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Naito C, Kosar K, Kishimoto E, Pena L, Huang Y, Hao K, Bernieh A, Kasten J, Villa C, Kishnani P, Deeksha B, Gu M, Asai A. Induced pluripotent stem cell (iPSC) modeling validates reduced GBE1 enzyme activity due to a novel variant, p.Ile694Asn, found in a patient with suspected glycogen storage disease IV. Mol Genet Metab Rep 2024; 39:101069. [PMID: 38516405 PMCID: PMC10955421 DOI: 10.1016/j.ymgmr.2024.101069] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/14/2024] [Accepted: 03/05/2024] [Indexed: 03/23/2024] Open
Abstract
Background Glycogen Storage disease type 4 (GSD4), a rare disease caused by glycogen branching enzyme 1 (GBE1) deficiency, affects multiple organ systems including the muscles, liver, heart, and central nervous system. Here we report a GSD4 patient, who presented with severe hepatosplenomegaly and cardiac ventricular hypertrophy. GBE1 sequencing identified two variants: a known pathogenic missense variant, c.1544G>A (p.Arg515His), and a missense variant of unknown significance (VUS), c.2081T>A (p. Ile694Asn). As a liver transplant alone can exacerbate heart dysfunction in GSD4 patients, a precise diagnosis is essential for liver transplant indication. To characterize the disease-causing variant, we modeled patient-specific GBE1 deficiency using CRISPR/Cas9 genome-edited induced pluripotent stem cells (iPSCs). Methods iPSCs from a healthy donor (iPSC-WT) were genome-edited by CRISPR/Cas9 to induce homozygous p.Ile694Asn in GBE1 (iPSC-GBE1-I694N) and differentiated into hepatocytes (iHep) or cardiomyocytes (iCM). GBE1 enzyme activity was measured, and PAS-D staining was performed to analyze polyglucosan deposition in these cells. Results iPSCGBE1-I694N differentiated into iHep and iCM exhibited reduced GBE1 protein level and enzyme activity in both cell types compared to iPSCwt. Both iHepGBE1-I694N and iCMGBE1-I694N showed polyglucosan deposits correlating to the histologic patterns of the patient's biopsies. Conclusions iPSC-based disease modeling supported a loss of function effect of p.Ile694Asn in GBE1. The modeling of GBE1 enzyme deficiency in iHep and iCM cell lines had multi-organ findings, demonstrating iPSC-based modeling usefulness in elucidating the effects of novel VUS in ultra-rare diseases.
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Affiliation(s)
- Chie Naito
- Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA
| | - Karis Kosar
- Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA
| | - Eriko Kishimoto
- Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA
| | - Loren Pena
- Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA
- Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH, USA
| | - Yilun Huang
- Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA
| | - Kaili Hao
- Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA
| | - Anas Bernieh
- Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA
- Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH, USA
| | - Jennifer Kasten
- Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA
- Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH, USA
| | - Chet Villa
- Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA
- Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH, USA
| | - Priya Kishnani
- Department of Pediatrics, Division of Medical Genetics, Duke Health, Durham, NC, USA
| | - Bali Deeksha
- Department of Pediatrics, Division of Medical Genetics, Duke Health, Durham, NC, USA
| | - Mingxia Gu
- Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA
- Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH, USA
| | - Akihiro Asai
- Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA
- Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH, USA
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Markussen KH, Corti M, Byrne BJ, Kooi CWV, Sun RC, Gentry MS. The multifaceted roles of the brain glycogen. J Neurochem 2024; 168:728-743. [PMID: 37554056 PMCID: PMC10901277 DOI: 10.1111/jnc.15926] [Citation(s) in RCA: 12] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/17/2023] [Revised: 07/04/2023] [Accepted: 07/07/2023] [Indexed: 08/10/2023]
Abstract
Glycogen is a biologically essential macromolecule that is directly involved in multiple human diseases. While its primary role in carbohydrate storage and energy metabolism in the liver and muscle is well characterized, recent research has highlighted critical metabolic and non-metabolic roles for glycogen in the brain. In this review, the emerging roles of glycogen homeostasis in the healthy and diseased brain are discussed with a focus on advancing our understanding of the role of glycogen in the brain. Innovative technologies that have led to novel insights into glycogen functions are detailed. Key insights into how cellular localization impacts neuronal and glial function are discussed. Perturbed glycogen functions are observed in multiple disorders of the brain, including where it serves as a disease driver in the emerging category of neurological glycogen storage diseases (n-GSDs). n-GSDs include Lafora disease (LD), adult polyglucosan body disease (APBD), Cori disease, Glucose transporter type 1 deficiency syndrome (G1D), GSD0b, and late-onset Pompe disease (PD). They are neurogenetic disorders characterized by aberrant glycogen which results in devastating neurological and systemic symptoms. In the most severe cases, rapid neurodegeneration coupled with dementia results in death soon after diagnosis. Finally, we discuss current treatment strategies that are currently being developed and have the potential to be of great benefit to patients with n-GSD. Taken together, novel technologies and biological insights have resulted in a renaissance in brain glycogen that dramatically advanced our understanding of both biology and disease. Future studies are needed to expand our understanding and the multifaceted roles of glycogen and effectively apply these insights to human disease.
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Affiliation(s)
- Kia H. Markussen
- Department of Molecular and Cellular Biochemistry, College of Medicine, University of Kentucky, USA
| | - Manuela Corti
- Department of Pediatrics, Powell Gene Therapy Center, College of Medicine, University of Florida, USA
| | - Barry J. Byrne
- Department of Pediatrics, Powell Gene Therapy Center, College of Medicine, University of Florida, USA
| | - Craig W. Vander Kooi
- Department of Biochemistry & Molecular Biology, College of Medicine, University of Florida, USA
- Center for Advanced Spatial Biomolecule Research, University of Florida
- Lafora Epilepsy Cure Initiative
| | - Ramon C. Sun
- Department of Biochemistry & Molecular Biology, College of Medicine, University of Florida, USA
- Center for Advanced Spatial Biomolecule Research, University of Florida
- Lafora Epilepsy Cure Initiative
| | - Matthew S. Gentry
- Department of Biochemistry & Molecular Biology, College of Medicine, University of Florida, USA
- Center for Advanced Spatial Biomolecule Research, University of Florida
- Lafora Epilepsy Cure Initiative
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Gümüş E, Özen H. Glycogen storage diseases: An update. World J Gastroenterol 2023; 29:3932-3963. [PMID: 37476587 PMCID: PMC10354582 DOI: 10.3748/wjg.v29.i25.3932] [Citation(s) in RCA: 23] [Impact Index Per Article: 11.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/28/2022] [Revised: 02/15/2023] [Accepted: 04/30/2023] [Indexed: 06/28/2023] Open
Abstract
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.
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Affiliation(s)
- Ersin Gümüş
- Department of Pediatric Gastroenterology, Hepatology and Nutrition, Hacettepe University Faculty of Medicine, Ihsan Dogramaci Children’s Hospital, Ankara 06230, Turkey
| | - Hasan Özen
- Department of Pediatric Gastroenterology, Hepatology and Nutrition, Hacettepe University Faculty of Medicine, Ihsan Dogramaci Children’s Hospital, Ankara 06230, Turkey
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Naik B, Kumar V, Goyal SK, Dutt Tripathi A, Mishra S, Joakim Saris PE, Kumar A, Rizwanuddin S, Kumar V, Rustagi S. Pullulanase: unleashing the power of enzyme with a promising future in the food industry. Front Bioeng Biotechnol 2023; 11:1139611. [PMID: 37449089 PMCID: PMC10337586 DOI: 10.3389/fbioe.2023.1139611] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/07/2023] [Accepted: 06/13/2023] [Indexed: 07/18/2023] Open
Abstract
Pullulanases are the most important industrial group of enzymes in family 13 glycosyl hydrolases. They hydrolyze either α-1,6 and α-1,4 or both glycosidic bonds in pullulan as well as other carbohydrates to produce glucose, maltose, and maltotriose syrups, which have important uses in food and other related sectors. However, very less reports are available on pullulanase production from native strains because of low yield issues. In line with the increasing demands for pullulanase, it has become important to search for novel pullulanase-producing microorganisms with high yields. Moreover, high production costs and low yield are major limitations in the industrial production of pullulanase enzymes. The production cost of pullulanase by using the solid-state fermentation (SSF) process can be minimized by selecting agro-industrial waste. This review summarizes the types, sources, production strategies, and potential applications of pullulanase in different food and other related industries. Researchers should focus on fungal strains producing pullulanase for better yield and low production costs by using agro-waste. It will prove a better enzyme in different food processing industries and will surely reduce the cost of products.
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Affiliation(s)
- Bindu Naik
- Department of Food Science and Technology, Graphic Era (Deemed to be University), Uttarakhand, India
| | - Vijay Kumar
- Himalayan School of Biosciences, Swami Rama Himalayan University, Dehradun, India
| | - S. K. Goyal
- Department of Agricultural Engineering, Institute of Agricultural Sciences, Banaras Hindu University, Varanasi, India
| | - Abhishek Dutt Tripathi
- Department of Dairy Science and Food Technology, Institute of Agricultural Sciences, Banaras Hindu University, Varanasi, India
| | - Sadhna Mishra
- Faculty of Agricultural Sciences, GLA University, Mathura, India
| | - Per Erik Joakim Saris
- Department of Microbiology, Faculty of Agriculture and Forestry, University of Helsinki, Helsinki, Finland
| | - Akhilesh Kumar
- Himalayan School of Biosciences, Swami Rama Himalayan University, Dehradun, India
| | - Sheikh Rizwanuddin
- Department of Food Science and Technology, Graphic Era (Deemed to be University), Uttarakhand, India
| | - Vivek Kumar
- Himalayan School of Biosciences, Swami Rama Himalayan University, Dehradun, India
| | - Sarvesh Rustagi
- Department of Food Technology, UCLAS, Uttaranchal University, Dehradun, India
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5
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Kiely BT, Koch RL, Flores L, Burner D, Kaplan S, Kishnani PS. A novel approach to characterize phenotypic variation in GSD IV: Reconceptualizing the clinical continuum. Front Genet 2022; 13:992406. [PMID: 36176296 PMCID: PMC9513518 DOI: 10.3389/fgene.2022.992406] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/12/2022] [Accepted: 08/23/2022] [Indexed: 11/13/2022] Open
Abstract
Purpose: Glycogen storage disease type IV (GSD IV) has historically been divided into discrete hepatic (classic hepatic, non-progressive hepatic) and neuromuscular (perinatal-congenital neuromuscular, juvenile neuromuscular) subtypes. However, the extent to which this subtype-based classification system accurately captures the landscape of phenotypic variation among GSD IV patients has not been systematically assessed. Methods: This study synthesized clinical data from all eligible cases of GSD IV in the published literature to evaluate whether this disorder is better conceptualized as discrete subtypes or a clinical continuum. A novel phenotypic scoring approach was applied to characterize the extent of hepatic, neuromuscular, and cardiac involvement in each eligible patient. Results: 146 patients met all inclusion criteria. The majority (61%) of those with sufficient data to be scored exhibited phenotypes that were not fully consistent with any of the established subtypes. These included patients who exhibited combined hepatic-neuromuscular involvement; patients whose phenotypes were intermediate between the established hepatic or neuromuscular subtypes; and patients who presented with predominantly cardiac disease. Conclusion: The application of this novel phenotypic scoring approach showed that-in contrast to the traditional subtype-based view-GSD IV may be better conceptualized as a multidimensional clinical continuum, whereby hepatic, neuromuscular, and cardiac involvement occur to varying degrees in different patients.
