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Newborn screening for MCADD. Dr Jean Kirk RHSC Edinburgh. MCADD. What is MCADD? How does it affect individuals who have it? What is known about long term effects? Feedback from newborn screening programmes in other countries Why is it being added to newborn screening in Scotland?.

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Newborn screening for MCADD


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    1. Newborn screening for MCADD Dr Jean Kirk RHSC Edinburgh

    2. MCADD • What is MCADD? • How does it affect individuals who have it? • What is known about long term effects? • Feedback from newborn screening programmes in other countries • Why is it being added to newborn screening in Scotland?

    3. What is MCADD?

    4. What is MCADD? Inherited disorder of one of the enzymes needed to break down fatty acids Medium Chain AcylCoA Dehydrogenase Deficiency

    5. What is MCADD? • It is an autosomal recessive disorder, first identified in 1976 • Carriers (parents) are not affected • Two carriers have a 1 in 4 chance of having an affected child • It is most common in people of North European origin

    6. Normal Fatty Acid Oxidation

    7. When is fatty acid breakdown activated? • Just after a feed • Fasted for a short time • Fasted for a longer time, glucose and insulin levels beginning to fall • Accelerated if unwell, vomiting, catabolic. Fatty acids become the energy source for the body & brain • Lack of insulin in diabetic ketoacidosis

    8. Fatty acid oxidation in MCADD

    9. MCAD deficiency • Relative lack of ketones produced for the amount of fatty acids broken down • Large quantities of toxic fatty acid intermediates produced that are encephalopathic • Infant becomes drowsy, comatose and increasingly hypoglycaemic • Rapid recovery when glucose given • replenishes circulating glucose • raises insulin levels. This switches off fatty acid oxidation & stops toxic intermediate production

    10. Diagnosis in children/adultswho have not been newborn screened Investigations carried out in selected individuals only • Older technology - urine organic acids • More recent - tandem mass spectrometry • Both detect compounds that are present in everyone in tiny amounts during normal fatty acid oxidation • But are increased due to the block in the main fatty acid oxidation pathway in MCAD deficiency. • Some markers are slightly increased even when person is well • More markers are abnormally increased when unwell • DNA mutations may also identify most cases

    11. MCAD DeficiencyDiagnosis at acute presentation

    12. urea adipate B-hydroxybutyrate 5OH hexanoate acetoacetate suberate octanoyl glucuronide suberylglycine urea lactate phosphate 7OH octanoate sebacate succinate internal standard carbohydrate phenylpropionylglycine hexanoylglycine 3OH sebacate MCADD Diagnosis at acute presentation by urine organic acids

    13. Internal standard hippurate urea p-OHphenylacetate phenylpropionylglycine hexanoylglycine aconitate p-cresol suberate lactate HMMA adipate MCAD Diagnosis Urine organic acids 24 hours later 5OHmethyl2furoate heptenedioate citrate

    14. How might MCADD affect individuals who have it? Typical MCADD case

    15. Typical MCADD presentation -medical history • Girl born by SVD at 41 weeks gestation • Birth weight 3.4kg • Normal development. Well and thriving • Fully vaccinated • Only child • Parents non smokers, both well

    16. Typical MCADD presentation -day before admission • Aged 17 months • Vomited twice in morning • Not keen to eat at lunchtime • Further large vomit in afternoon • Tired, irritable & shivery • Mother put her to bed • She slept soundly, which was unusual for her

    17. Typical MCADD presentation -day of admission • 8am roused slightly • Mum felt she was very tired & left her to sleep on • 10:30am tried to wake her - unarousable • Body rigid, eyes slightly open, pale • Did not stop breathing. No jerking of limbs • Called 999

    18. Typical MCADD presentation -in A/E • Pale unconscious, unresponsive to stimuli • Intermittent Kussmaul type spontaneous breathing • Intubated • Extension of lower limbs & fisting • Normal cardiac sounds, chest clear • BM stix – undetectable glucose

    19. Typical MCADD presentation -in A/E • Impossible to find venous access • Dextrose given intraperitoneally and eventually into external jugular vein • Acidotic – given sodium bicarbonate • Given mannitol because of decerebration • Lumbar puncture showed no increased pressure • CSF clear, Protein normal, • CSF glucose 0.7 (paired blood glucose 0.4)mmol/L

    20. Typical MCADD presentation -recovery from acute episode • Ventilated and glucose maintained above 4mmol/L • First urine passed sent for organic acid analysis • Diagnosis of MCADD made • Recovered rapidly and fully, discharged after 3 days • No further admissions • Now a very active healthy teenager

