Met3

Question 1

1. The carbon backbone of phenylalanine is broken down to which two compounds? [2]

Answer 1

• Acetoacetate (acetyl CoA can also be accepted) [1]*
• & Fumarate [1]*

Question 2

1. Considering Tyrosine metabolic pathway. Which two hormones are often low in PKU patients? [2]

Answer 2

• Thyroid hormones (Thyroxine)* [1]
• Catecholamines [epinephrine (adrenaline), norepinephrine (noradrenaline**)]* [1]

Question 3

1. Justify your reasoning: What would be the chance of Nùria’s baby having PKU if her boyfriend was a carrier for PKU. [2]

Answer 3

PKU is an autosomal recessive disorder (1) Nùria is homozygous so with a carrier boyfriend being heterozygous, here would be a 50% chance of an affected child and 50% would be carriers (1).

Question 4

1. Why is the treatment for PKU a managed diet rather than an exclusion diet? [1]

Answer 4

Because Phenylalanine is an essential Amino acid needed to make proteins in the body and they cannot be made without it [1]

Question 5

1. Give two other supplementations that might be part of the PKU diet and, for each, give the reason why? [2]

Answer 5

• Tyrosine [0.5] because phenylalanine cannot be broken down into tyrosine in PKU patients [0.5]*
• • Vitamins and minerals [0.5] Since the source of Amino Acid in PKU diet is synthetic amino acid and not meat [0.5] the diet often lacks minerals and vitamins (necessary for correct metabolism).*

Question 6

6) What is the mechanism of action of PPIs drugs like Omeprasol? Name the cells targeted, as well as the precise nature and localisation of the cellular target. (1 mark)

Answer 6

Proton pump inhibitors (PPIs) effectively block gastric acid secretion by irreversibly binding to and inhibiting the hydrogen ATPase pump that resides on the luminal surface of the parietal cell membrane.

Question 7

what are the two types of PKU?

Answer 7

oClassical PKU (this scenario)

oTetrahydrobiopterin (BH4) deficiency

Question 8

define PKU

Answer 8

•Inherited disorder that substantially increases levels of amino acid phenylalanine in the blood

Question 9

what are the signs and sympotoms of PKU - explain !

Answer 9

•Behavioural difficulties,
•Jerking movement
•Tremors and epilepsy
all bc CNS abnormalities: XS PKU disrupts NT synthesis

•Fairer skin
•Fair hair
•Blue eyes
all bc of reduced melanin levles

•Musty odour
•Eczema,
•Recurrent vomiting
all bc of ketones in the blood

Question 10

how do u diagnose PKU?

Answer 10

• Around 5 days of age all babies are offered the newborn blood spot screening to test for PKU amongst many other conditions
• Early diagnosis = long healthy lives
• Tested for phenylalanine levels and/or genetic tests

Question 11

which other tests do you test for with heel prick test?

Answer 11

• Medium chain acyl-CoA dehydrogenase deficiency
• Maple syrup urine disease
• Isovaleric acidaemia
• Glutaric aciduria type 1
• Homocystinuria

Question 12

how do you treat / manage classic PKU?

Answer 12

• Low-protein diet that completely avoids high-protein foods (such as meat, eggs and dairy products)
• Amino acid supplementation: ensure they’re getting all the nutrients required for normal growth
• Low-protein versions of common foods specifically designed for people with PKU and related conditions to incorporate into their diets

Question 13

what should occur during pregnancy with people with PKU? [3]

• what happens if mother not careful with diet?

Answer 13

• Pregnancy should be planned with good dietary control achieved before conceiving
• Need continuous monitoring of phe levels preconception and during pregnancy (between 2 and 6 mg/dL)

If mother not careful à baby may develop congenital heart disease, growth retardation, microcephaly and intellectual disability as a result

Question 14

1. What is the cause of PKU, its genetic inheritance and how would you describe the condition to a patient (3 marks)

Answer 14

PKU is a condition which is caused a mutation on the enzyme phenylalanine hydroxylase (or insufficiency of tetrahydrobiopterin) [1]

which therefore prevents conversion of phenylalanine into tyrosine.

The condition is normally autosomal recessive, which means that two individuals need to be carriers in order to for their offspring to have PKU.

