Neonatal Screening for Rare IEM

Question 1

What is screened in neonatal screening in the UK?

Answer 1

• Phenylketonuria
• MCAD deficiency
• MSUD
• IVA
• GA1
• Hcys
• Hypothyroidism
• Cystic fibrosis
• Sickle disease

Question 2

What are benefits and limitations of Biochemical Screening by TMS?

Answer 2

Has the potential to detect more than 60 IEM

• Amino acid disorders
• Fatty acid oxidation defects
• Organic acidaemias

Constraints and considerations

• Difficult to use screening experience of other countries
• Different genetic background
• Positive predictive value will vary
• Screening can occur at different days of life

Question 3

What is the screening strategy for Rare IEM neonatal screening?

Answer 3

• In order to minimise harm to families from false positive screening results a two-tier strategy for most conditions has been developed.
• 2nd tier additional test on original bloodspot card
• Need to be available quickly for condition with acute presentation

Question 4

What is MSUD?

Answer 4

Maple Syrup Urine Disease: Defect in branched chain 2-keto acid dehydrogenase complex

Question 5

What are clinical effects of MSUD?

Answer 5

The majority (75-80%) have the classical disease, presenting during the neonatal period:

• Encephalopathy
• Cerebral oedema
• Poor feeding
• Ketoacidosis
• Seizures
• Burnt sugar odour
• A rarer intermediate form is associated with failure to thrive, often no ketoacidosis but developmental delay

Question 6

What is the prevelance and screening target for MSUD?

Answer 6

• Prevalance: About 1:120,000
• Screening target: Leucine
• Second tier test: Alloisoleucine

Question 7

What is the treatment for MSUD?

Answer 7

• Low leucine diet
• Similar to PKU, specialist foods low in leucine for most protein intake
• Encephalopathy risk
  
  • Careful plasma amino acid monitoring
  • Emergency regime
  • Dialysis may be necessary sometimes

Question 8

What is Isovaleric acidaemia?

Answer 8

Isovaleric acidaemia: Deficiency of isovaleryl-CoA dehydrogenase involved in leucine catabolism.

Question 9

What are clinical effects of Isovaleric acidaemia?

Answer 9

• Acute neonatal presentations in the first two weeks of life. Infants are initially well, then develop vomiting and lethargy, progressing to coma.
• Acute presentations at a later age, usually precipitated by an infection.
• Chronic intermittent presentations, failure to thrive and/or developmental delay, usually within the first year.

Question 10

What is the prevelance and screening target for Isovaleric Acidaemia?

Answer 10

• Prevalance: about 1:150,000
• Screening target: isovaleryl carnitine
• Second Tier test: TMS assay specific for C5 carnitine, to exclude 2 methyl butyryl carnitine or pivaloyl carnitine which are isobaric compounds. IT is not used as much

Question 11

What is the treatment of IVA?

Answer 11

• Low protein diet
• Risk of acute metabolic decompensation so Ammonia monitoring and emergency regime, additional calorific support

Question 12

What is Pivaloylcarnitine?

Answer 12

• Pivaloylcarnitine is isobaric with isovalerylcarnitine
• Known and documented cause of interference with TMS assays
• Exogenous compound, 2 common sources of exposure
• Pivaloylcarnitine can be chromatographically separated from isovalerylcarnitine, 2-methylbutyrylcarnitine and valerylcarnitine (C5 isobars)

Question 13

What are 2 common sources of Pivaloylcarnitine?

Answer 13

Pivalic ester pro drugs

• Includes antibiotics such as Pivmecillinam

Some Nipple creams contains pivalate derivatives as emollient

• Appear to be the lanolin free creams eg Mustela nursing balm
• Listed in ingredients as ‘neopentanoate’ or ‘isodecylneopentanoate’

Question 14

What is the second tier test for IVA?

Answer 14

• Inclusion of C5 isobars as a second tier test on the original blood spot sample would have prevented the unnecessary referral of 14 babies between July 2012 and Jan 2017
• Simple test to set up – report as % of total C5
• Challenge would be ensuring continued competency due to infrequent nature of test and would lead to delay in referral, could be a problem at weekends
• Recent evidence indicates that babies with false positive screening results have an increased parental stress index score, increased number of hospital admissions and significant and lasting increase in parental anxiety

Question 15

What is Glutaric Aciduria 1 (GA1)?

Answer 15

Deficiency of Glutaryl-CoA Dehydrogenase which is involved in lysine catabolism

Question 16

What are clinical effects of Glutaric aciduria 1 (GA1)?

Answer 16

• About 70% of patients have an encephalopathic crisis, most commonly at around 9 months, with 90% by age 2 years precipitated by a non-specific intercurrent illness, gastrointestinal infection or pneumonia.
• Leads to dystonia and dyskinesia as permanent sequelae.
• Can cause frontal lobe atrophy in the brain

Question 17

What is the outcome of Glutaric aciduria 1?

Answer 17

• Of symptomatically diagnosed patients about 50% die before the age of 25 years.
• Survivors usually have severe handicap. But the risk of acute crises and neurological damage decreases markedly after the age of six years.

Question 18

What is the prevelance and screening target of Glutaryl Aciduria 1?

Answer 18

• Prevalance: about 1:100,000
• Screening target: Glutaryl Carnitine
• No second tier test

Question 19

What is an extrame presentation of GA1?

Answer 19

• Patients with GA1 can present with sub dural haemorrhage, and may have retinal haemorrhage
• Potential for confusion with physical abuse
• Take note of macrocephaly and cortical atrophy if MRI available
• Be aware that some GA1 patients are ‘non-secretors’

Question 20

What is Homocystinuria?

Answer 20

• Classical” homocystinuria is a defect in β-Cystathionine Synthase
• Pyridoxine responsive and pyridoxine unresponsive forms, in the UK 50% of patients are in each group

Question 21

What are clinical effects of Homocystinuria?

Answer 21

• Usually healthy at birth, the diagnosis is not usually made until the first 2-3 years of life.
• Myopia followed by dislocation of the lens
• Osteoporosis,
• Thinning and lengthening of the long bones
• Mental retardation and thromboembolism

Without treatment, 25% of patients will die before the age of 30, usually due to thromboembolism

Question 22

What is prevalance and screening target of Homocystinuria?

Answer 22

• Prevalance: About 1:150,000 , this is the generally accepted worldwide figure. Likely to be higher in UK (esp The North) due to “Celtic Gene’
• Screening Target: Methionine. Methionine is not raised in the Pyridoxine responsive forms
• Second Tier: Total homocysteine

Question 23

How does the plasma level affect the measurement of urine excretion?

Answer 23

• Homocystine does not appear in the urine until plasma total homocysteine exceeds 150 umol/L (ref <15)
• Urine analysis is less sensitive at detecting disordered metabolism

Question 24

What is the Natural Hisotry of Classical Homocystinuria?

Answer 24

• Lens dislocation: 82% dislocated by age 10 years
• Osteoporosis (x-ray): 64% with osteoporosis by age 15 yrs
• Vascular events: 27% had an event by age 15 years
• Death: 23% will not survive to age 30 years
• Mental Retardation – approx 50%