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When to consider an inborn error of metabolism: an approach to paediatric neurometabolic disorders.

Neurological symptoms are commonly the presenting problem in many inborn errors of metabolism (IEM). It is vital to identify treatable conditions early in order to reduce or prevent neurological impairment.

There is limited information available regarding the incidence and prevalence of IEM in South Africa. According to the current available published data, congenital hypothyroidism, (1) galactosaemia (2) and glutaric aciduria type 1 (3) are probably the top three treatable conditions. Mitochondrial disorders are an important group of metabolic errors, but remain difficult to diagnose. (4)

This article is intended as a brief guide to key features and available resources and does not deal with specific conditions and management issues.

A clinical approach to IEM with predominant neurological symptoms is discussed below.


Saudubray et al. defined three broad groups of IEM, summarised in Table I. (5), (6)


The patient's history is an important aspect in the identification of IEM. Key features in the history include:

* pregnancy

* miscarriages

* pre-eclampsia, haemolysis, abnormal liver functions, low platelets syndrome (HELLP), associated with disorders of fatty acid beta oxidation

* abnormal fetal movements

* family history

* consanguinity

* siblings with unexplained encephalopathy

* progressive neurological disorders in family members

* other factors

* trigger factors, e.g. fasting, exercise, fever, intake of specific foods

* unexplained 'cerebral palsy'

Clinical presentation

The presentation of IEM changes at different ages; the most important features are summarised below:

Neonatal period

* apnoea

* seizures

* dysmorphology

* hypotonia

* hypoglycaemia

* unexplained jaundic

Later presentation

Any unexplained neurological syndrome; static, intermittent or progressive with

* seizures/encephalopathy

* coma

* stroke

* spasticity

* dystonia/rigidity/choreoathetosis

* ataxia

* myopathy/ptosis

* neuropathy

* deafness.

Other organ involvement is common. The central nervous system (CNS) may be secondarily involved, as in galactosaemia.


Emergency or baseline investigations usually include:

* full blood count (FBC)

* acid base

* electrolytes

* urea, creatinine

* glucose - if low, ketones, insulin, free fatty acids

* liver functions

* calcium, magnesium

* clotting profile

* urine-reducing substances.

Ammonia and lactate tests are not readily available but are important - contact the nearest tertiary centre if an infant remains acidotic.

Lactate may be falsely elevated in a struggling child or after using a tourniquet. It will be elevated if there is respiratory or hepatic compromise or circulatory disturbance.

Further investigations are best done in consultation with the laboratory or relevant specialist and may include:

* amino and organic acids on blood and urine

* acylcarnitine profiles

* enzyme analyses

* genetic studies

* histology

* imaging.

If advice is not readily available, or the patient is critically ill, heel-prick blood spots on filter paper can be dried, stored frozen (-20 [degrees]C) and used for future genetic and biochemical testing. Frozen urine, heparinised plasma and EDTA blood samples are useful for analysis. A small sterile skin biopsy in culture medium for fibroblast culture would complete the samples required for further testing.


There are potentially treatable disorders where early intervention, as for galactosaemia and hypothyroidism, is imperative. Broad neonatal screening is the only way to effectively diagnose these disorders prior to clinical presentation. It is performed routinely in many countries, excluding South Africa. Research is required to delineate which conditions would be most cost effective to screen for in South Africa.

Treatment principles include:

* Treat correctable factors immediately: hypoglycaemia, acidosis, seizures, cardiac failure, hyperammonaemia.

* Start a galactose-free formula if galactose is present in the urine.

* Supplementation with pyridoxine, folinic acid or biotin may be effective for early-onset drug-resistant seizures if there is an underlying defect in any of these pathways.

* Severe hyperammonaemia may require dialysis.

Specific treatment requires the establishment of a diagnosis and a personalised management plan devised by the neurometabolic team, including therapists and a dietician.

Role of the family practitioner

* Recognition of the at-risk infant and appropriate referral.

* Baseline screening.

* Chronic care assistance in liaison with the paediatrician and tertiary care centre or subspecialist.

Role of the paediatrician

* Will vary depending on special interests/ area of practice.

* Recognition of the at-risk infant, baseline +/- specific investigations and imaging.

* Stabilisation, management of acute crises in liaison with subspecialist/tertiary centre.