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Affiliation(s)
- Bridget T. Kiely
- Duke University Medical Center, Department of Pediatrics, Division of Medical Genetics, Durham, NC, United States
| | - Rebecca L. Koch
- Duke University Medical Center, Department of Pediatrics, Division of Medical Genetics, Durham, NC, United States
| | - Leticia Flores
- Duke University Medical Center, Department of Pediatrics, Division of Medical Genetics, Durham, NC, United States
| | - Danielle Burner
- Duke University Medical Center, Department of Pediatrics, Division of Medical Genetics, Durham, NC, United States
| | - Samantha Kaplan
- Medical Center Library and Archives, Duke University School of Medicine, Durham, NC, United States
| | - Priya S. Kishnani
- Duke University Medical Center, Department of Pediatrics, Division of Medical Genetics, Durham, NC, United States
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Sullivan MA, Nitschke S, Skwara EP, Wang P, Zhao X, Pan XS, Chown EE, Wang T, Perri AM, Lee JPY, Vilaplana F, Minassian BA, Nitschke F. Skeletal Muscle Glycogen Chain Length Correlates with Insolubility in Mouse Models of Polyglucosan-Associated Neurodegenerative Diseases. Cell Rep 2020; 27:1334-1344.e6. [PMID: 31042462 DOI: 10.1016/j.celrep.2019.04.017] [Citation(s) in RCA: 40] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/04/2018] [Revised: 01/29/2019] [Accepted: 04/02/2019] [Indexed: 01/31/2023] Open
Abstract
Lafora disease (LD) and adult polyglucosan body disease (APBD) are glycogen storage diseases characterized by a pathogenic buildup of insoluble glycogen. Mechanisms causing glycogen insolubility are poorly understood. Here, in two mouse models of LD (Epm2a-/- and Epm2b-/-) and one of APBD (Gbe1ys/ys), the separation of soluble and insoluble muscle glycogen is described, enabling separate analysis of each fraction. Total glycogen is increased in LD and APBD mice, which, together with abnormal chain length and molecule size distributions, is largely if not fully attributed to insoluble glycogen. Soluble glycogen consists of molecules with distinct chain length distributions and differential corresponding solubility, providing a mechanistic link between soluble and insoluble glycogen in vivo. Phosphorylation states differ across glycogen fractions and mouse models, demonstrating that hyperphosphorylation is not a basic feature of insoluble glycogen. Lastly, model-specific variances in protein and activity levels of key glycogen synthesis enzymes suggest uninvestigated regulatory mechanisms.
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Affiliation(s)
- Mitchell A Sullivan
- Program in Genetics and Genome Biology, Hospital for Sick Children Research Institute, Toronto, ON M5G 0A4, Canada; Glycation and Diabetes, Translational Research Institute, Mater Research Institute - University of Queensland, Brisbane, QLD 4102, Australia
| | - Silvia Nitschke
- Program in Genetics and Genome Biology, Hospital for Sick Children Research Institute, Toronto, ON M5G 0A4, Canada
| | - Evan P Skwara
- Program in Genetics and Genome Biology, Hospital for Sick Children Research Institute, Toronto, ON M5G 0A4, Canada
| | - Peixiang Wang
- Program in Genetics and Genome Biology, Hospital for Sick Children Research Institute, Toronto, ON M5G 0A4, Canada
| | - Xiaochu Zhao
- Program in Genetics and Genome Biology, Hospital for Sick Children Research Institute, Toronto, ON M5G 0A4, Canada
| | - Xiao S Pan
- Program in Genetics and Genome Biology, Hospital for Sick Children Research Institute, Toronto, ON M5G 0A4, Canada; Institute of Medical Science, University of Toronto, Toronto, ON M5S 1A8, Canada
| | - Erin E Chown
- Program in Genetics and Genome Biology, Hospital for Sick Children Research Institute, Toronto, ON M5G 0A4, Canada; Institute of Medical Science, University of Toronto, Toronto, ON M5S 1A8, Canada
| | - Travis Wang
- Program in Genetics and Genome Biology, Hospital for Sick Children Research Institute, Toronto, ON M5G 0A4, Canada
| | - Ami M Perri
- Program in Genetics and Genome Biology, Hospital for Sick Children Research Institute, Toronto, ON M5G 0A4, Canada
| | - Jennifer P Y Lee
- Program in Genetics and Genome Biology, Hospital for Sick Children Research Institute, Toronto, ON M5G 0A4, Canada
| | - Francisco Vilaplana
- Division of Glycoscience, Department of Chemistry, KTH Royal Institute of Technology, AlbaNova University Centre, Stockholm 10691, Sweden
| | - Berge A Minassian
- Program in Genetics and Genome Biology, Hospital for Sick Children Research Institute, Toronto, ON M5G 0A4, Canada; Institute of Medical Science, University of Toronto, Toronto, ON M5S 1A8, Canada; Division of Neurology, Department of Pediatrics, University of Texas Southwestern, Dallas, TX 75390, USA
| | - Felix Nitschke
- Program in Genetics and Genome Biology, Hospital for Sick Children Research Institute, Toronto, ON M5G 0A4, Canada.
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Choi SY, Kang B, Choe JY, Lee Y, Jang HJ, Park HD, Lee SK, Choe YH. A Case of Glycogen Storage Disease IV with Rare Homozygous Mutations in the Glycogen Branching Enzyme Gene. Pediatr Gastroenterol Hepatol Nutr 2018; 21:365-368. [PMID: 30345254 PMCID: PMC6182483 DOI: 10.5223/pghn.2018.21.4.365] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/09/2018] [Revised: 03/13/2018] [Accepted: 03/17/2018] [Indexed: 11/14/2022] Open
Abstract
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.
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Affiliation(s)
- So Yoon Choi
- Department of Pediatrics, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea.,Department of Pediatrics, Haeundae Paik Hospital, Inje University College of Medicine, Busan, Korea
| | - Ben Kang
- Department of Pediatrics, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea.,Department of Pediatrics, School of Medicine, Kyungpook National University, Daegu, Korea
| | - Jae Young Choe
- Department of Pediatrics, School of Medicine, Kyungpook National University, Daegu, Korea
| | - Yoon Lee
- Department of Pediatrics, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea.,Department of Pediatrics, Korea University College of Medicine, Seoul, Korea
| | - Hyo Jeong Jang
- Department of Pediatrics, Keimyung University School of Medicine, Daegu, Korea
| | - Hyung-Doo Park
- Department of Laboratory Medicine and Genetics, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Suk-Koo Lee
- Department of Surgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Yon Ho Choe
- Department of Pediatrics, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
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Iijima H, Iwano R, Tanaka Y, Muroya K, Fukuda T, Sugie H, Kurosawa K, Adachi M. Analysis of GBE1 mutations via protein expression studies in glycogen storage disease type IV: A report on a non-progressive form with a literature review. Mol Genet Metab Rep 2018; 17:31-37. [PMID: 30228975 PMCID: PMC6140619 DOI: 10.1016/j.ymgmr.2018.09.001] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/12/2018] [Revised: 09/06/2018] [Accepted: 09/06/2018] [Indexed: 11/26/2022] Open
Abstract
Background Glycogen storage disease type IV (GSD IV), caused by GBE1 mutations, has a quite wide phenotypic variation. While the classic hepatic form and the perinatal/neonatal neuromuscular forms result in early mortality, milder manifestations include non-progressive form (NP-GSD IV) and adult polyglucosan body disease (APBD). Thus far, only one clinical case of a patient with compound heterozygous mutations has been reported for the molecular analysis of NP-GSD IV. This study aimed to elucidate the molecular basis in a NP-GSD IV patient via protein expression analysis and to obtain a clearer genotype-phenotype relationship in GSD IV. Case presentation A Japanese boy presented hepatosplenomegaly at 2 years of age. Developmental delay, neurological symptoms, and cardiac dysfunction were not apparent. Observation of hepatocytes with periodic acid-Schiff-positive materials resistant to diastase, coupled with resolution of hepatosplenomegaly at 8 years of age, yielded a diagnosis of NP-GSD IV. Glycogen branching enzyme activity was decreased in erythrocytes. At 13 years of age, he developed epilepsy, which was successfully controlled by carbamazepine. Molecular analysis In this study, we identified compound heterozygous GBE1 mutations (p.Gln46Pro and p.Glu609Lys). The branching activities of the mutant proteins expressed using E. coli were examined in a reaction with starch. The result showed that both mutants had approximately 50% activity of the wild type protein. Conclusion This is the second clinical report of a NP-GSD IV patient with a definite molecular elucidation. Based on the clinical and genotypic overlapping between NP-GSD IV and APBD, we suggest both are in a continuum.
