EndocrinologyTier 2Disease (DEADMAN)

Inborn errors of metabolism (IEMs)

Description

Inborn errors of metabolism are inherited enzyme/transporter defects disrupting a specific metabolic pathway (carbohydrate, amino acid, fatty acid, or organic acid metabolism) - typically presenting in infancy/childhood with metabolic crisis under catabolic stress, though some milder variants present later in life

Individually rare but collectively significant given the large number of distinct disorders, most detected through newborn screening programmes in many jurisdictions

Each IEM reflects a specific blocked metabolic step, causing accumulation of the pathway's substrate (sometimes directly toxic) and deficiency of its product - the specific clinical presentation (hypoglycaemia, metabolic acidosis, hyperammonaemia, or a combination) depends on which pathway is affected and explains why catabolic stress (fasting, intercurrent illness) typically precipitates acute decompensation by increasing flux through the blocked pathway

Newborn screening programmes (typically via dried blood spot testing) detect many IEMs pre-symptomatically, allowing early dietary/medical intervention before irreversible harm occurs
Later-presenting or screening-missed cases require a high index of suspicion in unexplained hypoglycaemia, metabolic acidosis, hyperammonaemia, or developmental regression, particularly with a compatible family history or consanguinity

Acute decompensation management prioritises stopping the catabolic trigger (providing glucose to halt catabolism/fasting-driven pathway flux) alongside disease-specific interventions (e.g. ammonia-scavenging therapy for urea cycle disorders, specific dietary restriction for the accumulating substrate)
Long-term management centres on dietary restriction of the problematic substrate (e.g. protein restriction in some amino acid disorders) and avoiding prolonged fasting/catabolic stress

Newborn screening programme detection, catabolic stress as the precipitant of acute decompensation, urea cycle disorders and hyperammonaemia, fatty acid oxidation defects and fasting-induced hypoglycaemia

Catabolic stress (fasting, intercurrent illness, surgery) is the classic precipitant of acute decompensation in inborn errors of metabolism, since it increases flux through the blocked metabolic pathway - providing glucose to halt catabolism is therefore a first-line, immediately actionable intervention in a suspected metabolic crisis, even before the specific enzyme defect is identified

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