* Referral as necessary for dialysis, intensive care monitoring and subspecialist investigation.

* Chronic care in liaison with subspecialist.

In summary

* If an infant or child's presentation is atypical or unexplained, think of metabolic causes.

* Acute presentation often resembles sepsis, with refractory acidosis, recurrent vomiting, seizures, or altered level of consciousness.

* Chronic presentation is easy to miss and includes failure to thrive, developmental delay, epilepsy, 'cerebral palsy' (especially dystonic), and unexplained intellectual disability.

* Thoroughly check the family history.

* Investigate if there is no clear cause for severe disability.

* The clinical findings are the key to guiding investigations.


Dr George van der Watt, Head of Chemical Pathology, Red Cross Children's Hospital and executive member of the Southern African Metabolic Disease Group.

References and further reading available at

Websites for further reading

Acute management protocols for known IEM (UK):

Human metabolome database: IEM protocols (USA):

Newborn screening: North West University: http://

North West University: SSIEM:

University of Cape Town Chemical Pathology and Metabolic laboratory:


* Sepsis is the most common differential diagnosis

* IEM predisposes to sepsis

* Severe acidosis, hyperammonaemia, organ failure and cerebral oedema are clinical emergencies
Table I. Classification of inborn errors of metabolism according to
Saudubray et al. (5), (6)

Groups of Characteristics Treatment principles

Disorders of * Accumulation of * Remove the toxin
intoxication toxic substances * Carnitine
 causes symptoms * Sodium benzoate
* Aminoacidopathies after a symptom-free * Exchange
(e.g. period transfusion
phenylketonuria) * Fetal development * Dialysis
* Organic acidurias is normal * Special diets
(propionic * Acute symptoms: * Vitamins
acidaemia) vomiting, lethargy,
* Urea cycle (e.g. coma, stroke
ornithine * Chronic: failureto
transcarbamylase thrive, developmental
deficiency) delay, cardiomyopathy
* Sugar * Triggers include
intolerances fever, intercurrent
(galactosaemia) illness or intake
* Metal of specific foods
intoxication * Recurrent ketosis,
(Menkes, Wilson acidosis and
disease) hyperammonaemia

Disorders of energy * The clinical * Avoid fasting
metabolism spectrum is hypoglycaemia
* Glycolysis influenced by the * Dietary
* Glycogenosis accumulation modification
* Gluconeogenesis of toxic compounds * Supplementation
* Creatine and the lack of with co-factors such
metabolism energy as co-enzyme Q10 and
* Pentose phosphate * Multi-organ carnitine
pathways presentation with * Management of
* Fatty acid wide range of epilepsy
oxidation defects symptoms and signs, * Specific enzyme
* Mitochondrial e.g. seizures, replacement therapy
disorders weakness, ptosis, (Pompe's)
 retinopathy, ataxia, * Monitor disease
 cardiomyopathy, liver progression and
 failure, support
 Fanconi's syndrome, where possible -
 sensorineural regular ECGs,
 deafness, endo- audiometry
 crine or
 * Onset at any age
 * Stepwise
 deterioration is
 typical; in children,
 there may be
 transient loss
 of skills following
 minor infections
 * Lactic acidosis is
 not always present
 * Non/hypoketotic
 hypoglycaemia is
 classic; a
 history may include
 seizures after
 cramps post
 exercise or sudden
 infant death

Disorders involving * Symptoms are * Enzyme replacement
complex molecules permanent, in lysosomal
Lysosomal progressive and disorders
disorders unrelated * Chenodeoxycholic
 to food or acid in
Peroxisomal intercurrent cerebroten-dinous
disorders illness xanthomatosis

Congenital disorder
of glycosylation

Disorders of

G T RIORDAN, MB ChB, FCPaed (SA), MMed (Paed Neuro)

Senior Specialist, Division of Paediatric Neurology, Red Cross War Memorial Children's Hospital, Cape Town


Professor and Head of Paediatric Neurology, Steve Biko Academic Hospital, University of Pretoria

Correspondence to: Gill Riordan (gillian.riordan@
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Title Annotation:More about ... Paediatric neurology
Author:Riordan, G T; Smuts, I
Publication:CME: Your SA Journal of CPD
Geographic Code:6SOUT
Date:Apr 1, 2011
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