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Affiliation(s)
- Hiroyuki Iijima
- Department of Endocrinology and Metabolism, Kanagawa Children's Medical Center, Mutsukawa 2-138-4, Minami-ku, Yokohama 232-8555, Japan
| | - Reiko Iwano
- Department of Endocrinology and Metabolism, Kanagawa Children's Medical Center, Mutsukawa 2-138-4, Minami-ku, Yokohama 232-8555, Japan
| | - Yukichi Tanaka
- Department of Pathology, Kanagawa Children's Medical Center, Mutsukawa 2-138-4, Minami-ku, Yokohama 232-8555, Japan
| | - Koji Muroya
- Department of Endocrinology and Metabolism, Kanagawa Children's Medical Center, Mutsukawa 2-138-4, Minami-ku, Yokohama 232-8555, Japan
| | - Tokiko Fukuda
- Department of Pediatrics, Hamamatsu University School of Medicine, Handayama, 1-20-1 Higashi-ku, Hamamatsu 431-3192, Japan
| | - Hideo Sugie
- Faculty of Health and Medical Sciences, Tokoha University, Sena, 1-22-1 Aoi-ku, Shizuoka 420-0911, Japan
| | - Kenji Kurosawa
- Division of Medical Genetics, Kanagawa Children's Medical Center, Mutsukawa 2-138-4, Minami-ku, Yokohama 232-8555, Japan
| | - Masanori Adachi
- Department of Endocrinology and Metabolism, Kanagawa Children's Medical Center, Mutsukawa 2-138-4, Minami-ku, Yokohama 232-8555, Japan
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Szymańska E, Szymańska S, Truszkowska G, Ciara E, Pronicki M, Shin YS, Podskarbi T, Kępka A, Śpiewak M, Płoski R, Bilińska ZT, Rokicki D. Variable clinical presentation of glycogen storage disease type IV: from severe hepatosplenomegaly to cardiac insufficiency. Some discrepancies in genetic and biochemical abnormalities. Arch Med Sci 2018; 14:237-247. [PMID: 29379554 PMCID: PMC5778435 DOI: 10.5114/aoms.2018.72246] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/19/2017] [Accepted: 06/26/2017] [Indexed: 12/20/2022] Open
Affiliation(s)
- Edyta Szymańska
- Department of Pediatrics, Nutrition and Metabolic Disorders, the Children’s Memorial Health Institute, Warsaw, Poland
| | - Sylwia Szymańska
- Department of Pathology, the Children’s Memorial Health Institute, Warsaw, Poland
| | - Grażyna Truszkowska
- Department of Medical Biology, Molecular Biology Laboratory, Institute of Cardiology, Warsaw, Poland
| | - Elżbieta Ciara
- Department of Medical Genetics, the Children’s Memorial Health Institute, Warsaw, Poland
| | - Maciej Pronicki
- Department of Pathology, the Children’s Memorial Health Institute, Warsaw, Poland
| | - Yoon S. Shin
- University Children’s Hospital and Molecular Genetics and Metabolism Laboratory, Munich, Germany
| | | | - Alina Kępka
- Department of Biochemistry, Radioimmunology and Experimental Medicine, the Children’s Memorial Health Institute, Warsaw, Poland
| | - Mateusz Śpiewak
- Cardiac Magnetic Resonance Unit, Institute of Cardiology, Warsaw, Poland
| | - Rafał Płoski
- Department of Medical Genetics, Centre of Biostructure, Medical University of Warsaw, Warsaw, Poland
| | - Zofia T. Bilińska
- Unit for Screening Studies in Inherited Cardiovascular Diseases, Institute of Cardiology, Warsaw, Poland
| | - Dariusz Rokicki
- Department of Pediatrics, Nutrition and Metabolic Disorders, the Children’s Memorial Health Institute, Warsaw, Poland
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10
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A Modified Enzymatic Method for Measurement of Glycogen Content in Glycogen Storage Disease Type IV. JIMD Rep 2016; 30:89-94. [PMID: 27344645 DOI: 10.1007/8904_2015_522] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/21/2015] [Revised: 11/11/2015] [Accepted: 11/16/2015] [Indexed: 12/17/2022] Open
Abstract
Deficiency of glycogen branching enzyme in glycogen storage disease type IV (GSD IV) results in accumulation of less-branched and poorly soluble polysaccharides (polyglucosan bodies) in multiple tissues. Standard enzymatic method, when used to quantify glycogen content in GSD IV tissues, causes significant loss of the polysaccharides during preparation of tissue lysates. We report a modified method including an extra boiling step to dissolve the insoluble glycogen, ultimately preserving the glycogen content in tissue homogenates from GSD IV mice. Muscle tissues from wild-type, GSD II and GSD IV mice and GSD III dogs were homogenized in cold water, and homogenate of each tissue was divided into two parts. One part was immediately clarified by centrifugation at 4°C (STD-prep); the other part was boiled for 5 min then centrifuged (Boil-prep) at room temperature. When glycogen was quantified enzymatically in tissue lysates, no significant differences were found between the STD-prep and the Boil-prep for wild-type, GSD II and GSD III muscles. In contrast, glycogen content for GSD IV muscle in the STD-prep was only 11% of that in the Boil-prep, similar to wild-type values. Similar results were observed in other tissues of GSD IV mice and fibroblast cells from a GSD IV patient. This study provides important information for improving disease diagnosis, monitoring disease progression, and evaluating treatment outcomes in both clinical and preclinical clinical settings for GSD IV. This report should be used as an updated protocol in clinical diagnostic laboratories.
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Nrf2-Mediated Regulation of Skeletal Muscle Glycogen Metabolism. Mol Cell Biol 2016; 36:1655-72. [PMID: 27044864 DOI: 10.1128/mcb.01095-15] [Citation(s) in RCA: 95] [Impact Index Per Article: 10.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/17/2015] [Accepted: 03/24/2016] [Indexed: 12/11/2022] Open
Abstract
Nrf2 (NF-E2-related factor 2) contributes to the maintenance of glucose homeostasis in vivo Nrf2 suppresses blood glucose levels by protecting pancreatic β cells from oxidative stress and improving peripheral tissue glucose utilization. To elucidate the molecular mechanisms by which Nrf2 contributes to the maintenance of glucose homeostasis, we generated skeletal muscle (SkM)-specific Keap1 knockout (Keap1MuKO) mice that express abundant Nrf2 in their SkM and then examined Nrf2 target gene expression in that tissue. In Keap1MuKO mice, blood glucose levels were significantly downregulated and the levels of the glycogen branching enzyme (Gbe1) and muscle-type PhKα subunit (Phka1) mRNAs, along with those of the glycogen branching enzyme (GBE) and the phosphorylase b kinase α subunit (PhKα) protein, were significantly upregulated in mouse SkM. Consistent with this result, chemical Nrf2 inducers promoted Gbe1 and Phka1 mRNA expression in both mouse SkM and C2C12 myotubes. Chromatin immunoprecipitation analysis demonstrated that Nrf2 binds the Gbe1 and Phka1 upstream promoter regions. In Keap1MuKO mice, muscle glycogen content was strongly reduced and forced GBE expression in C2C12 myotubes promoted glucose uptake. Therefore, our results demonstrate that Nrf2 induction in SkM increases GBE and PhKα expression and reduces muscle glycogen content, resulting in improved glucose tolerance. Our results also indicate that Nrf2 differentially regulates glycogen metabolism in SkM and the liver.
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12
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Stapleton DI, Lau X, Flores M, Trieu J, Gehrig SM, Chee A, Naim T, Lynch GS, Koopman R. Dysfunctional muscle and liver glycogen metabolism in mdx dystrophic mice. PLoS One 2014; 9:e91514. [PMID: 24626262 PMCID: PMC3953428 DOI: 10.1371/journal.pone.0091514] [Citation(s) in RCA: 41] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/20/2013] [Accepted: 02/11/2014] [Indexed: 12/25/2022] Open
Abstract
Background Duchenne muscular dystrophy (DMD) is a severe, genetic muscle wasting disorder characterised by progressive muscle weakness. DMD is caused by mutations in the dystrophin (dmd) gene resulting in very low levels or a complete absence of the dystrophin protein, a key structural element of muscle fibres which is responsible for the proper transmission of force. In the absence of dystrophin, muscle fibres become damaged easily during contraction resulting in their degeneration. DMD patients and mdx mice (an animal model of DMD) exhibit altered metabolic disturbances that cannot be attributed to the loss of dystrophin directly. We tested the hypothesis that glycogen metabolism is defective in mdx dystrophic mice. Results Dystrophic mdx mice had increased skeletal muscle glycogen (79%, (P<0.01)). Skeletal muscle glycogen synthesis is initiated by glycogenin, the expression of which was increased by 50% in mdx mice (P<0.0001). Glycogen synthase activity was 12% higher (P<0.05) but glycogen branching enzyme activity was 70% lower (P<0.01) in mdx compared with wild-type mice. The rate-limiting enzyme for glycogen breakdown, glycogen phosphorylase, had 62% lower activity (P<0.01) in mdx mice resulting from a 24% reduction in PKA activity (P<0.01). In mdx mice glycogen debranching enzyme expression was 50% higher (P<0.001) together with starch-binding domain protein 1 (219% higher; P<0.01). In addition, mdx mice were glucose intolerant (P<0.01) and had 30% less liver glycogen (P<0.05) compared with control mice. Subsequent analysis of the enzymes dysregulated in skeletal muscle glycogen metabolism in mdx mice identified reduced glycogenin protein expression (46% less; P<0.05) as a possible cause of this phenotype. Conclusion We identified that mdx mice were glucose intolerant, and had increased skeletal muscle glycogen but reduced amounts of liver glycogen.
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Affiliation(s)
- David I Stapleton
- Department of Physiology, The University of Melbourne, Melbourne, Victoria, Australia
| | - Xianzhong Lau
- Department of Physiology, The University of Melbourne, Melbourne, Victoria, Australia
| | - Marcelo Flores
- Department of Physiology, The University of Melbourne, Melbourne, Victoria, Australia
| | - Jennifer Trieu
- Department of Physiology, The University of Melbourne, Melbourne, Victoria, Australia
| | - Stefan M Gehrig
- Department of Physiology, The University of Melbourne, Melbourne, Victoria, Australia
| | - Annabel Chee
- Department of Physiology, The University of Melbourne, Melbourne, Victoria, Australia
| | - Timur Naim
- Department of Physiology, The University of Melbourne, Melbourne, Victoria, Australia
| | - Gordon S Lynch
- Department of Physiology, The University of Melbourne, Melbourne, Victoria, Australia
| | - René Koopman
- Department of Physiology, The University of Melbourne, Melbourne, Victoria, Australia
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13
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Dainese L, Monin ML, Demeret S, Brochier G, Froissart R, Spraul A, Schiffmann R, Seilhean D, Mochel F. Abnormal glycogen in astrocytes is sufficient to cause adult polyglucosan body disease. Gene 2012; 515:376-9. [PMID: 23266647 PMCID: PMC7126849 DOI: 10.1016/j.gene.2012.12.065] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/17/2012] [Accepted: 12/03/2012] [Indexed: 11/18/2022]
Abstract
Background A 45-year old woman of Cambodian ethnic background presented with fatal respiratory failure due to a severe diaphragmatic dysfunction. Two years before, she had developed early onset of urinary symptoms. Methods and results Neuroimaging showed atrophy of the spine and medulla as well as a leukodystrophy affecting both supra- and infra-tentorial regions. At autopsy, polyglucosan bodies (PB) were seen in several peripheral tissues, including the diaphragm, and nervous tissues such as peripheral nerves, cerebral white matter, basal ganglia, hippocampus, brainstem and cerebellum. Immunohistochemistry and electron microscopy of the brain revealed an exclusive astrocytic localization of the PB. The diagnosis of adult polyglucosan body disease (APBD) was confirmed by enzymatic and molecular studies. Conclusion Storage of abnormal glycogen in astrocytes is sufficient to cause the leukodystrophy of APBD. Since brain glycogen is almost exclusively metabolized in astrocytes, this observation sheds light on the pathophysiology of APBD. In addition, this is the first report of an APBD patient presenting with a subacute diaphragmatic failure.
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Affiliation(s)
- Linda Dainese
- AP-HP, Department of Neuropathology, Hospital La Salpêtrière, Paris, France
- University Pierre and Marie Curie, Paris, France
- University of Insubria, Varese, Italy
| | - Marie-Lorraine Monin
- University Pierre and Marie Curie, Paris, France
- INSERM UMR S975, Brain and Spine Institute, Hospital La Salpêtrière, Paris, France
| | - Sophie Demeret
- AP-HP, Department of Neurology, Hospital La Salpêtrière, Paris, France
| | - Guy Brochier
- Institute of Myology, Histopathology Laboratory, Hospital La Salpêtrière, Paris, France
| | - Roseline Froissart
- Laboratory of Inborn Errors of Metabolism, Hospices Civils de Lyon, Bron, France
| | - Anne Spraul
- AP-HP, Laboratory of Biochemistry, Hospital Bicêtre, Le Kremlin Bicêtre, France
| | - Raphael Schiffmann
- Institute of Metabolic Disease, Baylor Research Institute, Dallas, TX, USA
| | - Danielle Seilhean
- AP-HP, Department of Neuropathology, Hospital La Salpêtrière, Paris, France
- University Pierre and Marie Curie, Paris, France
- INSERM UMR S975, Brain and Spine Institute, Hospital La Salpêtrière, Paris, France
| | - Fanny Mochel
- University Pierre and Marie Curie, Paris, France
- INSERM UMR S975, Brain and Spine Institute, Hospital La Salpêtrière, Paris, France
- AP-HP, Department of Genetic, Hospital La Salpêtrière, Paris, France
- Corresponding author at: INSERM UMR S975, Brain and Spine Institute, Hôpital de La Salpêtrière, Paris, France 75013. Tel.: + 33 1 57 27 46 82.
