papers
48 drug discovery papers about Glycogen storage disease type IV , with 1 first-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
48 drug discovery papers about Glycogen storage disease type IV , with 1 first-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
categories:
Small molecules
proteins
2025-12-18 | Systemic Disease Progression and Neurodegeneration in the Gbe1ys/ys Mouse Model of Glycogen Storage Disease Type IV.
Glycogen storage disease type IV (GSD IV) is a rare autosomal recessive disorder caused by glycogen branching enzyme (GBE1) deficiency, resulting in the accumulation of insoluble polyglucosan. The Gbe1ys/ys mouse model, carrying the p.Y329S variant, recapitulates features of adult-onset GSD IV, also known as adult polyglucosan body disease. However, the natural progression of the disease in this model is not fully understood. This study presents a longitudinal analysis of Gbe1ys/ys mice from 1 to 12 months of age, quantitatively tracking polyglucosan accumulation and correlating it with progressive histopathologic, motor, and behavioral changes. Polyglucosan bodies were detected as early as 1 month, with significant neurodegeneration and astrogliosis by 6 months. Notably, serum neurofilament light chain levels increased with disease progression, identifying neurofilament light chain as a potential noninvasive biomarker of neurodegeneration in GSD IV. Systemic involvement, including severe splenomegaly and gastrointestinal abnormalities, indicates broader effects of GBE1 deficiency beyond the central nervous system. These findings provide important insights into the natural history of GSD IV, establish key disease milestones for therapeutic intervention, and refine the clinical understanding of GSD IV and adult polyglucosan body disease.
2025-12-17 | Unifying the communities of early-onset glycogen storage disease type IV and adult polyglucosan body disease through a genetic prevalence study of GBE1 -related disease
ABSTRACT Glycogen storage disease type IV (GSD IV) is an autosomal recessive disorder caused by pathogenic variants in GBE1 , resulting in deficient glycogen branching enzyme (GBE) activity and formation of abnormal glycogen (“polyglucosan”). GSD IV manifests across a spectrum of clinical dimensions – including hepatic, neurologic, muscular, and cardiac involvement – which vary in severity. The early-onset forms, historically referred to as Andersen disease, present at different stages ranging from in utero to adolescence. The adult-onset form, referred to as adult polyglucosan body disease (APBD), typically presents in middle to late adulthood. To date, no epidemiological study of GSD IV has been performed. Understanding the global prevalence of GSD IV is critical to increase disease awareness, improve diagnostic rates, inform therapeutic development, and engage pharmaceutical companies. In collaboration with the Rare Genomes Project at the Broad Institute of MIT and Harvard and the APBD Research Foundation, this study curated variants in GBE1 and calculated prevalence across nine genetic ancestry groups. The estimated global carrier frequency of GSD IV is 1 in 243 individuals, and the global genetic prevalence is 1 in 235,784 individuals. Based on the 2024 world population, the estimated number of affected individuals with GSD IV is approximately 34,800. These estimates highlight a significant underdiagnosis of GSD IV and underscore the urgent need for increased awareness of this metabolic disorder. This model of collaboration between researchers, patient advocacy organizations, and genetic data sharing programs provides a framework for estimating the prevalence of other rare diseases in the global population. Graphical abstract Created in BioRender. Koch, R. (2025) https://BioRender.com/j0sg30n .
2025-10-01 | S5884 Suspected Glycogen Storage Disease in a Young Adult With Cryptogenic Cirrhosis: A Case Report
Introduction: Glycogen storage diseases (GSD) are inherited metabolic disorders of carbohydrate metabolism. GSD type III (Cori’s disease) and type IV (Andersen’s disease) have been associated with liver cirrhosis and hepatocellular carcinoma. We describe a rare case of GSD and cirrhosis in a patient with a history of childhood seizures and hypoglycemia. Case Description/Methods: A 38-year-old man with no known medical history presented with intermittent hematochezia without abdominal pain, weight loss, or fever. He was hemodynamically stable with an unremarkable exam. Labs showed hemoglobin 13.8 g/dL, platelets 64,000/uL, international normalized ratio 1.3, alanine aminotransferase 158 U/L, aspartate aminotransferase 260 U/L. Alkaline phosphatase and gamma-glutamyl transferase were minimally elevated. C-reactive protein was 75.8 mg/dL. Computed tomography (CT) showed cirrhosis, portal hypertension, and splenomegaly. He denied herbal supplements, intravenous drug, or heavy alcohol use. Family history was non-contributory. Abdominal magnetic resonance imaging (MRI) revealed multiple enhancing liver lesions not seen on computed tomography 1 week prior, suggesting rapid development. Upper endoscopy showed large esophageal varices and portal hypertensive gastropathy. Colonoscopy showed mild portal colopathy and hemorrhoids. Workup for chronic liver disease was negative, including viral hepatitis, autoimmune markers, iron/copper studies, and tumor markers. Biopsy of the largest lesion and background tissue showed cirrhosis with ballooning degeneration, clear cell change, and glycogenated hepatocytes. PAS staining without diastase confirmed glycogen accumulation. No malignancy, steatosis, or iron/copper overload was seen. In absence of classic risk factors and unusual histology, rare causes of cirrhosis were considered. A family member later recalled childhood hypoglycemia and seizures, which had resolved without diagnosis. These, along with imaging and biopsy findings, raised suspicion for late-presenting GSD. Repeat MRI at 3 months showed complete resolution of the liver lesions, suggesting a metabolic rather than neoplastic process. Genetic testing was initiated for confirmation. Discussion: This case illustrates an atypical presentation of cryptogenic cirrhosis and portal hypertension in a young adult with suspected GSD. The spontaneous resolution of liver lesions, glycogenated hepatocytes, and childhood hypoglycemia support a metabolic etiology. GSD should be considered in unexplained liver disease, even in adults. Early recognition using detailed history and genetic testing is essential for management and counseling.
2025-04-01 | Glycogen storage disease, an uncommon cause of portal hypertension in adulthood.
