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Kalkan Uçar S, Elek A, Yazıcı H, Atik Altınok Y, Yüksel Yanbolu A, Erdem F, Yoldaş Çelik M, Aykut A, Durmaz A, Canda E, Çoker M. Nutritional management and geno-phenotyping of clinical nutrition in patients with glycogen storage diseases type VI and IX. Eur J Clin Nutr 2025:10.1038/s41430-025-01614-0. [PMID: 40211049 DOI: 10.1038/s41430-025-01614-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/12/2024] [Revised: 03/12/2025] [Accepted: 03/25/2025] [Indexed: 04/12/2025]
Abstract
BACKGROUND/OBJECTIVES Glycogen storage diseases type VI (GSD-VI) and type IX (GSD-IX) are rare inherited metabolic disorders caused by enzyme deficiencies that disrupt glycogen metabolism. The aim of this study was to analyze the clinical features, nutritional management and geno-phenotyping of clinical nutrition in a cohort of patients with GSD-VI and GSD-IX. SUBJECTS/METHODS A retrospective cohort study was conducted with 16 patients with GSD-VI and GSD-IX. Demographic characteristics, clinical and laboratory findings, and nutritional treatment outcomes were collected and analyzed. RESULTS The mean patient age was 10.57 years (±4.81). The distribution of the diagnoses was as follows: GSD-IXa (3), GSD-IXb (6), GSD-IXc (1), and GSD-VI (6). The average age at diagnosis was 36.5 months (±42.2) (13-114 months) in the GSD-VI group. Among the GSD-IX subgroups, the mean age at diagnosis varied: 23.3months (±4.16) for GSD-IXa, 35.7months (±17.5) for GSD-IXb, and 78months for GSD-IXc. Over the course of the study (4.5 ± 1.77 years), protein intake in GSD VI patients increased by 1.05 g/kg/day (91.3% increase), while in GSD IX patients, it rose by 1.09 g/kg/day (94% rise). Uncooked cornstarch (UCS) started at 1 g/kg/day for GSD-VI and 0.85 g/kg/day for GSD-IX, later reduced to 0.71 g/kg/day (29% decrease) and 0.52 g/kg/day (60% reduction), respectively. CONCLUSION Overall, this paper provides valuable insights into managing GSDVI and GSDIX patients, emphasizing the role of a high-protein diet aligned with the disease's pathophysiology and the potential of genotyping to enhance nutritional treatment protocols.
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Affiliation(s)
- Sema Kalkan Uçar
- Department of Pediatrics, Division of Metabolism and Nutrition, Ege University Medical Faculty, Izmir, Turkey.
| | | | - Havva Yazıcı
- Department of Pediatrics, Division of Metabolism and Nutrition, Ege University Medical Faculty, Izmir, Turkey
| | - Yasemin Atik Altınok
- Department of Pediatrics, Division of Metabolism and Nutrition, Ege University Medical Faculty, Izmir, Turkey
| | - Ayşe Yüksel Yanbolu
- Department of Pediatrics, Division of Metabolism and Nutrition, Ege University Medical Faculty, Izmir, Turkey
| | - Fehime Erdem
- Department of Pediatrics, Division of Metabolism and Nutrition, Ege University Medical Faculty, Izmir, Turkey
| | - Merve Yoldaş Çelik
- Department of Pediatrics, Division of Metabolism and Nutrition, Ege University Medical Faculty, Izmir, Turkey
| | - Ayça Aykut
- Department of Genetics, Ege University Medical Faculty, Izmir, Turkey
| | - Asude Durmaz
- Department of Genetics, Ege University Medical Faculty, Izmir, Turkey
| | - Ebru Canda
- Department of Pediatrics, Division of Metabolism and Nutrition, Ege University Medical Faculty, Izmir, Turkey
| | - Mahmut Çoker
- Department of Pediatrics, Division of Metabolism and Nutrition, Ege University Medical Faculty, Izmir, Turkey
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2
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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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3
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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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4
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Huang K, Duan HQ, Li QX, Luo YB, Bi FF, Yang H. Expanding the clinicopathological-genetic spectrum of glycogen storage disease type IXd by a Chinese neuromuscular center. Front Neurol 2022; 13:945280. [PMID: 36034300 PMCID: PMC9406516 DOI: 10.3389/fneur.2022.945280] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/16/2022] [Accepted: 07/19/2022] [Indexed: 11/29/2022] Open
Abstract
Background Glycogen storage disease (GSDs) is characterized by abnormally inherited glycogen metabolism. GSD IXd, which is caused by mutations in the PHKA1 gene, is an X-linked rare disease with mild myopathic symptoms. To date, only 13 patients with GSD IXd have been reported. In this study, we aimed to expand the clinicopathological-genetic spectrum of GSD IXd at a neuromuscular center in China. Methods Data on patients diagnosed with GSD IXd at our neuromuscular center were collected retrospectively. Clinical features, electrophysiology, muscle pathology, and genetic information were analyzed. Results Between 2015 and 2021, three patients were diagnosed with GSD IXd based on clinical manifestations, pathological findings, and genetic testing. One patient presented with mitochondrial myopathy. All patients exhibited muscle weakness and elevated levels of creatine kinase. Electromyography-detected myopathic changes were found in two patients, whereas one patient refused to undergo this examination. Pathological examinations in all patients revealed subsarcolemmal accumulation of glycogen under PAS staining. All patients had mutations in the PHKA1 gene and the patient with mitochondrial myopathy also had a mutation in the MT-TL1 gene. Conclusion Our study expands the clinicogenotype and phenotype of GSD IXd in a Chinese population. Our study also expands the known mutation spectrum for GSD IXd, contributing to a better characterization and understanding of this ultrarare neuromuscular disorder.
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Affiliation(s)
- Kun Huang
- Department of Neurology, Xiangya Hospital, Central South University, Changsha, Hunan Province, China
- National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, Hunan Province, China
| | - Hui-Qian Duan
- Department of Neurology, Xiangya Hospital, Central South University, Changsha, Hunan Province, China
- National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, Hunan Province, China
| | - Qiu-Xiang Li
- Department of Neurology, Xiangya Hospital, Central South University, Changsha, Hunan Province, China
- National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, Hunan Province, China
| | - Yue-Bei Luo
- Department of Neurology, Xiangya Hospital, Central South University, Changsha, Hunan Province, China
- National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, Hunan Province, China
| | - Fang-Fang Bi
- Department of Neurology, Xiangya Hospital, Central South University, Changsha, Hunan Province, China
- National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, Hunan Province, China
| | - Huan Yang
- Department of Neurology, Xiangya Hospital, Central South University, Changsha, Hunan Province, China
- National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, Hunan Province, China
- *Correspondence: Huan Yang
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Massese M, Tagliaferri F, Dionisi-Vici C, Maiorana A. Glycogen storage diseases with liver involvement: a literature review of GSD type 0, IV, VI, IX and XI. Orphanet J Rare Dis 2022; 17:241. [PMID: 35725468 PMCID: PMC9208159 DOI: 10.1186/s13023-022-02387-6] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/24/2022] [Accepted: 06/06/2022] [Indexed: 12/31/2022] Open
Abstract
Background Glycogen storage diseases (GSDs) with liver involvement are classified into types 0, I, III, IV, VI, IX and XI, depending on the affected enzyme. Hypoglycemia and hepatomegaly are hallmarks of disease, but muscular and renal tubular involvement, dyslipidemia and osteopenia can develop. Considering the paucity of literature available, herein we provide a narrative review of these latter forms of GSDs. Main body Diagnosis is based on clinical manifestations and laboratory test results, but molecular analysis is often necessary to distinguish the various forms, whose presentation can be similar. Compared to GSD type I and III, which are characterized by a more severe impact on metabolic and glycemic homeostasis, GSD type 0, VI, IX and XI are usually known to be responsive to the nutritional treatment for achieving a balanced metabolic homeostasis in the pediatric age. However, some patients can exhibit a more severe phenotype and an important progression of the liver and muscular disease. The effects of dietary adjustments in GSD type IV are encouraging, but data are limited. Conclusions Early diagnosis allows a good metabolic control, with improvement of quality of life and prognosis, therefore we underline the importance of building a proper knowledge among physicians about these rare conditions. Regular monitoring is necessary to restrain disease progression and complications.
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Affiliation(s)
- Miriam Massese
- Division of Metabolism, Department of Pediatric Subspecialties, Ospedale Pediatrico Bambino Gesù, IRCCS, Piazza S. Onofrio 4, 00165, Rome, Italy.,Center for Rare Diseases and Birth Defects, Department of Woman and Child Health and Public Health, Fondazione Policlinico Universitario A. Gemelli IRCCS, Rome, Italy
| | - Francesco Tagliaferri
- Division of Metabolism, Department of Pediatric Subspecialties, Ospedale Pediatrico Bambino Gesù, IRCCS, Piazza S. Onofrio 4, 00165, Rome, Italy.,SCDU of Pediatrics, Azienda Ospedaliero-Universitaria Maggiore Della Carità, University of Piemonte Orientale, Novara, Italy
| | - Carlo Dionisi-Vici
- Division of Metabolism, Department of Pediatric Subspecialties, Ospedale Pediatrico Bambino Gesù, IRCCS, Piazza S. Onofrio 4, 00165, Rome, Italy
| | - Arianna Maiorana
- Division of Metabolism, Department of Pediatric Subspecialties, Ospedale Pediatrico Bambino Gesù, IRCCS, Piazza S. Onofrio 4, 00165, Rome, Italy.