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14
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Cardiac Involvement in Glycogen Storage Disease Type IV: Two Cases and the Two Ends of a Spectrum. Case Rep Med 2012; 2012:764286. [PMID: 23056054 PMCID: PMC3463931 DOI: 10.1155/2012/764286] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/11/2012] [Revised: 08/13/2012] [Accepted: 08/22/2012] [Indexed: 12/16/2022] Open
Abstract
Glycogen storage disease type IV (GSD IV) is an autosomal recessive disorder due to the deficiency of α 1,4-glucan branching enzyme, resulting in an accumulation of amylopectin-like polysaccharide in various systems. We describe two cases, a 23-year-old girl with dilated cardiomyopathy who presented with progressive dyspnea and fatigue and a 28-year-old girl with hypertrophic cardiomyopathy who was asymptomatic, secondary to the accumulation of amylopectin-like fibrillar glycogen, in heart. In both patients, the diagnosis was confirmed by enzyme assessment. Our patients showed that GSD IV is not only liver or skeletal muscle disease, but also it can be presented in different form of the spectrum of cardiomyopathy from dilated to hypertrophic and from asymptomatic to decompensated heart failure. Also, to our knowledge, this is the first hypertrophic cardiomyopathy case due to GSD IV in the literature.
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15
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Tiberia E, Turnbull J, Wang T, Ruggieri A, Zhao XC, Pencea N, Israelian J, Wang Y, Ackerley CA, Wang P, Liu Y, Minassian BA. Increased laforin and laforin binding to glycogen underlie Lafora body formation in malin-deficient Lafora disease. J Biol Chem 2012; 287:25650-9. [PMID: 22669944 DOI: 10.1074/jbc.m111.331611] [Citation(s) in RCA: 35] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/06/2022] Open
Abstract
The solubility of glycogen, essential to its metabolism, is a property of its shape, a sphere generated through extensive branching during synthesis. Lafora disease (LD) is a severe teenage-onset neurodegenerative epilepsy and results from multiorgan accumulations, termed Lafora bodies (LB), of abnormally structured aggregation-prone and digestion-resistant glycogen. LD is caused by loss-of-function mutations in the EPM2A or EPM2B gene, encoding the interacting laforin phosphatase and malin E3 ubiquitin ligase enzymes, respectively. The substrate and function of malin are unknown; an early counterintuitive observation in cell culture experiments that it targets laforin to proteasomal degradation was not pursued until now. The substrate and function of laforin have recently been elucidated. Laforin dephosphorylates glycogen during synthesis, without which phosphate ions interfere with and distort glycogen construction, leading to LB. We hypothesized that laforin in excess or not removed following its action on glycogen also interferes with glycogen formation. We show in malin-deficient mice that the absence of malin results in massively increased laforin preceding the appearance of LB and that laforin gradually accumulates in glycogen, which corresponds to progressive LB generation. We show that increasing the amounts of laforin in cell culture causes LB formation and that this occurs only with glycogen binding-competent laforin. In summary, malin deficiency causes increased laforin, increased laforin binding to glycogen, and LB formation. Furthermore, increased levels of laforin, when it can bind glycogen, causes LB. We conclude that malin functions to regulate laforin and that malin deficiency at least in part causes LB and LD through increased laforin binding to glycogen.
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Affiliation(s)
- Erica Tiberia
- Program in Genetics and Genome Biology, The Hospital for Sick Children, Toronto, Ontario M5G 1X8, Canada
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16
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Magoulas PL, El-Hattab AW, Roy A, Bali DS, Finegold MJ, Craigen WJ. Diffuse reticuloendothelial system involvement in type IV glycogen storage disease with a novel GBE1 mutation: a case report and review. Hum Pathol 2012; 43:943-51. [DOI: 10.1016/j.humpath.2011.10.001] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/13/2011] [Revised: 09/08/2011] [Accepted: 10/07/2011] [Indexed: 10/14/2022]
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17
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Li SC, Chen CM, Goldstein JL, Wu JY, Lemyre E, Burrow TA, Kang PB, Chen YT, Bali DS. Glycogen storage disease type IV: novel mutations and molecular characterization of a heterogeneous disorder. J Inherit Metab Dis 2010; 33 Suppl 3:S83-S90. [PMID: 20058079 DOI: 10.1007/s10545-009-9026-5] [Citation(s) in RCA: 26] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/23/2009] [Revised: 11/24/2009] [Accepted: 11/27/2009] [Indexed: 10/20/2022]
Abstract
Glycogen storage disease type IV (GSD IV; Andersen disease) is caused by a deficiency of glycogen branching enzyme (GBE), leading to excessive deposition of structurally abnormal, amylopectin-like glycogen in affected tissues. The accumulated glycogen lacks multiple branch points and thus has longer outer branches and poor solubility, causing irreversible tissue and organ damage. Although classic GSD IV presents with early onset of hepatosplenomegaly with progressive liver cirrhosis, GSD IV exhibits extensive clinical heterogeneity with respect to age at onset and variability in pattern and extent of organ and tissue involvement. With the advent of cloning and determination of the genomic structure of the human GBE gene (GBE1), molecular analysis and characterization of underlying disease-causing mutations is now possible. A variety of disease-causing mutations have been identified in the GBE1 gene in GSD IV patients, many of whom presented with diverse clinical phenotypes. Detailed biochemical and genetic analyses of three unrelated patients suspected to have GSD IV are presented here. Two novel missense mutations (p.Met495Thr and p.Pro552Leu) and a novel 1-bp deletion mutation (c.1999delA) were identified. A variety of mutations in GBE1 have been previously reported, including missense and nonsense mutations, nucleotide deletions and insertions, and donor and acceptor splice-site mutations. Mutation analysis is useful in confirming the diagnosis of GSD IV--especially when higher residual GBE enzyme activity levels are seen and enzyme analysis is not definitive--and allows for further determination of potential genotype/phenotype correlations in this disease.
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Affiliation(s)
- Sing-Chung Li
- School of Nutrition and Health Science, Taipei Medical University, Taipei, Taiwan
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18
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Lee YC, Chang CJ, Bali D, Chen YT, Yan YT. Glycogen-branching enzyme deficiency leads to abnormal cardiac development: novel insights into glycogen storage disease IV. Hum Mol Genet 2010; 20:455-65. [DOI: 10.1093/hmg/ddq492] [Citation(s) in RCA: 32] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/13/2022] Open
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19
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Rothacker D, Winterroth A, Buller M, Vogel M, Zhou H, Kistner G, Gillessen-Kaesbach G, Kohlhase J. [Glycogenosis type IV (Andersen disease). Clinical data, pathology, and genetics in a fatal perinatal case]. DER PATHOLOGE 2010; 31:293-6. [PMID: 20532556 DOI: 10.1007/s00292-010-1290-5] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/28/2022]
Abstract
Here we report the case of a newborn with glycogenosis type IV (Andersen disease), who died shortly after birth. The diagnosis was established in the first instance by light microscopy and histochemistry, and subsequently ultrastructurally. DNA could be extracted from a fibroblast cell culture by sequencing the causative GBE1 gene (glycogen branching enzyme 1). Two compound heterozygous mutations in the gene were identified. The differential diagnosis should include Lafora disease as well as polyglucosan body disease. Since there is no effective therapy for glycogenosis type IV to date, prenatal diagnosis is mandatory.
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Affiliation(s)
- D Rothacker
- Gemeinschaftspraxis für Pathologie, Ellerried 7, 19061, Schwerin, Deutschland.
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20
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Pal K, Kumar S, Sharma S, Garg SK, Alam MS, Xu HE, Agrawal P, Swaminathan K. Crystal structure of full-length Mycobacterium tuberculosis H37Rv glycogen branching enzyme: insights of N-terminal beta-sandwich in substrate specificity and enzymatic activity. J Biol Chem 2010; 285:20897-903. [PMID: 20444687 DOI: 10.1074/jbc.m110.121707] [Citation(s) in RCA: 60] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/06/2022] Open
Abstract
The open reading frame Rv1326c of Mycobacterium tuberculosis (Mtb) H37Rv encodes for an alpha-1,4-glucan branching enzyme (MtbGlgB, EC 2.4.1.18, Uniprot entry Q10625). This enzyme belongs to glycoside hydrolase (GH) family 13 and catalyzes the branching of a linear glucose chain during glycogenesis by cleaving a 1-->4 bond and making a new 1-->6 bond. Here, we show the crystal structure of full-length MtbGlgB (MtbGlgBWT) at 2.33-A resolution. MtbGlgBWT contains four domains: N1 beta-sandwich, N2 beta-sandwich, a central (beta/alpha)(8) domain that houses the catalytic site, and a C-terminal beta-sandwich. We have assayed the amylase activity with amylose and starch as substrates and the glycogen branching activity using amylose as a substrate for MtbGlgBWT and the N1 domain-deleted (the first 108 residues deleted) MtbDelta108GlgB protein. The N1 beta-sandwich, which is formed by the first 105 amino acids and superimposes well with the N2 beta-sandwich, is shown to have an influence in substrate binding in the amylase assay. Also, we have checked and shown that several GH13 family inhibitors are ineffective against MtbGlgBWT and MtbDelta108GlgB. We propose a two-step reaction mechanism, for the amylase activity (1-->4 bond breakage) and isomerization (1-->6 bond formation), which occurs in the same catalytic pocket. The structural and functional properties of MtbGlgB and MtbDelta108GlgB are compared with those of the N-terminal 112-amino acid-deleted Escherichia coli GlgB (ECDelta112GlgB).
