UK Newborn Screening for X-ALD - progress from a lab perspective

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1 UK Newborn Screening for X-ALD - progress from a lab perspective Mrs. Leila Cornes Senior Clinical Scientist, Newborn Screening Southmead Hospital, Bristol May 2016

2 C26:0-lysoPC C26:0-lysophosphatidylcholine has been shown to be a reliable test in several US studies. High in all males and some females with ALD High in babies with various other peroxisomal defects such as PBDs Existing equipment Samples collected routinely R= C26:0

3 USA screening New York state - began in January 2014 Has screened ~570,000 babies so far identified 39 with ALD (18 boys, 21 girls) 9 others had high C26:0-lysoPC but not ALD Of those 9 8 had PBDs 1 unexplained (Aicardi Goutieres Syndrome) Connecticut state Pilot started 1 st Oct 2015 Going live officially mid-2016 (soon!) California will begin screening in June 2016

4 Connecticut Use negative ion LC-MS/MS assay described by Chris Haynes Screened 23,000 infants so far Identified 2 newborn boys*, 1 girl* and one 2 year old male sibling! 3 other girls had borderline high C26:0-lysoPC, but normal levels when repeated on a second sample. No PBD s yet *awaiting confirmatory tests on 1 boy and 1 girl. first-baby-with-ald-identified-in-ct/

5 In two years

6 Method plan Measure C26:0-lysoPC in newborn bloodspots using a column and MS/MS. Separates it from other interfering compounds Based on the method published by C Haynes (CDC) in 2012 and refined in It s currently used for screening in Connecticut and is working well.

7 Practical Work

8 Samples CDC have prepared bloodspots with known added amounts of C26:0-lysoPC, low medium and high. Ann Moser has provided anonymised venous samples from adults with ALD, including males, female carriers and other peroxisomal disorders. Applying for ethical approval... To anonymise 3000 recent bloodspot samples and measure C26:0-lysoPC in males and females, to see what the levels are in the general newborn UK population.

9 Samples Also applying for ethical approval... To ask children/young people age 25 or younger With ALD (or another peroxisomal disease, inc female carriers of ALD To retrieve their newborn bloodspots from storage Measure C26:0-lysoPC Compare results to the levels in the general UK newborn population

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12 Consent forms Two forms to choose from One for a parent to complete on behalf of a child One for young people age to consent for their own sample to be included in the study Focus group tomorrow 11 11:30am Help make sure the documents are clear and understandable

13 Summary Internationally, a lot of progress has been made in the last few years. Progress in UK is picking up pace, especially this year. More lab work needed to show the test works well in the UK population. Focus group tomorrow 11 11:30am All welcome

14 Acknowledgements Ann Moser Marcus Williams Anny Brown Heather Brown (Waters) Dr Colin Steward ALDlife The Showering Fund Chris Haynes (CDC) Joe Orsini (NY) Adrienne Manning (Connecticut)

15 Further Information

16 UK Screening Timeline 1960 s Phenylketonuria (PKU) 1980 Congenital Hypothyroidism (CHT) 2006 Cystic Fibrosis (CF) 2008 MCADD 2009 Sickle Cell disease (SCD) 2015 Homocystinuria (HCU) MSUD Glutaric Aciduria type 1 (GA1) Isovaleric Aciduria (IVA)?next... X-ALD, SCID, others?

17 first-baby-with-ald-identified-in-ct/

18 C26:0-lysoPC

19 What is the purpose of the study? Why have I been invited? Do I have to take part? What will happen to me if I take part? What are the possible benefits of taking part? What are the possible disadvantages and risks of taking part?

20 If the information above has interested you and you are considering participation, please read the following information before making any decision. What if relevant new information becomes available? What will happen if I don t want to carry on with the study? What if there is a problem? Will my taking part in this study be kept confidential? What will happen to any samples I give?

21 Cut-off: example graph Unaffected X- ALD

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23 My plan UK population screened at 5-8 days of age, whereas USA 1-2 days. Show that the test can tell the difference between ALD and unaffected newborns in UK Prove that the test is reliable and gives consistent results, without false positives (or minimal). Robust method for testing hundreds of bloodspots a day, quickly and cheaply.

24 Method improvement Improved run time from 3.5 mins to 1 minute per sample C24:0-lysoPC also measured to provide a second check.

25 Criteria for screening tests The Condition Should be an important health problem Should be adequately understood - development from latent to declared disease i.e. epidemiology If carriers are identified as a result of screening the natural history of this group of people should be understood, including the psychological implications.

26 Criteria for screening tests The Test There should be a simple, safe, precise and validated screening test. The distribution of test values in the target population should be known and a suitable cut-off level defined and agreed. Positive test - Agreed policy on further tests and on the choices available to those individuals.

27 Criteria for screening tests The Treatment Effective treatment Evidence that early treatment leads to better outcomes than late treatment. The benefit from the screening programme should outweigh the harm (both physical and psychological caused by the test, diagnostic procedures and also treatment). Value for money - Cost (including testing, diagnosis and treatment etc.) should be economically balanced in relation to expenditure on medical care as a whole.

28 Method plan R= C26:0 C26:0-lysophosphatidylcholine

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