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İnci A, Kılıç Yıldırım G, Cengiz Ergin FB, Sarı S, Eğritaş Gürkan Ö, Okur İ, Biberoğlu G, Bükülmez A, Ezgü FS, Dalgıç B, Tümer L. Expected or unexpected clinical findings in liver glycogen storage disease type IX: distinct clinical and molecular variability. J Pediatr Endocrinol Metab 2022; 35:451-462. [PMID: 35038814 DOI: 10.1515/jpem-2021-0278] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/16/2021] [Accepted: 12/22/2021] [Indexed: 11/15/2022]
Abstract
OBJECTIVES To reveal the different clinical presentations of liver glycogen storage disease type IX (GSD IX), which is a clinically and genetically heterogeneous type of glycogenosis. METHODS The data from the electronic hospital records of 25 patients diagnosed with liver GSD IX was reviewed. Symptoms, clinical findings, and laboratory and molecular analysis were assessed. RESULTS Of the patients, 10 had complaints of short stature in the initial presentation additionally other clinical findings. Elevated serum transaminases were found in 20 patients, and hepatomegaly was found in 22 patients. Interestingly, three patients were referred due to neurodevelopmental delay and hypotonia, while one was referred for only autism. One patient who presented with neurodevelopmental delay developed hepatomegaly and elevated transaminases during the disease later on. Three of the patients had low hemoglobin A1C and fructosamine values that were near the lowest reference range. Two patients had left ventricular hypertrophy. Three patients developed osteopenia during follow-up, and one patient had osteoporosis after puberty. The most common gene variant, PHKA2, was observed in 16 patients, 10 variants were novel and six variants were defined before. Six patients had variants in PHKG2, two variants were not defined before and four variants were defined before. PHKB variants were found in three patients. One patient had two novel splice site mutations in trans position. It was revealed that one novel homozygous variant and one defined homozygous variant were found in PHKB. CONCLUSIONS This study revealed that GSD IX may present with only hypotonia and neurodevelopmental delay without liver involvement in the early infantile period. It should be emphasized that although liver GSDIX is thought of as a benign disease, it might present with multisystemic involvement and patients should be screened with echocardiography, bone mineral densitometry, and psychometric evaluation.
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Affiliation(s)
- Aslı İnci
- Department of Pediatric Metabolism and Nutrition, Gazi University School of Medicine, Ankara, Turkey
| | - Gonca Kılıç Yıldırım
- Department of Pediatric Metabolism and Nutrition, Osmangazi University School of Medicine, Eskisehir, Turkey
| | - Filiz Başak Cengiz Ergin
- Department of Pediatric Metabolism and Nutrition, Gazi University School of Medicine, Ankara, Turkey
| | - Sinan Sarı
- Department of Pediatric Gastroenterology and Hepatology, Gazi University School of Medicine, Ankara, Turkey
| | - Ödül Eğritaş Gürkan
- Department of Pediatric Gastroenterology and Hepatology, Gazi University School of Medicine, Ankara, Turkey
| | - İlyas Okur
- Department of Pediatric Metabolism and Nutrition, Gazi University School of Medicine, Ankara, Turkey
| | - Gürsel Biberoğlu
- Department of Pediatric Metabolism and Nutrition, Gazi University School of Medicine, Ankara, Turkey
| | - Ayşegül Bükülmez
- Department of Pediatric Gastroenterology and Hepatology, Afyon Kocatepe University School of Medicine, Afyon, Turkey
| | - Fatih Süheyl Ezgü
- Department of Pediatric Metabolism and Nutrition, Gazi University School of Medicine, Ankara, Turkey
| | - Buket Dalgıç
- Department of Pediatric Gastroenterology and Hepatology, Gazi University School of Medicine, Ankara, Turkey
| | - Leyla Tümer
- Department of Pediatric Metabolism and Nutrition, Gazi University School of Medicine, Ankara, Turkey
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7
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Benner A, Alhaidan Y, Lines MA, Brusgaard K, De Leon DD, Sparkes R, Frederiksen AL, Christesen HT. PHKA2 variants expand the phenotype of phosphorylase B kinase deficiency to include patients with ketotic hypoglycemia only. Am J Med Genet A 2021; 185:2959-2975. [PMID: 34117828 PMCID: PMC8518678 DOI: 10.1002/ajmg.a.62383] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/26/2020] [Revised: 05/11/2021] [Accepted: 05/23/2021] [Indexed: 12/05/2022]
Abstract
Idiopathic ketotic hypoglycemia (IKH) is a diagnosis of exclusion with glycogen storage diseases (GSDs) as a differential diagnosis. GSD IXa presents with ketotic hypoglycemia (KH), hepatomegaly, and growth retardation due to PHKA2 variants. In our multicenter study, 12 children from eight families were diagnosed or suspected of IKH. Whole‐exome sequencing or targeted next‐generation sequencing panels were performed. We identified two known and three novel (likely) pathogenic PHKA2 variants, such as p.(Pro869Arg), p.(Pro498Leu), p.(Arg2Gly), p.(Arg860Trp), and p.(Val135Leu), respectively. Erythrocyte phosphorylase kinase activity in three patients with the novel variants p.(Arg2Gly) and p.(Arg860Trp) were 15%–20% of mean normal. One patient had short stature and intermittent mildly elevated aspartate aminotransferase, but no hepatomegaly. Family testing identified two asymptomatic children and 18 adult family members with one of the PHKA2 variants, of which 10 had KH symptoms in childhood and 8 had mild symptoms in adulthood. Our study expands the classical GSD IXa phenotype of PHKA2 missense variants to a continuum from seemingly asymptomatic carriers, over KH‐only with phosphorylase B kinase deficiency, to more or less complete classical GSD IXa. In contrast to typical IKH, which is confined to young children, KH may persist into adulthood in the KH‐only phenotype of PHKA2.
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Affiliation(s)
- Anne Benner
- Hans Christian Andersen Children's Hospital, Odense University Hospital, Odense, Denmark.,Department of Clinical Research, Faculty of Health Sciences, University of Southern Denmark, Odense, Denmark
| | - Yazeid Alhaidan
- Department of Clinical Research, Faculty of Health Sciences, University of Southern Denmark, Odense, Denmark.,Department of Clinical Genetics, Odense University Hospital, Odense, Denmark.,Department of Medical Genomics Research, King Abdullah international medical research center, NGHA, Riyadh, Saudi Arabia
| | - Matthew A Lines
- Department of Medical Genetics, Alberta Children's Hospital, University of Calgary, Calgary, Canada
| | - Klaus Brusgaard
- Department of Clinical Research, Faculty of Health Sciences, University of Southern Denmark, Odense, Denmark.,Department of Clinical Genetics, Odense University Hospital, Odense, Denmark
| | - Diva D De Leon
- Division of Endocrinology and Diabetes, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA.,Department of Pediatrics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA
| | - Rebecca Sparkes
- Department of Medical Genetics, Alberta Children's Hospital, University of Calgary, Calgary, Canada
| | - Anja L Frederiksen
- Department of Clinical Genetics, Aalborg University Hospital, Aalborg, Denmark.,Department of Clinical Medicine, Aalborg University Hospital, Aalborg, Denmark
| | - Henrik T Christesen
- Hans Christian Andersen Children's Hospital, Odense University Hospital, Odense, Denmark.,Department of Clinical Research, Faculty of Health Sciences, University of Southern Denmark, Odense, Denmark.,OPAC, Odense Pancreas Center, Odense University Hospital, Odense, Denmark
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8
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Morales JA, Tise CG, Narang A, Grimm PC, Enns GM, Lee CU. Profound neonatal lactic acidosis and renal tubulopathy in a patient with glycogen storage disease type IXɑ2 secondary to a de novo pathogenic variant in PHKA2. Mol Genet Metab Rep 2021; 27:100765. [PMID: 34277355 PMCID: PMC8261893 DOI: 10.1016/j.ymgmr.2021.100765] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/12/2021] [Revised: 04/21/2021] [Accepted: 04/22/2021] [Indexed: 12/04/2022] Open
Abstract
The phenotype of individuals with glycogen storage disease (GSD) IX appears to be highly variable, even within subtypes. Features include short stature, fasting hypoglycemia with ketosis, hepatomegaly, and transaminitis. GSD IXɑ2 is caused by hemizygous pathogenic variants in PHKA2, and results in deficiency of the phosphorylase kinase enzyme, particularly in the liver. Like other GSDs, GSD IXɑ2 can present with hypoglycemia and post-prandial lactic acidosis, but has never been reported in a newborn, nor with lactic acidosis as the presenting feature. Here we describe the clinical presentation and course of a newborn boy with profound neonatal lactic and metabolic acidosis, renal tubulopathy, and sensorineural hearing loss (SNHL) diagnosed with GSD IXɑ2 through exome sequencing. Review of the literature suggests this case represents an atypical and severe presentation of GSD IXɑ2 and proposes expansion of the phenotype to include neonatal lactic acidosis and renal tubulopathy.
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Affiliation(s)
- J Andres Morales
- Department of Pediatrics, Division of Medical Genetics, Stanford University, United States of America
| | - Christina G Tise
- Department of Pediatrics, Division of Medical Genetics, Stanford University, United States of America
| | - Amrita Narang
- Department of Pediatrics, Division of Gastroenterology, Stanford University, United States of America
| | - Paul C Grimm
- Department of Pediatrics, Division of Nephrology, Stanford University, United States of America
| | - Gregory M Enns
- Department of Pediatrics, Division of Medical Genetics, Stanford University, United States of America
| | - Chung U Lee
- Department of Pediatrics, Division of Medical Genetics, Stanford University, United States of America
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9
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Bisciglia M, Froissart R, Bedat-Millet AL, Romero NB, Pettazzoni M, Hogrel JY, Petit FM, Stojkovic T. A novel PHKA1 mutation associating myopathy and cognitive impairment: Expanding the spectrum of phosphorylase kinase b (PhK) deficiency. J Neurol Sci 2021; 424:117391. [PMID: 33799212 DOI: 10.1016/j.jns.2021.117391] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/21/2020] [Revised: 02/22/2021] [Accepted: 03/12/2021] [Indexed: 11/18/2022]
Abstract
Muscle phosphorylase kinase b deficiency (PhK) is a rare disorder of glycogen metabolism characterized by exercise-induced myalgia and cramps, myoglobinuria and progressive muscle weakness. PhK deficiency is due to mutations in the PHKA1 gene inherited in an X-linked manner and is associated to glycogenosis type VIII (GSD VIII also called GSD IXd). PHKA1 gene codes for the αM subunit of the PhK, a multimeric protein complex responsible for the control of glycogen breakdown in muscle. Until now, few patients have been reported with X-linked recessive muscle PhK deficiency due to PHKA1 mutations. All reported patients presented with exercise intolerance and mild myopathy and one of them had cognitive impairment, leading to speculate about a central nervous system involvement in GSD VIII. Here we report in a sibling a novel mutation in the PHKA1 gene associated with a progressive myopathy, exercise intolerance, muscle hypertrophy and cognitive impairment as an associated feature. This report expands the genetic and clinical spectrum of the extremely rare PHKA1-related PhK deficiency and presents new evidences about its involvement in brain development.