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Affiliation(s)
- Kuntal Pal
- Department of Biological Sciences, National University of Singapore, Singapore 117543
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21
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Lamperti C, Salani S, Lucchiari S, Bordoni A, Ripolone M, Fagiolari G, Fruguglietti ME, Crugnola V, Colombo C, Cappellini A, Prelle A, Bresolin N, Comi GP, Moggio M. Neuropathological study of skeletal muscle, heart, liver, and brain in a neonatal form of glycogen storage disease type IV associated with a new mutation in GBE1 gene. J Inherit Metab Dis 2009; 32 Suppl 1:S161-8. [PMID: 19357989 DOI: 10.1007/s10545-009-1134-8] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/08/2009] [Revised: 02/18/2009] [Accepted: 02/20/2009] [Indexed: 10/20/2022]
Abstract
Glycogen storage disease type IV (GSD IV, or Andersen disease) is an autosomal recessive disorder due to the deficiency of 1,4-alpha-glucan branching enzyme (or glycogen branching enzyme, GBE1), resulting in an accumulation of amylopectin-like polysaccharide in muscle, liver, heart and central and peripheral nervous system. Typically, the presentation is in childhood with liver involvement up to cirrhosis. The neuromuscular form varies in onset (congenital, perinatal, juvenile and adult) and in severity. Congenital cases are rare, and fewer than 20 cases have been described and genetically determined so far. This form is characterized by polyhydramnios, neonatal hypotonia, and neuronal involvement; hepatopathy is uncommon, and the babies usually die between 4 weeks and 4 months of age. We report the case of an infant who presented severe hypotonia, dilatative cardiomyopathy, mild hepatopathy, and brain lateral ventricle haemorrhage, features consistent with the congenital form of GSD IV. He died at one month of life of cardiorespiratory failure. Muscle biopsy and heart and liver autoptic specimens showed many vacuoles filled with PAS-positive diastase-resistant materials. Electron-microscopic analysis showed mainly polyglucosan accumulations in all the tissues examined. Postmortem examination showed the presence of vacuolated neurons containing this abnormal polysaccharide. GBE1 biochemical activity was virtually absent in muscle and fibroblasts, and totally lacking in liver and heart as well as glycogen synthase activity. GBE1 gene sequence analysis revealed a novel homozygous nonsense mutation, p.E152X, in exon 4, correlating with the lack of enzyme activity and with the severe neonatal involvement. Our findings contribute to increasing the spectrum of mutation associated with congenital GSD IV.
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Affiliation(s)
- C Lamperti
- Fondazione Ospedale Maggiore Policlinico, Maniagalli and Regina Elena, IRCCS, Milan, Italy
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22
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Jimenez-Mallebrera C, Nascimento A, Cusi V, Corbera JR, Rolland MO, Froissart R, Olivé M, Ferrer I, Colomer J. Glycogen branching enzyme deficiency in an infant with severe congenital hypotonia: an emerging diagnosis of muscle weakness in the perinatal period. Histopathology 2009; 54:765-8. [DOI: 10.1111/j.1365-2559.2009.03281.x] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/30/2022]
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Ban HR, Kim KM, Jang JY, Kim GH, You HW, Kim K, Yu E, Kim DY, Kim KH, Lee YJ, Lee SG, Park YN, Koh H, Chung KS. Living Donor Liver Transplantation in a Korean Child with Glycogen Storage Disease Type IV and a GBE1 Mutation. Gut Liver 2009; 3:60-3. [PMID: 20479904 DOI: 10.5009/gnl.2009.3.1.60] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/27/2008] [Accepted: 11/06/2008] [Indexed: 11/04/2022] Open
Abstract
Glycogen storage disease type IV (GSD-IV) is an autosomal recessive disease caused by a deficient glycogen branching enzyme (GBE), encoded by the GBE1 gene, resulting in the accumulation of abnormal glycogen deposits in the liver and other tissues. We treated a 20-month-old girl who presented with progressive liver cirrhosis and was diagnosed with GSD-IV, as confirmed by GBE1 gene mutation analysis, and underwent living related heterozygous donor liver transplantation. Direct sequencing of the GBE1 gene revealed that the patient was compound heterozygous for a known c.1571G>A (p.Gly264Glu) mutation a novel c.791G>A (Arg524Gln) mutation. This is the first report of a Korean patient with GSD-IV confirmed by mutation analysis, who was treated successfully by liver transplantation.
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Affiliation(s)
- Hye Ryun Ban
- Department of Pediatrics, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
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24
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Eminoglu TF, Tumer L, Okur I, Olgunturk R, Hasanoglu A, Gonul II, Dalgic B. Multisystem involvement in a patient due to accumulation of amylopectin-like material with diminished branching enzyme activity. J Inherit Metab Dis 2008; 31 Suppl 2:S255-9. [PMID: 18392749 DOI: 10.1007/s10545-008-0819-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/28/2007] [Revised: 01/17/2008] [Accepted: 01/22/2008] [Indexed: 11/29/2022]
Abstract
We report a 13-year-old boy with multisystem involvement secondary to accumulation of amylopectin-like material. He was born to consanguineous parents at full term without any complications and his maternal perinatal history was uneventful. His parents were cousins. He had normal growth and development except for his weight. His sister died from an unexplained cardiomyopathy at the age of 8 years. Our patient's initial symptom was severe heart failure. Since he also had a complaint of muscle weakness, electromyography was performed which showed muscle involvement. The diagnosis was suggested by tissue biopsy of skeletal muscle showing intracellular, basophilic, diastase-resistant, periodic acid-Schiff-positive inclusion bodies and was confirmed by the presence of a completed branching enzyme deficiency. Similar intracytoplasmic inclusion-like bodies were also found in liver biopsy, but very few in number compared with the skeletal muscle. The patient died from an intercurrent infection. Postmortem endomyocardial biopsy revealed the same intracytoplasmic inclusions as described above affecting almost all myocardial cells. Ultrastructural examination of liver biopsy was nondiagnostic; however, myocardium showed prominent, large, intracytoplasmic deposits. Glycogen branching enzyme gene sequence was normal, and thus classical branching enzyme deficiency was excluded. Our patient represents the first molecular study performed on a patient in whom there was multiple system involvement secondary to accumulation of amylopectin-like material. We suggest that this is an as yet undefined and different phenotype of glycogen storage disease associated with multisystemic involvement.
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Affiliation(s)
- T F Eminoglu
- Department of Pediatric Metabolism and Nutrition, Gazi University Hospital, Besevler, Ankara, 06510, Turkey.
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25
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Raju GP, Li HC, Bali DS, Chen YT, Urion DK, Lidov HGW, Kang PB. A case of congenital glycogen storage disease type IV with a novel GBE1 mutation. J Child Neurol 2008; 23:349-52. [PMID: 18230843 DOI: 10.1177/0883073807309248] [Citation(s) in RCA: 16] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/15/2022]
Abstract
Glycogen storage disease type IV (Andersen disease) is a rare metabolic disorder characterized by deficient glycogen branching enzyme activity resulting in abnormal, amylopectin-like glycogen deposition in multiple organs. This article reports on an infant with the congenital neuromuscular subtype of glycogen storage disease type IV who presented with polyhydramnios, hydrops fetalis, bilateral ankle contractures, biventricular cardiac dysfunction, and severe facial and extremity weakness. A muscle biopsy showed the presence of material with histochemical and ultrastructural characteristics consistent with amylopectin. Biochemical analysis demonstrated severely reduced branching enzyme activity in muscle tissue and fibroblasts. Genetic analysis demonstrated a novel deletion of exon 16 within GBE1, the gene associated with glycogen storage disease type IV. Continued genetic characterization of glycogen storage disease type IV patients may aid in predicting clinical outcomes in these patients and may also help in identifying treatment strategies for this potentially devastating metabolic disorder.
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Affiliation(s)
- G Praveen Raju
- Department of Neurology, Children's Hospital Boston and Harvard Medical School, 300 Longwood Avenue, Boston, MA, USA
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26
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Foà PP. Glucagon. ERGEBNISSE DER PHYSIOLOGIE, BIOLOGISCHEN CHEMIE UND EXPERIMENTELLEN PHARMAKOLOGIE 2007; 60:141-219. [PMID: 4298671 DOI: 10.1007/bfb0107253] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/09/2023]
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Ozen H. Glycogen storage diseases: new perspectives. World J Gastroenterol 2007; 13:2541-2553. [PMID: 17552001 PMCID: PMC4146814 DOI: 10.3748/wjg.v13.i18.2541] [Citation(s) in RCA: 172] [Impact Index Per Article: 9.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/30/2007] [Revised: 03/30/2007] [Accepted: 03/31/2007] [Indexed: 02/06/2023] Open
Abstract
Glycogen storage diseases (GSD) are inherited metabolic disorders of glycogen metabolism. Different hormones, including insulin, glucagon, and cortisol regulate the relationship of glycolysis, gluconeogenesis and glycogen synthesis. The overall GSD incidence is estimated 1 case per 20000-43000 live births. There are over 12 types and they are classified based on the enzyme deficiency and the affected tissue. Disorders of glycogen degradation may affect primarily the liver, the muscle, or both. Type Ia involves the liver, kidney and intestine (and Ib also leukocytes), and the clinical manifestations are hepatomegaly, failure to thrive, hypoglycemia, hyperlactatemia, hyperuricemia and hyperlipidemia. Type IIIa involves both the liver and muscle, and IIIb solely the liver. The liver symptoms generally improve with age. Type IV usually presents in the first year of life, with hepatomegaly and growth retardation. The disease in general is progressive to cirrhosis. Type VI and IX are a heterogeneous group of diseases caused by a deficiency of the liver phosphorylase and phosphorylase kinase system. There is no hyperuricemia or hyperlactatemia. Type XI is characterized by hepatic glycogenosis and renal Fanconi syndrome. Type II is a prototype of inborn lysosomal storage diseases and involves many organs but primarily the muscle. Types V and VII involve only the muscle.
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Affiliation(s)
- Hasan Ozen
- Division of Gastroenterology, Hepatology and Nutrition, Hacettepe University Children's Hospital, Ankara, Turkey.
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Fyfe JC, Kurzhals RL, Hawkins MG, Wang P, Yuhki N, Giger U, Van Winkle TJ, Haskins ME, Patterson DF, Henthorn PS. A complex rearrangement in GBE1 causes both perinatal hypoglycemic collapse and late-juvenile-onset neuromuscular degeneration in glycogen storage disease type IV of Norwegian forest cats. Mol Genet Metab 2007; 90:383-92. [PMID: 17257876 PMCID: PMC2063609 DOI: 10.1016/j.ymgme.2006.12.003] [Citation(s) in RCA: 14] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/06/2006] [Revised: 12/08/2006] [Accepted: 12/08/2006] [Indexed: 01/21/2023]
Abstract
Deficiency of glycogen branching enzyme (GBE) activity causes glycogen storage disease type IV (GSD IV), an autosomal recessive error of metabolism. Abnormal glycogen accumulates in myocytes, hepatocytes, and neurons, causing variably progressive, benign to lethal organ dysfunctions. A naturally occurring orthologue of human GSD IV was described previously in Norwegian forest cats (NFC). Here, we report that while most affected kittens die at or soon after birth, presumably due to hypoglycemia, survivors of the perinatal period appear clinically normal until onset of progressive neuromuscular degeneration at 5 months of age. Molecular investigation of affected cats revealed abnormally spliced GBE1 mRNA products and lack of GBE cross-reactive material in liver and muscle. Affected cats are homozygous for a complex rearrangement of genomic DNA in GBE1, constituted by a 334 bp insertion at the site of a 6.2 kb deletion that extends from intron 11 to intron 12 (g. IVS11+1552_IVS12-1339 del6.2kb ins334 bp), removing exon 12. An allele-specific, PCR-based test demonstrates that the rearrangement segregates with the disease in the GSD IV kindred and is not found in unrelated normal cats. Screening of 402 privately owned NFC revealed 58 carriers and 4 affected cats. The molecular characterization of feline GSD IV will enhance further studies of GSD IV pathophysiology and development of novel therapies in this unique animal model.
