Neonatal Biochemistry Investigation for Inherited Metabolic Disorders (IMDs)
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1 Neonatal Biochemistry Investigation for Inherited Metabolic Disorders (IMDs) Anne Green Birmingham Children s Hospital Leeds May 2005
2 Overview of how IMDs present cases Range of Disorders & Incidence disorders presenting in the newborn Approach to Investigation
3 Presentation of IMD Intrauterine HELLP AFLP
4 HELLP - Haemolysis - Elevated Liver Enzymes - Low Platelets AFLP - Acute Fatty Liver of Pregnancy - severe liver dysfunction - thrombocytopenia
5 LCHADD Long chain 3-hydroxy acyl CoA dehydrogenase deficiency - defect of mitochondrial fat oxidation (1990) - hypoketotic hypoglycaemia - metabolic collapse (esp. liver) - death - other problems include: - myopathy and cardiomyopathy - retinitis pigmentosa - FTT with diarrhoea and vomiting - common mutation G1528C
6 HELLP/AFLP and LCHADD (Wilcken et al, 1993) 11 pregnancies in 5 mothers (HELLP) 6 LCHADD babies In pregnancies where foetus has LCHADD, the frequency of preeclampsia related conditions is high
7 HELLP/AFLP and LCHADD (Ibdah et al 1996) 16 families with LCHADD - 12 different mutations - G1528C found in 50% of mutant alleles - 11 women had AFLP - All these women were carrying foetuses with G1528C (5 homozygous, 6 heterozygous) LCHADD G1528C mutation associated with AFLP
8 Fatty Acid Oxidation Defects in the Foetus which can cause AFLP/HELLP LCHADD MCADD Carnitine Palmitoyl transferase type 1 SCADD
9 Case 1 1 month - presented to A&E with hypoglycaemia - collapse ITU Died - post mortem fatty acid changes in liver/kidney - LCHADD diagnosed P.M. (skin fibroblasts)
10 Case 1 Mother 35/40 HELLP Cord blood diagnosis LCHADD (acyl carnitines) Treatment - MCT
11 Investigation of HELLP and AFLP Mother - organic acids (urine) - carnitine, acyl carnitines (blood) - glucose, lactate, (free fatty acids, 3- hydroxybutyrate) - +/- LCHADD DNA Baby - organic acids (urine) - carnitine, acyl carnitines (blood) - LCHADD DNA -? fibroblasts fat oxidation ( esp if baby dies)
12 Presentation of IMD Intrauterine HELLP AFLP Birth Hydrops Dysmorphism
13 Fetal and Neonatal Hydrops Hydrops IMDs are present in approx. 1-2% of nonimmune hydrops fetalis Investigate if unexplained, familial or history of still-births/neonatal deaths/ spontaneous abortions
14 Investigation for Neonatal/Foetal Hydrops skin (chromosomes &? enzymes) blood- haemoglobinopathies placenta - histology urine (IMD) (amniotic fluid) liver/muscle- histology/biochemistry
15 Presentation of IMD Intrauterine HELLP AFLP Birth Hydrops Dysmorphism
16 IMD & Dysmorphism in the neonate Menkes Zellwegers and Z like (Perox disorders) Lysosomal GM2,ML2,MPS,Multiple sulphatase Congenital hypothyroidism Maternal PKU CDGS Cholesterol synthesis defects GA II Sulphite/xanthine oxidase Congenital lactic acidoses Mevalonic kinase
17 Presentation & IMD Intrauterine Birth SUDI
18 SUDI cases 1999/ age at death < >14 age in months
19 Sudden Unexpected Death in Infancy ( SUDI) Explained SUDI infection (respiratory,cns, GI) cardiovascular accident/trauma metabolic SIDS no cause of death is found after a thorough post mortem examination
20 Investigation of SUDI Non accidental injury radiology exam forensic investigation option Infection Metabolic
21 Sudden Unexpected Death in Infancy Working Group RCPath & RCPCH ( Sept 2004) Baroness Helena Kennedy
22 SUDI Immediate Specimen Collection Blood blood culture blood spots - IMD blood - lithium heparin Chromosomes Blood serum Toxicology Nasopharyngeal aspirate & swabs Urine Tox & IMD
23 Biochemical Investigations Amino acids ( blood &urine) Organic acids (urine) Acyl carnitines(blood spot)
24 Metabolic Investigations Quantitative plasma amino acids All show similar abnormalities grossly increased glutamine, glycine, alanine and proline consistent with acute collapse taurine, aspartate, serine, ornithine increased consistent with haemolysis/autolysis
25 Quantitative plasma amino acids (µm) Upper limit of normal indicated by shaded area tau thr glu pro ala AAB cys ile tyr orn his
26 Acyl carnitines in SUDI cases blood spots +/- plasma analysed by tandem mass spectrometry
27 Acyl carnitine results in SUDI most specimens show increased free carnitine increased short chain acyl carnitines decreased long chain acyl carnitines
28 Metabolic Investigations ( if indicated) Cultured fibroblasts enzymes DNA
29 IMD diagnoses in SUDI cases Carnitine transporter LCHADD - 2 Citrullinaemia
30 Sick Neonate Well at birth/no signs or symptoms Family History Consanguinity Sibling illness/death Presentation Non specific ( eg poor feeding, hypotonia) Symptoms relate to feeding Clues Smell Hair/skin Biochemical features
31 Presentation in the neonate Hypoglycaemia Acid base disturbance Metabolic acidosis Respiratory alkalosis Liver dysfunction/organomegaly Jaundice Hepatitis Liver failure Neurological dysfunction Seizures Hypotonia Conscious level Encepaholopathy
