No abstract

Carnitine palmitoyltransferase 2 (CPT2) deficiency, the most common inherited disease of the mitochondrial long-chain fatty acid (LCFA) oxidation, may result in distinct clinical phenotypes, namely a mild adult muscular form and a severe hepatocardiomuscular disease with an onset in the neonatal period or in infancy. In order to understand the mechanisms underlying the difference in severity between these phenotypes, we analyzed a cohort of 20 CPT2-deficient patients being affected either with the infantile (seven patients) or the adult onset form of the disease (13 patients). Using a combination of direct sequencing and denaturing gradient gel electrophoresis, 13 CPT2 mutations were identified, including five novel ones, namely: 371G>A (R124Q), 437A>C (N146T), 481C>T (R161W), 983A>G (D328G), and 1823G>C (D608H). After updating the spectrum of CPT2 mutations (n=39) and genotypes (n=38) as well as their consequences on CPT2 activity and LCFA oxidation, it appears that both the type and location of CPT2 mutations and one or several additional genetic factors to be identified would modulate the LCFA flux and therefore the severity of the disease.

Carnitine palmitoyltransferase 2 (CPTII) deficiency is among the most common inborn errors of mitochondrial fatty acid ␤-oxidation (FAO). Clinical phenotype varies in relation to the metabolic block, as assessed by studies of FAO in patient fibroblasts. Thus, fibroblasts from patients with mild manifestations have appreciable residual CPTII enzyme activity, in contrast to those from severely affected patients. In the present study, we hypothesized that the hypolipidemic drug bezafibrate, acting as an activator of the peroxisome proliferator-activated receptor ␣ might stimulate FAO in CPTII-deficient cells. Data obtained show that bezafibrate treatment of mild-type CPTII-deficient cells resulted in a time-and dose-dependant increase in CPTII mRNA (from ϩ47% to ϩ66%) and residual enzyme activity (from ϩ54% to 135%), and led to normalization Abbreviations FAO, mitochondrial fatty acid ␤-oxidation CPTII, carnitine palmitoyltransferase 2 CPTI, carnitine palmitoyltransferase 1 PPAR␣, peroxisome proliferator-activated receptor ␣ LCFA, long-chain fatty acid CPTII (EC 2.3.1.21) deficiency (OMIM: 600650) is one of the most common inborn error of FAO (1, 2). CPTII plays a pivotal role in the transport of LCFA into the mitochondria. Indeed, LCFA, which cannot readily cross the mitochondrial membranes, are transferred from the cytosol to the mitochondrial matrix through the sequential action of CPTI and CPTII, located in the outer and inner mitochondrial membranes, respectively. CPTI and CPTII catalyze the trans-esterification of long-chain acyl-CoA into long-chain acylcarnitine in the cytosol, and the reverse reaction in the mitochondrial matrix, respectively. This acylcarnitine shuttle is completed by the action of the carnitine/acylcarnitine translocase. In the mitochondrial matrix, fatty acids are oxidized to acetyl-CoA through the four steps of intra-mitochondrial ␤-oxidation leading to ATP production. CPTII deficiencies have been divided into three major clinical forms (1, 3). The mild form consists in recurrent attacks of rhabdomyolysis, usually triggered by prolonged exercise, fasting, or infections in teenagers. Life-threatening complications, e.g. acute renal failure and respiratory insufficiency, occasionally occur during episodes of rhabdomyolysis. The severe form of CPTII deficiency is characterized by acute liver failure with hypoketotic hypoglycemia and serious cardiac damages in the neonatal period or infancy. Finally, an intermediate juvenile form with hepatic, cardiac, and myopathic involvement has also been described. The clinical severity is usually related to the severity of the metabolic block (2). The severe neonatal form of CPTII deficiency is generally associated with extremely low levels of residual enzyme activity in the patient's fibroblasts, whereas a significant residual enzyme activity is detected in the milder form (1, 4). Owing to the possible occurrence of life-threatening events that can barely be prevented by classical dietary approaches (fat-restricted diet, medium-chain triglyceride supp...