See also

Key points

1. Metabolic disorders present at all ages with a variety of symptoms and signs that mimic common childhood illness. A high index of suspicion is needed to make a diagnosis
2. Consider a metabolic disorder in any newborn with unexplained encephalopathy or progressive illness, particularly following an uncomplicated pregnancy and birth
3. Once suspected, consult the metabolic team urgently
4. Collection of appropriate urine and blood samples during an acute illness is the key to diagnosis, but should not delay management

Background

• Metabolic disorders are a large group of inherited conditions resulting from a block (partial or complete) to a pathway in the body’s metabolism, or defects in the transport of substances
• Though individually rare, collectively they represent an important cause of childhood morbidity and mortality
• Newborn screening will diagnose many but not all metabolic disorders. A newborn may also become unwell before results are available
• Diagnosis and management should always involve close liaison with a metabolic team

Assessment

Acute presentations where a metabolic disorder should be considered

• Confusion or lethargy that may progress to coma, without clear evidence of injury, intoxication or other neurological event
• Newborn with poor feeding, weak suck or hypotonia, often after asymptomatic period
• Recurrent seizures
• Presumed sepsis with poor response to treatment
• Unexplained shock or cardiac failure
• Rapid, deep breathing +/- progression to apnoea
• Infant with Brief Resolved Unexplained Event (especially if recurrent)
• Unexpected blood gas derangement (metabolic acidosis, respiratory alkalosis or hypoglycaemia)
• Liver dysfunction, hepatomegaly or splenomegaly
• Any acute presentation with multisystem involvement

History

• Family history (a pre-existing family history is uncommon)
• parental consanguinity
• unexplained paediatric death (especially neonatal males)
• relatives with similar presentations or unexplained neurodevelopmental disorders
• Pregnancy and antenatal history
• illness in pregnancy
• diet including vegetarian/vegan diet and hyperemesis
• HELLP syndrome (foetus may have a fatty acid oxidation disorder)
• acute fatty liver of pregnancy
• Neonatal period:
• suspected sepsis without evidence of infection
• lethargy, poor feeding/weak suck
• vomiting, weight loss
• respiratory compromise, apnoea
• hypotonia
• progressive encephalopathy 
• seizures
• liver dysfunction
• Progression of symptoms across childhood:
• developmental delay or regression
• recurrent unexplained vomiting
• recurrent illness precipitated by catabolic episodes (infection, exercise, fasting) or certain foods or medicines
• aversion to certain foods eg protein, fruit
• unexplained neurological symptoms (behavioural changes, encephalopathy, seizures, ataxia)
• unexplained exercise intolerance (myalgia, rhabdomyolysis)
• acquired hepatomegaly and/or splenomegaly

Examination

• Facial dysmorphism or coarsening of features
• Lethargy
• Hypotonia
• Altered conscious state or encephalopathy
• Dehydration
• Jaundice
• Hepatosplenomegaly
• Tachypnoea, apnoea
• Cardiac failure
• Ocular changes (cataracts, retinal changes, optic atrophy, strabismus)
• Unusual body odour eg maple syrup in MSUD, sweaty feet in isovaleric aciduria
• Skin eg xanthomas, nodules, kinky hair, rash
• Growth parameters

Interpretation of clinical findings should always be made in consultation with a metabolic team

Management

Investigations

Metabolites indicative of metabolic disorders are best detected at time of acute presentation

Careful collection and handling of blood, urine and CSF samples is important, but should not delay management of the unwell child

First line investigations (collection as per local hospital protocol)

• Blood:
• venous or capillary blood gas
• glucose (point of care testing appropriate)
• serum lactate (venous sample)
• serum ammonia (transfer sample urgently)
• other tests as clinically indicated eg FBC, UEC, LFT, CRP, cultures
• Urine
• ketones, glucose, pH
• metabolic screen (including ammino acids and organic acids)

Interpretation of first-line investigations:

• Interpretation must take account of the clinical context - unwell children without an underlying metabolic disorder frequently have deranged blood gas values
• Consult the metabolic team urgently to discuss abnormal results
• The acid-base state, glucose levels, ketones and ammonia may help to classify the type of metabolic disorder (see table in additional notes)
• Hyperammonaemia is a medical emergency

Second line investigations

• As advised by metabolic team

Treatment

Principles of management
These apply to the unwell child with a suspected metabolic disorder, and for subsequent presentations where a diagnosis is already known

Children with a known metabolic disorder will likely have their own emergency management plan

• Resuscitation
  • recognition and management of the unwell child is the priority
  • consult resuscitation guidelines as required
  • treat hypoglycaemia, seizures and/or altered conscious state
  • treat underlying or precipitating illness eg sepsis, gastroenteritis
• Early consultation with metabolic team
  • as soon as a metabolic disorder is suspected
  • for children who present with a known metabolic condition, access the child’s emergency management plan
• Stop intake of any triggering factors
  •  eg stop feeds
    
• Maintain hydration
  • use intravenous or nasogastric fluids to correct dehydration and replace ongoing losses eg vomiting, diarrhoea
• Prevent catabolism
  • intravenous fluids such as glucose 10% with sodium chloride 0.9% is standard first-line treatment for an unwell child with a metabolic disorder, except for mitochondrial conditions (these require glucose 5% with sodium chloride 0.9%)
  • special metabolic formula or additional IV lipids/nutrition may be required after discussion with the metabolic team  
• Enhance disposal of toxic metabolites
  • intravenous medications to chelate or divert toxic metabolites, or replenish deficient metabolites, depending on metabolic disorder in consultation with the metabolic team
  • haemofiltration in ICU may be required if there is a rapid deterioration due to accumulation of toxic metabolites

Peri-operative management of a child with a known or suspected metabolic disorder should:

• always be planned early with the metabolic team
• generally avoid prolonged fasting with provision of sufficient calories (using IV glucose-containing solutions) to prevent catabolism

Consider consultation with local paediatric team when

Any child with a suspected metabolic disease

Consider transfer when

A child requiring care beyond the comfort level of the hospital
 
For emergency advice and paediatric or neonatal ICU transfers, see Retrieval Services

Consider discharge when

Following discussion with local metabolic service

Additional notes

Interpretation of initial investigations

• Serves as a guide only: consult the metabolic team with abnormal results
• Table below is most relevant for neonates and small infants
• Must also take account of the clinical context, including the period of fasting prior, hydration status, stage of illness and what fluids or other management have already been started
• An unwell child without a metabolic disorder may have lactic acidosis, respiratory alkalosis hypoglycaemia and ketonaemia 

¹ Inappropriately low
² Calculate by using (Na) – (Cl + HCO3). Normal 8 to 16 mmol/L

Additional Resources

• Vademecum Metabolicum
• IEM base

Last updated June 2022