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Quaglia A, Roberts EA, Torbenson M. Developmental and Inherited Liver Disease. MACSWEEN'S PATHOLOGY OF THE LIVER 2024:122-294. [DOI: 10.1016/b978-0-7020-8228-3.00003-x] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/02/2025]
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Wicker C, Cano A, Decostre V, Froissart R, Maillot F, Perry A, Petit F, Voillot C, Wahbi K, Wenz J, Laforêt P, Labrune P. French recommendations for the management of glycogen storage disease type III. Eur J Med Res 2023; 28:253. [PMID: 37488624 PMCID: PMC10364360 DOI: 10.1186/s40001-023-01212-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/01/2022] [Accepted: 07/05/2023] [Indexed: 07/26/2023] Open
Abstract
The aim of the Protocole National De Diagnostic et de Soins/French National Protocol for Diagnosis and Healthcare (PNDS) is to provide advice for health professionals on the optimum care provision and pathway for patients with glycogen storage disease type III (GSD III).The protocol aims at providing tools that make the diagnosis, defining the severity and different damages of the disease by detailing tests and explorations required for monitoring and diagnosis, better understanding the different aspects of the treatment, defining the modalities and organisation of the monitoring. This is a practical tool, to which health care professionals can refer. PNDS cannot, however, predict all specific cases, comorbidities, therapeutic particularities or hospital care protocols, and does not seek to serve as a substitute for the individual responsibility of the physician in front of his/her patient.
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Affiliation(s)
- Camille Wicker
- Maladies métaboliques et hépatiques pédiatriques, CHRU Hautepierre, 1 Avenue Molière, 67200, Strasbourg, France
| | - Aline Cano
- Centre de Référence des Maladies Héréditaires du Métabolisme- CHU La Timone Enfants, 264 rue Saint-Pierre, 13385, Marseille cedex 5, France
| | - Valérie Decostre
- Institut de myologie, Groupe Hospitalier Pitié-Salpêtrière, APHP. Université Paris Sorbonne, 47-83 boulevard de l'Hôpital, 75651, Paris Cedex 13, France
| | - Roseline Froissart
- Centre de Biologie et pathologie Est, maladies héréditaires du métabolisme, HFME, 59, Boulevard Pinel, 69677, Bron Cedex, France
| | - François Maillot
- Médecine Interne, Centre Référence Maladies Métaboliques, hôpital Bretonneau, 2 boulevard Tonnelé, 37044, Tours cedex 9, France
| | - Ariane Perry
- Pédiatrie, Centre de Référence Maladies Héréditaires du Métabolisme Hépatique, Hôpital Antoine Béclère, APHP Université Paris-Saclay, 92141, Clamart Cedex, France
| | - François Petit
- Laboratoire de génétique, Hôpital Antoine Béclère, APHP. Université Paris-Saclay, 92141, Clamart Cedex, France
| | - Catherine Voillot
- Pédiatrie, Centre de Référence Maladies Héréditaires du Métabolisme Hépatique, Hôpital Antoine Béclère, APHP Université Paris-Saclay, 92141, Clamart Cedex, France
| | - Karim Wahbi
- Service de cardiologie - Hôpital Cochin, APHP. Université Paris Centre, 27 rue du Faubourg Saint-Jacques, 75014, Paris, France
| | - Joëlle Wenz
- Service d'hépatologie et transplantation hépatique pédiatriques, hôpital Bicêtre, APHP. Université Paris-Saclay, 94276, Le Kremlin Bicêtre Cedex, France
| | - Pascal Laforêt
- Neurologie, Centre de Référence Maladies Neuromusculaires Nord/Est/Ile de France Hôpital Raymond Poincaré, AP-HP, Université Paris Saclay, 104 Boulevard Raymond Poincaré, 92380, Garches, France
| | - Philippe Labrune
- Pédiatrie, Centre de Référence Maladies Héréditaires du Métabolisme Hépatique, Hôpital Antoine Béclère, APHP Université Paris-Saclay, 92141, Clamart Cedex, France.
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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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Lim JA, Choi SJ, Gao F, Kishnani PS, Sun B. A Novel Gene Therapy Approach for GSD III Using an AAV Vector Encoding a Bacterial Glycogen Debranching Enzyme. MOLECULAR THERAPY-METHODS & CLINICAL DEVELOPMENT 2020; 18:240-249. [PMID: 32637453 PMCID: PMC7327847 DOI: 10.1016/j.omtm.2020.05.034] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 01/17/2020] [Accepted: 05/27/2020] [Indexed: 12/25/2022]
Abstract
Glycogen storage disease type III (GSD III) is an inherited disorder caused by a deficiency of glycogen debranching enzyme (GDE), which results in the accumulation of abnormal glycogen (limit dextrin) in the cytoplasm of liver, heart, and skeletal muscle cells. Currently, there is no curative treatment for this disease. Gene therapy with adeno-associated virus (AAV) provides an optimal treatment approach for monogenic diseases like GSD III. However, the 4.6 kb human GDE cDNA is too large to be packaged into a single AAV vector due to its small carrying capacity. To overcome this limitation, we tested a new gene therapy approach in GSD IIIa mice using an AAV vector ubiquitously expressing a smaller bacterial GDE, Pullulanase, whose cDNA is 2.2 kb. Intravenous injection of the AAV vector (AAV9-CB-Pull) into 2-week-old GSD IIIa mice blocked glycogen accumulation in both cardiac and skeletal muscles, but not in the liver, accompanied by the improvement of muscle functions. Subsequent treatment with a liver-restricted AAV vector (AAV8-LSP-Pull) reduced liver glycogen content by 75% and reversed hepatic fibrosis while maintaining the effect of AAV9-CB-Pull treatment on heart and skeletal muscle. Our results suggest that AAV-mediated gene therapy with Pullulanase is a possible treatment for GSD III.
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Affiliation(s)
- Jeong-A Lim
- Division of Medical Genetics, Department of Pediatrics, Duke University School of Medicine, Durham, NC, USA
| | - Su Jin Choi
- Division of Medical Genetics, Department of Pediatrics, Duke University School of Medicine, Durham, NC, USA
| | - Fengqin Gao
- Division of Medical Genetics, Department of Pediatrics, Duke University School of Medicine, Durham, NC, USA
| | - Priya S Kishnani
- Division of Medical Genetics, Department of Pediatrics, Duke University School of Medicine, Durham, NC, USA
| | - Baodong Sun
- Division of Medical Genetics, Department of Pediatrics, Duke University School of Medicine, Durham, NC, USA
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Halaby CA, Young SP, Austin S, Stefanescu E, Bali D, Clinton LK, Smith B, Pendyal S, Upadia J, Schooler GR, Mavis AM, Kishnani PS. Liver fibrosis during clinical ascertainment of glycogen storage disease type III: a need for improved and systematic monitoring. Genet Med 2019; 21:2686-2694. [PMID: 31263214 DOI: 10.1038/s41436-019-0561-7] [Citation(s) in RCA: 30] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/12/2018] [Accepted: 05/21/2019] [Indexed: 02/07/2023] Open
Abstract
PURPOSE In glycogen storage disease type III (GSD III), liver aminotransferases tend to normalize with age giving an impression that hepatic manifestations improve with age. However, despite dietary treatment, long-term liver complications emerge. We present a GSD III liver natural history study in children to better understand changes in hepatic parameters with age. METHODS We reviewed clinical, biochemical, histological, and radiological data in pediatric patients with GSD III, and performed a literature review of GSD III hepatic findings. RESULTS Twenty-six patients (median age 12.5 years, range 2-22) with GSD IIIa (n = 23) and IIIb (n = 3) were enrolled in the study. Six of seven pediatric patients showed severe fibrosis on liver biopsy (median [range] age: 1.25 [0.75-7] years). Markers of liver injury (aminotransferases), dysfunction (cholesterol, triglycerides), and glycogen storage (glucose tetrasaccharide, Glc4) were elevated at an early age, and decreased significantly thereafter (p < 0.001). Creatine phosphokinase was also elevated with no significant correlation with age (p = 0.4). CONCLUSION Liver fibrosis can occur at an early age, and may explain the decrease in aminotransferases and Glc4 with age. Our data outlines the need for systematic follow-up and specific biochemical and radiological tools to monitor the silent course of the liver disease process.
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Affiliation(s)
- Carine A Halaby
- Division of Medical Genetics, Department of Pediatrics, Duke University Medical Center, Durham, NC, USA
| | - Sarah P Young
- Division of Medical Genetics, Department of Pediatrics, Duke University Medical Center, Durham, NC, USA
| | - Stephanie Austin
- Division of Medical Genetics, Department of Pediatrics, Duke University Medical Center, Durham, NC, USA
| | - Ela Stefanescu
- Division of Medical Genetics, Department of Pediatrics, Duke University Medical Center, Durham, NC, USA
| | - Deeksha Bali
- Division of Medical Genetics, Department of Pediatrics, Duke University Medical Center, Durham, NC, USA
| | - Lani K Clinton
- Department of Pathology, Duke University Medical Center, Durham, NC, USA
| | - Brian Smith
- Division of Neonatal-Perinatal Medicine, Department of Pediatrics, Duke University Medical Center, Durham, NC, USA
| | - Surekha Pendyal
- Division of Medical Genetics, Department of Pediatrics, Duke University Medical Center, Durham, NC, USA
| | - Jariya Upadia
- Division of Medical Genetics, Department of Pediatrics, Duke University Medical Center, Durham, NC, USA
| | - Gary R Schooler
- Department of Radiology, Duke University Medical Center, Durham, NC, USA
| | - Alisha M Mavis
- Division of Gastroenterology, Hepatology and Nutrition, Department of Pediatrics, Duke University Medical Center, Durham, NC, USA
| | - Priya S Kishnani
- Division of Medical Genetics, Department of Pediatrics, Duke University Medical Center, Durham, NC, USA.
