Unformatted text preview: Glycogen Storage Disease(s) Glycogen Storage Disease(s) Points of discussion Basic biochemistry of glucose and glycogen metabolism. Definition and pathophysiology of GSD. Incidence & inheritance. Classification and clinical types. Hepatic glycogenoses. Muscle glycogenoses. Basic biochemistry Glucose is the principle substrate of energy metabolism in humans. The ultimate fate of glucose depends on body needs ; thus glucose may be: Oxidized to give energy or Stored as glycogen (muscles, liver) or Converted to triglycerides, amino acids and proteins. Cont. Cont.
Glycogen is a glucose polymer joined in straight chains by alpha 1,4 linkages and branched at intervals of 4 to 6 residues by alpha 1,6 linkages. It forms a tree like molecule and can have a molecular weight of many millions. Glycogen is the storage form of glucose and is found in abundance in the liver, muscles and kidneys. Glycogen polymer Biochemical terms * Glycolysis: The oxidation of glucose to pyruvate with generation of ATP for energy ( 2 moles of ATP per glucose molecule). Takes place in the cytoplasm of the cell. May also occur in the absence of O2, in which case pyruvate is converted to lactate. Cont. Cont.
Glycogenesis: The conversion of excess glucose to glycogen for storage. Begins with the phosphorylation of glucose to glucose6phosphate, which is then isomerized to glucose1phosphate and added to a glycogen primer, uridine diphosphoglucose (UDPG). * Catalyzed by glycogen synthetase, which exists in 2 forms; an active (D or dependent) form and an inactive (L or independent) form. Cont. Cont.
* Glycogenolysis: The degradation of glycogen to glucose. A phosphorylase enzyme splits the alpha 1,4 linkage releasing glucose1phosphate, a debranching enzyme then splits the alpha 1,6 linkage. The phosphorylase enzyme has two forms; an inactive form (phosphorylase b) and an active form (phosphorylase a). Conversion to the active form is catalyzed by phosphorylase b kinase. Cont. Cont.
The glucose1phosphate can then be isomerized to glucose6phosphate and either enter glycolysis or be hydrolysed to free glucose. The latter step is catalyzed by a glucose6 phosphatase enzyme and facilitated by a translocase that transports glucose6phosphate across the microsomal membrane. Glycogenolysis Regulation of glycogen metabolism Regulation of glycogen metabolism
Cyclic AMP activates a cAMPdependent protein kinase which in turn activates both phosphorylase b kinase ( to promote glycogenolysis) and glycogen synthetase kinase (to promote glycogenesis) thus keeping a state of balance in glycogen turnover. Adrenaline and glucagon activate glycogenolysis and inhibit glycogenesis, while insulin does the opposite. Definition of GSD and their pathophysiology A group of inherited disorders caused by a defect in glycogen metabolism characterized by impaired conversion of glycogen to free glucose resulting in the accumulation of normal and abnormal glycogen in tissues. Disruption of glycogen metabolism also affects other biochemical pathways as the body seeks alternative fuel sources. Accumulation of abnormal metabolic byproducts can damage other organs. Cont. Cont.
The system for glycogen metabolism relies on a complex system of enzymes. These enzymes are responsible for creating glycogen from glucose, transporting the glycogen to and from storage areas within cells, and extracting glucose from the glycogen as needed. Both creating and tearing down the glycogen macromolecule are multistep processes requiring a different enzyme at each step. If one of these enzymes is defective and fails to complete its step, the process halts. Incidence and mode of inheritance Incidence and mode of inheritance
The overall frequency of all forms of GSD is approximately one in 20,00025,000 live births. The most common forms of GSD are Types I, II, III, V and IX, which may account for more than 90% of all cases. The most common form is Type Ia, or Von Gierke disease, which occurs in one out of every 100,000 births. Other forms are so rare that reliable statistics are not available. Cont. Cont.
All GSD are inherited as an autosomal recessive trait except two; phosphoglycerate kinase deficiency (a muscle glycogenoses) and one form of phosphorylase kinase deficiency ( a hepatic glycogenoses), both of which are Xlinked diseases. Most are childhood disorders, only few (like type V, McArdle disease) are adult disorders. Classification and clinical types Classification and clinical types
Historically, GSD were categorized numerically in the order in which the enzymatic defects were identified ( type I, II, III etc.) and named after the person who discovered each type (Von Gierke, Pompe, Cori etc.). Clinically, GSD are classified according to the main organ involved and two main categories are born; GSD involving principally the liver (hepatic glycogenoses) and those principally involving the muscles (muscle glycogenoses). Almost 20 diseases are described. Hepatic glycogenosis Principally involve the liver. Four common clinical findings: 1) Hepatomegaly, which may be massive. 2) Recurrent hypoglycemia. 3) Growth retardation and delayed puberty. 4) Abnormal blood results involving any of the following: cholesterol, triglycerides, uric acid, aminotransferases, blood lactate or neutrophils. Cont. Cont.
