Glycogen Storage disease 2 Flashcards
What gene does the defect that causes GSD occur in and what does it effect
- Chromosome 17
2. Effects response elements on promoter
Give an example of a response element that is affected
- Glucocorticoid
What is glucocorticoid and give an example
- It is a hormone
2. e.g. cortisol
What happens to cortisol if blood glucose drops
- It may be secreted
- Can pass through the plasma membrane as made from cholesterol
- Once in the cytoplasm it binds to a receptor- glucocorticoid receptor
- Once it binds to the receptor the complex translocates into the nucleus
- Once inside the nucleus, the complex can bind to glucocorticoid response elements and can enhance or inhibit gene expression
- e.g. G6Pase gene- cortisol increases the expression
What are the symptoms of GSD1
- Protruding abdomen
- Fasting- induced hypoglycaemia
- Growth retardation
What causes a protruding abdomen
- Enlarged liver- hepatomegaly
2. Caused by increased glucogen deposition
What causes induced hypoglycaemia when fastign
- Reduced G6Pase so can’t convert G6P –> Glucose
2. Can’t finish of glycogen breakdown or gluconeogenesis
What causes growth retardation
- Lack of energy
What are the typical glucose concentrations in mM1 for normal people and GSD
- Normal = around 5-5.5
2. GSD= <4
What are the symptoms of hypoglycaemia
- Autonomic- hunger, tremor, sweating
2. Neuroglycopenia- fatigue, paresthesia, personality changes, seizure, coma, impaired brain function
What are 4 biochemical characteristics caused by GSD1
- Hypoglycaemia
- Hyperlacticacidemia
- Hyperlipidemia
- Hyperuricemia
What causes hyperlacticacidemia
- Increase in lactate
- In glycogen breakdown in the muscle lactate is produced and leaves the muscle going to liver
- In the liver lactate is converted to pyruvate and then back to glucose
- BUT in GSD1, G6P can’t be converted to G so [G6P] increases
- G6P is converted to lactate in glycolysis which increases [lactate]
- Why there is increased deposition of glycogen in the liver–>hepatomegaly
What is the normal and GSD1 concentrations of triglycerides and cholesterol in mg/dl
- Triglycerides: normal-<150, GSD1-600
2. Cholesterol: normal-<200, GSD1- 400-600
When does hyperlipidemia tend to occur and what happens
- Puberty
2. Develop xanthoma- deposition of lipid over extensor surfaces e.g elbows
What are the 2 causes of hyperlipidemia
- Increased glycerol
2. Increased fatty acids
Why is there an increase in glycerol in GSD1
- In liver there is an increase in G6P which is in equilibrium with F6P which can be converted to Fructose-1,6-diphosphate
- Fructose-1,6-diphosphate is broken down to GAP (glyceraldehyde-3-phosphate) and DHAP (dihydroxyacetone phosphate) in equilibrium with each other
- Only GAP continues along glycolysis
- In GSD1, DHAP is converted to glycerol-3-phosphate
- Glycerol-3-phosphate is converted to glycerol
Why is there an increase in fatty acid synthesis in GSD1
- Increased G6P which increases fatty acid biosynthesis as it increases pyruvate concentration
- Pyruvate can enter the TCA cycle- in mitochondria where it is converted to acetyl-CoA
- Acetyl-CoA is converted to citrate by citrate synthase
- Citrate doesn’t enter TCA it instead exits mitochondria into cytoplasm and is converted back to Acetyl-CoA by ATP citrate lyase
- More acetyl-CoA in the cytoplasm
- Acetyl-CoA is converted to malonyl CoA by acetyl CoA carboxylase (catalyses first step in fatty acid + cholesterol biosynthesis)
What is hyperuricemia
- Elevated levels of uric acid
Why is there elevated levels of uric acid in GSD1
- Predominantly thought o be because of increased lactate which is excreted in the kidneys in preference to uric acid
- Uric acid is also a breakdown product of purine catabolism
- Increase in G6P, increases pentose phosphate pathway converting it to purines, so increased catabolism so increased uric acid
What is the main symptom of hyperuricemia
- Gout- causes intense pain
- Due to deposition of uric acid in the synovia of joints
- e.g. great toe, foot, ankle
