NORTHERN IRELAND NEWBORN BLOODSPOT SCREENING PROGRAMME

Transcription

1 NORTHERN IRELAND NEWBORN BLOODSPOT SCREENING PROGRAMME APPROVED GUIDANCE, PROTOCOLS AND OPERATING PROCEDURES DOCUMENTS FOR MEDIUM CHAIN ACYL CoA DEHYDROGENASE DEFICIENCY (MCADD) SCREENING REVISED

2 MCADD SOP DOCUMENT / INDEX SCREENING PATHWAY STAGE Ascertainment of Family History and Antenatal and postnatal management Blood Spot Prescreening information and consent MCADD Screening and Diagnostic Pathway DOCUMENT TITLE MCADD Sibling Testing Protocol MCADD Family History Algorithm MCADD Family History Antenatal Referral to Genetic Counselling Team Prescreening Parental Information Leaflet Northern Ireland Blood Spot Consent Policy (Revised 2014) MCADD Newborn Screening Pathway MCADD Calculation of C8:C10 Ratio MCADD Diagnostic Protocol APPENDIX No. A3a A3b A3c AJ AK A2a A2b A8 Clinical Referral/ Clinical Management MCADD Clinical Referral and Clinical A9 Management Protocol Initial Clinical Referral Guidelines and Standards A11 Notification of a Presumptive Positive to Clinical Service MCADD Appointment and Contact Information for Parents MCADD Letter to GP MCADD Letter to A&E/Hospital MCADD is suspected leaflet MCADD and your child leaflet MCADD Information Sheet for Parents /Carers MCADD Letter to Dietician A5 AC A6 A7 AB AD AE AF Post Diagnosis Feedback Presumptive Positive Feedback to CHS AG MCADD Identified Outside AI Screening Report to UKNSPC General Responsibilities and Contact Information AA Laboratory Guide to Newborn Screening in the UK for MCADD (2010) AH N.B. Extended Mutation Screening is carried out according to UK standards as defined in MCADD Diagnostic Protocol (see Appendix A8).

3 APPENDIX 3a MCADD Sibling testing Next baby A new baby has a 1:4 risk of having MCADD and it is important to test at the earliest opportunity. For guidance on testing and management whilst awaiting results refer to MCADD genetic / biochemical sibling testing protocol (Section A). Older siblings Older siblings may be at risk of MCADD even though they may have been asymptomatic to date. It is therefore very important that they are tested as soon as the diagnosis on the proband has been confirmed. Please refer to MCADD genetic / biochemical sibling testing protocol (Section B). 3 MCADD genetic / biochemical sibling testing protocol MCADD Genetic / biochemical sibling test protocol A. Protocol for management of at risk delivery neonatal testing for siblings born after proband diagnosis When to test and samples taken hours: C8, qualitative urinary organic acids and genotyping Write on blood spot card Family history of MCADD Day 5-8: Routine newborn screen Write on blood spot card Family history of MCADD Management Prior to results It is essential to ensure that the baby maintains a good milk intake. A term baby should be fed every 4 hours and a preterm baby every 3 hours. Exclusively breast fed babies are particularly at risk in the first 72 hours when the supply of breast milk is poor; top up feeds of expressed breast or formula milk ** may be necessary in the first hours until a good milk supply is established. If oral feeds are not tolerated or if the baby is unwell in any way, urgent referral should be made to a paediatrician for review and consideration of nasogastric tube feeds or commencing intravenous glucose*. If MCADD confirmed: Follow the standard MCADD clinical and dietary management guidelines* B. Testing siblings born before proband diagnosis When to test Offer to test if sibling has not been previously screened for MCADD and if: Proband has abnormal biochemistry at follow-up visit Or 2 recognised disease causing mutations on genotyping Sibling samples 1. C8 and qualitative urinary organic acids ** Northern Ireland guidance specifies that all breastfed babies with a family history of MCADD should be given top-up FORMULA milk feeds routinely from birth and for the first three complete days of life. In addition, all babies with a family history of MCADD (irrespective of feeding method) require urgent paediatric assessment within two hours of birth to assess feeding (to ensure good intake).

4 2. DNA send for genotyping once definite MCADD diagnosis secured in proband (2 disease causing mutations identified) Management Before the results are available and thereafter if MCADD confirmed: Follow the standard MCADD clinical and dietary management guidelines* C. Genetic counselling In most instances questions about genetic inheritance and risk will be dealt with by the metabolic team, but if there are any outstanding issues, or discussion about prenatal diagnosis, further genetic counselling is available through the local Genetics Service. *For more information please refer to MCADD management and dietary guidelines at Further information / protocols can also be accessed at Taken from Section 3.2 and Appendix 3 of A Laboratory Guide to Newborn Screening in the UK for Medium-chain Acyl-CoA Dehydrogenase Deficiency (MCADD), (2010), UK Newborn Screening Programme Centre, London. Pages 10 and 32. Available at

5 APPENDIX 3b NORTHERN IRELAND NEWBORN BLOOD SPOT SCREENING PROGRAMME ASCERTAINMENT / FOLLOW-UP AND MANAGEMENT OF FAMILY HISTORY OF MCADD INFORMATION FLOWS (INCLUDING POST DELIVERY MANAGEMENT) FINAL 07/01/2014 V2 MIDWIFERY RESPONSIBILITIES (AT TIME OF BOOKING FOR MATERNITY CARE) Enquire re history of MCADD in the pregnant woman or the family of the baby s father; Record outcome of enquiry in NIMATS and the Maternity Hand-Held Record (MH-HR). No history of MCADD No further action (Infant will be offered routine blood spot screening at Day 5) History/probable history of MCADD Refer immediately to Genetic Services, using referral letter (see Addendum 1), cc to obstetric, paediatric/neonatal and paediatric metabolic consultants and the GP. GENETIC SERVICES RESPONSIBILITIES (BEFORE DELIVERY) Consult with family to discuss potential risk to baby and care management; Record outcome and any necessary action in the Infant Care Plan within the Infant Chart of the MH-HR; Write back to the referring maternity service and c.c. to the obstetric, paediatric/neonatal and paediatric metabolic consultants and the GP to advise on the outcome of referral. to advise on the outcome of referral. NO INCREASED RISK OF MCADD INCREASED RISK OF MCADD IDENTIFIED 1 IDENTIFIED MIDWIFERY / NEONATAL NURSING2 RESPONSIBILITIES (AT TIME OF DELIVERY) Contact the Neonatologist/Paediatrician immediately to effect paediatric assessment within 2 hours of birth; 3 Refer to the Infant Care Plan within the Infant Chart of the MH-HR; Arrange early blood spot sample collection (24-48 hours of age); 4, 5 Ensure term babies are fed every four hours and preterm babies every three hours. BREASTFEEDING? No No additional feeding management to above regimen required Yes PROVIDE REGULAR (4 hourly for term and 3 hourly for preterm babies) TOP-UP FORMULA MILK FEEDS FROM BIRTH AND FOR THE FIRST THREE COMPLETE DAYS OF LIFE. NEWBORN SCREENING LABORATORY RESPONSIBILITIES Test early sample and report to the Paediatric Metabolic Service (irrespective of outcome). PAEDIATRIC METABOLIC SERVICE RESPONSIBILITIES Contact family to inform them of result; Write to the obstetric, paediatric/neonatal consultants, Genetic Service and the GP to provide result. MCADD not suspected MCADD suspected Initiate clinical referral/clinical management protocol 5 Notes 1 Early testing, feeding management and early paediatric assessment should be put in to operation where the family history of MCADD has not been identified prior to delivery and there has not been opportunity to refer to Genetics. 2 Where infant is in a neonatal unit. 3 Immediate medical assessment is required if the baby is not feeding well or becomes unwell. 4 The early sample should not be collected before the baby is 24 hours old as MCADD test results may not be accurate. Samples should be clearly marked MCADD family history (top right-hand corner of blood spot card). 5 A full blood spot card should be taken and submitted to the regional newborn screening laboratory as normal, at Day 5.

6 Referral Letter to Genetic Services re. MCADD Family History APPENDIX 3c TRUST LOGO Addressograph label Mother s Name:. Address:.. Maternity Unit:.. Consultant Obstetrician:. Consultant Paediatrician:. GP: HC: Hospital No:.. Parity:. DOB:.. EDD:. Tel:... Date: Our Ref: Your Ref: Genetic Counselling Team (urgent MCADD referral) N.I. Regional Genetics Service Level A Belfast City Hospital Lisburn Rd Belfast BT9 7AB Dear Genetic Counselling Team RE: Family History of MCADD The above named woman is pregnant and she has informed us that there is a family history of MCADD. I would be grateful if you could arrange an appointment for her at the Regional Genetic Counselling Clinic to discuss her unborn baby s potential risks and care management plan. She has been asked to bring her Maternity Hand Held Record (MHHR) to the appointment. Please document your opinion and recommended management plan in the Infant Care Plan section within the Infant Chart of her MHHR and inform her Obstetrician, Paediatrician, the Consultant in Paediatric Metabolic Services and GP in writing. Yours sincerely Name:.Status::. cc Consultant Obstetrician Consultant Paediatrician Dr Siobhan O Sullivan, Consultant in Paediatric Metabolic Services, RBHSC, 180 Falls Road, Belfast BT12 6AB General Practitioner Copy for parent s information to be filed in MHHR

7 Appendix J Newborn blood spot screening for your baby In the first week after birth, you will be offered a blood spot screening test for your baby. Why should babies be screened? Newborn blood spot screening identifies babies who may have rare but serious conditions. Most babies who are screened will not have any of the conditions but, for the small numbers who do, the benefits of screening are enormous. Early treatment can improve their health and prevent severe disability or even death.

8 Appendix J What are newborn babies screened for? All babies in Northern Ireland are offered screening for phenylketonuria, congenital hypothyroidism, cystic fibrosis, sickle cell disorders and MCADD (medium chain acyl CoA dehydrogenase deficiency). Phenylketonuria About 1 in 6,000 babies born in Northern Ireland has phenylketonuria (PKU). Babies with this inherited condition are unable to process a substance in their food called phenylalanine. If untreated, they will develop serious, irreversible, mental disability. Screening means babies with PKU can be treated early through a special diet, which will prevent severe disability and allow them to lead a normal life. If babies are not screened, but are later found to have PKU, it may be too late for the special diet to make a real difference. Congenital hypothyroidism About 1 in 3,000 babies born in Northern Ireland has congenital hypothyroidism (CHT). Babies with CHT do not have enough of the hormone thyroxine. Without this hormone, they do not grow properly and can develop serious, permanent, physical and mental disability. Screening means babies with CHT can be treated early with thyroxine medicine, which will prevent serious disability and allow them to develop normally. If babies are not screened and are later found to have CHT, it may be too late to prevent them becoming seriously disabled.

9 Appendix J Cystic fibrosis About 1 in 2,500 babies born in Northern Ireland has cystic fibrosis (CF). This inherited condition can affect the digestion and lungs. Babies with CF may not gain weight well and may have frequent chest infections. Screening means babies with CF can be treated early with a high-energy diet, medicines and physiotherapy. Although children with CF may still become very ill, early treatment is thought to help them live longer, healthier lives. If babies are not screened for CF and they do have the condition, they can be tested later, but parents may have an anxious time before CF is recognised. Screening for CF includes testing some babies for the most common gene alterations that cause the condition. This means screening may identify some babies who are likely to be genetic carriers of CF. These babies may need further testing to find out if they are a healthy carrier or have CF. Sickle cell disorders About one in 5,000 babies born in Northern Ireland has a sickle cell disorder (SCD). These inherited conditions affect the red blood cells. Babies with an SCD have red blood cells that can change to a sickle shape and become stuck in the small blood vessels. This can cause pain and damage to the baby s body, serious infection, or even death. Screening means babies with an SCD can receive early treatment, including immunisations and antibiotics, which, along with parent education, will help prevent serious illness and allow children to live healthier lives.

10 Appendix J Screening may also identify babies who are genetic carriers of an SCD or another unusual red blood cell disorder. Carriers of sickle cell disorders are healthy and do not require treatment. Rarely, screening identifies other conditions, such as thalassaemia, which may affect red blood cells. MCADD About 1 in 10,000 babies born in Northern Ireland has MCADD. Babies with this inherited condition have problems breaking down fats to make energy for the body. This can lead to serious illness or even death. Screening means most babies with MCADD can be recognised early, allowing special attention to be given to their diet, including making sure they feed regularly. This care can prevent serious illness and allow babies with MCADD to develop normally. Screening babies for MCADD is important so that those with the condition can be identified before they become suddenly and seriously ill.

11 Appendix J What if there is a family history of MCADD? Before your baby is born, you should inform the health professional (obstetrician or midwife) looking after you if you or your partner has a family history of MCADD. You will be offered referral to a genetic specialist, who will be able to answer any questions or discuss any concerns you may have. You may be advised that your baby needs early screening. Details of the information given to you about early screening and anything special you will need to do after your baby is born will be recorded in your maternity hand-held record. If early screening is recommended, the midwife/nurse will collect a small sample of blood from your baby s heel onto a blood spot card marked MCADD family history. This will happen between hours following birth and results will usually be available within 48 hours of the sample being taken. Babies who are screened early because there is a family history of MCADD will still need to have a routine blood spot screening test when they are five days old. Where there is a family history of MCADD, it is important to ensure that your baby has a good milk intake. A term baby should be fed every four hours from birth, and a pre-term baby every three hours. There are particular risks in the first 72 hours for breastfed babies due to the amount and content of breast milk during this period. It is therefore recommended that breastfed babies receive top-ups of formula milk until a good supply of breast milk is established. Will blood spot screening in Northern Ireland show up anything else? Blood spot screening may also identify a number of rare metabolic diseases such as homocystinuria and tyrosinaemia.

12 Appendix J How will the midwife/nurse take the blood spots? The midwife/nurse will prick your baby s heel using a special device to collect some drops of blood onto a card. The heel prick may be uncomfortable and your baby may cry. How can you help? Make sure your baby is warm and comfortable. Be ready to feed and/or cuddle your baby. Are repeat blood samples ever needed? Occasionally, the midwife or health visitor will contact you and ask to take a second blood sample from your baby s heel. This may be because there was not enough blood collected previously or the first result was unclear. The repeat results are usually normal. Screening is recommended Screening your baby for all these conditions is strongly recommended, but it is not compulsory. If you do not want your baby screened for any or all of these conditions, discuss it with your midwife. All your decisions will be recorded in your notes and in your baby s personal child health record ( Red Book ). If you think your baby may not have been screened, speak to your midwife or GP. How will you hear about the results? Most babies will have normal results, indicating that they are not thought to have any of these conditions. A health professional will usually inform parents of the screening results and record them in the personal child health record ( Red Book ) before the baby is eight weeks old. If you have not been given the results by the time your baby is eight weeks old, please speak to your health visitor.