Other findings are disease specific. Development of cirrhosis is rare, except in type IV (Andersen disease) in which development of cirrhosis, liver cell failure and death is before the fifth year of life in many cases, and in some cases with type IIIa (Cori disease). Von Gierke disease (Type Ia GSD)
Caused by glucose6phosphatase deficiency in liver, kidneys and small intestine. Children often have dolllike faces with fat cheeks, relatively thin extremities, short stature and a protuberant abdomen. The kidneys are enlarged, but the heart and spleen are of normal size. There is a prolonged bleeding time as a result of defective platelets aggregation/adhesion. Cont. Cont.
Virtually all females have polycystic ovaries, as an ultrasound finding, but without clinical features of acne or hirsutism. Long term complications (2nd and 3rd decade of life) include hyperuricemia and gout, dyslipidemia, atherosclerosis, osteopenia and bone fractures, hepatic adenomas, which can turn malignant and renal impairement and proteinuria, which might progress to renal failure requiring dialysis or transplantation. Diagnosis of hepatic glycogenoses Diagnosis of hepatic glycogenoses
1) Glucagon challenge (historical): Intramuscular administration of glucagon results in poor blood glucose level elevation, and elevates levels of lactate. 2) Liver biopsy: The biopsy sample istested for its glycogen content (which is increased) and assayed for enzyme activity and presence (which is defective or absent). Cont. Cont.
Liver histology reveals ,in addition, steatosis typically with absence of fibrosis. 3) DNA based gene mutation analysis: The genes for many enzymes , which their defects or deficiencies are responsible for GSD have been encoded and mutations have been identified. Molecular technologies have provided a noninvasive way of diagnosis, and prenatal diagnosis is being developed as well. Treatment of hepatic glycogenoses Treatment of hepatic glycogenoses
Some types are relatively easy to control through symptom management and dietary therapy. In more severe cases, receiving an organ transplant (e.g. liver) is the only option. In the most severe cases, there are no available treatments and the victim dies within the first few years of life. Cont. Cont.
The key to managing hepatic glycogenoses is to maintain normal levels of blood glucose through a combination of: 1) Nocturnal high carbohydrate enteral feeding , through a nasogastric tube if necessary, (usually for infants and children). 2) Frequent highcarbohydrate meals during the day. 3) Regular oral doses of uncooked cornstarch (slow release form of glucose) every 4 6 hours at a dose of 2g/kg. Cont. Cont.
Fructose and galactose can not be converted to glucose so their dietary intake should be restricted. Dietary supplement of vitamins and calcium may be required. Symptomatic treatment of dyslipidemias, gout and other metabolic abnormalities. Muscle glycogenoses Principally involve the muscles (skeletal and/or cardiac). Two groups: 1) Muscleenergy impairment: Exercise intolerance and muscle cramps. Rhabdomyolysis and myoglubinuria on strenuous exercise. Evidence of hemolysis and hemolytic anemia in some cases. Cont. Cont.
2) Progressive skeletal myopathy and/or cardiomyopathy: Skeletal muscle weakness and atrophy. Cardiomyopathy with cardiac enlargement and heart failure. * Both groups show elevated CK levels at rest with further rise after exercise. Exercise also elevates levels of blood ammonia, inosine, hypoxanthine and uric acid. Diagnosis 1) Lack of an increase in blood lactate and exaggerated blood ammonia elevations after an ischemic exercise test are indicative of muscle glycogenoses and suggest a defect in the conversion of glycogen or glucose to lactate. 2) Muscle biopsy with enzymatic assay of responsible enzymes. 3) DNA based gene mutation analysis. Treatment of muscle glycogenoses Treatment of muscle glycogenoses
Definitive therapy is not currently available Avoidance of strenuous exercise can prevent major episodes of rhabdomyolysis. High protein diet. Creatine supplements have improved muscle function in some patients. Clinical trials of enzyme replacement therapy have begun. Preliminary data have shown improvement in some patients. Gene therapy is still experimental in these cases. Prenatal diagnosis of GSD Through chorionic villi sampling and amniocentesis the disorder can be detected prior to birth. Some types of GSD can be detected even before conception occurs, if both parents are tested for the presence of the defective gene. Before undergoing such testing, the prospective parents should meet with a genetic counselor and other professionals in order to make an informed decision. Screening for GSD Just like all other genetically inherited disorders, relatives of the victim must be screened for the presence of the abnormal gene so that early recognition and early intervention, if necessary can be implicated. ...
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