RARE DISEASE
Glycogen storage disease due to glycogen branching enzyme deficiency
Glycogen storage disease due to glycogen branching enzyme deficiency
Glycogen storage disease due to glycogen branching enzyme deficiency
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 due to glycogen branching enzyme deficiency, 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 due to glycogen branching enzyme deficiency, with 1 first-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
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.
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.
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.
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.
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Drug Discovery Landscape
2 orphan drug designations for Glycogen storage disease due to glycogen branching enzyme deficiency.
2 orphan drug designations for Glycogen storage disease due to glycogen branching enzyme deficiency.
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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