New insights into carnitine‐acylcarnitine translocase deficiency from 23 cases: Management challenges and potential therapeutic approaches

Abstract

Background Carnitine acyl‐carnitine translocase deficiency (CACTD) is a rare autosomal recessive disorder of mitochondrial long‐chain fatty‐acid transport. Most patients present in the first two days of life, with hypoketotic hypoglycaemia, hyperammonaemia, cardiomyopathy or arrhythmia, hepatomegaly and elevated liver enzymes. Method Multi‐centre international retrospective chart review of clinical presentation, biochemistry, treatment modalities including diet, subsequent complications, and mode of death of all patients. Results Twenty‐three patients from nine tertiary metabolic units were identified. Seven attenuated patients of Pakistani heritage, 6 of these homozygous c.82G>T, had later onset manifestations and long‐term survival without chronic hyperammonemia. Of the sixteen classical cases, fifteen had cardiac involvement at presentation comprising cardiac arrhythmias (9/15), cardiac arrest (7/15) and cardiac hypertrophy (9/15). Where recorded, ammonia levels were elevated in all but one severe case (13/14 measured) and 14/16 had hypoglycaemia. Nine classical patients survived longer‐term – most with feeding difficulties and cognitive delay. Hyperammonaemia appears refractory to ammonia scavenger treatment and carglumic acid, but responds well to high glucose delivery during acute metabolic crises. High‐energy intake seems necessary to prevent decompensation. Anaplerosis utilizing therapeutic D,L‐3‐hydroxybutyrate, Triheptanoin and increased protein intake, appeared to improve chronic hyperammonemia and metabolic stability where trialled in individual cases. Conclusion CACTD is a rare disorder of fatty acid oxidation with a preponderance to severe cardiac dysfunction. Long‐term survival is possible in classical early‐onset cases with long‐chain fat restriction, judicious use of glucose infusions, and medium chain triglyceride supplementation. Adjunctive therapies supporting anaplerosis may improve longer‐term outcomes.