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Glycogen Storage Disorders

Terms in this set (43)

Glucose-6-Phosphatase Deficiency
Type 1/Von Gierkes disease
Accounts for 25% of GSD cases
Has two subtypes, 1a and 1b
Type 1a
Due to deficiency of the glucose-6-phosphatase enzyme in liver, kidney and other organs of the body.
Type 1b
Caused by a deficiency in glucose-6-phosphate translocase (G6PT), G-6-Pase's transporter enzyme
Neutrophils are affected, causing higher susceptibility to bacterial/viral infections
Can also develop chronic pancreatitis, chronic inflammatory bowel disease, and Crohn's disease.
Hepatomegaly
Swelling of the liver
Glucose-6-Phosphatase Deficiency Symptoms
Hypoglycemia a few hours after eating
Chronic hunger, fatigue, and irritability
Hepatomegaly and kidney enlargement
Build up of metabolic byproducts in blood
Proteinuria
Possibly hepatic adenomas around puberty
Possible kidney disease
If untreated it can lead to delayed growth/development, high blood pressure and abnormal metabolite levels
Hepatic adenomas
Benign tumors in the liver
In rare instances these can develop into liver cancer
Develops around puberty in Glucose-6-Phosphate Deficiency sometimes
AMD (Acid Maltase Deficiency)
aka Pompe Disease, Type 2
Autosomal recessive genetic disease
Caused by a lack of function of the enzyme acid alpha-1,4-glucosidase
Also belongs to a group of metabolic diseases called lysosomal storage disorders (LSDs)
Glycogen that enters the lysosomes is not broken down, but builds up and disrupts the normal functions of the lysosome. The lysosomes grow larger over time and eventually breakdown, disrupting function of the cell and organs they make up
Categorized into infantile or late onset
Lysosomes
Found in variable amounts in varied sizes in the cell
Keep cells working well by collecting anything that there is too much of in the cells. The substances they collect are then recycled into smaller parts and released into the cell again to be reused or disposed out of the cell.
Infantile-onset Acid Maltase Deficiency
Signs usually begin at age 4-8 months old with weakness and floppiness, are unable to hold up their heads and can't do other motor tasks common for their age, such as rolling over
Muscles of limbs look normal but are weak
Breathing muscles are weak
Cardiomyopathy
Heart progressively fails in its blood pumping function.
Without treatment, they usually die within 12 months
Late-onset Acid Maltase Deficiency
Signs usually occur after the age of one or two
Muscles slowly become weaker, esp large muscles of the legs, trunk and later the arms. Due to muscle weakness, walking/climbing stairs becomes difficult.
An early finding is difficulty with nighttime breathing and over time breathing becomes more difficult
Respiratory failure is the most common cause of death
Cardiomyopathy
Heart muscle thickening
Enzyme replacement therapy (ERT)
A synthetic (recombinant, genetically-engineered) form of acid alpha glucosidase.
Given to patients as an IV infusion (an injection given over time directly into a vein)
Glycogen Debrancher Deficiency Disease
aka Cori Disease, Forbes Disease, Limit Dextrinosis
Improper processing causes glycogen to be stored in tissues of the body but this abnormal glycogen isn't soluble and causes damage to tissues where it collects
Also causes hypoglycemia (low blood sugar) because glucose sugar can't be released
Two subtypes - a and b
Glycogen debranching enzyme (GDE)
Along with another enzyme, phosphorylase, helps break down the branches of glycogen to release free glucose. Deficiency of this results in glycogen with short outer chains in liver, muscle, and heart tissues.
Type 3a
Have GDE deficiency in liver and muscle (including sometimes the heart muscle)
Causes muscle weakness which can cause loss of mobility in a person's 50s and 60s
Type 3b
Have GDE deficiency only in the liver
Found in less than 15% of cases
Type 3 GSD symptoms
Infancy and childhood show small stature, large liver, distended abdomen, hypotonia and hypoglycemia.
Some liver symptoms (enlarged liver) often improve with age and may disappear after puberty.
In some patients liver cirrhosis can occur due to accumulation of abnormal glycogen.
Hypotonia
Poor muscle tone
Glycogen Brancher Deficiency
aka Andersen Disease, Amylopectinosis, Adult Polyglucosan Body Disease (APBD), Type 4
Glycogen that does accumulate has very long outer branches. This structural abnormality is thought to trigger the body's immune system, causing the body to attack the glycogen and the tissues in which it is stored.
Death typically occurs by five years of age.
Muscle Phosphorylase Deficiency
aka McArdle Disease, Myophosphorylase Deficiency, Type 5
Glucose can not be released from the glycogen stored in skeletal muscles to create energy which is the main source of energy for anaerobic activity. The body struggles to find other sources of energy to complete exercise. Muscle is broken down to create energy
Muscle Phosphorylase Deficiency symptoms
Muscle pain, muscle cramping, muscle fatigue, and muscle tenderness
Rhabdomyolysis and the release of the red protein myoglobin, which can accumulate in the kidney
Myoglobinuria may develop, as evidenced by dark-red or red-brown urine
Serum creatine kinase levels will be greatly elevated.
Can cause myopathies later in life
Rhabdomyolysis
Breakdown of muscle
