Glycogen Storage Diseases Flashcards
Glycogenesis
- To start the process of glycogenesis, glucose is phosphorylated by glucokinase (liver) or hexokinase (muscle) to produce glucose-6-phosphate (glucose6P).
- After a meal, glucose is diverted to the synthesis of hepatic glycogen to replace what has been lost since the last meal.
- This response is controlled largely by increased amounts of insulin in the blood as well as by the marked increased concentration of glucose6P in the liver cell that occurs after a carbohydrate meal.
- In muscle, glycogen is replaced after intense exercise during which glycogen has been used.
- The glucose6P is then converted to glucose-1-phosphate (reverse of the reaction used during glycogenolysis).
- glucose 1P + uridine monophosphate (UMP —> UDP - glucose
-The UMP is derived from UTP.
•UDP-glucose is the substrate for glycogen synthase, the principal and regulated enzyme of glycogenesis.
- Glycogen synthase is active in its dephosphorylated state by the action of protein phosphatase, which is activated by insulin.
- Any glycogen synthase that remains phosphorylated is activated allosterically by glucose6P.
•These combined effects ensure that glycogen, which had been utilized to maintain glucose homeostasis since the last meal or for driving muscle contractions is replenished.
Glycogenesis - Adding Branches
- The highly branched structure of glycogen permits exclusion of water to decrease a tissue osmotic effect and to increases its efficiency as a substrate for glycogen phosphorylase, which catalyzes the removal of glucose units from the ends of branches.
- The formation of branches is catalyzed by branching enzyme that moves seven glucose residues from the end of a growing chain to an interior area where a branch can be attached.
Glycogenolysis
- Glycogen phosphorylase [GP] is the key regulated enzyme that removes sugar residues from glycogen.
- GP catalyzes hydrolysis of glucose residues from the ends of branches and phosphorylation of these residues.
- This enzyme contains binding sites for its substrates (glycogen, Pi), a cofactor (pyridoxal phosphate), an allosteric activator (AMP), and allosteric inhibitors (ATP, glucose, glucose-6-phosphate).
- Certain hormone signals [i.e., glucagon, epinephrine] activate GP by phosphorylation of the enzyme.
- The product of the reaction is glucose-1-phosphate that is rearranged to glucose6P.
- In liver, to ensure the glucose6P is dephosphorylated to glucose via glucose 6-phosphatase (G6Pase), glycolysis is inhibited by fructose-2,6-bisphosphate (F2,6BP) at phosphofructokinase-1 (PFK-1) under conditions of food deprivation.
- Glucose-6-phosphatase is unique to tissues producing glucose (i.e., liver and kidney).
- Other tissues, such as muscle, lack G6Pase so that glucose6P from glycogenolysis proceeds directly through glycolysis to produce pyruvate that is either converted to lactate via lactate dehydrogenase (LDH) under anaerobic conditions or aerobically to CO2 via pyruvate dehydrogenase (PDH) and the citric acid cycle (CAC)
Glcogenolysis - Debranching
- The combined actions of a debranching enzyme and a transferase move the final four residues of a branch to the end of a chain so that they can be removed by glycogen phosphorylase.
- Glucose-1-phosphate, the product from glycogen phosphorylase, is converted to glucose6P via phosphoglucomutase.
- The final residue that forms the alpha-1,6 linkage is removed by a 1,6-glucosidase enzyme releasing free glucose directly.
Glycogenolysis in the Lysosome
- Lysosomes can store some glycogen. Its conversion to glucose is catalyzed by the lysosomal acid maltase (alpha-1,4-glucosidase).
- Homozygous deficiency of this enzyme causes accumulation of lysosomal glycogen in all types of cells.
