10.5 Inborn errors of metabolism
Inborn errors of metabolism (IEM), or metabolic disorders, are clinical conditions that result from a block in one of the metabolic or biochemical pathways in the body. Although individually uncommon, collectively metabolic disorders are frequent. The main forms of presentation are:
• acute decompensations – at any age, usually triggered by an intercurrent illness or dietary changes
IEM, particularly in those presenting acutely, remain underdiagnosed. Diagnostic clues such as:
are often overlooked or are misinterpreted as being due to a precipitating infection or dehydration. Investigations often have the highest yield during an acute decompensation. Rapid diagnosis and institution of appropriate therapy are essential to avoid death or permanent neurological damage.
• Inborn errors of metabolism, particularly those presenting acutely, remain significantly underdiagnosed.
• Presence of hypoglycaemia, presence or inappropriate absence of ketoacidosis, metabolic or lactic acidosis, or respiratory alkalosis should raise suspicion of a disorder of metabolism.
• In a child presenting acutely with a metabolic acidosis or hypoglycaemia, it is essential that the first urine passed is analysed for organic acids, as the diagnostic metabolites can clear quickly once intravenous glucose is given.
• Plasma ammonium values increase markedly if the specimen is allowed to sit around – collect the sample on ice and analyse it quickly.
• Abnormal liver function tests are not always indicative of hepatic pathology; for example, increased levels of aspartate and alanine aminotransferase (AST and ALT) occur in muscle disease also warranting the need to check creatine kinase levels.
• Pan-hypopituitarism can present in the neonatal period with hypoglycaemia plus conjugated hyperbilirubinaemia.
Acute metabolic decompensation
Acute metabolic decompensations can occur at any age and are generally a result of either accumulation of a specific toxin or an energy deficiency or both.
Neonatal presentations
Neonates have limited physiological repertoire to deal with stress, and an acutely unwell neonate with an IEM will look similar to that of other neonatal emergencies (e.g. sepsis, duct-dependent cardiac lesion). The placenta acts as an excellent filtration device, so the ‘toxin accumulation’ decompensations often occur at day 2–5 of life.
The following can act as clues to prompt consideration of an IEM in an acutely unwell neonate:
• Specific pattern of biochemical derangements (Table 10.5.1). (Note that ketosis in a neonate is always abnormal and must prompt consideration of an IEM)
• Multisystem organ involvement
• Specific end-organ involvement
• Family history of neonatal deaths or sudden infant death syndrome
Older children
Acute metabolic presentations in children beyond the neonatal period are normally precipitated by a viral illness associated with loss of appetite or vomiting. Ingestion of large amounts of protein or deliberately fasting (e.g. for surgery) can also precipitate an acute decompensation in some disorders. Protein aversion in a child warrants consideration of an IEM, especially a urea cycle defect or an organic aciduria.
Hyperammonaemia
Joseph was born at term to non-consanguineous parents. He fed well on the breast initially and was discharged to home on day 2 of life. On day 3 he was noted by his mother to be sleepy and feeding poorly. By that afternoon he could not be roused for feeds and he presented to the emergency department. He was afebrile and a septic workup was negative. Blood gases revealed a respiratory alkalosis and the alert paediatric registrar ordered a plasma ammonium, which was 830 mmol/L (normal < 60) . He was treated with peritoneal dialysis, sodium benzoate, sodium phenylbutyrate (alternative pathways to excrete nitrogen) and arginine, and his ammonium level gradually returned to normal. Plasma amino acid analysis showed high glutamine and low citrulline concentrations, and his urine was positive for orotic acid. DNA studies confirmed ornithine transcarbamylase deficiency, and testing showed his mother was a carrier.
Hyperammonaemia often causes a respiratory alkalosis. Findings and possible causes of hyperammonaemia may be:
OTC deficiency is an X-linked disorder, so an extended family pedigree on the maternal side may be useful. Females heterozygous for the gene may be symptomatic. Children with milder or partial deficiencies of urea cycle enzymes, including some females who are heterozygous for OTC deficiency, present later in life, usually after a high protein intake or with catabolism with an intercurrent illness. Abdominal pain and vomiting are early symptoms.
Hypoglycaemia
Rebecca, aged 18 months, was noted to have a protuberant abdomen. She had hepatomegaly, but no splenomegaly. Liver function test results were normal. Four months later she was noted not to be using her left arm and further testing revealed a left hemiplegia. Investigations at that time revealed marked hyperlipidaemia and an appropriate diet was introduced. A further 5 months later, she presented acutely with anorexia due to an upper respiratory tract infection. She was tachypnoeic and sweating, but conscious. Her blood glucose level was 0.8 mmol/L and her bicarbonate level was 12 mmol/L (normal range 22–33) with a high anion gap. Further testing showed a lactate of 15.0 mmol/L (normal 0.7–2.5). With correction of the blood glucose, the lactate concentration returned to normal.
Glycogen storage disease was suspected and confirmed by a liver biopsy, which showed glycogen accumulation in the liver and a deficiency of glucose-6-phosphatase (glycogen storage disease type 1b). Hyperlipidaemia is a feature of this disorder. The brain can learn to use lactate as an alternate fuel and that is why Rebecca was conscious with such a low blood glucose value.
Hypoglycaemia is a common issue in general paediatrics; it is always abnormal in children, and must be investigated and managed promptly. See Figures 10.5.1–10.5.3 for an overview of the practical approaches to refining a differential diagnosis of hypoglycaemia and an investigation pathway and the Practical points box on hypoglycaemia, below.
Fig. 10.5.3 Differential diagnoses of hypoglycaemia associated with inappropriately low ketone levels.
Tests to be collected at the time of hypoglycaemia are:
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