glycogen storage diseases
Saturday 28 January 2006
Definition: Glycogenoses are a number of genetic syndromes have been identified that result from some metabolic defect in the synthesis or catabolism of glycogen.
The best understood and most important glycogenoses includes the glycogen storage diseases (GSDs), resulting from a hereditary deficiency of one of the enzymes involved in the synthesis or sequential degradation of glycogen.
A glycogen storage disease (GSD) is the result of an enzyme defect. These enzymes normally catalyze reactions that ultimately convert glycogen compounds to glucose. Enzyme deficiency results in glycogen accumulation in tissues. In many cases, the defect has systemic consequences, but in some cases, the defect is limited to specific tissues. Most patients experience muscle symptoms such as weakness and cramps, although certain GSDs manifest as specific syndromes, such as hypoglycemic seizures or cardiomegaly.
glycogen storage disease type 0 (GSD0) (MIM.240600) - Glycogen synthase deficiency
glycogen storage disease type 1a (GSD1a) (MIM.232200) - Glucose-6-phosphatase deficiency (von Gierke disease)
glycogen storage disease type 1b (GSD1b) (MIM.232220)
glycogen storage disease type 1c (GSD1c) (MIM.232240)
glycogen storage disease type 2 (GSD2) (MIM.232300) - Acid maltase deficiency (Pompe disease)
glycogen storage disease type 3 (GSD3) (MIM.232400)- Debranching enzyme deficiency (Forbes-Cori disease)
glycogen storage disease type 4 (GSD4) (amylopectinosis) (MIM.232500) - Transglucosidase deficiency (Andersen disease, amylopectinosis)
glycogen storage disease type 5 (GSD5) (MIM.232600) - Myophosphorylase deficiency (McArdle disease)
glycogen storage disease type 6 (GSD6) (MIM.232700) - Phosphorylase deficiency (Hers disease)
glycogen storage disease type 7 (GSD7) (MIM.232800) - Phosphofructokinase deficiency (Tarui disease)
glycogen storage disease type 8 (GSD8) (MIM.)
glycogen storage disease type 9a (GSD9a) (MIM.306000)
glycogen storage disease type 10 (GSD10)
glycogen storage disease type 11 (GSD11)
glycogen storage disease type 12 (GSD12)
glycogen storage disease type 13 (GSD13)
glycogen storage disease type 14 (GSD14)
Although at least 14 unique GSDs are discussed in the literature, the 4 that cause clinically significant muscle weakness are Pompe disease (GSD type II, acid maltase deficiency), Cori disease (GSD type III, debranching enzyme deficiency), McArdle disease (GSD type V, myophosphorylase deficiency), and Tarui disease (GSD type VII, phosphofructokinase deficiency).
One form, von Gierke disease (GSD type Ia, glucose-6-phosphatase deficiency), causes clinically significant end-organ disease with significant morbidity.
The remaining GSDs are not benign but are less clinically significant; therefore, the physician should consider the aforementioned GSDs when initially entertaining the diagnosis of a GSD. Interestingly, GSD type 0, which is due to defective glycogen synthase, is also recognized.
These inherited enzyme defects usually present in childhood, although some, such as McArdle disease and Pompe disease, have separate adult-onset forms.
In general, GSDs are inherited as autosomal-recessive conditions. Several different mutations have been reported for each disorder.
Diagnosis depends on patient history and physical examination, muscle biopsy, electromyelography, ischemic forearm test, and creatine kinase level. Biochemical assay for enzyme activity is the method of definitive diagnosis.
