Hypoglycaemia due to inherited metabolic disease — formative SAQs

SAQ 1 (10 marks)

A 14-month-old boy is brought to the emergency department after being found unresponsive in his cot in the morning. He had a viral illness with poor oral intake for 36 hours. On examination he is seizing, with a bedside glucose of 1.1 mmol/L. He has mild hepatomegaly. The team draws bloods before treating: insulin detectable, beta-hydroxybutyrate 0.3 mmol/L, free fatty acids markedly elevated, lactate normal, ammonia normal. [1] [6]

a) Explain why this biochemical profile — hypoglycaemia with inappropriately low ketones but high free fatty acids — points to a fatty-acid oxidation defect, and name the most likely diagnosis. (3 marks) [6] [1]

b) Describe the immediate resuscitation you deliver, and justify why a critical sample was drawn before treatment. (3 marks) [1]

c) Outline the long-term management plan, including the emergency sick-day advice you give the family. (2 marks) [6]

d) Explain the significance of this presentation for the family, including recurrence risk and the role of newborn screening. (2 marks) [6] [1]

SAQ 2 (10 marks)

A term neonate, large for gestational age, develops persistent hypoglycaemia from 24 hours of age requiring a glucose infusion of 14 mg/kg/min to maintain glucose above 3 mmol/L. The critical sample during hypoglycaemia shows a measurable insulin, suppressed beta-hydroxybutyrate and suppressed free fatty acids, and a normal lactate. A glucagon bolus during hypoglycaemia raises the glucose by 2.5 mmol/L. [2] [1]

a) Name the diagnosis, and explain how the critical-sample pattern and the glucagon response support it. (3 marks) [1] [2]

b) Outline the medical management ladder, including why diazoxide may fail and what is used when it does. (3 marks) [2]

c) Explain the diffuse-versus-focal distinction in congenital hyperinsulinism, how it is resolved, and why it changes the surgical decision. (2 marks) [2]

d) Contrast this child's ketone and free-fatty-acid profile with that of a child with glycogen storage disease type I, explaining the biochemical basis. (2 marks) [4] [1]

Marking guide

SAQ 1. The profile is the signature of a fatty-acid oxidation defect: glucose is low, but the body has mobilised fat (free fatty acids high) yet cannot convert it into ketones (beta-hydroxybutyrate inappropriately low), because the beta-oxidation pathway is blocked. The most likely diagnosis is medium-chain acyl-CoA dehydrogenase (MCAD) deficiency, the commonest FAOD, presenting classically in a toddler after a fast with vomiting and reduced intake. Insulin is appropriately suppressed, distinguishing it from congenital hyperinsulinism, where insulin would be inappropriately measurable and free fatty acids suppressed. The immediate resuscitation is an intravenous dextrose bolus (2 mL/kg of 10% dextrose) followed by a continuous infusion at 6–9 mg/kg/min titrated to a safe glucose, plus cessation of the fast; the critical sample was essential because the hormone and metabolite profile normalises the moment glucose is corrected, and a missed sample can delay the diagnosis until a fatal recurrence. Long-term management is fasting avoidance, frequent feeds, an emergency sick-day plan (high-carbohydrate intake and early presentation at the first sign of illness), and carnitine supplementation where indicated. For the family, MCAD deficiency is autosomal recessive with a 25 percent recurrence risk, carrier testing of siblings is offered, and newborn screening by tandem mass spectrometry now detects most cases before the first decompensation — which is why a missed or screen-negative case presenting as near-sudden-death is a recognised catastrophe. [1] [6]

SAQ 2. The diagnosis is congenital hyperinsulinism. The pattern is diagnostic: a measurable insulin at a low glucose is itself pathological, and the suppressed beta-hydroxybutyrate and free fatty acids reflect insulin's anabolic action (switching off lipolysis and ketogenesis); the positive glucagon response (rise > 1.5–2.0 mmol/L) confirms glycogen is mobilisable under high insulin, and the high glucose requirement (> 10–12 mg/kg/min) is a further clue. The medical ladder is diazoxide (a KATP-channel opener and first-line) — but the recessive KATP-channel forms are typically diazoxide-unresponsive, in which case sirolimus (an mTOR inhibitor) and octreotide or lanreotide (somatostatin analogues) are used as medical suppressants. The diffuse-versus-focal distinction is pivotal: a focal lesion (paternally inherited mutation with somatic loss of the maternal allele) is curable by limited pancreatectomy, while diffuse disease requires medical suppression or near-total pancreatectomy (which trades hypoglycaemia for diabetes and exocrine insufficiency); the distinction is made by the genetic pattern and 18-fluorodopa positron-emission tomography. In contrast, glycogen storage disease type I shows hypoglycaemia with high lactate (glucose-6-phosphate shunted to lactate), hyperuricaemia, hepatomegaly, and an appropriate ketotic response (the fat-oxidation pathway is intact) — the opposite of the hypoketotic, insulin-driven profile of congenital hyperinsulinism. [1] [2] [4]