Amino-acid disorders including phenylketonuria and MSUD — formative SAQs

SAQ 1 (10 marks)

A term male neonate is well at birth and on breast and formula feeds. At 72 hours of age he becomes lethargic, feeds poorly, vomits, and is found with opisthotonic posturing and intermittent dystonia. The nursing staff note a sweet, caramel-like smell to his urine. A blood gas shows a high anion-gap metabolic acidosis with ketosis; the ammonia is normal. [7] [8]

a) Explain why this picture of a well neonate deteriorating 48 to 120 hours into feeds with ketoacidosis and an odour is classic for maple syrup urine disease, and name the single most specific confirmatory metabolite. (3 marks) [7]

b) Outline the acute management, naming the four moves of the shared metabolic protocol and the rationale for supplementing isoleucine and valine while restricting leucine. (4 marks) [7] [8]

c) Describe the role of extracorporeal removal, including the leucine threshold or trajectory that would trigger it, and explain why outcome tracks time on the toxic metabolite. [7] (3 marks) [7]

SAQ 2 (10 marks)

A 24-year-old woman with phenylketonuria attends clinic wanting to plan a pregnancy. She is on a relaxed diet and her phenylalanine is 1100 micromol/L. Separately, you are asked about a tall, thin 8-year-old with a dislocated lens, intellectual disability and a previous deep-vein thrombosis. [1] [11]

a) Explain the maternal PKU syndrome, the mechanism by which maternal phenylalanine injures a genetically normal fetus, and the only preventive strategy. (4 marks) [1] [2]

b) Name the treatment phenylalanine target this woman must reach before conception and through the first trimester, and outline how you would counsel and manage her transition to pregnancy. (3 marks) [2]

c) For the 8-year-old, name the likely diagnosis, the two bedside features that distinguish it from Marfan syndrome, and the confirmatory laboratory finding (including the direction of the methionine). (3 marks) [11]

Marking guide

SAQ 1. The neonate is well at birth because the maternal placenta clears the accumulating metabolite, then deteriorates once protein-containing feeds load a blocked branched-chain pathway beyond what little residual activity remains (typically 48 to 120 hours). The maple-syrup, caramel or earwax odour from the branched-chain ketoacids is pathognomonic. The most specific confirmatory metabolite is allo-isoleucine on quantitative plasma amino acids, accompanied by raised leucine, isoleucine and valine. The acute protocol is (1) stop natural protein, (2) switch off catabolism with glucose and insulin and intralipid — the single most important physiological move — (3) start a branched-chain-amino-acid-free formula with added isoleucine and valine, which re-enter the cycle and promote protein synthesis so leucine falls faster, and (4) clear the toxin with haemofiltration or dialysis if leucine is very high or the child is comatose. Extracorporeal removal is triggered by a leucine above roughly 1000 micromol/L with encephalopathy or a clearly rising trend despite medical therapy, aiming to halve leucine within hours, because every hour of cerebral oedema adds to permanent injury — outcome tracks time on the toxic metabolite. [7]

SAQ 2. The maternal PKU syndrome is the pattern of microcephaly, congenital heart disease, intrauterine growth restriction and intellectual disability in a fetus exposed in utero to a high maternal phenylalanine, who may NOT inherit PKU. Phenylalanine crosses the placenta freely and, via competition at the large neutral amino acid transporter, disrupts fetal brain development during organogenesis. The only prevention is strict phenylalanine control to 120 to 360 micromol/L achieved BEFORE conception and through the first trimester, because waiting for a positive pregnancy test misses the critical organogenic window. The candidate should counsel that pregnancy must be planned, arrange tight metabolic follow-up, and rehearse the transition to adult metabolic obstetric care. For the 8-year-old, the diagnosis is classical homocystinuria (cystathionine beta-synthase deficiency); the two distinguishing bedside features are downward lens dislocation (Marfan dislocates upward) and a thrombotic tendency plus intellectual disability that Marfan does not cause. The confirmatory finding is a markedly elevated total homocysteine with a HIGH methionine — a LOW methionine would redirect to a remethylation defect. [1]