Question 15

3. Name the co factor required by phenylalanine hydroxylase ( 1 mark)

Answer 15

Tetrahydrobiopterin

Question 16

4. Why is Nuria asked to go on a low protein diet (2 marks)

Answer 16

Phenylalanine is an amino acid and is normally present in protein based foods, such having too much protein could lead to a build-up of phenylalanine. In this case as Nuria is pregnant, if she has excess phenylalanine can affect the development of the foetus.

Question 17

explain the normal metabolism of PKU

Answer 17

1. Converted to tyrosine by phenylalanine hyroxylase
2. From tyrosine is then converted to p-hydroxyphenylpyruvate via tyrosine aminotransferase. As this reaction occurs, alpha ketoglutarate is converted to glutamate.
3. p-hydroxyphenylpyruvate then converted to fumarate and acetoacetate
4. It also requires the coenzyme biopterin which is similar to folate in structure
5. Phenylalanine hydroxylase is present in the liver
6. tetrahydrobiopterin (BH4) is a cofactor

Question 18

which gene has an enzyme in it to cause PKU?

Answer 18

Mutation in phenylalanine hydroxylase (PAH) gene prevents phenylalanine  tyrosine

Question 19

why is raised PKU levels bad?

• in classic PKU?
• in type 2 PKU?

Answer 19

1. Phenylalanine is direct cause of neurotoxicity in PKU
2. Type 1: Classic / Primary PKU:
   
   1. Reduction in tyrosine
      
      1. Tyrosine important in the production of:
         
         1. DOPA makes adrenaline and Noradrenaline (therefore risk of Parkinsons)
         2. Melanin!
3. Type 2: Defect in dihydrobipterin reductase enzymes​
   
   1. The defects in these enzymes causes the accumulation of phenylalanine.
   2. This in turn causes a side reaction to occur.
   3. This produces toxic phenylpyruvate and phenylethyamine

Question 20

what dietary changes needed for PKU? [4]

Answer 20

1. Restriction of dietary protein and phe intake (200-500g per day). But need to be careful not cut out all amino acids
2. Amino acid supplements – especially other amino acids.
3. Still need some phe – restricted diet NOT elimination
4. The sweetener aspartamine must also be avoided

Question 21

PKU arises because of a mutation in the gene that codes for WHAT? [1]

Answer 21

Both disorders are the result of mutations in the gene for Both disorders are the result of mutations in the gene for phenylalanine hydroxylase (PAH),

Question 22

in normal phe metabolism, which enzyme converts phe –> to tyrosine

Answer 22

Converted to tyrosine by phenylalanine hyroxylase

Question 23

PKU can cause the build up of which two ketones in the brain? [2]

which molecule can XS phe be converted to by transamination? [1]

Answer 23

1. Phenylalanine can cause build up of ketones in the brain (due to how is broken down): phenyl acetate and phenyl lactose: both toxic!
2. Phenylalanine accumulation –> (transmaination reaction)_ phenyl pyruvate

Question 24

how does cofactor work in normal people?

what is produced if this is not made in PKU patients? [2]

Answer 24

1. This transfers electrons to molecular oxygen in order to form tyrosine.
2. This is necessary to allow the enzyme to work to convert the amino acid to tyrosine
3. 4. This produces toxic phenylpyruvate and phenylethyamine

Question 25

why does PKU have more of an affect on child than adult?

Answer 25

1. **Effect on adult patient**: 1. Less of an effect than as a child **because blood brain barrier develops so can keep phe out.** 2. This is why important to have altered diet during pregnancy!

Question 26

what specifically must be avoided in PKU patients?

Answer 26

1. **The sweetener aspartamine must also be avoided**

Question 27

1. 20-50% of all patients with PKU respond to treatment OF WHAT? [1]

Answer 27

**BH4 – causes significant reduction in blood phe levels**

Question 28

Answer 28

Question 29

effect of PKU on the developing BBB?

Answer 29

excess **phenyl pyruvate** (generated by XS Phe side reactions) **overloads BBB transporters** therefore **preventing entry of other AAs - teratogenic** notwithstanding Phe's own teratogenic effect on foetal brain