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Affiliation(s)
- Michela Bisciglia
- Centre de Référence Neuromusculaire Erasme-HUDERF, Service de Neurologie, Cliniques Universitaires de Bruxelles, Hôpital Erasme, Université Libre de Bruxelles (ULB), Route de Lennik 808, 1070 Bruxelles, Belgique..
| | - Roseline Froissart
- Biochemical and Molecular Biology Department, Centre de Biologie et de Pathologie Est, Hospices Civils de Lyon, 69500 Bron, France.
| | - Anne Laure Bedat-Millet
- Service de Neurologie, Centre Hospitalier de Rouen, Hôpital Charles Nicolle, 76038 Rouen, France.
| | - Norma Beatriz Romero
- APHP-GH Pitié-Salpêtrière, Centre de référence des maladies neuromusculaires Nord/Est/Ile de France, Myology Institute, Paris, France; APHP-GH Pitié-Salpêtrière, Unité de Morphologie Neuromusculaire « Risler », Myology Institute, Sorbonne Université, INSERM, Hôpital Pitié-Salpêtrière, Paris, France.
| | - Magali Pettazzoni
- Biochemical and Molecular Biology Department, Centre de Biologie et de Pathologie Est, Hospices Civils de Lyon, 69500 Bron, France.
| | - Jean-Yves Hogrel
- APHP-GH Pitié-Salpêtrière, Centre de référence des maladies neuromusculaires Nord/Est/Ile de France, Myology Institute, Paris, France.
| | - François M Petit
- AP-HP. Université Paris Saclay, Laboratoire de génétique moléculaire, Hôpital Antoine Béclère, Clamart, France.
| | - Tanya Stojkovic
- APHP-GH Pitié-Salpêtrière, Centre de référence des maladies neuromusculaires Nord/Est/Ile de France, Myology Institute, Paris, France.
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10
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Degrassi I, Deheragoda M, Creegen D, Mundy H, Mustafa A, Vara R, Hadzic N. Liver histology in children with glycogen storage disorders type VI and IX. Dig Liver Dis 2021; 53:86-93. [PMID: 32505569 DOI: 10.1016/j.dld.2020.04.017] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/02/2020] [Revised: 04/03/2020] [Accepted: 04/16/2020] [Indexed: 12/11/2022]
Abstract
BACKGROUND Glycogen storage diseases (GSD) type VI and IX are caused by liver phosphorylase system deficiencies and the two types are clinically indistinguishable. AIM As the role of liver biopsy is increasingly questioned, we aim to assess its current value in clinical practice. METHODS We retrospectively reviewed children with diagnosis of GSD VI and IX at a paediatric liver centre between 2001 and 2018. Clinical features, molecular analysis and imaging were reviewed. Liver histology was reassessed by a single histopatologist. RESULTS Twenty-two cases were identified (9 type VI, 9 IXa, 1 IXb and 3 IXc). Features at presentation were hepatomegaly (95%), deranged AST (81%), short stature (50%) and failure to thrive (4%). Liver biopsy was performed in 19 patients. Fibrosis varied in GSD IXa with METAVIR score between F1-F3 and ISHAK score of F2-F5. METAVIR score was F2-F3 in GSD VI and F3-F4 in GSD IXc. Hepatocyte glycogenation, mild steatosis, lobular inflammatory activity and periportal copper binding protein staining were also demonstrated. CONCLUSIONS Although GSD VI and IX are considered clinically mild, chronic histological changes of varying severity could be seen in all liver biopsies. Histopathological assessment of the liver involvement is superior to biochemical parameters, but definitive classification requires a mutational analysis.
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Affiliation(s)
- Irene Degrassi
- Paediatric Service for Hepatology, Gastroenterology and Nutrition, King's College Hospital, Denmark Hill, SE5 9RS, London UK; Pediatric Intermediate Care Unit, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Via della Commenda 9, 20122 Milan Italy.
| | - Maesha Deheragoda
- Paediatric Service for Hepatology, Gastroenterology and Nutrition, King's College Hospital, Denmark Hill, SE5 9RS, London UK.
| | - David Creegen
- Metabolic Service, Evelina London Children's Hospital, Westminster Bridge Road, SE1 7EH, London UK.
| | - Helen Mundy
- Metabolic Service, Evelina London Children's Hospital, Westminster Bridge Road, SE1 7EH, London UK.
| | - Ahlam Mustafa
- Paediatric Service for Hepatology, Gastroenterology and Nutrition, King's College Hospital, Denmark Hill, SE5 9RS, London UK.
| | - Roshni Vara
- Metabolic Service, Evelina London Children's Hospital, Westminster Bridge Road, SE1 7EH, London UK.
| | - Nedim Hadzic
- Paediatric Service for Hepatology, Gastroenterology and Nutrition, King's College Hospital, Denmark Hill, SE5 9RS, London UK.
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Fernandes SA, Cooper GE, Gibson RA, Kishnani PS. Benign or not benign? Deep phenotyping of liver Glycogen Storage Disease IX. Mol Genet Metab 2020; 131:299-305. [PMID: 33317799 PMCID: PMC7953588 DOI: 10.1016/j.ymgme.2020.10.004] [Citation(s) in RCA: 22] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/25/2020] [Revised: 10/07/2020] [Accepted: 10/08/2020] [Indexed: 01/06/2023]
Abstract
INTRODUCTION Liver Glycogen Storage Disease Type IX (GSD IX) is one of the most common forms of GSD. It is caused by a deficiency in enzyme phosphorylase kinase (PhK), a complex, hetero-tetrameric enzyme comprised of four subunits - α, β, γ, and δ - each with tissue specific isoforms encoded by different genes. Until the recent availability of gene panels and exome sequencing, the diagnosis of liver GSD IX did not allow for differentiation of these subtypes. This study presents the first comprehensive literature review for liver GSD IX subtypes - GSD IX α2, β, and γ2. We aim to better characterize the natural history of liver GSD IX and further investigate if there are subtype-specific differences in clinical presentation. METHODS A comprehensive literature review was performed with the help of a medical librarian at Duke University Medical Center to gather all published patients of liver GSD IX. Our refined search yielded 74 articles total. Available patient data were compiled into an excel spreadsheet. Data were analyzed via descriptive statistics. The number of patients with specific symptoms were individually summed and reported as a percentage of the total number of patients for which data were available or were averaged and reported as a mean numerical value. Published pathology reports were scored using the International Association of the Study of the Liver Scale. RESULTS There were a total of 183 GSD IX α2 patients, 17 GSD IX β patients, and 30 GSD IX γ2 patients. Average age at diagnosis was 4 years for GSD IX α2 patients, 2.34 years for GSD IX β patients, and 1.81 years for GSD IX γ2 patients. Hepatomegaly was reported in 164/176 (93.2%) of GSD IX α2 patients, 16/17 (94.1%) of GSD IX β patients, and 30/30 (100%) of GSD IX γ2 patients. Fasting hypoglycemia was reported in 53/121 (43.8%) of GSD IX α2 patients, 8/16 (50%) of GSD IX β patients, and 18/19 (94.7%) of GSD IX γ2 patients. Liver biopsy pathology reports were available and interpreted for 46 GSD IX α2 patients, 3 GSD IX β patients, and 24 GSD IX γ2 patients. 22/46 (47.8%) GSD IX α2 patients, 1/3 (33.3%) GSD IX β patients, and 23/24 (95.8%) GSD IX γ2 patients with available pathology reports documented either some degree of fibrosis or cirrhosis. CONCLUSION Our comprehensive review demonstrates quantitatively that the clinical presentation of GSD IX γ2 patients is more severe than that of GSD IX α2 or β patients. However, our study also shows the existence of a severe phenotype in GSD IX α2, evidenced by early onset liver pathology in conjunction with clinical symptoms. There is need for a more robust natural history study to better understand the variability in liver pathophysiology within liver GSD IX; in addition, further study of mutations and gene mapping could bring a better understanding of the relationship between genotype and clinical presentation.
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Affiliation(s)
- Samuela A Fernandes
- Division of Medical Genetics, Department of Pediatrics, Duke University School of Medicine, Durham, NC, USA
| | - Gabrielle E Cooper
- Division of Medical Genetics, Department of Pediatrics, Duke University School of Medicine, Durham, NC, USA
| | - Rebecca Anne Gibson
- 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.