13 Appendix J If your baby is thought to have one of the conditions, he or she will need further tests to confirm the results. You will normally be contacted within three or four weeks of the initial test being carried out. The purpose of screening is to identify babies more likely to have these conditions. Screening is not 100% accurate. What happens to your baby s blood spots after screening? After screening, newborn blood spots are stored for at least five years and they may be used in a number of ways: To check the result or for other tests recommended by your doctor. To improve the screening programme. For public health monitoring and research to help improve the health of babies and their families in the UK. This will not identify your baby and you will not be contacted. The use of these blood spots is governed by a code of practice, available from your midwife. Alternatively, you can visit: There is a small chance researchers may want to invite you or your child to take part in future research linked to the blood spot programme. If you do not wish to receive invitations to take part in research, please let your midwife know. For further information, ask your midwife or visit: For further information about family history of MCADD, visit: For translations of this leaflet, ask your midwife or visit:

14 Appendix J For local information: All retained records relating to newborn blood spot screening meet the requirements of the 1998 Data Protection Act. This leaflet is based on high-quality research evidence and the views of parents and health professionals. It has been adapted in Northern Ireland with the permission of the UK Newborn Screening Programme Centre. Public Health Agency, Ormeau Avenue Unit, 18 Ormeau Avenue, Belfast BT2 8HS Tel: Textphone/Text Relay: /12

15 Appendix K NORTHERN IRELAND NEWBORN BLOOD SPOT SCREENING PROGRAMME CONSENT POLICY / PROCEDURE Information Provision By the third trimester1 pregnant women should be told about the newborn blood spot screening programme (see Addendum A, page 3) and given the blood spot prescreening parental information leaflet. This should be recorded in the Maternity Hand-Held Record. Suggested recording on Maternity Hand-Held Record: Newborn blood spot screening discussed. Leaflet given. Following birth the newborn blood spot pre-screening parental information leaflet should be provided to parents at least one day before the blood spot screen is offered and the test discussed (see Addendum A). This should be recorded in the Maternity Hand-Held /Professional Record. Suggested recording on Maternity Hand-Held/Professional Record: Newborn blood spot screening discussed and recommended. Leaflet given. Where a baby is admitted to a special care facility2 and BEFORE the first blood transfusion, two blood spots should be taken for newborn sickle cell disorders (SCD) screening. However, parental consent to testing for SCD is not sought until the offer of screening at Day 5 (see Revised Northern Ireland Pre-transfusion SCD Protocol). Parental Consent / Decline To Blood Spot Screening Parents may opt out of the programme or may decline any one or more of the tests offered in the blood spot screening programme, i.e. phenylketonuria (PKU), homocystinuria, tyrosinaemia, congenital hypothyroidism (CHT), medium chain acyl coa dehydrogenase deficiency (MCADD), SCD or cystic fibrosis (CF)*. The consent process (or decline) does not require a parental signature but health practitioners should document the parent s decision in the Maternity HandHeld/Professional Record and within the personal child health record (PCHR).3 Suggested recording on PCHR and Maternity Hand-Held/Professional Record: The parent consents to the screening programme: Newborn blood spot screening performed with parental consent. OR The parent declines all or part of the screening programme: Parent declined ALL / named test(s)* blood spot screening. Clarified decision. Discussed reason (record reason given). Told to contact midwife/hv/gp if parent changes decision. For CF screening, consent and decline is to the approved Northern Ireland CF Screening Protocol, which in 0.5% of cases will involve genetic testing. No alternative CF screening protocol can be offered. Revised Final 4th March 2014 Page 1 of 4

16 Appendix K Parental Decline Information Flow 1. Where a parent declines all or part of the newborn blood spot screening programme the practitioner offering the test should clearly record the details of decline on the blood spot card (top right-hand corner of the card in block capitals) and forward the card as normal to the newborn blood spot screening laboratory. Date of decline should be recorded in the Date of Specimen area of the card. 2. Details of the decline should also be clearly documented in the baby s personal child health record (PCHR)3 as well as in the maternity handheld/professional record. 3. The practitioner offering the newborn blood spot screening programme is responsible for informing the GP if one or more tests have been declined. 4. The newborn screening laboratory will routinely report declined screens to the Child Health System (CHS)4 along with other results. 5. CHS will record the outcome of screening on the baby s CHS record using the status code 02 (from information received from the laboratory). 6. CHS will send a copy of the laboratory report to the baby s GP and forward the original reports to the health visitor as normal. 7. All results (including declined screens) will be reported in duplicate and health visitors will be required to insert a copy of the results into the PCHR (after page 23). The response to the offer of screening can only be recorded as Yes or Declined at time of offer. Where parents do not give consent or wish to defer their decision, the outcome of offer should be recorded as Declined. The practitioner should follow guidance on declined screening (see Parental Decline Information Flow (1-7 above) and Addendum A, Information Given to Parents Parental Decline to Screening). Opting Out of Future Contact For Research Purposes Where parents indicate that they do not wish to be invited to take part in any possible future research involving the blood spot, the practitioner taking the blood spot sample should document this on the blood spot card (top right-hand corner of the card in block capitals) before sending it to the newborn blood spot screening laboratory. Suggested recording on blood spot card and Maternity Hand-Held/Professional Record: No research contact The parents will not be contacted regarding patient identifiable research. 1 Blood spot screening information should be shared along with information about Newborn Examination and Newborn Hearing screening before 30 weeks gestation. 2 The responsibility for the offer and testing of infants admitted to special care facilities, including NICU, PICU, SCUBU, infant surgery etc., lies with nursing staff in the special care facility. 3 Practitioners offering the blood spot screening programme should circle either Yes or No against Parental Consent Obtained within the Newborn Blood spot section of page 23 of the PCHR. Details of decline should be recorded in the Discharge Note section of page Blood spot screening information is managed by local Child Health Offices in the Northern CHS area and by the CHS Bureau / Central Offices in Southern, Eastern and Western CHS areas. Revised Final 4th March 2014 Page 2 of 4

17 Appendix K Addendum A INFORMATION GIVEN TO PARENTS ABOUT THE NEWBORN BLOOD SPOT During Pregnancy The need to collect some drops of blood from the baby s heel when 5 days old; The blood is used to test for very rare conditions phenylketonuria (PKU), homocystinuria, tyrosinaemia, congenital hypothyroidism (CHT), sickle cell disorders (SCD), cystic fibrosis (CF) and medium chain acyl coa dehydrogenase deficiency (MCADD); The midwife will talk more about the tests after the baby is born; Screening for these conditions is strongly recommended; Screening is important because if a baby has one of the conditions, it can be diagnosed and treated quickly to prevent potentially serious health problems; Where there is a family history of MCADD practitioners MUST offer referral to a genetic specialist during pregnancy. Where an increased risk of MCADD is identified, baby will require early screening (between 24 and 48 hours following birth), urgent paediatric assessment within 2 hours of birth (to assess feeding to ensure good intake) and regular feeding (every 4 hours for term and every 3 hours for preterm babies) from birth. All breastfed babies with a family history of MCADD should be given regular (4 hourly for term and 3 hourly for preterm infants) top-up formula milk feeds from birth and for the first three complete days of life. If they have any questions about blood spot screening they can speak to their midwife. Following Birth Include information above and take time to explain: Information about the conditions that are being screened for; Sometimes a second heel prick is needed; They will receive the results by the 6-8 Week Health Review and the health visitor will usually let the parent know the results; Testing for cystic fibrosis (CF) and sickle cell disorders (SCD) can provide some information about the baby s genes. Some babies will be found to be carriers of CF, the sickle cell gene or other unusual haemoglobins. This does not mean that the baby will necessarily have the condition; The screening tests are not 100% accurate but are the best possible way to identify babies who are likely to have the conditions; Parents can decline all or some of the tests. They can discuss this with their midwife; If they have any concerns or questions they should speak to their midwife; Revised Final 4th March 2014 Page 3 of 4

18 Appendix K Blood spot cards are stored for a minimum of 5 years, used to check the screening results and other tests recommended by the doctor. They are also used for public health monitoring and research to help improve the health of babies and their families in the UK. No babies are identified with this and parents will not be contacted; There are occasions when parents may be invited to take part in other research linked to the blood spot. If parents do not want to receive invitations this will be recorded on the blood spot card and the parents will not be contacted. Where an infant has received a blood transfusion before the Day 5 test and a pre-transfusion SCD blood spot test has not been taken 5 Where a pre-transfusion SCD test has not been taken for an infant transfused before the Day 5 blood spot test, it is important for the practitioner to explain to the parent at time of offer that it will be necessary for the newborn blood spot screening laboratory to arrange a DNA test for SCD. The practitioner taking the Day 5 blood spot test needs to clearly indicate on the blood spot card that the infant has had a blood transfusion as well as record the date and time of completion of the latest blood transfusion. The DNA testing for SCD information leaflet should be given to the parents (see Addendum A, Revised Northern Ireland Pre-transfusion SCD Protocol). Parents need to be aware of the following: A DNA test for the sickle cell gene is used for babies who have not had a Pretransfusion SCD blood test but have had a blood transfusion before the Day 5 test. The DNA test looks for sickle cell genes to identify babies who have sickle cell disease or those who carry the sickle cell gene. The test does NOT identify babies with other rare haemoglobin conditions or those who are carriers of other unusual haemoglobin variants. Parental Decline to Screening All decisions will be respected. Would the parents like to discuss the tests with another person? Would the parents be willing to explain their reasons for their decision? Explain the need for the parents to inform health practitioners if their baby becomes unwell that they have not been tested for (name of condition). The baby can be screened when older 6 but if the baby does have one of the conditions the benefits of the tests are smaller if done when the child is older. 5 See Revised Northern Ireland Pre-transfusion SCD Protocol 6 Screening for PKU, homocystinuria, tyrosinaemia, CHT, MCADD and SCD is offered up to the age of 1 year. CF screening is only appropriate for infants up to 8 weeks of age (<57days). Revised Final 4 th March 2014 Page 4 of 4

19 Appendix 2a MCADD newborn screening protocol tant Letter

20 Appendix 2b Dec MCADD - Methodology for C8:C10 Ratio tant Letter Review date Dec. 2012

21 Appendix 8 2nd Edition Dec Review date Dec. 2012

22 2 nd Edition Dec Review date Dec. 2012

23 2 nd Edition Dec Review date Dec. 2012

24 APPENDIX 9 (NI) Revised V1 07/01/14 NORTHERN IRELAND MCADD CLINICAL REFERRAL AND CLINICAL MANAGEMENT PROTOCOL * Presumptive positive MCADD** LABORATORY RESPONSIBILITIES 1 On same day (as report is available in laboratory) notify MCADD Metabolic Specialist (Consultant or Specialist Registrar) by telephone and in hard copy; notify MCADD suspected result to CHS (in duplicate). MCADD METABOLIC SPECIALIST RESPONSIBILITIES On same day (as notified by Laboratory) arrange first review appointment (to take place within 24 hrs); contact GP by phone to advise of screening result and request GP to make appropriate face to face contact with the family that day; fax/ the following information to GP: GP letter, MCADD is suspected leaflet, A&E letter, contact details for MCADD specialist team and appointment time and location; request GP to give the above information (except GP letter) when first family contact is made. GP RESPONSIBILITIES On same day (as contacted by MCADD Metabolic Specialist) make Face to Face contact with family to inform them of presumptive positive screening result; provide hard copies of above information to family; establish if family will be able to attend the First Review contact, as appointed; contact MCADD Metabolic Specialist to advise that contact has taken place and advise of the outcome of appointment offer. MCADD METABOLIC SPECIALIST RESPONSIBILITIES First Review by MCADD Metabolic Team face to face within 24 hours of screening result obtain consent for DNA testing; take diagnostic samples; *** provide Dietetic review/emergency regimen (ER) teaching; Metabolic Specialist to ensure: Family has received: MCADD metabolic specialist team contact details, A&E letter, appropriate dietary and ER guidelines Letters have been sent to GP, local paediatrician, local dietitian, as necessary; st provide appointment time and location for 1 Follow-Up Visit. st 1 follow up visit st within 5 working days of 1 face to face review Clinical review and results: Octanoylcarnitine (C8), qual urine organic acid (UOA), 985A>G mutation analysis Arrange sibling screening if MCADD confirmed**** If diagnosis not confirmed see diagnostic protocol*** Advise re need for early screening of future babies. nd 2 follow up visit st within 15 working days of 1 follow up visit Clinical review and results:extended mutation screening, quantitative UOA. Arrange sibling screening if MCADD confirmed **** Advise re need for early screening of future babies. MCADD CONFIRMED5 MCADD CONFIRMED5 No Yes Yes Weaning follow up visit Dietetic and clinical review (weaning) at 4-6 mths of age. Further follow up visits as needed No Post-weaning follow up visit Dietetic and clinical post-weaning No further action

25 APPENDIX 9 (NI) Revised V1 07/01/14 * See MCADD Clinical Referral Guidelines and Standards for further details (UK MCADD Laboratory Handbook (December 2010) Appendix 10) ** See MCADD Screening Protocol for details (UK MCADD Laboratory Handbook (December 2010) Appendix 2) *** See MCADD Diagnostic Protocol for details (UK MCADD Laboratory Handbook (December 2010 Appendix 8) **** See MCADD Sibling Protocol for details (UK MCADD Laboratory Handbook (December 2010) Appendix 3) 1 As per UK standards and guidance (see Appendix H), the newborn screening laboratory operates both daily testing and result services Monday-Friday, excluding statutory holidays. Presumptive positive results identified on Fridays / before Bank Holidays (up to 3.30pm) are notified to the MCADD Metabolic Specialist and all efforts are made to ensure that First Review with the family takes place the following day. 2 See Appendix 5 - N Ireland version Presumptive Positive MCADD Letter to GP, which has been adapted from the UK MCADD Laboratory Handbook Appendix 6. 3 See Appendix B for MCADD Is Suspected information leaflet for parents. 4 See Appendix 7 - N Ireland version MCADD A&E Letter, which has been adapted from UK MCADD Laboratory Handbook Appendix 7. 5 MCADD Metabolic Specialist to inform GP and Laboratory in writing when diagnosis is confirmed. Laboratory to notify CHS of confirmed case. CHS to record diagnosis on CHS, using ICD10 and provide hard copy of diagnostic feedback to the family HV. N.B. In relation to MCADD Sibling Testing Protocol, Northern Ireland guidance specifies that all breastfed babies with a family history of MCADD should be given top-up FORMULA milk feeds routinely from birth and for the first three complete days of life. In addition, all babies with a family history of MCADD (irrespective of feeding method) require urgent paediatric assessment within two hours of birth to assess feeding (to ensure good intake). Immediate medical assessment is required if the baby is not feeding well or becomes unwell. Practitioners should refer to the Infant Care Plan within the Infant Chart of the Maternity Hand-Held Record.

26 Appendix 10 2nd Edition Dec Review date Dec. 2012

27 2 nd Edition Dec Review date Dec. 2012

28 2 nd Edition Dec Review date Dec. 2012

29 2 nd Edition Dec Review date Dec. 2012

30 N Ireland Final Version - 14 th January 2009 Appendix 5 (NI) Laboratory Notification of Presumptive Positive MCADD to the Metabolic Specialist Team For Patient's Notes Baby's Name: Sex: D.O.B: Health + Care Number: Address: Trust of Residence: GP: To the Metabolic Consultant, Specimen Date: Date of Receipt of Specimen: Date of Report: The above baby was found to have a positive newborn screening test result for medium-chain acyl-coa dehydrogenase deficiency (MCADD). The blood spot octanoylcarnitine (C8) was mol/l whole blood (mean of triplicate results). (The screening tests for phenylketonuria, congenital hypothyroidism, tyrosinaemia type I, homocystinuria are, and cystic fibrosis is ) The acylcarnitine full scan analysis shows:- Recommended action as per MCADD clinical management protocol and diagnostic protocols:- First review appointment to take place within 24 hrs Venous blood from baby for acylcarnitines (C8 and full scan), DNA (985A>G and extended mutation analysis) Urine for qualitative/ quantitative organic acid analysis Reported to: Date Signed: Date Review date July 2010

31 Final Version 18 th February 2009 APPENDIX C MCADD METABOLIC SERVICES APPOINTMENT AND CONTACT INFORMATION FOR FAMILY To the parent / guardian of: Baby s Name: Baby s DOB: / / Address: An appointment has been made for you and your baby to see Dr, at the MCADD Metabolic Clinic as follows: DATE: TIME: / / am / pm (please delete as appropriate) LOCATION:. If there is anything you would like to discuss with the doctor before the appointment please contact the following number:. Signed: Status: Date: / /

32 APPENDIX 6 MCADD LETTER TO GP N Ireland Revised September 2013 [Date] Dear Doctor Re: [insert full name and date of birth of child] [Name of child] has been detected on newborn screening to have a positive (abnormal) test for medium-chain acyl-coa dehydrogenase deficiency (MCADD). This is a rare inherited enzyme deficiency which reduces the metabolism of fat into energy. A child with this condition is at risk from hypoglycaemia, coma and death with fasting and particularly during intercurrent illnesses when the demand for energy increases and calorie intake is often reduced. He/she may appear drowsy or lethargic, vomit, have seizures or have a deteriorating conscious level. Hypoglycaemia is a late sign; treatment must be initiated if [Name of child] is unwell even if the blood sugar is normal. A patient with MCADD requires no special treatment when well apart from avoiding prolonged fasts. Breastfeeding is not contraindicated but it is important to ensure that the infant is feeding adequately. Formula feeds rich in medium chain triglycerides (MCT) should be avoided. The family will be taught to use an Emergency Regimen (ER) during intercurrent illness, details of which will be sent to you. The aim is to supply readily available calories to avoid mobilising the fat stores and therefore avoid decompensation. Oral Rehydration Therapy (ORT) solutions do not contain sufficient calories to avoid decompensation, and if used require fortifying with glucose polymer. The family will have a recipe for this. If the ER is not tolerated, or the child s condition deteriorates, then urgent admission to the local hospital should be arranged for an intravenous 10% dextrose infusion with appropriate electrolyte additives. A copy of the A&E letter the parents will be given is attached. When the child is well, they should return to their usual feeds. The positive test so far is a screening test, and therefore it is essential to meet with the family to further explain the condition and to confirm the diagnosis. This will entail blood and urine tests. As discussed on the phone, the parents are to attend [Appointment location] at [appointment time] to be seen by the metabolic team. If the parents would like to discuss any matters prior to this review, Dr Siobhan O Sullivan or Dr Grainne Connolly may be contacted on (or via Royal Hospitals switchboard). The long-term prognosis for MCADD is very good once diagnosed providing that the emergency regimen is followed as directed. Immunisations should be undertaken as normal, and general care is unaltered. The condition is inherited in an autosomal recessive fashion, with a 1:4 risk of recurrence in each pregnancy. Once the diagnosis has been confirmed, screening of any siblings will be offered. If you have any further questions, please do not hesitate to contact either of us via the number above. With kind regards Yours sincerely Dr Siobhan O Sullivan Consultant Paediatrician Enclosures for parents: A&E letter MCADD is Suspected parental information leaflet Contact information MCADD Team and appointment details

