European Journal of Human Genetics - Abstract of article: High incidence and variable clinical outcome of cardiac hypertrophy due to ACAD9 mutations in childhood

European Journal of Human Genetics - Abstract of article: High incidence and variable clinical outcome of cardiac hypertrophy due to ACAD9 mutations in childhood

High incidence and variable clinical outcome of cardiac hypertrophy due to ACAD9 mutations in childhood

Marie Collet¹, Zahra Assouline¹, Damien Bonnet¹, Marlène Rio¹, Franck Iserin¹, Daniel Sidi¹, Alice Goldenberg², Caroline Lardennois², Metodi Dimitrov Metodiev¹, Birgit Haberberger³, Tobias Haack³, Arnold Munnich¹, Holger Prokisch³ and Agnès Rötig¹

1. ¹Departments of Pediatric, Cardiology and Genetics and INSERM U1163, Université Paris Descartes-Sorbonne Paris Cité, Institut Imagine, Hôpital Necker-Enfants-Malades, Paris, France
2. ²Unité de Génétique Clinique, Department of Neonatal Medicine – Neuropediatrics and Functional Education, CHU de Rouen, Hôpital Charles Nicolle, Rouen, France
3. ³Institute of Human Genetics, Helmholtz Zentrum, Munchen, Germany

Correspondence: Dr A Rötig, Departments of Pediatric, Cardiology and Genetics and INSERM U1163, Université Paris Descartes-Sorbonne Paris Cité, Institut Imagine, Hôpital Necker-Enfants-Malades, 149 Rue de Sèvres, Paris 75015, France. Tel: +33 (0) 142754322; Fax: +33 (0) 142754224; E-mail:agnes.rotig@inserm.fr

Received 19 June 2015; Revised 5 October 2015; Accepted 13 October 2015
Advance online publication 16 December 2015

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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.