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Khan HH, Parr L, Jay A, Raza S, Lyons H, Kumar S. Glycogen Storage Disease Type IX due to a Novel Mutation in PHKA2 Gene. Case Rep Pediatr 2020; 2020:8836534. [PMID: 33014498 PMCID: PMC7520001 DOI: 10.1155/2020/8836534] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/19/2020] [Revised: 09/05/2020] [Accepted: 09/14/2020] [Indexed: 11/17/2022] Open
Abstract
We report a case of a 17-month-old male with a history of developmental delay with poor muscle control, hepatomegaly, and transaminitis. Ultrasound of abdomen revealed hepatomegaly with a liver span of 13 cm, homogeneous parenchyma, and normal spleen size. Liver and muscle biopsies were obtained: the liver biopsy revealed distended hepatocytes with excessive glycogen accumulation and fine septate fibrosis. Biopsy of the right vastus lateralis muscle showed focal swollen glycogen containing mitochondria. For the developmental delay, a chromosomal microrarray was ordered. The chromosomal microarray revealed the patient to have 1q21 duplication syndrome and 16p11.2 deletion syndrome. Given the liver and muscle biopsy findings, a glycogen storage disease panel was sent which identified the patient to be hemizygous for a variant of uncertain significance denoted as p.Gly 131Val, c.392G > T in the PHKA2 gene. PKHA2 gene encodes the alpha subunit of hepatic phosphorylase kinase. This change in the PHKA2 gene was in a highly conserved region and had been reported in another patient with decreased enzymatic activity of the phosphorylase kinase and who had symptoms of GSD IX. Based on this, the patient was started on treatment for GSD IX, and his family met with a dietician.
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Affiliation(s)
- Hamza Hassan Khan
- Department of Pediatrics, Ascension St. John Children's Hospital, Detroit, MI, USA
| | - Lauren Parr
- Department of Pediatrics, Ascension St. John Children's Hospital, Detroit, MI, USA
| | - Allison Jay
- Department of Medical Genetics, Ascension St. John Children's Hospital, Detroit, MI, USA
| | - Saleem Raza
- Department of Pediatrics, Ascension St. John Children's Hospital, Wayne State University, School of Medicine, Detroit, MI, USA
| | - Hernando Lyons
- Department of Pediatric Gastroenterology, Ascension St. John Children's Hospital, Wayne State University, School of Medicine, Detroit, MI, USA
| | - Sanjay Kumar
- Department of Pediatric Gastroenterology, Ascension St. John Children's Hospital, Wayne State University, School of Medicine, Detroit, MI, USA
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13
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Leuzinger Dias C, Maio I, Brandão JR, Tomás E, Martins E, Santos Silva E. Fatty Liver Caused by Glycogen Storage Disease Type IX: A Small Series of Cases in Children. GE-PORTUGUESE JOURNAL OF GASTROENTEROLOGY 2019; 26:430-437. [PMID: 31832499 DOI: 10.1159/000496571] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/19/2018] [Accepted: 12/18/2018] [Indexed: 12/11/2022]
Abstract
Background The prevalence of non-alcoholic fatty liver disease (NAFLD) affecting children and adolescents has increased dramatically in recent years. This increase is most probably related to the obesity pandemic and the high consumption of fructose. However, hepatic steatosis has some rare causes (e.g., some metabolic diseases) of which clinicians should be aware, particularly (but not only) when patients are non-obese or non-overweight. Differential diagnosis is notably important when pathologies have a specific treatment, such as for glycogenosis type IX (GSD-IX). Aims To contribute to the knowledge on the differential diagnosis of NAFLD in paediatric age and to the clinical, biochemical, molecular, and histological characterisations of GSD-IX, a rare metabolic disorder. Methods We performed a retrospective study of a small series of cases (n = 3) of GSD-IX diagnosed in the past 6 years, who were currently being followed up in the Units of Gastroenterology or Metabolic Diseases of the Paediatric Division of our hospital and whose clinical presentation was NAFLD in paediatric age. Results Three male patients were diagnosed with NAFLD before 2 years of age, 2 with confirmed diagnosis before the age of 3 years (alanine aminotransferase [ALT], liver ultrasound, and molecular analysis) and 1 whose diagnosis was confirmed at 11 years (ALT, liver ultrasound, liver histology, and molecular analysis). None of the patients were obese or overweight, and the daily fructose consumption was unknown. The outcome was favourable in all 3 patients, with follow-up periods ranging from 2 to 6 years. Conclusion The decision on how far the search for secondary causes of NAFLD should go can be difficult, and GSD-IX must be on the list of possible causes.
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Affiliation(s)
| | - Inês Maio
- Gastroenterology Unit, Paediatrics Division, Child and Adolescent Department, Centro Materno-Infantil do Norte, Centro Hospitalar Universitário do Porto, Porto, Portugal
| | - José Ricardo Brandão
- Pathologic Anatomy Division, Hospital Geral de Santo António, Centro Hospitalar Universitário do Porto, Porto, Portugal
| | - Edite Tomás
- Paediatrics Division, Centro Hospital de Tâmega e Sousa, Porto, Portugal
| | - Esmeralda Martins
- Instituto de Ciências Biomédicas Abel Salazar, Porto, Portugal.,Metabolic Diseases Unit, Pediatrics Division, Child and Adolescent Department, Centro Materno-Infantil do Norte, Centro Hospitalar Universitário do Porto, Porto, Portugal
| | - Ermelinda Santos Silva
- Instituto de Ciências Biomédicas Abel Salazar, Porto, Portugal.,Gastroenterology Unit, Paediatrics Division, Child and Adolescent Department, Centro Materno-Infantil do Norte, Centro Hospitalar Universitário do Porto, Porto, Portugal
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14
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Kishnani PS, Goldstein J, Austin SL, Arn P, Bachrach B, Bali DS, Chung WK, El-Gharbawy A, Brown LM, Kahler S, Pendyal S, Ross KM, Tsilianidis L, Weinstein DA, Watson MS. Diagnosis and management of glycogen storage diseases type VI and IX: a clinical practice resource of the American College of Medical Genetics and Genomics (ACMG). Genet Med 2019; 21:772-789. [PMID: 30659246 DOI: 10.1038/s41436-018-0364-2] [Citation(s) in RCA: 77] [Impact Index Per Article: 12.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/24/2018] [Accepted: 10/15/2018] [Indexed: 01/10/2023] Open
Abstract
PURPOSE Glycogen storage disease (GSD) types VI and IX are rare diseases of variable clinical severity affecting primarily the liver. GSD VI is caused by deficient activity of hepatic glycogen phosphorylase, an enzyme encoded by the PYGL gene. GSD IX is caused by deficient activity of phosphorylase kinase (PhK), the enzyme subunits of which are encoded by various genes: ɑ (PHKA1, PHKA2), β (PHKB), ɣ (PHKG1, PHKG2), and δ (CALM1, CALM2, CALM3). Glycogen storage disease types VI and IX have a wide spectrum of clinical manifestations and often cannot be distinguished from each other, or from other liver GSDs, on clinical presentation alone. Individuals with GSDs VI and IX can present with hepatomegaly with elevated serum transaminases, ketotic hypoglycemia, hyperlipidemia, and poor growth. This guideline for the management of GSDs VI and IX was developed as an educational resource for health-care providers to facilitate prompt and accurate diagnosis and appropriate management of patients. METHODS A national group of experts in various aspects of GSDs VI and IX met to review the limited evidence base from the scientific literature and provided their expert opinions. Consensus was developed in each area of diagnosis, treatment, and management. Evidence bases for these rare disorders are largely based on expert opinion, particularly when targeted therapeutics that have to clear the US Food and Drug Administration (FDA) remain unavailable. RESULTS This management guideline specifically addresses evaluation and diagnosis across multiple organ systems involved in GSDs VI and IX. Conditions to consider in a differential diagnosis stemming from presenting features and diagnostic algorithms are discussed. Aspects of diagnostic evaluation and nutritional and medical management, including care coordination, genetic counseling, and prenatal diagnosis are addressed. CONCLUSION A guideline that will facilitate the accurate diagnosis and optimal management of patients with GSDs VI and IX was developed. This guideline will help health-care providers recognize patients with GSDs VI and IX, expedite diagnosis, and minimize adverse sequelae from delayed diagnosis and inappropriate management. It will also help identify gaps in scientific knowledge that exist today and suggest future studies.
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Affiliation(s)
| | | | | | - Pamela Arn
- Nemours Children's Clinic, Jacksonville, FL, USA
| | - Bert Bachrach
- University of Missouri Health System, Columbia, MO, USA
| | | | - Wendy K Chung
- Columbia University Medical Center, New York, NY, USA
| | | | - Laurie M Brown
- University of Florida College of Medicine, Gainesville, FL, USA
| | | | | | - Katalin M Ross
- Connecticut Children's Medical Center, Hartford, CT, USA
| | | | - David A Weinstein
- University of Connecticut School of Medicine, Connecticut Children's Hospital, Hartford, CT, USA
| | - Michael S Watson
- American College of Medical Genetics and Genomics, Bethesda, MD, USA.
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15
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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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Zhang J, Yuan Y, Ma M, Liu Y, Zhang W, Yao F, Qiu Z. Clinical and genetic characteristics of 17 Chinese patients with glycogen storage disease type IXa. Gene 2017. [PMID: 28627441 DOI: 10.1016/j.gene.2017.06.026] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/25/2022]
Abstract
Glycogen storage disease (GSD) type IXa is caused by PHKA2 mutation, which accounts for about 75% of all the GSD type IX cases. Here we first summarized the clinical data and analyzed the PHKA2 gene of 17 Chinese male patients suspected of having GSD type IXa. Clinical symptoms of our patients included hepatomegaly, growth retardation, and liver dysfunction. The clinical and biochemical manifestations improved and even disappeared with age. We detected 14 mutations in 17 patients, including 8 novel mutations; exons 2 and 4 were hot spots in this research. In conclusion, glycogen storage disease type IXa is a mild disorder with a favorable prognosis, and there was no relationship between genotype and phenotype of this disease.