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Abdullah IS, Teh SH, Khaidizar FD, Ngu LH, Keng WT, Yap S, Mohamed Z. Intron retention is among six unreported AGL mutations identified in Malaysian GSD III patients. Genes Genomics 2019; 41:885-893. [PMID: 31028654 DOI: 10.1007/s13258-019-00815-9] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/07/2018] [Accepted: 04/02/2019] [Indexed: 11/30/2022]
Abstract
BACKGROUND Glycogen storage disease type III is an autosomal recessive disorder that is caused by deficiencies of the glycogen debranching enzyme. Mutations within the AGL gene have been found to be heterogeneous, with some common mutations being reported in certain populations. The mutation spectrum of AGL gene in the multi-ethnic Malaysian population is still unknown. OBJECTIVE The present study seeks to determine the mutation spectrum of the AGL gene in Malaysian population. METHODS A total of eleven patients (eight Malay, two Chinese and one Bajau) were investigated. Genomic DNA was extracted and subsequently the AGL gene was amplified using specific primers and sequenced. Mutations found were screened in 150 healthy control samples either by restriction enzyme digestion assay or TaqMan® SNP Genotyping assay. RESULTS We identified six unreported mutations (c.1423+1G>T, c.2914_2915delAA, c.3814_3815delAG, c.4333T>G, c.4490G>A, c.4531_4534delTGTC) along with three previously reported mutations (c.99C>T, c.1783C>T, c.2681+1G>A). One of the six unreported mutation causes abnormal splicing and results in retention of intron 12 of the mature transcript, while another is a termination read-through. One of the reported mutation c.2681+1G>A was recurrently found in the Malay patients (n = 7 alleles; 31.8%). CONCLUSION The mutation spectrum of the AGL gene in Malaysian patients has shown considerable heterogeneity, and all unreported mutations were absent in all 150 healthy control samples tested.
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Affiliation(s)
- Ili Syazwana Abdullah
- Genetics and Molecular Biology Unit, Institute of Biological Sciences, Faculty of Science, University of Malaya, 50603, Kuala Lumpur, Malaysia
| | - Ser-Huy Teh
- Genetics and Molecular Biology Unit, Institute of Biological Sciences, Faculty of Science, University of Malaya, 50603, Kuala Lumpur, Malaysia
| | - Fiqri Dizar Khaidizar
- Centre for Research in Biotechnology for Agriculture, University of Malaya, 50603, Kuala Lumpur, Malaysia
| | - Lock-Hock Ngu
- Genetics Department, Kuala Lumpur Hospital, 50586, Kuala Lumpur, Malaysia
| | - Wee-Teik Keng
- Genetics Department, Kuala Lumpur Hospital, 50586, Kuala Lumpur, Malaysia
| | - Sufin Yap
- Division of Inherited Metabolic Disorders, Department of Paediatrics, University Malaya Medical Centre and Faculty of Medicine, University of Malaya, 50603, Kuala Lumpur, Malaysia.,Department of Inherited Metabolic Diseases, Sheffield Children's Hospital, NHS Foundation Trust, Western Bank, S10 2TH, Sheffield, UK
| | - Zulqarnain Mohamed
- Genetics and Molecular Biology Unit, Institute of Biological Sciences, Faculty of Science, University of Malaya, 50603, Kuala Lumpur, Malaysia. .,Institute of Advanced Studies, University of Malaya, 50603, Kuala Lumpur, Malaysia.
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Abstract
Most of the glycogen metabolism disorders that affect skeletal muscle involve enzymes in glycogenolysis (myophosphorylase (PYGM), glycogen debranching enzyme (AGL), phosphorylase b kinase (PHKB)) and glycolysis (phosphofructokinase (PFK), phosphoglycerate mutase (PGAM2), aldolase A (ALDOA), β-enolase (ENO3)); however, 3 involve glycogen synthesis (glycogenin-1 (GYG1), glycogen synthase (GSE), and branching enzyme (GBE1)). Many present with exercise-induced cramps and rhabdomyolysis with higher-intensity exercise (i.e., PYGM, PFK, PGAM2), yet others present with muscle atrophy and weakness (GYG1, AGL, GBE1). A failure of serum lactate to rise with exercise with an exaggerated ammonia response is a common, but not invariant, finding. The serum creatine kinase (CK) is often elevated in the myopathic forms and in PYGM deficiency, but can be normal and increase only with rhabdomyolysis (PGAM2, PFK, ENO3). Therapy for glycogen storage diseases that result in exercise-induced symptoms includes lifestyle adaptation and carefully titrated exercise. Immediate pre-exercise carbohydrate improves symptoms in the glycogenolytic defects (i.e., PYGM), but can exacerbate symptoms in glycolytic defects (i.e., PFK). Creatine monohydrate in low dose may provide a mild benefit in PYGM mutations.
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Affiliation(s)
- Mark A Tarnopolsky
- Division of Neuromuscular & Neurometabolic Disorders, Departments of Pediatrics and Medicine, McMaster University, Hamilton Health Sciences Centre, Rm 2H26, Hamilton, ON, L8S 4L8, Canada.
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[Molecular and clinical characterization of Colombian patients suffering from type III glycogen storage disease]. BIOMEDICA 2018; 38:30-42. [PMID: 29809327 DOI: 10.7705/biomedica.v38i0.3454] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/22/2016] [Revised: 04/10/2017] [Indexed: 11/21/2022]
Abstract
INTRODUCTION Type III glycogen storage disease (GSD III) is an autosomal recessive disorder in which a mutation in the AGL gene causes deficiency of the glycogen debranching enzyme. The disease is characterized by fasting hypoglycemia, hepatomegaly and progressive myopathy. Molecular analyses of AGL have indicated heterogeneity depending on ethnic groups. The full spectrum of AGL mutations in Colombia remains unclear. OBJECTIVE To describe the clinical and molecular characteristics of ten Colombian patients diagnosed with GSD III. MATERIALS AND METHODS We recruited ten Colombian children with a clinical and biochemical diagnosis of GSD III to undergo genetic testing. The full coding exons and the relevant exon-intron boundaries of the AGL underwent Sanger sequencing to identify mutation. RESULTS All patients had the classic phenotype of the GSD III. Genetic analysis revealed a mutation p.Arg910X in two patients. One patient had the mutation p.Glu1072AspfsX36, and one case showed a compound heterozygosity with p.Arg910X and p.Glu1072AspfsX36 mutations. We also detected the deletion of AGL gene 3, 4, 5, and 6 exons in three patients. The in silico studies predicted that these defects are pathogenic. No mutations were detected in the amplified regions in three patients. CONCLUSION We found mutations and deletions that explain the clinical phenotype of GSD III patients. This is the first report with a description of the clinical phenotype and the spectrum of AGL mutations in Colombian patients. This is important to provide appropriate prognosis and genetic counseling to the patient and their relatives.
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Quaglia A, Roberts EA, Torbenson M. Developmental and Inherited Liver Disease. MACSWEEN'S PATHOLOGY OF THE LIVER 2018:111-274. [DOI: 10.1016/b978-0-7020-6697-9.00003-0] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/02/2025]
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Sun B, Brooks ED, Koeberl DD. Preclinical Development of New Therapy for Glycogen Storage Diseases. Curr Gene Ther 2016; 15:338-47. [PMID: 26122079 DOI: 10.2174/1566523215666150630132253] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/26/2014] [Revised: 03/24/2015] [Accepted: 04/01/2015] [Indexed: 02/07/2023]
Abstract
Glycogen storage disease (GSD) consists of more than 10 discrete conditions for which the biochemical and genetic bases have been determined, and new therapies have been under development for several of these conditions. Gene therapy research has generated proof-of-concept for GSD types I (von Gierke disease) and II (Pompe disease). Key features of these gene therapy strategies include the choice of vector and regulatory cassette, and recently adeno-associated virus (AAV) vectors containing tissue-specific promoters have achieved a high degree of efficacy. Efficacy of gene therapy for Pompe disease depend upon the induction of immune tolerance to the therapeutic enzyme. Efficacy of von Gierke disease is transient, waning gradually over the months following vector administration. Small molecule therapies have been evaluated with the goal of improving standard of care therapy or ameliorating the cellular abnormalities associated with specific GSDs. The receptor-mediated uptake of the therapeutic enzyme in Pompe disease was enhanced by administration of β2 agonists. Rapamycin reduced the liver fibrosis observed in GSD III. Further development of gene therapy could provide curative therapy for patients with GSD, if efficacy from preclinical research is observed in future clinical trials and these treatments become clinically available.
