Organic acidaemias (OAs) & Urea cycle disorders (UCDs) PRESENTATION & MANAGEMENT

Transcription

1 Great Ormond Street Hospital London 20/04/2018 Organic acidaemias (OAs) & Urea cycle disorders (UCDs) PRESENTATION & MANAGEMENT Spyros P. Batzios, MD, MSc, PhD

2 OAs & UCDs How do they present? neonatal infantile neurological intermittent

3 OAs & UCDs How do they present? neonatal infantile neurological acute symptoms in the neonate non specific signs non highly suggestive non specific clues intermittent

4 OAs & UCDs Neonatal presentation initially well (onset towards end of first week of life) lethargy/poor feeding/vomiting/dehydration weight loss tachypnoea encephalopathy +/- neurological signs: hypotonia seizures loss of reflexes apnoeas

5 Is it metabolic??? sepsis Rule out poor breast feeding birth asphyxia Metabolic diseases might be associated and/or triggered by infections!

6 Is it metabolic??? Think Metabolic when: initial symptom free interval history of consanguinity family history (previous - unexplained - neonatal deaths) deterioration despite symptomatic treatment

7 Case 1 male Asian infant consanguineous parents perinatal history: BW 2360g emergency CS at 36 weeks Apgar score: 8 5 & 9 10 initially well

8 Case 1 Day 2 fed poorly transferred to SCBU Day 3 more unwell feeding difficulties jaundice jitteriness weight loss forced breathing/apnoeas reduced conscious level

9 Case 1 What kind of investigations are needed? Rule out SEPSIS FBC & differential CRP blood cultures

10 Case 1 Immediate investigations (parallel to screening for sepsis) NH 3 blood gas glucose lactate LFTs electrolytes (+chloride) urine ketones

11 Case 1 ph 7,02 HCO 3 12 BE - 14 NH mmol/l lactate 3.7 mmol/l glucose 2.4 mmol/l chloride 102 mmol/l urine positive for ketones calcium 1.2 mmol/l, magnesium 0.8 mmol/l Hb 10.5, PLTs , Neutrophils 0.9

12 Metabolic acidosis Investigations anion gap: Na (HCO3 + Cl) normal value 12 (range 8-16) normal anion gap renal/gastrointestinal loss of HCO 3 increased anion gap extra ACID

13 Organic acids carbon containing acidic compounds normally do not accumulate in body rapidly to non-acidic end products excreted as water soluble metabolites if produced in excess or metabolism blocked concentrations increase in tissues, blood & urine METABOLIC ACIDOSIS

14 Organic acids Metabolic pathways of relevance for organic acidaemias Amino acids Neurotransmitters Carbohydrates Drugs and special diets Organic acids Microorganisms Cholesterol Purines/Pyrimidines Fatty acids

15 Organic acidaemias (OAs) Any disorder detected by analysis of the urine organic acids

16 Organic acidaemias (OAs) characterized by the excretion of non-amino organic acids dysfunction of a specific step in amino acid catabolism the pathophysiology results from: accumulation of precursors deficiency of products of the affected pathway precursors are toxic or are metabolized to toxic compounds: brain kidney liver pancreas retina

17 Incidence of OAs MMA PA IVA MSUD 1 : 50,000 live births 1 : 100,000 live births 1 : 100,000 live births 1 : 200,000 live births collectively MORE COMMON than PKU

18 Diagnostic work-up FBC U/Es NH 3 blood gas/anion gap glucose lactate urine ketones plasma amino acids acylcarnitine profile urine organic acids

19 Emergency treatment in OAs the goal is to STOP PROTEIN/PROMOTE ANABOLISM Infusion rates of Glu 10% Age (years) Weight (Kgr) Rate Amount mg/kg/min 150 ml/kg/day mg/kg/min 120 ml/kg/day >6 <30 6 mg/kg/min 90 ml/kg/day > mg/kg/min 67 ml/kg/day >6 >50 3 mg/kg/min 45 ml/kg/day If hyperglycaemia then start insulin, DO NOT REDUCE the glucose infusion

20 Emergency treatment in OAs stop protein intake (24-48hrs) provide generous calories aggressive treatment of acidosis with Na bicarbonate consider haemofiltration/dialysis carnitine supplementation ( mg/kg/day) Na benzoate 250 mg/kg/day (in case of hyperammonaemia)

21 OAs & UCDs Neonatal presentation initially well (onset towards end of first week of life) lethargy/poor feeding/vomiting/dehydration weight loss tachypnoea encephalopathy +/- neurological signs: hypotonia seizures loss of reflexes apnoeas

22 OAs & UCDs Any differences in clinical presentation? OAs acidosis UCDs alkalosis weight loss +++ weight loss + hypocalcaemia neutropenia hyperammonaemia ++ hyperammonaemia +++ (rapidly increasing)

23 OAs & UCDs Any differences in clinical presentation? OAs acidosis UCDs alkalosis weight loss +++ weight loss + hypocalcaemia neutropenia hyperammonaemia ++ hyperammonaemia +++ (rapidly increasing)

24 Encephalopathy & hyperammonaemia Hyperammonaemia Acidosis No acidosis Ketones? Amino acids? Prominent Hypoketotic Specific profile OAs FAODs Citrullinaemia Argininaemia Non specific profile OTC? orotic acid?

