LECTURE - Newborn Metabolic Screening

Question 1

a population-based program for identifying treatable neonatal or childhood disorders in infants if left undiagnosed results in irreversible damage

Answer 1

newborn screening (NBS)

Question 2

key points of NBS

Answer 2

• population-based; EVERY newborn is assessed
• treatable
• severe phenotype if left untreated

Question 3

first NBS test

Answer 3

• PKU; Phenylketonuria

- due to defect in the enzyme Phenylalanine hydroxylase (PAH) = irreversible neurological damage

Question 4

tandem mass spec (triple quadrupole) advantages

Answer 4

• high sensitivity = analyse many analytes from small vols (dry blood spots)
• high specificity = decreased false positive identification of metabolites
• rapid testing = can be fully automated ~3 minutes
• inexpensive sample testing = even though instrumentation is expensive (routing run is manageable though)

Question 5

limitations of tandem mass spec

Answer 5

compounds w same MW
- similar fragments appear as compounds of interest (eg. maple syrup rine disease MSUD due to leucine (isoleucine and alloisoleucine have ~MW)

Question 6

positive predictive value (PPV)

Answer 6

PPV = TP/[TP+FP]

• PPV is sacrificed (reduced) at the expense of high diagnostic sensitivity
• high sensitivity = low false neg rate = prevention of MISSED cases by increasing false positive rate

Question 7

methods for improving PPV

Answer 7

• improve primary testing through use of additional markers/ratios
  > MCAD = C8 & C8/C10, C8/C2, C10:1
• add a second test
  > additional 1st tier test (right away); Succinylacetone for Hereditary Tyrosinemia; PPV increase from 1.5% to ~40%
  > introduction of 2nd tier testing; TGAL for galactosemia;molecular testing; steroid profiling for CAG (Congenital Adrenal Hyperplasia)

Question 8

initial screen results reported by NMS lab within __ days of age excluding _______ _______

Answer 8

10 days of age
cystic fibrosis
(97.3%)

Question 9

what happens following a positive NMS?

Answer 9

• genetic counselor for NMS lab contacts appropriate departments at the closest treatment centres (North vs South)
  > contact is based on screen result
• each disease = specialized follow-up testing and medical management as required
• results of testing reported back to NMS lab (to assess the effectiveness of their screen)

Question 10

inherited metabolic diseases

Answer 10

• negative effect on individual; dependent on the metabolic function of the affected biochemical rxn

> accumulation of toxic substrates and their metabolites
accumulation of non -metabolized substrates
deficiency of rxn product
overproduction of a rxn product
insufficient provision of cellular energy

Question 11

clinical presentation of PKU

Answer 11

progressive, irreversible neurological impairments affecting cognitive and physical function

• behavioural issues = hyperactive, purposeless movements
  > aggressiveness
  > anxiety and social withdrawal
• urine has a mousy odour (phenylacetic acid excretion)

Question 12

clinical presentation of PKU

Answer 12

progressive, irreversible neurological impairments affecting cognitive and physical function

• behavioural issues = hyperactive, purposeless movements
  > aggressiveness
  > anxiety and social withdrawal
• urine has a mousy odour (phenylacetic acid excretion)

Question 13

PKU metabolic alteration

Answer 13

PU- phenylalanine hydroxylase (PAH) deficiency => decreased tyosine
> Tyrosine is important for melanin syntheis, dopamine and norepi
> imbalanced large neutral AA concentrations in brain affect TYR hydroxylation and TRP carboxylation to dopamine and serotonin

Question 14

treatment for PKU

Answer 14

• PHE restricted diet (below 360umol/L)
• potential for response to kuvan (sapropterin) = cofactor for PAH
• TYR supplementation

Question 15

outcomes for treatment of PKU

Answer 15

• near-normal intellectual development following diet uuntil adolescence
• some behavioural effects when off diet as an adult
• concern with pregnancy = maternal PKU

Question 16

following synthesis from PHE, TYR can be metabolized to

Answer 16

fumarate and acetoacetate

Question 17

what happens to phenylalanine, tyrosine, and phenylpyvi acid in PKU?

Answer 17

• phenylalaine = increases
• phenylpyruvic acid increases (toxic byproduct of phenylalanine - after transamination)
• tyrosine decreases

Question 18

deficiency in FAH afects

Answer 18

liver and kidney function

Question 19

succinylcetoacetate and … acetone

Answer 19

tyrosine metaboism

- detected in blood and urine

Question 20

T or F. tandem mass spec detection of succinylacetone is more sensitive and specific than TYR

Answer 20

T! particularly in child w impaired liver function

Question 21

where can succinylacetone be measured?

Answer 21

plasma and rine

• TYR, PHE, MET, and 5-ALA also elevated
• can be measured prenatal in amniotic fluid

= impaired liver function, coagulopathy, and hypoalbuminemia

Question 22

hereditary tyrosinemia (type I)

Answer 22

• clinically variable, presenting across the lifespan with variability within families
• further classified based on age of onset and subsequently the severity of damage to liver (increases with age)

Question 23

what is NTBC

Answer 23

potent inhibitor of 4-hydroxyphenylpyruvate dioxygenase

= prevents yrosine degradation, and production of succinylaccetone

Question 24

treatment and outcomes for PHE and TYR

Answer 24

• resitrct diet
• significant learning difficulties and cognitive deficits affecting performance abilities = unknown
• NTBC
• liver transplant = lifelong immunosuppressive therapy