Glycogen storage diseases are inborn errors of metabolism, with an estimated incidence of 1 in 10,000. Type IV represents 3% of this diseases (GBE1 gene 3p14 involvement), presenting with varied clinical features, including a milder form of hepatic involvement, with hepatic integrity described up to 19 years of age. We present a 22-year-old woman with a history of low weight since childhood, she presented episodes of hematemesis and melena, and she underwent panendoscopy, documenting esophageal varices requiring variceal ligation. Extensive studies demonstrated indirect signs of portal hypertension, partial portal vein thrombosis, and multiple liver lesions, located in segments V, VI and VII, with an irregular heterogeneous morphology, partially defined borders, with a peripheral hypodense halo, the hyperdense center even in simple and porta phases, with the largest lesion being 8.2 × 7.8 × 8.1 cm. A defect in the filling of the left branch of the portal vein was identified, as well as compression of the right branch due to mass effect. Differential diagnoses included cholangiocarcinoma, hepatocellular carcinoma, and hepatic tuberculosis. Infectious-viral or autoimmune etiologies were ruled out through investigation. Percutaneous liver biopsy guided by ultrasound was performed. The histopathological report showed morphological findings suggestive of metabolic deposit disease. Tiny intracytoplasmic granules, PAS positive, F2 fibrosis on the metavir scale (Masson's trichrome staining); all of these findings consistent with glycogen storage disease type IV (branching enzyme deficiency) with non-progressive hepatic subtype was reached. Based on the history and evolution of the patient she was at the advanced stage of the disease with evidence of fibrosis and portal hypertension. She presented a torpid clinical course, with poor oral tolerance, we identified she had cardiomyopathy with left ventricular hypertrophy, manifesting with cardiac arrhythmia, managed with medical treatment. This was a challenging case, as the diagnosis was made at an advanced stage of the disease, with multiple complications, limiting the prognosis and therapeutic options for the patient. She was referred to the genetics service for further evaluation. We present a clinical case of a challenging diagnosis, due to the multiple clinical expressions and variants of glycogen storage disease. It can primarily affect the liver, heart, and neuromuscular system, according to enzymatic deficiency, with milder phenotypes having residual enzymatic activity.
2016-12-01 | Alglucosidase alfa treatment alleviates liver disease in a mouse model of glycogen storage disease type IV
Patients with progressive hepatic form of GSD IV often die of liver failure in early childhood. We tested the feasibility of using recombinant human acid-α glucosidase (rhGAA) for treating GSD IV. Weekly intravenously injection of rhGAA at 40 mg/kg for 4 weeks significantly reduced hepatic glycogen accumulation, lowered liver/body weight ratio, and reduced plasma ALP and ALT activities in GSD IV mice. Our data suggests that rhGAA is a potential therapy for GSD IV.
cell therapies
2023-12-11 | [Infant glycogen storage disease type Ⅳ: a clinicopathological and genetic characteristics analysis of five cases].
Objective: To investigate the clinical pathology and gene mutation characteristics of patients with glycogen storage disease type Ⅳ (GSD Ⅳ). Methods: The clinical data, liver histopathology and ultrastructural morphology, and gene sequencing results of 5 GSD Ⅳ cases diagnosed in the Children's Hospital Affiliated to Shanghai Jiaotong University School of Medicine and the Children's Hospital of Fudan University from January 2015 to February 2022 were collected and analyzed retrospectively. Results: Among the 5 cases, 3 were male and 2 were female, ranging in age from 4 months to 1 year and 9 months. The clinical manifestations included fever, hepatosplenomegaly, liver insufficiency, growth retardation and hypotonia. Four cases had liver biopsy showing ground-glass-like changes in hepatocytes with intracytoplasmic inclusion bodies and varying degrees of fibrosis. Liver electron microscopy in 2 cases showed that the level of glycogen increased to varying degrees, and the cytoplasm was filled with low electron density substances. Genetic testing revealed that 3 cases had compound heterozygous variants in GBE1 gene; 1 case had a single pathogenic variant in GBE1 gene; and 1 case was deceased with no genetic testing, but each parent was tested for a heterozygous variant in the GBE1 gene. A total of 9 GBE1 gene mutations were detected, 3 of which were reported mutations and 6 novel mutations. One case died of liver cirrhosis, and 1 case underwent autologous liver transplantation. After transplantation, the liver function basically returned to normal, and the growth and development improved; the other 3 cases were managed through diet control and symptomatic treatment. Conclusions: CSD Ⅳ is an extremely rare inherited metabolic disease caused by GBE1 gene mutation, often presenting with hepatic and neuromuscular disorders, with heterogeneous clinical manifestations. The diagnosis mainly depends on histopathology and a pedigree gene analysis. 目的： 探讨糖原贮积病Ⅳ型（glycogen storage disease typeⅣ，GSD Ⅳ）的临床病理及基因突变特点。 方法： 收集上海交通大学医学院附属儿童医院及复旦大学附属儿科医院2015年1月至2022年2月确诊的5例GSD Ⅳ病例的临床资料、肝脏病理组织学、超微结构形态及基因测序结果，并对其进行回顾性分析。 结果： 5例病例中男患儿3例，女患儿2例，年龄为4个月至1岁9个月，主要表现为发热、肝脾肿大、肝功能不全、生长发育迟缓及肌力、肌张力低下。其中4例行肝脏活检，显示肝细胞毛玻璃样改变伴胞质内包涵体及不同程度纤维化。2例行肝脏电镜检查，显示糖原水平不同程度增多，胞质内充满低电子密度物质。基因检测发现其中3例GBE1基因存在复合杂合变异；1例检测到GBE1基因单个致病性变异；1例因死亡未能行基因检测，其父母各检测出GBE1基因有一个杂合变异。病例共检测到9种GBE1基因突变类型，3种为已报道的突变，6种为新的突变。1例因肝硬化死亡；1例行亲体肝移植，移植后肝功能基本恢复正常，生长发育情况得到改善；另外3例主要以饮食控制调整，支持对症治疗。 结论： GSD Ⅳ是由GBE1基因突变所致的一种极为罕见的遗传代谢性疾病，常累及肝脏及神经肌肉，临床表现有异质性，其诊断主要依据组织病理学及家系基因分析。.
2022-11-08 | Case report: Familial glycogen storage disease type IV caused by novel compound heterozygous mutations in a glycogen branching enzyme 1 gene
Glycogen storage disease type IV (GSD IV), caused by a mutation in the glycogen branching enzyme 1 (GBE1) gene, is a rare metabolic disorder with an autosomal recessive inheritance that involves the liver, neuromuscular, and cardiac systems. Here, we reported a case of familial GSD IV induced by novel compound heterozygous mutations in GBE1. The proband (at age 1) and her younger brother (at age 10 months) manifested hepatosplenomegaly, liver dysfunction, and growth retardation at onset, followed by progressive disease deterioration to liver cirrhosis with liver failure. During the disease course, the proband presented rare intractable asymptomatic hypoglycemia. The liver pathology was in line with GSD IV. Both cases carried pathogenic compound heterozygous mutations in GBE1 mutations, i.e., a missense mutation (c.271T>A, p . W91R) in exon 2 and a deletion mutation in partial exons 3–7. Both mutations are first reported. The internationally pioneered split-liver transplantation was performed during progression to end-stage liver disease, and the patients had normal liver function and blood glucose after. This study broadens the mutation spectrum of the GBE1 gene and the phenotypic spectrum of GSD IV.