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Herlin B, Laforět P, Labrune P, Fournier E, Stojkovic T. Peripheral neuropathy in glycogen storage disease type III: Fact or myth? Muscle Nerve 2015; 53:310-2. [DOI: 10.1002/mus.24977] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 11/14/2015] [Indexed: 11/10/2022]
Affiliation(s)
- Bastien Herlin
- AP-HP, G-H Pitié-Salpêtrière, Institut de Myologie, centre de référence des maladies neuromusculaires Paris Est; 75013 Paris France
| | - Pascal Laforět
- AP-HP, G-H Pitié-Salpêtrière, Institut de Myologie, centre de référence des maladies neuromusculaires Paris Est; 75013 Paris France
| | - Philippe Labrune
- AP-HP, Hôpitaux Universitaires Paris-Sud - Hôpital Antoine Béclère, Centre de Référence des maladies héréditaires du métabolisme hépatique, service de Pédiatrie, Clamart, and Université Paris Sud; UFR Le Kremlin-Bicêtre France
| | - Emmanuel Fournier
- AP-HP, G-H Pitié-Salpêtrière, Département de Neurophysiologie; Paris France
| | - Tanya Stojkovic
- AP-HP, G-H Pitié-Salpêtrière, Institut de Myologie, centre de référence des maladies neuromusculaires Paris Est; 75013 Paris France
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Allegrini D, Autelitano A, Fogagnolo P, De Cillà S, Piozzi E, Mazza M, Paci S, Montanari C, Riva E, Rossetti L. Lens opacities in glycogenoses type I and III. CANADIAN JOURNAL OF OPHTHALMOLOGY 2015; 50:480-4. [PMID: 26651310 DOI: 10.1016/j.jcjo.2015.08.008] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/19/2015] [Revised: 07/25/2015] [Accepted: 08/11/2015] [Indexed: 10/22/2022]
Abstract
OBJECTIVE The glycogen storage diseases (GSD) or glycogenoses comprise several inherited diseases caused by abnormalities of the enzymes that regulate the synthesis or degradation of glycogen. This report presents lens opacities not previously described in patients with type I or III GSD. PARTICIPANTS Eleven patients with type I and III GSD. METHODS We examined a series of 11 consecutive patients (aged 13-40 years) with type I and III GSD by full ophthalmologic examination. RESULTS We found changes of the lens on 7 of 11 patients (aged 23-40 years) with glycogenoses I and III. In 6 patients, the lens showed multiple, bilateral, punctate, and peripheral opacities; only 1 patient showed a posterior subcapsular opacity in both eyes. We did not observe changes in the cornea and the posterior pole correlated to the accumulation of glycogen and lipids. CONCLUSIONS In this series, we found that 60% of patients with type I and III GSD show lens opacities. These opacities are bilateral, peripheral, multiple, and small; they do not give any visual disturbance. Considering that subjects with age ranging from 13 to 23 years had no lens opacities, we postulate that they could progressively develop over time because of exposure to recurrent attacks of hypoglycemia, which lead to a progressive depletion of hexokinase.
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Affiliation(s)
| | | | | | - Stefano De Cillà
- Eye Clinic, San Paolo Hospital, University of Milan, Milan; Unit of Ophthalmology(,) Maggiore della Carità Hospital, Novara
| | - Elena Piozzi
- Unit of Pediatric Ophthalmology, Niguarda-Cà Granda Hospital
| | - Marco Mazza
- Unit of Pediatric Ophthalmology, Niguarda-Cà Granda Hospital
| | - Sabrina Paci
- Department of Pediatrics, San Paolo Hospital, University of Milan, Milan, Italy
| | - Chiara Montanari
- Department of Pediatrics, San Paolo Hospital, University of Milan, Milan, Italy
| | - Enrica Riva
- Department of Pediatrics, San Paolo Hospital, University of Milan, Milan, Italy
| | - Luca Rossetti
- Eye Clinic, San Paolo Hospital, University of Milan, Milan
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Mogahed EA, Girgis MY, Sobhy R, Elhabashy H, Abdelaziz OM, El-Karaksy H. Skeletal and cardiac muscle involvement in children with glycogen storage disease type III. Eur J Pediatr 2015; 174:1545-1548. [PMID: 25948107 DOI: 10.1007/s00431-015-2546-0] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/03/2014] [Revised: 04/09/2015] [Accepted: 04/14/2015] [Indexed: 10/23/2022]
Abstract
UNLABELLED Glycogen storage disease type III (GSD III) may present with hepatic disease or may involve both skeletal and cardiac muscles as well. To assess the prevalence of neuromuscular and cardiac involvement in a group of children with GSD III, 28 children with GSD III, diagnosed by enzymatic assay, were enrolled in the study after an informed consent was obtained from their parents/guardians and after the study protocol was approved by our institutional ethical committee. Their mean age was 6.6 + 3.1 years. All cases were assessed neurologically by clinical examination, electromyography (EMG), and nerve conduction velocity. The heart was examined clinically by electrocardiogram and echocardiography. Seventeen patients (61 %) had myopathic changes by EMG, three of them had associated neuropathic changes. Creatine phosphokinase (CPK) was elevated in all myopathic cases except one. Children with myopathic changes were significantly older (p = 0.02), and CPK was significantly higher (p < 0.0001). Nine cases had left ventricular (LV) hypertrophy, seven of them had myopathic changes by EMG. CONCLUSION Myopathic changes are not uncommon in children with GSD III. Myopathic changes tend to occur in older age and are associated with higher CPK level. Cardiac muscle involvement is less common in this age group and may, on occasion, occur alone without skeletal muscle involvement. Despite mild degrees of affection in this age group, it is recommended to perform prospective annual screening using EMG and echocardiography in order to augment dietary therapy regimen to prevent progression to life threatening complications.
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Affiliation(s)
- Engy A Mogahed
- Department of Pediatrics, Kasr Alainy Medical School, Cairo University, Cairo, Egypt.
| | - Marian Y Girgis
- Department of Pediatrics, Kasr Alainy Medical School, Cairo University, Cairo, Egypt.
| | - Rodina Sobhy
- Department of Pediatrics, Kasr Alainy Medical School, Cairo University, Cairo, Egypt.
| | - Hala Elhabashy
- Clinical Neurophysiology, Kasr Alainy Medical School, Cairo University, Cairo, Egypt.
| | - Osama M Abdelaziz
- Department of Pediatrics, Kasr Alainy Medical School, Cairo University, Cairo, Egypt.
| | - Hanaa El-Karaksy
- Department of Pediatrics, Kasr Alainy Medical School, Cairo University, Cairo, Egypt.
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Preisler N, Haller RG, Vissing J. Exercise in muscle glycogen storage diseases. J Inherit Metab Dis 2015; 38:551-63. [PMID: 25326273 DOI: 10.1007/s10545-014-9771-y] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/07/2014] [Accepted: 09/09/2014] [Indexed: 12/11/2022]
Abstract
Glycogen storage diseases (GSD) are inborn errors of glycogen or glucose metabolism. In the GSDs that affect muscle, the consequence of a block in skeletal muscle glycogen breakdown or glucose use, is an impairment of muscular performance and exercise intolerance, owing to 1) an increase in glycogen storage that disrupts contractile function and/or 2) a reduced substrate turnover below the block, which inhibits skeletal muscle ATP production. Immobility is associated with metabolic alterations in muscle leading to an increased dependence on glycogen use and a reduced capacity for fatty acid oxidation. Such changes may be detrimental for persons with GSD from a metabolic perspective. However, exercise may alter skeletal muscle substrate metabolism in ways that are beneficial for patients with GSD, such as improving exercise tolerance and increasing fatty acid oxidation. In addition, a regular exercise program has the potential to improve general health and fitness and improve quality of life, if executed properly. In this review, we describe skeletal muscle substrate use during exercise in GSDs, and how blocks in metabolic pathways affect exercise tolerance in GSDs. We review the studies that have examined the effect of regular exercise training in different types of GSD. Finally, we consider how oral substrate supplementation can improve exercise tolerance and we discuss the precautions that apply to persons with GSD that engage in exercise.
