title: A novel SLC25A20 splicing mutation in patients of different ethnic origin with neonatally lethal carnitine-acylcarnitine translocase (CACT) deficiency.
abstract: Carnitine-acylcarnitine translocase (CACT) deficiency is a rare disorder of fatty acid oxidation associated with high mortality. Two female newborns of different ethnic origin (the first 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) deficiency; the latter was excluded by demonstrating normal CPT2 activity in fibroblasts. 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 confined to a single family or ethnic group. Analysis of fibroblast 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 confirmed to produce skipping of exons 3 or 3 plus 4. CACT activity in both patients' fibroblasts was near-zero. For both families, prenatal diagnosis of an unaffected 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 deficiency, illustrating that mutation analysis is a rapid and reliable approach to first-line diagnosis of CACT deficiency.
authors.affiliation: Department of Clinical Biochemistry, Hadassah - Hebrew University Medical Center, Jerusalem, Israel. korman@hadassah.org.il
authors.forename: Stanley H
authors.initials: SH
authors.lastname: Korman
authors.forename: James J
authors.initials: JJ
authors.lastname: Pitt
authors.forename: Avihu
authors.initials: A
authors.lastname: Boneh
authors.forename: Imad
authors.initials: I
authors.lastname: Dweikat
authors.forename: Mokhtar
authors.initials: M
authors.lastname: Zater
authors.forename: Vardiella
authors.initials: V
authors.lastname: Meiner
authors.forename: Alisa
authors.initials: A
authors.lastname: Gutman
authors.forename: Michèle
authors.initials: M
authors.lastname: Brivet
mesh_terms: D000592:Amino Acid Metabolism, Inborn Errors / Q000201:enzymology / Q000208:ethnology / Q000235:genetics*; D018076:DNA, Complementary / Q000235:genetics; D017809:Fatal Outcome; D005260:Female; D005804:Genes, Lethal; D006801:Humans; D007231:Infant, Newborn; D026901:Membrane Transport Proteins / Q000032:analysis / Q000172:deficiency* / Q000235:genetics*; D009154:Mutation; D012326:RNA Splicing / Q000235:genetics; D017422:Sequence Analysis, DNA
chemical_list: D018076:DNA, Complementary; D026901:Membrane Transport Proteins; C120109:SLC25A20 protein, human