2022-03-21 | Liver transplantation in glycogen storage disease: a single-center experience
Glycogen storage diseases (GSDs) are inherited glycogen metabolic disorders which have various subtypes. GSDs of type I, III, IV, VI, and IX show liver involvement and are considered as hepatic types of GSDs. Thus, liver transplantation (LT) has been proposed as a final therapy for these types of GSD. LT corrects the primary hepatic enzyme defect; however, the long-term outcomes of LT in these patients have not been extensively evaluated so far. There are few reports in the English literature about the outcome of GSD patients after LT. There has been no report from Iran. The present retrospective study aimed to evaluate the long-term outcomes of eight patients with GSD types I, III, and IV who underwent LT in the affiliated hospitals of Shiraz University of Medical Sciences, from March 2013 to June 2021. During this period, there were no patients with GSD VI and IX identified in this center.The median time of diagnosis of the GSDs and at transplant was 1 year and 11 years, respectively. All eight transplanted patients were alive at the time of follow-up in this study. None of them required a re-transplant. All of the patients showed normalized liver enzymes after LT with no sign of hypoglycemia.LT is an achievable treatment for end-stage hepatic involvement of GSDs with a cure for metabolic deficiency. Our experience in these eight patients shows a favorable outcome with no mortality and no major complication.
2021-02-19 | Liver Transplantation for Glycogen Storage Disease Type IV
Glycogen storage disease type IV (GSD IV) is a rare autosomal recessive disorder caused by glycogen–branching enzyme (GBE) deficiency, leading to accumulation of amylopectin–like glycogen that may damage affected tissues. The clinical manifestations of GSD IV are heterogeneous; one of which is the classic manifestation of progressive hepatic fibrosis. There is no specific treatment available for GSD IV. Currently, liver transplantation is an option. It is crucial to evaluate long–term outcomes of liver transplantation. We reviewed the published literature for GSD IV patients undergoing liver transplantation. To date, some successful liver transplantations have increased the quantity and quality of life in patients. Although the extrahepatic manifestations of GSD IV may still progress after transplantation, especially cardiomyopathy. Patients with cardiac involvement are candidates for cardiac transplantation. Liver transplantation remains the only effective therapeutic option for treatment of GSD IV. However, liver transplantation may not alter the extrahepatic progression of GSD IV. Patients should be carefully assessed before liver transplantation.
2018-10-12 | A Case of Glycogen Storage Disease IV with Rare Homozygous Mutations in the Glycogen Branching Enzyme Gene
Glycogen storage disease (GSD) IV is a rare autosomal recessive inherited disorder caused by mutations in the gene coding for glycogen branching enzyme leading to progressive liver disease. GSD IV is associated with mutations in GBE1, which encodes the glycogen branching enzyme. We report a case of GSD IV with rare homozygous mutations in the GBE1 gene (c.791G>A (p.Gly264Glu), which was successfully treated by liver transplantation.
small molecules
2025-12-22 | Biopsy-Proven Reversal of F4 Cirrhosis in Classic Hepatic Glycogen Storage Disease Type IV: A 42-Year Follow-Up Without Transplantation.
Classic hepatic glycogen storage disease IV (GSD-IV) is widely regarded as an irreversible disorder that causes fatal cirrhosis by the age of 5 years unless liver transplantation is performed. We describe the first patient with biopsy-proven classic hepatic GSD-IV who survived into middle adulthood without transplantation and showed histological reversal of cirrhosis. We followed an infant diagnosed at 11 months with hepatosplenomegaly, severe aminotransferase elevation, and near-absent erythrocyte branching enzyme activity. Liver biopsies at ages 4 and 12 years confirmed polyglucosan-laden METAVIR F4 cirrhosis, and two episodes of variceal bleeding were controlled endoscopically and surgically. Thereafter, without disease-specific therapy, the aminotransferase level, platelet count, and portal hemodynamics gradually normalized. A third biopsy at age 43 showed complete disappearance of polyglucosan bodies and regression of fibrosis to F0, despite persistently minimal enzyme activity and compound heterozygous GBE1 variants in trans: c.137A > C p.(Gln46Pro) and the novel c.1340T > C p.(Leu447Pro). This unprecedented case demonstrates that biochemical and histological remission is possible in classic hepatic GSD-IV despite persistently deficient branching-enzyme activity. Early, aggressive management of portal hypertension may therefore permit long-term survival and full histological recovery, challenging the transplant-first paradigm and supporting individualized, transplant-sparing care.
2022-01-27 | Glycogen synthase downregulation rescues the amylopectinosis of murine RBCK1 deficiency
Abstract Longer glucan chains tend to precipitate. Glycogen, by far the largest mammalian glucan and the largest molecule in the cytosol with up to 55 000 glucoses, does not, due to a highly regularly branched spherical structure that allows it to be perfused with cytosol. Aberrant construction of glycogen leads it to precipitate, accumulate into polyglucosan bodies that resemble plant starch amylopectin and cause disease. This pathology, amylopectinosis, is caused by mutations in a series of single genes whose functions are under active study toward understanding the mechanisms of proper glycogen construction. Concurrently, we are characterizing the physicochemical particularities of glycogen and polyglucosans associated with each gene. These genes include GBE1, EPM2A and EPM2B, which respectively encode the glycogen branching enzyme, the glycogen phosphatase laforin and the laforin-interacting E3 ubiquitin ligase malin, for which an unequivocal function is not yet known. Mutations in GBE1 cause a motor neuron disease (adult polyglucosan body disease), and mutations in EPM2A or EPM2B a fatal progressive myoclonus epilepsy (Lafora disease). RBCK1 deficiency causes an amylopectinosis with fatal skeletal and cardiac myopathy (polyglucosan body myopathy 1, OMIM# 615895). RBCK1 is a component of the linear ubiquitin chain assembly complex, with unique functions including generating linear ubiquitin chains and ubiquitinating hydroxyl (versus canonical amine) residues, including of glycogen. In a mouse model we now show (i) that the amylopectinosis of RBCK1 deficiency, like in adult polyglucosan body disease and Lafora disease, affects the brain; (ii) that RBCK1 deficiency glycogen, like in adult polyglucosan body disease and Lafora disease, has overlong branches; (iii) that unlike adult polyglucosan body disease but like Lafora disease, RBCK1 deficiency glycogen is hyperphosphorylated; and finally (iv) that unlike laforin-deficient Lafora disease but like malin-deficient Lafora disease, RBCK1 deficiency’s glycogen hyperphosphorylation is limited to precipitated polyglucosans. In summary, the fundamental glycogen pathology of RBCK1 deficiency recapitulates that of malin-deficient Lafora disease. Additionally, we uncover sex and genetic background effects in RBCK1 deficiency on organ- and brain-region specific amylopectinoses, and in the brain on consequent neuroinflammation and behavioural deficits. Finally, we exploit the portion of the basic glycogen pathology that is common to adult polyglucosan body disease, both forms of Lafora disease and RBCK1 deficiency, namely overlong branches, to show that a unified approach based on downregulating glycogen synthase, the enzyme that elongates glycogen branches, can rescue all four diseases.
