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

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

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

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

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

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

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

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

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

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

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

Case 1 ph 7,02 HCO 3 12 BE - 14 NH 3 160 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 190 000, Neutrophils 0.9

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

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

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

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

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

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

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

Emergency treatment in OAs the goal is to STOP PROTEIN/PROMOTE ANABOLISM Infusion rates of Glu 10% Age (years) Weight (Kgr) Rate Amount 0-2 10 mg/kg/min 150 ml/kg/day 2-6 8 mg/kg/min 120 ml/kg/day >6 <30 6 mg/kg/min 90 ml/kg/day >6 30-50 4.5 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

Emergency treatment in OAs stop protein intake (24-48hrs) provide generous calories aggressive treatment of acidosis with Na bicarbonate consider haemofiltration/dialysis carnitine supplementation (100 200 mg/kg/day) Na benzoate 250 mg/kg/day (in case of hyperammonaemia)

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

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

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

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

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

Urea cycle NAGS

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)

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) 100-300 mm argininosuccinic acid Argininosuccinic aciduria >1000 mm orotic acid Citrullinaemia I

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

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

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 0-2 10 mg/kg/min 150 ml/kg/day 2-6 8 mg/kg/min 120 ml/kg/day >6 <30 6 mg/kg/min 90 ml/kg/day >6 30-50 4.5 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

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

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

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

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

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

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

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

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

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

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

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

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

Biotinidase deficiency TREATABLE DISORDER: supplement with Biotin

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

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

MMA (mmol/mol creatinine) Enhance enzyme activity In vivo response to Vitamin B12 Vitamin B12 challenge 10 9 8 7 6 5 4 3 2 1 0 pre pre pre 3 6 9 25 Days case 1 case 2 case 3 case 4 case 5

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

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

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

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

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

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

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

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

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

Treatment in OAs & UCDs 1 1 2

Treatment in OAs & UCDs 1 1 2?

Treatment in OAs & UCDs 1 1 3?

Treatment in OAs & UCDs 1 1 9?

Treatment in OAs & UCDs 1 1 99?

Treatment in OAs & UCDs Complications

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

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

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

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

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