week 10 - metabolic disorders 2

Question 1

What is Glycogen Storage Disease (GSD)

Answer 1

Genetic condition that affects the enzymes involved in the storage or breakdown of glycogen.

Question 2

Describe the structure and function of glycogen?

Answer 2

Branched polysaccharide of glucose.
Glycogen is a form of energy storage
Stored in liver and skeletal muscle

Question 3

Give a brief overview of GSD type 1 aka Von Gierke’s disease

Answer 3

There are 2 subtypes:
GSD 1a is where there is an issue with glucose-6-phosphatase
GSD 1b is when there is an issue with glucose-6-phosphate translocase

Both the enzymes are needed for the release of glucose, so in GSD 1a and 1b there is a failure of glycogenolysis (breaking down glycogen to produce glucose)

Question 4

Describe the genetics of GSD type 1

Answer 4

It is autosomal recessive - so parents can be carriers and not affected and give birth to an affected child

Question 5

Describe how an affected baby in the womb may be healthy but when born starts to suffer from the disease

Answer 5

Because the baby in the womb has it’s mother’s glucose transferred to it via the placenta

Question 6

What are the symptoms of GSD 1?

Answer 6

Primary symptoms:
Hypoglycaemia (low blood sugar)
Hepatomegaly (enlarged liver)
Increased infection (in 1b)

Secondary symptoms:
Increase in uric acid in the blood caused by low serum insulin
Increase in lactic acid in blood
Hepatic adenoma
IBS in 1b

Question 7

Treatment for GSD type 1?

Answer 7

High glucose/high starch foods bc the body can’t produce glucose

Avoiding other sugars

Nocturnal gastric infusion

Filgrastim - treats low neutrophil count in GSD 1b by stimulating bone marrow

Gene therapy

Question 8

What are the side effects of treatment for GSD 1?

Answer 8

Pancreatic hypertrophy - enlarged pancreas

Enlarged spleen, low platelet count, anaemia in 1b

Question 9

What is the pathophysiology of GSD 1?
(what can GSD 1 lead to)

Answer 9

Hypoglycaemia
Lactic acidosis
Hyperuricemia
Hepatomegaly
Hepatic adenoma

Question 10

How does hypoglycaemia (low blood sugar) occur in GSD 1?

Answer 10

Because glucose can’t be produced as there is failure in the enzymes that break down glycogen into glucose. So therefore there is low glucose sugar in the blood

The only way to increase blood glucose is via a high glucose diet.

Question 11

How can lactic acidosis arise in GSD 1?

Answer 11

Lactic acidosis is an increase in lactic acid in the blood.

It occurs from impaired gluconeogenesis (new glucose being made)

It occurs when there is an accumulation of G6P which inhibits the conversion of lactate to pyruvate.

Causes discomfort in muscles

Question 12

How does hyperuricemia occur in GSD 1?

Answer 12

This is where there is high levels of uric acid in the blood.
The high levels of uric acid are caused by the kidneys not being able to excrete enough uric acid.
This can lead to kidney stones, gout etc

Question 13

How does hepatomegaly arise in GSD 1?

Answer 13

It is when you have an enlarged liver.
It is caused by an accumulation of glycogen in the liver as it isn’t being broken down into glucose.
Causes a protruding abdomen

Question 14

How does hepatic adenoma arise in GSD 1?

Answer 14

It is a benign tumour of the liver, aetiology unknown.
Can progress to carcinoma.
You can reduce the size of the tumour by controlling your blood glucose levels.

Question 15

Ho is GSD 1 diagnosed?

Answer 15

Genetic testing
Blood tests to check lactate, uric acid, glucose levels
Check neutrophil count as low neutrophil count only affects 1b
Biopsy of the liver

Question 16

Give a brief overview of GSD type 2? aka Pompe disease

Answer 16

An autosomal recessive disease
It is caused by a deficiency in alpha-glucosidase (GAA)
It impairs glycogenolysis (breaking down glucose) because GAA usually degrades glycogen polymers to glucose in the lysosomes,
so if there is a deficiency in GAA glycogen cannot break down in to glucose
damages muscle cells

Question 17

What are the symptoms of GSD 2?

