Phenotypic variability among first‐degree relatives with carnitine palmitoyltransferase II deficiency

Abstract

Carnitine palmitoyltransferase (CPT) II deficiency disorders are clinically very variable. To examine the cause(s) of variable symptoms in first-degree relatives with CPT II deficiency, four sisters with various combinations of mutations and polymorphisms in the CPT2 gene were studied, together with 20 sedentary and 24 trained healthy female subjects. One sister, whose symptoms began at age 7 years, was more severely affected than her older sister, whose symptoms began at age 16 years; both were compound heterozygotes for the common S113L mutation and Q413fs, and for the common CPT2 polymorphisms, V3681 and M647V. A third sister became hypoglycemic with fasting, was heterozygous for the S113L mutation, and homozygous for the polymorphism variants. The fourth sister was asymptomatic, heterozygous for the Q413fs mutation, and homozygous for the normal polymorphisms. Residual CPT II activity in skeletal muscle and cultured skin fibroblasts from the two myopathic sisters, and palmitate oxidation in fibrobasts, were abnormally low; cellular and total body fat oxidation were also diminished. Muscle function and fat oxidation were nomal at rest, but a switch to carbohydrate utilization occurred at lower exercise intensities than in sedentary and trained individuals, respectively. Reliance on carbohydrates during stress and hormonal alterations may explain, in part, the variance in ages of onset and serverity of symptoms in myopathic patients.

Anesthetic management of a parturient with carnitine palmitoyltransferase ii deficiency

“…Carnitine palmitoyltransferase II deficiency may present with considerable heterogeneity. 5 There is a fatal neonatal form and a severe infantile form which result in seizures, hypoketotic hypoglycemia, hepatomegaly, cardiomegaly and cardiac arrhythmias.…”

Carnitine Palmitoyltransferase II Deficiency: A Clinical, Biochemical, and Molecular Review

“…Phenotypic variability has been known to occur in siblings with the same genotype (Handig et al, 1996;Vladutiu et al, 2002a), suggesting other environmental or genetic factors may play a role in the predisposition to disease severity. Although the genotype has clearly been associated with disease severity in many cases of CPT II deficiency, it is becoming accepted that the best predictive indicator may be the residual level of LCFA oxidation, typically performed in cultured cells (Thuillier et al, 2000).…”

Influence of exercise on nutritional requirements

“…In addition, endurance athletes have a significantly greater innate (genetic) FO as shown by the analysis of white blood cell fat oxidation . The latter appears to be a good estimate of the genetic predisposition for FO (Vladutiu et al 2002;Pendergast et al 2004). This can best be seen by comparing the percentage of energy from fats and carbohydrates from the sedentary subjects in Fig.…”

“…Studies have demonstrated that a fat droplet is adjacent to about 26% of the mitochondria where fat is transported through the mitochondrial membranes (Hoppeler et al 1999). Genetic defects in CPTI or CPTII result in a significant reduction in fat oxidation, increased glycogen use, exercise intolerance and in some cases, myopathy (Vladutiu et al 2002). The availability of fat and CHO has the potential to alter the patterns of substrate oxidation as the metabolism of these substrates is interrelated.…”

“…It requires greater oxygen for oxidation. Fat also protects vital organs, provides insulation, transports fat-soluble vitamins, and serves as a precursor of steroid hormones, bile acids and vitamin E. FFAs are transported with short chains freely diffusing and longer chains transported via transporters carnitine palmitoyltransferase II (CPTII) (MIM # 600649) and CPTII (MIM # 255110) through the mitochondrial membrane (outer and inner, respectively) (Vladutiu et al 2002). Studies have demonstrated that a fat droplet is adjacent to about 26% of the mitochondria where fat is transported through the mitochondrial membranes (Hoppeler et al 1999).…”