A novel SLC25A20 splicing mutation in patients of different ethnic origin with neonatally lethal carnitine-acylcarnitine translocase (CACT) deficiency

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Year of Publication: 
Imad Dweikat
Stanley H. Korman
James J. Pitt
Avihu Boneh
Mokhtar Zater
Vardiella Meiner
Alisa Gutman
Michèle Brivet
Preferred Abstract (Original): 

Abstract : Carnitine-acylcarnitine translocase (CACT) deWciency is a rare disorder of fatty acid oxidation associated with high mortality. Two female newborns of diVerent ethnic origin (the Wrst Anglo-Celtic and the second Palestinian Arab) both died after sudden collapse on day 2 of life. Both had elevated bloodspot long-chain acylcarnitines consistent with either CACT or carnitine palmitoyltransferase II (CPT2) deWciency; the latter was excluded by demonstrating normal CPT2 activity in Wbroblasts. Direct sequencing of all SLC25A20 (CACT) gene exons and exon–intron boundaries revealed that Patient 1 was compound heterozygous for a novel c.609-3c > g (IVS6-3c > g) mutation on the paternal allele and a previously described c.326delG mutation on the maternal allele. Patient 2 was homozygous for the same, novel c.609-3c > g mutation. Previously reported SLC25A20 mutations have been almost exclusively conWned to a single family or ethnic group. Analysis of Wbroblast cDNA by RT-PCR, agarose gel electrophoresis and sequencing of extracted bands showed that both mutations produce aberrant splicing. c.609-3C > G results in exon 7 skipping leading to a frameshift with premature termination seven amino acids downstream. c.326delG was conWrmed to produce skipping of exons 3 or 3 plus 4. CACT activity in both patients’ Wbroblasts was near-zero. For both families, prenatal diagnosis of an unaVected fetus was performed by mutation analysis on CVS tissue in a subsequent pregnancy. Due to the urgency of prenatal diagnosis in the second family, molecular diagnosis was performed prior to demonstration of CACT enzyme deWciency, illustrating that mutation analysis is a rapid and reliable approach to Wrst-line diagnosis of CACT deWciency. © 2006 Elsevier Inc. All rights reserved.