1. Does this ill child have a metabolic disease? ► General Intro ► Disease Presentation & Investigation  Acute Neonatal  Recurrent Encephalopathy  Hyperammonaemia  Hypoglycaemia

3. Inherited Metabolic Diseases ► Individually rare diseases  collectively ‘common’  ?1 in 800 ► Ubiquitous presentation  Modern TB ► Likely to present in  general paediatric  neonatal  speciality paediatric practice

4. Collection of diagnoses ► 6PKU ► 4Urea cycle ► 1MSUD ► 1Tyrosinaemia ► 4Organic acidaemia ► 6Fatty acid oxidation disorders (5 MCAD) ► 2X linked & 1 neonatal adrenoleucodystrophy ► 3Galactosaemia ► 1L 2 hydroxyglutaric aciduria ► 2Ketothiolase deficiency ► 1Transient neonatal hyperammonaemia ► 7 Mucopolysaccharidoses ► 1GSD ► 1 Mucolipidosis ► 2 Ceroid lipofuscinosis ► 1 Gauchers disease ► 1 Refsums disease ► 2 Steroid sulphatase def’y ► 1 Cystinuria ► 1 Orotic aciduria ► 5 Hypercholesterolaemia ► 2 Mitochondrial cytopathy ► 2 Segawa disease

8. The Metabolically ill Infant and Child If You Don’t Think You Won’t Look If You Don’t Look You Won’t Find If You Don’t Find You Can’t Treat

9. Acute presentations ► Neonatal  Apparent sepsis  Neurological deterioration  Hypoglycaemia  Liver dysfunction  E coli septicaemia

10. Inborn Metabolic Errors Are easy!

11. IEMs ABC D XY

12. IEMs AB C D X Y E

13. ► Accumulation / excess storage metabolites  Antenatal or postnatal ► Toxicity of metabolites ► Energy insufficiency ► Specific deficiency ► Combination

14. Genetics ► All types of inheritance  Recessive  X linked  Dominant  Mitochondrial DNA ► Mutation/s + genetics define level of enzyme activity ► Enzyme activity informs severity and timing of presentation  e.g. OCT deficiency, PKU

16. Four Basic Clinical Groups  Acute neonatal symptoms ► Present at birth ► Symptom free interval  Later onset acute/intermittent  Chronic progressive general  Specific symptoms of a disorder

17. History Clues ► Age onset ► Disease progression ► Precipitating factors  Milk feeds  Weaning  Infection  Fasting ► Sibling death ► Maternal HELLP and AFLP syndromes

18. Acute neonatal symptoms ► Present at birth ► Toxic type ► Energy deficient ► Hypoglycaemia

19. Acute neonatal symptoms ► From birth  Facial dysmorphism  Profound hypotonia  Seizures  Liver disorder  ? Peroxisomal disorder  ? Respiratory chain  ? Carbohydrate Deficient Glycoprotein disorder (CDG)  Zellwegers syndrome

20. Zellweger ► Zellweger disease - antenatal onset  Neurological - disorder neuronal migration  Hepatic - jaundice, bleeding, ^ ALT, mild cirrhosis on biopsy  Cardiac anomaly - 32% VSD : 22% aortic  Renal cysts  Calcific stippling of patella  Eyes - ERG always abnormal  Death in 1-2 yrs ► Diagnosis  ^VLCFA  ^pristanic, phytanic acids & some bile acids  hypoprothrombinaemia

21. IEMs E AB C D X Y

22. Acute Neonatal Symptoms Toxic Type ► Symptom free interval ► Unexpected/”mysterious” deterioration ► Poor sucking / feeding ► Encephalopathy ► Hiccups, apnoea ► Bradycardia, hypothermia ► Relative hypertonia, Opisthotonus ► Pedalling/boxing ► Tremors / jerks  True seizures rare ► Odour eg MSUD/IVA ► Coma

23. Acute neonatal symptoms ► Energy deficient  non specific symptoms ► +/- symptom free interval ► severe generalised hypotonia ► then rapidly progressive neurological deterioration ► cardiomyopathy ► lactic acidosis common ► Hypoglycaemia ► hepatomegaly ► liver dysfunction

24. Acute neonatal symptoms Watch out for ► initial respiratory alkalosis ► neutropaenia ► thrombocytopaenia ► pancytopaenia ► clotting disturbance ► vomiting ► abdominal distention ► IMD may mimic infection