2020-03-05 | Discovery and Development of Small-Molecule Inhibitors of Glycogen Synthase
The overaccumulation of glycogen appears as a hallmark in various glycogen storage diseases (GSDs), including Pompe, Cori, Andersen, and Lafora disease. Accumulating evidence suggests that suppression of glycogen accumulation represents a potential therapeutic approach for treating these GSDs. Using a fluorescence polarization assay designed to screen for inhibitors of the key glycogen synthetic enzyme, glycogen synthase (GS), we identified a substituted imidazole, (rac)-2-methoxy-4-(1-(2-(1-methylpyrrolidin-2-yl)ethyl)-4-phenyl-1H-imidazol-5-yl)phenol (H23), as a first-in-class inhibitor for yeast GS 2 (yGsy2p). Data from X-ray crystallography at 2.85 Å, as well as kinetic data, revealed that H23 bound within the uridine diphosphate glucose binding pocket of yGsy2p. The high conservation of residues between human and yeast GS in direct contact with H23 informed the development of around 500 H23 analogs. These analogs produced a structure–activity relationship profile that led to the identification of a substituted pyrazole, 4-(4-(4-hydroxyphenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl)pyrogallol, with a 300-fold improved potency against human GS. These substituted pyrazoles possess a promising scaffold for drug development efforts targeting GS activity in GSDs associated with excess glycogen accumulation.
2019-11-12 | Guaiacol as a drug candidate for treating adult polyglucosan body disease.
Adult polyglucosan body disease (APBD) is a late-onset disease caused by intracellular accumulation of polyglucosan bodies, formed due to glycogen-branching enzyme (GBE) deficiency. To find a treatment for APBD, we screened 1,700 FDA-approved compounds in fibroblasts derived from APBD-modeling GBE1-knockin mice. Capitalizing on fluorescent periodic acid-Schiff reagent, which interacts with polyglucosans in the cell, this screen discovered that the flavoring agent guaiacol can lower polyglucosans, a result also confirmed in APBD patient fibroblasts. Biochemical assays showed that guaiacol lowers basal and glucose 6-phosphate-stimulated glycogen synthase (GYS) activity. Guaiacol also increased inactivating GYS1 phosphorylation and phosphorylation of the master activator of catabolism, AMP-dependent protein kinase. Guaiacol treatment in the APBD mouse model rescued grip strength and shorter lifespan. These treatments had no adverse effects except making the mice slightly hyperglycemic, possibly due to the reduced liver glycogen levels. In addition, treatment corrected penile prolapse in aged GBE1-knockin mice. Guaiacol's curative effects can be explained by its reduction of polyglucosans in peripheral nerve, liver, and heart, despite a short half-life of up to 60 minutes in most tissues. Our results form the basis to use guaiacol as a treatment and prepare for the clinical trials in APBD.
gene therapies
2021-09-24 | GYS1 or PPP1R3C deficiency rescues murine adult polyglucosan body disease.
Adult polyglucosan body disease (APBD) is an adult-onset neurological variant of glycogen storage disease type IV. APBD is caused by recessive mutations in the glycogen branching enzyme gene, and the consequent accumulation of poorly branched glycogen aggregates called polyglucosan bodies in the nervous system. There are presently no treatments for APBD. Here, we test whether downregulation of glycogen synthesis is therapeutic in a mouse model of the disease. We characterized the effects of knocking out two pro-glycogenic proteins in an APBD mouse model. APBD mice were crossed with mice deficient in glycogen synthase (GYS1), or mice deficient in protein phosphatase 1 regulatory subunit 3C (PPP1R3C), a protein involved in the activation of GYS1. Phenotypic and histological parameters were analyzed and glycogen was quantified. APBD mice deficient in GYS1 or PPP1R3C demonstrated improvements in life span, morphology, and behavioral assays of neuromuscular function. Histological analysis revealed a reduction in polyglucosan body accumulation and of astro- and micro-gliosis in the brains of GYS1- and PPP1R3C-deficient APBD mice. Brain glycogen quantification confirmed the reduction in abnormal glycogen accumulation. Analysis of skeletal muscle, heart, and liver found that GYS1 deficiency reduced polyglucosan body accumulation in all three tissues and PPP1R3C knockout reduced skeletal muscle polyglucosan bodies. GYS1 and PPP1R3C are effective therapeutic targets in the APBD mouse model. These findings represent a critical step toward the development of a treatment for APBD and potentially other glycogen storage disease type IV patients.
2021-01-06 | Efficient correction of a deleterious point mutation in primary horse fibroblasts with CRISPR-Cas9.
Phenotypic selection during animal domestication has resulted in unwanted incorporation of deleterious mutations. In horses, the autosomal recessive condition known as Glycogen Branching Enzyme Deficiency (GBED) is the result of one of these deleterious mutations (102C > A), in the first exon of the GBE1 gene (GBE1102C>A). With recent advances in genome editing, this type of genetic mutation can be precisely repaired. In this study, we used the RNA-guided nuclease CRISPR-Cas9 (clustered regularly-interspaced short palindromic repeats/CRISPR-associated protein 9) to correct the GBE1102C>A mutation in a primary fibroblast cell line derived from a high genetic merit heterozygous stallion. To correct this mutation by homologous recombination (HR), we designed a series of single guide RNAs (sgRNAs) flanking the mutation and provided different single-stranded donor DNA templates. The distance between the Cas9-mediated double-stranded break (DSB) to the mutation site, rather than DSB efficiency, was the primary determinant for successful HR. This framework can be used for targeting other harmful diseases in animal populations.
proteins
2025-12-18 | Systemic Disease Progression and Neurodegeneration in the Gbe1ys/ys Mouse Model of Glycogen Storage Disease Type IV.
