Fax +41 61 306 12 34 E-Mail karger@karger.ch www.karger.com Letter to the Editor Eur Neurol 2012;68:108–110 DOI: 10.1159/000339310 OPA3-Related Autosomal Dominant Optic Atrophy and Cataract with Ataxia and Areflexia X. Ayrignac a C. Liauzun c G. Lenaers c D. Renard a P. Amati-Bonneau d J. de Sèze e H. Dollfus f C. Hamel b, c D. Bonneau d P. Labauge a a Department of Neurology and b Reference Center ‘Affections Sensorielles Génétiques’, Ophthalmological Department, Montpellier University Hospital, and c Montpellier Neurosciences Institute, INSERM U1051, Montpellier , d Biochemistry and Genetic Department, Angers University Hospital and UMR-INSERM, U1083-CNRS, Angers, e Department of Neurology and f Genetic Department, Strasbourg University Hospital, Strasbourg, France atrophy and nystagmus since the first year of life, (2) progressive loss of vision, and (3) bilateral cerulean cataract at age 37. Addi- tional symptoms consisted of intractable constipation alternating with severe diar- rhea since childhood, together with gait unsteadiness, paresthesias in the four ex- tremities, cramps, and burning pain in the lower limbs since the age of 35. Clinical ex- amination at the age of 38 showed cere- bellar ataxia, lower limb areflexia, pin- prick and light-touch hypoesthesia, and pes cavus. Ophthalmological examination showed a visual acuity of 1/10 in both eyes. Eye fundus examination disclosed bilater- al optic atrophy. Goldmann visual field ex- amination revealed bilateral central sco- toma, and slit-lamp examination showed bilateral cerulean cataract. Electroreti- nography was normal and visual-evoked potentials showed bilateral optic nerve dysfunction. Motor as well as sensory nerve conduction studies, myography, and motor-evoked potentials were all normal. Somatosensory-evoked potentials dis- closed prolonged latencies of cortical as well as lumbar potentials. Brain MRI only showed mild cerebellar atrophy and MR spectroscopy was normal. Blood tests in- cluding serum lactate and pyruvate con- centrations were normal. Dear Sir, Hereditary optic atrophies refer to a heterogeneous group of genetic disorders in which the most common form is auto- somal dominant optic atrophy (ADOA). Only two genes, i.e. OPA1 and OPA3, have been identified in ADOA so far [1–3]. Mu- tations in OPA1 are responsible for 60– 80% of familial cases of ADOA while OPA3 has been implicated in only two families with ADOA and associated cata- ract (ADOAC) [2, 3]. Additional neurolog- ical signs have been reported in about 20% of OPA1-mutated patients and have also been described in some OPA3-mutated pa- tients [2, 3]. Recessive mutations in OPA3 are responsible for type III 3-methylgluta- conic aciduria (the so-called Costeff syn- drome) consisting of early-onset bilateral optic atrophy, spasticity, extrapyramidal signs, and cognitive deficit [4]. Here we de- scribe a third family harboring a dominant mutation in OPA3 responsible for ADOAC with additional neurological features. Ophthalmological signs of this 38-year- old woman consisted of (1) bilateral optic Received: March 20, 2012 Accepted: May 6, 2012 Published online: July 10, 2012 Dr. Xavier Ayrignac Service de Neurologie CHU Gui de Chauliac, 80 Ave. Augustin Fliche FR–34295 Montpellier (France) Tel. +33 4 67 33 74 13, E-Mail xavier.ayrignac  @  yahoo.fr © 2012 S. Karger AG, Basel 0014–3022/12/0682–0108$38.00/0 Accessible online at: www.karger.com/ene The proband’s 39-year-old brother had bilateral optic atrophy without additional neurological symptoms and her 63-year- old mother showed bilateral atrophy optic, nystagmus, generalized areflexia, and se- vere decrease of vibration sense in the low- er limbs. In all affected patients, the ten primary mtDNA mutations causing Leber heredi- tary optic neuropathy were excluded by di- rect sequencing. The direct sequencing of coding exons and exon-intron boundaries of OPA3 evidenced the heterozygous c.313C 1G (p.Q105E) mutation in exon 2 in all 3 affected patients. Analysis of the pro- band’s fibroblasts using immunohisto- chemistry and specific antibodies raised against the peptides corresponding to OPA3 exon 2 and exon 2b revealed uniform mitochondrial localization of both OPA3 isoforms, a normal reticulated mitochon- drial network and fluorescence labeling in- tensities similar to those found in age- and sex-matched control fibroblasts (fig. 1a). Quantifications of OPA3 mRNA variants showed a global increase in the expression of the OPA3 variant 1, supporting a domi- nant negative effect of the mutation (fig. 1b). Treatment with two different apoptotic drugs further substantiates a deficit in cell survival in patient cells (fig. 1c). X. Ayrignac and C. Liauzun contributed equally to this work.