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Affiliation(s)
- Jiangwei Zhang
- Department of Pediatrics, Peking University International Hospital, Beijing 102206, China
| | - Yuheng Yuan
- Department of Pediatrics, Peking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing 100730, China
| | - Mingsheng Ma
- Department of Pediatrics, Peking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing 100730, China.
| | - Yan Liu
- Department of Pediatrics, Peking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing 100730, China
| | - Weimin Zhang
- Genetics Research Laboratory, Peking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing 100730, China
| | - Fengxia Yao
- Genetics Research Laboratory, Peking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing 100730, China
| | - Zhengqing Qiu
- Department of Pediatrics, Peking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing 100730, China.
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17
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Bali DS, Goldstein JL, Fredrickson K, Austin S, Pendyal S, Rehder C, Kishnani PS. Clinical and Molecular Variability in Patients with PHKA2 Variants and Liver Phosphorylase b Kinase Deficiency. JIMD Rep 2017; 37:63-72. [PMID: 28283841 DOI: 10.1007/8904_2017_8] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/10/2016] [Revised: 12/29/2016] [Accepted: 01/30/2017] [Indexed: 03/17/2023] Open
Abstract
Glycogen storage disease (GSD) type IX is a rare disease of variable clinical severity affecting primarily the liver tissue. Individuals with liver phosphorylase b kinase (PhK) deficiency (GSD IX) can present with hepatomegaly with elevated serum transaminases, ketotic hypoglycemia, hyperlipidemia, and poor growth with considerable variation in clinical severity. PhK is a cAMP-dependent protein kinase that phosphorylates the inactive form of glycogen phosphorylase, phosphorylase b, to produce the active form, phosphorylase a. PhK is a heterotetramer; the alpha 2 subunit in the liver is encoded by the X-linked PHKA2 gene. About 75% of individuals with liver PhK deficiency have mutations in the PHKA2 gene; this condition is also known as X-linked glycogenosis (XLG). Here we report the variability in clinical severity and laboratory findings in 12 male patients from 10 different families with X-linked liver PhK deficiency caused by mutations in PHKA2. We found that there is variability in the severity of clinical features, including hypoglycemia and growth. We also report additional PHKA2 variants that were identified in 24 patients suspected to have liver PhK deficiency. The basis of the clinical variation in GSDIX due to X-linked PHKA2 gene mutations is currently not well understood. Creating systematic registries, and collecting longitudinal data may help in better understanding of this rare, but common, glycogen storage disorder. SYNOPSIS Liver phosphorylase b kinase (PhK) deficiency caused due to mutations in X-linked PHKA2 is highly variable.
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Affiliation(s)
- Deeksha S Bali
- Department of Pediatrics, Duke Medicine, Durham, NC, USA. .,Biochemical Genetics Laboratory, Duke Medicine, 801-6 Capitola Drive, Durham, NC, 27713, USA.
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18
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Hodax JK, Uysal S, Quintos JB, Phornphutkul C. Glycogen storage disease type IX and growth hormone deficiency presenting as severe ketotic hypoglycemia. J Pediatr Endocrinol Metab 2017; 30:247-251. [PMID: 28085675 DOI: 10.1515/jpem-2016-0342] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/29/2016] [Accepted: 11/28/2016] [Indexed: 12/14/2022]
Abstract
BACKGROUND Glycogen storage disease (GSD) type IX and growth hormone (GH) deficiency cause ketotic hypoglycemia via different mechanisms and are not known to be associated. We describe a patient presenting with severe ketotic hypoglycemia found to have both GSD IX and isolated GH deficiency. CASE PRESENTATION A 3-year-and-11-month-old boy with a history of prematurity, autism, developmental delay, seizures, and feeding difficulty was admitted for poor weight gain and symptomatic hypoglycemia. He was nondysmorphic, with a height of 93.8 cm (2%, -1.97 SDS), and has no hepatomegaly. He developed symptomatic hypoglycemia, with a serum glucose level of 37 mg/dL after 14 h of fasting challenge. Critical sample showed a GH of 0.24 ng/mL. GH provocative stimulation testing was done with a peak GH of 2.8 ng/mL. Brain magnetic resonance imaging showed a hypoplastic pituitary gland. Given the clinical symptoms, suspicion for mitochondrial disease was high. Dual Genome Panel by Massively Parallel Sequencing revealed a hemizygous variant c.721A>G (p1241V) in the X-linked PHKA2 gene, a causative gene for GSD IX. Red blood cell PhK enzyme activity testing was low, supporting the diagnosis. CONCLUSIONS Given the patient's developmental delays that were not explained by GH deficiency alone, further investigation showed two unrelated conditions resulting in deranged metabolic adaptation to fasting leading to severe hypoglycemia.
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19
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A new variant in PHKA2 is associated with glycogen storage disease type IXa. Mol Genet Metab Rep 2017; 10:52-55. [PMID: 28116244 PMCID: PMC5233919 DOI: 10.1016/j.ymgmr.2017.01.003] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/29/2016] [Revised: 01/01/2017] [Accepted: 01/02/2017] [Indexed: 01/31/2023] Open
Abstract
Glucogenosis type IX is caused by pathogenic variants of the PHKA2 gene. Herein, we report a patient with clinical symptoms compatible with Glycogen Storage Disease type IXa. PYGL, PHKA1, PHKA2, PHKB and PHKG2 genes were analyzed by Next Generation Sequencing (NGS). We identified the previously undescribed hemizygous missense variant NM_000292.2(PHKA2):c.1963G > A, p.(Glu655Lys) in PHKA2 exon 18. In silico analyses showed two possible pathogenic consequences: it affects a highly conserved amino acid and disrupts the exon 18 canonical splice donor site. The variant was found as a "de novo" event.
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20
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Chen MA, Weinstein DA. Glycogen storage diseases: Diagnosis, treatment and outcome. ACTA ACUST UNITED AC 2016. [DOI: 10.3233/trd-160006] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Affiliation(s)
| | - David A. Weinstein
- Glycogen Storage Disease Program, University of Florida College of Medicine, Gainesville, FL, USA
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21
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MacDonald MJ, Hasan NM, Ansari IUH, Longacre MJ, Kendrick MA, Stoker SW. Discovery of a Genetic Metabolic Cause for Mauriac Syndrome in Type 1 Diabetes. Diabetes 2016; 65:2051-9. [PMID: 27207549 DOI: 10.2337/db16-0099] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/19/2016] [Accepted: 03/28/2016] [Indexed: 12/13/2022]
Abstract
A mechanistic cause for Mauriac syndrome, a syndrome of growth failure and delayed puberty associated with massive liver enlargement from glycogen deposition in children with poorly controlled type 1 diabetes, is unknown. We discovered a mutation in the catalytic subunit of liver glycogen phosphorylase kinase in a patient with Mauriac syndrome whose liver extended into his pelvis. Glycogen phosphorylase kinase activates glycogen phosphorylase, the enzyme that catalyzes the first step in glycogen breakdown. We show that the mutant subunit acts in a dominant manner to completely inhibit glycogen phosphorylase kinase enzyme activity and that this interferes with glycogenolysis causing increased levels of glycogen in human liver cells. It is known that even normal blood glucose levels physiologically inhibit glycogen phosphorylase to diminish glucose release from the liver when glycogenolysis is not needed. The patient's mother possessed the same mutant glycogen phosphorylase kinase subunit, but did not have diabetes or hepatomegaly. His father had childhood type 1 diabetes in poor glycemic control, but lacked the mutation and had neither hepatomegaly nor growth failure. This case proves that the effect of a mutant enzyme of glycogen metabolism can combine with hyperglycemia to directly hyperinhibit glycogen phosphorylase, in turn blocking glycogenolysis causing the massive liver in Mauriac disease.
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Affiliation(s)
- Michael J MacDonald
- Childrens Diabetes Center, University of Wisconsin School of Medicine and Public Health, Madison, WI
| | - Noaman M Hasan
- Childrens Diabetes Center, University of Wisconsin School of Medicine and Public Health, Madison, WI
| | - Israr-Ul H Ansari
- Childrens Diabetes Center, University of Wisconsin School of Medicine and Public Health, Madison, WI
| | - Melissa J Longacre
- Childrens Diabetes Center, University of Wisconsin School of Medicine and Public Health, Madison, WI
| | - Mindy A Kendrick
- Childrens Diabetes Center, University of Wisconsin School of Medicine and Public Health, Madison, WI
| | - Scott W Stoker
- Childrens Diabetes Center, University of Wisconsin School of Medicine and Public Health, Madison, WI
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22
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Roscher A, Patel J, Hewson S, Nagy L, Feigenbaum A, Kronick J, Raiman J, Schulze A, Siriwardena K, Mercimek-Mahmutoglu S. The natural history of glycogen storage disease types VI and IX: Long-term outcome from the largest metabolic center in Canada. Mol Genet Metab 2014; 113:171-6. [PMID: 25266922 DOI: 10.1016/j.ymgme.2014.09.005] [Citation(s) in RCA: 65] [Impact Index Per Article: 5.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/01/2014] [Revised: 09/07/2014] [Accepted: 09/08/2014] [Indexed: 01/22/2023]
Abstract
OBJECTIVES Glycogen storage disease (GSD) types VI and IX are caused by phosphorylase system deficiencies. To evaluate the natural history and long-term treatment outcome of the patients with GSD-VI and -IX, we performed an observational retrospective case study of 21 patients with confirmed diagnosis of GSD-VI or -IX. METHODS All patients with GSD-VI or -IX, diagnosed at The Hospital for Sick Children, were included. Electronic and paper charts were reviewed for clinical features, biochemical investigations, molecular genetic testing, diagnostic imaging, long-term outcome and treatment by two independent research team members. All information was entered into an Excel database. RESULTS We report on the natural history and treatment outcomes of the 21 patients with GSD-VI and -IX and 16 novel pathogenic mutations in the PHKA2, PHKB, PHKG2 and PYGL genes. We report for the first time likely liver adenoma on liver ultrasound and liver fibrosis on liver biopsy specimens in patients with GSD-VI and mild cardiomyopathy on echocardiography in patients with GSD-VI and -IXb. CONCLUSION We recommend close monitoring in all patients with GSD-VI and -IX for the long-term liver and cardiac complications. There is a need for future studies if uncooked cornstarch and high protein diet would be able to prevent long-term complications of GSD-VI and -IX.
