Metabolism 6 - GSDs

Question 1

What is glycogen storage disease?

Answer 1

A defect in glycogen metabolism

Question 2

In Type I GSD which enzyme is defective?

Which organs are most affected?

How is glycogen affected in these structures?

Answer 2

G6Pase
or transport system

Liver + kidney

Increased amount
Normal structure

Question 3

What causes GSD Type I?

How is this inherited?

Answer 3

A missense mutation in the G6Pase gene in chromosome 17

Autosomal recessive manner

Question 4

How are different types of GSD type I caused?

Give examples

Answer 4

By defects in the multicomponent transport system

Type 1a = G6Pase
Type 1aSP = stabliising protein
Type 1b = T1
Type 1c = T3

Question 5

What is GSD1?

Which processes are affected?

Answer 5

Inadequate conversion of G6P to glucose

Glycogenolysis
Gluconeogenesis

Question 6

What are the symptoms of GSD Type I?

Answer 6

> protruding abdomen due to hepatomegaly
> growth failure
> fasting induced hypoglycaemia
> hyperlacticacidemia
> hyperlipidaemia
> hyperuricemia

Question 7

What is an enlarged liver called?

Answer 7

Hepatomegaly

Question 8

What is fasting hypoglycaemia?

Answer 8

Inability to produce glucose in times of deprivation

due to a blockage at the last step of glycogenolysis + gluconeogenesis

Question 9

What is the normal range for blood glucose conc?

What about in those with GSD1?

Answer 9

5.0-5.5mM

<4.0mM

Question 10

What is hyperlacticacidemia?

Answer 10

In GSD1 excess G6P can’t be converted to glucose

• > enters glycolytic pathway
• > converted into pyruvate
• > converted into lactate in liver

Question 11

What are the symptoms of hyperglycaemia?

Answer 11

Autonomic:
>sweating
>tremor
>hungry

Impaired brain function (neuroglucopenia):
>seizure
>coma
>parasthesia
>personality change
>fatigue

Question 12

What is hyperlipidaemia?

Answer 12

Fat deposits (=xanthomas) due to increased fatty acids, cholesterol + triglycerides

Question 13

What are the 2 causes of hyperlipidaemia?

Answer 13

Enhanced glycerol synthesis
- increased flux of G6P through glycolytic pathway

Increased fatty acid synthesis

• conversion of G6P
• > Malonyl CoA

Question 14

Why does increased glycerol synthesis lead to increased lipids?

Answer 14

Glycerol forms the backbone of triglycerides

Question 15

What is hyperuricemia?

What does this cause?

Answer 15

Increased uric acid

Deposition of uric acid crystals in the synovia of joints

Question 16

What are the 2 possible mechanisms for hyperuricemia?

Answer 16

Increased purine synthesis

Reduced uric acid clearance from kidney

Question 17

What are the treatments for GSD1?

Answer 17

> dietary intervention to avoid hypoglycaemia

• frequent meals
• nocturnal feeding via nasogastric tube

> liver transplantation
kidney transplant if renal failure occurs

Question 18

G6Pase is expressed in which tissues (and which cells)?

Answer 18

Liver
- hepatocytes
Intestine
- enterocytes 
Kidney

Question 19

Describe the conversion of G6P to malomyl coA

Answer 19

G6P
->->-> pyruvate 
-> acetyl coA 
(via PDH)
-> citrate
-> oxaloacetate + acetyl CoA (via citrate lyase)
-> malonyl coA 
(via acetyl CoA carboxylase)

Question 20

What is malonyl coA the 1st step of?

Answer 20

Biosynthesis of fatty acids + cholesterol

Question 21

Describe how higher levels of DHAP lead to high levels of glycerol

Answer 21

DHAP
-> glycerol 3 phosphate
 (via glycerol 3 phosphate dehydrogenase) 
-> glycerol 
(via glycerol kinase)

Question 22

Describe the process of increased purine synthesis and how this leads to hyperuricemia

Answer 22

G6P

• > ribose 5 phosphate
• > increased purine synthesis

Guanine + adenine

• > xanthine
• > uric acid

Question 23

Describe reduced uric acid clearance from the kidney

Answer 23

Uric acid + lactate compete for excretion

-> more lactate excreted
= uric acid accumulates in blood