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Association for Glycogen Storage Disease. People with Glycogen Storage Disease Type Ib may also. Because the diet for Type I Glycogen Storage Disease is. Type 1 Glycogen Storage Disease;. How is type I glycogen storage disease. Start studying Glycogen Storage diseases. Learn vocabulary. Type IV glycogen storage disease;. GSD type 1a/ 1b. Home Glycogen Storage Disease ProgramNutrition Corner. Glycogen Storage Disease Type 0.
Glycogen storage disease type IGlycogen storage disease type I (GSD I) or von Gierke disease, is the most common of the glycogen storage diseases. This genetic disease results from deficiency of the enzymeglucose- 6- phosphatase, and has an incidence in the American population of approximately 1 in 5. Since these are the two principal metabolic mechanisms by which the liver supplies glucose to the rest of the body during periods of fasting, it causes severe hypoglycemia and results in increased glycogen storage in liver and kidneys. Both organs function normally in childhood, but are susceptible to a variety of problems in adult years. Other metabolic derangements include lactic acidosis and hyperlipidemia. Frequent or continuous feedings of cornstarch or other carbohydrates are the principal treatment. Other therapeutic measures may be needed for associated problems.
The disease was named after German doctor Edgar von Gierke. Maternal glucose transferred across the placenta prevents hypoglycemia in a fetus with GSD I, but the liver is enlarged with glycogen at birth.
The inability to generate and release glucose soon results in hypoglycemia, and occasionally in lactic acidosis fulminant enough to appear as a primary respiratory problem in the newborn period. Neurological manifestations are less severe than if the hypoglycemia were more acute. The brain's habituation to mild hypoglycemia is at least partly explained by use of alternative fuels, primarily lactate. More commonly, infants with GSD I tolerate without obvious symptoms a chronic, mild hypoglycemia, and compensated lactic acidosis between feedings.
GLYCOGEN STORAGE DISEASE TYPE 1. A new variant of glycogen storage disease type I probably due to. Bone mineralisation in type 1 glycogen storage disease.
Blood glucose levels are typically 2. M). These infants continue to need oral carbohydrates every few hours. Many never sleep through the night even in the second year of life.
They may be pale, clammy, and irritable a few hours after a meal. Developmental delay is not an intrinsic or inevitable effect of glucose- 6- phosphatase deficiency but is common if the diagnosis is not made in early infancy. Although mild hypoglycemia for much of the day may go unsuspected, the metabolic adaptations described above make severe hypoglycemic episodes, with unconsciousness or seizure, uncommon before treatment. Episodes which occur are likely to happen in the morning before breakfast. GSD I is therefore a potential cause of ketotic hypoglycemia in young children.
Once the diagnosis has been made, the principal goal of treatment is to maintain an adequate glucose level and prevent hypoglycemia. Hepatomegaly and liver problems. Glycogen also accumulates in kidneys and small intestine. Hepatomegaly, usually without splenomegaly, begins to develop in fetal life and is usually noticeable in the first few months of life. By the time the child is standing and walking, the hepatomegaly may be severe enough to cause the abdomen to protrude. The liver edge is often at or below the level of the umbilicus. Other liver functions are usually spared, and liver enzymes and bilirubin are usually normal.
Glucose- 6- phosphatase deficiency increases the risk of hepatic adenoma. There is some evidence that metabolic control of the disease is a factor. In an episode of metabolic decompensation, lactic acid levels abruptly rise and can exceed 1. M, producing severe metabolic acidosis. Uric acid, ketoacids, and free fatty acids further increase the anion gap. Manifestations of severe metabolic acidosis include vomiting and hyperpnea, which can exacerbate hypoglycemia by reducing oral intake. Repeated episodes of vomiting with hypoglycemia and dehydration may occur in infancy and childhood, precipitated by (or mimicking) infections such as gastroenteritis or pneumonia.
Growth failure. Triglycerides in the 4. Cholesterol is only mildly elevated. Immobilisation of fats results in an increase in Fatty Acids and ketone bodies. Hyperuricemia and joint problems.
Increased purine catabolism is an additional contributing factor. Uric acid levels of 6–1. GSD I. Allopurinol may be needed to prevent uric acid nephropathy and gout. Kidney effects. This does not usually cause clinical problems in childhood, with the occasional exception of a Fanconi syndrome with multiple derangements of renal tubular reabsorption, including proximal renal tubular acidosis with bicarbonate and phosphate wasting. However, prolonged hyperuricemia can cause uric acid nephropathy. In adults with GSD I, chronic glomerular damage similar to diabetic nephropathy may lead to renal failure.
Bowel effects. Granulocyte colony- stimulating factor (G- CSF, e. It may cause clinically significant bleeding, especially epistaxis. Neurodevelopmental effects. Normal neuronal and muscle cells do not express glucose- 6- phosphatase, so GSD I causes no other neuromuscular effects.
