Organic acidaemias — formative SAQs

SAQ 1 (10 marks)

A term male infant is well at birth but at 60 hours of age becomes lethargic, vomits repeatedly, is hypotonic, and has a generalised seizure. Blood gas shows a pH 7.18, bicarbonate 10, and a high anion gap of 24, with moderate ketosis and a lactate of 5.2 mmol/L. The ammonia returns at 280 micromoles per litre. Sepsis cultures are pending. [1] [3]

a) Explain why this picture of a well neonate deteriorating 24 to 72 hours into feeds with a high-anion-gap metabolic acidosis and ketosis is a classic organic acidaemia presentation, and contrast the acid-base profile with that of a urea cycle disorder. (3 marks) [1]

b) Describe the first-tier metabolic panel you order to identify the accumulating organic acid, and explain how the acylcarnitine profile and urinary organic acids distinguish propionic acidaemia, methylmalonic acidaemia and isovaleric acidaemia. (3 marks) [1]

c) Outline the role of L-carnitine, calorie loading, and extracorporeal removal in this child, including the ammonia and acidosis severity that would prompt haemofiltration. (2 marks) [1]

d) Discuss the prognostic significance of the number and severity of acute decompensations, and outline the family emergency sick-day plan that prevents recurrence. (2 marks) [3]

SAQ 2 (10 marks)

A two-year-old girl with known methylmalonic acidaemia (MMA) is reviewed in the metabolic clinic. She has had three acute decompensations in the past year, her estimated glomerular filtration rate has fallen from 75 to 40 mL/min/1.73m², and her plasma methylmalonic acid remains high despite a protein-restricted diet and carnitine. Her genotype shows a MUT (methylmalonyl-CoA mutase) defect. [6] [10]

a) Explain why MMA causes progressive renal failure, relating the mechanism to the Schumann study on mitochondrial damage in renal epithelial cells, and outline the renal surveillance required. (3 marks) [10]

b) Describe how you would assess cobalamin (vitamin B12) responsiveness at diagnosis, explain why a MUT-type defect is typically B12-nonresponsive, and discuss how this defines the prognosis and the transplantation pathway. (3 marks) [6]

c) Outline the role and timing of kidney and liver transplantation in severe MMA, including what transplantation can and cannot achieve, referencing the Sen ACMG statement and the Molema European overview. (2 marks) [6]

d) Contrast the clinical course and management of MMA with that of glutaric aciduria type 1, explaining why prevention of the first acute crisis is the central goal in GA1. (2 marks) [4]

Marking guide

SAQ 1. The neonate is well at birth because the maternal placenta clears toxic metabolites, then deteriorates once protein-containing feeds generate branched-chain amino-acid catabolism that the blocked enzyme cannot complete, typically at 24 to 72 hours. The accumulating toxic organic acids (propionic, methylmalonic, isovaleric) consume bicarbonate and produce a high-anion-gap metabolic acidosis with ketosis and raised lactate, and they inhibit the urea cycle to produce secondary hyperammonaemia. This contrasts with a urea cycle disorder, which gives a normal anion gap with a respiratory alkalosis and primary hyperammonaemia — the single most important discriminator. The first-tier panel is blood gas, glucose, lactate, ketones, ammonia (free-flowing, on ice), acylcarnitines, urinary organic acids, plasma amino acids, and liver function and coagulation. Propionic acidaemia shows raised propionylcarnitine (C3) with 3-hydroxypropionate and methylcitrate in urine; methylmalonic acidaemia shows raised C3 with methylmalonic acid in urine; isovaleric acidaemia shows raised isovalerylcarnitine (C5) with isovalerylglycine and 3-hydroxyisovalerate. L-carnitine conjugates the accumulating acyl-CoA esters to form acylcarnitines for renal excretion, removing the toxin and replenishing CoA — given from the first hour. Calorie loading (10% glucose + intralipid ± insulin) switches off catabolism. Haemofiltration is indicated for refractory metabolic acidosis, severe or rising hyperammonaemia despite medical therapy, or deepening encephalopathy. The Nizon cohort shows neurological outcome is dominated by the number and severity of decompensations — each untreated crisis adds permanent basal-ganglia injury. The emergency sick-day plan teaches the family to stop natural protein, increase calories from glucose and the special formula, and present early for intravenous management at the first sign of illness. [1] [3]

SAQ 2. MMA causes a progressive tubulointerstitial nephropathy leading to chronic renal failure because the accumulating propionyl-CoA and methylmalonic acid are directly toxic to renal tubular epithelial mitochondria — the Schumann study demonstrated that mitochondrial damage in renal epithelial cells is potentiated by protein exposure in propionic aciduria, providing the molecular basis for the nephropathy. Renal surveillance requires regular monitoring of eGFR, electrolytes, and urine for tubular dysfunction, and the falling eGFR (75 to 40) signals the need to consider transplantation. Cobalamin responsiveness is assessed by a trial: measuring urinary methylmalonic acid excretion before and after intramuscular hydroxocobalamin, with a substantial fall defining a responsive subtype (cblA, cblB). A MUT-type defect (a defect in the methylmalonyl-CoA mutase enzyme itself) is typically B12-nonresponsive because the cofactor pathway is intact but the apoenzyme is defective — this defines a worse prognosis and the need for transplantation. For severe MMA, kidney transplantation addresses the renal failure and liver transplantation corrects the metabolic defect; combined transplantation may be considered. Transplantation restores metabolic stability and removes the constant threat of decompensation, but it cannot reverse established neurological injury or basal-ganglia damage — it is complementary to, not a substitute for, excellent emergency care. GA1 differs because its central risk is acute striatal necrosis after a febrile illness: the macrocephaly-hypotonia prodrome is the window, and aggressive emergency management of any intercurrent illness (lysine and tryptophan restriction, carnitine, calorie loading) to prevent the first crisis is the central goal, because once striatal necrosis occurs the severe dystonia is permanent. [4] [6] [10]