Glycogen Storage Diseases
- Type II - Pompe disease – lysosomal glucosidase
- Type I – Von Gierke disease – glucose-6-Pase
- Type III – Cori disease – debranching enzyme
- Type V – McArdle disease – muscle phosphorylase
- Type VI – Hers disease – liver phosphorylase
- Type 0 – glycogen synthase
- Type IV – Andersen disease – branching enzyme
GSD Type II Pompe Disease
*Defect of lysosomal storage of glycogen; acid maltase: alpha-1,4-glucosidase
*Affects wide range of cell types
- Infants: hypotonia, weakness, areflexia, cardiomegaly, hypertrophic cardiomyopathy, some hepatomegaly [no hypoglycemia]
- Juvenile/adult form: motor delay; progressive myopathy – skeletal muscle only
- Heart failure leads to early death
- Enzyme replacement therapy - alglucosidase alfa [lumizyme]*
*For 2016, Lumizyme was ranked the costliest drug per patient, average of $630,159
Type II Pompe Disease Histology
GSD Type I Von Gierke Disease
- IA: Glucose-6-phosphatase [most common form]
- IB: Glucose-6P transporter
Workup for GSD Type I Von Gierke Disease
- Glucose (fasting hypoglycemia; monitoring therapy)
- Liver enzymes – AST and ALT (hepatomegaly)
- Plasma lactate elevated (lactic acidosis)
- Plasma bicarbonate (decreased due to acidosis)
- Uric acid (decreased due to acidosis)
- Plasma lipids (elevated cholesterol and triglyceride)
- Hb/Hct (anemia due to chronic hepatic disease)
- Serum alpha-fetoprotein (hepatocellular carcinoma marker - adenoma)
- Imaging:
- Hepatic ultrasonography (diagnosis and monitoring therapy)
- Renal ultrasonography (nephrolithiasis)
- CT/MRI (monitor adenomas)
GSD Type I Von Gierke Disease Overview
- GSD Type I (von Gierke disease) usually involves a lack or reduced activity of glucose-6- phosphatase (Type Ia) that is located in the endoplasmic reticulum).
- Less frequently the disease can be a consequence of a deficiency in the transporter for glucose6P (Type Ib).
-In Type Ib the substrate fails to reach the glucose-6-phosphatase enzyme in the ER lumen.
- Overall GSD type I occurs in about 1 per 100,000 live births.
- The disease is inherited as an autosomal recessive disorder.
- A variety of mutations have been identified in Caucasians, Hispanics, Chinese, and the Ashkenazi Jews; the most common being a R83C mutation found to be prevalent in all groups listed except Chinese. Amongst the non-Ashkenazi Jews in North Africa the incidence is reportedly as much as 1 in 5500. Overall about 25% of the cases of GSD are type I.
GSD Type I Von Gierke Disease Clinical Features
The disease presents in infants with major symptoms that include:
•Hepatomegaly leading to a protruding abdomen.
-The hepatomegaly contributes to development of at least one hepatic adenoma, usually in the teen years, in as high as 75% of the patients but less commonly do these adenomas become malignant (10% of adenomas).
- Hepatomegaly may also lead to pancreatitis that is another factor which, along with hepatomegaly and nephrolithiasis, can cause abdominal pain.
- Metabolic derangements are common and include hypoglycemia, lactic acidosis and hyperuricemia.
-The extent of hypoglycemia varies but can lead to serious complications ranging from seizures to coma and death.
•Recall that the kidney contains glucose-6-phosphatase activity, so that glycogen accumulates in this organ as well.
-Elevated uric acid (90% of patients) due to the acidosis leads to gouty arthritis.
•Type Ia patients almost always exhibit dyslipidemia with markedly elevated serum triacylglycerol (hypertriglyceridemia – nearly 100%), and moderately increased VLDL, LDL and cholesterol (hypercholesterolemia – 75%).
-The elevated lipids can manifest as xanthomas and contribute to pancreatitis.
•Patients often exhibit platelet dysfunction.
- Anemia is found in ~80% of patients.
- Type Ib patients may have neutropenia and neutrophil abnormalities.
• GI:
-Infections, abscesses and inflammatory bowel disease are common in type Ib but less so in type Ia patients.
• Endocrine:
- Growth failure, even in treated patients is common (90%) with final height being in the 5th -10th percentiles.
- Less commonly features can include muscle hypotonia, delayed psychomotor development and recurrent infections, the latter being most common in type Ib (41%) compared to type Ia (3%).
- Hormonal imbalances also can lead to bone disorders (osteopenia or fractures – 25%). These imbalances likely also account for delayed onset of puberty and subsequent development.
- Polycystic ovary disease may also be present in females.
• Renal:
- Nephrolithiasis is common. Kidney damage (focal segmental glomerulosclerosis) can lead to further complications of proteinuria (65%), hypertension and chronic renal failure.
