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

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.