Glycogen storage diseases (GSDs) are inherited inborn errors of metabolism (IEM) involving carbohydrate metabolism. IEMs are often caused by single gene mutations that encode specific proteins: they are very relevant to pediatrics since these diseases may first manifest themselves in neonates or early childhood. IEMs should be considered in the differential diagnosis of any sick neonate. In general, IEMs result from the lack or insufficient level of specific enzymes that are needed to: (1) convert fat or carbohydrates to energy; (2) breakdown amino acids or other metabolites, allowing them to accumulate and become toxic. GSDs, depending on the specific type, can result from a failure to convert glycogen into energy and/or a toxic glycogen accumulation. All GSDs are due to a failure to use or store glycogen . Glycogen is a branched polymer with its monomeric units being glucose (Figure 1). After a meal, the level of glucose in plasma increases and stimulates the storage of excess glucose in cytoplasmic glycogen spherical. The liver contains the highest percent glycogen by weight (about 10%) whereas muscle can store about 2% by weight. Nevertheless, since the total muscle mass is greater than liver mass, the total mass of glycogen in muscle is about twice that of the liver. When needed, the glycogen polymer can be broken down into glucose monomers and utilized for energy production. Many of the enzymes and transporters for these processes are key to the etiology of GSDs. An increasing number of GSDs are being identified, but some are very rare. We will review the GSD type 0, 1, 2, 3, 4, 5, and 6 (see Figure 1). In the past, GSDs were also named by the discovering physician, as indicated in Table 1.
The etiology of GSD is best understood by following the metabolic events leading to the synthesis (glycogenesis) and degradation of glycogen (glycogenolysis) . Genetic defects in the enzymes and transporters involved in either glycogenesis or glycogenolysis are actual or potential causes of all GSDs. Excess dietary glucose is stored in glycogen and glycogen synthesis is, in part, accomplished by glycogen synthase (GS). As indicated in Table 1, there are two distinct forms of glycogen synthase, one in the liver encoded by the GYS2 gene and one in skeletal muscle encoded by the GYS1 gene. Both forms of GS work by linking (alpha-1,4 links) a glucose monomer to the growing glycogen polymer. As indicated in Figure 1, glycogen has two different types of linkages, alpha-1,4 links, and alpha-1,6 links. About 95% of linkages in glycogen are alpha-1,4 links. The absence or malfunction of liver glycogen synthase due to mutations in the GYS2 gene will prevent glycogen from being synthesized in the liver, and this is the cause of GSD type 0a (Table 1). Similarly, the absence or malfunction of muscle glycogen synthase due to mutations in the GYS1 gene will prevent glycogen from being synthesized in muscles, and this is the cause of GSD type 0b (Table 1).
While glycogen synthase can catalyze the alpha-1,4 glucose linkages in glycogen, a different enzyme, glycogen branching enzyme (GBE1 gene symbol), is needed to produce the branching alpha-1,6 linkages (Figure 1). Mutations in the glycogen branching enzyme can result in the production of glycogen with an abnormal structure, and this is the cause of GSD type 4 (Table 1). The abnormal glycogen structures are called polyglucosan bodies: they can accumulate in all cells, but most markedly in liver and muscle cells. Polyglucosan bodies do not effectively undergo glycogenolysis, and in muscle tissue, this can cause weakness and myopathy. In the liver, the accumulation of polyglucosan bodies causes hepatomegaly.
While GSD 0a and GSD 0b are due to insufficient storage of glycogen, most GSDs are due to an inability to remove glucose from glycogen (glycogenolysis) resulting in excess glycogen tissue storage. The first step in glycogenolysis is the release of glucose-1-phosphate (G-1-P) from glycogen by the action of glycogen phosphorylase.
glycogen + P -> glycogen(n-1) + G-1-P
GSD type 5 is caused by mutations in the glycogen phosphorylase gene specific for muscle (PYGM). Mutations in the glycogen phosphorylase gene specific for liver (PYGL) cause GSD type 6.
The glucose-1-phosphate released by glycogen phosphorylase is converted to glucose-6-phosphate (G-6-P) by the action of phosphoglucomutase.
G-1-P -> G-6-P
Glucose-6-phosphate in the liver is, in turn, converted to glucose by glucose-6-phosphatase (gene name G6PC) and the resulting glucose is released into the blood as an energy source for other tissues/organs, such as the brain (see Figure 2).
G-6-P -> G + P (liver not muscle) -> into blood
It should be noted that muscle lacks glucose-6-phosphatase and therefore does not release glucose into the blood. GSDs type 1 is the result of genetic disorders in the metabolism of glucose-6-phosphatase . GSD type Ia (also called von Gierke disease) is caused by mutations in the G6PC gene (Table 1). Glucose-6-phosphate is synthesized in the cytoplasm of hepatocytes and must be transported into the lumen of the endoplasmic reticulum (ER) where it is acted upon by glucose-6-phosphatase yielding glucose which is transported back to the cytoplasm and then through the hepatic GLUT2 transporter into the blood. Glucose-6-phosphate translocase1 (G6PT1) is the transporter protein that provides a G-6-P channel between the cytoplasm and the E. The G6PT protein is made of three subunits termed G6PT1, G6PT2, and G6PT3 (see Figure 2). Mutations in the SLC37A4 gene, which encodes the G6PT1 protein, are responsible for GSD type Ib (Figure 1). Fanconi-Bickel disease is a rare GSD caused by a GLUT2 deficiency (gene name SLC2A2). GLUT2 deficiency results in a failure to export glucose, an increased intracellular glucose level and reduced degradation of glycogen: eventually there is increased glycogen storage and hepatomegaly.