Branching enzyme defect results in an abnormal glycogen structure that is unique to Andersen disease (GSD type IV). Clinically, hepatosplenomegaly, cirrhosis of the liver, and hepatic failure are major concerns.
|GSD0||MIM.240600||Glycogen synthase deficiency||-||Gene||MIM|
|GSD1a||MIM.232200||Glucose-6-phosphatase deficiency||von Gierke disease|
|GSD2||MIM.232300||Acid maltase deficiency||Pompe disease|
|GSD3||MIM.232400||Debranching enzyme deficiency||Forbes-Cori disease||AGL||MIM.610860|
|GSD4||MIM.232500||Transglucosidase deficiency||Andersen disease, amylopectinosis||GBE1||MIM.607839|
|GSD5||MIM.232600||Myophosphorylase deficiency||McArdle disease|
|GSD6||MIM.232700||Phosphorylase deficiency||Hers disease|
|GSD7||MIM.232800||Phosphofructokinase deficiency||Tarui disease|
Glycogen is a storage form of glucose. Glycogen synthesis begins with the conversion of glucose to glucose-6-phosphate by the action of a hexokinase (glucokinase). A phosphoglucomutase then transforms the glucose-6-phosphate to glucose-1-phosphate, which, in turn, is converted to uridine diphosphoglucose.
A highly branched, large polymer is then built up (molecular weight, up to 100 million), containing up to 10,000 glucose molecules linked together by α-1,4-glucoside bonds. The glycogen chain and branches continue to be elongated by the addition of glucose molecules mediated by glycogen synthetases.
During degradation, distinct phosphorylases in the liver and muscle split glucose-1-phosphate from the glycogen until about four glucose residues remain on each branch, leaving a branched oligosaccharide called limit dextrin. This can be further degraded only by the debranching enzyme. In addition to these major pathways, glycogen is also degraded in the lysosomes by acid maltase. If the lysosomes are deficient in this enzyme, the glycogen contained within them is not accessible to degradation by cytoplasmic enzymes such as phosphorylases.
On the basis of specific enzyme deficiencies and the resultant clinical pictures, glycogenoses have traditionally been divided into a dozen or so syndromes designated by roman numerals, and the list continues to grow. Rather than describing each syndrome, we offer a more manageable classification that is based on the pathophysiology of these disorders.34 According to this approach, glycogenoses can be divided into three major subgroups.
The liver is a key player in glycogen metabolism. It contains enzymes that synthesize glycogen for storage and ultimately break it down into free glucose, which is then released into the blood. An inherited deficiency of hepatic enzymes that are involved in glycogen metabolism therefore leads not only to the storage of glycogen in the liver, but also to a reduction in blood glucose level (hypoglycemia).
Deficiency of the enzyme glucose-6-phosphatase (von Gierke disease, or type I glycogenosis) is a prime example of the hepatic-hypoglycemic form of glycogen storage disease. Other examples include lack of liver phosphorylase and debranching enzyme, both involved in the breakdown of glycogen. In all of these cases, glycogen is stored in many organs, but the hepatic enlargement and hypoglycemia dominate the clinical picture.
In the striated muscles, as opposed to the liver, glycogen is used predominantly as a source of energy. This is derived by glycolysis, which leads ultimately to the formation of lactate.
If the enzymes that fuel the glycolytic pathway are deficient, glycogen storage occurs in the muscles and is associated with muscular weakness owing to impaired energy production.
Examples in this category include deficiencies of muscle phosphorylase (McArdle disease, or type V glycogenosis), muscle phosphofructokinase (type VII glycogen storage disease), and several others. Typically, patients with the myopathic forms present with muscle cramps after exercise and a failure of exercise-induced rise in blood lactate levels owing to a block in glycolysis.
Glycogen storage diseases associated with (1) deficiency of α-glucosidase (acid maltase) and (2) lack of branching enzyme do not fit into the hepatic or myopathic categories just described. They are associated with glycogen storage in many organs and death early in life.
Acid maltase is a lysosomal enzyme, and hence its deficiency leads to lysosomal storage of glycogen (type II glycogenosis, or Pompe disease) in all organs, but cardiomegaly is most prominent.
Brancher glycogenosis (type IV) is associated with widespread deposition of an abnormal form of glycogen with detrimental effects on the brain, heart, skeletal muscles, and liver.
muscular dystrophy by Washington Deceit (1)
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Glycogen storage disease by Washington Deceit
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McAdams AJ, Hug G, Bove KE. Glycogen storage disease, types I to X: criteria for morphologic diagnosis. Hum Pathol. 1974 Jul;5(4):463-87. PMID: 4525190