Pyruvate carboxylase deficiency type C; variable presentation and beneficial effect of triheptanoin

Abstract

AbstractPyruvate carboxylase is a mitochondrial enzyme essential for the tricarboxylic acid cycle (TCA), gluconeogenesis and fatty‐acid synthesis. Pyruvate carboxylase deficiency (PCD) mostly presents with life‐limiting encephalopathy (types A/B). A milder type C presentation is rare, with a comparatively favourable prognosis. Therapies remain essentially supportive. Triheptanoin is an odd‐chain triglyceride, with the potential to replenish TCA intermediates (anaplerosis), and its metabolites cross the blood–brain‐barrier. Outcomes of triheptanoin treatment in PCD types A/B have been disappointing, but have not been reported in type C. Here, we present two new patients with PCD type C, and report the response to treatment with triheptanoin in one. Patient 1 (P1) presented with neonatal‐onset lactic acidosis and recurrent symptomatic lactic acidosis following exercise and during illnesses, with frequent hospitalisations. Speech development was delayed. MRI‐brain showed delayed cerebral myelination. Patient 2 (P2) presented with episodic ketoacidosis, hyperlactataemia and hypoglycaemia at 2 years of age, with gross motor delay and mild global volume loss on MRI brain. Treatment with triheptanoin was commenced in P1 at 3 years of age with up‐titration to 35 mL/day (25% of daily energy intake) over 6 months, due to transient diarrhoea. Dietary long‐chain triglycerides were restricted, with fat‐soluble vitamin supplementation. Subsequently, hospitalisations during intercurrent illnesses decreased, post‐exertional hyperlactataemia resolved and exercise tolerance improved. Continued developmental progress was observed, and repeat MRI 18 months after initiation showed improved myelination. Triheptanoin was well‐tolerated and appeared efficacious during 2 years' follow‐up, and has potential to restore energy homeostasis and myelin synthesis in PCD type C.