Glycogen storage disease type IV (GSD IV) is a rare autosomal recessive disorder caused by glycogen branching enzyme (GBE1) deficiency, resulting in the accumulation of insoluble polyglucosan. The Gbe1ys/ys mouse model, carrying the p.Y329S variant, recapitulates features of adult-onset GSD IV, also known as adult polyglucosan body disease. However, the natural progression of the disease in this model is not fully understood. This study presents a longitudinal analysis of Gbe1ys/ys mice from 1 to 12 months of age, quantitatively tracking polyglucosan accumulation and correlating it with progressive histopathologic, motor, and behavioral changes. Polyglucosan bodies were detected as early as 1 month, with significant neurodegeneration and astrogliosis by 6 months. Notably, serum neurofilament light chain levels increased with disease progression, identifying neurofilament light chain as a potential noninvasive biomarker of neurodegeneration in GSD IV. Systemic involvement, including severe splenomegaly and gastrointestinal abnormalities, indicates broader effects of GBE1 deficiency beyond the central nervous system. These findings provide important insights into the natural history of GSD IV, establish key disease milestones for therapeutic intervention, and refine the clinical understanding of GSD IV and adult polyglucosan body disease.
2025-12-17 | Unifying the communities of early-onset glycogen storage disease type IV and adult polyglucosan body disease through a genetic prevalence study of GBE1 -related disease
ABSTRACT Glycogen storage disease type IV (GSD IV) is an autosomal recessive disorder caused by pathogenic variants in GBE1 , resulting in deficient glycogen branching enzyme (GBE) activity and formation of abnormal glycogen (“polyglucosan”). GSD IV manifests across a spectrum of clinical dimensions – including hepatic, neurologic, muscular, and cardiac involvement – which vary in severity. The early-onset forms, historically referred to as Andersen disease, present at different stages ranging from in utero to adolescence. The adult-onset form, referred to as adult polyglucosan body disease (APBD), typically presents in middle to late adulthood. To date, no epidemiological study of GSD IV has been performed. Understanding the global prevalence of GSD IV is critical to increase disease awareness, improve diagnostic rates, inform therapeutic development, and engage pharmaceutical companies. In collaboration with the Rare Genomes Project at the Broad Institute of MIT and Harvard and the APBD Research Foundation, this study curated variants in GBE1 and calculated prevalence across nine genetic ancestry groups. The estimated global carrier frequency of GSD IV is 1 in 243 individuals, and the global genetic prevalence is 1 in 235,784 individuals. Based on the 2024 world population, the estimated number of affected individuals with GSD IV is approximately 34,800. These estimates highlight a significant underdiagnosis of GSD IV and underscore the urgent need for increased awareness of this metabolic disorder. This model of collaboration between researchers, patient advocacy organizations, and genetic data sharing programs provides a framework for estimating the prevalence of other rare diseases in the global population. Graphical abstract Created in BioRender. Koch, R. (2025) https://BioRender.com/j0sg30n .
2025-10-01 | S5884 Suspected Glycogen Storage Disease in a Young Adult With Cryptogenic Cirrhosis: A Case Report
Introduction: Glycogen storage diseases (GSD) are inherited metabolic disorders of carbohydrate metabolism. GSD type III (Cori’s disease) and type IV (Andersen’s disease) have been associated with liver cirrhosis and hepatocellular carcinoma. We describe a rare case of GSD and cirrhosis in a patient with a history of childhood seizures and hypoglycemia. Case Description/Methods: A 38-year-old man with no known medical history presented with intermittent hematochezia without abdominal pain, weight loss, or fever. He was hemodynamically stable with an unremarkable exam. Labs showed hemoglobin 13.8 g/dL, platelets 64,000/uL, international normalized ratio 1.3, alanine aminotransferase 158 U/L, aspartate aminotransferase 260 U/L. Alkaline phosphatase and gamma-glutamyl transferase were minimally elevated. C-reactive protein was 75.8 mg/dL. Computed tomography (CT) showed cirrhosis, portal hypertension, and splenomegaly. He denied herbal supplements, intravenous drug, or heavy alcohol use. Family history was non-contributory. Abdominal magnetic resonance imaging (MRI) revealed multiple enhancing liver lesions not seen on computed tomography 1 week prior, suggesting rapid development. Upper endoscopy showed large esophageal varices and portal hypertensive gastropathy. Colonoscopy showed mild portal colopathy and hemorrhoids. Workup for chronic liver disease was negative, including viral hepatitis, autoimmune markers, iron/copper studies, and tumor markers. Biopsy of the largest lesion and background tissue showed cirrhosis with ballooning degeneration, clear cell change, and glycogenated hepatocytes. PAS staining without diastase confirmed glycogen accumulation. No malignancy, steatosis, or iron/copper overload was seen. In absence of classic risk factors and unusual histology, rare causes of cirrhosis were considered. A family member later recalled childhood hypoglycemia and seizures, which had resolved without diagnosis. These, along with imaging and biopsy findings, raised suspicion for late-presenting GSD. Repeat MRI at 3 months showed complete resolution of the liver lesions, suggesting a metabolic rather than neoplastic process. Genetic testing was initiated for confirmation. Discussion: This case illustrates an atypical presentation of cryptogenic cirrhosis and portal hypertension in a young adult with suspected GSD. The spontaneous resolution of liver lesions, glycogenated hepatocytes, and childhood hypoglycemia support a metabolic etiology. GSD should be considered in unexplained liver disease, even in adults. Early recognition using detailed history and genetic testing is essential for management and counseling.
2025-04-01 | Glycogen storage disease, an uncommon cause of portal hypertension in adulthood.
Glycogen storage diseases are inborn errors of metabolism, with an estimated incidence of 1 in 10,000. Type IV represents 3% of this diseases (GBE1 gene 3p14 involvement), presenting with varied clinical features, including a milder form of hepatic involvement, with hepatic integrity described up to 19 years of age. We present a 22-year-old woman with a history of low weight since childhood, she presented episodes of hematemesis and melena, and she underwent panendoscopy, documenting esophageal varices requiring variceal ligation. Extensive studies demonstrated indirect signs of portal hypertension, partial portal vein thrombosis, and multiple liver lesions, located in segments V, VI and VII, with an irregular heterogeneous morphology, partially defined borders, with a peripheral hypodense halo, the hyperdense center even in simple and porta phases, with the largest lesion being 8.2 × 7.8 × 8.1 cm. A defect in the filling of the left branch of the portal vein was identified, as well as compression of the right branch due to mass effect. Differential diagnoses included cholangiocarcinoma, hepatocellular carcinoma, and hepatic tuberculosis. Infectious-viral or autoimmune etiologies were ruled out through investigation. Percutaneous liver biopsy guided by ultrasound was performed. The histopathological report showed morphological findings suggestive of metabolic deposit disease. Tiny intracytoplasmic granules, PAS positive, F2 fibrosis on the metavir scale (Masson's trichrome staining); all of these findings consistent with glycogen storage disease type IV (branching enzyme deficiency) with non-progressive hepatic subtype was reached. Based on the history and evolution of the patient she was at the advanced stage of the disease with evidence of fibrosis and portal hypertension. She presented a torpid clinical course, with poor oral tolerance, we identified she had cardiomyopathy with left ventricular hypertrophy, manifesting with cardiac arrhythmia, managed with medical treatment. This was a challenging case, as the diagnosis was made at an advanced stage of the disease, with multiple complications, limiting the prognosis and therapeutic options for the patient. She was referred to the genetics service for further evaluation. We present a clinical case of a challenging diagnosis, due to the multiple clinical expressions and variants of glycogen storage disease. It can primarily affect the liver, heart, and neuromuscular system, according to enzymatic deficiency, with milder phenotypes having residual enzymatic activity.
