Mutations in the liver glycogen synthase gene in children with hypoglycemia due to glycogen storage disease type 0.

Orho, M.; Bosshard, Nils U.; Buist, Neil R. M.; Gitzelmann, R; Aynsley-Green, A; Blümel, Peter; Gannon, Mary C.; Nuttall, Frank Q.; Groop, Leif

doi:10.1172/jci2890

Cited by 109 publications

(117 citation statements)

References 33 publications

(41 reference statements)

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“…[1] All of the adults with GSD0 have done well, and there is reason to believe that the prognosis is excellent for these patients despite the lack of reported older individuals. A 26-year old with GSD0 gave birth to a healthy term infant, but overnight hypoglycemia and ketonemia developed in the 2 nd and 3 rd trimesters when extra supplementation was not provided.…”

Section: Natural History and Prognosismentioning

confidence: 99%

“…[1] Although GSD0 has been classified as a glycogen storage disease (GSD), this is a misnomer. In contrast to all other types of glycogenoses, which are characterized by increased glycogen storage, deficiency of glycogen synthase causes a marked decrease in liver glycogen content.…”

mentioning

confidence: 99%

“…[2] Although the disease was described in 1963, only 20 cases of GSD0 have been reported in the literature. [1,[3][4][5][6][7][8][9] Confusion regarding the phenotype of the disease and prior dependence on a liver biopsy to establish the diagnosis may account for the apparent rarity of the disorder. There is, however, increasing evidence that GSD0 has been under-diagnosed.…”

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confidence: 99%

“…[6,12] Discovery of the GYS2 gene, which encodes for the liver-specific form of glycogen synthase, has enabled investigators to clarify the clinical characteristics of the disease caused by deficiency of this enzyme. [1] This review will summarize recent research which suggests that GSD0 is an under-diagnosed entity and will describe the clinical characteristics of the 20 reported cases.…”

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confidence: 99%

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Hepatic glycogen synthase deficiency: An infrequently recognized cause of ketotic hypoglycemia

Weinstein

Correia

Saunders

et al. 2006

Molecular Genetics and Metabolism

110

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The glycogen storage diseases comprise several inherited diseases caused by abnormalities of enzymes that regulate the synthesis or degradation of glycogen. In contrast to the classic hepatic glycogen storage diseases that are characterized by fasting hypoglycemia and hepatomegaly, the liver is not enlarged in GSD0. Patients with GSD0 typically have fasting ketotic hypoglycemia without prominent muscle symptoms. Most children are cognitively and developmentally normal. Short stature and osteopenia are common features, but other long-term complications, common in other types of GSD, have not been reported in GSD0. Until recently, the definitive diagnosis of GSD0 depended on the demonstration of decreased hepatic glycogen on a liver biopsy. The need for an invasive procedure may be one reason that this condition has been infrequently diagnosed. Mutation analysis of the GYS2 gene (12p12.2) is a non-invasive method for making this diagnosis in patients suspected to have this disorder. This mini-review discusses the pathophysiology of this disorder, use of mutation analysis to diagnose GSD0, and the clinical characteristics of all reported cases of GSD0.

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Section: Natural History and Prognosismentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

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Hepatic glycogen synthase deficiency: An infrequently recognized cause of ketotic hypoglycemia

Weinstein

Correia

Saunders

et al. 2006

Molecular Genetics and Metabolism

110

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“…For instance, the amount of muscle glycogen, expressed as a fraction of body mass, is ϳ10-fold lower in mice than in humans (12,13), whereas the corresponding values for liver glycogen are comparable (14). Thus, the relative role of these two glycogen storage depots may be different between the two species.…”

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Exercise Capacity of Mice Genetically Lacking Muscle Glycogen Synthase

