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Terms in this set (3)

Defects in glycogen synthase:

Causes type 0 glycogen storage disease

Serious form of disease. 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.


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 G6P transporter


Protruding abdomen due to hepatomegaly
Hepatic adenoma in teens (75%) with 10% becoming malignant Pancreatitis


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 prevent
hypoglycemia, avoid saturated fats/cholesterol, nasogastric tube
feeding 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 "main" chain; and glucosidase cuts the alpha-1,6 linkage
between the branch and the main stem.

Errors in any of the three prevent glycogen from being completely mobilized to glucose.

Occasionally ketoacidosis, growth retardation, hyperlipidemia Adult hypotonia and muscle wasting Polycystic ovaries

Tests: Glucose (fasting hypoglycemia), liver enzymes (AST/ALT), serum creatine kinase (muscle damage), hepatic US (liver size),
female felvic US (polycystic ovaries), abdominal CT (HCC), fasting
glucagon challenge (decreased response), ischemic forearm muscle test (decreased lactate output), EMG (myopathy)

Treatment: avoid fasting. High protein diet (favors gluconeogenesis)

Defects in glycogen phosphorylase (muscle specific)

Type V GSD, McArdle Disease
Can't remove glucose units from glycogen in the muscle tissue

Can't exercise for more than a few seconds--once creatine
kinase 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 to
rhabdomyolysis), 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


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
a. GSD type 0- glycogen synthase defect: Defect in glycogen synthase. Autosomal recessive. Patients present with fasting hypoglycemia and ketosis usually in early childhood. Following a meal, glycogen can not be stored leading to acute postprandial hyperglycemia and lactic academia. Clinical consequences include neurological damage, short stature and osteopenia. Skeletal muscle has a GYS1 isoform where the enzyme activity is normal as is the content of glycogen. Given that glucose cannot be stored, in times of energy need such as night, there will not be an abundance of glycogen in order to provide energy for growth. Growth hormone is released at night and depends on adequate blood glucose levels to function. Likewise, reduced blood glucose levels will also be associated with reduced IGF that mediates the effects of growth hormone on bone, cartilage and muscle cell proliferation. Given that glycogen stores will be low or non existent (at least in the liver-skeletal muscle should be ok), the body will rely on gluconeogenesis to provide glucose for key structures (brain and red blood cells). As such, the blood levels of alanine and lactate may be reduced since they are both two major gluconeogenic precursors.
i. Laboratory tests: Serum glucose (testing for hypoglycemia), serum electrolytes (testing for metabolic acidosis based on anion gap), urine ketones (testing for ketosis), fasting serum lactate, liver enzymes (AST/ALT levels)- mild hepatocellular damage may be evident, testing for hypoalanimemia.
ii. Treatment: Avoidance of fasting given that the patient will not have a built up storage of glycogen via glycogen synthase deficiency. However, avoiding excessive carbohydrate intake is important to limit the possibility of lactic academia. Cornstarch may be given to a patient to maintain blood glucose levels while they sleep since raw cornstarch is a complex glucose polymer that is acted on slowly by pancreatic amylase over a 6 hour period.

