ChemPath: Metabolic Screening and Disorders 1 ✔️

Question 1

Types of inheritance, most common to least common:

Answer 1

Autosomal > X-linked > mitochondrial > Y-linked

Question 2

Which database keeps track of all inherited metabolic disorders?

Answer 2

OMIM (Online Mendelian Inheritance in Man)

Question 3

What are the main consequences of deficient enzyme activity in a metabolic pathway?
e.g. A <—-> B <–X–> C

Answer 3

Lack of end-product (e.g. C)

Build-up of precursors (e.g. A + B)

Abnormal or toxic metabolites

Question 4

What are the criteria for inherited metabolic disorder screening (in neonates)? (Wilson and Junger Criteria)

Answer 4

1. Must be an important health problem.
2. Must have an accepted treatment in the guidelines.
3. Facilities for diagnosis and treatment.
4. Latent or early symptomatic stage.
5. Suitable test or examination.
6. Test should be acceptable to the population.
7. Natural history of disease is understood.
8. Agreed policy on whom to treat as patients.
9. Economically balanced (i.e. cost effectiveness of screening and treating vs not).
10. Continuing process (keep updating what is screened for)

Question 5

What is phenylketonuria (PKU) caused by?

Answer 5

• Phenylalanine hydroxylase deficiency
• This enzyme is responsible for converting phenylalanine to tyrosine
• Deficiency results in an accumulation of phenylalanine, which is TOXIC

Question 6

Which abnormal metabolites are produced in PKU?

Answer 6

Phenylpyruvate

Phenylacetic acid (detected in the urine)

Question 7

What is the main consequence of untreated PKU?

Answer 7

Low IQ (IQ<50)
No physical symptoms

Question 8

How is PKU investigated?

Answer 8

Blood phenylalanine level

Question 9

Describe the treatment of PKU.

Answer 9

• Monitor the diet and ensure that the patient is having enough phenylalanine (but not too much)
• This must be started within the first 6 weeks of life

Question 10

When is the Guthrie test (AKA heel prick test) performed in the UK?

Answer 10

5-8 days after birth

Question 11

What is congenital hypothyroidism usually caused by?

Answer 11

Dysgenesis or agenesis of the thyroid gland
Prevalence = 1:4000
Added to UK screening in 1970

NOTE: diagnosis is based on high TSH, PV+ve 60-70%

Question 12

Is sickle cell disease screened for in the UK?

Answer 12

YES!
Added to UK screening programme in 2006

Question 13

What is cystic fibrosis (CF) and what is it caused by?

Answer 13

Screening for CF added in 2007
6 classes of defect in the transmembrane conductance regulator i.e. failure of Cl- movement from inside epithelial cell into lumen –> increased reabsorption of Na+/H2O –> viscous secretions –> ductule blockage

Lungs –> recurrent infections
Pancreas –> malabsorption, steatorrhoea, diabetes
Liver –> cirrhosis

Question 14

How many classes of cystic fibrosis are there?

Answer 14

6

Question 15

Outline the pathophysiology of cystic fibrosis.

Answer 15

• Failure of the cystic fibrosis transmembrane conductance regulator means that chloride ions cannot move into the lumen from the cells, resulting in increased water absorption and very thick secretions

Question 16

What is the screening test for cystic fibrosis?

Answer 16

High serum immune reactive trypsinogen (IRT)

Question 17

Describe the process of screening and diagnosis of cystic fibrosis.

Answer 17

• If IRT > 99.5^th centile in 3 bloodspots, move on to mutation detection
• There are >500 mutations that can cause cystic fibrosis, but FOUR are very common
• If you detect 2/4 mutations, diagnose CF
• If you detect 1/4 mutations, extend test to panel of 28 mutations
• If you detect 0/4 mutations, repeat IRT at day 21-28

Question 18

Describe the pathophysiology of Medium chain AcylCoA dehydrogenase (MCAD) deficiency.

Answer 18

Added to UK screening in 2009

• This is a fatty acid oxidation disorder
• To breakdown fatty acid, it must be transported into a mitochondria to enter the beta-oxidation pathway
• The carnitine shuttle is what transports fats into the mitochondria where it will be broken down into smaller and smaller chains by the process of fatty acid oxidation
• Without MCAD, you will not produce acetyl-CoA from medium fatty acid chains, which is necessary in the TCA cycle to produce ketones (which spares glucose)
• Fat is used when fasting in between meals in order to spare your glucose stores
• In MCAD deficiency, the patient is unable to break down fats so they become very hypoglycaemic in between meals and this can cause death

NOTE: SCAD stands for short CAD, MCAD stands for medium CAD, LCAD stands for long CAD

Question 19

What is the screening test for MCAD deficiency?

Answer 19

Measuring C6-C10 acylcarnitines by tandem MS

Question 20

Outline the treatment of MCAD deficiency.

Answer 20

Make sure the child never becomes hypoglycaemic, and hence is never reliant on fats as a source of energy.

Question 21

What is homocystinuria caused by?

Answer 21

Failure of remethylation of homocysteine

This is being screened for in Wales

Question 22

What are the clinical features of homocystinuria?

Answer 22

• Lens dislocation
• Mental retardation
• Thromboembolism

Question 23

Which conditions are currently being trialled for inclusion in the newborn screening programme?

Answer 23

• Homocystiinuria
• Isovaleric acidaemia
• Glutaric aciduria type I
• Maple syrup urine disease
• Long-chain acyl-CoA dehydrogenase deficiency

Question 24

What is sensitivity? What is specificity?

Answer 24

Sensitivity is about in who the disease is PRESENT
Sensitivity equation = True positive / total disease present (e.g. 48 people tested positive but actually 50 people have it, then sensitivity = 96%)

Specificity is about in who the disease is ABSENT
Specificity equation = True negative / total disease absent (e.g. 100 people tested negative and all 100 people don’t have it, then specificity = 100%)

Question 25

What are predictive values?

Answer 25

Predictive values refer to the test itself

Question 26

What is a positive predictive value (PV+ve)?

Answer 26

The true positive results out of the total number of positive results
True positive / total positive
e.g. if you had 100 positive results but only 80 were true positives, then PV+ve is 80%.

Question 27

What is a negative predictive value (PV-ve)?

Answer 27

The true negative results out of the total number of negative results
True negative / total negative
e.g. if you had 100 negative results but only 95 were true negatives, then PV-ve is 95%.

Question 28

What can affect predictive value?

Answer 28

PREVALENCE
less prevalent = less PV+ve