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Affiliation(s)
- Nicolai Preisler
- Neuromuscular Research Unit, Section 3342, Department of Neurology, Rigshospitalet, University of Copenhagen, Blegdamsvej 9, 2100, Copenhagen, Denmark,
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15
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Limongelli G, D’Alessandro R, Maddaloni V, Rea A, Sarkozy A, McKenna WJ. Skeletal muscle involvement in cardiomyopathies. J Cardiovasc Med (Hagerstown) 2013; 14:837-61. [DOI: 10.2459/jcm.0b013e3283641c69] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/30/2022]
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16
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Ko JS, Moon JS, Seo JK, Yang HR, Chang JY, Park SS. A mutation analysis of the AGL gene in Korean patients with glycogen storage disease type III. J Hum Genet 2013; 59:42-5. [PMID: 24257475 DOI: 10.1038/jhg.2013.117] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/26/2013] [Revised: 09/20/2013] [Accepted: 09/27/2013] [Indexed: 11/09/2022]
Abstract
Glycogen storage disease type III (GSD III) is an autosomal recessive disorder that is characterized by the excessive accumulation of abnormal glycogen in the liver and muscles and is caused by a deficiency in glycogen debranching enzyme (amylo-1,6-glucosidase, 4-alpha-glucanotransferase (AGL)) activity. To investigate the molecular characteristics of GSD III patients in Korea, we have sequenced the AGL gene in eight children with GSD III. All patients were compound heterozygotes. We identified 10 different mutations (five novel and five previously reported). The novel mutations include one nonsense (c.1461G>A, p.W487X), three splicing (c.293+4_293+6delAGT in IVS4, c.460+1G>T in IVS5, c.2682-8A>G in IVS21) and one missense mutation (c.2591G>C, p.R864P). Together, p.R285X, c.1735+1G>T and p.L1139P accounted for 56% of all alleles, while the remaining mutations are heterogeneous. These three mutations can be common in Korea, and further larger studies are needed to confirm our findings.
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Affiliation(s)
- Jae Sung Ko
- Department of Pediatrics, Seoul National University College of Medicine, Seoul, Korea
| | - Jin Soo Moon
- Department of Pediatrics, Seoul National University College of Medicine, Seoul, Korea
| | - Jeong Kee Seo
- Department of Pediatrics, Seoul National University College of Medicine, Seoul, Korea
| | - Hye Ran Yang
- Department of Pediatrics, Seoul National University College of Medicine, Seoul, Korea
| | - Ju Young Chang
- Department of Pediatrics, Seoul National University College of Medicine, Seoul, Korea
| | - Sung Sup Park
- Department of Laboratory Medicine, Seoul National University College of Medicine, Seoul, Korea
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17
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Ben Rhouma F, Azzouz H, Petit FM, Khelifa MB, Chehida AB, Nasrallah F, Parisot F, Lasram K, Kefi R, Bouyacoub Y, Romdhane L, Baussan C, Kaabachi N, Ben Dridi MF, Tebib N, Abdelhak S. Molecular and biochemical characterization of a novel intronic single point mutation in a Tunisian family with glycogen storage disease type III. Mol Biol Rep 2013; 40:4197-202. [PMID: 23649758 DOI: 10.1007/s11033-013-2500-z] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/13/2013] [Accepted: 04/27/2013] [Indexed: 10/26/2022]
Abstract
Genetic deficiency of the glycogen debranching enzyme causes glycogen storage disease type III, an autosomal recessive inherited disorder. The gene encoding this enzyme is designated as AGL gene. The disease is characterized by fasting hypoglycemia, hepatomegaly, growth retardation, progressive myopathy and cardiomyopathy. In the present study, we present clinical features and molecular characterization of two consanguineous Tunisian siblings suffering from Glycogen storage disease type III. The full coding exons of the AGL gene and their corresponding exon-intron boundaries were amplified for the patients and their parents. Gene sequencing identified a novel single point mutation at the conserved polypyrimidine tract of intron 21 in a homozygous state (IVS21-8A>G). This variant cosegregated with the disease and was absent in 102 control chromosomes. In silico analysis using online resources showed a decreased score of the acceptor splice site of intron 21. RT-PCR analysis of the AGL splicing pattern revealed a 7 bp sequence insertion between exon 21 and exon 22 due to the creation of a new 3' splice site. The predicted mutant enzyme was truncated by the loss of 637 carboxyl-terminal amino acids as a result of premature termination. This novel mutation is the first mutation identified in the region of Bizerte and the tenth AGL mutation identified in Tunisia. Screening for this mutation can improve the genetic counseling and prenatal diagnosis of GSD III.
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Affiliation(s)
- Faten Ben Rhouma
- Laboratoire de Genomique Biomedicale et Oncogenetique LR11IPT05, Institut Pasteur de Tunis, 1002, Tunis, Tunisia
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18
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Preisler N, Pradel A, Husu E, Madsen KL, Becquemin MH, Mollet A, Labrune P, Petit F, Hogrel JY, Jardel C, Maillot F, Vissing J, Laforêt P. Exercise intolerance in Glycogen Storage Disease Type III: weakness or energy deficiency? Mol Genet Metab 2013; 109:14-20. [PMID: 23507172 DOI: 10.1016/j.ymgme.2013.02.008] [Citation(s) in RCA: 32] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/12/2013] [Accepted: 02/12/2013] [Indexed: 11/22/2022]
Abstract
Myopathic symptoms in Glycogen Storage Disease Type IIIa (GSD IIIa) are generally ascribed to the muscle wasting that these patients suffer in adult life, but an inability to debranch glycogen likely also has an impact on muscle energy metabolism. We hypothesized that patients with GSD IIIa can experience exercise intolerance due to insufficient carbohydrate oxidation in skeletal muscle. Six patients aged 17-36-years were studied. We determined VO 2peak (peak oxygen consumption), the response to forearm exercise, and the metabolic and cardiovascular responses to cycle exercise at 70% of VO 2peak with either a saline or a glucose infusion. VO 2peak was below normal. Glucose improved the work capacity by lowering the heart rate, and increasing the peak work rate by 30% (108 W with glucose vs. 83 W with placebo, p=0.018). The block in muscle glycogenolytic capacity, combined with the liver involvement caused exercise intolerance with dynamic skeletal muscle symptoms (excessive fatigue and muscle pain), and hypoglycemia in 4 subjects. In this study we combined anaerobic and aerobic exercise to systematically study skeletal muscle metabolism and exercise tolerance in patients with GSD IIIa. Exercise capacity was significantly reduced, and our results indicate that this was due to a block in muscle glycogenolytic capacity. Our findings suggest that the general classification of GSD III as a glycogenosis characterized by fixed symptoms related to muscle wasting should be modified to include dynamic exercise-related symptoms of muscle fatigue. A proportion of the skeletal muscle symptoms in GSD IIIa, i.e. weakness and fatigue, may be related to insufficient energy production in muscle.
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Affiliation(s)
- Nicolai Preisler
- Neuromuscular Research Unit, Department of Neurology, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark.
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19
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Sentner CP, Caliskan K, Vletter WB, Smit GPA. Heart Failure Due to Severe Hypertrophic Cardiomyopathy Reversed by Low Calorie, High Protein Dietary Adjustments in a Glycogen Storage Disease Type IIIa Patient. JIMD Rep 2011; 5:13-6. [PMID: 23430911 DOI: 10.1007/8904_2011_111] [Citation(s) in RCA: 31] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/23/2011] [Revised: 09/30/2011] [Accepted: 10/25/2011] [Indexed: 01/12/2023] Open
Abstract
In glycogen storage disease type III (GSD III), deficiency of the debranching enzyme causes storage of an intermediate glycogen molecule (limit dextrin) in the affected tissues. In subtype IIIa hepatic tissue, skeletal- and cardiac muscle tissue is affected, while in subtype IIIb only hepatic tissue is affected. Cardiac storage of limit dextrin causes a form of cardiomyopathy, which resembles primary hypertrophic cardiomyopathy on cardiac ultrasound. We present a 32-year-old GSD IIIa patient with severe left ventricular hypertrophy (LVH) first diagnosed at the age of 8 years. LVH remained stable and symptomless until the patient presented at age 25 years with increasing dyspnea, fatigue, obesity, and NYHA (New York Heart Association) functional classification two out of four. Dyspnea, fatigue, and obesity progressed, and at age 28 years she was severely symptomatic with NYHA classification 3+ out of 4. On echocardiogram and electrocardiogram, the LVH had progressed as well. Initially, she was rejected for cardiac transplantation because of severe obesity. Therefore, a 900 cal, high protein diet providing 37% of total energy was prescribed during 4 months on which 10 kg weight loss was achieved. However, her symptoms as well as the electrocardiographic and echocardiographic LVH indices had improved dramatically - ultimately deferring cardiac transplantation. Thereafter, the caloric intake was increased to 1,370 cal per day, and the high protein intake was continued providing 43% of total energy. After 3 years of follow-up, the patient remains satisfied with reasonable exercise tolerance and minor symptoms in daily life.
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Affiliation(s)
- Christiaan P Sentner
- Department of Metabolic Diseases, Beatrix Children's Hospital, University Medical Centre Groningen, Hanzeplein 1, 30.001, 9700 RB, Groningen, The Netherlands,
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Valayannopoulos V, Bajolle F, Arnoux JB, Dubois S, Sannier N, Baussan C, Petit F, Labrune P, Rabier D, Ottolenghi C, Vassault A, Broissand C, Bonnet D, de Lonlay P. Successful treatment of severe cardiomyopathy in glycogen storage disease type III With D,L-3-hydroxybutyrate, ketogenic and high-protein diet. Pediatr Res 2011; 70:638-41. [PMID: 21857385 DOI: 10.1203/pdr.0b013e318232154f] [Citation(s) in RCA: 85] [Impact Index Per Article: 6.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
Glycogen storage disease type III (GSD III) due to debranching enzyme deficiency presenting usually with hepatomegaly and hypoglycemia may be responsible for severe cardiomyopathy which is often fatal. Current treatment of GSD III is based on frequent high-carbohydrate meals that have no effect on the cardiomyopathy. We describe a 2-mo-old infant presenting with a familial form of GSD III complicated with cardiomyopathy. As conventional treatment was unable to improve his sister's cardiomyopathy who was deceased at age 11 mo, we proposed an experimental treatment combining the use of synthetic ketone bodies (D,L-3-OH butyrate) as an alternative energy source, 2:1 ketogenic diet to reduce glucose intake and high-protein diet to enhance gluconeogenesis. Twenty-four months after the onset of this treatment, echocardiography showed an improvement of cardiomyopathy. Growth and liver size remained normal, and no side effects were observed. Blood glucose levels remained within the normal range and insulin levels decreased. These findings show that synthetic ketone bodies as well as low-carbohydrate, high-lipid, and high-protein diet may be a more beneficial therapeutic choice therapeutic choice for GSD III patients with cardiomyopathy. These encouraging data need to be confirmed in more GSD III patients presenting with cardiac or muscular symptoms.
