title: High incidence and variable clinical outcome of cardiac hypertrophy due to ACAD9 mutations in childhood.
abstract: Acyl-CoA dehydrogenase family, member 9 (ACAD9) mutation is a frequent, usually fatal cause of early-onset cardiac hypertrophy and mitochondrial respiratory chain complex I deficiency in early childhood. We retrospectively studied a series of 20 unrelated children with cardiac hypertrophy and isolated complex I deficiency and identified compound heterozygosity for missense, splice site or frame shift ACAD9 variants in 8/20 patients (40%). Age at onset ranged from neonatal period to 9 years and 5/8 died in infancy. Heart transplantation was possible in 3/8. Two of them survived and one additional patient improved spontaneously. Importantly, the surviving patients later developed delayed-onset neurologic or muscular symptoms, namely cognitive impairment, seizures, muscle weakness and exercise intolerance. Other organ involvement included proximal tubulopathy, renal failure, secondary ovarian failure and optic atrophy. We conclude that ACAD9 mutation is the most frequent cause of cardiac hypertrophy and isolated complex I deficiency. Heart transplantation in children surviving neonatal period should be considered with caution, as delayed-onset muscle and brain involvement of various severity may occur, even if absent prior to transplantation.
authors.affiliation: Departments of Pediatric, Cardiology and Genetics and INSERM U1163, Université Paris Descartes-Sorbonne Paris Cité, Institut Imagine, Hôpital Necker-Enfants-Malades, Paris, France.
authors.forename: Marie
authors.initials: M
authors.lastname: Collet
authors.affiliation: Departments of Pediatric, Cardiology and Genetics and INSERM U1163, Université Paris Descartes-Sorbonne Paris Cité, Institut Imagine, Hôpital Necker-Enfants-Malades, Paris, France.
authors.forename: Zahra
authors.initials: Z
authors.lastname: Assouline
authors.affiliation: Departments of Pediatric, Cardiology and Genetics and INSERM U1163, Université Paris Descartes-Sorbonne Paris Cité, Institut Imagine, Hôpital Necker-Enfants-Malades, Paris, France.
authors.forename: Damien
authors.initials: D
authors.lastname: Bonnet
authors.affiliation: Departments of Pediatric, Cardiology and Genetics and INSERM U1163, Université Paris Descartes-Sorbonne Paris Cité, Institut Imagine, Hôpital Necker-Enfants-Malades, Paris, France.
authors.forename: Marlène
authors.initials: M
authors.lastname: Rio
authors.affiliation: Departments of Pediatric, Cardiology and Genetics and INSERM U1163, Université Paris Descartes-Sorbonne Paris Cité, Institut Imagine, Hôpital Necker-Enfants-Malades, Paris, France.
authors.forename: Franck
authors.initials: F
authors.lastname: Iserin
authors.affiliation: Departments of Pediatric, Cardiology and Genetics and INSERM U1163, Université Paris Descartes-Sorbonne Paris Cité, Institut Imagine, Hôpital Necker-Enfants-Malades, Paris, France.
authors.forename: Daniel
authors.initials: D
authors.lastname: Sidi
authors.affiliation: Unité de Génétique Clinique, Department of Neonatal Medicine - Neuropediatrics and Functional Education, CHU de Rouen, Hôpital Charles Nicolle, Rouen, France.
authors.forename: Alice
authors.initials: A
authors.lastname: Goldenberg
authors.affiliation: Unité de Génétique Clinique, Department of Neonatal Medicine - Neuropediatrics and Functional Education, CHU de Rouen, Hôpital Charles Nicolle, Rouen, France.
authors.forename: Caroline
authors.initials: C
authors.lastname: Lardennois
authors.affiliation: Departments of Pediatric, Cardiology and Genetics and INSERM U1163, Université Paris Descartes-Sorbonne Paris Cité, Institut Imagine, Hôpital Necker-Enfants-Malades, Paris, France.
authors.forename: Metodi Dimitrov
authors.initials: MD
authors.lastname: Metodiev
authors.affiliation: Institute of Human Genetics, Helmholtz Zentrum, Munchen, Germany.
authors.forename: Birgit
authors.initials: B
authors.lastname: Haberberger
authors.affiliation: Institute of Human Genetics, Helmholtz Zentrum, Munchen, Germany.
authors.forename: Tobias
authors.initials: T
authors.lastname: Haack
authors.affiliation: Departments of Pediatric, Cardiology and Genetics and INSERM U1163, Université Paris Descartes-Sorbonne Paris Cité, Institut Imagine, Hôpital Necker-Enfants-Malades, Paris, France.
authors.forename: Arnold
authors.initials: A
authors.lastname: Munnich
authors.affiliation: Institute of Human Genetics, Helmholtz Zentrum, Munchen, Germany.
authors.forename: Holger
authors.identifier: 0000-0003-2379-6286
authors.initials: H
authors.lastname: Prokisch
authors.affiliation: Departments of Pediatric, Cardiology and Genetics and INSERM U1163, Université Paris Descartes-Sorbonne Paris Cité, Institut Imagine, Hôpital Necker-Enfants-Malades, Paris, France.
authors.forename: Agnès
authors.initials: A
authors.lastname: Rötig
mesh_terms: D044944:Acyl-CoA Dehydrogenases / Q000235:genetics* / Q000378:metabolism; D006332:Cardiomegaly / Q000235:genetics* / Q000473:pathology; D002478:Cells, Cultured; D002648:Child; D002675:Child, Preschool; D042967:Electron Transport Complex I / Q000172:deficiency* / Q000235:genetics; D005260:Female; D016368:Frameshift Mutation; D006801:Humans; D007223:Infant; D008297:Male; D028361:Mitochondrial Diseases / Q000235:genetics* / Q000473:pathology; D059645:Mutation Rate; D020125:Mutation, Missense; D013577:Syndrome
chemical_list: D044944:Acyl-CoA Dehydrogenases; C549517:ACAD9 protein, human; D042967:Electron Transport Complex I