b. GSD type IV (branching enzyme defect): Also known as Andersen disease- affects glycogen synthesis. GSD-IV presents with abnormal glycogen structure and is not commonly linked to hypoglycemia early on in the disease. Autosomal recessive. Patients usually present early in life with hepatomegaly and failure to thrive. Liver disease can cause portal hypertension which leads to esophageal varices, encephalopathy, splenomegaly, ascites and/or diminished renal function. On biopsy, the liver reveals an accumulation of glycogen as fibrillar aggregates. Serious morbidity is linked to hepatic failure and hepatosplenomegaly. Biochemically, the structure of glycogen will lack branches and look more like amylose. The branched structures normally prevent hydration and excess water intake, however the absence of significant branches the hydroxyl groups of the glucose residues instead become hydrates leading to hepatomegaly (swollen liver). As opposed to glycogen synthase diseases, there will be some glycogen available during fasting so fasting hypoglycemia wont normally occur. The liver damage however caused by the swelling may lead to impaired metabolism which eventually may lead to hypoglycemia downstream.
i. Tests: Cultured fibroblasts from liver tissue can be tested for the level of branching enzyme activity for a definitive diagnosis (less branching= greater chance of type 4 diagnosis). Serum creatine kinase (testing for possible neuromuscular involvement), fasting hypoglycemia (indication of disease progression, should be negative acutely), liver enzymes (AST/ALT) to indentify hepatocellular damage, enzyme analysis in fibroblasts to measure branching, imaging for hepatosplenomegaly, liver biopsy, ischemic forearm tests (lack of lactate production during exercise)
ii. Treatment options: Liver transplant is the main option. Diet therapy may limit hepatomegaly, hypoglycemia and lessen symptoms but only with partial success.
c. GSD type 1a/ 1b (glucose 6 phosphatase/ G6P transporter defect): GSD type 1 is referred to as von gierks disease. Type 1 a (most common) involves a lack or reduced activity of glucose 6 phosphotase located in the ER. Glucose 6 phosphatase is important for the conversion of glycogen to glucose since glucose 6 phophotase will convert glucose 6 phoshate back into glucose into the blood stream. The "b" form of the condition is not a defect in glucose 6 phosphotase but rather the transporter that brings the glucose 6-phosphate into the ER for phosphate removal. Autosomal recessive. R83C mutation found in white people, Hispanics, and Ashkenazi jews. Major symptoms include hepatomegaly, protruding abdomen seen in infants. Hepatomegaly may lead to pancreatitis which may cause abdominal pain. The kidney had glucose 6 phosphotase as well so glucose 6 phosphate will accumulate in that organ as well. Patients often times have elevated uric acid levels leading to gouty arthritis. Type 1a patients commonly have elevated serum triglyceride levels with moderately increased VLDL, LDL and cholesterol (xanthomas on physical examination). Anemia is found in 80% of patients, type 1b patients may have neutropenia and neutrophil abnormalities. GI infections, abscesses and IBD are common in type 1b but less so in type 1a. Growth failure, heiht being in the 5th-10th percentile. Potential muscle hypotonia, delayed psychomotor development and recurrent infections. Hormonal imbalances lead to bone disorders. May lead to delayed onset of puberty and subsequent development. Renal uric acid kidney stones also common. The abundance of glucose 6 phosphate will drive glycolysis forward up to a point. There will be a threshold reached where glucose 6 phosphate glycolysis breakdown will no longer be pushed forward and the abundance of glucose 6 phosphate will inhibit the activation of glycogenolysis that is activated by glucagon following food deprivation.
i. Laboratory tests: Serum AST/ ALT levels (mild elevation due to hepatomegaly), Hb (anemia associated with chronic disease of the liver), plasma glucose (fasting hypoglycemia, used to assess therapeutic sufficiency), plasma lactate (elevated), plasma bicarbonate (lowered due to metabolic acidosis), uric acid (elevated due to acidosis), plasma lipids (elevated cholesterol and triglycerides), serum alpha fetoprotein (marker for hepatocellular carcinoma in patients with hepatic adenoma). Hepatic ultrasonography (monitor size of the liver as well as the appearance of adenomas), renal ultrasonography (determination of nephrolithiasis), CT/ MRI (more costly tests to monitor adenomas). Also, a fasting glucose test may be performed. Normally, glucose levels will rise but because glycogen can not adequately be converted into glucose, blood glucose levels will not rise.
ii. Treatment: It's important to maintain blood glucose levels. Nasogastric feeding tubes are required. Diet must be monitored with a goal of maintaining an appropriate balance between blood glucose and liver glycogen stores. Excessive carbohydrate levels should also be avoided and because hyperlipidemia can occur, high intake of saturated fats and cholesterol should be avoided. Hepatic adenoma formation may require surgical removal.

d. GSD type 3: debrancher enzyme defect. Also known as Cori disease or Forbes disease. A lack of reduced activity of the debranching enzyme of glycogen that leaves glycogen with short branches of 2-4 glucose residues. Most patients have type 3a that affects both liver and muscle. Type 3b affects liver only. Type 3c is linked to a defect of the glucosidase activity and type 3d is linked to a defect of the transferase activity. Autosomal recessive disease. Frequency high in inuits and Sephardic jews from north Africa. Hepatomegaly and hypoglycemia are characteristic for this disease. Ketoacidosis is also common. Minimal hyperlipidemia as well as growth retardation may occur but not as much as GSD1. GSD3 is linked to muscle involvement which separates it from GSD 1. GSD 3a may also present with cardiomyopathy. Female adult patients may exhibit polycystic ovaries. The short branches present are opent to hydration (leading to hepatomegaly) but also may interfere with glycogen phosphorylase action. Hypoglycemia is less severe given that the glycogen molecule is partially degraded. The presence of ketoacidosis, hyperlipidemia and growth retardation are less characteristic. Excessive storage of glycogen in muscle causes damage to the tissue leading to leakage of creating kinase into the circulation.
i. Laboratory tests
1. Blood glucose (significant fasting hypoglycemia)
2. Liver tests (transaminases, prothrombin)
3. Blood ketones, lactate and uric acid (helps with differential diagnosis)
4. Serum CK (elevated due to muscle damage in type 3a only)
5. Fibroblast debrancher activity
ii. Imaging studies
1. Abdominal ultrasound (elevated size of liver)
2. Female pelvic ultrasound (detection of polycystic ovaries)
3. Abdominal CT of cirrhotic patients (needed for detection of hepatocellular carcinoma)

iii. Other tests:
1. Electromyography: shows myopathy changes
2. Ischemic forearm muscle test (abnormally low lactate output)
3. Glucagon fasting test (normal blood glucose increase at 2 h but no effect after 6-8 h)
iv. Treatment: avoid episodes of hypoglycemia. A high protein diet is useful because gluconeogenesis is still functional. Amino acids will elevate the levels of GIP which will enhance conversion of dietary amino acids to glucose