Metabolic Disorders Screening 1

Question 1

How are inherited disorder inherited?

Answer 1

Chromosomal
Mendelian- Polygenic or monogenic

Question 2

What results in deficient enzymes?

Answer 2

Deficient enzyme activity may be due to lack of enzyme or reduced enzyme activity due to defects of post-translational modification, assembly or transportation or to defects of cofactor activation

Question 3

What does deficient enzyme lead to?

Answer 3

Lack of end product
Build up of precursor
Abnormal toxic metabolites

Question 4

What is the IMD screening criteria?

Answer 4

Important health problem
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 understood
Agreed policy on whom to treat as patients
Economically balanced
Continuing process

Question 5

What is Phenylketonuria?

Answer 5

Phenylalanine hydroxylase deficiency

Question 6

What is the presentation of classical PKU?

Answer 6

ID<50
Common
Blood Phe
>400 mutations
Treatment effective

Question 7

What is sensitivity?

Answer 7

True positive / Total disease present

Question 8

What is specificity?

Answer 8

True negative / Total disease absent

Question 9

What is PPV?

Answer 9

True positive / Total positive

Question 10

What is NPV?

Answer 10

True negative/Total negative

Question 11

How are specimens collected for inherited metabolic diseases?

Answer 11

5-8 days of life (in UK) Heel prick capillary from posterior medial third of foot Blood spotted onto Guthrie card (thick
filter paper)

Question 12

What happens after the Guthrie card is made?

Answer 12

Bloodspot card sent to specialist laboratory in pre-paid, pre-addressed envelope
17 laboratories in the UK
UK Newborn Screening Laboratories Network (UKNSLN)
Bloodspots punched out,
elute blood sample
measure phenylalanine

Question 13

Other than PKU what is another important condition screened for at birth?

Answer 13

Congenital hypothyroidism added 1970
Incidence 1:4000
Inherited in only 15%
Usually dysgenesis/agenesis of thyroid gland
Not always detected clinically
Based on high TSH (in UK)
PPV+ve c.60-70%

Question 14

When were PKU, hypothyroid, SCD, CF and MCADD added to the screening newborn?

Answer 14

PKU from 1969
Congenital hypothyroidism added 1970
Sickle cell disease added 2006
Cystic fibrosis added 2007

Medium chain AcylCoA dehydrogenase (MCADD) added 2009

Others: 
maple syrup urine disease (MSUD) 
isovaleric acidaemia (IVA) 
glutaric aciduria type 1 (GA1) 
homocystinuria (pyridoxine unresponsive) (HCU)

Question 15

Why should CF be screened for?

Answer 15

Incidence 1:2500
Added due to irrefutable evidence that early intervention improves outcome

Question 16

What is the pathology of CF?

Answer 16

6 classes of defect.
Failure of Cl- ion movement from inside epithelial cell into lumen

increased reabsorption of Na+ /H2O

viscous secretions

ductule blockage

Question 17

What are the complications of CF?

Answer 17

Lungs – recurrent infection
Pancreas –malabsorption, steatorrhoea, diabetes
Liver – cirrhosis

Question 18

What may be high in a babe with CF?

Answer 18

Neonate – high blood immune reactive trypsin (IRT)

Question 19

How do you screen and diagnose CF?

Answer 19

Question 20

How is mass spec used?

Answer 20

Structure-related fragments separate according
to mass and charge creating a unique fingerprint

Question 21

What is tandem MS used to screen for?

Answer 21

Amino acid disorders
Fatty acid oxidation disorders
Urea cycle disorders
Organic acidurias

Question 22

What is MCADD caught by?

Answer 22

Incidence 1 in 10,000
Screened using acylcarnitine levels by tandem MS

Question 23

What does Homocystineuria cause?

Answer 23

Lens dislocation
Mental retardation
Thromboembolism