New insights into carnitine-acylcarnitine translocase deficiency from twenty-three cases: management challenges and potential therapeutic approaches.

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. This article is protected by copyright. All rights reserved.