    21. MCADD acute presentation • Triggered by prolonged fasting, leading to what would normally be a ketotic state • This happens after a shorter time in infants and young children • Entirely well when normally fed • Treatment by oral or iv glucose raises circulating glucose levels • suppresses fatty acid oxidation and • rapidly reverses all biochemical and clinical abnormalities

    22. Typical MCADD presentation-follow up • Advice given on avoiding long periods of fasting (tailored to age of child) • If unwell, not eating, vomiting, give oral glucose, sugary drinks, glucose polymer • If unable to tolerate take to hospital immediately for iv glucose • With this management very few MCADD children have a serious second decompensation • Early recognition of danger period and glucose administration can completely avoid further life threatening attacks

    23. What is known about long term effects of MCADD?

    24. MCADD in Scotland • No diagnoses made before mid 1980s – technology was not available. • 48 Scottish cases diagnosed since – from 3 days to adult • Most diagnosed patients alive & well • A small number of deaths and unexplained sibling deaths • A few patients have significant brain damage secondary to their first severe decompensation

    25. MCADD in the UK 1994-6 Age at first recorded attack 100 75 Surviving Deaths 50 Cumulative percentage 25 0 0 50 100 150 200 250 Age (weeks) 56 cases – 5 from Scotland Pollitt RJ & Leonard JV Arch Dis Child 1998; 79: 116-119

    26. MCADD in the UK 1994-6 Age at first recorded attack 100 75 Surviving Deaths 50 Cumulative percentage 25 7patients became unwell in neonatal period 3 died 0 0 50 100 150 200 250 Age (weeks) Some neonates were tested because of an affected older sibling Pollitt RJ & Leonard JV Arch Dis Child 1998; 79: 116-119

    27. Symptomatic MCADD and fatal outcome

    28. MCADD survivors & neurocognitive impairment

    29. Long term consequences of MCADD survivors Iafolla A et al Arch Dis Child 1994; 67: 142-145

    30. Newborn Screening for MCADD

    31. Criteria for population screening programme • Important health problem • Accepted treatment • Facilities for diagnosis • Latent stage • Suitable test • Acceptable test • Natural history understood • Policy on whom to treat • Economically balanced

    32. UK 1:12,600 D 1:9,900 USA 1:17,000 Japan 1:51,000 Aus 1:21,300 Incidence of MCADD from newborn screening Grosse SD et al Genet Med 2006; 8: 205-212

    33. Newborn screening for MCADD – suitable test • First line test - Measurement of octanoyl carnitine (C8) in newborn screening dried bloodspot by tandem mass spectrometry • False negatives rare • False positives (prems, ill, some MCADD carriers) • Second line test: acylcarnitine profile by tandem mass spectrometry is practically diagnostic for MCADD • Diagnosis confirmed on second sample by repeat acylcarnitine, urine organic acid analysis, DNA mutations, enzymology if necessary

    34. Newborn blood spot acylcarnitine profile: MCADD

    35. Outcome of newborn screening for MCADD • Potential fatal crisis before screening result • Fatal crisis after diagnosis • 2/29 MCADDs died at 10 months in Germany • USA - two deaths in MCADD diagnosed by screening • Neurocognitive outcome otherwise normal Poorer verbal and specific executive functioning in those presenting clinically compared with screening diagnosed Joy P et al Child Neuropsychol 2009; 15: 8-20

    36. MCADD prevalence from clinical detection and screening

    37. Discrepancy between clinical and screening ascertainment • Failure to diagnose MCADD in those presenting clinically • Failure to become symptomatic • Mild mutations detected by screening that might never present clinically • Temperature sensitive mutant 199T>C • Allele frequency 1/500 • Detected by screening if compound with 985G>A • Not associated with symptoms

    38. Summary • MCADD may present acutely • Acute presentation may result in death or serious morbidity • Treatment is simple and effective in preventing crises • Knowledge that a child is affected with MCADD is key in preventing future crises

    39. MCADD newborn screening is well established in many countries eg Australia, USA, Germany, Denmark, Netherlands Newborn screening for MCADD in the UK – pilot project

    40. Routine screening in England • Rolled out at end of study period • Now complete • Using same methods • Same is proposed in Scotland • Starting ….2010?

    41. Sheffield experience(with thanks to Mark Sharrard) • February 2004 - July 2008 • 299,030 babies screened • 52 screening positives (C8≥0.5µmol/L) • One sib screened day 1 • 29 definite MCADD (23 985G>A homozygotes) • 6 uncertain MCADD (4 199T>C) • 10 simple heterozygotes • 7 not MCADD • Prevalence 1/8,544 (all), 1/10,311 (definite) • PPV 63.7% (all), 55.8% (definite)

    42. Outcomes of MCADD in Sheffield area • No deaths • No serious decompensations • No false negatives