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Affiliation(s)
- John C Fyfe
- Laboratory of Comparative Medical Genetics, College of Veterinary Medicine, Michigan State University, East Lansing, MI 48824, USA.
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Ryman BE, Whelan WJ. New aspects of glycogen metabolism. ADVANCES IN ENZYMOLOGY AND RELATED AREAS OF MOLECULAR BIOLOGY 2006; 34:285-443. [PMID: 4335607 DOI: 10.1002/9780470122792.ch6] [Citation(s) in RCA: 14] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/10/2023]
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L'herminé-Coulomb A, Beuzen F, Bouvier R, Rolland MO, Froissart R, Menez F, Audibert F, Labrune P. Fetal type IV glycogen storage disease: clinical, enzymatic, and genetic data of a pure muscular form with variable and early antenatal manifestations in the same family. Am J Med Genet A 2006; 139A:118-22. [PMID: 16278887 DOI: 10.1002/ajmg.a.30945] [Citation(s) in RCA: 40] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/11/2022]
Abstract
We report on a family of three consecutive fetuses affected by type IV glycogen storage disease (GSD IV). In all cases, cervical cystic hygroma was observed on the 12-week-ultrasound examination. During the second trimester, fetal hydrops developed in the first pregnancy whereas fetal akinesia appeared in the second pregnancy. The diagnosis was suggested by microscopic examination of fetal tissues showing characteristic inclusions exclusively in striated fibers, then confirmed by enzymatic studies on frozen muscle. Antenatal diagnosis was performed on the third and fourth pregnancies: cervical cystic hygroma and low glycogen branching enzyme (GBE) activity on chorionic villi sample (CVS) were detected in the third pregnancy whereas ultrasound findings were normal and GBE activity within normal range on CVS in the fourth pregnancy. Molecular analysis showed that the mother was heterozygous for a c.1471G > C mutation in exon 12, leading to the replacement of an alanine by a tyrosine at codon 491 (p.A491T); the father was heterozygous for a c.895G > T mutation in exon 7, leading to the creation of a stop codon at position 299 (p.G299X). GSD IV has to be considered in a context of cervical cystic hygroma with normal karyotype, particularly when second trimester hydrops or akinesia develop. Enzymatic analysis of GBE must be performed on CVS or amniotic cells to confirm the diagnosis. Characteristic intracellular inclusions are specific to the disease and should be recognized, even in macerated tissues after fetal death. Genetic analysis of the GBE gene may help to shed some light on the puzzling diversity of GSD IV phenotypes.
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Akman HO, Karadimas C, Gyftodimou Y, Grigoriadou M, Kokotas H, Konstantinidou A, Anninos H, Patsouris E, Thaker HM, Kaplan JB, Besharat I, Hatzikonstantinou K, Fotopoulos S, Dimauro S, Petersen MB. Prenatal diagnosis of glycogen storage disease type IV. Prenat Diagn 2006; 26:951-5. [PMID: 16874838 DOI: 10.1002/pd.1533] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/09/2022]
Abstract
BACKGROUND Glycogen storage disease type IV (GSD-IV) is a rare autosomal recessive disorder due to mutations in the GBE1 gene causing deficiency of the glycogen branching enzyme (GBE). Prenatal diagnosis has occasionally been performed by the measurement of the GBE activity in cultured chorionic villi (CV) cells. METHODS Two unrelated probands with severe hypotonia at birth and death during the neonatal period were diagnosed with GSD-IV on the basis of postmortem histological findings. DNA analysis revealed truncating GBE1 mutations in both families. RESULTS Prenatal diagnosis was performed in subsequent pregnancies by determination of branching enzyme activity and DNA analysis of CV or cultured amniocytes. Detailed autopsies of the affected fetuses at 14 and 24 weeks of gestation demonstrated intracellular inclusions of abnormal glycogen characteristic of GSD-IV. CONCLUSION Prenatal diagnosis of GSD-IV by DNA analysis is highly accurate in genetically confirmed cases.
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Affiliation(s)
- H Orhan Akman
- Department of Neurology, College of Physicians and Surgeons, Columbia University, New York, NY, USA
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Davies JK, Wells DJ, Liu K, Whitrow HR, Daniel TD, Grignani R, Lygate CA, Schneider JE, Noël G, Watkins H, Carling D. Characterization of the role of gamma2 R531G mutation in AMP-activated protein kinase in cardiac hypertrophy and Wolff-Parkinson-White syndrome. Am J Physiol Heart Circ Physiol 2005; 290:H1942-51. [PMID: 16339829 DOI: 10.1152/ajpheart.01020.2005] [Citation(s) in RCA: 61] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
Abstract
AMP-activated protein kinase (AMPK) is the downstream component of a protein kinase cascade that plays a key role in the regulation of energy metabolism. In humans, mutations in the gamma2-subunit of AMPK cause cardiac hypertrophy associated with Wolff-Parkinson-White syndrome, characterized by ventricular preexcitation. The effect of these mutations on AMPK activity and in development of the disease is enigmatic. Here we report that transgenic mice with cardiac-specific expression of gamma2 harboring a mutation of arginine residue 531 to glycine (RG-TG) develop a striking cardiac phenotype by 4 wk of age, including hypertrophy, impaired contractile function, electrical conduction abnormalities, and marked glycogen accumulation. At this stage, AMPK activity isolated from hearts of RG-TG mice was almost completely abolished but could be restored after phosphorylation by an upstream AMPK kinase. At 1 wk of age, there was no detectable evidence of a cardiac phenotype, and AMPK activity in RG-TG hearts was similar to that in nontransgenic, control mice. We propose that mutations in gamma2 lead to suppression of total cardiac AMPK activity secondary to increased glycogen accumulation. The subsequent decrease in AMPK activity provides a mechanism that may explain the development of cardiac hypertrophy in this model.
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Affiliation(s)
- Joanna K Davies
- Cellular Stress Group, Medical Research Council Clinical Sciences Centre, Hammersmith Campus, Imperial College London, London W12 ONN, UK
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Bruno C, van Diggelen OP, Cassandrini D, Gimpelev M, Giuffrè B, Donati MA, Introvini P, Alegria A, Assereto S, Morandi L, Mora M, Tonoli E, Mascelli S, Traverso M, Pasquini E, Bado M, Vilarinho L, van Noort G, Mosca F, DiMauro S, Zara F, Minetti C. Clinical and genetic heterogeneity of branching enzyme deficiency (glycogenosis type IV). Neurology 2005; 63:1053-8. [PMID: 15452297 DOI: 10.1212/01.wnl.0000138429.11433.0d] [Citation(s) in RCA: 86] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022] Open
Abstract
BACKGROUND Glycogen storage disease type IV (GSD-IV) is a clinically heterogeneous autosomal recessive disorder due to glycogen branching enzyme (GBE) deficiency and resulting in the accumulation of an amylopectin-like polysaccharide. The typical presentation is liver disease of childhood, progressing to lethal cirrhosis. The neuromuscular form of GSD-IV varies in onset (perinatal, congenital, juvenile, or adult) and severity. OBJECTIVE To identify the molecular bases of different neuromuscular forms of GSD-IV and to establish possible genotype/phenotype correlations. METHODS Eight patients with GBE deficiency had different neuromuscular presentations: three had fetal akinesia deformation sequence (FADS), three had congenital myopathy, one had juvenile myopathy, and one had combined myopathic and hepatic features. In all patients, the promoter and the entire coding region of the GBE gene at the RNA and genomic level were sequenced. RESULTS Nine novel mutations were identified, including nonsense, missense, deletion, insertion, and splice-junction mutations. The three cases with FADS were homozygous, whereas all other cases were compound heterozygotes. CONCLUSIONS This study expands the spectrum of mutations in the GBE gene and confirms that the neuromuscular presentation of GSD-IV is clinically and genetically heterogeneous.
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Affiliation(s)
- C Bruno
- Neuromuscular Disease Unit, Department of Pediatrics, University of Genova, Istituto Giannina Gaslini, Largo G. Gaslini 5, I-16147 Genova, Italy.
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Tay SKH, Akman HO, Chung WK, Pike MG, Muntoni F, Hays AP, Shanske S, Valberg SJ, Mickelson JR, Tanji K, DiMauro S. Fatal infantile neuromuscular presentation of glycogen storage disease type IV. Neuromuscul Disord 2004; 14:253-60. [PMID: 15019703 DOI: 10.1016/j.nmd.2003.12.006] [Citation(s) in RCA: 51] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2003] [Revised: 12/19/2003] [Accepted: 12/23/2003] [Indexed: 11/24/2022]
Abstract
Glycogen storage disease type IV or Andersen disease is an autosomal recessive disorder due to deficiency of glycogen branching enzyme. Typically, glycogen storage disease type IV presents with rapidly progressive liver cirrhosis and death in childhood. Variants include a cardiopathic form of childhood, a relatively benign myopathic form of young adults, and a late-onset neurodegenerative disorder (adult polyglucosan body disease). A severe neuromuscular variant resembling Werdnig-Hoffmann disease has also been described in two patients. The objective was to describe two additional infants with the neuromuscular variant and novel mutations in the GBE1 gene. Branching enzyme assay, Western blot, RT-PCR and sequencing were performed in muscle biopsies from both patients. The cDNA of patient 1 was subcloned and sequenced to define the mutations. Muscle biopsies showed accumulation of periodic acid Schiff-positive, diastase-resistant storage material in both patients and increased lysosomal enzyme activity in patient 1. Branching enzyme activity in muscle was negligible in both patients, and Western blot showed decreased branching enzyme protein. Patient 1 had two single base pair deletions, one in exon 10 (1238delT) and the other in exon 12 (1467delC), and each parent was heterozygous for one of the deletions. Patient 2 had a large homozygous deletion that spanned 627 bp and included exons 8-12. Patient 1, who died at 41 days, had neurophysiological and neuropathological features of Spinal Muscular Atrophy. Patient 2, who died at 5(1/2) weeks, had a predominantly myopathic process. The infantile neuromuscular form of glycogen storage disease type IV is considered extremely rare, but our encountering two patients in close succession suggests that the disease may be underdiagnosed.