25. Acute Neonatal Acute Neonatal Symptoms Initial Investigations ► Blood  FBC, clotting  U&E, (anion gap)  Glucose  Gases  Uric acid  LFT  Ammonia  Lactate  Calcium

26. Anion Gap ► = ( Na+K ) - (Cl+HCO3) ► 8 to 16 mmol/L when not including [K+] ► 10 to 20 mmol/L when including [K+].

27. Acute Neonatal Acute Neonatal Symptoms Initial Investigations ► Blood  FBC, clotting  U&E, (anion gap)  Glucose  Gases  Uric acid  LFT  Ammonia  Lactate  Calcium ► Urine  Odour  Ketones ► Ketonuria is an indicator for a metabolic disease in the newborn.  Reducing substances  Ph

28. Interpretation  Ketones+++ NH3 +/- ► MSUD  Acidosis++ NH3 +/++ lactate+/- cytopaenia ► Organicacidurias   Increased Uric acid is indicative for organic aciduria   Thrombocytopenia and Neutropenia are criteria for severity in organic aciduria  NH3++/+++ acidosis - lactate +/- ► Urea cycle ► Fatty acid oxidation

29. Interpretation  Lactate +++ acidosis ++ ketones ++ ► Respiratory chain ► “Cong lactic acidosis”  Liver+++ acidosis++ lactate ++ hypoglycemia++ ► GSD i, iii  LFT abn Liver +, NH3 +/- ► Galactosaemia tyrosinaemia HFI

30. Acute Neonatal Symptoms Acute Neonatal Symptoms Further Investigations ► Blood  Amino acids  Carnitine T & Free  Acyl carnitines ► Specific tests  Eg Gal-1-PUT ► Urine  Amino acids  Organic acids ► CSF+/-  Lactate  glycine

31. Recurrent Encephalopathy ► May be well for years ► Cause not immediately obvious ► Child seems sicker than expected for apparent illness ► Rarely of sudden onset ► Encephalopathy preceeds hypoglycaemia ► Consider in any type of coma or encephalopathy ( including DKA)

32. Recurrent Encephalopathy ► Well between episodes BUT  May suffer neurological damage during episodes (MCAD, OCT)  Many are treatable  Early diagnosis is important ► Most metabolic encephalopathies do not have focal neuro signs BUT  Strokes, ataxia, ► It does not quite fit ► D&V more ill than expected ► Unexpected “psychiatric illness ”

33. Recurrent encephalopathy ► “ Metabolic” investigations  glucose  ketones  ammonia  lactate  blood gases  FBC  carnitines  acyl carnitines ► Urine  Odour  Ketones  Amino acids  Organic acids ► CSF+/-  Glucose  Lactate  Glycine

34. Recurrent Encephalopathy Metabolic causes ► Fatty acid oxidation disorders  MCAD ► Carnitine disorders ► Urea cycle disorders ► Organic acidaemias ► Respiratory chain defects

35. Recurrent Encephalopathy Consider also ► Stroke like episodes  MELAS  Homocystinuria ► Total homocysteine   organic acidaemias   ornithine carbamyl transferase deficiency  Carbohydrate Deficient Glycoprotein syndromes (CDG) ► (sialotransferrin) ► Macrocephaly  Glutaric aciduria I ► Frontal atrophy  CDG syndromes

36. HYPERAMMONAEMIA Differential diagnosis ► ► INHERITED DISORDERS ► ► Urea cycle disorders ► ► Organic acidaemias ► ► Fatty acid oxidation disorders ► ► Other inborn errors (OAT,PC, HHH syndrome, etc) ► ACQUIRED DISORDERS ► Liver disease ► Poisoning ► ‘Reye’s syndrome’ – acquired – aspirin + viral infection ► Sodium valproate toxicity ► Asparaginase toxicity ► Urinary tract infection with stasis

37. Hyperammonaemia Mainly neurological presentation ► Inhibits neurotransmitters ► NH3 + glutamate = glutamine ► Osmotic load = cerebral oedema ► Careful sampling is important ► ► Values of 100 mmol/l may be significant, but usually >200 mmol/l ► Ammonia level not a good predictor of severity but >350 expect neuro sequelae

38. Hyperammonaemia ► ► Brain stem stimulant  tachypnoea ► ► Cyclical vomiting  Check in all children in acute episode ► ► anorexia ► ► Lethargy ► ► Failure to thrive ► ► Delayed development ► ► Faddy eating ► Acute encephalopathy ► irritability ► headache ► confusion ► ataxia / slurring of speech ► bizarre behaviour ► focal neurological signs ► fluctuating level of consciousness ► coma