25 Hyperammonaemia Neonatal period: NH 3 > 150 mmol/l After neonatal period: NH 3 > 50 (-100) mmol/l HYPERAMMONAEMIA Astrocyte Glutamine Accumulation Astrocyte Swelling Astrocyte Dysfunction Cerebral Edema ENCEPHALOPATHY Brain Stem Compression Brusilow 1996

26 Causes of hyperammonaemia increased production of NH 3 (bacterial overgrowth) reduced capacity of detoxification by the liver insufficient glutamine synthesis: glutamate dehydrogenase defect glutamine synthetase deficiency insufficient flux through the urea cycle: urea cycle disorders defects in other metabolic pathways limiting UC substrates (mito: AcCoA, Glu, Arg, Orn; cyto: Asp) iatrogenic: 5-fluorouracil, valproate, arginine deficiency, inadequate TPN

27 Causes of hyperammonaemia increased production of NH 3 (bacterial overgrowth) reduced capacity of detoxification by the liver insufficient glutamine synthesis: glutamate dehydrogenase defect glutamine synthetase deficiency insufficient flux through the urea cycle: urea cycle disorders defects in other metabolic pathways limiting UC substrates (mito: AcCoA, Glu, Arg, Orn; cyto: Asp) iatrogenic: 5-fluorouracil, valproate, arginine deficiency, inadequate TPN

28 Urea cycle the sole source of endogenous production of: arginine ornithine citrulline principal mechanism for clearance of waste nitrogen principal mechanism for metabolism of other nitrogenous compounds

29 Urea cycle NAGS

30 Urea cycle disorders (UCDs) inherited deficiencies of urea cycle enzymes or transport proteins NH 3 detoxification hyperammonaemia cummulative incidence approx. 1 : 8,000 live births most common defect: OTC-deficiency (1 : 14,000) Autosomal recessive mode of inheritance exception: OTC deficiency (X-linked)

31 Diagnostic work-up of hyperammonaemia Plasma/Urine amino acids, urine organic acids/orotic acid, acylcarnitines Plasma citrulline Other features Diagnosis Low (usually) orotic acid OTC Specific acylcarnitines and organic acids -n orotic acid Organic acidurias, e.g. PA or MMA CPS or NAGS deficiency >30 mm orotic acid Lysinuric protein intolerance >50 mm -n orotic acid, lactate Pyruvate carboxylase deficiency (neonatal form) mm argininosuccinic acid Argininosuccinic aciduria >1000 mm orotic acid Citrullinaemia I

32 Treatment of hyperammonaemia START treatment before cause is known (while investigations are underway)

33 Hyperammonaemia Which of the following 3 treatment approaches would you consider important? A. Stop feeds and start IV 10% dextrose B. Stop feeds and start IV 0.9% saline C. Start chlorpromazine D. Give mannitol E. Start IV sodium benzoate, sodium phenylbutyrate F. Haemofiltration G. Start TPN H. Give dexamethasone I. Load with phenytoin

34 Emergency treatment in hypernh 3 the goal is to STOP PROTEIN INTAKE/PROMOTE ANABOLISM Infusion rates of Glu 10% Age (years) Weight (Kgr) Rate Amount mg/kg/min 150 ml/kg/day mg/kg/min 120 ml/kg/day >6 <30 6 mg/kg/min 90 ml/kg/day > mg/kg/min 67 ml/kg/day >6 >50 3 mg/kg/min 45 ml/kg/day If hyperglycaemia then start insulin, DO NOT REDUCE the glucose infusion

35 Emergency treatment in hypernh 3 Clearance of toxic metabolites Pharmacological Na Benzoate: 250 mg/kg/90 min mg/kg/day (1g in 50ml 5 or 10 % glucose) Na load: 3.5 mmol Na/500mg Na Phenylbutyrate: 250 mg/kg/90 min mg/kg/day (1g in 50ml 5-10 % glucose) Na load: 2.7 mmol Na/500mg

36 Emergency treatment in hypernh 3 Clearance of toxic metabolites Dialysis: WHEN? blood ammonia >400 mol/l no response to pharmacological treatment within 4-6 hours