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Affiliation(s)
- Stacey K H Tay
- Department of Neurology, College of Physicians and Surgeons, Columbia University, 4-420, 630 West 168th Street, New York, NY 10032, USA
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Giuffrè B, Parini R, Rizzuti T, Morandi L, van Diggelen OP, Bruno C, Giuffrè M, Corsello G, Mosca F. Severe neonatal onset of glycogenosis type IV: clinical and laboratory findings leading to diagnosis in two siblings. J Inherit Metab Dis 2004; 27:609-19. [PMID: 15669676 DOI: 10.1023/b:boli.0000042980.45692.bb] [Citation(s) in RCA: 15] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/12/2022]
Abstract
Glycogenosis type IV is an autosomal recessive disease, exceptionally diagnosed at birth: only very few reports of the fatal perinatal neuromuscular form have been described. We report on two sibling male newborns who died at 10 and 4 weeks of age with clinical signs of a systemic storage disease. Prenatal history included polyhydramnios, reduced fetal movements and fetal hydrops, and Caesarean section was performed at 36 weeks of gestational age because of fetal distress. At birth, both babies showed severe hypotonia, hyporeflexia and no spontaneous breathing activity. They never showed active movements, sucking and swallowing and were respirator-dependent until death. A muscle biopsy revealed, in both patients, the presence of PAS-positive and partially diastase-resistant cytoplasmic inclusions containing granular and filamentous amylopectin-like material. This suggested that the stored material consisted of abnormal glycogen. At autopsy, ultrastructural examination of cardiac and skeletal muscle, liver, kidney and brain showed PAS-positive diastase-resistant eosinophilic cytoplasmic inclusions. Determination of branching enzyme activity, in cultured fibroblasts from the second patient, showed markedly reduced enzyme activity, confirming diagnosis of glycogenosis type IV. Our patients showed the full spectrum of both prenatal signs (hydrops, polyhydramnios) and postnatal signs (hypotonia, hyporeflexia, absence of active movements, cardiomegaly), which have been reported previously. They suffered from a very severe form of glycogenosis type IV with clinical and histological involvement of many tissues and organs. Diagnosis was accomplished on the second baby and required several biochemical and histological studies, in order to rule out both neuromuscular disorders and the most common storage diseases with neonatal onset. In our experience, the correct interpretation of the histological findings was essential in the search for the diagnosis.
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Affiliation(s)
- B Giuffrè
- Dipartimento di Neonatologia, Istituti Clinici di Perfezionamento, Milan, Italy.
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Klein CJ, Boes CJ, Chapin JE, Lynch CD, Campeau NG, Dyck PJB, Dyck PJ. Adult polyglucosan body disease: Case description of an expanding genetic and clinical syndrome. Muscle Nerve 2003; 29:323-8. [PMID: 14755501 DOI: 10.1002/mus.10520] [Citation(s) in RCA: 32] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
A non-Jewish patient is described who had adult polyglucosan body disease (APBD) and glycogen branching enzyme (GBE) deficiency without GBE mutation. A heterozygous polymorphism (Val160Ile) was found, and also discovered in 1 of 50 normal individuals. Magnetic resonance imaging demonstrated increased T2 signal in the midbrain, medullary olives, dentate nuclei, cerebellar peduncles, and internal and external capsules, with vermian atrophy. Both muscle and nerve biopsy revealed perivascular inflammatory infiltrates. These findings expand the clinical and genetic spectrum of APBD. Factors other than mutation of the expressed GBE gene may cause enzyme deficiency and varied expression and development of APBD.
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Affiliation(s)
- Christopher J Klein
- Department of Neurology, Mayo Clinic and Mayo Foundation, 200 First Street SW, Rochester, Minnesota 55905, USA.
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Bhuiyan J, Al Odaib AN, Ozand PT. A simple, rapid test for the differential diagnosis of glycogen storage disease type 3. Clin Chim Acta 2003; 335:21-6. [PMID: 12927680 DOI: 10.1016/s0009-8981(03)00234-1] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/02/2023]
Abstract
BACKGROUND Type 3 glycogen storage disease is an inborn error of metabolism in young infants that often requires extensive workup. However, this disease manifests with few symptoms other than hepatosplenomegaly. At adolescence, this disease may cause myopathy and cardiomyopathy. Since a significant portion of referrals to pediatrics is for evaluation of a hepatosplenomegaly, the differential diagnosis of this disease assumes importance. METHODS The clinical and biochemical findings in 26 patients with the type 3 glycogen storage disease were investigated. Biochemical parameters included ALT, AST, total CK and CK-MB. RESULTS Changes in ALT, AST and total CK were observed to varying degrees. However, CK was found to be a diagnostic indicator for type 3 glycogen storage disease and appears to be a pathognomic marker. CONCLUSIONS Use of CK may reduce the need for extensive diagnostic profiles and aid in the rapid identification and initiation of management for patients presenting with hepatosplenomegaly.
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Affiliation(s)
- Jalaluddin Bhuiyan
- Department of Pathology and Laboratory Medicine, Section of Clinical Biochemistry, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia
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Pederson BA, Csitkovits AG, Simon R, Schroeder JM, Wang W, Skurat AV, Roach PJ. Overexpression of glycogen synthase in mouse muscle results in less branched glycogen. Biochem Biophys Res Commun 2003; 305:826-30. [PMID: 12767905 DOI: 10.1016/s0006-291x(03)00862-3] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/19/2022]
Abstract
Glycogen, a branched polymer of glucose, serves as an energy reserve in many organisms. The degree of branching likely reflects the balance between the activities of glycogen synthase and branching enzyme. Mice overexpressing constitutively active glycogen synthase in skeletal muscle (GSL30) have elevated muscle glycogen. To test whether excess glycogen synthase activity affected glycogen branching, we examined the glycogen from skeletal muscle of GSL30 mice. The absorption spectrum of muscle glycogen determined in the presence of iodine was shifted to higher wavelengths in the GSL30 animals, consistent with a decrease in the degree of branching. As judged by Western blotting, the levels of glycogenin and the branching enzyme were also elevated. Branching enzyme activity also increased approximately threefold. However, this compared with an increase in glycogen synthase of some 50-fold, so that the increase in branching enzyme in response to overexpression of glycogen synthase was insufficient to synthesize normally branched glycogen.
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Affiliation(s)
- Bartholomew A Pederson
- Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, and Indiana University Center for Diabetes Research, Indianapolis, IN 46202-5122, USA
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Cavanagh JB. Corpora-amylacea and the family of polyglucosan diseases. BRAIN RESEARCH. BRAIN RESEARCH REVIEWS 1999; 29:265-95. [PMID: 10209236 DOI: 10.1016/s0165-0173(99)00003-x] [Citation(s) in RCA: 188] [Impact Index Per Article: 7.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 10/18/2022]
Abstract
The history, characters, composition and topography of corpora amylacea (CA) in man and the analogous polyglucosan bodies (PGB) in other species are documented, noting particularly the wide variation in the numbers found with age and in neurological disease. Their origins from both neurons and glia and their probable migrations and ultimate fate are discussed. Their presence is also noted in other organs, particularly in the heart. The occurrence in isolated cases of occasional 'massive' usually focal accumulations of similar polyglucosan bodies in association with certain chronic neurological diseases is noted and the specific conditions Adult Polyglucosan body disease and type IV glycogenosis where they are found throughout the nervous system in great excess is discussed. The distinctive differences of CA from the PGB of Lafora body disease and Bielschowsky body disease are emphasised. When considering their functional roles, a parallel is briefly drawn on the one hand between normal CA and the bodies in the polyglucosan disorders and on the other with the lysosomal system and its associated storage diseases. It is suggested that these two systems are complementary ways by which large, metabolically active cells such as neurons, astrocytes, cardiac myocytes and probably many other cell types, dispose of the products of stressful metabolic events throughout life and the continuing underlying process of aging and degradation of long lived cellular proteins. Each debris disposal system must be regulated in its own way and must inevitably, a priori, be heir to metabolic defects that give rise in each to its own set of metabolic disorders.
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Affiliation(s)
- J B Cavanagh
- Department of Clinical Neurosciences, Institute of Psychiatry, De Crespigny Avenue, London SE5 8AF, UK
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Bao Y, Kishnani P, Wu JY, Chen YT. Hepatic and neuromuscular forms of glycogen storage disease type IV caused by mutations in the same glycogen-branching enzyme gene. J Clin Invest 1996; 97:941-8. [PMID: 8613547 PMCID: PMC507139 DOI: 10.1172/jci118517] [Citation(s) in RCA: 105] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/31/2023] Open
Abstract
Glycogen storage disease type IV (GSD-IV) is an autosomal recessive disease resulting from deficient glycogen-branching enzyme (GBE) activity. The classic and most common form is progressive liver cirrhosis and failure leading to either liver transplantation or death by 5 yr of age. However, the liver disease is not always progressive. In addition, a neuromuscular type of the disease has been reported. The molecular basis of GSD-IV is not known, nor is there a known reason for the clinical variability. We studied the GBE gene in patients with various presentations of GSD-IV. Three point mutations in the GBE gene were found in two patients with the classical presentation: R515C, F257L, and R524X. Transient expression experiments showed that these mutations inactivated GBE activity. Two point mutations, L224P and Y329S, were detected in two separate alleles of a patient with the nonprogressive hepatic form. The L224P resulted in complete loss of GBE activity, whereas the Y329S resulted in loss of approximately 50% of GBE activity. The Y329S allele was also detected in another patient with the nonprogressive form of GSD-IV but not in 35 unrelated controls or in patients with the more severe forms of GSD-IV. A 210-bp deletion from nucleotide 873 to 1082 of the GBE cDNA was detected in a patient with the fatal neonatal neuromuscular presentation. This deletion, representing the loss of one full exon, was caused by a 3' acceptor splicing site mutation (ag to aa). The deletion abolished GBE activity. Our studies indicate that the three different forms of GSD-IV were caused by mutations in the same GBE gene. The data also suggest that the significant retention of GBE activity in the Y329S allele may be a reason for the mild disease. Further study of genotype/phenotype correlations may yield useful information in predicting the clinical outcomes.
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Affiliation(s)
- Y Bao
- Department of Pediatrics, Duke University Medical Center, Durham, North Carolina 27710, USA
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Rosenthal P, Podesta L, Grier R, Said JW, Sher L, Cocjin J, Watanabe F, Vasiliauskas E, van de Velde R, Makowka L. Failure of liver transplantation to diminish cardiac deposits of amylopectin and leukocyte inclusions in type IV glycogen storage disease. LIVER TRANSPLANTATION AND SURGERY : OFFICIAL PUBLICATION OF THE AMERICAN ASSOCIATION FOR THE STUDY OF LIVER DISEASES AND THE INTERNATIONAL LIVER TRANSPLANTATION SOCIETY 1995; 1:373-6. [PMID: 9346615 DOI: 10.1002/lt.500010607] [Citation(s) in RCA: 23] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/05/2023]
Abstract
Orthotopic liver transplantation has been used to treat glycogen storage disease type IV. Most long-term surviving patients who have undergone liver transplantation have been free of neuromuscular and cardiac morbidity, and regression of cardiac amylopectin infiltration has been reported after liver transplantation. Leukocyte inclusions in glycogen storage disease type IV have also been reported. We present the case of a child who underwent orthotopic liver transplantation for glycogen storage disease type IV. In contrast to previous reports, at autopsy 2 1/2 years after transplantation, there was massive amylopectin deposits in his heart. Further, peripheral leukocytes never showed loss of amylopectin inclusions after transplantation. Orthotopic liver transplantation for type IV glycogen storage disease may not, in all cases, result in improvement in other affected organs. Consideration of multiorgan transplantation appears warranted.
