Variable phenotypes associated with a protein truncation mutation in carnitine palmitoyltransferase II deficiency. G.D. Vladutiu¹, E. Quackenbush², B.E. Hainline³, D. Smail¹, M.J. Bennett⁴. 1) Dept Pediatrics, State Univ. of NY at Buffalo, Buffalo, NY; 2) Dept Neurology, Children's Hospital, Boston, MA; 3) Dept Pediatrics, Riley Hospital, Indianapolis, IN; 4) Dept Pathology, Univ. of Texas Southwestern Medical Center, Dallas, TX.
   Carnitine palmitoyltransferase (CPT) II deficiency presents in 3 forms: a common adult-onset myopathy with exercise-induced pain, stiffness, and myoglobinuria, a rare lethal infantile form, and a hepatomuscular form. A single mutation, Ser113Leu, accounts for ~60% of mutant alleles in the adult disorder. We recently described a 2-bp deletion (413 delAG) in several adult compound heterozygotes. This mutation truncates the protein by one-third and is predicted to be lethal in the homozygous state. A newborn Caucasian male presented with hyperkalemia, renal cysts, and respiratory distress. Mild dysmorphic features included a high forehead, low-set posteriorly rotated ears, bilaterally undescended testes and hypoplastic toenails. Calcifications were present in the liver and cysts were found in the kidneys. Head ultrasound showed abnormalities in the parietal and frontal periventricular regions and in the basal ganglia. Lactate, pyruvate and dicarboxylic acids were elevated in the urine. The patient developed unstable cardiac function and died on the 4th day of life. CPT II activity was 18 and 28% of normal in cultured skin fibroblasts and skeletal muscle, respectively. Heterozygosity was found only for the 413 delAG mutation. A mixed race male presented at 13 months with hypoglycemia and vomiting following an 11 hr overnight fast. Physical exam was essentially normal; reduced plasma carnitine was found. While hypoglycemia and vomiting occur periodically, the patient is stable at 4 yrs of age on a low-fat diet, carnitine and MCT oil. CPT II activity in cultured fibroblasts was 18% of normal. DNA analysis revealed compound heterozygosity for the 413 delAG mutation and for Pro50His, a mutation associated with the adult form of the disease. Our findings show that the 413 delAG mutation is associated with multiple forms of CPT II deficiency and that combinations of mutant alleles appear to dictate the severity of the phenotype.