Carnitine/Acylcarnitine Translocase Deficiency (Neonatal Phenotype): Successful Prenatal and Postmortem Diagnosis Associated with a Novel Mutation in a Single Family

• Published in: Molecular genetics and metabolism Vol. 73; no. 1; pp. 64 - 70
• Main Authors: Yang, Bing-Zhi, Mallory, Jason M., Roe, Diane S., Brivet, Michele, Strobel, G.D., Jones, Kerri M., Ding, Jia-Huan, Roe, Charles R.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.05.2001
• Subjects: Base Sequence; Carnitine Acyltransferases - deficiency; Carnitine Acyltransferases - genetics; Carnitine Acyltransferases - metabolism; carnitine/acylcarnitine translocase; DNA - chemistry; DNA - genetics; DNA - metabolism; DNA Mutational Analysis; DNA Restriction Enzymes - metabolism; Exons - genetics; Family Health; Fatal Outcome; fatty acid β-oxidation; gene; Humans; Infant, Newborn; Male; Mitochondria - metabolism; Mutation; Oxidation-Reduction; Phenotype; Polymerase Chain Reaction; postmortem diagnosis; Prenatal Diagnosis; RNA, Messenger - genetics; RNA, Messenger - metabolism; Sequence Deletion; postmortem diagnosis; mutation; fatty acid β-oxidation; carnitine/acylcarnitine translocase; prenatal diagnosis; gene
• ISSN: 1096-7192; 1096-7206
• DOI: 10.1006/mgme.2001.3162

The neonatal phenotype of carnitine-acylcarnitine translocase (CACT) deficiency is one of the most severe and usually lethal mitochondrial fat oxidation disorders characterized by hypoketotic hypoglycemia, hyperammonemia, cardiac abnormalities, and early death. In this study, the proband was the daughter of consanguineous Hispanic parents. At 36 h of life, she had bradycardia 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 proband) with [16-2H3]palmitic acid and analysis by tandem mass spectrometry revealed an increasedconcentration of [16-2H3]palmitoylcarnitine, suggesting the diagnoses of either CACT or carnitine palmitoyltransferase II (CPT-II) deficiency. CACT enzyme activity was absent in both cell lines. Molecular investigation of cDNA from the dead proband and her affected sibling revealed aberrant CACT cDNA species, including exon 3 skipping, both exon 3 and 4 skipping, and a 13-bp insertion at cDNA position 388. Investigation of these cell lines for mutations affecting CACT RNA processing by analysis of CACT gene sequences, including intron and exon boundaries, revealed a single 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 were homozygous for this deletion.