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Affiliation(s)
- P Rosenthal
- Liver Transplant Service, Cedars-Sinai Medical Center, Los Angeles, CA, USA
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Tang TT, Segura AD, Chen YT, Ricci LM, Franciosi RA, Splaingard ML, Lubinsky MS. Neonatal hypotonia and cardiomyopathy secondary to type IV glycogenosis. Acta Neuropathol 1994; 87:531-6. [PMID: 8059607 DOI: 10.1007/bf00294181] [Citation(s) in RCA: 49] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/28/2023]
Abstract
A neonate with deficiency of branching enzyme (glycogenosis type IV) presented symptoms of severe hypotonia pre- and postnatally, and dilated cardiomyopathy in early infancy. The classical clinical manifestation of liver cirrhosis was not present, although amylopectin-like inclusions were found in the hepatocytes. In contrast to a previous report, the neurons in the brain stem and spinal anterior horns contained PAS-positive, diastase-resistant deposits. The combined involvement of the muscles and motor neurones could account for the severity of hypotonia. The muscle biopsy, electromyogram and biochemical and enzyme assays were helpful in establishing the diagnosis.
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Affiliation(s)
- T T Tang
- Department of Pathology, Children's Hospital of Wisconsin, Milwaukee
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Starzl TE, Demetris AJ, Trucco M, Murase N, Ricordi C, Ildstad S, Ramos H, Todo S, Tzakis A, Fung JJ. Cell migration and chimerism after whole-organ transplantation: the basis of graft acceptance. Hepatology 1993; 17:1127-52. [PMID: 8514264 PMCID: PMC2964270] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/05/2022]
Abstract
Improvements in the prevention or control of rejection of the kidney and liver have been largely interchangeable (1 , 2 ) and then applicable, with very little modification, to thoracic and other organs. However, the mechanism by which anti rejection treatment permits any of these grafts to be “accepted” has been an immunological enigma (3 , 4 ). We have proposed recently that the exchange of migratory leukocytes between the transplant and the recipient with consequent long-term cellular chimerism in both is the basis for acceptance of all whole-organ allografts and xenografts (5 ). Although such chimerism was demonstrated only a few months ago, the observations have increased our insight into transplantation immunology and have encouraged the development of alternative therapeutic strategies (6 ).
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Affiliation(s)
- T E Starzl
- Department of Surgery, University of Pittsburgh Health Science Center, Pennsylvania 15213
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Starzl TE, Demetris AJ, Trucco M, Murase N, Ricordi C, Ildstad S, Ramos H, Todo S, Tzakis A, Fung JJ, Nalesnik M, Zeevi A, Rudert WA, Kocova M. Cell migration and chimerism after whole-organ transplantation: the basis of graft acceptance. Hepatology 1993. [PMID: 8514264 DOI: 10.1002/hep.1840170629] [Citation(s) in RCA: 495] [Impact Index Per Article: 15.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
Improvements in the prevention or control of rejection of the kidney and liver have been largely interchangeable (1, 2) and then applicable, with very little modification, to thoracic and other organs. However, the mechanism by which anti rejection treatment permits any of these grafts to be “accepted” has been an immunological enigma (3, 4). We have proposed recently that the exchange of migratory leukocytes between the transplant and the recipient with consequent long-term cellular chimerism in both is the basis for acceptance of all whole-organ allografts and xenografts (5). Although such chimerism was demonstrated only a few months ago, the observations have increased our insight into transplantation immunology and have encouraged the development of alternative therapeutic strategies (6).
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Affiliation(s)
- T E Starzl
- Department of Surgery, University of Pittsburgh Health Science Center, Pennsylvania 15213
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45
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Thon V, Khalil M, Cannon J. Isolation of human glycogen branching enzyme cDNAs by screening complementation in yeast. J Biol Chem 1993. [DOI: 10.1016/s0021-9258(18)53204-x] [Citation(s) in RCA: 27] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/22/2022] Open
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Starzl TE, Demetris AJ, Trucco M, Ricordi C, Ildstad S, Terasaki PI, Murase N, Kendall RS, Kocova M, Rudert WA. Chimerism after liver transplantation for type IV glycogen storage disease and type 1 Gaucher's disease. N Engl J Med 1993; 328:745-9. [PMID: 8437594 PMCID: PMC2963442 DOI: 10.1056/nejm199303183281101] [Citation(s) in RCA: 197] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/30/2023]
Abstract
BACKGROUND Liver transplantation for type IV glycogen storage disease (branching-enzyme deficiency) results in the resorption of extrahepatic deposits of amylopectin, but the mechanism of resorption is not known. METHODS We studied two patients with type IV glycogen storage disease 37 and 91 months after liver transplantation and a third patient with lysosomal glucocerebrosidase deficiency (type 1 Gaucher's disease), in whom tissue glucocerebroside deposition had decreased 26 months after liver replacement, to determine whether the migration of cells from the allograft (microchimerism) could explain the improved metabolism of enzyme-deficient tissues in the recipient. Samples of blood and biopsy specimens of the skin, lymph nodes, heart, bone marrow, or intestine were examined immunocytochemically with the use of donor-specific monoclonal anti-HLA antibodies and the polymerase chain reaction, with preliminary amplification specific to donor alleles of the gene for the beta chain of HLA-DR molecules, followed by hybridization with allele-specific oligonucleotide probes. RESULTS Histopathological examination revealed that the cardiac deposits of amylopectin in the patients with glycogen storage disease and the lymph-node deposits of glucocerebroside in the patient with Gaucher's disease were dramatically reduced after transplantation. Immunocytochemical analysis showed cells containing the HLA phenotypes of the donor in the heart and skin of the patients with glycogen storage disease and in the lymph nodes, but not the skin, of the patient with Gaucher's disease. Polymerase-chain-reaction analysis demonstrated donor HLA-DR DNA in the heart of both patients with glycogen storage disease, in the skin of one of them, and in the skin, intestine, blood, and bone marrow of the patient with Gaucher's disease. CONCLUSIONS Systemic microchimerism occurs after liver allotransplantation and can ameliorate pancellular enzyme deficiencies.
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Affiliation(s)
- T E Starzl
- Pittsburgh Transplant Institute, University of Pittsburgh Health Science Center
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Selby R, Starzl TE, Yunis E, Todo S, Tzakis AG, Brown BI, Kendall RS. Liver transplantation for type I and type IV glycogen storage disease. Eur J Pediatr 1993; 152 Suppl 1:S71-6. [PMID: 8319729 PMCID: PMC2974302 DOI: 10.1007/bf02072093] [Citation(s) in RCA: 32] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/29/2023]
Abstract
Progressive liver failure or hepatic complications of the primary disease led to orthotopic liver transplantation in eight children with glycogen storage disease over a 9-year period. One patient had glycogen storage disease (GSD) type I (von Gierke disease) and seven patients had type IV GSD (Andersen disease). As previously reported [19], a 16.5-year-old-girl with GSD type I was successfully treated in 1982 by orthotopic liver transplantation under cyclosporine and steroid immunosuppression. The metabolic consequences of the disease have been eliminated, the renal function and size have remained normal, and the patient has lived a normal young adult life. A late portal venous thrombosis was treated successfully with a distal splenorenal shunt. Orthotopic liver transplantation was performed in seven children with type N GSD who had progressive hepatic failure. Two patients died early from technical complications. The other five have no evidence of recurrent hepatic amylopectinosis after 1.1-5.8 postoperative years. They have had good physical and intellectual maturation. Amylopectin was found in many extrahepatic tissues prior to surgery, but cardiopathy and skeletal myopathy have not developed after transplantation. Postoperative heart biopsies from patients showed either minimal amylopectin deposits as long as 4.5 years following transplantation or a dramatic reduction in sequential biopsies from one patient who initially had dense myocardial deposits. Serious hepatic derangement is seen most commonly in types I and IV GSD. Liver transplantation cures the hepatic manifestations of both types. The extrahepatic deposition of abnormal glycogen appears not to be problematic in type I disease, and while potentially more threatening in type IV disease, may actually exhibit signs of regression after hepatic allografting.
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Affiliation(s)
- R Selby
- Department of Surgery, Children's Hospital, University of Pittsburgh, Pennsylvania 15213
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Schröder JM, May R, Shin YS, Sigmund M, Nase-Hüppmeier S. Juvenile hereditary polyglucosan body disease with complete branching enzyme deficiency (type IV glycogenosis). Acta Neuropathol 1993; 85:419-30. [PMID: 7683169 DOI: 10.1007/bf00334454] [Citation(s) in RCA: 45] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/26/2023]
Abstract
Polyglucosan body diseases in adults, contrary to infantile cases (Andersen's disease or type IV glycogenosis or amylopectinosis), are usually not associated with a significant deficiency of the branching enzyme (= amylo-1,4-1,6 transglucosidase). We, therefore, report on a 19-year-old male with complete branching enzyme deficiency presenting with severe myopathy, dilative cardiomyopathy, heart failure, dysmorphic features, and subclinical neuropathy. His 14-year-old brother had similar symptoms and was erroneously classified by a previous muscle biopsy as having central core disease but could later be identified as also having polyglucosan body myopathy. The skeletal muscle, endomyocardiac, and sural nerve biopsies as well as the autopsy revealed extraordinarily severe deposits of polyglucosan bodies not only in striated and smooth muscle fibers, but also in histiocytes, fibroblasts, perineurial cells, axons and astrocytes. Occasional paracrystalline mitochondrial inclusions were also noted. Thus, this patient represents to our knowledge the first juvenile, familial case of polyglucosan body disease with total branching enzyme deficiency and extensive polyglucosan body storage.
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Affiliation(s)
- J M Schröder
- Institut für Neuropathologie, Rheinisch-Westfälische Technische Hochschule Aachen, Germany
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Penchansky L, Agostini RM, Jaffe R. Leukocyte inclusions in glycogen storage disease, type IV. PEDIATRIC PATHOLOGY 1992; 12:903-5. [PMID: 1333075 DOI: 10.3109/15513819209024249] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/26/2022]
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Sokal EM, Van Hoof F, Alberti D, de Ville de Goyet J, de Barsy T, Otte JB. Progressive cardiac failure following orthotopic liver transplantation for type IV glycogenosis. Eur J Pediatr 1992; 151:200-3. [PMID: 1601012 DOI: 10.1007/bf01954384] [Citation(s) in RCA: 49] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/27/2022]
Abstract
Orthotopic liver transplantation (OLT) has been proposed to treat patients with type IV glycogenosis because of early progressive cirrhosis. Reports have shown absence of disease progression in other organs after OLT and even regression of cardiac amylopectin infiltration in one case. We describe a 15-month-old child in whom a liver transplant was performed for type IV glycogenosis. There were no clinical signs of extrahepatic disease before OLT. Nine months later, the patient developed progressive cardiac insufficiency and died from cardiac failure. Because of massive amylopectin deposits, decreased myofibrils in cardiac cells, and exclusion of other causes of cardiac failure, death was attributed to amylopectionosis. Our observation contrasts with the Pittsburgh experience and suggests that cardiac amylopectionosis may progress after OLT.
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Affiliation(s)
- E M Sokal
- Department of Paediatrics, Université Catholique de Louvain, Hôpital St. Luc, Brussels, Belgium
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