- Damage due to both uric acid stones and kidney accumulation of glycogen leads to decreased creatinine clearance.
• Mortality has become less of an issue with the development of therapies that help reduce the severe complications.
Biochemistry of GSD Type I Von Gierke Disease
- Glucose-6-phosphatase is an essential enzyme for both glycogenolysis and gluconeogenesis.
- In GSD Type I, glycogenolysis occurs up to the production of glucose6P; carbons are then pushed through the glycolytic pathway.
- So why does glycogen accumulate leading to hepatomegaly?
- The capacity for glycolysis to process glucose6P following food deprivation is limited by the hormonal controls that decrease glycolysis and enhance gluconeogenesis.
- This capacity is not zero because there is always residual enzymatic activity even in an ‘inhibited’ state.
•The limitation of glycolysis causes an increase in the concentration of glucose6P, which counteracts to some extent for the activation of glycogenolysis by glucagon following food deprivation.
Biochemistry of GSD Type I Von Gierke Disease Part II
The limitation of glycolysis causes an increase in the concentration of glucose6P, which counteracts to some extent for the activation of glycogenolysis by glucagon following food deprivation.
Biochemistry of GSD Type I Von Gierke Disease Part III
- The inability to convert lactate or alanine to glucose means that lactic acidemia and hyperalaninemia become a consequence of food deprivation.
- The acidosis created by the lactic acid lowers the solubility and hence excretion of uric acid by the kidney; hence the development of hyperuricemia.
- Lactate, alanine and carbons from limited glycogen breakdown all will end up as pyruvate that is converted to acetyl CoA.
-Acetyl CoA is a precursor to synthesis of fatty acids and cholesterol that contribute to the formation and secretion of VLDL; hence the development of hypertriglyceridemia and hypercholesterolemia
GSD Type I Von Gierke Disease and Growth Failure
- In terms of growth failure, hypoglycemia reduces the secretion of insulin-like growth factor (IGF) by liver.
- IGF production and secretion is controlled by growth hormone, whose primary role is metabolic in promoting an increase of blood glucose.
- In the face of fasting hypoglycemia, the metabolic effects of growth hormone are retained in an attempt to maintain glucose homeostasis.
- Concurrently its stimulation of IGF-I secretion is curtailed because of the energy costs associated with growth; a second measure to preserve blood glucose.
GSD Type I Von Gierke Disease Histology
- Deficiency of glucose-6-phosphatase results in accumulation of glycogen in hepatocytes (left – compare to normal on right).
- The liver is enlarged. The hepatocytes are swollen and a mosaic histological pattern with compression of the sinusoids is seen.
GSD Type I Von Gierke Disease Treatment
- Avoid fasting
- Nasogastric tube feeding – young infants
- Avoiding excessive carb intake to prevent lactic acidemia.
- Uncooked cornstarch
-The raw cornstarch is a complex glucose polymer, which is acted on slowly by pancreatic amylase over about a 6-hour period
- Avoid sat. fats/cholesterol because of hyperlipidemia
- Surgical removal of adenomas
Liver resection in glycogen storage disease type Ia. Multiple tumor nodules with smooth borders; uninvolved parenchyma pale ; bar = 5cm
GSD Type III Cori Disease
- IIIA/B: Debranching enzyme
- IIIC: Glucosidase
- IIID: Transferase
- GSD Type III (Cori disease) is caused by a lack or reduced activity of the debranching enzyme leaving glycogen with short branches of 2-4 glucose residues.
- There are four types of clinical manifestations.
- Most patients (80%) have type IIIa that affects both liver and muscle.
- Type IIIb affects liver only.
- Type IIIc is associated with a defect of the glucosidase activity
- Type IIId a defect of the transferase activity.
- The disease is inherited as an autosomal recessive disorder.
- The incidence is about 1 in 25,000 births. GSD Type III accounts for about 25% of all GSD cases. Frequency of the disease is high in the following populations: Inuits and Sephardic Jews originating in North Africa (~1:5000).
Growth and Development GSD Type III Cori Disease
- Growth and development in a patient with type IIIb glycogen storage disease.
- Debrancher deficiency in liver but normal activity in muscle.
- Child: hepatomegaly, hypoglycemia, and growth retardation.