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Affiliation(s)
- Vassili Valayannopoulos
- Reference Center for Inherited Metabolic Disorders, Necker-Enfants Malades Hospital and Paris Descartes University, 75015 Paris, France.
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21
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Molecular and biochemical characterization of Tunisian patients with glycogen storage disease type III. J Hum Genet 2011; 57:170-5. [PMID: 22089644 DOI: 10.1038/jhg.2011.122] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/09/2022]
Abstract
Glycogen storage disease type III (GSD III) is an autosomal recessive inborn error of metabolism caused by mutations in the glycogen debranching enzyme amylo-1,6-glucosidase gene, which is located on chromosome 1p21.2. GSD III is characterized by the storage of structurally abnormal glycogen, termed limit dextrin, in both skeletal and cardiac muscle and/or liver, with great variability in resultant organ dysfunction. The spectrum of AGL gene mutations in GSD III patients depends on ethnic group. The most prevalent mutations have been reported in the North African Jewish population and in an isolate such as the Faroe Islands. Here, we present the molecular and biochemical analyses of 22 Tunisian GSD III patients. Molecular analysis revealed three novel mutations: nonsense (Tyr1148X) and two deletions (3033_3036del AATT and 3216_3217del GA) and five known mutations: three nonsense (R864X, W1327X and W255X), a missense (R524H) and an acceptor splice-site mutation (IVS32-12A>G). Each mutation is associated to a specific haplotype. This is the first report of screening for mutations of AGL gene in the Tunisian population.
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Echocardiographic manifestations of Glycogen Storage Disease III: increase in wall thickness and left ventricular mass over time. Genet Med 2010; 12:413-23. [PMID: 20526204 DOI: 10.1097/gim.0b013e3181e0e979] [Citation(s) in RCA: 30] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/22/2023] Open
Abstract
PURPOSE Glycogen Storage Disease Type III, glycogen debranching enzyme deficiency, causes accumulation of glycogen in liver, skeletal, and cardiac muscle. Some patients develop increased left ventricular thickness by echocardiography, but the rate of increase and its significance remain unclear. METHODS We evaluated 33 patients with Glycogen Storage Disease Type III, 23 with IIIa and 10 with IIIb, ages 1 month to 55.5 years, by echocardiography for wall thickness, left ventricular mass, shortening and ejection fractions, at 1 time point (n = 33) and at 2 time points in patients with more than 1 echocardiogram (13 of the 33). RESULTS Of 23 cross-sectional patients with type IIIa, 12 had elevated left ventricular mass, 11 had elevated wall thickness. One type IIIb patient had elevated left ventricular mass but four had elevated wall thickness. For those with multiple observations, 9 of 10 with type IIIa developed increased left ventricular mass over time, with three already increased at first measurement. Shortening and ejection fractions were generally normal. CONCLUSION Elevated left ventricular mass and wall thickness is more common in patients with type IIIa but develops rarely in type IIIb, although ventricular systolic function is preserved. This suggests serial echocardiograms with attention to left ventricular thickness and mass are important for care of these patients.
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23
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Clemente M, Gussinyer M, Arranz JA, Riudor E, Yeste D, Albisu M, Carrascosa A. Glycogen storage disease type III with hypoketosis. J Pediatr Endocrinol Metab 2010; 23:833-6. [PMID: 21073127 DOI: 10.1515/jpem.2010.134] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/03/2023]
Abstract
A rare case of glycogen storage disease type III with unusually absent ketone body production during hypoglycemia is presented. A 10-month-old boy presented with asymptomatic hepatomegaly. GOT/GPT 2555/1160 IU/L, CK 302 IU/L, triglycerides 1223 mg/dL, cholesterol 702 mg/dL and uric acid 7.9 mg/dL. After a 9-hour fast, glucose was 27 mg/dL and adequate lipolysis without ketogenesis was observed (total/free carnitine 34.5/20 micromol/L, free fatty acids 1620 micromol/L and beta-hydroxybutyrate 172 micromol/L). Result of MCT (medium-chain triglycerides) load test: basal hydroxybutyrate 29 micromol/L rose to 5748 micromol/L. Treatment with a fat-restricted diet supplemented with formula containing MCT was initiated and the patient presented a satisfactory initial evolution. Three months later, CK were 3000 IU/L. Muscle biopsy was diagnostic of glycogenosis. Enzymatic activity in skin fibroblasts was 0% for amylo-1,6-glucosidase. The diagnosis of glycogenosis type III was established. Echocardiography performed at that time showed non-obstructive ventricular hypertrophy. Until now hypoketosis during hypoglycemia has only been described in glycogenosis type I.
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Affiliation(s)
- Maria Clemente
- Pediatric Endocrine Service, Children's Hospital Vall d'Hebron, Autonomous University of Barcelona and Center for Biomedical Research on Rare Diseases, Barcelona, Spain.
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24
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Wary C, Nadaj-Pakleza A, Laforêt P, Claeys KG, Carlier R, Monnet A, Fleury S, Baligand C, Eymard B, Labrune P, Carlier PG. Investigating glycogenosis type III patients with multi-parametric functional NMR imaging and spectroscopy. Neuromuscul Disord 2010; 20:548-58. [DOI: 10.1016/j.nmd.2010.06.011] [Citation(s) in RCA: 27] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/23/2010] [Revised: 05/27/2010] [Accepted: 06/07/2010] [Indexed: 10/19/2022]
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25
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Inborn errors of energy metabolism associated with myopathies. J Biomed Biotechnol 2010; 2010:340849. [PMID: 20589068 PMCID: PMC2877206 DOI: 10.1155/2010/340849] [Citation(s) in RCA: 35] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/29/2009] [Revised: 01/19/2010] [Accepted: 02/22/2010] [Indexed: 12/31/2022] Open
Abstract
Inherited neuromuscular disorders affect approximately one in 3,500 children. Structural muscular defects are most common; however functional impairment of skeletal and cardiac muscle in both children and adults may be caused by inborn errors of energy metabolism as well. Patients suffering from metabolic myopathies due to compromised energy metabolism may present with exercise intolerance, muscle pain, reversible or progressive muscle weakness, and myoglobinuria. In this review, the physiology of energy metabolism in muscle is described, followed by the presentation of distinct disorders affecting skeletal and cardiac muscle: glycogen storage diseases types III, V, VII, fatty acid oxidation defects, and respiratory chain defects (i.e., mitochondriopathies). The diagnostic work-up and therapeutic options in these disorders are discussed.
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27
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Hobson-Webb LD, Austin SL, Bali DS, Kishnani PS. The electrodiagnostic characteristics of Glycogen Storage Disease Type III. Genet Med 2010; 12:440-5. [DOI: 10.1097/gim.0b013e3181cd735b] [Citation(s) in RCA: 27] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/25/2022] Open
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Dagli AI, Zori RT, McCune H, Ivsic T, Maisenbacher MK, Weinstein DA. Reversal of glycogen storage disease type IIIa-related cardiomyopathy with modification of diet. J Inherit Metab Dis 2009; 32 Suppl 1:S103-6. [PMID: 19322675 PMCID: PMC3808093 DOI: 10.1007/s10545-009-1088-x] [Citation(s) in RCA: 50] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/30/2008] [Revised: 01/07/2009] [Accepted: 01/26/2009] [Indexed: 10/21/2022]
Abstract
Glycogen storage disease type III (GSD III) is caused by a deficiency in debranching enzyme, which leads to an accumulation of abnormal glycogen called limit dextrin in affected tissues. Muscle and liver involvement is present in GSD type IIIa, while the defect is limited to the liver only in GSD type IIIb. Besides skeletal muscle involvement, a cardiomyopathy resembling idiopathic hypertrophic cardiomyopathy is seen. Management consists of maintaining normoglycaemia by supplementation with cornstarch therapy and/or protein. While studies are lacking regarding the best treatment for skeletal muscle disease, a high-protein diet was previously reported to be beneficial. No cases of improvement in cardiomyopathy have been reported. Our patient presented in infancy with hypoglycaemia and hepatomegaly. His prescribed management consisted of cornstarch supplementation and a high-protein diet providing 20% of his total energy needs. At 16 years of age, he developed a severe cardiomyopathy with a left ventricular mass index of 209 g/m(2). The cardiomyopathy remained stable on a protein intake of 20-25% of total energy. At age 22 years, the diet was changed to increase his protein intake to 30% of total energy and minimize his cornstarch therapy to only what was required to maintain normoglycaemia. Dramatic improvement in the cardiomyopathy occurred. Over one year, his left ventricular mass index decreased from 159.7 g/m(2) to 78 g/m(2) (normal 50-86 g/m(2)) and the creatine kinase levels decreased from 455 U/L to 282 U/L. Avoidance of overtreatment with carbohydrate and a high-protein diet can reverse and may prevent cardiomyopathy.