33 MCADD A&E / Hospital Letter APPENDIX 7 Northern Ireland Final 14 th January 2009 To Whom It May Concern: This child has (or is currently being investigated for a positive newborn screening test for) medium-chain acyl-coa dehydrogenase deficiency (MCADD). Children with MCADD have a reduced ability to metabolise fat to provide energy. Infections, fasting, vomiting or diarrhoea result in the accumulation of medium chain fats, which form toxic metabolites. This can lead to serious illness with encephalopathy and even death. Hypoglycaemia may only occur at a relatively late stage; treatment must not be delayed just because the blood glucose is normal. Treatment aims to inhibit mobilisation of fat by providing ample glucose. During intercurrent infections, parents will use an emergency regimen (ER) of frequent glucose polymer drinks but if this is not tolerated or there is clinical deterioration they have been instructed to attend the hospital urgently for further management. Assess Brief parent-held guide to MCADD hospital management* Responsiveness / conscious level record Glasgow coma score U&E, Blood Gases, Glucose (stick test + laboratory measurement), other tests as indicated Vomiting or diarrhoea or not tolerating feed/er or altered consciousness or blood glucose < 3.0 mmol/l 1. IV 10% glucose bolus 2ml/kg (200 mg/kg) 2. If poor circulation / shock, follow with 20ml/kg 0.9% sodium chloride 3. Whilst the maintenance fluid is being made up, continue 10% glucose at 5ml/kg/hr 4. Maintenance fluid given as 10% glucose with 0.45% sodium chloride. This solution can be made up as follows: Remove and discard 50ml from a 500 ml bag of 0.45% sodium chloride & 5% glucose solution, then add 50ml of 50% glucose to the fluid remaining in the bag 5. Correct any fluid / electrolyte deficits; add potassium once U&E status is known 6. Admit & notify metabolic team (contact details below) 7. Monitor blood glucose 4 hourly during acute phase 8. Adjust IV infusion rate to maintain blood glucose 4-8 mmol/l 9. Continue infusion until blood glucose stable and tolerating usual oral feeds Asymptomatic and glucose < 3.0 mmol/l Oral or nasogastric ER until glucose within normal range and clinically recovered and stable Note: Oral rehydration solutions do not contain sufficient glucose to avoid decompensation and therefore, if prescribed, must be fortified with glucose polymer see MCADD Dietary Information Sheets for ER recipe, available at Please notify the metabolic team below if this child is admitted. [INSERT CONTACT DETAILS FOR METABOLIC TEAM] If you have any questions, please do not hesitate to contact the metabolic team as above. *MCADD dietary management guidelines are available at *Further detailed information/protocols can also be accessed at Review date July 2010

34 APPENDIX B Medium-chain acyl-coa dehydrogenase deficiency (MCADD) is suspected 5 year old boy with MCADD What is my baby s screening result? When your baby was about one week old, your midwife took some blood from your baby s heel. This blood test is offered to all newborn babies and tests for some rare conditions, including MCADD. This screening test result suggests that your baby may have MCADD. Your baby now needs further tests to check whether she/he has MCADD or not. This leaflet gives you some information about MCADD and what happens next.

35 APPENDIX B What is MCADD? 5 month old girl with MCADD During long periods between eating, the body breaks down its own fat stores to produce energy. People with MCADD lack one of the enzymes needed to do this. They can break down the stored fat partly but not completely. There is a hold up at the medium-chain fat step where the enzyme needed to complete the breakdown is not working properly. This causes a build up of medium-chain fats. Sometimes we need to break down fats quickly, for example, when we have not eaten for some while or when we have an infection. People with MCADD can t do this. The medium-chain fats can build up and make toxic substances that may lead to serious symptoms. If this condition is not diagnosed early or is ignored and not treated by following simple advice from a specialist medical team, it could lead to serious illness and possibly death. Fortunately once diagnosed MCADD is usually quite straightforward to manage and children with this condition usually lead healthy normal lives.

36 APPENDIX B What happens next? You have been given an appointment to see a specialist medical team. They will discuss the screening test result with you arrange for your baby to have a blood test and a urine test give you more advice about feeding your baby until the results of these further tests are known usually the results are available within 2 weeks support you now and in the future if your baby has a confirmed diagnosis of MCADD give you advice on what to do if your baby is not feeding well for any reason let your family doctor know about your baby s tests and MCADD give you written information about MCADD to share with your family and local hospital answer any questions you have What treatment is available for MCADD? MCADD is treated by diet. When the child is well, there is no specific dietary management apart from avoiding long periods without food. The well child can be on a normal, healthy diet. During illness an emergency diet of very frequent drinks containing glucose polymer is needed to supply energy.

37 APPENDIX B Parents of babies with MCADD often ask the following questions: How should I feed my baby until I see the specialist medical team? You can breast feed or bottle feed your baby with normal infant formula. You should feed your baby 3 to 4 hourly day and night, or more often if demanded. Your baby should not fast (go without a feed) for longer than 6 hours. If your baby is not feeding well, contact your doctor. It is important to tell them that MCADD is suspected. Why do some children have MCADD? MCADD is an inherited condition due to an altered gene. It is not caused by anything which happened during pregnancy. Everyone carries a few genes that become altered in some way and are passed on sometimes unknowingly in families. A baby with MCADD has inherited two copies of an altered gene, one from each parent, which together cause MCADD. When two people with this gene alteration have a baby, they have a 1 in 4 (25%) chance in every pregnancy of having a child with MCADD. There is nothing the parents could have done to prevent their child having MCADD.

38 APPENDIX B What is life like for children with MCADD? Children with MCADD are able to live full and active lives, just like any other children, provided they eat regularly and avoid long periods without food. In case of illness, when a child is not able to eat or keep food down, a visit to hospital may be needed to make sure the child quickly gets glucose. 5 month old girl with MCADD

39 APPENDIX B Where can I find more information or support? You can find more information about MCADD on the UK Newborn Screening Programme Centre website ( and follow the Public Information link. Climb (the National Information Centre for Metabolic Diseases) provides information and support for people with MCADD and their families. You can contact them as follows: Climb Building, 176 Nantwich Rd, Crewe CW2 6BG Telephone helpline: (freephone) or Website: info@climb.org.uk

40 Baby being screened APPENDIX B If your baby becomes unwell before your hospital appointment with the specialist medical team you should seek medical advice. It is important that the healthcare professional you contact is aware of this screening result for MCADD and we suggest that you show them this leaflet.

41 APPENDIX B Updated: November Review date: November 2012 All records kept relating to newborn blood spot screening meet the requirements of the 1998 Data Protection Act. This leaflet is based on high-quality research evidence and the views of parents and health professionals. It has been produced by the UK Newborn Screening Programme Centre, which is funded by the Department of Health for the whole of the UK. Crown Copyright 2010 A UK National Screening Committee publication

42 APPENDIX D Screening Programmes MCADD and your child The following gives you information about MCADD and how your child will be followed-up by health care professionals.

43 What is MCADD? It is a metabolic disorder where the child has difficulty breaking down fats quickly enough to provide energy. This only becomes a problem during illness or prolonged periods of not eating. MCADD itself does not cause any other illnesses. Children with MCADD can lead normal, healthy and active lives as long as they adhere to guidelines. About 1 in 10,000 babies born in the UK have MCADD. Newborn screening allows us to identify these babies who have this lifelong condition. What causes MCADD? APPENDIX D MCADD is an inherited genetic condition due to an altered gene. It is not caused by anything which happened during pregnancy. There is nothing the parents could have done to prevent their baby having MCADD. Everyone has a number of genes that are altered in some way which are passed on unknowingly in families. A baby with MCADD has inherited two copies of an altered gene, one from each parent, which together cause MCADD. When two carriers with this gene alteration have a baby, they have a 1 in 4 (25%) chance in every pregnancy of having a baby with MCADD. This is known as autosomal recessive inheritance.

44 APPENDIX D How MCADD is inherited You Your partner Usual gene Usual gene Altered gene Altered gene Altered genes only Usual gene and altered gene Usual gene and altered gene Usual genes only Child has MCADD (1 in 4 chance) 25% Child is a carrier (2 in 4 chance) 50% Child is a carrier Child is not affected (1 in 4 chance) 25% How is MCADD treated? Children with MCADD do not require any special medications. The day to day management is simple; to avoid prolonged periods without feeding/eating. Children should eat a normal healthy diet and be treated like any other child. However, during illness children need to be managed correctly to prevent serious illness or even death. If your child becomes unwell or is not feeding well they should be given a special drink (glucose polymer based), frequently, and without delay, day and night. This is called the Emergency Regimen. The special drink is given to provide the body with plenty of energy and to help prevent the breakdown of body fats. If you think your child is not responding to the treatment or is not able to take all of it, you should take your child to the hospital.

45 APPENDIX D Depending on the illness your child may be given glucose via an intravenous drip into the vein. This care can prevent serious illness and allow your child to develop normally. At hospital appointments with your MCADD team you will be given written and verbal guidance on the management of illness. This will cover when you are at home, in hospital and when travelling abroad. You will also be advised on how long, generally, your child may go without food or drink. There are 3 stages which the medical team will follow once your child is suspected of having MCADD. Stage 1: First contact This contact will have been either from your GP, paediatrician, midwife, health visitor or nurse specialist. You should have been given or had access to: MCADD is suspected leaflet (includes UK Newborn Screening Programme Centre website address and links to parent support group) screening.nhs.uk/mcaddsuspected A letter for you to keep should you need to take your child to an Accident and Emergency Department explaining your child s condition and treatment needs - MCADD A&E letter nhs.uk/mcaddparentinfo Contact numbers for your MCADD team Details of the time and location of an appointment with your MCADD team.

46 APPENDIX D Stage 2: First hospital review You have been seen either within a Specialist Metabolic Centre or by a MCADD Designated Team within 24 hours of being contacted. This is called the first face-to-face review. During this meeting, the following should have happened: Discussion of the screening result with the team and what it means for you and your child Repeat blood test and also a urine test to confirm the diagnosis. These tests are: * Blood spot - this is a repeat of the test taken by your midwife on the blood spot card * Urine - this also shows some chemicals that confirm the diagnosis of MCADD * Blood test for DNA this is taken so we can look more specifically at the type of gene alteration that your child has Discussion with the dietitian about normal feeding patterns Advice on the Emergency Regimen and discussion of what you need to do if your child is unwell or, for any reason not feeding Answer any questions you may have.

47 APPENDIX D You will receive additional written information that will include: MCADD Dietary Management Guidelines Samples of the glucose polymer powder to make the Emergency Regimen drinks and a prescription letter to obtain further supplies from your GP British Inherited Metabolic Disease Group (BIMDG) Emergency Management Guidelines to be used by medical teams if admitted to hospital A list of all contact numbers that you will need in case you are worried or need to seek advice about your child Details of the date and time of your next appointment. If you have not received any of the above then please let your MCADD team know so they can provide you with them. The team will contact your GP, local paediatrician and health visitor and let them know about your baby s tests and MCADD.

48 APPENDIX D Stage 3: Follow-up visits First follow-up visit within 5 working days of screen positive result. The results of the repeat blood test and urine should be available within 5 working days to be discussed with you. The DNA result may take slightly longer if extended DNA screening is needed. If diagnosis is not yet confirmed at the first follow-up visit, the outstanding test results will be available within a further 15 working days when a second follow-up visit will be scheduled, if necessary. If diagnosis is confirmed, and you have been seen by a MCADD Designated Team you will be offered a referral to a Specialist Metabolic Centre. There are a few Specialist Metabolic Centres in the UK. This will give you and your child access to professionals who have specialist knowledge of this condition. They will work together with your designated team to provide necessary care for your child. Future appointments following diagnosis You will be seen regularly as agreed between you and your MCADD team in the first few years of your child s life. The frequency of these appointments will reduce as your child gets older. Your child will be followed through to adulthood and beyond within adult services, as necessary. The appointments will allow assessment of your child. The specialist dietitian will discuss age appropriate advice on feeding; e.g. when to wean, safe fasting times and illness management (including preparation and use of Emergency Regimen feeds). You will also have access to a specialist nurse for advice and support.

49 Will my other children need to be tested? Older siblings who have not been screened may be at risk of MCADD even though they may have had no symptoms. It is therefore very important they are tested, if they have not been previously screened for MCADD. Your MCADD team will discuss this and you may be asked to bring any siblings to the hospital at the first follow-up appointment. Future pregnancies APPENDIX D A new baby from the same parents has a 1 in 4 chance of having MCADD and it is important they are tested hours following birth. Let your MCADD team know about your pregnancy. You should also inform your midwife that you have a child with MCADD and early testing of your new baby is required. Your MCADD team will be able provide management guidelines including feeding advice and information on testing your baby. You should ask your midwife to write the information received into your maternity notes or birth plan.

50 APPENDIX D Frequently Asked Questions What happens if my child will not take the emergency drink? If your child will not take the emergency drink but is clearly unwell then he/she should go to the hospital. As your child gets older the made up emergency drinks (of glucose polymer) can be flavoured with squash, to improve the taste. Sugar free and low calorie drinks are NOT suitable. Will my local hospital know what to do if my child is unwell? As MCADD is a rare condition it is recognised that many doctors/nurses will not be familiar with it. They will be provided with management guidelines in order to treat your child s condition effectively. Your clinical nurse specialist/ MCADD team will also liaise with your local hospital and provide the appropriate education. Please take your BIMDG Emergency Management Guidelines, MCADD Dietary Management Guidelines and glucose polymer powder with you. What is the difference between a MCADD Specialist Team and a MCADD Designated Team? There are only a few MCADD Specialist Teams within the UK. A MCADD Specialist Team is made up of: A consultant in paediatric inherited metabolic disease A specialist paediatric metabolic dietitian A metabolic clinical nurse specialist It is strongly recommended that you have access to a MCADD Specialist Team by telephone. A MCADD Designated Team is usually provided in a local hospital. The team must include a paediatrician trained to receive MCADD referrals and have a paediatric dietitian. What should I do if I lose my documents? Contact your MCADD team and let them know, then they can send you out new copies.

51 APPENDIX D Photo 5

52 APPENDIX D Who can offer advice to my wider family on the risk of MCADD for their children? Your MCADD team or the family GP can refer to a genetic counsellor for genetic advice and discuss the implications for relatives having children. Is MCADD like diabetes? Diabetes and MCADD are two very different medical conditions, despite both having a risk of low blood glucose levels. The management of these conditions is NOT the same. A child with MCADD who becomes unwell should be started on treatment BEFORE the blood glucose levels drop; therefore measuring blood glucose levels is not recommended or necessary. Should my child be immunised? Your child should have all the usual immunisations or medical treatment needed for other conditions. More frequently asked questions are available from

53 APPENDIX D Glossary Clinical nurse specialist (CNS) - An experienced nurse who has specialist knowledge in a chosen area of health care. Consultant paediatrician with inherited metabolic disease expertise - A doctor who has trained specifically in the care of children but also has knowledge and experience with metabolic disorders. Enzyme - Proteins that speed up chemical reactions (or steps) in a metabolic pathway in the body. Genes - The instructions given to our body when we are conceived that make us what we are. They are strung together in long strands of material called DNA. Intravenous fluids - Fluids given through a drip into the vein. Medium-chain triglycerides (MCT) - A special type of fat which someone with MCADD cannot break down to make energy. Inherited metabolic disease - A group of inherited disorders caused by a block in a chemical pathway in the body due to a faulty enzyme. In MCADD, the enzyme that is not working properly causes a build-up of medium-chain fats which make toxic substances that may lead to serious symptoms. Specialist dietitian - An experienced dietitian who has specialist knowledge in a chosen area of dietetics.