Liver Phosphorylase Deficiency
aka Hers Disease, Type 6
The most frequent first symptoms include an enlarged liver and hypoglycemia. Children have growth retardation
Similar to, but more mild than G-6-Pase deficiency
Elevated ketone concentrations in the blood and urine after a period of fasting
Liver Phosphorylase Deficiency treatment
Cornstarch and a high protein diet is recommended in an effort to achieve normal labs and normal growth, improving growth velocity and bone density in this condition, and reducing the frequency of hypoglycemia and ketosis.
Muscle Phosphofructokinase Deficiency
aka Tarui Disease type 7
Effective glycogen breakdown (glycolysis) during muscle stress cannot be accomplished
More severe than phosphorylase defciency
Myoglobinuria
Dark-red or red-brown urine caused by the release of the red protein myoglobin upon protein breakdown.
Muscle Phosphofructokinase Deficiency Symptoms
Early onset of fatigue and muscle pain with exercise.
Body breaks down muscle when trying to attain energy, causing muscle pain, cramping, fatigue, muscle tenderness.
Release of myoglobin may lead to myoglobinuria
May also display a hemolytic anemia
Phosphorylase Kinase Deficiency (PHK)
aka Type 9
either autosomal recessive or X-linked recessive disease
Glycogen builds up in the tissues of the body because it cannot be completely metabolized
Some glucose is created in the early steps of glycogen breakdown, but not enough for normal function
Phosphorylase Kinase Deficiency (PHK) symptoms
Hypoglycemia that can lead to seizures, more likely to occur after fasting
Glycogen accumulation in various tissues/organs like liver, muscle and blood, but rarely in the heart
Liver irritation, enlarged liver, growth retardation, mild delay in motor development, and elevated blood lipids are common
Usually improves with age, children reach full growth
Phosphorylase Kinase
There are multiple genes that provide the instructions to make the four pieces/subunits (i.e. alpha, beta, gamma, and delta) that make up this enzyme.
Activates glycogen phosphorylase through covalent modulation by adding phosphate group
Phosphorylase Kinase Deficiency (PHK) X-linked
Makes up 75% of cases
Mainly affects boys
Genetic changes affect the alpha-subunit of PHK genes (PHKA1 and PHKA2)
Main organs affected are blood cells, muscle and liver. Hepatomegaly (large liver)
Growth retardation
Mild to moderately elevated cholesterol and fat in blood and liver enzymes.
Phosphorylase Kinase Deficiency (PHK) autosomal recessive
Caused by mutations in PHKG2 gene or the PHKB gene
PHKB gene mutations cause the mildest symptoms
Can cause both liver and muscle glycogen accumulation but patients usually have liver complications.
PHKG2 gene changes are particularly associated with recurrent hypoglycemia, hepatomegaly and rarely liver fibrosis.
Glycogen Synthase Deficiency
aka Type 0
Autosomal recessive genetic disease
Low amounts of glycogen in the liver leave them with hypoglycemia in between meals.
Signs usually appear in late infancy when late night feedings stop
Glycogen Synthase Deficiency Sypmtoms
Infants may show early-morning (before breakfast) drowsiness, appearance of looking pale, vomiting and fatigue, and sometimes convulsions
Mild growth delay
Early fatigue and muscle cramping may occur during exercise while the body tries to create energy from accumulated lactic acid
Liver is not enlarged
Increased glucose and ketones in urine may occur in the morning, causing false diabetes diagnosis
Glucokinase
Glucose → G6P Irreversible step.
Uses ATP → ADP
1st step of glycolysis
Found in liver and pancreatic Beta cells .
Low affinity (High Km), High capacity (Low Vmax).
Induced by insulin
No feedback inhibition (vs. hexokinase which is negatively regulated by G6P).
Amount of glucose in Beta cells determines amount of insulin released.
Deficiency = MODY - rare form of diabetes characterized by mild hyperglycemia.
Hexokinase
Phosphorylation of glucose to yeild glucose-6-phosphate. 1st step of glycolysis.
UBIQUITOUS.
High affinity (low Km) but Low capacity (high Vmax)
Feedback inhibited by glucose-6-phosphate.
Phosphoglucomutase
Enzyme of glycogenolysis that catalyzes the breakdown of glucose 1-phosphate to glucose 6-phosphate which can enter glycolysis or gluconeogenesis.
UDP-glucose pyrophosphorylase
G1P is converted to UDP-glucose. This is the substrate for glycogen synthase.
This reaction requires hydrolysis of UTP
Glycogen Synthase
Catalyzes addition of glucose to glycogen chain
Turned on by insulin and removing phosphate group
Turned off by epinepherine and glucagon and by protein kinase (adding phosphate group)
Primary target of insulin's stimulatory effects
Branching enzyme
Transfers 7 glucose residues from alpha-1,4 glycogen polymer to form an alpha-1,6 growing branch
Glycogen phosphorylase
Removes Glucose from the 1,4 chain of glycogen.
RATE LIMITING STEP OF GLYCOGENOLYSIS.
Deficient in McArdle's disease (type 5 GSD)
glucose-6-phosphatase
Converts G6P to Glucose.
Muscles and brain do NOT have this, so they cannot complete gluconeogenesis.
This is deficient in Von Gierke's disease (Type 1 GSD)
Acid Maltase
Deficiency causes glycogen deposition in heart and muscle with muscle weakness and heart failure
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Glycogen storage disorders

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