2016-12-01 | Alglucosidase alfa treatment alleviates liver disease in a mouse model of glycogen storage disease type IV
Patients with progressive hepatic form of GSD IV often die of liver failure in early childhood. We tested the feasibility of using recombinant human acid-α glucosidase (rhGAA) for treating GSD IV. Weekly intravenously injection of rhGAA at 40 mg/kg for 4 weeks significantly reduced hepatic glycogen accumulation, lowered liver/body weight ratio, and reduced plasma ALP and ALT activities in GSD IV mice. Our data suggests that rhGAA is a potential therapy for GSD IV.
cell therapies
2023-12-11 | [Infant glycogen storage disease type Ⅳ: a clinicopathological and genetic characteristics analysis of five cases].
Objective: To investigate the clinical pathology and gene mutation characteristics of patients with glycogen storage disease type Ⅳ (GSD Ⅳ). Methods: The clinical data, liver histopathology and ultrastructural morphology, and gene sequencing results of 5 GSD Ⅳ cases diagnosed in the Children's Hospital Affiliated to Shanghai Jiaotong University School of Medicine and the Children's Hospital of Fudan University from January 2015 to February 2022 were collected and analyzed retrospectively. Results: Among the 5 cases, 3 were male and 2 were female, ranging in age from 4 months to 1 year and 9 months. The clinical manifestations included fever, hepatosplenomegaly, liver insufficiency, growth retardation and hypotonia. Four cases had liver biopsy showing ground-glass-like changes in hepatocytes with intracytoplasmic inclusion bodies and varying degrees of fibrosis. Liver electron microscopy in 2 cases showed that the level of glycogen increased to varying degrees, and the cytoplasm was filled with low electron density substances. Genetic testing revealed that 3 cases had compound heterozygous variants in GBE1 gene; 1 case had a single pathogenic variant in GBE1 gene; and 1 case was deceased with no genetic testing, but each parent was tested for a heterozygous variant in the GBE1 gene. A total of 9 GBE1 gene mutations were detected, 3 of which were reported mutations and 6 novel mutations. One case died of liver cirrhosis, and 1 case underwent autologous liver transplantation. After transplantation, the liver function basically returned to normal, and the growth and development improved; the other 3 cases were managed through diet control and symptomatic treatment. Conclusions: CSD Ⅳ is an extremely rare inherited metabolic disease caused by GBE1 gene mutation, often presenting with hepatic and neuromuscular disorders, with heterogeneous clinical manifestations. The diagnosis mainly depends on histopathology and a pedigree gene analysis. 目的： 探讨糖原贮积病Ⅳ型（glycogen storage disease typeⅣ，GSD Ⅳ）的临床病理及基因突变特点。 方法： 收集上海交通大学医学院附属儿童医院及复旦大学附属儿科医院2015年1月至2022年2月确诊的5例GSD Ⅳ病例的临床资料、肝脏病理组织学、超微结构形态及基因测序结果，并对其进行回顾性分析。 结果： 5例病例中男患儿3例，女患儿2例，年龄为4个月至1岁9个月，主要表现为发热、肝脾肿大、肝功能不全、生长发育迟缓及肌力、肌张力低下。其中4例行肝脏活检，显示肝细胞毛玻璃样改变伴胞质内包涵体及不同程度纤维化。2例行肝脏电镜检查，显示糖原水平不同程度增多，胞质内充满低电子密度物质。基因检测发现其中3例GBE1基因存在复合杂合变异；1例检测到GBE1基因单个致病性变异；1例因死亡未能行基因检测，其父母各检测出GBE1基因有一个杂合变异。病例共检测到9种GBE1基因突变类型，3种为已报道的突变，6种为新的突变。1例因肝硬化死亡；1例行亲体肝移植，移植后肝功能基本恢复正常，生长发育情况得到改善；另外3例主要以饮食控制调整，支持对症治疗。 结论： GSD Ⅳ是由GBE1基因突变所致的一种极为罕见的遗传代谢性疾病，常累及肝脏及神经肌肉，临床表现有异质性，其诊断主要依据组织病理学及家系基因分析。.
2022-11-08 | Case report: Familial glycogen storage disease type IV caused by novel compound heterozygous mutations in a glycogen branching enzyme 1 gene
Glycogen storage disease type IV (GSD IV), caused by a mutation in the glycogen branching enzyme 1 (GBE1) gene, is a rare metabolic disorder with an autosomal recessive inheritance that involves the liver, neuromuscular, and cardiac systems. Here, we reported a case of familial GSD IV induced by novel compound heterozygous mutations in GBE1. The proband (at age 1) and her younger brother (at age 10 months) manifested hepatosplenomegaly, liver dysfunction, and growth retardation at onset, followed by progressive disease deterioration to liver cirrhosis with liver failure. During the disease course, the proband presented rare intractable asymptomatic hypoglycemia. The liver pathology was in line with GSD IV. Both cases carried pathogenic compound heterozygous mutations in GBE1 mutations, i.e., a missense mutation (c.271T>A, p . W91R) in exon 2 and a deletion mutation in partial exons 3–7. Both mutations are first reported. The internationally pioneered split-liver transplantation was performed during progression to end-stage liver disease, and the patients had normal liver function and blood glucose after. This study broadens the mutation spectrum of the GBE1 gene and the phenotypic spectrum of GSD IV.