54 APPENDIX D More information You can find more information about MCADD on the UK Newborn Screening Programme Centre (UKNSPC) website - follow the public information link screening.nhs.uk/public uknewbornscreen@gosh.nhs.uk CLIMB (the National Centre for Metabolic Diseases) provides information and support for people with MCADD and their families. You can contact them as follows: Climb Climb building 176 Nantwich Road Crewe, CW2 6BG Telephone helpline: (Freephone) or info.svcs@climb.org.uk

55 APPENDIX D Questions

56 APPENDIX D Your MCADD team

57 APPENDIX D A UK National Screening Committee publication 1st edition April Review date April 2016.

58 MCADD MEDIUM CHAIN ACYL CoA DEHYDROGENASE DEFICIENCY APPENDIX E Information sheets for parents/carers

59 APPENDIX E Contents For all ages PAGE 1 Contact names, telephone and bleep numbers 3 Around 2 weeks old Infant feeding: age under 1 year 4 Emergency Regimen: for infants age under 1 year 5 Emergency Regimen recipes: for infants age under 1 year 10% Carbohydrate 6 4 to 6 months old 2 Weaning diet 7 1 year old Children s diet: from 1 year 8 Emergency Regimen: for children from 1 year 9 Emergency Regimen recipes: for children age 1 to 2 years 15% Carbohydrate 10 Alternative Emergency Regimen drinks: for children age 1 to 2 years 15% Carbohydrate 11 2 years old 2 3 Emergency Regimen recipes: for children age over 2 years 20% Carbohydrate 12 Alternative Emergency Regimen drinks: for children age over 2 years 20% Carbohydrate years old 2 3 Emergency Regimen recipes: for children age over 10 years 25% Carbohydrate 14 Alternative Emergency Regimen drinks: for children age over 10 years 25% Carbohydrate 15 Dietetic products 16 MEDIUM CHAIN ACYL Co A DEHYDROGENASE DEFICIENCY MCADD 2

60 APPENDIX E INFORMATION SHEET FOR PARENTS/CARERS 1 Contact names, telephone and bleep numbers Name Telephone Bleep/Pager Metabolic centre Consultant Consultant s secretary Metabolic registrar Dietitian Ward Clinical nurse specialist Local hospital Consultant Consultant s secretary Registrar Dietitian Ward MEDIUM CHAIN ACYL Co A DEHYDROGENASE DEFICIENCY MCADD 3

61 APPENDIX E INFORMATION SHEET FOR PARENTS/CARERS 2 Around 2 weeks old Infant feeding: age under 1 year Does my baby need a special feed? No you can breast feed or give normal infant formula. Why is regular feeding necessary? Babies with MCADD have a problem in making enough energy from their body fat stores when fasting (going without a feed) for too long. How long can my baby fast (go without a feed) for? Your baby can fast for up to 6 hours. As your baby gets older they will be able to fast for longer. Newborn and young infants normally demand feed every 3 to 4 hours. When your baby begins to sleep longer at night, give a feed just before they go to bed, once during the night (you may need to wake your baby for this feed) and on waking in the morning. What should I do if my baby will not wake for a feed during the night? If your baby will not wake or take a feed during the night and is fasting for longer than the recommended time contact your hospital doctor for further advice. What are Medium Chain Triglycerides (MCTs)? These are a type of fat but not the main fat found in food. MCTs need to be avoided because your baby cannot readily use these to make energy. Do any feeds contain MCTs? Some specialised infant formulas contain added MCTs. If your baby is prescribed a specialised formula check with your Doctor or Dietitian it does not contain MCTs. What should I do if my baby becomes unwell and / or feeds poorly? Follow the Emergency Regimen (ER) plan (see ER information sheets). The ER is a special feeding plan: glucose polymer feeds are given to provide your baby with energy these feeds are given frequently day and night to reduce the length of time your baby fasts for. MEDIUM CHAIN ACYL Co A DEHYDROGENASE DEFICIENCY MCADD 4

62 APPENDIX E INFORMATION SHEET FOR PARENTS/CARERS 3 Around 2 weeks old Emergency Regimen (ER): for infants age under 1 year What is the Emergency Regimen? This is a special feeding plan used if your baby is unwell and/or is not feeding well: glucose polymer feeds are given to provide your baby with energy these feeds are given frequently day and night to reduce the length of time your baby fasts for. When should I give the ER? Any time your baby is not feeding well, this is usually during illness Step 1: if you are unsure if your baby is unwell, give a glucose polymer feed and continue to assess Step 2: if your baby is definitely unwell, start the full ER of frequent glucose polymer feeds Step 3: if your baby is not getting better, not tolerating or refusing to take the glucose polymer feeds contact your hospital doctor or go to your local hospital. If you go to hospital take your A & E letter, ER information sheets, glucose polymer and scoops. Should I contact the hospital doctor if my baby is on the ER? Yes if: you are concerned and want advice your baby is frequently vomiting feeds your baby has diarrhoea, unless very mild your baby refuses ER feeds your baby is drowsy, floppy, not responding normally ( glazed look ) your baby is not improving on ER feeds. How do I make the ER feeds? Glucose polymer powder is dissolved in cooled, boiled water to make the feed (see ER recipes for infants). How do I give the ER? Give feeds every 2 or 3 hours day and night. First try to give your baby s usual formula. If this is not tolerated give the ER feeds of glucose polymer. If your baby is vomiting give small frequent sips of feed. My baby is breast fed how do I give the ER? Try to breast feed every 2 to 3 hours day and night. If your baby is not breast feeding well try giving ER feeds of glucose polymer from a bottle. If your baby refuses a bottle contact your hospital doctor or go to your local hospital. When can I stop giving the ER feeds? As your baby starts to recover you can return to their normal feeds and routine. Try to do this within 48 hours of starting the ER feeds. Where do I get glucose polymer from? Glucose polymers eg Caloreen, Maxijul, Polycal, Polycose, Vitajoule are available on prescription from your GP. What are oral rehydration solutions? Doctors may prescribe oral rehydration solutions eg Dioralyte, Electrolade, Rapolyte to treat diarrhoea and vomiting. These solutions contain very little glucose, so glucose polymer should always be added to provide more energy (see ER recipes: for infants age under 1 year ). MEDIUM CHAIN ACYL Co A DEHYDROGENASE DEFICIENCY MCADD 5

63 APPENDIX E INFORMATION SHEET FOR PARENTS/CARERS 4 Around 2 weeks old Emergency Regimen recipes: for infants age under 1 year 10% Carbohydrate Small volume recipe 20g or level unpacked scoops of *glucose polymer made up to 200ml with cooled boiled water. Or Large volume recipe 100g or level unpacked scoops *glucose polymer made up to 1000ml with cooled boiled water. Or Oral rehydration solution recipe 1 sachet of Dioralyte or Electrolade or Rapolyte add 200ml cooled boiled water add 15g or level unpacked scoops of *glucose polymer. * Caloreen, Maxijul, Polycal, Polycose, Vitajoule Suggested feed volumes Age 0-3 months Feed: 45-80ml every 2 hours or ml every 3 hours day and night Age 4-6 months Feed: ml every 2 hours or ml every 3 hours day and night Age 7-9 months Feed: ml every 2 hours or ml every 3 hours day and night Age months Feed: 100ml every 2 hours or 150ml every 3 hours day and night MEDIUM CHAIN ACYL Co A DEHYDROGENASE DEFICIENCY MCADD 6

64 APPENDIX E INFORMATION SHEET FOR PARENTS/CARERS 2 4 to 6 months old Weaning diet: from around 6 months When can I wean my baby? You can wean your baby at the normal time around 6 months (26 weeks) of age. Does my baby need a special diet? No wean your baby onto a normal diet. Your health visitor will be able to provide advice on normal weaning. Home cooked and/or commercial baby foods can be given. As weaning progresses try to give your baby starchy foods such as cereals, potato, pasta, rice, bread, or chapati at each main meal. These foods provide a good source of energy. When can I give my baby cows milk to drink? Your baby can have cows milk as a drink from 1 year of age. It is best to continue to breast feed or give infant formula until then. As solids increase your baby will take fewer milk feeds. Do any foods contain MCTs? MCTs are only found in a very few foods but not in sufficient quantity to cause a problem. Coconut is the only exception. Small amounts of coconut as an ingredient in a food may be given. Pure coconut and coconut oil should be avoided. How often to feed your baby How often do I need to feed my baby? It is still important your baby does not fast for too long overnight and feeds regularly during the day. At night continue to give your baby a feed just before they go to bed, once during the night (you may need to wake your baby for this feed) and on waking in the morning. How long can my baby fast for? Now your baby is getting older they can fast for longer overnight. Provided your baby is well and feeding normally they can fast for: 8 hours from 4 months of age 10 hours from 8 months of age. What should I do if my baby will not wake for a night feed? If your baby will not wake or take a feed during the night and is fasting for longer than the recommended time contact your hospital doctor for further advice. Feeding during illness What should I do if my baby becomes unwell and / or feeds poorly? Follow the Emergency Regimen (ER) plan (see ER information sheets). The ER is a special feeding plan: glucose polymer feeds are given to provide your baby with energy these feeds are given frequently day and night to reduce the length of time your baby fasts for. MEDIUM CHAIN ACYL Co A DEHYDROGENASE DEFICIENCY MCADD 7

65 APPENDIX E INFORMATION SHEET FOR PARENTS/CARERS 2 1 year old Children s diet: from 1 year Does my child need a special diet? No your child can have a normal diet. Try to include starchy foods such as cereals, potato, rice, pasta, bread or chapati at each meal. These foods provide a good source of energy. Do any foods contain MCTs? MCTs are only found in a very few foods but not in sufficient quantity to cause a problem. Coconut is the only exception. Small amounts of coconut as an ingredient in a food may be given. Pure coconut and coconut oil should be avoided. How often to feed your child How often does my child need to eat? Your child can just eat normally. Give regular meals (3 main meals) and a bedtime snack. Does my child need to have snacks between main meals? No these are not normally needed. How long can my child fast for overnight? Providing your child is well and feeding normally they can fast for: 12 hours overnight. It is important to give a starchy bedtime snack eg cereal and milk, biscuits, sandwich and not to miss or have a late breakfast. What should I do if my child misses a meal? Missed meals should be replaced with a starchy snack or sugary drink (see Emergency Regimen recipes for children and Alternative Emergency Regimen drinks for children). Feeding during illness What should I do if my child becomes unwell and / or is not eating? Follow the Emergency Regimen (ER) plan (see Emergency Regimen information sheets for children). The ER is a special feeding plan: glucose polymer drinks are given to provide your child with energy these feeds are given frequently day and night to reduce the length of time your child fasts for. MEDIUM CHAIN ACYL Co A DEHYDROGENASE DEFICIENCY MCADD 8

66 APPENDIX E INFORMATION SHEET FOR PARENTS/CARERS 3 1 year old Emergency Regimen (ER): for children from 1 year What is the Emergency Regimen? This is a special feeding plan used if your child is unwell and/or is not feeding well: glucose polymer drinks are given to provide your child with energy these feeds are given frequently day and night to reduce the length of time your child fasts for. When should I give the ER? Any time your child is not eating well; this is usually during illness Step 1: if you are unsure if your child is unwell, give a glucose polymer drink and continue to assess Step 2: if your child is definitely unwell, start the full ER of frequent glucose polymer drinks Step 3: if your child is not getting better, not tolerating or refusing to take the glucose polymer drinks contact your hospital doctor or go to your local hospital. If you go to hospital take your A & E letter, ER information sheets, glucose polymer and scoops. Should I contact the Hospital doctor if my child is on the ER? Yes if: if you are concerned and want advice your child is frequently vomiting feeds your child has diarrhoea, unless very mild your child refuses ER feeds your child is drowsy, floppy, not responding normally ( glazed look ) your child is not improving on ER feeds. How do I make the ER drinks? Glucose polymer is dissolved in water to make the drinks (see ER recipes for children). How do I give the ER? Give glucose polymer drinks or alternative drinks every 2 or 3 hours day and night. If your child is vomiting give the drinks as small frequent sips. Can I give any other drinks? Yes commercial drinks can be given but you may need to add extra glucose polymer (see Alternative ER drinks). Low calorie drinks are not suitable because they are too low in energy. When can I stop giving the ER drinks? When your child starts eating again you can give fewer ER drinks but continue some night drinks. ER drinks can be stopped once your child is eating normally again. Try to do this within 48 hours of starting the ER. Where do I get glucose polymer from? Glucose polymers eg Caloreen, Maxijul, Polycal, Polycose, Vitajoule are available on prescription from your GP. What are oral rehydration solutions? Doctors often prescribe oral rehydration solutions eg Dioralyte, Electrolade, Rapolyte to treat diarrhoea and vomiting. These solutions contain very little glucose, so glucose polymer should always be added to provide more energy (see ER recipes for children). MEDIUM CHAIN ACYL Co A DEHYDROGENASE DEFICIENCY MCADD 9

67 APPENDIX E INFORMATION SHEET FOR PARENTS AND CARERS 4 1 year old Emergency Regimen recipes: for children age 1 to 2 years 15% Carbohydrate Small volume recipe 30g or level unpacked scoops of *glucose polymer made up to 200ml with cooled boiled water. Or Large volume recipe 150g or level unpacked scoops *glucose polymer made up to 1000ml with cooled boiled water. Or Oral rehydration solution recipe (12% Carbohydrate) 1 sachet of Dioralyte or Electrolade or Rapolyte add 200ml cooled boiled water add 20g or level unpacked scoops of *glucose polymer. * Caloreen, Maxijul, Polycal, Polycose, Vitajoule Suggested drink volumes Age 1 to 2 years Aim 1200ml in 24 hours Offer: 100ml every 2 hours or 150ml every 3 hours day and night MEDIUM CHAIN ACYL Co A DEHYDROGENASE DEFICIENCY MCADD 10

68 APPENDIX E INFORMATION SHEET FOR PARENTS AND CARERS 5 1 year old Alternative Emergency Regimen drinks: for children age 1 to 2 years 15% Carbohydrate How to make 15% carbohydrate drinks (15g carbohydrate per 100ml) from commercial drinks Look at the nutrition information label per 100ml: if 9 to12g carbohydrate per 100ml: add level scoop *glucose polymer per 100ml eg Fruit juices Fruit Shoot and Fruit Shoot 100% (all flavours) J 2 O (all flavours) Carton Ribena (original blackcurrant, strawberry, apple) Fizzy drinks eg: Coca Cola, Fanta, Sprite, 7UP, Pepsi Regular 13-16g carbohydrate per 100ml can be used eg 15% glucose polymer drink add squash to flavour 1 sachet Maxijul (132g) add water up to 800ml * Caloreen, Maxijul, Polycal, Polycose, Vitajoule UPDATED APRIL 2008 PLEASE NOTE: The sugar content of commercial drinks can change! Always check the label (home and abroad). Low calorie drinks eg: Diet, Lite, No added sugar, Sugar free should not be substituted for sugary drinks because they are too low in energy. Artificial sweeteners do not provide calories. MEDIUM CHAIN ACYL Co A DEHYDROGENASE DEFICIENCY MCADD 11

69 APPENDIX E INFORMATION SHEET FOR PARENTS AND CARERS 2 2 years old Emergency Regimen recipes: for children age over 2 years 20% carbohydrate Small volume recipe 40g or level unpacked scoops of *glucose polymer made up to 200ml with cooled boiled water. Or Large volume recipe 200g or level unpacked scoops *glucose polymer made up to 1000ml with cooled boiled water. Or Oral rehydration solution recipe (12% Carbohydrate) 1 sachet of Dioralyte or Electrolade or Rapolyte add 200ml cooled boiled water add 20g or level unpacked scoops of *glucose polymer. * Caloreen, Maxijul, Polycal, Polycose, Vitajoule Suggested drink volumes Age 2 years: aim 1200ml in 24 hours Offer 100ml every 2 hours or 150ml every 3 hours day and night Age 3 and 4 years: aim 1300ml to 1400ml in 24 hours Offer 110ml every 2 hours or 170ml every 3 hours day and night Age 5 and 6 years: aim 1500ml to 1600ml in 24 hours Offer 130ml every 2 hours or 200ml every 3 hours day and night Age 7 and 8 years: aim 1700ml in 24 hours Offer 135ml every 2 hours or 210ml every 3 hours day and night Age 9 years: aim 1800ml in 24 hours Offer 150ml every 2 hours or 220ml every 3 hours day and night MEDIUM CHAIN ACYL Co A DEHYDROGENASE DEFICIENCY MCADD 12

70 APPENDIX E INFORMATION SHEET FOR PARENTS AND CARERS 3 2 years old Alternative Emergency Regimen drinks: for children age over 2 years 20% carbohydrate How to make 20% carbohydrate drinks (20g carbohydrate per 100ml) from commercial drinks Look at the nutrition information label per 100ml: if 9 to 12g carbohydrate per 100ml: Add level scoops *glucose polymer per 100ml eg Fruit juices Fruit Shoot and Fruit Shoot 100% (all flavours) J 2 O (all flavours) Carton Ribena (original blackcurrant, strawberry, apple) Fizzy drinks eg: Coca Cola, Fanta, Sprite, 7UP, Pepsi Regular if 13 to 16g carbohydrate per 100ml: Add level scoop *glucose polymer per 100ml 17 to 20g carbohydrate per 100ml can be used eg 20% glucose polymer drink add squash to flavour 1 sachet Maxijul (132g) add water up to 600ml Lucozade Energy (all flavours), not sport variety Tesco Active sparkling orange drink, not isotonic variety * Caloreen, Maxijul, Polycal, Polycose, Vitajoule UPDATED APRIL 2008 PLEASE NOTE: The sugar content of commercial drinks can change! Always check the label (home and abroad). Low calorie drinks eg: Diet, Lite, No added sugar, Sugar free should not be substituted for sugary drinks because they are too low in energy. Artificial sweeteners do not provide calories. MEDIUM CHAIN ACYL Co A DEHYDROGENASE DEFICIENCY MCADD 13

71 APPENDIX E INFORMATION SHEET FOR PARENTS AND CARERS 2 10 years old Emergency Regimen recipes: for children age over 10 years 25% carbohydrate Small volume recipe 50g or level unpacked scoops of *glucose polymer made up to 200ml with cooled boiled water. Or Large volume recipe 250g or level unpacked scoops *glucose polymer made up to 1000ml with cooled boiled water. Or Oral rehydration solution recipe (12% Carbohydrate) 1 sachet of Dioralyte or Electrolade or Rapolyte add 200ml cooled boiled water add 20g or level unpacked scoops of *glucose polymer. * Caloreen, Maxijul, Polycal, Polycose, Vitajoule Suggested drink volumes Age 10 years: aim 1800ml in 24 hours Offer 150ml every 2 hours or 220ml every 3 hours day and night Age 11, 12 and 13 years: aim 2000ml in 24 hours Offer 170ml every 2 hours or 250ml every 3 hours day and night Age 14 and 15 years: aim 2200ml in 24 hours Offer 180ml every 2 hours or 270ml every 3 hours day and night Age 16, 17 and 18 years: aim 2400ml in 24 hours Offer 200ml every 2 hours or 300ml every 3 hours day and night MEDIUM CHAIN ACYL Co A DEHYDROGENASE DEFICIENCY MCADD 14