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Affiliation(s)
- A I Dagli
- Raymond C. Philip Research and Education Unit, Division of Genetics, Department of Pediatrics, University of Florida, Gainesville, Florida, USA.
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Labrune P, Eberschweiler PT, Boudjemline AM, Hubert-Buron A, Petit F, Gajdos V. Histoire naturelle des glycogénoses avec atteinte hépatique. Presse Med 2008; 37:1172-7. [DOI: 10.1016/j.lpm.2007.09.023] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/05/2007] [Revised: 09/05/2007] [Accepted: 09/26/2007] [Indexed: 12/01/2022] Open
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30
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Kim KO, Lee HJ, Choi JW, Eun JR, Choi JH. An adult case of glycogen storage disease type IIIa. THE KOREAN JOURNAL OF HEPATOLOGY 2008; 14:219-25. [DOI: 10.3350/kjhep.2008.14.2.219] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/05/2022]
Affiliation(s)
- Kyeong Ok Kim
- Department of Internal Medicine, Yeungnam University College of Medicine, Daegu, Korea
| | - Heon Ju Lee
- Department of Internal Medicine, Yeungnam University College of Medicine, Daegu, Korea
| | - Jae Won Choi
- Department of Internal Medicine, Yeungnam University College of Medicine, Daegu, Korea
| | - Jong Ryul Eun
- Department of Internal Medicine, Yeungnam University College of Medicine, Daegu, Korea
| | - Joon Hyuk Choi
- Department of Pathologic Medicine, Yeungnam University College of Medicine, Daegu, Korea
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31
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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: 174] [Impact Index Per Article: 9.7] [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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Ogimoto A, Okubo M, Okayama H, Shin YS, Endo Y, Ebara T, Inoue K, Ohtsuka T, Tahara H, Murase T, Higaki J. A Japanese Patient With Cardiomyopathy Caused by a Novel Mutation R285X in the AGL Gene. Circ J 2007; 71:1653-6. [PMID: 17895567 DOI: 10.1253/circj.71.1653] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/09/2022]
Abstract
Left ventricular hypertrophy (LVH) is primarily or secondarily caused by a cardiovascular or systemic disease. The pattern of LVH is distinctive in hypertrophic or metabolic cardiomyopathy and differs from that seen in LVH caused by hypertension or aortic stenosis. A 42-year-old Japanese man had LVH similar to that with hypertrophic cardiomyopathy. The patient was diagnosed with glycogen storage disease type IIIa (GSD-IIIa). Echocardiography showed that he had severe LVH, and concomitant hepatomegaly and hypoglycemia, which led to measurement of glycogen debranching enzyme (GDE) activity; it was undetectable. Sequence analysis of the AGL gene encoding GDE showed a novel nonsense mutation: a C-to-T transition at codon 285 in exon 8, resulting in substitution of the arginine codon by the stop codon (R285X). The patient was homozygous for the mutation. Cardiomyopathy in this patient was caused by a nonsense mutation in the AGL gene. Five other Japanese GSD-IIIa patients over 30 years of age have all presented with cardiomyopathy, as well as hepatomegaly and hypoglycemia. Patients with LVH associated with hepatomegaly and hypoglycemia should undergo biochemical and genetic analyses for GSD-IIIa.
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Affiliation(s)
- Akiyoshi Ogimoto
- Department of Integrated Medicine and Informatics, Ehime University Graduate School of Medicine, Shitsukawa, To-o 791-0295, Japan.
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33
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Bhatti S, Parry E. Successful pregnancy in a woman with glycogen storage disease type III. Aust N Z J Obstet Gynaecol 2006; 46:168-9. [PMID: 16638043 DOI: 10.1111/j.1479-828x.2006.00549.x] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/28/2022]
Affiliation(s)
- Shazia Bhatti
- Department of Obstetrics and Gynaecology, National Women's Hospital, Auckland, New Zealand.
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Abstract
Glycogen storage disease type III (GSD III) was diagnosed in 4 Inuit children (3 confirmed, 1 suspected case) at our institution over the last decade. This rare autosomal recessive disease, which results from a deficiency of the debranching enzyme required for complete degradation of the glycogen molecule, has not been previously described in this population. The possible clinical presentations are heterogeneous, as is the spectrum of severity of this disease. The long-term sequelae can be severe, including recurrent hypoglycemia, hepatic cirrhosis and progressive muscle weakness. These 4 cases would suggest an increased prevalence of GSD III in the Inuit population. Therefore, it is important for health care providers caring for this population to consider and recognize this rare but serious disease.
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Affiliation(s)
- Paul James A Zimakas
- Department of Pediatric Endocrinology, Montreal Children's Hospital, McGill University Health Centre, Montréal, Que
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35
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Lam CW, Lee ATC, Lam YY, Wong TW, Mak TWL, Fung WC, Chan KC, Ho CS, Tong SF. DNA-based subtyping of glycogen storage disease type III: mutation and haplotype analysis of the AGL gene in Chinese. Mol Genet Metab 2004; 83:271-5. [PMID: 15542399 DOI: 10.1016/j.ymgme.2004.07.017] [Citation(s) in RCA: 18] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/26/2004] [Revised: 07/25/2004] [Accepted: 07/29/2004] [Indexed: 11/30/2022]
Abstract
Glycogen storage disease type III (GSD III) is an inborn error of glycogen metabolism caused by a deficiency of glycogen debranching enzyme (AGL). Here, we investigate two unrelated Hong Kong Chinese GSD III patients and identify a novel 5-base pair deletional mutation, 2715_2719delTCAGAin exon 22, in one patient and a nonsense mutation, 1222C>T (R408X) in exon 11, in another patient. Since GSD IIIb is only caused by mutation in exon 3 of the AGL gene, we diagnose our patients to have GSD IIIa, which is consistent with the clinical diagnosis. Until now, R408X has only been reported in Faroe Islands GSDIII patients and was thought to demonstrate a founder effect. In this study, haplotyping of the disease-bearing chromosomes in the AGL locus by 19 intragenic single nucleotide polymorphisms shows that R408X is linked with IVS16+8T and IVS23-21T in our patient while R408X is linked with IVS16+8C and IVS23-21A in the Faroe Islands. The different haplotypes of R408X in Chinese and Faroese indicated that R408X is a recurrent mutation.
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Affiliation(s)
- Ching-Wan Lam
- Department of Chemical Pathology, The Chinese University of Hong Kong, Prince of Wales Hospital, Hong Kong, China.
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36
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Mohart D, Russo P, Tobias JD. Perioperative management of a child with glycogen storage disease type III undergoing cardiopulmonary bypass and repair of an atrial septal defect. Paediatr Anaesth 2002; 12:649-54. [PMID: 12358666 DOI: 10.1046/j.1460-9592.2002.00942.x] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/20/2022]
Abstract
The glycogen storage diseases (GSD) are a heterogenous group of inherited disorders involving one of the several steps of glycogen synthesis or degradation. Type III GSD, also known as Cori's or Forbe's disease, results from a deficiency of the enzyme, amylo-1,6-glucosidase, which is responsible for the breakdown or debranching of the glycogen molecule during catabolism. As a result of this deficiency, inadequate glycogen breakdown occurs, resulting in hypoglycaemia during periods of fasting or stress, as well as storage of excessive glycogen, predominantly in the liver. Glycogen accumulation in the liver leads to hepatogmegaly and, in some instances, hepatic dysfunction with cirrhosis in the third and fourth decades of life. Additionally, deficiency of the enzyme in skeletal and cardiac muscle can lead to skeletal muscle weakness and cardiomyopathy. We present a 28-month-old girl who presented for anaesthetic care for cardiopulmonary bypass and closure of an atrial septal defect. The potential perioperative implications of GSD type III are discussed.
