Metabolic Disorders and Screening

Question 1

What is the catalogue of metabolic diseases called?

Answer 1

OMIM

Question 2

When do you perform genetic testing for metabolic disorders?

Answer 2

To confirm a diagnosis

If there is strong family history

Question 3

What does enzyme deficiency cause in terms of outproducrts?

Answer 3

NO end product
Build up of precursors
Possible toxicity of precursors /other byproducts produced

Question 4

What enzyme is deficient in phenylketonuria? What deficiency does this cause?

Answer 4

Phenylalanine hydroxylase is deficient

This normally converts phenylalanine to tyrosine

Question 5

What excess/abnormal metabolites occur in phenylketonuria?

Answer 5

It leads to an excess of phenylalanine (TOXIC)

Also excess of abnormal metabolites (phenylpyruvate, phenyl acetic acid)

Question 6

What is the key clinical feature of PHENYLKETONURIA?

Answer 6

LOW IQ (<50)
As phenylalanine is toxic to CNS

Question 7

How do you investigate phenylketonuria?

Answer 7

Blood phenylalanine levels

Question 8

Is genetic testing appropriate for phenylketonuria?

Answer 8

NO because there are too many variants

Question 9

What is appropriate tx for phenylketonuria?

Answer 9

Phenylalanine scarce diet

Started in first 6 weeks of life

Question 10

What is sensitivity?

Answer 10

True positives / total number of people with disease

Question 11

What is specificity?

Answer 11

True negatives / total number of people without the disease

Question 12

Which sensitivity / specificity need to be prioritised in screening?

Answer 12

SENSITIVITY

So you do not miss someone with the disease

Question 13

What occurs with very rare diseases?

Answer 13

Lots of FALSE POSITIVES

Question 14

When is Gunthie test done?

Answer 14

5-8 days

Question 15

How does Gunthie test check for phenylketonuria?

Answer 15

Measures phenylalanine in blood spot on the paper

Question 16

What diseases are tested for in Gunthie test?

Answer 16

Pietro Has Stopped Chirpsing Me

Phenylketonuria 
Congenital hypothyroidism 
Sickle cell disease
Cystic Fibrosis 
MCAD deficiency

Question 17

Explain MCAD deficiency

Answer 17

A fatty acid oxidation disorder

MCAD is missing, so you cannot turn fatty acids to acetyl CoA

Question 18

When does MCAD deficiency typically cause death?

Answer 18

When a baby is fasting / in between meals

They become hypoglycaemic > can’t break down fats > die

Question 19

How do you screen for MCAD deficiency?

Answer 19

C6-C10 acylcarnitines using tandem MS

Question 20

How do you treat MCAD deficiency?

Answer 20

Ensure that baby never becomes hypogycaemic

As such never becomes reliant on fats as a source of energy

Question 21

What additional disease does Wales screen for?

Answer 21

Homocystinuria

Question 22

What is homocystinuria?

Answer 22

Failure of remethylation of homocysteine

Question 23

What are clinical features of homocysteinuria?

Answer 23

Lens dislocation
Mental retardation
Thromboembolism

Question 24

mutation of which receptor is responsible for cystic fibrosis?

Answer 24

CFTR (cystic fibrosis transmembrane conductance regulatorI)

Question 25

What does CFTR mutation lead to?

Answer 25

CFTR mutation means failure of Cl ions to move from epithelial cell into lumen
This leads to increased Na and water reabsorption into cells
So secretions become thick

Question 26

Which organs does CF manifest?

Answer 26

Lungs - recurrent infections
Pancreas - malabsorption, staethorroea, diabetes
Liver - cirrhosis

Question 27

How doe you screen for CF?

Answer 27

High Immune Reactive Trypsinogen (IRT)

Question 28

How do you make a dx using IRT?

Answer 28

IRT above 99.5 percentile in 3 bloodspots > look for mutations
Look for 4 MOST common mutations