72 APPENDIX E INFORMATION SHEET FOR PARENTS AND CARERS 3 10 years old Alternative Emergency Regimen drinks: for children age over 10 years 25% carbohydrate How to make 25% carbohydrate drinks (25g carbohydrate per 100ml) from commercial drinks Look at the nutrition information label per 100ml: if 9 to 12g carbohydrate per 100ml: Add level scoops *glucose polymer per 100ml eg Fruit juices Fruit Shoot and Fruit Shoot 100% (all flavours) J 2 O (all flavours) Carton Ribena (original blackcurrant, strawberry, apple) Fizzy drinks eg: Coca Cola, Fanta, Sprite, 7UP, Pepsi Regular if 13 to 16g carbohydrate per 100ml: Add level scoop *glucose polymer per 100ml if 17 to 20g carbohydrate per 100ml: Add level scoop *glucose polymer per 100ml eg 20% glucose polymer drink add squash to flavour 1 sachet Maxijul (132g) add water up to 600ml Lucozade Energy (all flavours), not sport variety Tesco Active sparkling orange drink, not isotonic variety 25% carbohydrate drink 25% glucose polymer drink add squash to flavour 1 sachet Maxijul (132g) add water up to 500ml * Caloreen, Maxijul, Polycal, Polycose, Vitajoule UPDATED APRIL 2008 PLEASE NOTE: The sugar content of commercial drinks can change! Always check the label (home and abroad). Low calorie drinks eg: Diet, Lite, No added sugar, Sugar free should not be substituted for sugary drinks because they are too low in energy. Artificial sweeteners do not provide calories. MEDIUM CHAIN ACYL Co A DEHYDROGENASE DEFICIENCY MCADD 15

73 APPENDIX E INFORMATION SHEET FOR PARENTS/CARERS Dietetic products PRODUCT MANUFACTURER Caloreen Maxijul Polycal Polycose Vitajoule Dioralyte Electrolade Raployte Nestle SHS/Nutricia Nutricia Abbott Laboratories Vitaflo Sanofi-Aventis Thornton and Ross KoGEN MEDIUM CHAIN ACYL Co A DEHYDROGENASE DEFICIENCY MCADD 16

74 APPENDIX F 2 nd Edition Dec MCADD dietitian letter tant Letter Dear [Date] Re: [Insert full name and date of birth of child] [Name of child] has been detected on newborn screening to have a positive (abnormal) test for medium-chain acyl-coa dehydrogenase deficiency (MCADD). Confirmatory testing is in progress. MCADD is a rare inherited disorder causing a block in the metabolism of fat into energy. A child with this condition is at risk from hypoglycaemia, coma and death with fasting and particularly during intercurrent illnesses when the body s demand for energy increases and food intake is often reduced. S/he may appear drowsy or lethargic, vomit, have seizures or have a deteriorating conscious level. Hypoglycaemia is a late sign, and therefore treatment must be initiated if [name of child] is unwell even if the blood sugar is normal. MCADD requires no special dietary treatment when the child is well apart from avoiding long periods without feeds or food. Parents/carers are instructed on maximum safe fasting times for age (these times get longer with age). Babies can be breast or bottle fed. Specialised infant formula or enteral feeds with added medium-chain triglycerides (MCT) should be avoided. When intercurrent illnesses occur, MCADD is treated with an Emergency Regimen (ER) of high energy feeds/drinks (glucose polymer) or, if unable to tolerate these for whatever reason (such as vomiting), with intravenous 10% dextrose and electrolyte additives. The aim is to supply readily available energy to avoid decompensation. If the ER is not tolerated, or the child s condition deteriorates, then urgent admission to the local hospital should be arranged for an intravenous 10% dextrose infusion. When the child is well, they should return to their usual feeds. The family have been instructed on maximum safe fasting times when well and preparation and use of the Emergency Regimen (ER), details of which are enclosed. Oral Rehydration Solutions (ORS) do not contain sufficient energy to avoid decompensation, and therefore require fortifying with glucose polymer. The family also have a recipe for this. The Dietary Management Guidelines for MCADD are available at and The long-term prognosis for MCADD is very good once the diagnosis is known as treatment is straightforward, hence its introduction into the newborn screening programme. The condition is inherited in an autosomal recessive fashion, with a 1 in 4 risk of recurrence in each pregnancy. Once the diagnosis has been confirmed, testing of any siblings will be arranged. If you have any questions, please do not hesitate to contact the metabolic dietetic team on [contact number/details]. With kind regards Yours sincerely Review date Dec. 2012

75 Final Version 22 nd February 2012 Appendix G N. IRELAND NEWBORN BLOODSPOT SCREENING PROGRAMME PRESUMPTIVE POSITIVE REFERRAL FEEDBACK TO CHS CONFIRMATION OF DIAGNOSIS Newborn Blood Spot Screening laboratory to complete and forward to the CHS Manager 1 in the baby s CHS area of birth, following clinical assessment and diagnostic feedback. Baby s Name: Baby s DOB: / / Address: CONDITION ICD10 CONFIRMED POSITIVE Phenylketonuria E70.0 MCADD E71.31 Cystic Fibrosis E84.9 Carrier of C F Gene Z14.1 Congenital Hypothyroidism E03.1 Homocystinuria E72.1 Sickle Cell Disorder D57.1 Sickle Cell Carrier D57.3 Other Clinically Significant Disorder Carrier of Other Haemoglobin Other Benign Condition Other (please specify) CONFIRMED NEGATIVE Comments Signed: Date: / / PRINT NAME: 1 CHS Manager to record confirmed positive on CHS, using ICD10. Confirmed negative should be recorded in the Medical Notes screen of CHS for blood spot screening services audit purposes. The original should be forwarded directly to the family health visitor (marked: Private and Confidential Addressee Only, with a CHS return to address).

76 Appendix I Screening Programmes UK Newborn Screening Programme Centre (UKNSPC) Notification of medium-chain acyl-coa dehydrogenase deficiency (MCADD) diagnosis for babies/children not identified through the newborn screening programme (No patient identifiable data to be sent to the Programme Centre) Name of person completing this form address Section 1. Diagnostic results Name of Newborn Screening Laboratory Name of Lead Metabolic Clinician Gestational age at birth Fiscal year of birth Ethnicity of baby (ONS Code) Age at initial clinical referral Age at first appointment with designated clinician Reason for referral to Metabolic Team Blood acylcarnitines (µmol/l and age) c.985a>g mutation analysis Qualitative urinary organic acids Organic acids consistent with MCADD Quantitative urinary hexanoylglycine Extended mutation screening (EMS) Was there a previous diagnosis of Not MCADD, MCADD unlikely, Likely unaffected MCADD carrier or Unaffected MCADD carrier? If yes to the above, please detail further biochemical investigations undertaken outside of MCADD Diagnostic Protocol. Homozygous/heterozygous/none Completed yes/no Yes/no Completed yes/no if yes, give age and result (µmol/mmol creat) Completed yes/no if yes, give age at result, EMS laboratory, result and any commentary on clinical significance as reported from EMS laboratory. If yes, please specify Was baby screened? If yes, complete section 2, If no, go to section 3. Section 2. Screening results Clinical diagnosis before screening Yes/no Age at first blood spot Age at receipt of sample in laboratory 1. MCADD not suspected C8 <0.40 µmol/l C8 = Mean C8 <0.50 µmol/l C8= Mean C µmol/l but mean C8:C10 ratio <1.0 C8 = C8:C10= 2. MCADD suspected C µmol/l but insufficient to re-test C8= C µmol/l and C8:C10 ratio 1.0 C8 = Non-identifiable notification of MCADD diagnosis to UKNSPC 1

77 Appendix I Comments/observations/other information (e.g. full scan on eluate completed and results) Section 3. Reason C8:C10= Not screened (not eligible) Infant/child moved into UK over 1 year of age Babies who died prior to screening Not screened (eligible) Parents declined screening for MCADD Parents declined further investigations False negative screen Baby/child who was screened and reported as condition not suspected that subsequently has a confirmed diagnosis and the screening result is confirmed. Had any of the following occurred: Dextrose administration prior to blood collection, later screening of a moved-in, older baby, delayed transit of sample (>14 days), blood transfusion <72 hours prior to blood collection, or card contaminated with moisture with no repeat sample available? Screening programme deviation No sample taken Sample not taken at appropriate time Sample did not arrive in laboratory Test failure/lab error 1. NBS lab 2. Genetic lab Screen positive baby not referred/did not attend clinical appointment (no failsafe) Has this been reported as a serious incident? Please indicate hours/days of age If yes, please specify. Yes/No Once completed please forward to the UKNSPC at uknewbornscreen@gosh.nhs.uk Non-identifiable notification of MCADD diagnosis to UKNSPC 2

78 APPENDIX A MCADD SCREENING AND CLINICAL MANAGEMENT SERVICES RESPONSIBILITIES AND CONTACT INFORMATION SERVICE / AREA Regional Newborn Screening Laboratory Service Regional Metabolic Services PERSON WITH RESPONSIBILITY DELEGATED / ALTERNATIVE DELEGATED CONTACT (NOT TO BE USED FOR URGENT COMMUNICATION) (028) Jennifer.Cundick@belfasttrust.hscni.net (028) David.Cardy@belfasttrust.hscni.net (028) Siobhan.O Sullivan@belfasttrust.hscni.net (028) Grainne.Connolly@belfasttrust.hscni.net (028) Carol.Beattie@hscni.net Georgie Clawson (028) Georgie.Clawson@hscni.net Nicola Cunningham (028) Nicola.Cunningham@hscni.net Dr Jennifer Cundick Mr David Cardy Dr Siobhan O Sullivan Dr Grainne Connolly Public Health Agency Lead ADDRESS TELEPHONE Dr Carol Beattie Revised 8th January 2014

79 APPENDIX A SERVICE / AREA Trust Provider Leads PERSON WITH RESPONSIBILITY DELEGATED / ALTERNATIVE DELEGATED CONTACT BHSCT Miss Ruth Clarke Ms Christina Menage NHSCT Mrs Sinead O Kane Mrs Brigid McKeown SEHSCT Mrs Marian Campbell Mrs Esther Hylands SHSCT Mrs Joanne McGlade Carol Murphy WHSCT Mrs Amanda Sayers Ms Denise Armstrong ADDRESS TELEPHONE (NOT TO BE USED FOR URGENT COMMUNICATION) (028) Ruth.Clarke@belfasttrust.hscni.net (028) Christina.Menage@belfasttrust.hscni.net (028) Sinead.OKane@northerntrust.hscni.net Brigid.McKeown@northerntrust.hscni.net (028) Marian.Campbell@setrust.hscni.net Esther.Hylands@setrust.hscni.net (028) Joanne.McGlade@southerntrust.hscni.net (028) Carol.Murphy@southerntrust.hscni.net (028) Amanda.Sayers@westerntrust.hscni.net (028) Denise.Armstrong@westerntrust.hscni.net Revised 8th January 2014

80 APPENDIX A SERVICE / AREA Child Health System Services PERSON WITH RESPONSIBILITY Northern Mr Byron Graham DELEGATED / ALTERNATIVE DELEGATED CONTACT TELEPHONE ADDRESS (NOT TO BE USED FOR URGENT COMMUNICATION) (028) Byron.Graham@northerntrust.hscni.net Mrs Gwen Gillespie (028) Gwen.Gillespie@northerntrust.hscni.net Southern Mrs Valerie Doyle (028) Valerie.Doyle@southerntrust.hscni.net Mrs Sally Adams (028) Sally.Adams@southerntrust.hscni.net Eastern Mrs Maria Monaghan (028) Maria.Monaghan@belfasttrust.hscni.net Mr David Hunter (028) David.Hunter1@belfasttrust.hscni.net Western Ms Jackie Hamilton (028) (Option 3) Jackie.Hamilton@westerntrust.hscni.net Mrs Kathleen Durey (028) Kathleen.Durey@westerntrust.hscni.net Revised 8 th January 2014

81 Appendix H A Laboratory Guide to Newborn Screening in the UK for MEDIUM-CHAIN ACYL-CoA DEHYDROGENASE DEFICIENCY UK Newborn Screening Programme Centre

82 Appendix H

83 Appendix H MCADD A Laboratory Guide to Newborn Screening in the UK for MEDIUM-CHAIN ACYL-CoA DEHYDROGENASE DEFICIENCY Handbook for laboratories incorporating: Background of MCADD newborn screening programme Screening laboratory organisation Screening protocol Pre-analytical aspects Analysis of octanoylcarnitine Acylcarnitine full scan analysis Quality and performance monitoring Clinical referral Reporting to child health records departments Laboratory standards Associated protocols and documents Major contributions from: Dr Guy Besley, Ms Melanie Downing, Dr Philippa Goddard, Prof Anne Green, Dr Helena Kemp, Ms Juliet Oerton, Dr Morteza Pourfarzam, Mr Charles Turner and for second revised edition: Prof Kim Bartlett, Dr Guy Besley, Dr Philippa Goddard UK Newborn Screening Programme Centre

84 Appendix H This is the 2 nd edition of the guide A Laboratory Guide to Newborn Screening in the UK for medium-chain acyl-coa dehydrogenase deficiency (MCADD) (OMIM # October 2010 Review date October 2012 This document has been published by the UK Newborn Screening Programme Centre, which is funded by the Department of Health on behalf of all four UK countries. A UK National Screening Committee publication ISBN number UK Newborn Screening Programme Centre Level 5, Frontage Building Great Ormond Street Hospital for Children NHS Trust Great Ormond Street London WC1N 3JH Phone: / 7884 Fax:

85 Contents Appendix H PAGE 1 Introduction Background of MCADD screening programme Definition of MCADD and clinical presentation Screening laboratory organisation Screening protocol National screening protocol Sibling testing Late testing Pre-analytical aspects Specimen requirements Factors affecting the screening result Potential for false negatives Potential for false positives Analysis of octanoylcarnitine and decanoylcarnitine Methodology Calculation of C8:C10 ratio Internal Quality Control (IQC) Performance criteria Action on discrepant replicates Acylcarnitine full scan analysis Procedure for extraction and analysis of acylcarnitines from dried blood spots (DBS) Interpretation of acylcarnitine scan Stability of acylcarnitines in DBS Quality and performance monitoring External quality control assurance Normal population data (octanoylcarnitine) Reporting of positive cases to UKNSPC Clinical referral Responsibility for communications / clinical liaison Follow-up of presumptive positive cases consistent with MCADD Diagnostic specimen requirements Coordination of screening follow-up results / requesting of extended mutation analysis...20

86 Appendix H 9 Reporting to child health records departments Laboratory standards for newborn screening for MCADD Generic Organisation Analytical processes Performance standards, including diagnostic tests References and further reading...23 Appendices...25 A1 The UKCSNS-MCADD study...25 A2 MCADD newborn screening protocol...26 A3 MCADD genetic / biochemical sibling testing protocol...27 A4 Guidance on discrepant replicates...28 A5 Template for notification of presumptive positive for designated (or specialist) MCADD team...29 A6 Template for GP letter...30 A7 Template for A&E letter...31 A8 MCADD diagnostic protocol...33 A9 MCADD clinical management protocol...36 A10 MCADD initial clinical referral guidelines and standards...37

87 Appendix H 1. Introduction This handbook is provided for newborn screening laboratories as a guide for the implementation of newborn screening for MCADD in the UK. The handbook is available as a pdf file on the UK Newborn Screening Programme Centre (UKNSPC) website At the time of going to print, every attempt has been made to provide the correct up to date information. If there are any errata or comments, please send them to the UK Newborn Screening Programme Centre, Level 5, Frontage Building, Great Ormond Street Hospital, Great Ormond Street, London, WC1N 3JH (uknewbornscreen@gosh.nhs.uk) for incorporation into the next edition. 1.1 Background In March 2004, the Department of Health and the National Screening Committee (NSC) commissioned a pilot newborn screening study, The UK Collaborative Study of Newborn Screening for Medium-chain acyl-coa Dehydrogenase Deficiency (UKCSNS-MCADD), from six laboratories in England (see Appendix 1 for further details). This study provided data / information on the clinical and cost effectiveness of screening for MCADD and the feasibility of implementation. Subsequently, in May / June 2006 sufficient evidence and analysis was made available for the NSC to make the recommendation that newborn screening of all babies would be clinically and cost effective in the UK. In February 2007, the Minister for Public Health (England) announced that all parents would be offered screening for MCADD for their baby. MCADD screening was officially announced in the Chief Executive s Bulletin (Issue 355, 2-8 February 2007) and has Gateway reference number The UK Newborn Screening Programme Centre was asked to lead implementation across England. Screening for MCADD became universal in England from April The original screening protocol was updated in February 2010 to include the C8:C10 ratio which was endorsed by the MCADD Screening Programme Board. The C8:C10 ratio was introduced on the 1st April Definition of MCADD and clinical presentation MCADD is an autosomal recessively inherited defect of fatty acid oxidation due to deficiency of the enzyme medium-chain acyl-coa dehydrogenase. This enzyme is required for the metabolism of medium-chain fatty acids and is necessary to enable the body to use its own fat reserves to produce energy in periods of fasting or stress. Deficiency of medium-chain acyl-coa dehydrogenase causes a block in the medium-chain length step of fat oxidation (carbon chain lengths C6-C12). This leads to a build up of medium-chain fatty acids, in particular octanoylcarnitine (C8) and its metabolites and results in inefficient breakdown of fat. Medium chain fatty acid metabolism in fat oxidation defects Fatty acids with chain lengths as below C12 C10 sebacic acid Octanoylcarnitine 7-hydroxyoctanoate C8 suberic acid Hexanoylglycine 5-hydroxyhexanoate C6 adipic acid C4 December A Laboratory Guide to Newborn Screening in the UK for medium-chain acyl-coa dehydrogenase deficiency (MCADD) 7

