Neonatal presentations of Inborn Errors of Metabolism

1. Neonatal presentations of Inborn Errors of Metabolism Andrew Morris Royal Manchester Children’s Hospital

2. Time of presentation Deterioration after initial period of health At birth In utero

3. Presentations in utero Family history - proven or suspected IEM Hydrops fetalis on U/S scan Occasionally due to lysosomal disorders Maternal AFLP or HELLP syndrome Occasionally fetus has a fat oxidation disorder, usually LCHAD deficiency

4. Presentations at birth Dysmorphic syndromes Severe hypotonia Seizures / apnoea

5. Dysmorphism at birth Peroxisomal disorders e.g. Zellweger syndrome

6. Dysmorphism at birth Lysosomal disorders e.g.Mucolipidosis type II

7. Dysmorphism at birth Disorders of cholesterol synthesis e.g. Smith-Lemli-Opitz syndrome

8. Dysmorphism at birth Congenital defects of glycosylation

9. Inborn errors presenting at birth Severe hypotonia Peroxisomal disorders Congenital defects of glycosylation Non-ketotic hyperglycinaemia

10. Presentions at birth (or later) Seizures / apnoea Peroxisomal & mitochondrial disorders Non-ketotic hyperglycinaemia Molybdenum cofactor deficiency Pyridoxine dependency Hypoglycaemia & hyperammonaemia

11. Pyridoxine dependent seizures Deficiency of α-aminoadipic semialdehyde dehydrogenase (antiquitin) accumulation of a chemical which inactivates pyridoxal phosphate Pyridoxal-P is a cofactor in neurotransmitter metabolism Diagnosis can be confirmed by measuring α-AASA in urine

12. Pyridoxal-P responsive seizures Resembles pyridoxine dependency but requires pyridoxal phosphate (NG) Deficiency of pyridoxine 5-phosphate oxidase (involved in converting pyridoxine to pyridoxal-P)

13. Clues to an Inborn Error Deterioration after an initial period of health Hypoglycaemia Acid-base disturbance Encephalopathy Liver disease Cardiac problems / sudden death

14. Hypoglycaemia Usually due to prematurity, IUGR, hypothermia etc If severe, recurrent, other features of IEM Fat oxidation disorders Organic acidaemias Glycogen storage disease type I Fructose bisphosphatase deficiency Hyperinsulinism Adrenal insufficiency Deterioration after an initial period of health

15. Acid-base disturbance Metabolic acidosis Usually due to sepsis, heart disease etc If primary Organic acidaemias (esp. if ketonuria) Defects of gluconeogenesis (with hypoglycaemia) Congenital lactic acidoses (± multisystem disease or brain malformation) Deterioration after an initial period of health

16. Acid-base disturbance Respiratory alkalosis (self ventilating) Hyperammonaemia Deterioration after an initial period of health

17. Encephalopathy Conditions with Hyperammonaemia Hypoglycaemia Acidosis Seizures MSUD Deterioration after an initial period of health

18. Deterioration after an initial period of health Liver disease Neonatal haemochromatosis Mitochondrial disease Galactosaemia Tyrosinaemia type I Niemann-Pick type C α-1-antitrypsin deficiency etc.

19. Cardiomyopathy Fat oxidation disorders (hypertrophic) Mitochondrial disorders (varaible) Pompe disease (hypertrophic) Arrhythmias / sudden death Fat oxidation disorders Mitochondrial disorders Deterioration after an initial period of health

20. Neonatal presentations of IEMs In uteroe.g.Hydrops fetalis At birthDysmorphism Hypotonia Seizures LaterHypoglycaemia Acid / base disturbance Encephalopathy Liver disease Cardiac problems or sudden death

22. Pyridoxine dependent seizures Seizures often start in utero Multiple types, resistant to anticonvulsants Usually dramatic response to IV pyridoxine apnoea for 24 hours Long-term: language problems Pyridoxine also non-specific anticonvulsant

23. Non-ketotic hyperglycinaemia Severe hypotonia Lethargy / coma Hiccups Seizures (initially myoclonic) Recurrent apnoea (usually within 1st 2 days)

24. Non-ketotic hyperglycinaemia Investigations EEG - burst suppression CSF:plasma glycine >0.08 Low glycine cleavage enzyme in liver or transformed lymphoblasts Mutation studies difficult – 3 genes

25. Non-ketotic hyperglycinaemia Treatment Sodium benzoate (lowers plasma glycine) Dextromethorphan (NMDA antagonist) Outcome Intractable seizures Almost always profound handicap Few patients with milder handicap reported Few reports of transient NKH

26. Molybdenum cofactor deficiency Intractable seizures Poor development Spasticity Dislocated lenses Investigation Urine: sulphite Plasma: sulphocysteine, low urate Treament: symptomatic

27. Galactosaemia Presentation Usually 4–12 days Failure to thrive, vomiting Liver failure initially unconjugated jaundice Cataracts Occasionally, Gram –ve sepsis

29. Galactosaemia Investigation Urine reducing substances (if on milk) Red cell Gal-1-PUT or Beutler screening test If transfused Red cell Gal-1-P Parental Gal-1-PUT (heterozygous levels?)

30. Galactosaemia Treatment Soya-based formula or pregestamil Minimal galactose diet Long-term complications Learning difficulties esp speech delay, dyspraxia Shy personality Ovarian failure

31. Tyrosinaemia type I Variable presentation (2 weeks – adulthood) Liver failure in infancy Prominent coagulopathy Later also rickets or porphyria-like crises Investigation Urine succinylacetone Mutation analysis / enzyme assay

32. Tyrosinaemia type I Treatment Nitisinone (NTBC) Inhibits tyrosine breakdown Low tyrosine diet Outcome Generally good Monitor for hepatocellular carcinoma

33. Management if IEM in family Review diagnosis & history in index case Diagnostic tests Prenatal Cord blood (galactosaemia) Later: leucine at 12-24 hrs in MSUD serial ammonias in UCD, OAs definitive tests

34. Management if IEM in family Management Drugs from birth e.g. sodium benzoate ? in utero e.g. pyridoxine Diet - no galactose - restrict protein, long-chain fat Energy - enteral or IV - top-ups in MCADD if breast-fed

35. Hydrops fetalis Anaemia – isoimmunisation etc Chromosomal / malformation syndromes Congenital infections Lysosomal disorders Histology Amniotic fluid MPS & oligosaccharides Chorionic cell culture for enzymology