CPTII deficiency: a therapeutical approach

Abstract

Fatty acid oxidation is a major metabolic pathway for maintaining energy homeostasis. It is especially important during fasting, but also supports the extra energy required in strenuous conditions such as prolonged exercise, exposure to extreme temperatures, fever, illness, and even emotional stress. Long-chain fatty acids (LCFA) are the most abundant fatty acids in the human diet and in body stores and so their metabolism is of critical importance. Oxidation of fatty acids, including LCFA, takes place predominantly in the mitochondria. While short and medium-chain fatty acids can freely diffuse from the cytoplasm into the mitochondria, LCFA need a transport system. Known as the carnitine shuttle, it is comprised of three enzymes: carnitine palmitoyltransferase I and II (CPT I and II), and carnitine acylcarnitine translocase (CACT). Pathogenic mutations in the genes encoding for these enzymes result in an impaired LCFA transportation and so in a LCFA oxidation disorder in which the energy homeostasis is compromised. Among the rare LCFA oxidation defects, CPT II deficiency is the most common inherited disorder. Signs and symptoms can manifest as early as a few hours after birth, but may also only appear during adulthood, with a great variation in clinical severity between patients. The three clinical presentations are lethal neonatal form, severe infantile hepatocardiomuscular form, and myopathic form. While the first two are severe multisystemic diseases characterized by liver failure with hypoketotic hypoglycemia, cardiomyopathy, seizures, and early death, the latter is characterized by exercise-induced muscle pain and weakness, sometimes associated with myoglobinuria. Classically, management of this disorder is based upon a high-carbohydrate/low-fat regimen, supplemented with medium-chain triglycerides (MCT) and carnitine, as well as avoidance of fasting and/or exercise. The aim of this review is to contextualize the rationale behind the classic treatment for CPTII deficiency, to bring focus on new treatments currently being proposed and implemented, and to explore future research possibilities for treatment of this disease.