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Affiliation(s)
- Anne Roscher
- Division of Clinical and Metabolic Genetics, Department of Pediatrics, University of Toronto, Toronto, ON, Canada; Medical University of Vienna, Department of Pediatric and Adolescent Medicine, Vienna, Austria
| | - Jaina Patel
- Division of Clinical and Metabolic Genetics, Department of Pediatrics, University of Toronto, Toronto, ON, Canada
| | - Stacy Hewson
- Division of Clinical and Metabolic Genetics, Department of Pediatrics, University of Toronto, Toronto, ON, Canada
| | - Laura Nagy
- Division of Clinical and Metabolic Genetics, Department of Pediatrics, University of Toronto, Toronto, ON, Canada
| | - Annette Feigenbaum
- Division of Clinical and Metabolic Genetics, Department of Pediatrics, University of Toronto, Toronto, ON, Canada; Department of Pediatrics & Biochemical Genetics, Rady Children's Hospital-San Diego, University of California, San Diego, CA, USA
| | - Jonathan Kronick
- Division of Clinical and Metabolic Genetics, Department of Pediatrics, University of Toronto, Toronto, ON, Canada
| | - Julian Raiman
- Division of Clinical and Metabolic Genetics, Department of Pediatrics, University of Toronto, Toronto, ON, Canada
| | - Andreas Schulze
- Division of Clinical and Metabolic Genetics, Department of Pediatrics, University of Toronto, Toronto, ON, Canada; Genetics and Genome Biology Research Program, Research Institute, The Hospital for Sick Children, Toronto, ON, Canada
| | - Komudi Siriwardena
- Division of Clinical and Metabolic Genetics, Department of Pediatrics, University of Toronto, Toronto, ON, Canada
| | - Saadet Mercimek-Mahmutoglu
- Division of Clinical and Metabolic Genetics, Department of Pediatrics, University of Toronto, Toronto, ON, Canada; Genetics and Genome Biology Research Program, Research Institute, The Hospital for Sick Children, Toronto, ON, Canada.
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Albash B, Imtiaz F, Al-Zaidan H, Al-Manea H, Banemai M, Allam R, Al-Suheel A, Al-Owain M. Novel PHKG2 mutation causing GSD IX with prominent liver disease: report of three cases and review of literature. Eur J Pediatr 2014; 173:647-53. [PMID: 24326380 DOI: 10.1007/s00431-013-2223-0] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/13/2013] [Accepted: 11/20/2013] [Indexed: 10/25/2022]
Abstract
Glycogen storage disease type IX (GSD IX) is a common form of glycogenosis due to mutations in PHKA1, PHKA2, or PHKB and PHKG2 genes resulting in the deficiency of phosphorylase kinase. The first two genes are X-linked while the latter two follow an autosomal recessive inheritance. The majority of cases of GSD IX are attributed to defects in PHKA2 which usually cause a mild disease. We report three patients with PHKG2-related GSD IX presenting with significant hepatic involvement, fibrosis, and cirrhosis. Interestingly, the homozygosity mapping resolved a dilemma about an erroneously normal phosphorylase kinase activity in patient 1. The novel mutation found in all the three patients (p.G220E) affects the catalytic subunit of the phosphorylase kinase. Increasing evidence shows that patients with PHKG2 mutations have a severe hepatic phenotype within the heterogeneous GSD IX disorder. Therefore, defect in PHKG2 should be considered in patients with suspected glycogenosis associated with significant liver fibrosis and cirrhosis.
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24
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Bali DS, Goldstein JL, Fredrickson K, Rehder C, Boney A, Austin S, Weinstein DA, Lutz R, Boneh A, Kishnani PS. Variability of disease spectrum in children with liver phosphorylase kinase deficiency caused by mutations in the PHKG2 gene. Mol Genet Metab 2014; 111:309-313. [PMID: 24389071 PMCID: PMC3952947 DOI: 10.1016/j.ymgme.2013.12.008] [Citation(s) in RCA: 41] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/01/2013] [Revised: 12/12/2013] [Accepted: 12/12/2013] [Indexed: 11/23/2022]
Abstract
Liver phosphorylase b kinase (PhK) deficiency (glycogen storage disease type IX), one of the most common causes of glycogen storage disease, is caused by mutations in the PHKA2, PHKB, and PHKG2 genes. Presenting symptoms include hepatomegaly, ketotic hypoglycemia, and growth delay. Clinical severity varies widely. Autosomal recessive mutations in the PHKG2 gene, which cause about 10-15% of cases, have been associated with severe symptoms including increased risk of liver cirrhosis in childhood. We have summarized the molecular, biochemical, and clinical findings in five patients, age 5-16 years, diagnosed with liver PhK deficiency caused by PHKG2 gene mutations. We have identified five novel and two previously reported mutations in the PHKG2 gene in these five patients. Clinical severity was variable among these patients. Histopathological studies were performed for four of the patients on liver biopsy samples, all of which showed signs of fibrosis but not cirrhosis. One of the patients (aged 9 years) developed a liver adenoma which later resolved. All patients are currently doing well. Their clinical symptoms have improved with age and treatment. These cases add to the current knowledge of clinical variability in patients with PHKG2 mutations. Long term studies, involving follow-up of these patients into adulthood, are needed.
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Affiliation(s)
- Deeksha S Bali
- Department of Pediatrics, Box 103856, Duke University Health System, Durham, NC 27710, USA.
| | - Jennifer L Goldstein
- Department of Pediatrics, Box 103856, Duke University Health System, Durham, NC 27710, USA.
| | - Keri Fredrickson
- Department of Pediatrics, Box 103856, Duke University Health System, Durham, NC 27710, USA.
| | - Catherine Rehder
- Clinical Molecular Diagnostic Laboratory, 4425 Ben Franklin Blvd, Duke University Health System, Durham, NC 27704, USA.
| | - Anne Boney
- Department of Pediatrics, Box 103856, Duke University Health System, Durham, NC 27710, USA.
| | - Stephanie Austin
- Department of Pediatrics, Box 103856, Duke University Health System, Durham, NC 27710, USA.
| | - David A Weinstein
- Glycogen Storage Disease Program, PO Box 100296, University of Florida College of Medicine, Gainesville, FL 32610, USA.
| | - Richard Lutz
- University of Nebraska Medical Center, Munroe-Meyer Institute for Genetics & Rehabilitation, 985440 Nebraska Medical Center, USA.
| | - Avihu Boneh
- Metabolic Genetics, Victorian Clinical Genetics Services, The Murdoch Children's Research Institute, Royal Children's Hospital Melbourne, Department of Paediatrics, University of Melbourne, Flemington Road, Parkville 3052, Australia.
| | - Priya S Kishnani
- Department of Pediatrics, Box 103856, Duke University Health System, Durham, NC 27710, USA.
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Achouitar S, Goldstein JL, Mohamed M, Austin S, Boyette K, Blanpain FM, Rehder CW, Kishnani PS, Wortmann SB, den Heijer M, Lefeber DJ, Wevers RA, Bali DS, Morava E. Common mutation in the PHKA2 gene with variable phenotype in patients with liver phosphorylase b kinase deficiency. Mol Genet Metab 2011; 104:691-4. [PMID: 21911307 DOI: 10.1016/j.ymgme.2011.08.021] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/22/2011] [Revised: 08/19/2011] [Accepted: 08/19/2011] [Indexed: 11/23/2022]
Abstract
We found that the missense mutation p.Pro1205Leu in the PHKA2 gene is a common cause of hepatic phosphorylase-kinase deficiency in Dutch patients, suggesting a founder-effect. Most patients presented with isolated growth delay and diarrhea, prior to the occurrence of hepatomegaly, delaying diagnosis. Tetraglucoside excretion correlated with disease severity and was used to follow compliance. The clinical presentation and therapeutic requirements in the same mutation carriers were variable, and PhK deficiency necessitated tube-feeding in some children.
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Affiliation(s)
- Samira Achouitar
- Department of Pediatrics, Institute for Genetic and Metabolic Disease, Radboud University Nijmegen Medical Center, The Netherlands
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26
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Davit-Spraul A, Piraud M, Dobbelaere D, Valayannopoulos V, Labrune P, Habes D, Bernard O, Jacquemin E, Baussan C. Liver glycogen storage diseases due to phosphorylase system deficiencies: diagnosis thanks to non invasive blood enzymatic and molecular studies. Mol Genet Metab 2011; 104:137-43. [PMID: 21646031 DOI: 10.1016/j.ymgme.2011.05.010] [Citation(s) in RCA: 39] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/08/2011] [Revised: 05/11/2011] [Accepted: 05/11/2011] [Indexed: 10/18/2022]
Abstract
Glycogen storage disease (GSD) due to a deficient hepatic phosphorylase system defines a genetically heterogeneous group of disorders that mainly manifests in children. We investigated 45 unrelated children in whom a liver GSD VI or IX was suspected on the basis of clinical symptoms including hepatomegaly, increased serum transaminases, postprandial lactatemia and/or mild fasting hypoglycemia. Liver phosphorylase and phosphorylase b kinase activities studied in peripheral blood cells allowed to suspect diagnosis in 37 cases but was uninformative in 5. Sequencing of liver phosphorylase genes was useful to establish an accurate diagnosis. Causative mutations were found either in the PYGL (11 patients), PHKA2 (26 patients), PHKG2 (three patients) or in the PHKB (three patients) genes. Eleven novel disease causative mutations, five missense (p.N188K, p.D228Y, p.P382L, p.R491H, p.L500R) and six truncating mutations (c.501_502ins361pb, c.528+2T>C, c.856-29_c.1518+614del, c.1620+1G>C, p.E703del and c.2313-1G>T) were identified in the PYGL gene. Seventeen novel disease causative mutations, ten missense (p.A42P, p.Q95R, p.G131D, p.G131V, p.Q134R, p.G187R, p.G300V, p.G300A, p.C326Y, p.W820G) and seven truncating (c.537+5G>A, p.G396DfsX28, p.Q404X, p.N653X, p.L855PfsX87, and two large deletions) were identified in the PHKA2 gene. Four novel truncating mutations (p.R168X, p.Q287X, p.I268PfsX12 and c.272-1G>C) were identified in the PHKG2 gene and three (c.573_577del, p.R364X, c.2427+3A>G) in the PHKB gene. Patients with PHKG2 mutations evolved towards cirrhosis. Molecular analysis of GSD VI or IX genes allows to confirm diagnosis suspected on the basis of enzymatic analysis and to establish diagnosis and avoid liver biopsy when enzymatic studies are not informative in blood cells.
