PKU and MCADD

Question 1

What is Classical PKU?

Answer 1

• Deficiency of enzyme Phenylalanine hydroxylase which converts the amino acid phenylalanine to tyrosine.
• Gives rise to a build up of phenylalanine in blood with relatively low tyrosine.
• Treated by low protein/phenylalanine diet

Question 2

What are the genetic about PKU?

Answer 2

• Autosomal Recessive
• PKU gene (PAH) found on chromosome 12. No common mutation
• Incidence approx 1 in 10,000 births. Approximately 1 in 50 of the population are carriers and are asymptomatic

Question 3

What are symptoms of Untreated PKU?

Answer 3

• Delayed mental and social skills
• Fair hair and skin, blue eyes in most cases – lower melanin due to tyrosine being used for production of melanin
• Head size significantly below normal
• Hyperactivity
• Jerking movements of the arms or legs
• Intellectual impairment
• Seizures
• Skin rashes
• Tremors
• Unusual positioning of hands

Question 4

How is screening for PKU conducted?

Answer 4

• PKU first condition to be screened for in the UK
• Ideal screening candidate
• Known incidence and natural history, latent asymptomatic phase, cost effective treatment, vastly improved quality of life
• Screening commenced in the late 1960s/early 1970s
• Many historical methods used for screening
• Urine screening preceded a more organised bloodspot programme
• Sensitive, specific, high throughput screening now uses tandem mass spectrometry analysis of dried blood spots

Question 5

What may also be detected by newborn screening for PKU?

Answer 5

• Galactosaemia
• Liver Disease
• Tyrosinaemia Type 1
• Pterin disorders

Question 6

What is Tandem Mass Spectrometry?

Answer 6

• Measures mass to charge ratios of metabolites before and after they have been fragmented by collision with inert gas
• Groups of similar molecules fragment in the same way and can be measured together. i.e. amino acids

Question 7

What prompts referral for PKU?

Answer 7

• Initial phenylalanine value > 200µmol/L
• Repeat in duplicate and measure tyrosine
• Average of all three Phe values >240µmol/L referred for clinical follow up
• If average of tyrosine values >240µmol/L should advise that this may indicate an abnormality but not PKU

Question 8

What is the ocnfirmatory testing that is done for PKU?

Answer 8

• Blood phenylalanine level by quantitative plasma amino acid analysis
• DNA not helpful for clinical management
• Blood spot DHPR and pterins sent to Birmingham
  
  • Test for pterin defect. 1-2% of cases of PKU due to pterin defects rather than phenylalanine hydroxylase

Question 9

How is Tyrosinaemia Type 1 picked up?

Answer 9

Can be picked up but only if Phe raised

• Not all babies with Tyrosinaemia type 1 have a raised a raised phenylalanine
• Leeds and Manchester screen for it using 2nd tier test succinylacetone if tyr > 300µmol/L

Question for national screening targeting succinylacetone(SA)

Question 10

What Pterin Disorders?

Answer 10

• Caused by deficiency of one of the enzymes responsible for tetrahydro biopterin synthesis or regeneration
• BH4 is cofactor for phenylalanine hydroxylase PAH, tyrosine hydroxylase TH and tryptophan hydroxylase TPH
• TH and TPH are responsible for the synthesis of neurotransmitters from tyrosine and tryptophan

1-2% of PKU screened positive patients will have pterin defect in UK. Some populations have markedly more pterin defects

Question 11

What are Pterin Disorders associated with Phenylalanine?

Answer 11

Synthesis Disorders

• GTPCH – guanosine tryphosphate cyclohydratase
• PTPS (commonest) – 6-pyruvoyl tetrahydropterin synthetase

Recycling disorders

• DHPR (commonest) – dihydropteridine reductase
• PCD - pterin-4a-carbinolamine dehydratase (primapterinuria)

Question 12

What is the treatment of PKU in the early years?

Answer 12

• Regular blood samples for phenylalanine monitoring
• Treated with restricted diet with small amount normal milk and phenylalanine free milk formula.
• Given advice about diet when weaning.
• Supplement with Phe free products

Question 13

What is the ongoing treatment for PKU?

Answer 13

• Diet based on protein exchange system. Risk of dietary deficiencies
• Number of exchanges tolerated varies with different patients and also with growth.
• Target phenylalanine levels vary with age.
• Diet now considered life long
• Supplemented with Phe free products e.g. most fruit, fats, sugars, some vegetables
• Biopterin supplementation

Question 14

What is used for Biopterin supplementation?

Answer 14

• Kuvan is an artificial tetrahydrobipterin helps to stabilise proteins
• Pharmacological dose of BH4 may help if residual PAH activity remains
• May decrease blood Phe concentrations and increase dietary Phe tolerance

Licensed in Europe and the USA, but only for pregnancy in UK

Question 15

What is Maternal PKU?

Answer 15

• Syndrome affecting the offspring of PKU mothers not on a Phe restricted diet
• Pathogenesis not fully understood and largely preventable
• Phe is transported across the placenta to the foetus
• Phe is teratogenic and babies were born with dysmorphism

Question 16

What are clinical presentation of Maternal PKU?

Answer 16

• Microcephaly
• Low birth weight
• Dysmorphic features
• Developmental delay
• Congenital Heart defects
• Other malformations
• Behavioural issues

Question 17

How is Maternal PKU monitored and managed?

Answer 17

• Best outcome if pre-conception dietary control
• 4 weeks good control before stopping contraception
• Aim for levels <360µmol/L throughout pregnancy (formerly 100-250µmol/L)
• If already pregnant aim for good dietary control by 8-10 weeks as this helps with heart development, IQ and growth

Question 18

What are problems associated with Maternal PKU mangement?

Answer 18

• May be off phe restricted diet
• Used to normal food
• Poor cooking and organisation skills
• How to satisfy appetite
• Optimal outcome requires multidisciplinary team input