Chem Path 5 - Metabolic Disorders and Screening 1

Question 1

Which database keeps track of all inherited metabolic disorders?

Answer 1

OMIM

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 converting 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

Homocystinuria

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 > 99.5th 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, extent test to panel of 28 mutations

If you detect 0/4 mutations, repeat IRT at day 21-28