2022-03-21 | Liver transplantation in glycogen storage disease: a single-center experience
Glycogen storage diseases (GSDs) are inherited glycogen metabolic disorders which have various subtypes. GSDs of type I, III, IV, VI, and IX show liver involvement and are considered as hepatic types of GSDs. Thus, liver transplantation (LT) has been proposed as a final therapy for these types of GSD. LT corrects the primary hepatic enzyme defect; however, the long-term outcomes of LT in these patients have not been extensively evaluated so far. There are few reports in the English literature about the outcome of GSD patients after LT. There has been no report from Iran. The present retrospective study aimed to evaluate the long-term outcomes of eight patients with GSD types I, III, and IV who underwent LT in the affiliated hospitals of Shiraz University of Medical Sciences, from March 2013 to June 2021. During this period, there were no patients with GSD VI and IX identified in this center.The median time of diagnosis of the GSDs and at transplant was 1 year and 11 years, respectively. All eight transplanted patients were alive at the time of follow-up in this study. None of them required a re-transplant. All of the patients showed normalized liver enzymes after LT with no sign of hypoglycemia.LT is an achievable treatment for end-stage hepatic involvement of GSDs with a cure for metabolic deficiency. Our experience in these eight patients shows a favorable outcome with no mortality and no major complication.
2021-02-19 | Liver Transplantation for Glycogen Storage Disease Type IV
Glycogen storage disease type IV (GSD IV) is a rare autosomal recessive disorder caused by glycogen–branching enzyme (GBE) deficiency, leading to accumulation of amylopectin–like glycogen that may damage affected tissues. The clinical manifestations of GSD IV are heterogeneous; one of which is the classic manifestation of progressive hepatic fibrosis. There is no specific treatment available for GSD IV. Currently, liver transplantation is an option. It is crucial to evaluate long–term outcomes of liver transplantation. We reviewed the published literature for GSD IV patients undergoing liver transplantation. To date, some successful liver transplantations have increased the quantity and quality of life in patients. Although the extrahepatic manifestations of GSD IV may still progress after transplantation, especially cardiomyopathy. Patients with cardiac involvement are candidates for cardiac transplantation. Liver transplantation remains the only effective therapeutic option for treatment of GSD IV. However, liver transplantation may not alter the extrahepatic progression of GSD IV. Patients should be carefully assessed before liver transplantation.
2018-10-12 | A Case of Glycogen Storage Disease IV with Rare Homozygous Mutations in the Glycogen Branching Enzyme Gene
Glycogen storage disease (GSD) IV is a rare autosomal recessive inherited disorder caused by mutations in the gene coding for glycogen branching enzyme leading to progressive liver disease. GSD IV is associated with mutations in GBE1, which encodes the glycogen branching enzyme. We report a case of GSD IV with rare homozygous mutations in the GBE1 gene (c.791G>A (p.Gly264Glu), which was successfully treated by liver transplantation.
small molecules
2025-12-22 | Biopsy-Proven Reversal of F4 Cirrhosis in Classic Hepatic Glycogen Storage Disease Type IV: A 42-Year Follow-Up Without Transplantation.
Classic hepatic glycogen storage disease IV (GSD-IV) is widely regarded as an irreversible disorder that causes fatal cirrhosis by the age of 5 years unless liver transplantation is performed. We describe the first patient with biopsy-proven classic hepatic GSD-IV who survived into middle adulthood without transplantation and showed histological reversal of cirrhosis. We followed an infant diagnosed at 11 months with hepatosplenomegaly, severe aminotransferase elevation, and near-absent erythrocyte branching enzyme activity. Liver biopsies at ages 4 and 12 years confirmed polyglucosan-laden METAVIR F4 cirrhosis, and two episodes of variceal bleeding were controlled endoscopically and surgically. Thereafter, without disease-specific therapy, the aminotransferase level, platelet count, and portal hemodynamics gradually normalized. A third biopsy at age 43 showed complete disappearance of polyglucosan bodies and regression of fibrosis to F0, despite persistently minimal enzyme activity and compound heterozygous GBE1 variants in trans: c.137A > C p.(Gln46Pro) and the novel c.1340T > C p.(Leu447Pro). This unprecedented case demonstrates that biochemical and histological remission is possible in classic hepatic GSD-IV despite persistently deficient branching-enzyme activity. Early, aggressive management of portal hypertension may therefore permit long-term survival and full histological recovery, challenging the transplant-first paradigm and supporting individualized, transplant-sparing care.
2022-01-27 | Glycogen synthase downregulation rescues the amylopectinosis of murine RBCK1 deficiency
Abstract Longer glucan chains tend to precipitate. Glycogen, by far the largest mammalian glucan and the largest molecule in the cytosol with up to 55 000 glucoses, does not, due to a highly regularly branched spherical structure that allows it to be perfused with cytosol. Aberrant construction of glycogen leads it to precipitate, accumulate into polyglucosan bodies that resemble plant starch amylopectin and cause disease. This pathology, amylopectinosis, is caused by mutations in a series of single genes whose functions are under active study toward understanding the mechanisms of proper glycogen construction. Concurrently, we are characterizing the physicochemical particularities of glycogen and polyglucosans associated with each gene. These genes include GBE1, EPM2A and EPM2B, which respectively encode the glycogen branching enzyme, the glycogen phosphatase laforin and the laforin-interacting E3 ubiquitin ligase malin, for which an unequivocal function is not yet known. Mutations in GBE1 cause a motor neuron disease (adult polyglucosan body disease), and mutations in EPM2A or EPM2B a fatal progressive myoclonus epilepsy (Lafora disease). RBCK1 deficiency causes an amylopectinosis with fatal skeletal and cardiac myopathy (polyglucosan body myopathy 1, OMIM# 615895). RBCK1 is a component of the linear ubiquitin chain assembly complex, with unique functions including generating linear ubiquitin chains and ubiquitinating hydroxyl (versus canonical amine) residues, including of glycogen. In a mouse model we now show (i) that the amylopectinosis of RBCK1 deficiency, like in adult polyglucosan body disease and Lafora disease, affects the brain; (ii) that RBCK1 deficiency glycogen, like in adult polyglucosan body disease and Lafora disease, has overlong branches; (iii) that unlike adult polyglucosan body disease but like Lafora disease, RBCK1 deficiency glycogen is hyperphosphorylated; and finally (iv) that unlike laforin-deficient Lafora disease but like malin-deficient Lafora disease, RBCK1 deficiency’s glycogen hyperphosphorylation is limited to precipitated polyglucosans. In summary, the fundamental glycogen pathology of RBCK1 deficiency recapitulates that of malin-deficient Lafora disease. Additionally, we uncover sex and genetic background effects in RBCK1 deficiency on organ- and brain-region specific amylopectinoses, and in the brain on consequent neuroinflammation and behavioural deficits. Finally, we exploit the portion of the basic glycogen pathology that is common to adult polyglucosan body disease, both forms of Lafora disease and RBCK1 deficiency, namely overlong branches, to show that a unified approach based on downregulating glycogen synthase, the enzyme that elongates glycogen branches, can rescue all four diseases.