39. Hyperammonaemia ► Treatment  Emergency regimen ► Avoid catabolism ► High CHO feeds only  10% dextrose IV+/- insulin IV ► Drugs  Arginine  Benzoate  Phenylbutyrate ► Haemofiltration ► Haemodialysis ► Treat cerebral oedema

40. Healthy Children: Response to fasting

41. Hypoglycaemia ► May be the end result of a metabolic disease - sick ► May be the primary symptom ► What is the timing of hypo  Fasting  Postprandial  Intercurrent illness ► Hepatomegaly?  Permanent  Transient ► Ketosis? ► Lactate++? ► Liver dysfunction? ► Short stature?

42. Hypoglycaemia investigations When hypo ► lactate ► Ketones ► FFA ► urate ► CK ► lipids ► GH ► insulin ► cortisol Others ► carnitine ► acyl carnitine ► LFT ► Aminoacids ► Urine (first available)  aminoacids  organic acids  reducing substances  ketones

43. Hypoglycaemia - Permanent hepatomegaly ► “All metabolic” ► Fasting hypo/ ketosis / lactate +  Glycogen storage disease ► Trigly > cholesterol I ► Chol > trigly III ► Urate ++ I ► Creat kinase ++ III ► Lactate ++ I ► Liver failure / short fast  Galactosaemia  Tyrosinaemia ► Postprandial  Hereditary fructose intolerance

44. Hypoglycaemia - No Permanent Hepatomegaly ► Ketosis  Organicaciduria  MSUD  Ketotic hypoglycaemia  Adrenal insufficieny ► Without ketosis  Fatty acid oxidation disorder  Hyperinsulinism  Growth hormone deficiency

45. Diagnostic algorithm METABOLIC ACIDOSIS HYPERAMMONEMIA Ketonuria Hyperlactatemia Hypoglycemia Major hyperlactatemiaMaple Syrup Urine Disease (MSUD) HypoglycemiaOrganic aciduria Organic aciduria Pyroglutamic aciduria Non-ketonic hyperglycinemia Sulfite oxydase deficiency - XO Urea Cycle Disorders Respiratory chain Fatty acid oxydation Variant hyperinsulinism (glutamate dehydrogenase) Fatty acid oxydation Glycogen storage disease Glyconeogenesis defects Mitochondrial defect no yes

47. ► Best Practice Guidelines ► Contents ► Guidelines for the Biochemical Investigation of Patients with Foetal and Neonatal Hydrops Guidelines for the Biochemical Investigation of Patients with Foetal and Neonatal Hydrops Guidelines for the Biochemical Investigation of Patients with Foetal and Neonatal Hydrops ► Guidelines for Investigation of Fits and Seizures (Instruction Sheet for CSF sample collection ) Guidelines for Investigation of Fits and Seizures (Instruction Sheet for CSF sample collection ) Guidelines for Investigation of Fits and Seizures (Instruction Sheet for CSF sample collection ) ► Guidelines for the Investigation of Hypoglycaemia in Infants and Children Guidelines for the Investigation of Hypoglycaemia in Infants and Children Guidelines for the Investigation of Hypoglycaemia in Infants and Children ► Guidelines for the Investigation of Hyperammonaemia for Inherited Metabolic Disorders Guidelines for the Investigation of Hyperammonaemia for Inherited Metabolic Disorders Guidelines for the Investigation of Hyperammonaemia for Inherited Metabolic Disorders ► Appendix - Notes on the measurement of ammonia in blood/plasma Appendix - Notes on the measurement of ammonia in blood/plasma Appendix - Notes on the measurement of ammonia in blood/plasma ► Skin Biopsy - Information Sheet for parents/carers Skin Biopsy - Information Sheet for parents/carers Skin Biopsy - Information Sheet for parents/carers ► Skin Biopsy - Consent form Skin Biopsy - Consent form Skin Biopsy - Consent form ► Neonatal Jaundice in Inherited Metabolic Disorders Neonatal Jaundice in Inherited Metabolic Disorders Neonatal Jaundice in Inherited Metabolic Disorders

48. Inherited Metabolic Diseases Practice points ► More common than expected ► Can present in unexpected ways ► If you do not think about the possibility you will not make the diagnosis  Lower threshold to investigate ► Be aware significance of NH 3 level ► Hypoglycaemia is a late event