title: Lethal Neonatal Progression of Fetal Cardiomegaly Associated to ACAD9 Deficiency.
abstract: ACAD9 (acyl-CoA dehydrogenase 9) is an essential factor for the mitochondrial respiratory chain complex I assembly. ACAD9, a member of acyl-CoA dehydrogenase family, has high homology with VLCAD (very long-chain acyl-CoA dehydrogenase) and harbors a homodimer structure. Recently, patients with ACAD9 deficiency have been described with a wide clinical spectrum ranging from severe lethal form to moderate form with exercise intolerance.We report here a prenatal presentation with intrauterine growth retardation and cardiomegaly, with a fatal outcome shortly after birth. Compound heterozygous mutations, a splice-site mutation - c.1030-1G>T and a missense mutation - c.1249C>T; p.Arg417Cys, were identified in the ACAD9 gene. Their effect on protein structure and expression level was investigated. Protein modeling suggested a functional effect of the c.1030-1G>T mutation generating a non-degraded truncated protein and the p.Arg417Cys, creating an aberrant dimer. Our results underscore the crucial role of ACAD9 protein for cardiac function.
authors.affiliation: Department of Metabolic Biochemistry, Rouen University Hospital, 1 Rue de Germont, 76031, Rouen, France.
authors.forename: Jennifer
authors.initials: J
authors.lastname: Lagoutte-Renosi
authors.affiliation: UMR 6014 CNRS COBRA, IRCOF, Normandie Université, Institute of Research for Innovation in Biomedicine, University of Rouen, Mont-Saint-Aignan, France.
authors.forename: Isabelle
authors.initials: I
authors.lastname: Ségalas-Milazzo
authors.affiliation: Pathology Laboratory, Rouen University Hospital, Rouen, France.
authors.forename: Marie
authors.initials: M
authors.lastname: Crahes
authors.affiliation: Department of Metabolic Biochemistry, Rouen University Hospital, 1 Rue de Germont, 76031, Rouen, France.
authors.forename: Florian
authors.initials: F
authors.lastname: Renosi
authors.affiliation: Glyco-MEV EA 4358, Normandie Université, Institute of Research for Innovation in Biomedicine, University of Rouen, Mont-Saint-Aignan, France.
authors.forename: Laurence
authors.initials: L
authors.lastname: Menu-Bouaouiche
authors.affiliation: NeoVasc Region-Inserm Team ERI28, Laboratory of Microvascular Endothelium and Neonate Brain Lesions, Institute of Research for Innovation in Biomedicine, University of Rouen, Rouen, France.|Department of Neonatology, Rouen University Hospital, Rouen, France.
authors.forename: Stéphanie
authors.initials: S
authors.lastname: Torre
authors.affiliation: Department of Neonatology, Rouen University Hospital, Rouen, France.
authors.forename: Caroline
authors.initials: C
authors.lastname: Lardennois
authors.affiliation: Department of Pediatrics and Genetics, Hôpital Necker-Enfants Malades, Paris, France.
authors.forename: Marlène
authors.initials: M
authors.lastname: Rio
authors.affiliation: NeoVasc Region-Inserm Team ERI28, Laboratory of Microvascular Endothelium and Neonate Brain Lesions, Institute of Research for Innovation in Biomedicine, University of Rouen, Rouen, France.|Department of Neonatology, Rouen University Hospital, Rouen, France.
authors.forename: Stéphane
authors.initials: S
authors.lastname: Marret
authors.affiliation: Department of Metabolic Biochemistry, Rouen University Hospital, 1 Rue de Germont, 76031, Rouen, France.|NeoVasc Region-Inserm Team ERI28, Laboratory of Microvascular Endothelium and Neonate Brain Lesions, Institute of Research for Innovation in Biomedicine, University of Rouen, Rouen, France.
authors.forename: Carole
authors.initials: C
authors.lastname: Brasse-Lagnel
authors.affiliation: Pathology Laboratory, Rouen University Hospital, Rouen, France.|NeoVasc Region-Inserm Team ERI28, Laboratory of Microvascular Endothelium and Neonate Brain Lesions, Institute of Research for Innovation in Biomedicine, University of Rouen, Rouen, France.
authors.forename: Annie
authors.initials: A
authors.lastname: Laquerrière
authors.affiliation: Department of Metabolic Biochemistry, Rouen University Hospital, 1 Rue de Germont, 76031, Rouen, France. soumeya.bekri@chu-rouen.fr.|NeoVasc Region-Inserm Team ERI28, Laboratory of Microvascular Endothelium and Neonate Brain Lesions, Institute of Research for Innovation in Biomedicine, University of Rouen, Rouen, France. soumeya.bekri@chu-rouen.fr.
authors.forename: Soumeya
authors.initials: S
authors.lastname: Bekri
keywords: ACAD9; Fetal cardiomegaly; Mitochondrial respiratory chain; β-Oxidation