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Affiliation(s)
- Anne Davit-Spraul
- Biochemistry Unit, CHU Bicêtre, Assistance Publique-Hôpitaux de Paris, France.
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27
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Echaniz-Laguna A, Akman HO, Mohr M, Tranchant C, Talmant-Verbist V, Rolland MO, Dimauro S. Muscle phosphorylase b kinase deficiency revisited. Neuromuscul Disord 2010; 20:125-7. [DOI: 10.1016/j.nmd.2009.11.004] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/04/2009] [Revised: 08/24/2009] [Accepted: 11/04/2009] [Indexed: 10/20/2022]
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Chen ST, Chen HL, Ni YH, Chien YH, Jeng YM, Chang MH, Hwu WL. X-linked liver glycogenosis in a Taiwanese family: transmission from undiagnosed males. Pediatr Neonatol 2009; 50:230-3. [PMID: 19856867 DOI: 10.1016/s1875-9572(09)60068-1] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/01/2022] Open
Abstract
X-linked liver glycogenosis (XLG), also known as glycogen storage disease type-lXa, is characterized by hepatomegaly, abnormal liver functions and growth retardation. It is caused by mutations in the PHKA2 gene that encodes the alpha-subunit of phosphorylase kinase (PHK). XLG can be divided into two subtypes: XLG-I, with a deficiency in PHK activity in peripheral blood cells and the liver; and XLG-II, with normal PHK activity in vitro. This report describes two boys who presented with hepatomegaly and abnormal liver function. Pedigree analysis revealed them to be fifth-degree relatives, with the disease transmitted through undiagnosed grandfathers. Liver histology confirmed GSD diagnosis, and both cases had a deficiency in PHK activity in red blood cells and liver tissues. This is the first report of XLG-I in the ethnic-Chinese population in Taiwan. This report indicates that XLG may be undiagnosed or underestimated. A correct diagnosis is necessary for proper management and genetic counseling.
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Affiliation(s)
- Szu-Ta Chen
- Department of Pediatrics, National Taiwan University Children's Hospital and National Taiwan University College of Medicine, Taipei, Taiwan
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29
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Wang Y, Xiong Y, Ren Z, Yang C, Li F, Lei M, Zuo B, Xu D. Isolation, expression patterns and SNP frequencies of the porcine PHKG2 gene. Livest Sci 2009. [DOI: 10.1016/j.livsci.2008.07.026] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/21/2022]
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3D mapping of glycogenosis-causing mutations in the large regulatory alpha subunit of phosphorylase kinase. Biochim Biophys Acta Mol Basis Dis 2008; 1782:664-70. [DOI: 10.1016/j.bbadis.2008.09.011] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/13/2008] [Revised: 09/15/2008] [Accepted: 09/19/2008] [Indexed: 11/20/2022]
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Winchester JS, Rouchka EC, Rowland NS, Rice NA. In Silico characterization of phosphorylase kinase: evidence for an alternate intronic polyadenylation site in PHKG1. Mol Genet Metab 2007; 92:234-42. [PMID: 17692548 PMCID: PMC2706538 DOI: 10.1016/j.ymgme.2007.06.015] [Citation(s) in RCA: 15] [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: 06/25/2007] [Accepted: 06/25/2007] [Indexed: 01/21/2023]
Abstract
Phosphorylase kinase (PhK), the key enzyme that regulates glycogenolysis, has traditionally been thought to be expressed predominantly in muscle and liver. In this study, we show by two different database searches (Expressed Sequence Tag and UniGene) that PhK gene expression occurs in at least 28-36 different tissues, and that the genes encoding the alpha, beta, and gamma subunits of PhK undergo extensive transcriptional processing. In particular, we have identified exon 6 of PHKG1 as a 3' composite terminal exon due to the presence of a weak polyadenylation and cleavage site in intron 6. We have verified biochemically that transcriptional processing of PHKG1 does occur in vivo; mRNA corresponding to the alternate variant is expressed in skeletal muscle, brain, heart, and tongue. In silico translation of this mRNA yields a PhK gamma subunit that contains the first 181 residues of the protein, followed by an additional 21 amino acids. The implication of this alternate processing is discussed within the context of gamma catalysis and regulation.
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Affiliation(s)
| | - Eric C. Rouchka
- Department of Computer Engineering and Computer Science, University of Louisville, Louisville, Kentucky 40292, USA
| | | | - Nancy A. Rice
- Corresponding Author: Nancy A. Rice, Ph.D., Department of Biology, 1906 College Heights Boulevard #11080, Western Kentucky University, Bowling Green, Kentucky 42101-1080, Telephone: 270.745.5995, Telefax: 270.745.6856,
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Fukao T, Zhang G, Aoki Y, Arai T, Teramoto T, Kaneko H, Sugie H, Kondo N. Identification of Alu-mediated, large deletion-spanning introns 19-26 in PHKA2 in a patient with X-linked liver glycogenosis (hepatic phosphorylase kinase deficiency). Mol Genet Metab 2007; 92:179-82. [PMID: 17581768 DOI: 10.1016/j.ymgme.2007.05.007] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/09/2007] [Revised: 05/09/2007] [Accepted: 05/09/2007] [Indexed: 11/20/2022]
Abstract
X-linked liver glycogenosis (XLG) is one of the most common glycogen storage diseases. We present the first case of a large PHKA2 gene deletion from intron 19 to intron 26 in an XLG patient. An aberrant cDNA with skipping of exons 20-26 was detected. Alu element-mediated unequal homologous recombination between an Alu-Jo in intron 19 and another Alu-Sg in intron 26 appears to be responsible for this deletion.
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Affiliation(s)
- Toshiyuki Fukao
- Department of Pediatrics, Graduate School of Medicine, Gifu University, Gifu 501-1194, Japan
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Beauchamp NJ, Dalton A, Ramaswami U, Niinikoski H, Mention K, Kenny P, Kolho KL, Raiman J, Walter J, Treacy E, Tanner S, Sharrard M. Glycogen storage disease type IX: High variability in clinical phenotype. Mol Genet Metab 2007; 92:88-99. [PMID: 17689125 DOI: 10.1016/j.ymgme.2007.06.007] [Citation(s) in RCA: 86] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/30/2007] [Revised: 06/14/2007] [Accepted: 06/15/2007] [Indexed: 10/23/2022]
Abstract
Glycogen storage disease type IX (GSD type IX) results from a deficiency of hepatic phosphorylase kinase activity. The phosphorylase kinase holoenzyme is made up of four copies of each of four subunits (alpha, beta, gamma and delta). The liver isoforms of the alpha-, beta- and gamma-subunits are encoded by PHKA2, PHKB and PHKG2, respectively. Mutation within these genes has been shown to result in GSD type IX. The diagnosis of GSD type IX is complicated by the spectrum of clinical symptoms, variation in tissue specificity and severity, and its inheritance, either X-linked or autosomal recessive. We investigated 15 patients from 12 families with suspected GSD type IX. Accurate diagnosis had been hampered by enzymology not being diagnostic in five cases. Clinical symptoms included combinations of hypoglycaemia, hepatosplenomegaly, short stature, hepatopathy, weakness, fatigue and motor delay. Biochemical findings included elevated lactate, urate and lipids. We characterised causative mutations in the PHKA2 gene in ten patients from eight families, in PHKG2 in two unrelated patients and in the PHKB gene in three patients from two families. Seven novel mutations were identified in PHKA2 (p.I337X, p.P498L, p.P869R, p.Y116_T120dup, p.R1070del, p.R916W and p.M113I), two in PHKG2 (p.L144P and p.H48QfsX5) and two in PHKB (p.Y419X and c.2336+965A>C). There was a severe phenotype in patients with PHKG2 mutations, a mild phenotype with patients PHKB mutations and a broad spectrum associated with PHKA2 mutations. Molecular analysis allows accurate diagnosis where enzymology is uninformative and identifies the pattern of inheritance permitting counselling and family studies.
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Affiliation(s)
- Nicholas James Beauchamp
- Academic Unit of Child Health, University of Sheffield, Stephenson Wing, Sheffield Children's NHS Foundation Trust, Western Bank, Sheffield S10 2TH, and Department of Paediatrics, Addenbrook's Hospital, Cambridge, UK.