- After puberty: no hepatomegaly or hypoglycemia
- No muscle weakness or atrophy in contrast to type IIIa patients, who exhibit progressive myopathy in adulthood.
GSD Type V McArdle Disease
- affects muscle glycogen phosphorylase
- Most patients first present in their teens or 20s.
- It is associated with immediate morbidity as a consequence of severe exercise intolerance.
- Initial symptoms include cramps, fatigue and/or pain after exercise.
- Some adult patients develop a proximal weakness or even a fixed motor weakness.
- no hypoglycemia
GSD Type V McArdle Disease Histology
A. sub-sarcolemmal vacuoles seen on H&E stain
B. dark-stained glycogen on PAS stain.
GSD Type V McArdle Disease Workup
- Serum creatine kinase (elevated due to muscle damage)
- Glucose (normal with fast)
- Urine myoglobin (elevated due to rhabdomyolysis)
- Ischemic forearm test (no increase lactate from muscle)
- Muscle Biopsy (diminished or no myophosphorylase)
Biochemisrty of GSD Type VI Hers Disease
- Symptoms are those expected when hepatic glycogenolysis is impaired.
- That the disease is typically mild suggests there is remaining significant enzymatic activity.
Biochemistry of GSD Type 0 Glycogen Synthase Defect
•As a consequence of a glycogen synthase defect, the content of glycogen in the liver will be low but of normal structure.
- Small amounts of glycogen still form because the defective enzyme has some minimal activity though in some patients it may too low to be accurately measured.
- In tissues that have the GYS1 isoform (e.g., skeletal muscle) the enzyme activity is normal as is the content of glycogen.
- During fasting, hypoglycemia results from the insufficient amounts of glycogen that can be mobilized for maintenance of blood glucose.
- Because growth hormone is released at night and growth depends on adequate blood glucose concentrations, untreated disease will lead to diminished growth and hence short stature.
- Fasting without proper blood glucose homeostasis has a negative effect on the secretion of insulin-like growth factor (IGF) by the liver.
- It is IGF that mediates the effects of growth hormone on bone, cartilage and muscle cell proliferation.
•The mechanism as to why fasting hypoglycemia is accompanied by ketosis remains unproven.
- One possibility is that with reduced fuel availability under hypoglycemic conditions, lipolysis will be accelerated even more, especially because blood insulin will be low even for a fasting state.
- Normally in starvation, ketosis is prevented because elevated ketone bodies promote a small release of insulin from the pancreatic beta-cells. Insulin in turn inhibits lipolysis.
- However, in these patients, insulin secretion is suppressed because of hypoglycemia and hence there may be poor feedback response to elevated ketone bodies.
•Because of reduced production of glucose from glycogen in fasting, initial dependence on gluconeogenesis following food deprivation becomes more critical. Consequently, the blood concentrations of lactate and alanine may be lower than normal since they are the two major gluconeogenic precursors. Postprandial lactic acidemia likely results from dietary glucose being diverted to lactic acid because of the limited ability of liver to form glycogen.
Biochemistry of GSD Type IV Anderson Disease Branching Enzyme Defect
•With a deficiency of branching enzyme, glycogen structure will be similar to plant amylose; long glucose polymers lacking branches.
- The lack of branches works well in plants as a way of storing water (e.g., potatoes).
- However, normally the highly branched structure of glycogen excludes water because of the hydrogen bonding that occurs between glucose residues on parallel branches. Instead lacking or with much fewer branches, the hydroxyl groups of the glucose residues instead become hydrated.
- This excessive water storage in the liver causes hepatomegaly because the cells become swollen.
- Because there is glycogen stored in the liver, albeit abnormally structured, glucose mobilization from glycogen will respond to fasting so that patients do not present with fasting hypoglycemia early in the disease.
- However, the liver damage caused by the hepatomegaly eventually leads to impaired metabolism as cells die.
-Consequently, later in the course of the disease patients may exhibit hypoglycemia following food deprivation.
GSD Type IV Anderson Disease Branching Enzyme Defect Histology
- Liver section from a patient with GSD IV stained with periodic acid-Schiff (PAS) after diastase treatment. Coarsely clumped cytoplasmic material representing accumulated abnormal glycogen resists diastase treatment; readily stained with PAS.
- Normally diastase removes glycogen
