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.
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 ?-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.
Hepatic forms
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.
Myopathic forms
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 ?-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.