88 Appendix H Complications typically arise during periods of stress caused by an illness / situation associated with fasting and / or vomiting, when the infant needs to break down fat quickly. Hypoglycaemia and a decompensated state develops which can result in serious life threatening symptoms including seizures, brain damage and even death. Symptoms are not apparent at birth and about one-third of cases of MCADD remain asymptomatic throughout life, however, symptoms can develop very quickly in affected infants who are not feeding well. Episodes of metabolic decompensation can be prevented through avoidance of fasting by close monitoring of the infant to determine safe time periods between meals and following a strict feeding schedule. MCADD mainly presents before the age of two years with a mean age of thirteen months, although neonatal presentations have also been reported (Wilcken et al. 1993). The diagnostic hallmark of MCADD is hypoketotic hypoglycaemia. An acidosis, a raised blood ammonia and abnormal liver function may also be present. The profile of blood acylcarnitines is unique and specific for MCADD and is usually diagnostic in both sick and well children, although false negatives can occur. Urine organic acids usually show characteristic acylglycine elevations (hexanoyl- and suberyl-glycine), although concentrations in non-crisis periods may be only minimally elevated. Fatty acid oxidation studies in cultured skin fibroblasts usually reveal abnormal profiles in MCADD patients. The gene for MCADD is located on chromosome 1p31. About 88% of clinically diagnosed MCADD cases are homozygous for the common c.985a>g mutation (Pollitt and Leonard 1998), however this percentage is lower (45-55%) in cases picked up through newborn screening in the UK. MCADD affects between one in 10,000 and one in 20,000 babies born in the UK and it has been reported that the UK population has a carrier frequency of between 1 in 52 and 1 in 83 (Seddon 1995). Published data suggest that MCADD due to the c.985a>g mutation is a disease of white ethnic origin and proposes a Northern European founder effect for this mutation (Gregersen et al. 1993). Results from the UKCSNS-MCADD support this, as the c.985a>g homozygous MCADD has not been found in black and Asian ethnic populations that have migrated to England (UKCSNS-MCADD, currently unpublished data). With early detection and monitoring, and avoidance of fasts, children diagnosed with MCADD can lead normal lives particularly as safe time between meals expands as they grow older. Further information can be obtained from a presentation prepared by the UKNSPC 8 UK Newborn Screening Programme Centre

89 Appendix H 2. Screening laboratory organisation MCADD screening is fully integrated within the existing blood spot screening programme and no additional blood sample is required. The screening test, assay of octanoylcarnitine (C8), is undertaken at the same time as the tests for other disorders, (phenylketonuria, cystic fibrosis, hypothyroidism and sickle cell disease), using blood from the same heel-prick blood sample, collected on the standard newborn screening collection card. C8 is measured by electrospray tandem mass spectrometry (MS/MS). No alternative method should be used. A back-up to the main instrument must be in place, i.e. a second MS/MS or arrangement with a neighbouring laboratory for measurement of the samples by MS/MS for short term instrument failures. All screening laboratories should have a formalised contingency plan for testing in the event of a major disaster. December A Laboratory Guide to Newborn Screening in the UK for medium-chain acyl-coa dehydrogenase deficiency (MCADD) 9

90 3.0 Screening protocol Appendix H 3.1 The national screening protocol The newborn screening protocol has been devised using the results from the UKCSNS-MCADD pilot study and been agreed and endorsed by the MCADD Screening Programme Board. It is expected that all centres will comply with the protocol. The protocol is intended to: Maximise early detection of MCADD so that appropriate early pre-symptomatic treatment can be initiated and the risk of acute, life-threatening episodes can be reduced and death avoided. Minimise detection of unaffected heterozygotes and other potential false positive cases. The standard protocol is summarised diagrammatically in Appendix 2. No alternative is to be offered. The first step is the C8 and C10 assay on underivatised blood spot samples using multiple reaction monitoring (MRM) mode acquisitions. If the initial C8 is 0.40 μmol/l, the original blood spot card should be re-tested in duplicate on the same day. If the mean of the three results is <0.50 μmol/l, the result is negative i.e. MCADD not suspected and there is no further action. If the mean of the three results is 0.50 μmol/l, calculate the C8:C10 ratio for each spot, then calculate the mean C8:C10 ratio from the triplicate results. If the mean C µmol/l AND the mean C8:C10 ratio 1.0, this is a presumptive positive (MCADD suspected) and the baby must be referred for clinical / diagnostic follow-up. A full acylcarnitine scan analysis should be carried out as soon as possible, ideally the same day, and if available, the result provided at the time of the referral. Referral is on the basis of the raised octanoylcarnitine and C8:C10 ratio result and independent of scan results. Full scan analysis should not delay referral to clinician. The scan can be undertaken on the original eluate (underivatised), or a further blood spot from the card can be punched for derivatised analysis. 3.2 Sibling testing Next baby A new baby has a 1:4 risk of having MCADD and it is important to test at the earliest opportunity. For guidance on testing and management whilst awaiting results refer to MCADD genetic / biochemical sibling testing protocol (Appendix 3, Section A). Older siblings Older siblings may be at risk of MCADD even though they may have been asymptomatic to date. It is therefore very important that they are tested as soon as the diagnosis on the proband has been confirmed. Please refer to MCADD genetic / biochemical sibling testing protocol (Appendix 3, Section B). 3.3 Late testing Babies who have not been screened during the newborn period should be screened (dried blood spot octanoylcarnitine) up to 12 months of age in line with the UKNSPC standards. It should be noted that older infants with MCADD may have C8 levels below the screening cut-off and there is a potential for false negative screening results (see 4.3). If MCADD is suspected, the infant should be referred to a clinician for diagnostic testing. 10 UK Newborn Screening Programme Centre

91 4. Pre-analytical aspects Appendix H 4.1 Specimen requirements MCADD screening requires the quantitative assay of octanoylcarnitine (C8) and decanoylcarnitine (C10). As for all screening tests, good quality blood spots are essential. Specimens that are overlayered by multiple applications are likely to give erroneous / misleading results and may result in false negatives or babies being recalled and investigated unnecessarily. Specimens should be transported to the laboratory in the usual way and be kept in a dry environment at room temperature or 4 ºC before analysis; storage after analysis should follow the guidelines provided by the UKNSPC Policies and standards for newborn blood spot screening in the UK. Further information is available at Factors affecting the screening result There is some evidence that C8 values are higher in the immediate neonatal period (1-2 days of life) compared to the rest of the neonatal period. Results from the UKCSNS-MCADD showed that C8 concentrations show little variation with age in normal babies during the screening time window, i.e. 5-8 days of age, and remain relatively constant during the first few weeks of life (Phillips et al. 2005, Khalid et al. 2010). Results also showed that C8 concentrations decrease slightly with increasing birth weight and in general, males have slightly higher C8 concentrations than females; these observations however are not significant for screening purposes. There are a number of factors which could theoretically reduce or increase C8 concentration in babies and could therefore pose a risk of false negative or false positive screening results. These are discussed below. 4.3 Potential for false negatives The effects of blood transfusion are unclear. Transfusions could result in a false negative result, as for other screening tests, and a repeat sample should therefore be taken after a reasonable time has elapsed. At least 72h is recommended, as for the other screening tests, to allow pre-transfusion levels to be reached. Dextrose administration in a sick neonate with MCADD prior to blood collection may reduce octanoylcarnitine level. Carnitine depletion has resulted in C8 levels below the screening cut-off in older children with MCADD who have presented clinically. Carnitine stores in newborns generally reflect maternal levels and low carnitine is sufficiently rare for this to be an exceedingly low risk of false negative screening results. No cases were found during the pilot study. This theoretical risk should be borne in mind if testing is delayed beyond the normal postnatal time-frame. Short delays in transit of the specimen have not been associated with altered C8 levels, blood spot cards can be accepted up to 14 days post specimen date, as for other tests. Hydrolysis of C8 can take place on blood spot cards which have not been stored dry and, theoretically, could result in false negative screening values. This has been observed on control / calibrator specimens stored over long periods. Blood spot cards which have been exposed to moisture should not be accepted. It is known that C8 falls in older infants (after approx 1 month of age) and infants with MCADD may have C8 levels below the screening cut-off (see Section 3.3 on late testing). December A Laboratory Guide to Newborn Screening in the UK for medium-chain acyl-coa dehydrogenase deficiency (MCADD) 11

92 4.4 Potential for false positives Appendix H Physiological stress in newborns can be associated with elevations of C8 above normal levels, particularly in heterozygote carriers of MCADD. False positives when screening at 5-8 days however is very rare. For further information on the interpretation of raised C8 in other conditions / situations, please refer to Section 6.2. Early sampling in the immediate postnatal period may give higher results as discussed above. Card contamination of unknown cause has resulted in 3 false positive results during the pilot study; a protocol for dealing with this is outlined in Section 5.5 Action on discrepant replicates and Appendix UK Newborn Screening Programme Centre

93 5. Analysis of octanoylcarnitine and decanoylcarnitine Detailed laboratory methods are not provided. Appendix H 5.1 Methodology Both octanoylcarnitine (C8) and decanoylcarnitine (C10) are measured in underivatised solvent extracts from dried blood spots using a tandem mass spectrometer with liquid chromatography sample introduction (LC/ MS/MS). Multiple reaction monitoring (MRM) acquisition mode must be used and analysis restricted to the specified analyte. There are no additional sample requirements as C8 and C10 analysis is incorporated into the same MS/MS method as the MRM analysis of phenylalanine (Phe) for phenylketonuria (PKU) screening. Table 1 shows MRM ion transitions used. Internal standards (IS) of deuterium labelled C8 and phenylalanine (e.g. 2 H 3 -C8 and 2 H 5 -Phe) prepared in a suitable solvent (e.g. 80% methanol or ethanol) are used to elute C8 and Phe from a punched dried blood spot disc in multiwell plates. Table 1. MRM transitions for C8, C10 and Phe analysis Metabolite Transition Example IS Transition C H 3 - C C H 3 - C Phe H 5 Phe MS/MS sampling can be direct from the original plate (with blood spots in situ) or the eluants may be transferred to a fresh plate before sampling. Preference for transfer will depend on systems in use and is a balance between transfer possibly reducing blockage rates and the fact that it has its own risks e.g. sample mix up / contamination (see Section 5.5 and Appendix 4 for guidance on discrepant replicates). Calibration options include simple ratio to a calibrated IS or use of a dried blood spot calibration curve on each batch. In-house calibrators or commercial kits may be used. Validation of analysis shall include automatic flagging of inadequate internal standard abundances by the analytical software and since sensitivity requirements for C8 are 100 fold that of Phe. Inspection of individual flow profiles and ion abundances is also recommended. 5.2 Calculation of C8:C10 ratio C10 should be measured in triplicate (i.e. singlicate analysis at the same time as the initial C8 measurement and further duplicate analyses when carrying out C8 repeat analyses where initial C µmol/l). If the triplicate C8 result is 0.50 µmol/l then calculate the mean C8:C10 ratio. For consistency between laboratories the ratio should be calculated using C10 measured using the d 3 C8 internal standard (it is recognised that some laboratories have d 3 C10 in their internal standard solution). It would be of value if those laboratories could collect comparative data for C10 and C8:C10 ratios obtained from using the d 3 C10 internal standard but to use the C10 value calculated using d 3 C8 for reporting. December A Laboratory Guide to Newborn Screening in the UK for medium-chain acyl-coa dehydrogenase deficiency (MCADD) 13

94 Appendix H This is summarised below: 5.3 Internal quality control (IQC) It is recommended that relevant levels of dried blood spot IQC are included at the beginning and end of each plate. Three levels of C8 and C10 are recommended: i) Normal ii) Medium, level around initial cut-off (i.e μmol/l) iii) High (e.g. 1 2 μmol/l) Suitable levels are not always available commercially so there may be a need for in-house preparations. The Centers for Disease Control and Prevention (CDC, USA) QC sets are a very useful supplement to any internal QC for monitoring long term stability of the assay (see Section 7 Quality and performance monitoring). Initial assay of C8 (underivatised, using d3c8 internal standard) C10 also to be measured at this stage Duplicate repeat assay of C8 and C10 (underivatised using d3c8 internal standard for both analytes) Calculate mean of triplicate C8 results Calculate the C8:C10 ratio for each spot, then calculate the mean C8:C10 ratio 5.4 Performance criteria Based on the performance during the pilot study, it is expected that laboratories should achieve the following: Precision: 4% at C8 = 1.0 μmol/l and 10% at C8 = 0.05 μmol/l 7% at C10 = 1.0 μmol/l and 10% at C10 = 0.05 μmol/l Sensitivity / linearity: C8 and C10 assay range 0.01 to 5.0 μmol/l 14 UK Newborn Screening Programme Centre

95 5.5 Action on discrepant replicates Appendix H If a sample has an initially raised C8 (above the screening protocol cut-off), which is clearly normal on duplicate repeat, a falsely elevated initial C8 is suspected and the protocol outlined in Appendix 4 should be followed. The same should apply to C10 values. December A Laboratory Guide to Newborn Screening in the UK for medium-chain acyl-coa dehydrogenase deficiency (MCADD) 15

96 6. Acylcarnitine full scan analysis Appendix H Full scan analysis should only be undertaken by laboratories with appropriate experience (see standards in Section 10.4). Screening laboratories may need to make arrangements for the scan to be done by a diagnostic laboratory; noting the urgency for the result. The choice of sample preparation (i.e. derivatised vs. underivatised) for acylcarnitine full scan analysis is dependent on local preference and experience. It is tempting to analyse acylcarnitines underivatised because of safety, cost and ease of sample preparation. However, derivatisation increases both the sensitivity and specificity of acylcarnitine analysis by MS/MS. Tandem mass spectrometric analysis of the crude blood extract for acylcarnitines by precursor ion scanning of m/z 85 is remarkably specific for these compounds. However interferences are known to occur when samples are analysed underivatised where a compound(s) with a molecular ion of m/z 288 gives rise to a fragment ion of m/z 85 mimicking octanoylcarnitine. Derivatisation by means of butylation adds 56 amu to the molecular weight of the native acylcarnitine. Hence, if after butylation a signal at m/z 288 shifts by 56 amu and its ion intensity ratio to octanoylcarnitine internal standard remains unchanged there is a very good chance that the signal represents only octanoylcarnitine otherwise it is due to interference or contamination. 6.1 Procedure for the extraction and analysis of acylcarnitines from dried blood spots It is advised that screening laboratories request details of the method from a laboratory in their buddy group which is experienced in the analysis of diagnostic acylcarnitines. 6.2 Interpretation of acylcarnitine scan All cases with a triplicate average of C μmol/l and C8:C10 ratio 1.0 are referred immediately and regardless of the scan pattern. The additional information from the scan is a useful guide in the consultation and should be provided to the clinician as soon as possible. MCADD metabolites MCADD suspected MCADD patients have increased blood octanoylcarnitine (C8) levels. In most patients the acylcarnitine scan profile also shows elevated C6, C10 and C10:1 signals with raised C8:C10 and C8:C6 ratios. There is often a low acetylcarnitine (C2) level with raised C8:C2 ratio. There is no accumulation of acylcarnitine species >C10 or <C6. In older patients carnitine insufficiency may develop and these patients tend to have a lower concentration of C8 together with low C2 and free carnitine (C0). Other conditions and multiple acyl-coa dehydrogenase deficiency (MADD) metabolites Increased C8 concentration may also be associated with conditions other than MCADD most notably prematurity and state of metabolic stress and induced lipolysis. In addition multiple acyl-coa dehydrogenase deficiency is characterised by elevated C8 together with accumulation of other short-, medium- and longchain acylcarnitines. Some of the rare causes of elevated blood C8 levels are listed in Table 2 on page 17. By using a second marker e.g. C8:C10, C8:C6 or C8:C2 ratios the specificity of C8 measurement for the diagnosis of MCADD may be improved (Chace et al. 1997, Clayton et al. 1998, Pourfarzam et al. 2001). Typical examples of blood full acylcarnitine profiles from MCADD and some non-mcadd cases, analysed as butyl ester derivatives, are shown in Figure 1 under Section 6.3 Stability of acylcarnitines in DBS. 16 UK Newborn Screening Programme Centre

