SHORT REPORT Mutations in the tricarboxylic acid cycle enzyme, aconitase 2, cause either isolated or syndromic optic neuropathy with encephalopathy and cerebellar atrophy Metodi Dimitrov Metodiev, 1 Sylvie Gerber, 1 Laurence Hubert, 1 Agnès Delahodde, 2 Dominique Chretien, 1 Xavier Gérard, 1 Patrizia Amati-Bonneau, 4 Marie-Christine Giacomotto, 5 Nathalie Boddaert, 3 Anna Kaminska, 3 Isabelle Desguerre, 3 Jeanne Amiel, 3 Marlène Rio, 3 Josseline Kaplan, 1 Arnold Munnich, 1,3 Agnès Rötig, 1 Jean Michel Rozet, 1 Claude Besmond 1 ▸ Additional material is published online only. To view please visit the journal online (http://dx.doi.org/10.1136/ jmedgenet-2014-102532). 1 UMR1163, Université Paris Descartes, Sorbonne Paris Cité, Institut IMAGINE, Paris, France 2 Institut de Génétique et Microbiologie UMR 8621, Université Paris-Sud, Orsay, France 3 Departments of Pediatrics, Radiology and Genetics, Hôpital Necker-Enfants Malades, Paris, France 4 Département de Biochimie et Génétique, CHU d’Angers, Angers, France 5 Service d’Ophtalmologie, Polyclinique du Maine, Laval, France Correspondence to Dr Agnès Rötig, Institut IMAGINE, 24 Bd du Montparnasse, Paris 75015, France; agnes.rotig@inserm.fr MDM, SG and LH contributed equally. Received 21 May 2014 Revised 30 September 2014 Accepted 10 October 2014 Published Online First 28 October 2014 To cite: Metodiev MD, Gerber S, Hubert L, et al. J Med Genet 2014;51: 834–838. ABSTRACT Background Inherited optic neuropathy has been ascribed to mutations in mitochondrial fusion/fission dynamics genes, nuclear and mitochondrial DNA- encoded respiratory enzyme genes or nuclear genes of poorly known mitochondrial function. However, the disease causing gene remains unknown in many families. Methods We used exome sequencing in order to identify the gene responsible for isolated or syndromic optic atrophy in five patients from three independent families. Results We found homozygous or compound heterozygous missense and frameshift mutations in the gene encoding mitochondrial aconitase (ACO2),a tricarboxylic acid cycle enzyme, catalysing interconversion of citrate into isocitrate. Unlike wild type ACO2, all mutant ACO2 proteins failed to complement the respiratory growth of a yeast aco1-deletion strain. Retrospective studies using patient-derived cultured skin fibroblasts revealed various degrees of deficiency in ACO2 activity, but also in ACO1 cytosolic activity. Conclusions Our study shows that autosomal recessive ACO2 mutations can cause either isolated or syndromic optic neuropathy. This observation identifies ACO2 as the second gene responsible for non-syndromic autosomal recessive optic neuropathies and provides evidence for a genetic overlap between isolated and syndromic forms, giving further support to the view that optic atrophy is a hallmark of defective mitochondrial energy supply. INTRODUCTION In the past few years, enzymopathies of the tricarboxylic acid cycle (TCA) have been reported to cause severe encephalopathies in humans, namely fumarase, succinate dehydrogenase (SDH), α-ketoglutarate dehydrogenase and succinyl- Coenzyme A (CoA) synthetase deficiencies. 1 Clinical features included seizures, muscle weakness, growth and developmental delay. On the other hand, muta- tions in another TCA enzyme, isocitrate dehydro- genase, have been reported to cause isolated retinitis pigmentosa. 2 Recently, missense mutations in yet another TCA enzyme, mitochondrial aconitase (ACO2), catalysing interconversion of citrate into isocitrate, have been reported in a sibship with infantile-onset encephalopathy, optic nerve involve- ment and cerebellar atrophy. 3 Hitherto however, no TCA enzyme mutation has been reported in isolated optic neuropathy. Studying a series of unexplained cases of optic atrophy, we found biallelic ACO2 mutations in five patients. ACO2 mutations caused either isolated or syndromic optic neuropathy, irrespective of the residual level of enzyme activity. These observations support the view that optic atrophy is a hallmark of defective mitochondrial energy supply and suggest that extraocular involvement is not related to sever- ity of the enzyme deficiency. MATERIALS AND METHODS Patients Patients 1 and 2 were two adult male sibs, born to unrelated parents of French origin and aged 41 years and 36 years, respectively. They presented with decreased visual acuity and pallor of the optic disc at 5 years and 3years of age, respectively, but no other concerns were noted. In their 20s, they had severely reduced visual acuity (20/150–20/100 for near vision and 20/200 for far vision), paracen- tral scotoma, red-green dyschromatopsia and marked temporal optic atrophy at the fundus. In their 40s, their optic atrophy remained stable ( figure 1A) and isolated. Optical coherence tomog- raphy shows marked bilateral reduction in the tem- poral superior and inferior retinal nerve fibre layers (RNFLs) with preservation of the nasal RNFL. None of them had overt extraocular symptoms. Patient 3, the first child of first cousin Algerian parents, was born in apparent death with apnoea, bradycardia and major cyanosis (birth weight: 3530 g, height: 50 cm, occipitofrontal head circum- ference (OFC): 38 cm, Apgar score, 3, 4 and 10). Fundus examination revealed a bilateral oedema of optic disks, but no overt retinal anomalies. Iterative episodes of apnoea, bradycardia, and oxygen desat- uration were suggestive of central apnoeas. Brain MRI showed moderate cerebellar atrophy with no 834 Metodiev MD, et al. J Med Genet 2014;51:834–838. doi:10.1136/jmedgenet-2014-102532 Genome-wide studies group.bmj.com on December 15, 2014 - Published by http://jmg.bmj.com/ Downloaded from