Genetics. Heterozygotecarriers are asymptomatic. As for other autosomal recessive diseases, the recurrence risk for each subsequent child of the same parents is 2. Prenatal diagnosis has been made by fetal liver biopsy at 1. Prenatal diagnosis is possible with fetal DNA obtained by chorionic villus sampling when a fetus is known to be at risk.
Glucose- 6- phosphatase is an enzyme located on the inner membrane of the endoplasmic reticulum. The catalytic unit is associated with a calcium binding protein, and three transport proteins (T1, T2, T3) that facilitate movement of glucose- 6- phosphate (G6. P), phosphate, and glucose (respectively) into and out of the enzyme. The most common forms of GSD I are designated GSD Ia and GSD Ib, the former accounting for over 8. A few rarer forms have been described. The metabolic characteristics of GSD Ia and Ib are quite similar, but Ib incurs a few additional problems (described below).
Metabolic pathophysiology. For about 3 hours after a carbohydrate- containing meal, high insulin levels direct liver cells to take glucose from the blood, to convert it to glucose- 6- phosphate (G6.
P) with the enzyme glucokinase, and to add the G6. P molecules to the ends of chains of glycogen (glycogen synthesis). Excess G6. P is also shunted into production of triglycerides and exported for storage in adipose tissue as fat. When 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 G6. P. This process is termed glycogenolysis. The G6. P remains within the liver cell unless the phosphate is cleaved by glucose- 6- phosphatase. This dephosphorylation reaction produces free glucose and free PO4anions.
The free glucose molecules can be transported out of the liver cells into the blood to maintain an adequate supply of glucose to the brain and other organs of the body. Glycogenolysis can supply the glucose needs of an adult body for 1. When fasting continues for more than a few hours, falling insulin levels permit catabolism of muscle protein and triglycerides from adipose tissue.
The products of these processes are amino acids (mainly alanine), free fatty acids, and lactic acid. Free fatty acids from triglycerides are converted to ketones, and to acetyl- Co. A. Amino acids and lactic acid are used to synthesize new G6. P in liver cells by the process of gluconeogenesis.
The last step of normal gluconeogenesis, like the last step of glycogenolysis, is the dephosphorylation of G6. P by glucose- 6- phosphatase to free glucose and PO4.
Thus glucose- 6- phosphatase mediates the final, key, step in both of the two main processes of glucose production during fasting. In fact the effect is amplified because the resulting high levels of glucose- 6- phosphate inhibit earlier key steps in both glycogenolysis and gluconeogenesis.
Pathophysiology. This inability to maintain adequate blood glucose levels during fasting results from the combined impairment of both glycogenolysis and gluconeogenesis. Fasting hypoglycemia is often the most significant problem in GSD I, and typically the problem that leads to the diagnosis. Chronic hypoglycemia produces secondary metabolic adaptations, including chronically low insulin levels and high levels of glucagon and cortisol. Lactic acidosis arises from impairment of gluconeogenesis.
Lactic acid is generated both in the liver and muscle and is oxidized by NAD+ to pyruvic acid and then converted via the gluconeogenic pathway to G6. P. Accumulation of G6. P inhibits conversion of lactate to pyruvate. The lactic acid level rises during fasting as glucose falls. In people with GSD I, it may not fall entirely to normal even when normal glucose levels are restored. Hypertriglyceridemia resulting from amplified triglyceride production is another indirect effect of impaired gluconeogenesis, amplified by chronically low insulin levels. During fasting, the normal conversion of triglycerides to free fatty acids, ketones, and ultimately acetyl- Co.
A is impaired. Triglyceride levels in GSD I can reach several times normal and serve as a clinical index of . It is also a byproduct of purine degradation. Uric acid competes with lactic acid and other organic acids for renal excretion in the urine. In GSD I increased availability of G6.
P for the pentose phosphate pathway, increased rates of catabolism, and diminished urinary excretion due to high levels of lactic acid all combine to produce uric acid levels several times normal. Although hyperuricemia is asymptomatic for years, kidney and joint damage gradually accrue. Diagnosis. If hepatomegaly, fasting hypoglycemia, and poor growth are accompanied by lactic acidosis, hyperuricemia, hypertriglyceridemia, and enlarged kidneys by ultrasound, gsd I is the most likely diagnosis.
The differential diagnosis list includes glycogenoses types III and VI, fructose 1,6- bisphosphatase deficiency, and a few other conditions (page 5), but none are likely to produce all of the features of GSD I. The next step is usually a carefully monitored fast. Hypoglycemia often occurs within six hours.
Glycogen Storage diseases Flashcards . Patients cannot make glycogen, so they have no glycogen stores. Fasting hypoglycemia occurs with ketosis and appears early in life (infancy to childhood). Often become hypoglycemic overnight- -can feed cornstarch before bed to keep blood glucose elevated. Morning lethargy that responds to feeding. Hyperglycemia after eating because glucose cannot be stored as glycogen; excess glucose gets pushed to lactate (lactic acidemia)Without treatment, patients do not grow well (short stature) and have osteopenia. Causes neurological damage.