37 Emergency treatment in hypernh 3 Clearance of toxic metabolites Dialysis: WHEN? in theoretical terms.....in practical terms

38 Emergency treatment in hypernh 3 Clearance of toxic metabolites To treat or not to treat? many days in coma NH3 >1000 mol/l poor neurological presentation

39 OAs & UCDs How do they present? neonatal infantile neurological intermittent

40 OAs & UCDs How do they present? neonatal infantile neurological intermittent

41 OAs & UCDs Neurological presentation in older patients mental retardation/developmental delay acute encephalopathy ataxia hypotonia movement disorder/dystonia neurodevelopmental regression seizures micro-, macrocephaly

42 OAs & UCDs Further clinical findings in older patients Failure to thrive Hepatomegaly Reye like symptoms Abnormal behaviour Psychiatric symptoms

43 OAs Principles of treatment Emergency treatment: at home in hospital Long-term treatment: enzyme activity toxic products disposal

44 OAs Principles of treatment Emergency treatment: at home in hospital Long-term treatment: enzyme activity toxic products disposal

45 Emergency treatment at home minimises fasting due to ilness glucose polymer in infants = 10% CHO given frequently (2-3 hourly) meet fluid and emergency requirements

46 Treatment of OAs Principles of treatment enzyme activity production of toxins disposal

47 Treatment of OAs Principles of treatment enzyme activity production of toxins disposal

48 Enhance enzyme activity co-factor responsive disorders holocarboxylase synthetase/biotinidase deficiency biotin MMA vitamin B12 MSUD thiamine

49 Case 2 neurological involvement: seizures ataxia hypotonia skin rash/alopecia laboratory findings: severe metabolic acidosis high lactate hypoglycaemia

50 Biotinidase deficiency TREATABLE DISORDER: supplement with Biotin

51 Enhance enzyme activity co-factor responsive disorders holocarboxylase synthetase/biotinidase deficiency biotin MMA vitamin B12 MSUD thiamine

52 Enhance enzyme activity co-factor responsive disorders holocarboxylase synthetase/biotinidase deficiency biotin MMA vitamin B12 MSUD thiamine

53 Enhance enzyme activity B12 responsive or non-responsive MMA??? Moras et al. Mol Gen Met 2007

54 MMA (mmol/mol creatinine) Enhance enzyme activity In vivo response to Vitamin B12 Vitamin B12 challenge pre pre pre Days case 1 case 2 case 3 case 4 case 5

55 Treatment of OAs Principles of treatment enzyme activity production of toxins disposal

56 Treatment of OAs Principles of treatment enzyme activity production of toxins low protein diet disposal

57 The Propionate pathway METRONIDAZOLE GUT BACTERIA propionate propionyl CoA methylmalonyl CoA succinyl CoA citric acid cycle

58 Treatment of OAs Principles of treatment enzyme activity production of toxins disposal

59 Treatment of OAs Principles of treatment enzyme activity production of toxins disposal

60 Treatment of OAs carnitine acyl carnitine acyl CoA CoA carnitine glycine (IVA) Na Benzoate/Phenylbutyrate cytosol mitochondrion renal replacement therapy

61 OAs Principles of treatment Emergency treatment: at home in hospital Long-term treatment: enzyme activity toxic products disposal

62 UCDs Principles of treatment Emergency treatment: at home in hospital Long-term treatment: toxic products low protein diet disposal NH3 scavengers, Citrulline/Arginine

63 Monitoring treatment in OAs & UCDs clinically (growth, skin, hair) diet inadequate rashes skin/hair abnormalites growth retardation oedema excess anorexia vomiting acidosis

64 Monitoring treatment in OAs & UCDs biochemically Blood full blood count Plasma Urine amino acids ammonia/lactate urea and electrolytes albumin creatinine urate iron, copper, zinc, selenium urea organic acids

65 Treatment in OAs & UCDs 1 1 2

66 Treatment in OAs & UCDs 1 1 2?

67 Treatment in OAs & UCDs 1 1 3?

68 Treatment in OAs & UCDs 1 1 9?

69 Treatment in OAs & UCDs ?

70 Treatment in OAs & UCDs Complications

71 Complications common complications recurrent episodes of decompensation feeding difficulties poor growth GOR

72 Complications neurologic complications (mainly MMA/PA) developmental delay movement disorders: motor dyspraxia severe choreo-athetosis stroke-like episodes

73 Complications metabolic toxic nephropathy in MMA increase of metabolites: methylmalonic acid methylcitrate osmotic effect urate others depletion of precursors: glutathionine vitamins others

74 Treatment outcome in OAs & UCDs mainly dependant on management of acute crisis and early diagnosis

75 Thank you