Answer 17

Infantile symptoms:
Muscle weakness
Respiratory deficiency
Hypertrophic cardiomyopathy
Swallowing difficulty
Hearing loss
Hypotonia (low levels of muscle tone)

Late onset symptoms:
Muscle weakness
Respiratory weakness
Balance issues
Scoliosis
Ptosis (drooping eyelids)

Question 18

Treatment for GSD 2?

Answer 18

Enzyme replacement therapy
High calorie diet
Speech therapy
Physiotherapy
Respiratory assistance

Question 19

What is the pathophysiology of GSD 2?

Answer 19

It can cause enlargement of the lysosomes and can cause them to rupture./
It disrupts the contractile units of the muscle leading to wasting

Question 20

How can you diagnose GSD 2?

Answer 20

Take a blood test to check GAA activity
Genetic testing for GAA mutations
Skin biopsy for GAA activity

Question 21

Give a brief summary of GSD type 4? aka Andersen disease

Answer 21

It is autosomal recessive
It is when there is a deficiency in the Glycogen branching enzyme (GBE)

GBE adds branching to growing glycogen polymers, in GSD 4, abnormal glycogen accumulates which damages liver and muscle cells

Question 22

What are the symptoms of GSD 4?

Answer 22

Progressive hepatic type:
Liver fibrosis
Cirrhosis
Hepatosplenomegaly
Reduced growth
Build up of fluid in abdominal cavity

Neuromuscular variants:
Muscle weakness
Muscle wasting
Severe cardiomyopathy
Heart enlargement due to weakness in heart muscle
Oedema

Question 23

How can you treat GSD 4?

Answer 23

Liver transplant
Manage Cirrhosis and heart dysfunction

Question 24

What is the pathophysiology of GSD 4?

Answer 24

It can cause an accumulation of structurally abnormal glycogen which interferes with liver function.
Leads to scar tissue

Question 25

How can you diagnose GSD 4?

Answer 25

By carrying out a GBE activity assay
Genetic testing for GBE mutations
Liver function tests
Abdominal ultrasound or CT scan

Question 26

Give a brief summary of GSD 5 aka McArdle disease?

Answer 26

It is autosomal recessive
Occurs when there is a mutation in the muscle isoform of glycogen phosphorylase (PYGM)
The function of PYGM is to catalyse glycogenolysis (the breaking up of glycogen to form glucose)
This causes muscle weakness and pain

Question 27

What are the symptoms of GSD5?

Answer 27

Progressive hepatic type:
Excessive intolerance
Myalgia
Fatigue
Painful cramps
Myoglobinuria (when there is myoglobin in the urine due to break down of skeletal muscle)

Long term:
Kidney failure
Progressive weakness
muscle loss

Question 28

How can you treat GSD 5?

Answer 28

Exercise plan but avoid anaerobic exercise

Consume glucose prior to exercise - this is so that there will then be glucose available in the blood bc with this disease glucose cannot be produced from glycogen
Creatine supplements
Maintain a balanced diet

Question 29

What is the pathophysiology oof GSD 5?

Answer 29

Accumulation of intramuscular glycogen
Lack of glucose for fuel in muscles
Rhabdomyolysis - breakdown of skeletal muscle which releases myoglobin
Kidney failure due to myoglobin accumulation in the kidneys tubules

Question 30

How can one diagnose GSD 5?

Answer 30

Muscle biopsy to detect PYGM
Genetic testing for PYGM mutations
Forearm ischaemic exercise test - there is increased ammonia and reduced lactate in blood in patients with GSD 5
Check the resting creatine kinase level - is increased in patients with GSD 5

Question 31

Give a brief summary of the mitochondria

Answer 31

It is an intracellular organelle which generates energy (ATP) for the cell
Not found in red blood cells

Question 32

What are 2 mitochondrial disease examples?

Answer 32

1. Leber Hereditary Optic Neuropathy
2. Mitochondrial Neurogastrointestinal Encephalopathy (MNGIE)