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Affiliation(s)
- David Mohart
- Department of Child Health, The University of Missouri, Columbia, MO 65212, USA
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37
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Lucchiari S, Fogh I, Prelle A, Parini R, Bresolin N, Melis D, Fiori L, Scarlato G, Comi GP. Clinical and genetic variability of glycogen storage disease type IIIa: seven novel AGL gene mutations in the Mediterranean area. AMERICAN JOURNAL OF MEDICAL GENETICS 2002; 109:183-90. [PMID: 11977176 DOI: 10.1002/ajmg.10347] [Citation(s) in RCA: 31] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/11/2022]
Abstract
Deficiency of amylo-1,6-glucosidase, 4-alpha-glucanotransferase enzyme (AGL or glycogen debrancher enzyme) is responsible for glycogen storage disease type III, a rare autosomal recessive disorder of glycogen metabolism. The AGL gene is located on chromosome 1p21, and contains 35 exons translated in a monomeric protein product. The disease has recognized clinical and biochemical heterogeneity, reflecting the genotype-phenotype heterogeneity among different subjects. The clinical manifestations of GSD III are represented by hepatomegaly, hypoglycemia, hyperlipidemia, short stature and, in a number of subjects, cardiomyopathy and myopathy. In this article, we discuss the genotypic-phenotypic heterogeneity of GSD III by the molecular characterization of mutations responsible for the disease on a collection of 18 independent alleles from the Mediterranean area. We identified by heteroduplex band shift, DNA direct sequencing, and restriction analysis, seven novel mutations (four nonsense point-mutations: R34X, S530X, R1218X, W1398X; two microinsertions: 1072insT and 4724insAA; and one bp deletion: 676DeltaG), together with two new cases carrying a IVS21 + 1 G --> A splicing site mutation previously described in Italian patients. Altogether, 15 alleles were characterized. The correlation between type of mutation and clinical severity was studied in six patients in whom both mutated alleles were detected. Our data confirm the extreme genetic heterogeneity of this disease, thus precluding a strategy of mutation finding based on screening of recurrent common mutations.
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Affiliation(s)
- S Lucchiari
- Centro Dino Ferrari, Dipartimento di Scienze Neurologiche, Universita' degli Studi di Milano, I.R.C.C.S. Ospedale Maggiore Policlinico, Milano, Italy
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38
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Toda G, Yoshimuta T, Kawano H, Yano K. Glycogen Storage Disease Associated With Left Ventricular Aneurysm in an Elderly Patient. ACTA ACUST UNITED AC 2001; 65:462-4. [PMID: 11348054 DOI: 10.1253/jcj.65.462] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/09/2022]
Abstract
Glycogen storage disease (GSD) types II, III, IV, and V may be associated with cardiomyopathy, but, with the exception of type III GSD, adult cases are extremely rare. A 62-year-old man was found to have GSD and a concomitant left ventricular aneurysm. He had been comparatively well until the age of 62 years, although he had suffered a cerebral infarction at the age of 35 years. The damage caused by glycogen deposition was strictly confined to the myocardium. Left ventriculography revealed a left ventricular aneurysm in the apex. The serial change on electrocardiogram, as well as the findings of the echocardiogram and of cardiac catheterization, resembled those of the dilated phase of hypertrophic cardiomyopathy. However, a left ventricular endomyocardial biopsy specimen revealed central vacuolar degeneration of myocytes with depositions of glycogen. The GSD type remains unknown in the present patient, because the activity of debranching enzyme (type III) measured from the skeletal muscle specimen was normal, whereas that of acid maltase (type II) was slightly low. It is possible that there is a specific malfunction of the acid maltase of the myocardium in the present patient.
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Affiliation(s)
- G Toda
- The Third Department of Internal Medicine, Nagasaki University School of Medicine, Japan.
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39
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Guertl B, Noehammer C, Hoefler G. Metabolic cardiomyopathies. Int J Exp Pathol 2000; 81:349-72. [PMID: 11298185 PMCID: PMC2517748 DOI: 10.1046/j.1365-2613.2000.00186.x] [Citation(s) in RCA: 86] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/15/2001] [Accepted: 01/29/2001] [Indexed: 01/27/2023] Open
Abstract
The energy needed by cardiac muscle to maintain proper function is supplied by adenosine Ariphosphate primarily (ATP) production through breakdown of fatty acids. Metabolic cardiomyopathies can be caused by disturbances in metabolism, for example diabetes mellitus, hypertrophy and heart failure or alcoholic cardiomyopathy. Deficiency in enzymes of the mitochondrial beta-oxidation show a varying degree of cardiac manifestation. Aberrations of mitochondrial DNA lead to a wide variety of cardiac disorders, without any obvious correlation between genotype and phenotype. A completely different pathogenetic model comprises cardiac manifestation of systemic metabolic diseases caused by deficiencies of various enzymes in a variety of metabolic pathways. Examples of these disorders are glycogen storage diseases (e.g. glycogenosis type II and III), lysosomal storage diseases (e.g. Niemann-Pick disease, Gaucher disease, I-cell disease, various types of mucopolysaccharidoses, GM1 gangliosidosis, galactosialidosis, carbohydrate-deficient glycoprotein syndromes and Sandhoff's disease). There are some systemic diseases which can also affect the heart, for example triosephosphate isomerase deficiency, hereditary haemochromatosis, CD 36 defect or propionic acidaemia.
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Affiliation(s)
- B Guertl
- Institute of Pathology, University of Graz, Austria.
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40
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Siciliano M, De Candia E, Ballarin S, Vecchio FM, Servidei S, Annese R, Landolfi R, Rossi L. Hepatocellular carcinoma complicating liver cirrhosis in type IIIa glycogen storage disease. J Clin Gastroenterol 2000; 31:80-2. [PMID: 10914784 DOI: 10.1097/00004836-200007000-00020] [Citation(s) in RCA: 36] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/22/2023]
Abstract
Type III glycogen storage disease (GSD III) is an autosomal recessive disorder characterized by the accumulation of abnormal glycogen in the liver and, in most patients, in the muscle. Although liver fibrosis is a well-known consequence of GSD III, until now only eight cases of liver cirrhosis and two cases of hepatocellular carcinoma have been described in patients affected by this disease. In this case report, the authors describe the clinical history of a patient affected by GSD III who developed severe liver disease during her adult life, progressing from fibrosis to cirrhosis and finally to hepatocellular carcinoma. Until now, the hepatic involvement in GSD III has been considered by most authors as mild and almost always self-limiting. This report, together with the previously published cases, clearly indicates that severe and progressive liver disease may complicate this metabolic disorder. These observations advise a careful hepatologic follow-up of patients affected by GSD III.
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Affiliation(s)
- M Siciliano
- Istituto di Patologia Medica, Facoltà di Medicina e Chirurgia Università Cattolica del Sacro Cuore, Roma, Italy
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41
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Fukuda T, Sugie H, Ito M. Novel mutations in two Japanese cases of glycogen storage disease type IIIa and a review of the literature of the molecular basis of glycogen storage disease type III. J Inherit Metab Dis 2000; 23:95-106. [PMID: 10801050 DOI: 10.1023/a:1005695229464] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/12/2022]
Abstract
We report two novel mutations in two Japanese patients with glycogen storage disease type IIIa (GSD IIIa). In addition, we review the literature on mutations in GSD III to understand better the molecular basis of GSD III. In our first case, the homozygous A-to-C mutation at the acceptor site of intron 5 (IVS5-2A > C) was identified. This leads to the skipping of exon 6 and the predicted mutant protein was found to be 68 amino acids shorter than normal. This is the first report of skipping exon 6, which encodes one of the putative active sites, resulting in a profoundly deleterious effect on debrancher activity. In our second case, the homozygous deletion of an A at position 4234 (4234delA) was identified; this induces a frameshift resulting in the appearance of a stop codon at amino acid position 1276 (1276X). In patients with GSD IIIa, several mutations of the debrancher gene located in the C-terminal region containing putative glycogen binding domains have been identified as well as 4234delA in our second case. On the other hand, specific localization of the mutations within exon 3 was proposed in patients with GSD IIIb.
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Affiliation(s)
- T Fukuda
- Department of Pediatric Neurology, Hamamatsu City Medical Center for Developmental Medicine, Takazono, Hamakita, Japan.
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42
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Abstract
There are 11 glycogen diseases (GSD), nine of which are associated with myopathy. Most of these glycogen storage myopathies are associated with dynamic symptoms and signs in that the major neuromuscular complaints are exercise-induced muscle pain, cramps, and myoglobinura (e.g., GSD V or McArdle's disease associated with myophosphorylase deficiency). The other types of glycogen storage myopathies are considered static in that they are associated with fixed weakness rather than dynamic symptoms and signs. The static glycogen storage myopathies include: GSD I or Pompe's disease (acid maltase or (-glucosidase deficiency), GSD II or Cori-Forbes disease (debranching enzyme deficiency), and GSD IV or Andersen's disease (branching enzyme deficiency). This article reviews the clinical, laboratory, electrophysiologic, histopathologic, and pathogenesis of these static GSD myopathies.
