Fatty-acid oxidation disorders — formative SAQs

SAQ 1 (10 marks)

A 14-month-old girl is brought to the emergency department with a two-day history of vomiting and lethargy following a febrile illness. She has not eaten for approximately 14 hours. On arrival she is drowsy, her bedside glucose is 1.8 mmol/L, and a point-of-care ketone measurement returns 0.1 mmol/L. [1] [5]

a) Explain why the combination of a low blood glucose with inappropriately low ketones is the signature of a fatty-acid oxidation disorder, and describe the physiological mechanism that produces this pattern. (3 marks) [1] [5]

b) Outline the immediate resuscitation you perform, including the specific intravenous therapy and why glucagon would be ineffective. (3 marks) [1] [2]

c) Describe the critical sample you collect at the time of hypoglycaemia and the first-tier diagnostic test that will localise the defect. Explain how plasma acylcarnitines would distinguish MCAD deficiency from a long-chain defect. (2 marks) [1]

d) Discuss the long-term management plan, including fasting avoidance, the emergency sick-day plan, and how newborn screening changed the prognosis of this condition. (2 marks) [5] [7]

SAQ 2 (10 marks)

A six-month-old boy presents with poor feeding, hypotonia and a gallop rhythm. Echocardiography confirms a dilated cardiomyopathy with an ejection fraction of 25 percent. His plasma total carnitine is profoundly low at 4 micromoles per litre. His mother had a sibling who died suddenly in infancy. [2] [1]

a) Name the most likely diagnosis, explain the pathophysiology, and describe why the maternal history is significant. (3 marks) [1]

b) Outline the treatment that produces a dramatic response in this condition, including the dose and route. (2 marks) [1] [2]

c) Contrast this condition with VLCAD deficiency: how do their acylcarnitine profiles, clinical phenotypes and management differ? (3 marks) [2]

d) Discuss the role of triheptanoin in long-chain fatty-acid oxidation disorders, including its mechanism of action and the evidence supporting its use. (2 marks) [9]

Marking guide

SAQ 1. During fasting, a normal child switches to beta-oxidation of fatty acids to generate ketone bodies (acetoacetate and beta-hydroxybutyrate) for the brain and ATP for heart and muscle. In a fatty-acid oxidation disorder (most commonly MCAD deficiency), the blocked pathway cannot generate ketones, so the glucose falls without the compensatory rise in ketones — producing the hypoketotic hypoglycaemia signature. The immediate resuscitation is IV 10 percent dextrose (2 mL/kg bolus then infusion at 6–8 mg/kg/min to maintain glucose above 5 mmol/L) to shut off lipolysis. Glucagon is ineffective because there is no insulin excess (unlike hyperinsulinism) — the problem is inability to use fat fuel, not excess insulin suppressing glucose output. The critical sample at hypoglycaemia includes glucose, insulin, C-peptide, beta-hydroxybutyrate, free fatty acids, cortisol, growth hormone, ammonia and plasma acylcarnitines — the first-tier test. MCAD deficiency shows elevated C8 (octanoylcarnitine); a long-chain defect shows elevated C14:1 or other long-chain species. Long-term management is fasting avoidance (age-appropriate safe intervals, cornstarch supplementation), a written emergency sick-day plan (stop fasting, give carbohydrate-rich fluids, present early), and MCAD has an excellent prognosis when identified by newborn screening — the Wilcken study (2009) demonstrated near-complete elimination of crisis-related death and disability in screened populations. [1] [5] [7]

SAQ 2. The diagnosis is primary carnitine transporter deficiency (OCTN2, SLC22A5). The pathophysiology is a defect in the cellular carnitine transporter causing profound systemic carnitine depletion — without carnitine, long-chain fatty acids cannot enter the mitochondrion for beta-oxidation, producing the energy-starved dilated cardiomyopathy, hypotonia and failure to thrive. The maternal sibling sudden death is consistent with an undiagnosed affected sibling. The treatment is high-dose oral carnitine supplementation (100–400 mg/kg/day), which restores plasma and tissue carnitine, reverses the cardiomyopathy, and is essentially curative — one of the most dramatic treatment responses in metabolic medicine. VLCAD deficiency differs: it is a defect in very-long-chain acyl-CoA dehydrogenase inside the mitochondrion (not a transport defect), shows elevated C14:1 acylcarnitine (not low total carnitine), and causes a spectrum from severe neonatal cardiomyopathy to late-onset exercise-induced rhabdomyolysis. VLCAD management includes a low-long-chain-fat diet with MCT supplementation, triheptanoin, and aggressive IV dextrose during illness — not carnitine replacement. Triheptanoin is a seven-carbon odd-chain triglyceride that bypasses the long-chain beta-oxidation block and provides anaplerotic substrate (propionyl-CoA) to replenish the citric acid cycle. The Vockley extension study (2023) demonstrated clinically meaningful reductions in rhabdomyolysis, cardiomyopathy and hospitalisation across the major LC-FAOD subtypes. [1] [2] [9]