INBORN ERRORS OF METABOLISM (IEM)

INTRODUCTION
IEM or inherited metabolic diseases are individually rare, but collectively
common. Establishing the diagnosis is important as defi nitive treatment
and prenatal diagnosis is available for some.
Some common fallacies about IEM are:
􀂙 These conditions are so rare that we do not see them at all.
Collectively, IEM incidence is estimated to be as common as 1-in-
5,000. In some populations, the incidence of organic acidurias alone
is 1-in-5,000
􀂙 The complex pathways need to be understood before a
diagnosis is made.
The pathophysiology of these diseases suggests a pattern of
how these conditions present, thus one can investigate the
patient broadly but with specifi c diff erentials in mind. A variety
of investigations can lead to a likely diagnosis, and this can be
confi rmed by enzyme/DNA assays if possible. A defi nitive diagnosis
is crucial if prospective prenatal counselling is to be considered
􀂙 When all diagnoses fail, consider IEM.
When all else fails, it is diffi cult to make a diagnosis. When the patient
is oliguric, it is diffi cult to get a good quantity of urine for tests. Even
in IEM patients, when there is multiple end-organ failure, secondary
changes can confuse the metabolic picture, e.g. secondary lactic
acidosis follows any severe decompensation of the organic acidurias
and this can mask the underlying condition
DIAGNOSIS
The classifi cation of IEM into two main groups based on the ‘size’ of the
off ending molecule is a good start to the understanding of IEM and thus
their diagnoses:
􀂙 For the ‘large’ molecule group, the prototypical condition is
the storage diseases. They have distinctive features, usually
multisystemic, predominantly neurological and the clinical
presentation is gradual and causes chronic clinical problems
􀂙 The ‘small’ molecule group is more relevant to this discussion as they
present more acutely and with more devastating eff ects; they are
also more likely to present early in life. The diagnosis is crucial as such
patients usually die quickly. As they are mainly autosomal recessive
conditions, the proband usually is an unexpected presentation.
The patients usually are relatively well and suddenly become sick.
The toxic metabolites are mainly ammonia, amino acids (glycine,
allo-isoleucine), acids (lactate, ketone) or organic acids, and sugars
(glucose, galactose)
Pointers to IEM
A high index of suspicion is needed:
􀂙 Family history of other aff ected children, early neonatal or infant
deaths in siblings, siblings with neurological/mental retardation
􀂙 Consanguinity in parents — Uncommon diseases occur commonly
within the aff ected families
􀂙 Neonates who are unwell after a period of being apparently healthy
􀂙 Urinary ketones in an acidotic neonate
􀂙 Recurrent encephalopathic episodes
􀂙 Persistent and recurrent acidosis
􀂙 Recurrent clinical problems despite negative results
􀂙 Thrombocytopaenia, leucopenia
INVESTIGATIONS
Consult a metabolic/genetic physician early for advice.
􀂙 FBC
􀂙 Biochemistry, electrolytes, creatinine, bicarbonate
􀂙 BSL
􀂙 Ammonia (lithium heparin tube)
􀂙 Urine ketones (dipstix — Ward level)
􀂙 Lactate (fl uoride tube)
􀂙 Pyruvate (fl uoride tube)
􀂙 Plasma amino acid (lithium heparin tube)
􀂙 Urine organic acid profi le
􀂙 Blood spots/EDTA blood (before any blood transfusion)
􀂙 Blood spot for expanded newborn screening
PRACTICAL POINTS
􀂙 In the course of investigating a sick neonate, a plasma ammonia
level is helpful and should be considered. Results should be traced
urgently
􀂙 Ammonia level of above 200μmol/L is signifi cant. Any level between
100–200μmol/L may require a repeat sampling depending on the
patient’s condition
􀂙 In the face of an elevated plasma ammonia level, check the anion
gap [(serum Na) - (serum Cl) - (serum HCO3)]. With a high anion gap
of 12, check the urine ketones. A positive urine ketones in a neonate