DISEASES FOR EXCESS OF CARBOHYDRATES.
Genetics and molecular biology Glycogen storage disease type I has an autosomal recessive pattern of inheritance. GSD Ia is inherited as an autosomal recessive disease. Heterozygote carriers (parents) are asymptomatic. As for other autosomal recessive diseases the recurrence ris! for each subse"uent child of the same parents is #$%. &renatal diagnosis has been made by fetal liver biopsy at '()## *ee!s of gestation but no fetal treatment has been proposed. &renatal diagnosis is possible *ith fetal D+A obtained by chorionic villus sampling *hen a fetus is !no*n to be at ris!. Glucose,-,phosphatase is an enzyme located on the inner membrane of the endoplasmic reticulum. .he catalytic unit is associated *ith a calcium binding protein and three transport proteins (.' .# ./) that facilitate movement of glucose,-,phosphate (G-&) phosphate and glucose (respectively) into and out of the enzyme. .he most common forms of GSD I are designated GSD Ia and GSD Ib the former accounting for over (0% of diagnosed cases and the latter for less than #0%. A fe* rarer forms have been described. GSD Ia results from mutations of G6PC the gene for glucose,-,phosphatase.1$2 G6PC is located on chromosome '3"#'.1-2 GSD Ib results from mutations of the gene for S45/3A6 or 7G-&.'7 the G-& transporter.[6] [7] GSD Ic results from mutations of S45'3A/ or S45/3A6.1(2 .he metabolic characteristics of GSD Ia and Ib are "uite similar but Ib incurs a fe* additional problems (described belo*). 8etabolic pathophysiology1edit2 Normal carbohydrate balance and maintenance of blood glucose levels[edit] Glycogen in liver and (to a lesser degree) !idneys serves as a form of stored rapidly accessible glucose so that the blood glucose level can be maintained bet*een meals. 9or about / hours after a carbohydrate,containing meal high insulin levels direct liver cells to ta!e glucose from the blood to convert it to glucose,-,phosphate (G-&) and to add the G-& molecules to the ends of chains of glycogen (glycogen synthesis). :;cess G-& is also shunted into production of triglycerides and e;ported for storage in adipose tissue as fat.
<hen digestion of a meal is complete insulin levels fall and enzyme systems in the liver cells begin to remove glucose molecules from strands of glycogen in the form of G-&. .his process is termedglycogenolysis. .he G-& remains *ithin the liver cell unless the phosphate is cleaved by glucose,-,phosphatase. .his dephosphorylation reaction produces free glucose and free &= 6 anions. .he free glucose molecules can be transported out of the liver cells into the blood to maintain an ade"uate supply of glucose to the brain and other organs of the body. Glycogenolysis can supply the glucose needs of an adult body for '#)'( hours. <hen fasting continues for more than a fe* hours falling insulin levels permit catabolism of muscle protein and triglycerides from adipose tissue. .he products of these processes are amino acids (mainlyalanine) free fatty acids and lactic acid. 9ree fatty acids from triglycerides are converted to !etones and to acetyl,5oA. Amino acids and lactic acid are used to synthesize ne* G-& in liver cells by the process of gluconeogenesis. .he last step of normal gluconeogenesis li!e the last step of glycogenolysis is the dephosphorylation of G-& by glucose,-,phosphatase to free glucose and &= 6. .hus glucose,-,phosphatase mediates the final !ey step in both of the t*o main processes of glucose production during fasting. In fact the effect is amplified because the resulting high levels of glucose,-,phosphate inhibit earlier !ey steps in both glycogenolysis and gluconeogenesis. Pathophysiology[edit] .he principal metabolic effects of deficiency of glucose,-,phosphatase are> hypoglycemia lactic acidosis hypertriglyceridemia hyperuricemia .he hypoglycemia of GSD I is termed 7fasting7 or 7post,absorptive7 meaning that it occurs after completion of digestion of a meal?usually about 6 hours later. .his inability to maintain ade"uate blood glucose levels during fasting results from the combined impairment of both glycogenolysis and gluconeogenesis. 9asting hypoglycemia is often the most significant problem in GSD I and typically the problem that leads to the diagnosis. 5hronic hypoglycemia produces secondary metabolic adaptations including chronically lo* insulin levels and high levels of glucagon and cortisol. Lactic acidosis arises from impairment of gluconeogenesis. 4actic acid is generated both in the liver and muscle and is o;idized by +AD@ to pyruvic acid and then converted via the gluconeogenenic path*ay to G-&. Accumulation of G-& inhibits conversion of lactate to pyruvate. .he lactic acid level rises during fasting as glucose falls. In people *ith GSD I it may not fall entirely to normal even *hen normal glucose levels are restored. Hypertriglyceridemia resulting from amplified triglyceride production is another indirect effect of impaired gluconeogenesis amplified by chronically lo* insulin levels. During fasting the normal conversion of triglycerides to free fatty acids !etones and ultimately glucose is impaired. .riglyceride levels in GSD I can reach several times normal and serve as a clinical inde; of 7metabolic control7. Hyperuricemia results from a combination of increased generation and decreased e;cretion