Testing: serum glucose (hypoglycemic during fasting period), urine ketones, fasting serum lactate, liver enzymes (mild hepatocellular damage), amino acids (hypoalaninemia due to gluconeogenesis), x- ray (for signs of osteopenia), fasting glucagon challenge (normally see rise in glucose but response will be limited in these patients), postprandial glucose challenge (will see hyperglycemia, increased lactate and alanine), oral hexose load (increases blood lactate)Treatment: Avoid fasting. Children require frequent feedings with protein- rich meals. Avoid excessive carb intake. Uncooked cornstarch at night to avoid nighttime hypoglycemia. Branching enzyme defects: Type IV glycogen storage disease; Andersen disease.
Presents with abnormal glycogen structure, however glycogen can still form. The defective branching enzyme causes the glycogen structure to look like amylose; straight, unbranched chains.
Glycogen accumulates as fibrillar aggregates. Symptoms: Presents in infancy to early childhood; hypoglycemia and severe liver disease with hepatomegaly and failure to thrive. Liver failure and cirrhosis by age 5.
Symptoms due to complications of liver cirrhosis: portal hypertension, esophageal varices, encephalopathy, splenomegaly, ascites, reduced renal function. Rarely, associated with hepatocellular carcinoma. Liver failure/cirrhosis and hepatosplenomegaly cause death. Testing: Serum glucose (hypoglycemia in between meals due to reduced substrate for glycogen phosphorylase, no hyperglycemia after meals), liver enzymes AST/ALT (hepatocellular damage due to cirrhosis, AST> ALT), serum creatinine kinase (branching enzyme defect also effects muscle), enzyme analysis in fibroblasts, imaging (to look for hepatomegaly), liver biopsy (to see liver dysfunction), ischemic forearm test (low lactate production with exercise)Treatment: Liver transplant. Diet and other therapies are only partially successful at limiting hepatomegaly, hypoglycemia. Defects in glucose- 6- phosphatase or glucose- 6- phosphate transporter: GSD type I, Von Gierke disease.
Type A: defect in glucose- 6- phosphatase (can't remove phosphate from glucose- 6- P; can't mobilize glycogen to glucose for peripheral tissues)Type B: defect in G6. P transporter. Symptoms: Protruding abdomen due to hepatomegaly. Hepatic adenoma in teens (7. Pancreatitis. Nephrolithiasis. Hypoglycemia that can lead to seizures or coma Lactic acidosis —> hyperuricemia —> gouty arthritis (lactic acid and uric acid compete for same renal transport mechanism) Dyslipidemia: increased tryglycerides, LDL, cholesterol. Tests: glucose (fasting hypoglycemia), liver enzymes AST/ALT (hepatomegaly), plasma lactate (elevated, lactic acidosis), plasma bicarbonate (decreased due to acidosis), uric acid (increased due to acidosis), plasma lipids (increased cholesterol and triglycerides), anemia, serum alpha- fetoprotein (to look for HCC), hepatic US (to look for hepatomegaly, tumors), renal US (nephrolithiasis), CT/MRI (monitor adenomas), fasting glucagon challenge (lack of response)Treatment: Avoid fasting, use uncooked cornstarch to preventhypoglycemia, avoid saturated fats/cholesterol, nasogastric tubefeeding for young infants, avoid excessive carb intake, surgery to remove adenomas.
Defects in debranching/transferase enzymes Type III GSD, Cori or Farber disease. Debranching enzymes cut the last three glucose molecules from a branch; transferases move the glucose subunits to the end of a long . High protein diet (favors gluconeogenesis)Defects in glycogen phosphorylase (muscle specific)Type V GSD, Mc.
Ardle Disease. Can't remove glucose units from glycogen in the muscle tissue. Symptoms. Can't exercise for more than a few seconds- -once creatinekinase is depleted, can't mobilize glycogen stores. No hypoglycemia. Presents in teens, early twenties.
Tests: serum creatine kinase (elevated due to muscle damage), glucose (normal with fasting), urine myoglobin (elevated due torhabdomyolysis), ischemic forearm test (no increased lactate from muscle), muscle biopsy (diminished or no myophosphorylase)Treatment: Maybe high protein diet or creatin supplements. Avoid intense exercise. Exercise slowly, with low intensity, to reach second wind (increased glucose transporters allow muscles to obtain enough energy)Defects in glycogen phosphorylase (liver specific)Type VI GSD, Hers disease. Can't remove glucose units from glycogen in the liver to maintain blood glucose in the post- absorptive state.
Symptoms. Presents in early childhood. Milder GSD, Hepatomegaly, Growth retardation.
Hypoglycemia, hyperlipidemia, ketosis (all mild) Mild lactic acidemia; does not cause hyperuricemia. Tests: glucose (mild hypoglycemia in 3- 5 hour fast), ketones (mild elevation with fast), serum lipids (mild hyperlipidemia) Treatment: Dietary restrictions.