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Key messages

  • Metabolic diseases are a significant cause of illness in the neonate.
  • Babies with unexplained encephalopathy require an urgent ammonia (request result in <60 mins). If the ammonia is >100 call PIPER (1300 137 650) immediately. PIPER will arrange retrieval, a bed at RCH PICU, and place you in a conference call with the RCH Metabolic physician for advice while retrieval is being organised.
  • In most but not all cases of metabolic disease the fetus is protected by the function of the placenta.
  • Many metabolic diseases may present in the first days of postnatal life and signs and symptoms can be subtle and non-specific mimicking common neonatal problems such as sepsis.
  • Metabolic diseases must be considered in any neonate if the clinical presentation is out of proportion with what is expected or is not readily explicable by more common causes of neonatal illness.

Patterns of presentation of metabolic disease in the neonate

The diverse nature of metabolic disease in the newborn is reflected in the modes by which metabolic abnormalities may present, which are summarised below.

Neurological presentation - Encephalopathy

Babies with unexplained encephalopathy require an urgent ammonia (request result in <60 mins). If the ammonia is >100 call PIPER immediately. PIPER will arrange retrieval, a bed at RCH PICU, and place you in a conference call with the RCH Metabolic physician for advice while retrieval is being organised.

Symptom-free interval followed by:

  • lethargy
  • poor feeding
  • vomiting
  •  weight loss
  •  tachypnoea
  • decreased perfusion
  • altered conscious state
  • seizures
  • coma.

Typical of:

  • organic acidoses (including maple syrup urine disease)
  • urea cycle disorders
  • fatty acid oxidation defects.

Other neurological abnormalities presenting as:

Typical of:

  • pyridoxine dependent seizures
  • pyridoxal phosphate responsive seizures
  • glucose transporter (GLUT-1) defect
  • non-ketotic hyperglycinaemia
  • molybdenum cofactor or sulphite oxidase deficiency.

Metabolic acidosis

Organic acidoses and primary lactic acidoses cause metabolic acidosis with increased anion gap.

Given that plasma lactate is now frequently measured in sick neonates, it is important to have a logical approach to high lactate levels:

  • First consider whether the sample is adequate.
  • Capillary or venous lactate levels may be very high in the face of normal arterial lactate.

Differential diagnosis high arterial lactate

If arterial lactate is persistently high (normal < 2.0 mmol/L) the differential diagnosis is:

Primary lactic acidoses (uncommon):

  • disorders of pyruvate metabolism
  • mitochondrial respiratory chain disorders.

Other metabolic diseases may be associated with lactic acidosis, for example:

  • fatty acid oxidation defects
  • organic acidoses
  • glycogen storage disorders.

Secondary lactic acidoses (common):

Severe organ dysfunction associated with:

  • decreased tissue perfusion
  • decreased oxygen delivery
  • increased metabolic demand

Hypoglycaemia

See hypoglycaemia

Low blood glucose in a neonate usually indicates:

  • glycogen depletion +/- inadequate gluconeongenesis
  • hyperinsulinism
  • manifestation of a metabolic disease
    • fatty acid oxidation defect
    • glycogen storage disease.
    • defects in gluconeogenesis
    • defects in ketone synthesis.

Cardiac disease

Cardiac failure, cardiomyopathy and conduction defects can occur in association with:

  • mitochondrial respiratory chain disorder
  • fatty acid oxidation disorder
  • lysosomal storage disorder, such as Pompe disease.

Liver dysfunction

Persistent hyperbilirubinaemia (usually conjugated) may be indicative of a metabolic disease:

  • galactosaemia
  • tyrosinaemia type 1
  • a1-antitrypsin deficiency
  • other.

Dysmorphic features

Metabolic diseases associated with dysmorphic features plus other clinical features include:

  • peroxisomal disorders (Zellweger syndrome and others)
  • disturbances of energy metabolism (such as pyruvate dehydrogenase deficiency)
  • defects in cholesterol biosynthesis (such as Smith-Lemli-Opitz syndrome)
  • lysomal storage disorders.

Refer to: Dysmorphology assessment of the newborn.

Fetal hydrops

A number of metabolic diseases, all individually rare, can cause fetal hydrops.

Approach to the diagnosis of metabolic disease

History and clinical information

Take a detailed history and conduct an examination to ascertain:

  • perinatal information:
    • previous pregnancy losses, history of SUDI
    • consanguinity
    • any problems during the pregnancy eg HELLP
    • maternal diet eg vegetarian/vegan
  • detailed clinical examination:
    • growth parameters
    • cardiorespiratory status
    • neurological status
    • odour of baby and urine (although most babies with malodorous urine do not have metabolic disease).

Initial metabolic tests for suspected metabolic disease

  • blood glucose
  • serum ammonia - NB. In unwell babies insist on a rapid turnaround time and review of result ( <60 mins)
  • acid-base status - primary respiratory alkalosis is a clinical clue for high ammonia
  • electrolytes
  • anion gap ([Na+ + K+] - [Cl- + HCO3-], normal < 12 mmol)
  • lactate - arterial sample
  • liver function tests
  • serum amino acids
  • urine organic acids
  • urinary reducing substances (Clinitest) remember that glucose is a reducing substance so if the Clinitest is positive, check the urine specifically for glucose using a glucose oxidase strip
  • urinary ketones - if positive in a neonate, often indicates a metabolic disease
  • urine metabolic screen. a sample of 5-10 mL of freshly-collected urine is needed for this test; the sample can be frozen prior to analysis if necessary
  • dried blood spot (newborn screening card) or plasma for carnitine and acylcarnitine profile.

