ChemPath: Metabolic Screening and Disorders 1

Question 1

Which database keeps track of all inherited metabolic disorders? What is the most common mode of inheritance?

Answer 1

OMIM
Autosomal

Question 2

What are the main consequences of deficient enzyme activity in the context of inherited metabolic disorders?

Answer 2

Lack of end-product

Build-up of precursors

Abnormal or toxic metabolites

Question 3

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

Answer 3

• It has to be an important health problem
• Must be accepted treatment
• Facilities for diagnosis and treatment
• Latent or early symptomatic stage
• Suitable test or examination
• Test should be acceptable to the population
• Natural history is understood
• Agreed policy on whom to treat as patients
• Economically balanced
• Continuing process (keep updating what is screened for)

Question 4

What is phenylketonuria caused by?

Answer 4

• Phenylalanine hydroxylase deficiency
• This enzyme is responsible for conerting phenylalanine to tyrosine
• Deficiency results in an accumulation of phenylalanine which is toxic

Question 5

Which abnormal metabolites are produced in PKU?

Answer 5

Phenylpyruvate

Phenylacetic acid (detected in the urine)

Question 6

What is the main consequence of untreated PKU?

Answer 6

Low IQ

Question 7

How is PKU investigated?

Answer 7

Blood phenylalanine level

Question 8

Describe the treatment of PKU.

Answer 8

• 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 9

When is the Guthrie test performed in the UK?

Answer 9

5-8 days after birth

Question 10

What is congenital hypothyroidism usually caused by?

Answer 10

• Thyroid dysgenesis or agenesis

NOTE: diagnosis is based on high TSH

Question 11

Describe the pathophysiology of MCAD deficiency.

Answer 11

• This is a fatty acid oxidation disorder
• The carnitine shuttle 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 fatty acids, 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 kill

Question 12

What is the screening test for MCAD deficiency?

Answer 12

Measuring C6-C10 acylcarnitines by tandem MS

Question 13

Outline the treatment of MCAD deficiency.

Answer 13

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

Question 14

What is homocystinuria caused by?

Answer 14

Failure of remethylation of homocysteine

Question 15

What are the clinical features of homocystinuria?

Answer 15

• Lens dislocation
• Mental retardation
• Thromboembolism

Question 16

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

Answer 16

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

Question 17

How many classes of cystic fibrosis are there?

Answer 17

6

Question 18

Outline the pathophysiology of cystic fibrosis.

Answer 18

• 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 19

What is the screening test for cystic fibrosis?

Answer 19

High serum immune reactive trypsinogen

Question 20

Describe the process of screening and diagnosis of cystic fibrosis.

Answer 20

• 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 21

Define sensitivity?

Answer 21

True positives/total number with disease

• correctly identifies those with disease

Question 22

Define specificity?

Answer 22

True negative/total number without disease
- correctly identifies those without disease

Question 23

Define PPV

Answer 23

true positives / total number positive

How many of those who test positive actually have disease
dependant on disease prevalence

Question 24

Define NPV

Answer 24

true negatives / total number negative

Question 26

In a screening test - what values do we want high?

Answer 26

dont want to miss early diagnosis

• Want to have as least true negatives = 100% sensitivity