Carnitine/acylcarnitine translocase deficiency (neonatal phenotype): Successful prenatal and postmortem diagnosis associated with a novel mutation ina single family

The neonatal phenotype of carnitine-acylcarnitine translocase (CACT) defici ency is one of the most severe and usually lethal mitochondrial fat oxidati on disorders characterized by hypoketotic hypoglycemia, hyperammonemia, car diac abnormalities, and early death. In this study, the proband was the dau ghter of consanguineous Hispanic parents. At 36 h of Life, she had bradycar dia and died at 4 days of age without a specific diagnosis. In a subsequent pregnancy, prenatal counseling and amniocentesis were provided. Incubation of the amniocytes from this pregnancy and fibroblasts (from the dead proba nd) with [16-H-2(3)]palmitic acid and analysis by tandem mass spectrometry revealed an increased concentration of [16-H-2(3)]palmitoylcarnitine, sugge sting the diagnoses of either CACT or carnitine palmitoyltransferase II (CP T-II) deficiency. CACT enzyme activity was absent in both cell Lines. Molec ular investigation of cDNA from the dead proband and her affected sibling r evealed aberrant CACT cDNA species, including exon 3 skipping, both exon 3 and 4 skipping, and a 13-bp insertion at cDNA position 388. Investigation o f these cell lines for mutations affecting CACT RNA processing by analysis of CACT gene sequences, including intron and exon boundaries, revealed a si ngle nucleotide G deletion at the donor site in intron 3 which resulted in exon skipping and a 13-bp insertion. The proband and her affected sibling w ere homozygous for this deletion. (C) 2001 Academic Press.