Include as much clinical information as possible on the request card to assist in the interpretation of the results.

These tests will help identify infants with a high likelihood of having a metabolic disease. Further tests may be required after discussion with a metabolic specialist.

The details and interpretation of these tests are beyond the scope of this guideline, please see references for details.

Initial management of suspected metabolic disease

If a metabolic disease is suspected, or the infant is significantly unwell, it is highly recommended that the case is discussed with a physician familiar with the management of metabolic disease in the neonate.

General measures

Infants with metabolic disease frequently require vigorous supportive measures to stabilise their physiological state. For example:

  • profound encephalopathy or apnoea requires:
    • mechanical ventilation +/- cerebral oedema management
    • If hyperammonemic - requires rapid transfer to RCH PICU for consideration of haemofiltration
  • circulatory failure requires:
    • intravascular volume expansion
    • inotrope therapy
  • seizures require:
    • trial of pyridoxine or pyridoxal phosphate as clinically indicated
    • anticonvulsant therapy
  • infections require:
    • antibiotic cover
  • metabolic acidosis may require sodium bicarbonate correction
    • beware of hypernatremia.

Specific therapy

In addition to general supportive measures some specific treatment should be instituted as soon as a metabolic disease is suspected.

In any case where metabolic disease appears likely:

  • cease oral feeds
  • commence 10% dextrose / electrolytes (milk is the source of toxic metabolites in many metabolic diseases). Give dextrose at an infusion rate of at least 6 mg/kg/min (= 3.6 mL/kg/hr of 10% dextrose)
  • Energivit is a high calorie feed (no amino acids) that enables much higher calorie provision than IV dextrose solutions. It can have a dramatic effect in acute severe hyperammonemia. Use in conjunction with RCH metabolic physician advice.

Consider a higher rate of dextrose infusion as many metabolic diseases are aggravated by tissue catabolism. Intralipids may be indicated to increase caloric intake but should be witheld for suspected fatty acid oxidation disorder.

Further specific therapies:

These are only ever prescribed in conjunction with a metabolic specialist in liaison with a neonatologist, paediatric intensivist or pending emergency retrieval. Most special care nurseries would not have these medications.

The use of sodium benzoate and arginine can be dangerous.

  1. Specific medications to increase disposal of toxic metabolites eg sodium benzoate and arginine for hyperammonaemia; carnitine for organic acidoses.
  2. Vitamins and cofactors to increase enzyme activity eg B12 and biotin for organic acidoses

Haemofiltration is indicated in severe cases or rapid neurological decline. Urgent transfer of the sick baby to an intensive care unit with haemofiltration capability is crucial.

Hyperammonaemia

These are interim measures to clear waste nitrogen; resolution of hyper-ammonaemic coma usually requires haemofiltration.

  • Sodium benzoate (250 mg/kg loading dose over 1-2 hrs, maintenance dose of 250 mg/kg/24 hrs).
  • Arginine (250 mg/kg loading dose over 2 hrs, maintenance dose of 250 mg/kg/24 hrs).

Guidelines for infusion are available in the Royal Children's Hospital Paediatric Pharmacopoeia.

Hypoglycaemia

For hypoglycaemia give:

  • dextrose infusion to maintain blood glucose level.

Metabolic acidosis

For metabolic acidosis:

  • Correct pH using sodium bicarbonate. The formula for ‘half-correction’ of a metabolic acidosis is
    • amount of HCO3- to infuse (in mEq) = (base deficit x weight) / 4.
  • Repeated NaHCO3 corrections may be required, in which case beware of hypernatraemia.

Suspected organic acidosis

The following may be prescribed in consultation with a metabolic diseases specialist while awaiting definitive results:

  • carnitine 100 mg/kg/day in four divided doses
  • biotin - 10-20 mg daily
  • hydroxocobalamin - 1 mg daily

More information

Clinical

References

  • Chakrapani A, Cleary MA, Wraith JE. Detection of inborn errors of metabolism in the newborn. Arch Dis Child 2001; 84: F205-10.
  • Hoffman GF, Nyhan WL, Zschocke J, Kahler SG, Mayatepek E. (2002) Inherited metabolic diseases- a clinical approach.. Philadelphia: Lippincott Williams & Wilkins.
  • Clarke J.T.R. A Clinical Guide to Inherited Metabolic Diseases. 3rd edition. Cambridge University Press.
  • Paediatric Handbook 9th edition (2015) Royal Children's Hospital.

Get in touch

Centre of Clinical Excellence - Women and Children
Safer Care Victoria

Version history

First published: August 2013

Last web update: October 2018

Review by: March 2020

Uncontrolled when downloaded

Page last updated: 12 Nov 2020

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