As mentioned above, glycogen is a branched polymer. While glycogen phosphorylase works well at removing glucose from alpha-(1,4)-linkages, it does not work at branch points. Branch points are alpha-1,6 linkages: a glycogen debranching enzyme (GDE) is required, which in mammals is called “ammylo-alpha-1,6-glucosidase, 4-alpha-Glucanotransferase” with the gene name AGL. GSD type 3 is caused by mutations in the AGL gene (Figure 1), resulting in either a nonfunctional GDE enzyme (GSD type 3a or type 3b) or a GDE with reduced function (GSD type 3c and 3d) .
GSD 2 is unique among GSD since it is also classified as lysosomal storage disease (LSD) . Lysosomes are subcellular organelles that recycle cellular macromolecules. All LSDs are caused by a missing or nonfunctional lysosomal enzyme. In the case of GSD 2, this enzyme is lysosomal acid alpha-glucosidase (gene name GAA), which breaks down glycogen into glucose for use as a cellular energy source. Mutation in the GAA gene results in the toxic accumulation of glycogen in lysosomes.
The overall incidence of GSD (all forms) in Europe, Canada, and the United States is estimated to be between 1 in 20,000 and 1 in 40,000. This incidence is probably an underestimate since some individuals can have a very mild form of GSD that is never diagnosed and other forms can result in fetal or neonatal sudden death and go undiagnosed. There are frequency differences between ethnic groups, e.g., GSD type 3 is more frequent in individuals of North African Jewish descent. GSD type 6 is more common in the old order Mennonite population than the general population.
Figure 1 summarizes the pathophysiology for each GSD, along with organ(s) affected, as well as the potential signs. In general, GSDs primarily affect the liver, skeletal muscle, or both. An inability to synthesize glycogen (e.g., GSD 2) or an inability to properly release glucose from glycogen can result in hypoglycemia and exercise intolerance. The inability to properly release glucose from glycogen can result in the abnormal accumulation of glycogen. In the liver (e.g., GSD type 3b and 3d) this can result in hepatomegaly with the potential for cirrhosis. In skeletal muscle, e.g., GSD 5, this can prevent proper muscle functioning, exercise intolerance and rhabdomyolysis.
GSDs are a diverse set of rare inborn errors of carbohydrate metabolism that can have a very variable phenotypic presentation even within same GSD type. Obtaining a family pedigree is useful in establishing the mode of inheritance. Most GSDs show an autosomal recessive inheritance, but a few, e.g., a subtype of GSD-IX) show an X-linked inheritance. Very general symptoms/signs would include:
In GSD Type 1, glycogenolysis in the liver results in increased lactic acid production (lactic acidosis) due to the intracellular accumulation of glucose-6-phosphate which stimulates the glycolytic pathway.
The evaluation would include (1) a biopsy of the affected tissue to measure glycogen content and appropriate enzymatic assays, (2) blood and urine tests, and (3) an MRI/CT scan. The blood tests would include serum glucose, anion gap, serum lactate, pH, serum uric acid, a lipid panel, serum gamma-glutamyltransferase, serum alkaline phosphatase, calcium, phosphorus, urea, and creatinine levels, complete blood count (CBC) and differential. Urine analysis would include testing for aminoaciduria, proteinuria, and microalbuminuria in older patients as well as excreted uric acid and calcium. Liver and kidney MRI (or CT) are routinely done for adults and ultrasonography for patients less than 16 years of age.
At present, there is no cure for any GSD, and most treatments attempt to alleviate signs/symptoms. Key overall goals are to treat or avoid hypoglycemia, hyperlactatemia, hyperuricemia, and hyperlipidemia. Hypoglycemia is avoided by consuming starch and an optimal, physically modified form, Glycosade, is now commercially available. Hyperuricemia is treated with allopurinol and hyperlipidemia with statins. GSD type 2 can now be treated with enzyme replacement therapy (ERT), using recombinant alglucosidase alfa (Lumizyme) which degrades lysosomal glycogen . There is ongoing research to use ERT with other forms of GSD. Liver transplantation should be considered for patients with GSD type 4 classical and progressive hepatic forms and for GSDs that have progressed to hepatic malignancy or failure.
GSDs are not common and should be managed with a multidisciplinary team including nurses and dietitians. At present, there is no cure for any GSD, and most treatments attempt to alleviate signs/symptoms. The key overall goals are to treat or avoid hypoglycemia, hyperlactatemia, hyperuricemia, and hyperlipidemia. These patients need lifelong monitoring and despite optimal treatment, the outcomes are poor.
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