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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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35
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Sijens PE, Smit GP, Borgdorff MAJ, Kappert P, Oudkerk M. Multiple voxel 1H MR spectroscopy of phosphorylase-b kinase deficient patients (GSD IXa) showing an accumulation of fat in the liver that resolves with aging. J Hepatol 2006; 45:851-5. [PMID: 17005290 DOI: 10.1016/j.jhep.2006.06.021] [Citation(s) in RCA: 14] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/21/2006] [Revised: 06/06/2006] [Accepted: 06/28/2006] [Indexed: 01/19/2023]
Abstract
BACKGROUND/AIMS Phosphorylase-b deficient patients suffer from glycogen storage disease (GSD IXa) leading to liver enlargement which usually resolves during puberty and adolescence. This pathology has not yet been documented by (1)H MR spectroscopy (MRS) investigation. METHODS MRS of eight GSD IXa patients was performed in this study to assess whether or not liver fat content is elevated in GSD IXa and decreases with aging. An improvement in our MRS method compared with previous liver fat MRS studies is that we measured a plane of liver voxels at once rather than a single MRS voxel, yielding a reliable determination of liver fat content. RESULTS Fat contents of 3.4-10% were observed in young GSD IXa patients, as compared with 0.5-0.9% in controls, these dropped to control levels in patients past age 40 (r = -0.82; P < 0.01). CONCLUSIONS Liver fat content is increased in glycogen storage disease (GSD IXa) and normalizes with ageing. Assessing liver fat levels in this population is a novel and interesting concept. This could potentially enhance the understanding of liver function in that 20% of the population who has increased liver fat.
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Affiliation(s)
- Paul E Sijens
- Radiology, University Medical Center Groningen, University of Groningen, Hanzeplein 1, 9713 GZ, The Netherlands.
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36
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Hidaka F, Sawada H, Matsuyama M, Nunoi H. A novel mutation of the PHKA2 gene in a patient with X-linked liver glycogenosis type 1. Pediatr Int 2005; 47:687-90. [PMID: 16354226 DOI: 10.1111/j.1442-200x.2005.02131.x] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/27/2022]
Affiliation(s)
- Fumio Hidaka
- Department of Pediatrics, Miyazaki Medical College, University of Miyazaki, Miyazaki, Japan
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37
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Burwinkel B, Rootwelt T, Kvittingen EA, Chakraborty PK, Kilimann MW. Severe phenotype of phosphorylase kinase-deficient liver glycogenosis with mutations in the PHKG2 gene. Pediatr Res 2003; 54:834-9. [PMID: 12930917 DOI: 10.1203/01.pdr.0000088069.09275.10] [Citation(s) in RCA: 38] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/06/2022]
Abstract
Phosphorylase kinase-deficient liver glycogenosis manifests in infancy with hepatomegaly, growth retardation, and elevated plasma aminotransferases and lipids. It can be caused by mutations in three different genes of phosphorylase kinase subunits: PHKA2, PHKB, and PHKG2. It is usually a benign condition, often with complete resolution of symptoms during puberty. A minority of patients displays a more severe phenotype with symptomatic fasting hypoglycemia and abnormal liver histology that may progress to cirrhosis. Three patients with liver cirrhosis in childhood analyzed previously all had PHKG2 mutations. This suggested that this genotype may generally cause a more severe clinical manifestation, but to date PHKG2 mutations have been identified in only seven patients. Here, we report mutation analysis in three new patients with liver phosphorylase kinase deficiency and recurrent hypoglycemia, liver fibrosis, and lack of glucagon response but no overt cirrhosis. In all three patients, PHKG2 mutations were found (H89fs[insC], E157K, D215N, W300X). Three of these mutations are novel, bringing the total number of distinct human PHKG2 mutations to 11, found in 10 patients. We conclude that liver phosphorylase kinase deficiency with a severe phenotype, with or without cirrhosis, is indeed often caused by PHKG2 mutations. These patients require active measures to maintain normoglycemia (raw cornstarch, nocturnal tube feeding), which may also alleviate growth retardation and the development of abnormal liver histology.
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Affiliation(s)
- Barbara Burwinkel
- Institut für Physiologische Chemie, Ruhr-Universität Bochum, D-44780 Bochum, Germany
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38
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Burwinkel B, Hu B, Schroers A, Clemens PR, Moses SW, Shin YS, Pongratz D, Vorgerd M, Kilimann MW. Muscle glycogenosis with low phosphorylase kinase activity: mutations in PHKA1, PHKG1 or six other candidate genes explain only a minority of cases. Eur J Hum Genet 2003; 11:516-26. [PMID: 12825073 DOI: 10.1038/sj.ejhg.5200996] [Citation(s) in RCA: 34] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/08/2022] Open
Abstract
Muscle-specific deficiency of phosphorylase kinase (Phk) causes glycogen storage disease, clinically manifesting in exercise intolerance with early fatiguability, pain, cramps and occasionally myoglobinuria. In two patients and in a mouse mutant with muscle Phk deficiency, mutations were previously found in the muscle isoform of the Phk alpha subunit, encoded by the X-chromosomal PHKA1 gene (MIM # 311870). No mutations have been identified in the muscle isoform of the Phk gamma subunit (PHKG1). In the present study, we determined Q1the structure of the PHKG1 gene and characterized its relationship to several pseudogenes. In six patients with adult- or juvenile-onset muscle glycogenosis and low Phk activity, we then searched for mutations in eight candidate genes. The coding sequences of all six genes that contribute to Phk in muscle were analysed: PHKA1, PHKB, PHKG1, CALM1, CALM2 and CALM3. We also analysed the genes of the muscle isoform of glycogen phosphorylase (PYGM), of a muscle-specific regulatory subunit of the AMP-dependent protein kinase (PRKAG3), and the promoter regions of PHKA1, PHKB and PHKG1. Only in one male patient did we find a PHKA1 missense mutation (D299V) that explains the enzyme deficiency. Two patients were heterozygous for single amino-acid replacements in PHKB that are of unclear significance (Q657K and Y770C). No sequence abnormalities were found in the other three patients. If these results can be generalized, only a fraction of cases with muscle glycogenosis and a biochemical diagnosis of low Phk activity are caused by coding, splice-site or promoter mutations in PHKA1, PHKG1 or other Phk subunit genes. Most patients with this diagnosis probably are affected either by elusive mutations of Phk subunit genes or by defects in other, unidentified genes.
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Affiliation(s)
- Barbara Burwinkel
- Institut für Physiologische Chemie, Ruhr-Universität Bochum, D-44780 Bochum, Germany
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Radziuk J, Pye S. Hepatic glucose uptake, gluconeogenesis and the regulation of glycogen synthesis. Diabetes Metab Res Rev 2001; 17:250-72. [PMID: 11544610 DOI: 10.1002/dmrr.217] [Citation(s) in RCA: 185] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/05/2023]
Abstract
Hepatic glycogen is replenished during the absorptive period postprandially. This repletion is prompted partly by an increased hepatic uptake of glucose by the liver, partly by metabolite and hormonal signals in the portal vein, and partly by an increased gluconeogenic flux to glycogen (glyconeogenesis). There is some evidence that the direct formation of glycogen from glucose and that formed by gluconeogenic pathways is linked. This includes: (i) the inhibition of all glycogen synthesis, in vivo, when gluconeogenic flux is blocked by inhibitors; (ii) a dual relationship between glucose concentrations, lactate uptake by the liver and glycogen synthesis (by both pathways) which indicates that glucose sets the maximal rates of glycogen synthesis while lactate uptake determines the actual flux rate to glycogen; (iii) the decrease of both gluconeogenesis and glycogen synthesis by the biguanide, metformin; and (iv) correlations between increased gluconeogenesis and liver glycogen in obese patients and animal models. The degree to which the liver extracts portal glucose is not entirely agreed upon although a preponderance of evidence points to about a 5% extraction rate, following meals, which is dependent on a stimulation of glucokinase. This enzyme may be linked to the expression of other enzymes in the gluconeogenic pathway. Perivenous cells in the liver may induce additional gluconeogenesis in the periportal cells by increasing glycolytically produced lactate. A number of potential mechanisms therefore exist which could link glycogen synthesis from glucose and gluconeogenic substrate.
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Affiliation(s)
- J Radziuk
- Diabetes and Metabolism Research Unit, Ottawa Hospital, 1053 Carling Avenue, Ottawa, Ontario, Canada K1Y 4E9.
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40
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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: 69] [Impact Index Per Article: 2.7] [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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Hendrickx J, Lee P, Keating JP, Carton D, Sardharwalla IB, Tuchman M, Baussan C, Willems PJ. Complete genomic structure and mutational spectrum of PHKA2 in patients with x-linked liver glycogenosis type I and II. Am J Hum Genet 1999; 64:1541-9. [PMID: 10330341 PMCID: PMC1377897 DOI: 10.1086/302399] [Citation(s) in RCA: 40] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/03/2022] Open
Abstract
X-linked liver glycogenosis (XLG) is probably the most frequent glycogen-storage disease. XLG can be divided into two subtypes: XLG I, with a deficiency in phosphorylase kinase (PHK) activity in peripheral blood cells and liver; and XLG II, with normal in vitro PHK activity in peripheral blood cells and with variable activity in liver. Both types of XLG are caused by mutations in the same gene, PHKA2, that encodes the regulatory alpha subunit of PHK. To facilitate mutation analysis in PHKA2, we determined its genomic structure. The gene consists of 33 exons, spanning >/=65 kb. By SSCP analysis of the different PHKA2 exons, we identified five new XLG I mutations, one new XLG II mutation, and one mutation present in both a patient with XLG I and a patient with XLG II, bringing the total to 19 XLG I and 12 XLG II mutations. Most XLG I mutations probably lead to truncation or disruption of the PHKA2 protein. In contrast, all XLG II mutations are missense mutations or small in-frame deletions and insertions. These results suggest that the biochemical differences between XLG I and XLG II might be due to the different nature of the disease-causing mutations in PHKA2. XLG I mutations may lead to absence of the alpha subunit, which causes an unstable PHK holoenzyme and deficient enzyme activity, whereas XLG II mutations may lead to in vivo deregulation of PHK, which might be difficult to demonstrate in vitro.
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Affiliation(s)
- J Hendrickx
- Department of Medical Genetics, University of Antwerp, Antwerp, Belgium.
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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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