Pederson

Cope

Schroeder

et al. 2005

Journal of Biological Chemistry

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The glucose storage polymer glycogen is generally considered to be an important source of energy for skeletal muscle contraction and a factor in exercise endurance. A genetically modified mouse model lacking muscle glycogen was used to examine whether the absence of the polysaccharide affects the ability of mice to run on a treadmill. The MGSKO mouse has the GYS1 gene, encoding the muscle isoform of glycogen synthase, disrupted so that skeletal muscle totally lacks glycogen. The morphology of the soleus and quadriceps muscles from MGSKO mice appeared normal. MGSKO-null mice, along with wild type littermates, were exercised to exhaustion. There were no significant differences in the work performed by MGSKO mice as compared with their wild type littermates. The amount of liver glycogen consumed during exercise was similar for MGSKO and wild type animals. Fasting reduced exercise endurance, and after overnight fasting, there was a trend to reduced exercise endurance for the MGSKO mice. These studies provide genetic evidence that in mice muscle glycogen is not essential for strenuous exercise and has relatively little effect on endurance.The two major repositories of glycogen, the polymeric storage form of glucose, are in the liver and skeletal muscle (1). In humans, these carbohydrate reserves are an important determinant of endurance upon sustained exercise, and muscle glycogen has long been viewed as a critical energy source during muscular activity (2-4). Depletion of muscle glycogen results in fatigue and impaired muscle performance and is a major determinant of endurance (2-5). Likewise, the ineffective utilization of muscle glycogen, as in patients with McArdle disease, leads to impaired exercise tolerance (6). In their "glycogen shunt" hypothesis, Shulman and Rothman (7) propose that glycogenolysis is the predominant source of energy for muscle contraction with glycogen acting essentially as an intermediate for blood glucose to enter glycolysis. Increasing muscle glycogen by manipulating diet and exercise regimens, a procedure termed "carbohydrate loading" or "glycogen supercompensation" (8), is adopted by endurance athletes to delay the onset of fatigue (4, 9 -11).Although the importance of adequate muscle glycogen to sustain exercise in humans has been well documented, caution is needed in extrapolating findings in rodents to humans. For instance, the amount of muscle glycogen, expressed as a fraction of body mass, is ϳ10-fold lower in mice than in humans (12, 13), whereas the corresponding values for liver glycogen are comparable (14). Thus, the relative role of these two glycogen storage depots may be different between the two species. The relative importance of muscle and liver glycogen stores as fuel sources for exercise has been studied extensively in rats (15-17). Exhaustive exercise either by treadmill running or swimming resulted in a reduction of muscle glycogen by 70 or Ͼ90%, respectively (15, 16). Both exercise methods reduced liver glycogen Ͼ90%. Using less strenuous exercise regimens, muscle g...

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Metabolism: Hereditary Errors

Groop¹,

Rosengren²

2011

Encyclopedia of Life Sciences

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Inherited metabolic diseases can be both monogenic and polygenic. The monogenic forms are usually rare and are characterised by early onset. Examples include maturity‐onset diabetes of the young (MODY), phenylketonuria and glycogen storage diseases. The polygenic metabolic diseases result from a complex interaction of genetic variants and environmental factors. Type 1 and type 2 diabetes are typical examples. Important progress has been made in unravelling the genetic background of the common forms of diabetes. For type 2 diabetes, close to 50 loci have been consistently associated with increased disease risk. The findings have provided novel pathophysiological insights and suggest that type 2 diabetes occurs when the pancreatic islets fail to compensate for the increased insulin demands in states of insulin resistance. The exact disease mechanisms associated with the genetic variants are however in most cases not completely known. Novel approaches, including deoxyribonucleic acid (DNA) sequencing, are likely to give a more comprehensive picture of the genetic background. Key Concepts: Genetic factors play an important role in most metabolic disorders. Monogenic metabolic diseases such as MODY have high penetrance and early onset. The common metabolic disorders have typically a polygenic inheritance. Type 1 and type 2 diabetes have a complex pathogenesis and result from a combination of environmental and genetic factors. Genome‐wide association studies have identified a large number of disease susceptibility variants for type 2 diabetes. Identification of genetic risk variants is invaluable for improving the pathophysiological understanding.

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Mutations in the liver glycogen synthase gene in children with hypoglycemia due to glycogen storage disease type 0.

Cited by 109 publications

References 33 publications

Hepatic glycogen synthase deficiency: An infrequently recognized cause of ketotic hypoglycemia

Hepatic glycogen synthase deficiency: An infrequently recognized cause of ketotic hypoglycemia

Exercise Capacity of Mice Genetically Lacking Muscle Glycogen Synthase

Metabolism: Hereditary Errors

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