32 Case 2 Consanguinous parents, 2 older siblings both well 1 Sib died aged 4 days no Dx Normal birth 38/40 Well until 26 hours jittery, not feeding 40h seizures, floppy 45h hiccups, required ventilation
33 Case 2 ( cont d) Acid base normal Plasma ammonia normal Liver enzymes normal Calcium, Magnesium,Glucose normal Hb& FBC normal Lactate 3.5mmol/l ( sl increase)
34 Case 2 ( cont d) Amino acids(urine) Organic acids Increased urine glycine
35
36 Glycinuria Bacterial ( Hippuric acid) Valproate therapy Organic acid disorder eg MMA, PA, IVA Non ketotic hyperglycinaemia Iminoglycinuria Prolinaemia / Hydroxyprolinaemia Atypical persisitent hyperglycinaemia
37 Metabolic investigation csf glycine 205 µmol/l (<20) plasma glycine 1626 µmol/l (<700) csf:plasma glycine ratio 0.12 (<0.03) Consistent with non-ketotic hyperglycinaemia
38 csf/plasma glycine ratio in NKH csf glycine csf/plasma
39 Progress ventilation withdrawn died 24h later liver biopsy taken glycine cleavage enzyme undetectable ante-natal diagnosis possible
40 CSF quantitative amino acids 0.5ml clear csf in plain bottle (non traumatic) Glycine present at low concentrations (<20 µm) non ketotic hyperglycinaemia looking for high concentrations (usually >50 µm) Serine present at low concentrations (approx 40 µm) serine deficiency disorders looking for low concentrations (usually <20 µm)
41 Case 3 1 st child unrelated caucasian parents 38/40 well for first 24h 28h jittery ( plasma glucose 4mmol/l) 40h grunting respiration NNU peripheral shut down
42 Case 3 ( cont d) CSF glucose & protein normal Na,K Ca,Mg normal Started antibiotics ( infection screen awaited ) 50h convulsions Rx phenobarb 62 h unresponsive, hyperventilating 72h- further convulsions & Bradycardias 74h DIED? Sepsis
43 Case 3 cont d PM Fatty liver Urine Glutamine, alanine & citrulline +++ ASA anhydrides Oroticacid ++
44
45
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47 Case 4 Previous sib died at 2 days no diagnosis Age 4 days 24 hour history of poor feeding and excessive sleeping totally breast-fed on admission convulsing hypothermic hypoglycaemic (lab glucose 0.7 mmol/l)
48 Case 4 - metabolic Ix urine organic acids dicarboxylic aciduria glycine conjugates (C6,C8) plasma carnitine total 13 mmol/l (23-60) free 4 mmol/l (15-53)
49 Case 4 - metabolic Ix DNA G985 homozygote - medium chain acyl CoA dehydrogenase (MCAD) deficiency
50 MCAD deficiency commonest fatty acid oxidation disorder approx 1 in 10,000 births in UK peak age of presentation 12-18m 25% die during first attack readily treatable fasting tolerance improves with age
51 Case 4 - family history previous sib died at 2 days Coroner s PM neonatal infection due to prolonged rupture of membranes; no metabolic Ix tissue obtained for DNA analysis(retrospective) G985 homozygote
52 Lessons importance of family history relationship between symptoms and feeding MCAD can present in the neonatal period ( especially if breast fed)
53 Range of Disorders Intermediary metabolism intoxication Amino acids Organic acids Urea cycle Carbohydrates Purines/pyrimidines
54 Range of Disorders Intermediary metabolism intoxication Amino acids Organic acids Urea cycle Carbohydrates Purines/pyrimidines Energy production ( liver,heart,muscle,brain) Mit resp chain/electron transport disorders Fat oxidation Gluconeogenesis Glycogen storage
55 IMD Diagnoses at BCH* *excludes sibling diagnoses & at risk cases 0-7 days 7-14days days UCD 7 NKH Fat Ox Org acid 3 2 AA (Tyr& MSUD) 1 2 Galactosaemia 6 1 Zellweger 2 3 Elect Tr chain 2 GSD 2 SLO 1 Total
56 NKH UCD Galactosaemia Fat oxidation Organic acids
57 Approach to Investigation Newborn screening Sib testing Clinical Presentation
58 Newborn Screening Current universal screening PKU* Congenital hypothyroidism Duchenne ( Wales) Cystic Fibrosis ( some areas only) Sickle Cell disorders Plus MCADD in ~50% UK * plus other amino acids - MSUD, tyrosinaemia in some areas
59 Importance of Sib Testing When to test need to start treatment for baby when does biochem abnormality appear? How to test Metabolite Enzyme DNA
60 Approach to Investigations Ist line test CLUES to further tests 2nd line tests Metabolites 3 rd line tests Enymes DNA
61 First stage Investigations BLOOD Calcium Glucose Blood count Blood gases Sodium, potassium Liver function Urea, uric acid Lactate Ammonia FFA
62 First stage Investigations URINE Appearance & Smell Colour ph Reducing substances/glucose Ketones Ferric Chloride DNPH Cyanide Nitroprusside TLC MMA
63 Metabolites Amino acids (urine & plasma) Organic acids (urine) Acyl carnitines (blood) +/-vlcfa Discuss with Lab
64 Consider IMD Intrauterine SUDI Sick baby Summary Commonest disorders Intermediary metabolism Energy metabolism Staged approach to Ix
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