97 Appendix H Table 2: Rare causes of elevated blood octanoylcarnitine (C8) other than MCADD Condition Prematurity / very low birth weight Hypoxia / circulatory failure Acylcarnitine affected C6 and C8 C4, C6, C8, C10 and C12 State of metabolic stress and induced lipolysis C8, C10, C10:1, C12, C12:1, C14 and C14:1 MCT supplementation Valproate therapy Neonate born to riboflavin deficient mother Riboflavin deficiency Mitochondrial myopathy C8 and C10 C8 and C10 C6, C8, C10, C12 and C14 C6, C8, C10, C12 and C14 C8 and C10 Multiple acyl-coa dehydrogenase deficiency C4, C5, C6, C8, C10, C12, C14 and C14:1 A report should be issued for all acylcarnitine scans to the referring clinician as a defined pattern / category, see Table 3. Table 3: Reporting of acylcarnitine full scan analysis (Refer to Section 6.2 Interpretation of acylcarnitine scan). Acylcarnitine findings C8 with C6, C10, C10:1 C8 with C4, C5, C6, C10, C12, C14:1 and C14 C8 with findings not typical of MCADD or MADD e.g. C4-hydroxy Report to paediatrician C8 and acylcarnitine profile consistent with MCADD but requires confirmation C8 and acylcarnitine profile consistent with MADD but requires confirmation C8 with acylcarnitine profile not typical of MCADD or MADD, but requires further investigation MCADD medium-chain acyl-coa dehydrogenase deficiency, MADD multiple acyl-coa dehydrogenase deficiency In the unusual event that the acylcarnitine scan does not suggest MCADD, further investigations may be required at the first consultation, dependent on the findings from the scan and the clinical picture. 6.3 Stability of acylcarnitines in DBS At room temperature acylcarnitines in blood spotted on filter paper are slowly hydrolysed to free carnitine and their corresponding fatty acids. The rate of degradation depends on the carbon chain-length of the acyl group and the presence of functional groups. For saturated straight-chain acylcarnitines the stability of the carnitine esters in stored blood spots in general increases with the increasing chain-length of the acyl group. Thus at room temperature acetylcarnitine is degraded at the rate of up to about 20% per year and medium-chain acylcarnitines (i.e. C6, C8 & C10) degrade at the rate of up to 10% per year. The stability of acylcarnitines is significantly improved if dried blood spots are stored in sealed bags at low temperature. At 4 C the decrease in the concentrations of C6 and C8 is about 4% per year. In specimens stored at -20 C the decrease in the concentration of acetylcarnitine is less than 10% per year and those of C6, C8 and C10 are less than 3%. December A Laboratory Guide to Newborn Screening in the UK for medium-chain acyl-coa dehydrogenase deficiency (MCADD) 17

98 Appendix H #6-20 RT: AV: 7 SM: 5B NL: 1.77E7 F: + p sid= Full pr 85.00@-35.00[ ] 100 A - Normal 90 Relative Abundance m/z #6-20 RT: AV: 7 SM: 5B NL: 2.22E7 F: + p sid= Full pr 85.00@-35.00[ ] B - MCADD 90 Relative Abundance m/z #6-20 RT: AV: 7 SM: 5B NL: 1.43E7 F: + p sid= Full pr 85.00@-35.00[ ] C - MCADD 90 Relative Abundance m/z #6-20 RT: AV: 7 SM: 5B NL: 2.29E7 F: + p sid= Full pr 85.00@-35.00[ ] D - MADD 90 Relative Abundance m/z #6-20 RT: AV: 7 SM: 5B NL: 1.13E7 F: + p sid= Full pr 85.00@-35.00[ ] C2 500 E - Ketotic 45 C16 40 Relative Abundance d3-c d9-c16 d3-c0 15 C0 d3-c3 C d9-c8 C4 OH-C4 C5 300 C6 320 C8 340 m/z 360 C12 C10 C12: C14 C14:1 420 C18:1C18 C16: Figure 1: Acylcarnitine profiles from dried blood spots analysed as butyl ester derivatives A) a healthy neonate at the age of 5 days, B) and C) a neonate with MCADD at the age of 2 days and 8 days respectively, D) a neonate with multiple acyl-coa dehydrogenase deficiency (MADD) at the age of 5 days and E) a neonate in catabolic state and severe ketosis at the age of 6 days (NB. Please note different scale on y-axis in E). 18 UK Newborn Screening Programme Centre

99 Appendix H 7. Quality and performance monitoring Laboratories must establish appropriate quality and performance monitoring procedures as set out below. 7.1 External quality control assurance A scheme for monitoring the performance of the C8 assay set up at Birmingham Children s Hospital was in operation from March 2004 to April From 1 st April 2010, UKNEQAS included C8 and C10 in the newborn screening blood spot scheme. The purpose of the scheme is to provide a quality assessment of precision and accuracy for the analysis of C8 and C10 for laboratories that screen for MCADD by MS/MS. Four specimens are circulated on a monthly basis. All laboratories in the UK which screen for MCADD by MS/MS are expected to take part in this scheme. For more details please contact Finlay MacKenzie, UKNEQAS (Finlay.MacKenzie@uhb.nhs.uk). Laboratories undertaking acylcarnitine full scan analysis must participate and demonstrate good performance in an appropriate EQA scheme, e.g. ERNDIM ( or CDC ( 7.2 Normal population data (octanoylcarnitine) A programme for monitoring the performance of the octanoylcarnitine (C8) assay using whole population newborn screening data coordinated by the UCL Institute of Child Health (ICH), London, compared data from the six Phase 1 laboratories. This demonstrated good concordance in the population distribution of C8 values both within and between laboratories, and proved valuable as a quality assurance measure (see Khalid et al. 2010). 7.3 Reporting of positive cases to UKNSPC The ongoing monitoring of all cases which are presumptive positive at screening is being undertaken by the UKNSPC. This requires that ethnic group, screening results and diagnostic test results are reported using the Laboratory Notification Form (dated 14/06/2010). All screening laboratories are expected to contribute to this reporting. The laboratory notification form of presumptive positive screen is available at: Completed forms should be sent by to: christine.cavanagh@nhs.net Or by post to: Christine Cavanagh Programme Manager UK Newborn Screening Programme Centre Level 5, Frontage Building Great Ormond Street Hospital for Children NHS Trust Great Ormond Street London WC1N 3JH Tel: December A Laboratory Guide to Newborn Screening in the UK for medium-chain acyl-coa dehydrogenase deficiency (MCADD) 19

100 8. Clinical referral Appendix H 8.1 Responsibility for communications / clinical liaison It is essential that each screening laboratory, in collaboration with commissioners and local implementation groups, make detailed local arrangements for the follow-up of presumptive positive cases for all districts covered by their laboratory and clarifies responsibility for undertaking the MCADD Clinical Liaison Service (CLS) role as part of the referral process see protocol: Appendix 10 MCADD initial clinical referral guidelines and standards. The CLS role may be undertaken by person(s) based in the screening laboratory (i.e. a screening clinical nurse specialist or duty biochemist), in the designated clinical team or in the community, depending on local arrangements. 8.2 Follow-up for presumptive positive cases consistent with MCADD (See Section 3.1 and Appendix 2) These are babies with mean of triplicate C μmol/l and C8:C10 ratio 1.0 All presumptive positives should be referred to the designated (or specialist) MCADD team via the CLS (as per local arrangements) on the same day that the final screening result has become available. This must be reported both verbally as well as in writing a template is provided (Appendix 5) The first clinic appointment should take place within 24hrs of the final result becoming available A confirmatory acylcarnitine scan should have been undertaken and reported to the MCADD designated team (see Section 6.2) if possible in time for the clinic appointment. The CLS must contact the GP and: Coordinate local support Obtain a telephone number for the family Ensure that the family is seen by a health professional that day (e.g. GP / midwife / health visitor / clinical nurse specialist as per local protocol) Fax information as follows: - MCADD GP letter (Appendix 6) - MCADD is suspected leaflet (includes UK Newborn Screening Programme Centre website address and links to parent support group) - MCADD A&E letter (Appendix 7) - Contact numbers for the MCADD designated (or specialist) team - Details of the time and location of an appointment with the MCADD designated (or specialist) team. The recommended MCADD dietary (and other) guidelines can be accessed via the UKNSPC website ( 20 UK Newborn Screening Programme Centre

101 Appendix H 8.3 Diagnostic specimen requirements The diagnostic protocol is summarised diagrammatically in Appendix 8. Diagnostic tests provided externally will need to be charged for. In approximately 50% of cases the diagnosis will be confirmed following repeat C8, urine organic acids and DNA analysis for the common mutation (c.985a>g). For C8, qualitative urine organic acids and DNA (c.985a>g), results should be available within 5 working days after specimen collection. For the other cases, further investigations will be required, these are: Extended mutation screen (EMS) Until end of June 2010 samples for EMS were sent to: Dr. Brage Andresen Department of Biochemistry and Molecular Biology University of South Denmark Campusvej Odense M. Denmark Phone: Fax: bragea@bmb.sdu.dk As of 1 st July 2010, samples for EMS studies should be sent to one of two designated UK EMS laboratories as outlined below. It is the responsibility of the metabolic diagnostic laboratory to communicate with their EMS laboratory and to ensure samples are sent in a timely manner. EMS referral forms can be found at: West Midlands, Sheffield, Leeds, Liverpool, Manchester, Newcastle and Oxford are to send samples for EMS to:- Sheffield Laboratory Service Lead: Richard Kirk or Dr. Ann Dalton Sheffield Diagnostic Genetics Service Sheffield Children s NHS Foundation Trust Western Bank Sheffield S10 2TH Tel: Fax: Richard.Kirk@sch.nhs.uk or Ann.Dalton@sch.nhs.uk December A Laboratory Guide to Newborn Screening in the UK for medium-chain acyl-coa dehydrogenase deficiency (MCADD) 21

102 Bristol, Cambridge, GOSH, Portsmouth, SE Thames (Guy s) and SW Thames are to send samples for EMS to:- Guy s Laboratory Service lead: Kirsty Stewart or Dr. Stephen Abbs DNA Laboratory GSTS Pathology Floor 5 Tower Wing Guy s Hospital London SE1 9RT Appendix H Tel: Fax: Kirsty.Stewart@gsts.com or Stephen.Abbs@gsts.com The Metabolic Diagnostic laboratory working with the Inherited Metabolic Disorder team is responsible for sending samples for c.985a>g testing. Samples should be collected on 3 blood spot cards (ideally 4 good quality spots on each) at the first appointment by the Inherited Metabolic Disorder team. All 3 cards should be sent to the Metabolic Diagnostic laboratory. Card 1 is used for confirmatory biochemistry. Card 2 is sent for c.985a>g testing at partner molecular biology laboratory. Card 3 is held by the Metabolic Diagnostic laboratory until c.985a>g results have been obtained and is then sent to EMS laboratory (Guy s or Sheffield laboratory) if EMS is required. Samples for EMS screening should be sent with the appropriate EMS referral form (see: www. newbornbloodspot.screening.nhs.uk/mcadd) by the Metabolic Diagnostic laboratory via first class post. The Metabolic Diagnostic laboratory should alert the EMS laboratory that the sample has been dispatched for testing. The EMS laboratory should acknowledge receipt of card. EMS laboratory are to send reported results, via fax or to an NHS.net account to the Metabolic Diagnostic laboratory that requested the EMS. Quantitative organic acids (Hexanoylglycine) Quantitation requires a sensitive stable isotope dilution method, e.g. gas chromatography mass spectrometry, employing a standard curve or equivalent. UK Laboratories providing Quantitative Hexanoylglycine can be found on the MetBioNet website ( Specimen requirements 2 ml fresh random urine (no preservative), aliquoted from the sample used for qualitative organic acid analysis. Frozen -20 C. Send on dry ice. Note: Skin fibroblast fat oxidation studies are no longer included as part of the formal diagnostic protocol. If undertaken as part of any further follow-up this would be at local discretion and charged individually. 22 UK Newborn Screening Programme Centre

103 Appendix H 8.4 Coordination of screening follow-up results / requesting of extended mutation analysis All samples should be sent to the local metabolic diagnostic laboratory * for the following: DNA analysis for c.985a>g send sample Biochemistry Extended Mutation Screening (EMS) On learning the c.985a>g result and the biochemistry result the Metabolic Diagnostic laboratory will send a sample for EMS if required. Note: It is the responsibility of the Metabolic Diagnostic laboratory* to review results of c.985a>g analysis and biochemistry and, together with input from the clinician and decide whether EMS is required. EMS is required in the following circumstances 1 copy c.985a>g (regardless of biochemistry) No c.985a>g but with abnormal biochemistry Clinical reasons * If local arrangements differ from this for logistical reasons the responsibility for deciding whether EMS is required must be clear. December A Laboratory Guide to Newborn Screening in the UK for medium-chain acyl-coa dehydrogenase deficiency (MCADD) 23

104 Appendix H 9. Reporting to child health records departments Results should be reported using the latest version of the screening status codes - see below status codes in Section 9.1. It is recommended that the screening report for MCADD should be either MCADD not suspected (code 04) or MCADD suspected (code 08). It is a requirement that screening results (MCADD not suspected or suspected) are fed back to the child health records departments. It is recommended that child health records departments notify normal results to parents by letter. 9.1 Status codes The UKNSPC agreed status codes version 2.0 are detailed in Table 4 with specific comments with reference to MCADD. 24 UK Newborn Screening Programme Centre

105 Table 4. Status codes for MCADD Screening Status Code Suggested term displayed in child health system Appendix H Comment with reference to MCADD 01 Specimen received in laboratory 02 MCADD declined 03 MCADD repeat / further sample required Reason for repeat test will include the following: Too young for reliable screening Too soon after transfusion (<72 hours) Unsuitable sample Insufficient sample Unsatisfactory analysis 04 MCADD not suspected C8 > 0.4 μmol/l 05 Not applicable to MCADD 06 Not applicable to MCADD 07 Not applicable to MCADD 08 MCADD suspected According to the following criteria: C8 0.4 μmol/l (singlicate analysis) C8 0.5 μmol/l (re-test in duplicate, mean of 3 results) AND 09 MCADD not screened / screening incomplete* * this code applies to specimens collected and not analysed / result unreliable and in situations where a specimen is not collected C8:C10 ratio 1.0 (mean from triplicate results) Reason for no result will include the following: Died Unreliable result Moved out of area Not contactable, reasonable efforts made 10 Not applicable to MCADD Too old for screening (>1 year) December A Laboratory Guide to Newborn Screening in the UK for medium-chain acyl-coa dehydrogenase deficiency (MCADD) 25

106 10. Laboratory standards for newborn screening for MCADD 10.1 Generic Appendix H See the UKNSPC Policies and Standards at for process standards relating to timely sample collection, despatch and programme coverage Organisation Newborn screening for MCADD should be provided within the organisational structure of the newborn blood spot screening programme. It should be undertaken by specialist newborn screening laboratories already providing screening programmes for phenylketonuria, congenital hypothyroidism, cystic fibrosis and sickle cell disorders. Laboratories screening for MCADD must be accredited by Clinical Pathology Accreditation (UK). There must be a member of staff at consultant level responsible for MCADD screening with defined lines of accountability for all aspects of the service. There should be local policies and standard operating procedures describing the whole screening process including pre-analytical, analytical and post-analytical processes; these include reporting normal and abnormal results, referral and follow-up arrangements for presumptive positive cases. Processes must be provided in line with relevant national standards and guidance and should be reviewed periodically taking into account audit data, accumulating results, technical developments and local changes in healthcare provision Analytical processes Newborn screening for MCADD should be provided using the nationally agreed screening protocol with the screening tests, octanoylcarnitine (C8) and decanoylcarnitine (C10), performed using an underivatised MRM tandem mass spectrometric technique. The laboratory must undertake appropriate internal quality control procedures for the screening test and demonstrate satisfactory performance in an approved External Quality Assurance Scheme as part of UKNSPC Quality Management arrangements. Laboratories are expected to provide a completed notification form on each presumptive positive to the UKNSPC. Acylcarnitine full scan analysis must be undertaken in a timely manner by a laboratory with appropriate analytical and interpretive expertise. Laboratories must participate and demonstrate acceptable performance in an approved EQA scheme. Laboratories should provide data on screening performance to the UKNSPC as well as regional and local audit / quality management groups as required. The results and performance of the MCADD screening programme should be included within an annual report produced by the screening laboratory for circulation to local Directors of Public Health (and others as required). There must be a documented risk management policy for the laboratory aspects of the MCADD screening programme as part of an overall newborn screening risk management policy. 26 UK Newborn Screening Programme Centre

107 Appendix H 10.4 Performance standards, including diagnostic tests The laboratory analytical service should be configured to enable the MCADD newborn screening protocol (a raised octanoylcarnitine confirmed in triplicate, a raised C8:C10 ratio in triplicate and acylcarnitine full scan) to be completed within 4 working days from receipt of an adequate sample as core standard. Presumptive positive results (average of triplicate C8 and C8:C10 ratio) should be referred by the laboratory to the appropriate clinical team on the day they become available. This includes referral on Fridays prior to a weekend and a bank holiday. Follow-up diagnostic tests (including full acylcarnitine scan, urine organic acids and c.985a>g mutation analysis) must be undertaken in line with the diagnostic protocol by accredited laboratories who must participate and demonstrate acceptable performance in the relevant / accredited EQA schemes. Provision should be made to ensure results of these investigations are available within 5 working days from sample collection. The responsibility for this must be defined locally. Results of further follow-up diagnostic tests (EMS and quantitative hexanoylglycine) should be available within 20 working days of sample collection. December A Laboratory Guide to Newborn Screening in the UK for medium-chain acyl-coa dehydrogenase deficiency (MCADD) 27