2020-03-05 | Discovery and Development of Small-Molecule Inhibitors of Glycogen Synthase
The overaccumulation of glycogen appears as a hallmark in various glycogen storage diseases (GSDs), including Pompe, Cori, Andersen, and Lafora disease. Accumulating evidence suggests that suppression of glycogen accumulation represents a potential therapeutic approach for treating these GSDs. Using a fluorescence polarization assay designed to screen for inhibitors of the key glycogen synthetic enzyme, glycogen synthase (GS), we identified a substituted imidazole, (rac)-2-methoxy-4-(1-(2-(1-methylpyrrolidin-2-yl)ethyl)-4-phenyl-1H-imidazol-5-yl)phenol (H23), as a first-in-class inhibitor for yeast GS 2 (yGsy2p). Data from X-ray crystallography at 2.85 Å, as well as kinetic data, revealed that H23 bound within the uridine diphosphate glucose binding pocket of yGsy2p. The high conservation of residues between human and yeast GS in direct contact with H23 informed the development of around 500 H23 analogs. These analogs produced a structure–activity relationship profile that led to the identification of a substituted pyrazole, 4-(4-(4-hydroxyphenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl)pyrogallol, with a 300-fold improved potency against human GS. These substituted pyrazoles possess a promising scaffold for drug development efforts targeting GS activity in GSDs associated with excess glycogen accumulation.
2019-11-12 | Guaiacol as a drug candidate for treating adult polyglucosan body disease.
Adult polyglucosan body disease (APBD) is a late-onset disease caused by intracellular accumulation of polyglucosan bodies, formed due to glycogen-branching enzyme (GBE) deficiency. To find a treatment for APBD, we screened 1,700 FDA-approved compounds in fibroblasts derived from APBD-modeling GBE1-knockin mice. Capitalizing on fluorescent periodic acid-Schiff reagent, which interacts with polyglucosans in the cell, this screen discovered that the flavoring agent guaiacol can lower polyglucosans, a result also confirmed in APBD patient fibroblasts. Biochemical assays showed that guaiacol lowers basal and glucose 6-phosphate-stimulated glycogen synthase (GYS) activity. Guaiacol also increased inactivating GYS1 phosphorylation and phosphorylation of the master activator of catabolism, AMP-dependent protein kinase. Guaiacol treatment in the APBD mouse model rescued grip strength and shorter lifespan. These treatments had no adverse effects except making the mice slightly hyperglycemic, possibly due to the reduced liver glycogen levels. In addition, treatment corrected penile prolapse in aged GBE1-knockin mice. Guaiacol's curative effects can be explained by its reduction of polyglucosans in peripheral nerve, liver, and heart, despite a short half-life of up to 60 minutes in most tissues. Our results form the basis to use guaiacol as a treatment and prepare for the clinical trials in APBD.
gene therapies
2021-09-24 | GYS1 or PPP1R3C deficiency rescues murine adult polyglucosan body disease.
Adult polyglucosan body disease (APBD) is an adult-onset neurological variant of glycogen storage disease type IV. APBD is caused by recessive mutations in the glycogen branching enzyme gene, and the consequent accumulation of poorly branched glycogen aggregates called polyglucosan bodies in the nervous system. There are presently no treatments for APBD. Here, we test whether downregulation of glycogen synthesis is therapeutic in a mouse model of the disease. We characterized the effects of knocking out two pro-glycogenic proteins in an APBD mouse model. APBD mice were crossed with mice deficient in glycogen synthase (GYS1), or mice deficient in protein phosphatase 1 regulatory subunit 3C (PPP1R3C), a protein involved in the activation of GYS1. Phenotypic and histological parameters were analyzed and glycogen was quantified. APBD mice deficient in GYS1 or PPP1R3C demonstrated improvements in life span, morphology, and behavioral assays of neuromuscular function. Histological analysis revealed a reduction in polyglucosan body accumulation and of astro- and micro-gliosis in the brains of GYS1- and PPP1R3C-deficient APBD mice. Brain glycogen quantification confirmed the reduction in abnormal glycogen accumulation. Analysis of skeletal muscle, heart, and liver found that GYS1 deficiency reduced polyglucosan body accumulation in all three tissues and PPP1R3C knockout reduced skeletal muscle polyglucosan bodies. GYS1 and PPP1R3C are effective therapeutic targets in the APBD mouse model. These findings represent a critical step toward the development of a treatment for APBD and potentially other glycogen storage disease type IV patients.
2021-01-06 | Efficient correction of a deleterious point mutation in primary horse fibroblasts with CRISPR-Cas9.
Phenotypic selection during animal domestication has resulted in unwanted incorporation of deleterious mutations. In horses, the autosomal recessive condition known as Glycogen Branching Enzyme Deficiency (GBED) is the result of one of these deleterious mutations (102C > A), in the first exon of the GBE1 gene (GBE1102C>A). With recent advances in genome editing, this type of genetic mutation can be precisely repaired. In this study, we used the RNA-guided nuclease CRISPR-Cas9 (clustered regularly-interspaced short palindromic repeats/CRISPR-associated protein 9) to correct the GBE1102C>A mutation in a primary fibroblast cell line derived from a high genetic merit heterozygous stallion. To correct this mutation by homologous recombination (HR), we designed a series of single guide RNAs (sgRNAs) flanking the mutation and provided different single-stranded donor DNA templates. The distance between the Cas9-mediated double-stranded break (DSB) to the mutation site, rather than DSB efficiency, was the primary determinant for successful HR. This framework can be used for targeting other harmful diseases in animal populations.
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Drug Discovery Landscape
2 orphan drug designations for Glycogen storage disease type IV .
2 orphan drug designations for Glycogen storage disease type IV .
Drug | Therapy type | Regulator | Orphan designation | Approval | Sponsor |
|---|---|---|---|---|---|
N-(2-Methoxyethyl)-6-methyl-N-[(3-methyl-2-thienyl)methyl]-2-oxo-1,2-dihydropyridine-4-carboxamide | small molecules | EMA | 2025-01-16 | — | AdRes EU B.V. |
N-(2-Methoxyethyl)-6-methyl-N-[(3-methyl-2-thienyl)methyl]-2-oxo-1,2-dihydropyridine-4-carboxamide | small molecules | FDA | 2023-08-09 | — | Golden Heart Flower, Ltd. |
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