• Early recognition of IMD and prompt management are essential to prevent death or neurodisability
  • diagnosis of IMD in babies is often delayed owing to non-specific nature of clinical presentation and unfamiliarity with diagnostic tests
  • seek early advice from regional clinical IMD team at tertiary metabolic centre

Differential diagnosis (lists below are not comprehensive, discuss with clinical IMD team)

Specific indicators

Clinical context

• Unexplained and mysterious deterioration of baby (can be as short as 12 hr but more commonly after a symptom-free interval of 24 hr–14 days)

Family history

• Known metabolic disorders
• Unexplained neonatal or infant deaths
• Parental consanguinity

Obstetric history

• Acute fatty liver of pregnancy or HELLP syndrome may indicate a long chain fatty acid oxidation defect in the fetus. Test baby with plasma/blood spot acylcarnitines soon after birth

Non-specific indicators suggestive of metabolic disorder in an encephalopathic baby

• Encephalopathy in low-risk baby, or onset after period of normality
• Fluctuating consciousness and muscle tone
• Changes in muscle tone: 
  • axial hypotonia with limb hypertonia 
  • ‘normal’ tone in comatose baby
• Abnormal movements: 
  • myoclonic or boxing movements
  • tongue thrusting 
  • lip smacking
  • unexplained seizures/burst suppression/hypsarrythmia 
  • seizures are uncommon or occur late in babies with metabolic encephalopathy compared to hypoxic-ischaemic encephalopathy

• Whenever IMD suspected, perform required investigations without delay
  • in a sick child request urgent processing of investigations by metabolic biochemistry laboratory
• Seek early advice about appropriate investigations and management from IMD team at tertiary metabolic centre 

Urine

• Smell
• Ketostix: presence of large amounts of urinary ketones is usually abnormal in babies and could suggest IMD, especially organic acidaemias
• Freeze 15–20 mL urine for amino and organic acid analysis
• Metabolic screen (amino acids, organic acids, ketones, sugars)

Blood

• FBC, U&E, infection screen
• Glucose
• Blood gas (calculate anion gap)
• Ammonia
• Lactate
• Acylcarnitines, including free and total carnitine (bloodspot on Guthrie card/2 mL Li-Hep)
• Plasma amino acids (lithium heparin 2 mL)

Imaging

• Cranial ultrasound scan
• Ophthalmic examination

Unexplained/prolonged jaundice or liver synthetic dysfunction

Blood

• Galactosaemia screen [galactose-1-phosphate uridyltransferase (GALIPUT)/Beutler test] (urinary reducing substances can be negative after short period of galactose exclusion) 
  • cannot be performed reliably if transfused ≤90 days: measure galactose-1-phosphate (Gal-1-P) and urine galactitol (urine organic acids) 
• Total and conjugated bilirubin, liver function tests, including clotting studies
• Blood spot - succinylacetone (tyrosinaemia I)
• Ferritin
• Plasma - very long chain fatty acids only if dysmorphic and hypotonic*
• Plasma quantitative amino acids
• Alpha-1 antitrypsin (quantitative)
• Transferrin isoelectric focusing* (CDG)
• Consider Niemann-Pick disease type C (chitotriosidase, DNA-mutation analysis)*

Urine

• Organic acids (succinylacetone in tyrosinaemia I)
• Reducing substances: use Clinitest™
  • urinary dipsticks are glucose specific and miss galactose in babies with galactosaemia
  • negative Clinitest™ does not exclude galactosaemia 

Encephalopathy/epileptic encephalopathy/neonatal intractable seizures

Discuss with IMD team – some of the following investigations may be advised and a trial of treatment with pyridoxine/pyridoxal phosphate may be required in certain cases

• Urgent quantitative plasma amino acids and urine amino acids
• Paired blood and CSF amino acids (glycine, serine), (NKHG, serine synthesis deficiency)
  • CSF glucose, lactate (GLUT 1, mitochondrial disorder). Paired blood and CSF lactate with blood sample taken before CSF
• Plasma – very long chain fatty acids (peroxisomal disorder)
• Urine: 
  • dipstick for ketones
  • sulphite test for sulphite oxidase deficiency
• Plasma - uric acid (low in molybdenum cofactor deficiency)
• Pyridoxine responsive epilepsy (antiquitin deficiency) 
• Pyridoxal phosphate-responsive seizures 
  • consider CSF amino acids, CSF neurotransmitters, urine organic acid analysis
  • urine alpha-aminoadipic semialdehyde (AASA) (freeze urine and CSF samples immediately)

Hypoglycaemia (most informative when obtained at time of hypoglycaemia)

• Plasma non-esterified free fatty acids (FFA)
• Beta-hydroxybutyrate (ketones)
• Insulin and C-peptide
• Acylcarnitine profile, free and total carnitine
• Cortisol, growth hormone
• Urine for organic acids and ketones

Post-mortem (plan how best to use these precious samples in consultation with IMD team)

• Plasma (2–5 mL), urine (10–20 mL) and CSF (1 mL) frozen at −20°C
• Red cells: blood (5 mL) in lithium heparin stored at 4°C (fridge)
• Blood (5 mL) in EDTA: stored at 4°C (fridge) for DNA analysis
• Tissue biopsies
  • skin: store in viral culture medium or sodium chloride 0.9% at 4°C (fridge) (see Skin Biopsy guideline)
  • muscle and liver: take within 1 hr of death, snap freeze in liquid nitrogen
• Bile for acylcarnitine analysis – stable for longer than other body fluids

• Attend to Airway, Breathing and Circulation; ventilate if necessary
• Omit all protein, fat and galactose/lactose (milk) intake – do not give PN or parenteral lipid
• Commence glucose 10% IV infusion to provide 6–8 mg glucose/kg/min 
  • if hyperglycaemic (>15 mmol/L) or catabolic, start insulin infusion, under guidance from IMD team
  • if hypertonic (concentration of glucose >10%) infusion necessary, insert central line [see Long line (peripherally sited) guideline]
• Correct dehydration, acid-base and electrolyte disturbances
• Cover for infection
• Control seizures (avoid sodium valproate)
• When stable and appropriate, consider early transfer to tertiary metabolic centre 

• Must be led by IMD team 
• Use following as guide to general principles of management
• Check regularly that metabolic emergency medications mentioned below are in stock and available for emergency use

Neonatal hyperammonaemia

Medical emergency requiring prompt intervention to lower ammonia concentration 

• Renal replacement therapy (haemofiltration more efficient than peritoneal dialysis)
• Sodium benzoate
• Sodium phenylbutyrate
• L-arginine
• Carglumic acid (Carbaglu®)

Organic acidaemia

• Reduce/stop protein intake
• Glucose 10% infusion +/- insulin
• L-carnitine
• Carglumic acid (Carbaglu®)

Fatty acid oxidation disorders

• Avoid prolonged fast 
• Specific management guided by IMD team

Lactic acidosis

• Dichloroacetate
• Biotin
• L-carnitine
• Thiamine

Galactosaemia

• Dietary exclusion of galactose