108 Appendix H 11. References and further reading Chace, D.H., Hillman, S.L., van Hove, J.L.K., Naylor, E.W. (1997) Rapid diagnosis of MCAD deficiency: quantitative analysis of octanoylcarnitine and other acylcarnitines in newborn blood spots by tandem mass spectrometry. Clin Chem, 43, Clayton, P.T., Doig, M., Ghafari, S., Meaney, C., Taylor, C., Leonard, J.V., et al. (1998) Screening for mediumchain acyl-coa dehydrogenase deficiency using electrospray ionisation tandem mass spectrometry. Arch Dis Child, 79, Derks, T.G.J., et al. (2008) Neonatal screening for medium-chain acyl-coa deydrogenase (MCAD) deficiency in The Netherlands: The importance of enzyme analysis in order to ascertain true MCAD deficiency. J Inherit Metab Dis, 31, Downing, M., et al. (2005) Newborn screening for medium-chain acyl-coa dehydrogenase deficiency: acylcarnitine C8/C10 ratio at day 6 differentiates affected cases from carriers. J Inherit Metab Dis, 28(Suppl.1), 10. Goddard, P.E. (2004) Newborn screening for medium-chain acyl-coa dehydrogenase deficiency (MCADD) in the UK. J Fam Health Care, 14(4), Goddard, P.E., et al. (2005) Quality Assuring a Multicentre Newborn Screening Programme for MCADD in the UK. J Inherit Metab Dis, 28(Suppl.1), 119. Gregersen, N., Winter, V., Curtis, D., Deufel, T., Mack, M., Hendrickx, J., et al. (1993) Medium-chain acyl-coa dehydrogenase (MCAD) deficiency: the prevalent mutation G985 (K304E) is subject to a strong founder effect from northwestern Europe. Hum Hered, 43(6), Grosse, S.D., Khoury, M.J., Greene, C.L., Crider, K.S., Pollitt, R.J. (2006) The epidemiology of medium-chain acyl-coa dehydrogenase deficiency: an update. Gen Med, 8(4), Heptinstall, L.E., Till, J., Wraith, J.E., Besley, G.T. (1995) Common MCAD mutation in a healthy parent of two affected siblings. J Inherit Metab Dis, 18, Khalid, J.M., et al. (2008) Ethnicity of children with homozygous c.985a>g medium chain acyl-coa dehyrogenase deficiency: findings from screening approximately 1.1. million newborn infants. J Med Screening, 15(3), Khalid, J.M., et al. (2010) Relationship of Octanoylcarnitine Concentrations to Age at Sampling in Unaffected Newborns Screened for MCADD. Clinical Chemistry, 56(6), 1-7. Kirkpatrick, S., et al. (2005) Parental Responses to a Newborn Screening Diagnosis of Medium-Chain acyl- CoA Dehydrogenase Deficiency (MCADD). J Inherit Metab Dis, 28(Suppl.1), 10. Leonard, J.V., et al. (2006) Consensus case definitions for MCADD among infants with presumptive positive newborn screening results. J Inherit Metab Dis, 29(Suppl.1), 19. Oerton, J., et al. (2005) Predictive value, clinical status and genotype of medium-chain acyl-coa dehydrogenase deficiency (MCADD) ascertained by screening at one week of age using electrospray tandem mass spectrometry of underivatised blood spots: findings from a UK multicentre study. J Inherit Metab Dis, 28(Suppl.1), 9. Phillips, P., et al. (2005) Newborn screening for medium-chain acyl-coa dehydrogenase deficiency at one week of age: octanoylcarnitine distributions from a multicentre study using electrospray tandem mass 28 UK Newborn Screening Programme Centre

109 Appendix H spectrometry of underivatised blood spot samples. J Inherit Metab Dis, 28(Suppl.1), 9. Pollitt, R.J., Leonard, J.V. (1998) Prospective surveillance study of medium-chain acyl-coa dehydrogenase deficiency in the UK. Arch Dis Child, 79, Pourfarzam, M., Morris, A., Appleton, M., Craft, A., Bartlett, K. (2001) Neonatal screening for medium-chain acyl-coa dehydrogenase deficiency. Lancet, 358, Seddon, H.R., Green, A., Gray, R.G., Leonard, J.V., Pollitt, R.J. (1995) Regional variations in medium-chain acyl-coa dehydrogenase deficiency. Lancet, 345(8942), Shortland, G., et al. (2006) Newborn screening for MCADD: Findings from a multicentre prospective UK collaborative study. J Inherit Metab Dis, 29(Suppl. 1), 19. Wilcken, B., Carpenter, K.H., Hammond, J. (1993) Neonatal symptoms in medium-chain acyl coenzyme A dehydrogenase deficiency. Arch Dis Child, 69, Zytkovicz, T.H., Fitzgerald, E.F., Marsden, D., Larson, C.A., Shih, V.E., Johnson, D.M., et al. (2001) Tandemmass spectrometric analysis of amino, organic, and fatty acid disorders in newborn dried blood spots: a two year summary from the New England Newborn Screening Program. Clin Chem, 47, December A Laboratory Guide to Newborn Screening in the UK for medium-chain acyl-coa dehydrogenase deficiency (MCADD) 29

110 Appendix H Appendix 1 UKCSNS-MCADD study* Overview and early findings can be found at: * The UK Collaborative Study of Newborn Screening Medium-chain acyl-coa dehydrogenase deficiency 30 UK Newborn Screening Programme Centre

111 Appendix H Appendix 2 MCADD newborn screening protocol Routine newborn screening dried blood spot samples: Underivatised MRM Octanoylcarnitine (C8) Yes Re-test C8 in duplicate [B, C] 1 Test for C10 2 C8 >0.40 µmol/l [A] No C8 >0.50 µmol/l Mean [A,B,C] No MCADD not suspected No further action Yes Obtain C10 results 2 Calculate C8:C10 ratio If insufficient blood to re-test, but raised initial C8 ( 0.40) treat as MCADD suspected. 1 Refer to methodology for calculating C8:C10 ratio. Ratio 2 C8:C10 >1.0 No 2 Recommended to provide clinician with full acylcarnitine scan (on eluate and/or derivatised) as soon as possible. See MCADD Lab Handbook Section 6.2 for further guidance. 3 Yes MCADD suspected Referral to designated clinician3 See MCADD diagnostic protocol December A Laboratory Guide to Newborn Screening in the UK for medium-chain acyl-coa dehydrogenase deficiency (MCADD) 31

112 Appendix H Appendix 3 MCADD genetic / biochemical sibling testing protocol A. Protocol for management of at risk delivery neonatal testing for siblings born after proband diagnosis When to test and samples taken hours: C8, qualitative urinary organic acids and genotyping Write on blood spot card Family history of MCADD Day 5-8: Routine newborn screen Write on blood spot card Family history of MCADD Management Prior to results It is essential to ensure that the baby maintains a good milk intake. A term baby should be fed every 4 hours and a preterm baby every 3 hours. Exclusively breast fed babies are particularly at risk in the first 72 hours when the supply of breast milk is poor; top up feeds of expressed breast or formula milk may be necessary in the first hours until a good milk supply is established. If oral feeds are not tolerated or if the baby is unwell in any way, urgent referral should be made to a paediatrician for review and consideration of nasogastric tube feeds or commencing intravenous glucose*. If MCADD confirmed: Follow the standard MCADD clinical and dietary management guidelines* B. Testing siblings born before proband diagnosis When to test Offer to test if sibling has not been previously screened for MCADD and if: Or Proband has abnormal biochemistry at follow-up visit 2 recognised disease causing mutations on genotyping Sibling samples 1. C8 and qualitative urinary organic acids 2. DNA send for genotyping once definite MCADD diagnosis secured in proband (2 disease causing mutations identified) Management Before the results are available and thereafter if MCADD confirmed: Follow the standard MCADD clinical and dietary management guidelines* C. Genetic counselling In most instances questions about genetic inheritance and risk will be dealt with by the metabolic team, but if there are any outstanding issues, or discussion about prenatal diagnosis, further genetic counselling is available through the local Genetics Service. *For more information please refer to MCADD management and dietary guidelines at Further information / protocols can also be accessed at 32 UK Newborn Screening Programme Centre

113 Appendix H Appendix 4 Guidance on discrepant replicates If a sample has an initially raised C8 (above the screening protocol cut-off), which is clearly normal on duplicate repeat, a falsely elevated initial C8 is suspected. If there is no obvious contamination from the plates then the following procedure is recommended. Check persistence of C8 (mass 288) by performing an underivatised acylcarnitine full scan on the well that gave the raised result plus 2 normal samples and High QC from the same plate for comparison (if necessary reconstitute the well). If 288 persists: If no 288: Derivatise the transfer plate well that gave the raised result plus the same 2 normal and high QC samples from the plate Perform a derivatised acylcarnitine full scan (or product ion scan). Contamination not of sample origin, no further testing of samples in batch necessary but other non-sample sources of contamination may be sought. If C8 confirmed i.e. 344 detected * If C8 not confirmed i.e. no 344 Re-test the plate / whole batch to eliminate the possibility of sample mix up. Contamination is not due to genuine C8, no further testing of samples in batch necessary but should investigate other nonsample sources of 288 contamination. *When method involves eluate transfer from elution to transfer plate, can first attempt to identify any sample mix up at transfer stage by performing an underivatised acylcarnitine scan of the whole elution plate (reconstituted with 75 µl methanol). If any elution well shows increased C8 retest that sample. However, re-analysis of the elution plate is often not successful due to insufficient residual sample. December A Laboratory Guide to Newborn Screening in the UK for medium-chain acyl-coa dehydrogenase deficiency (MCADD) 33

114 Appendix H Appendix 5 Template for notification of presumptive positive for designated (or specialist) MCADD team (by Screening Laboratory to clinician) For Patient s Notes Baby s Name Gender D.O.B NHS Number Address GP To the Medical Consultant, Screening specimen date: The above baby was found to have a positive (abnormal) newborn screening test result for medium-chain acyl-coa dehydrogenase deficiency (MCADD). The blood spot octanoylcarnitine (C8) was µmol/l whole blood (mean of triplicate results) with the C8:C10 ratio as. (The screening tests for phenylketonuria, congenital hypothyroidism and sickle cell disease are, and cystic fibrosis is ). The acylcarnitine full scan analysis shows:- Recommended Action as per MCADD Screening Programme clinical management protocol and diagnostic protocol:- First review appointment to take place within 24 hrs Venous blood from baby for acylcarnitines (C8 and full scan), two (2) blood spot cards for DNA (c.985a>g and extended mutation analysis) Urine for qualitative / quantitative organic acid analysis Signed: Date Screening laboratory contact details: 34 UK Newborn Screening Programme Centre

115 Appendix H Appendix 6 Template for GP letter [Date] Dear Doctor Re: [insert full name and date of birth of child] [Name of child] has been detected on newborn screening to have a positive (abnormal) test for mediumchain acyl-coa dehydrogenase deficiency (MCADD). This is a rare inherited enzyme deficiency which reduces the metabolism of fat into energy. A child with this condition is at risk from hypoglycaemia, coma and death with fasting and particularly during intercurrent illnesses when the demand for energy increases and calorie intake is often reduced. He / she may appear drowsy or lethargic, vomit, have seizures or have a deteriorating conscious level. Hypoglycaemia is a late sign; treatment must be initiated if [name of child] is unwell even if the blood sugar is normal. A patient with MCADD requires no special treatment when well apart from avoiding prolonged fasts. Breastfeeding is not contraindicated but it is important to ensure that the infant is feeding adequately. Formula feeds rich in medium-chain triglycerides (MCT) should be avoided. The family will be taught to use an Emergency Regimen (ER) during intercurrent illness, details of which will be sent to you. The aim is to supply readily available calories to avoid mobilising the fat stores and therefore avoid decompensation. Oral Rehydration Therapy (ORT) solutions do not contain sufficient calories to avoid decompensation, and if used require fortifying with glucose polymer. The family will have a recipe for this. If the ER is not tolerated, or the child s condition deteriorates, then urgent admission to the local hospital should be arranged for an intravenous 10% dextrose infusion with appropriate electrolyte additives. A copy of the A&E letter the parents will be given is attached. When the child is well, they should return to their usual feeds. The positive test so far is a screening test, and therefore it is essential to meet with the family to further explain the condition and to confirm the diagnosis. This will entail blood and urine tests. As discussed on the phone, the parents are to attend [appointment location] at [appointment time] to be seen by the metabolic team. If the parents would like to discuss any matters prior to this review, [name of clinician] may be contacted on [contact number]. The long-term prognosis for MCADD is very good once diagnosed providing that the emergency regimen is followed as directed. Immunisations should be undertaken as normal, and general care is unaltered. The condition is inherited in an autosomal recessive fashion, with a 1:4 risk of recurrence in each pregnancy. Once the diagnosis has been confirmed, screening of any siblings will be offered. If you have any further questions, please do not hesitate to contact [name and contact details]. With kind regards Yours sincerely Enc: A&E letter December A Laboratory Guide to Newborn Screening in the UK for medium-chain acyl-coa dehydrogenase deficiency (MCADD) 35

116 Appendix H Appendix 7 MCADD A&E / Hospital Letter To Whom It May Concern: This child has (or is currently being investigated for a positive newborn screening test for) medium-chain acyl-coa dehydrogenase deficiency (MCADD). Children with MCADD have a reduced ability to metabolise fat to provide energy. Infections, fasting, vomiting or diarrhoea result in the accumulation of medium-chain fats, which form toxic metabolites. This can lead to serious illness with encephalopathy and even death. Hypoglycaemia may only occur at a relatively late stage; treatment must not be delayed just because the blood glucose is normal. Treatment aims to inhibit mobilisation of fat by providing ample glucose. During intercurrent infections, parents will use an Emergency Regimen (ER) of frequent glucose polymer drinks but if this is not tolerated or there is clinical deterioration they have been instructed to attend the hospital urgently for further management. Brief parent-held guide to MCADD hospital management* Assess Responsiveness / conscious level record Glasgow coma score U&E, Blood Gases, Glucose (stick test + laboratory measurement), other tests as indicated Vomiting or Diarrhoea or Not tolerating feed/er or Altered consciousness or Blood Glucose <3.0 mmol/l IV 10% glucose bolus 2 ml/kg (200 mg/kg) If poor circulation / shock, follow with 20 ml/kg 0.9% sodium chloride Whilst the maintenance fluid is being made up, continue 10% glucose at 5mL/kg/hr Maintenance fluid given as 10% glucose with 0.45% sodium chloride. This solution can be made up as follows: Remove and discard 50 ml from a 500 ml bag of 0.45% sodium chloride & 5% glucose solution, then add 50 ml of 50% glucose to the fluid remaining in the bag Correct any fluid / electrolyte deficits; add potassium once U&E status is known Admit & notify metabolic team (contact details below) Monitor blood glucose 4 hourly during acute phase Adjust IV infusion rate to maintain blood glucose 4-8 mmol/l Continue infusion until blood glucose stable and tolerating usual oral feeds Asymptomatic and glucose <3.0 mmol/l Oral or nasogastric ER until glucose within normal range and clinically recovered and stable Note: Oral rehydration solutions do not contain sufficient glucose to avoid decompensation and therefore, if prescribed, must be fortified with glucose polymer - see MCADD Dietary Information Sheets for ER recipe, available at 36 UK Newborn Screening Programme Centre

117 Appendix H Please notify the metabolic team below if this child is admitted. [INSERT CONTACT DETAILS FOR METABOLIC TEAM] If you have any questions, please do not hesitate to contact the metabolic team as above. *MCADD dietary management guidelines are available at *Further detailed information / protocols can also be accessed at December A Laboratory Guide to Newborn Screening in the UK for medium-chain acyl-coa dehydrogenase deficiency (MCADD) 37

118 Appendix H Appendix 8 MCADD diagnostic protocol All babies presumptive positive for MCADD at newborn screening FOLLOW-UP ANALYSES* (at first review appointment): Blood acylcarnitines (dried blood spot or plasma): C8 (duplicate) and acylcarnitines full scan Qualitative urine organic acid (UOA) analysis In cases where a diagnostic increase in hexanoylglycine is not detected using qualitative methods, quantitation (measured using a sensitive, stable isotope dilution method e.g. gas chromatography-mass spectrometry employing a standard curve or equivalent) should be performed. Dried blood spot (or liquid blood) for DNA: c.985a>g mutation analysis and Extended Mutation Screening (EMS) if required complete 3 separate blood spot cards, each sent for analysis at first review appointment (see Guidance notes) c.985a>g homozygous (2 copies) Yes MCADD No Yes No Biochemically Abnormal* c.985a>g heterozygous (1 copy) Yes EMS* Other mutation identified (with c.985a>g) No Biochemically Abnormal* Yes No NOT MCADD EMS* 2 mutations No EMS* 1 mutation only No Unaffected MCADD CARRIER Yes Yes MCADD No Yes MCADD UNLIKELY Review and consider need for further biochemical investigations Likely unaffected MCADD CARRIER Review and consider need for further biochemical investigations *See Guidance notes for details on page 39 for details 38 UK Newborn Screening Programme Centre