Inheritable Gierke's Disease - Essay Example

Von Gierke’s Disease s Introduction Named after the person who first described the disease, Von-Gierkes’s disease is a type I glycogen storage disease. It is an inheritable disease in which the body fails to breakdown the stored glycogen in the body. Under normal conditions excess glucose is stored in the form of glycogen in the liver. When the body is under stress and needs extra energy, the stored liver glycogen is converted to glucose which is used as the energy resource. However in patients suffering from the disease, expression of the enzyme responsible for the breaking up of liver glycogen is absent thereby the glycogen accumulates in the liver leading to abnormal conditions. Symptoms A number of symptoms may be seen in a patients suffering from the disorder. Common symptoms include constant hunger pangs, fatigue, irritation, nose bleeds etc. untreated children show several symptoms of hyperlipidemia, hyperurecimia, hepatomegaly and metabolic acidosis. Such children develop fat cheeks and short stature with protruding abdomen (Bali et al,2014). Frequent bleeding could be seen owing to loss of platelet functioning. Long term complications includes retarded brain functioning, osteoporosis, delay in puberty etc (Bali et al,2014) Diagnosis The most important diagnostic approach is to assess the enzyme. However further research have provided with more alternatives to enzyme assay approach. Several research studies have been conducted to understand definitive diagnosis.100% mutation in G6P had been seen among patients with Von Gierkes’s diseases. Seydewitz & Matern (2000) identified 5 different mutations in the gene and they concluded that molecular and genetic analysis was more reliable and accurate method than simple enzyme assays. Marcolongo et al (1998) studied the transport system of enzymes in patients with the disorder and found that more than one gene was responsible for the disorder. Through the studies Marcolongo et al suggested that the kinetic analysis of the G6P system could also be used as a diagnostic approach. Diagnosis at birth or even pre-natal diagnosis can be done for better results. Molecular analysis of the fetus can used to detect the present of genetic mutations and predicting occurrence of the diseases. Biochemistry Excess glucose in the body which remains unused is stored in form of glycogen. The degradation of glycogen is a biochemical process which involves several stages and is induced by a number of enzymes. The breaking down of glycogen in the liver is termed as glycogenolysis. The glycogen is first converted into glucose 1-phosphate by glycogen phosphorylase. The product, glucose 1 –phosphate is then converted to glucose-6-phosphate by phosphoglucomutase. The glucose-6-phosphate thus formed has several fates out of which one is being converted to glucose before release into the blood. This conversion is done by an important enzyme called glucose-6-phosphatase. However this process does not take place in a patient suffering from Von Gierkes’s disease. The degradation of glycogen is regulated by several enzymes but the most important one is glucose-6-phosphatase (G6P-ase) and mutations in this enzymes leads to onset of fatal Von Gierkes’s disease. Primarily this glycogen storage disease is an autosomal disorder .Lei et al (1995) studied the mutations in the enzyme and proposed two different models of G6P-ase catalysis model. The first model is the translocase-catalytic model according to which the disease is caused due to defect in the enzyme’s catalytic unit (stabilizing protein, glucose-6-phosphate, pyrophosphate and translocase). The second model is the conformation-substrate-transport model according to which “G6Pase is a single multifunctional membrane channel protein possessing both catalytic and substrate (or product) transport activities.” Calderbank et al (1959) conducted a study on fatal cases of Von Gierkes’s disease where they examined the liver and kidney tissues and the enzymatic activity. The results revealed that in patients with the disorder the isolated liver glycogen has a normal structure but the G6P-ase present in the liver of affected patients was present in much lesser quantities than the normal level. Pathophysiology Owing to mutations in the enzyme glucose-6-phosphotase, glycogen is not readily converted to glucose and hence glycogen accumulates in the hepatocytes of the liver. Abnormal accumulation of glycogen without timely depletion brings in several biochemical alterations in the human body. The most important alteration is hypoglycemia. Patients with insufficient G6P-ase enzyme fail to complete glycogenolysis and initiate gluconeogenesis hence there is a dearth of free glucose in the blood stream of the patient. This leads to inhibitions of secretion of insulin the body which automatically initiates glucagon release. Apart from hypoglycemia other abnormalities also occur. Hyperlactatemia is caused due to incomplete degradation of glucose-6-phosphate. This non-degraded G6P in the absence of enzymes is converted to lactate instead of glucose. This increases the lactate levels in the bloodstream. Metabolic acidosis is also caused due to accumulation of lactate. The increased accumulation of lactate in the blood also interferes with the excretory system of the body. Owing to the increased levels of lactate, the body adapts itself by eliminating lactate in the urine and reducing elimination of uric acid thereby increasing blood uric levels leading to an abnormal condition known as hyperuricemia. Another condition known as hyperlipidemia is also seen in patients with the metabolic disorder. It is caused due to increase in the production of triglycerides in the body and reduction in degradation of lipids in the body. Accumulation of triglycerides in the liver contributes towards the fatty liver abnormality which is already present in such patients. Uncommon Mutations The disease is inherited in an autosomal recessive pattern where there was 25% of being unaffected and effected and 50% of being a carrier. Genetic analyses have shown that mutations in the G6P gene which is located in the chromosome 17q21 resulted in causing the glycogen storage diseases. The common mutations that have been studied so far includes 54 missense, 17 insertion/deletions and 3 splicing mutations which have an effect on the enzymatic activity (Chou & Mansfield,2008). According to another study conducted by Chopra et al (2008) identified SRC-2 as an important regulator of glucose. It has been seen that SRC-2 acts as a coactivator and modulates G6Pase expression in the cells. Prevalence of the Disease 1 in 100,000 people suffer from the disease. Among Ashkanazi Jewish population the prevalence of the diseases is about 1 in 20,000 which is 5 times higher than the average rate (Ekstein et al,2004). Von Gierkes’s is the most common form of Glycogen storage diseases especially among the European population. Conclusion Von Gierkes’s is a potentially fatal genetic disorder. Several researches have successfully established the mutations responsible for the problem. The future research should be oriented towards understanding the molecular and biochemical processes and alterations associated with the diseases and designing proper diagnostic and management strategies. REFERENCES Bali et al.Genereviews.University of Washington:Seattle.print Calderbank et al. Biochemical investigation of a case of glycogen-storage disease (von Gierkes disease.Biochemistry Journal,1960,72,223-230. Chopra et al. Absence of the SRC-2 coactivator results in a glycogenopathy resembling Von Gierkes disease.Science,2008,322,1395-1399. Chou,J.Y. & Mansfield,B. Mutations in the Glucose-6-Phosphatase-α (G6PC) Gene that Cause Type Ia Glycogen Storage Disease. Human Mutation,2008,29,921-930. Ekstein, J.et al. Mutation frequencies for glycogen storage disease Ia in the Ashkenazi Jewish population. Am. J. Med. Genet,2004 129A,162-164. Lei et al. Mutations in the glucose-6-phosphatase gene are associated with glycogen storage disease types 1a and 1aSP but not 1b and 1c. J Clin Invest,1995,95,234-240. Marcolongo, P.et al. Liver microsomal transport of glucose-6-phosphate, glucose, and phosphate in type 1 glycogen storage diseases. J. Clin. Endocr. Metab.1998, 83, 224-229, Seydewitz, H. H., Matern, D. Molecular genetic analysis of 40 patients with glycogen storage disease type Ia: 100% mutation detection rate and 5 novel mutations.Human Mutation,2000, 15,115-116. Read More