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Affiliation(s)
- A A Amato
- Department of Neurology, Brigham and Women's Hospital; and Associate Professor, Department of Neurology, Harvard Medical School, Boston, MA 02115
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43
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Shaiu WL, Kishnani PS, Shen J, Liu HM, Chen YT. Genotype-phenotype correlation in two frequent mutations and mutation update in type III glycogen storage disease. Mol Genet Metab 2000; 69:16-23. [PMID: 10655153 DOI: 10.1006/mgme.1999.2953] [Citation(s) in RCA: 27] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
Abstract
Deficiency of glycogen debranching enzyme (AGL) activity causes glycogen storage disease type III (GSD-III). Generalized loss of AGL activity results in GSD-IIIa, and muscle-specific retention of AGL activity results in GSD-IIIb. To date, no common mutation has been described among GSD-III patients, except for three alleles; two linked specifically with GSD-IIIb, and the third found only in North African Jews with GSD-IIIa. Here we report two frequent mutations, each of which was found in the homozygous state in multiple patients, and each of which was associated with a subset of clinical phenotype in those patients with that mutation. A novel point mutation of a single T deletion at cDNA position 3964 (3964delT) was first detected in an African American patient, who has a severe phenotype and early onset of clinical symptoms. The second mutation was an A to G transition at position -12 upstream of the 3' splice site of intron 32 (IVS32-12A > G). This lesion, previously implicated as a IIIb mutation in a Japanese patient, was identified in a confirmed GSD-IIIa Caucasian patient presenting with mild clinical symptoms. These two mutations together account for more than 12% of the molecular defects in the GSD-III patients tested. Our molecular and clinical data suggest a genotype-phenotype correlation for each of these mutations. Furthermore, this current study, coupled with our previous reports, describes the molecular tools necessary for the development of a DNA-based diagnostic test for GSD-III.
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Affiliation(s)
- W L Shaiu
- Division of Medical Genetics, Duke University Medical Center, Durham, North Carolina, 27710, USA
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44
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Wolfsdorf JI, Holm IA, Weinstein DA. Glycogen storage diseases. Phenotypic, genetic, and biochemical characteristics, and therapy. Endocrinol Metab Clin North Am 1999; 28:801-23. [PMID: 10609121 DOI: 10.1016/s0889-8529(05)70103-1] [Citation(s) in RCA: 55] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
Abstract
The glycogen storage diseases are caused by inherited deficiencies of enzymes that regulate the synthesis or degradation of glycogen. In the past decade, considerable progress has been made in identifying the precise genetic abnormalities that cause the specific impairments of enzyme function. Likewise, improved understanding of the pathophysiologic derangements resulting from individual enzyme defects has led to the development of effective nutritional therapies for each of these disorders. Meticulous adherence to dietary therapy prevents hypoglycemia, ameliorates the biochemical abnormalities, decreases the size of the liver, and results in normal or nearly normal physical growth and development. Nevertheless, serious long-term complications, including nephropathy that can cause renal failure and hepatic adenomata that can become malignant, are a major concern in GSD-I. In GSD-III, the risk for hypoglycemia diminishes with age, and the liver decreases in size during puberty. Cirrhosis develops in some adult patients, and progressive myopathy and cardiomyopathy occur in patients with absent GDE activity in muscle. It remains unclear whether these complications of glycogen storage disease can be prevented by dietary therapy. Glycogen storage diseases caused by lack of phosphorylase activity are milder disorders with a good prognosis. The liver decreases in size, and biochemical abnormalities disappear by puberty.
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Affiliation(s)
- J I Wolfsdorf
- Department of Pediatrics, Harvard Medical School, Boston, Massachussetts, USA
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45
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Kiechl S, Willeit J, Vogel W, Kohlendorfer U, Poewe W. Reversible severe myopathy of respiratory muscles due to adult-onset type III glycogenosis. Neuromuscul Disord 1999; 9:408-10. [PMID: 10545045 DOI: 10.1016/s0960-8966(99)00038-3] [Citation(s) in RCA: 20] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/01/2023]
Abstract
Subacute severe myopathy of the respiratory muscles developed in a 47-year-old woman after a 3-week period of strict fasting. Histological and biochemical work-up of muscle biopsy specimens permitted the diagnosis of debrancher deficiency. The course of the disease was characterized by subacute respiratory failure and prolonged mechanical ventilation. After initiation of a high-protein diet the patient was successfully weaned from the respirator and recovered well. To our knowledge this is the first reported case of adult-onset debrancher deficiency myopathy presenting with subacute respiratory failure and responding to high-protein diet.
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Affiliation(s)
- S Kiechl
- Department of Neurology, Innsbruck University Clinic, Austria.
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46
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Kiechl S, Kohlendorfer U, Thaler C, Skladal D, Jaksch M, Obermaier-Kusser B, Willeit J. Different clinical aspects of debrancher deficiency myopathy. J Neurol Neurosurg Psychiatry 1999; 67:364-8. [PMID: 10449560 PMCID: PMC1736538 DOI: 10.1136/jnnp.67.3.364] [Citation(s) in RCA: 32] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/04/2022]
Abstract
OBJECTIVE To characterise the main clinical phenotypes of debrancher deficiency myopathy and to increase awareness for this probably underdiagnosed disorder. METHODS The diagnosis of debrancher deficiency was established by laboratory tests, EMG, and muscle and liver biopsy. RESULTS Four patients with debrancher deficiency myopathy were identified in the Tyrol, a federal state of Austria with half a million inhabitants. Clinical appearance was highly variable. The following phenotypes were differentiated: (1) adult onset distal myopathy; (2) subacute myopathy of the respiratory muscles; (3) severe generalised myopathy; and (4) minimal variant myopathy. Exercise intolerance was uncommon. The clinical course was complicated by advanced liver dysfunction in two patients and by severe cardiomyopathy in one. All had raised creatine kinase concentrations (263 to 810 U/l), myogenic and neurogenic features on EMG, and markedly decreased debrancher enzyme activities in muscle or liver biopsy specimens. The findings were substantiated by a review of 79 previously published cases with neuromuscular debrancher deficiency. CONCLUSIONS This study illustrates the heterogeneity of neuromuscular manifestations in debrancher deficiency. Based on the clinical appearance, age at onset, and course of disease four phenotypes may be defined which differ in prognosis, frequency of complications, and response to therapy.
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Affiliation(s)
- S Kiechl
- Department of Neurology, Innsbruck University Clinic, Innsbruck, Austria.
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47
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Abstract
The molecular pathology of classical glycogen storage disorders, glycogen synthase deficiency and Fanconi-Bickel syndrome is reviewed. The isolation of the respective cDNAs, the chromosomal localization of the genes and the elucidation of the genomic organization enabled mutation analysis in most disorders. The findings have shed light on the multi-protein structure of the glucose-6-phosphatase system, the phosphorylase kinase enzymatic complex and the molecular background of the differential tissue expression in debranching enzyme deficiency. The immediate practical benefit of these studies is our extending ability to predict the outcome of clinical variants and to offer genetic counseling to most families. The elucidation of the tertiary structure of these proteins and their structure-function relationship poses major challenges for the future.
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Affiliation(s)
- O N Elpeleg
- Metabolic Disease Unit, Shaare Zedek Medical Center, Jerusalem, Israel
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48
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Mendoza A, Fisher NC, Duckett J, McKiernan J, Preece MA, Green A, McKiernan PJ, Constantine G, Elias E. Successful pregnancy in a patient with type III glycogen storage disease managed with cornstarch supplements. BRITISH JOURNAL OF OBSTETRICS AND GYNAECOLOGY 1998; 105:677-80. [PMID: 9647162 DOI: 10.1111/j.1471-0528.1998.tb10186.x] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/30/2022]
Affiliation(s)
- A Mendoza
- Liver Unit, Queen Elizabeth Hospital, Birmingham, UK
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49
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Hashimoto M, Watanabe G, Yokoyama T, Tsutsumi K, Dohi T, Matsuda M, Okubo M, Nakamura N, Tsurumaru M. Case report: rupture of a gastric varix in liver cirrhosis associated with glycogen storage disease type III. J Gastroenterol Hepatol 1998; 13:232-5. [PMID: 10221829 DOI: 10.1111/j.1440-1746.1998.tb00643.x] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/09/2022]
Abstract
Glycogen storage disease type III, or Cori's disease, is caused by a deficiency of amylo-1,6-glucosidase (debranching enzyme), which leads to the storage of an abnormal glycogen in the liver and in skeletal and heart muscle. Glycogen storage disease type III is usually characterized by hepatic symptoms, growth failure and myopathy. Even though liver cirrhosis is reported, portal hypertension is a rare complication of this disease. We describe the case of a glycogen storage disease type III patient who was diagnosed at 3 years of age and developed complications (liver cirrhosis and rupture of a gastric varix) at 31 years of age. We discuss the histological progression to cirrhosis of the liver and describe the liver enzyme profile at 3 and 31 years of age.
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Affiliation(s)
- M Hashimoto
- Department of Digestive Surgery, Toranomon Hospital, Tokyo, Japan
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50
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Lee PJ, Deanfield JE, Burch M, Baig K, McKenna WJ, Leonard JV. Comparison of the functional significance of left ventricular hypertrophy in hypertrophic cardiomyopathy and glycogenosis type III. Am J Cardiol 1997; 79:834-8. [PMID: 9070576 DOI: 10.1016/s0002-9149(96)00885-5] [Citation(s) in RCA: 31] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/03/2023]
Abstract
A comparison of blood pressure response with exercise stress, thallium scintigraphy, and 24-hour electrocardiographic monitoring between 5 patients with left ventricular hypertrophy associated with glycogen storage disease type III and 10 matched patients with hypertrophic cardiomyopathy revealed normal results in the former group. These data highlight the importance of the etiology of left ventricular hypertrophy before the application of risk stratification.
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Affiliation(s)
- P J Lee
- Medical Unit, Institute of Child Health, London, United Kingdom
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