American Journal of Medical Genetics 138A:208–211 (2005) Optic Atrophy and Sensorineural Hearing Loss in a Family Caused by an R445H OPA1 Mutation Chunmei Li, 1,2 Gregory Kosmorsky, 3 Kang Zhang, 1 ** Bradley J. Katz, 1 Jian Ge, 2 and Elias I. Traboulsi 3 * 1 Department of Ophthalmology and Visual Sciences, John A Moran Eye Center, Program in Human Molecular Biology & Genetics, Eccles Institute of Human Genetics, University of Utah Health Sciences Center, Salt Lake City, Utah 2 Zhong Shan Ophthalmic Center, Sun Yat-Sen University; Guang Zhou, China 3 The Center for Genetic Eye Diseases, Cole Eye Institute, Cleveland Clinic Foundation, Cleveland, Ohio Autosomal dominant optic atrophy (ADOA) is the most common form of inherited optic atrophy. Four genetic loci have been associated with ADOA: OPA1, OPA2, OPA3, and OPA4. Out of these four loci, only one gene has been identified, OPA1. We previously described a unique syndrome of optic atrophy, sensorineural hearing loss, ptosis, and ophthalmoplegia in two unrelated families associated with an R445H mutation in OPA1. The R445H mutation is the only OPA1 mutation that has been associated with this syndrome. In this manuscript, we clinically characterize an unre- lated family with four members affected by optic atrophy and hearing loss without extraocular motility abnormalities or ptosis. This family also harbors the R445H mutation. These cases help illustrate the intra- and inter-family variability in phenotype associated with this mutation. As we continue to learn more about OPA1 and the function of its protein product, we will begin to understand the pathophysiology of optic atrophy. This understanding will ultimately lead to novel treatments directed toward preventing the visual loss and disability associated with this inherited disease. ß 2005 Wiley-Liss, Inc. KEY WORDS: optic atrophy; deafness; mito- chondria; OPA1; dynamin INTRODUCTION Autosomal dominant optic atrophy (ADOA) is the most common form of optic atrophy with an estimated prevalence of 1 in 50,000 individuals [Eliott et al., 1993; Kjer et al., 1996]. ADOA is a slowly progressive, bilateral atrophy of the optic nerves. It is characterized clinically by loss of visual acuity, cecocentral scotomas, and abnormalities of color vision [Hoyt, 1980]. Four loci for optic atrophy have been mapped: OPA1 (3q28-29), OPA2 (Xp11.4-11.21), OPA3 (19q13.2-13.3), and OPA4 (18q12.2-q12.3). Of these four loci, one gene (OPA1) has been identified, and mutations in OPA1 have been shown to cause optic atrophy with varying degrees of severity. As many as 89% of cases of ADOA may be associated with a mutation in OPA1 [Delettre et al., 2001] and at least 73 different mutations in OPA1 have been previously described [Baris et al., 2003]. In 1984, Treft et al. described an autosomal dominant disorder in 23 members of a large Utah family in which affected individuals exhibited progressive optic atrophy, sensorineural hearing loss, ptosis, ophthalmoplegia, ataxia, and a nonspecific myopathy [Treft et al., 1984]. The following year, Meire et al. reported an unrelated family from Belgium with a similar phenotype [Meire et al., 1985]. We subsequently identified an R445H OPA1 mutation in both the Utah family and the family from Belgium [Payne et al., 2004]. In this manuscript, we describe four members of an unrelated Ohio family with optic atrophy and hearing loss that also harbor the R445H mutation. MATERIALS AND METHODS This project was approved by the Institutional Review Boards of the Cleveland Clinic Foundation and University of Utah Health Sciences Center. Informed consent was obtained from all participants in accordance with HIPAA regulations. Six family members of a two-generation Caucasian family were examined. Subjects underwent ophthalmic examinations that included measurement of best-corrected visual acuity, visual field testing, assessment of extraocular motility, and ophthalmoscopy. Optic atrophy was rated as absent, mild, moderate, or severe by two of the authors (EIT and GK) based on ophthalmoscopy and review of fundus photographs. Some patients underwent assessment of color vision using either the Ishihara color plates or a customized computerized color vision test. Affected individuals underwent assessment of visual fields using automated threshold perimetry (Humphrey Visual Field Analyzer, Zeiss Humphrey Systems, Dublin, CA.) or Goldmann static perimetry. Patients underwent audiometric evaluation including pure tone average assessment, speech reception thresholds, and speech discrimination scoring for each ear. Normal hearing was defined as a pure tone average loss of less than or equal to 20 dB. Mild loss was defined as a 21 – 40 dB loss, moderate loss was defined as 41–60 dB loss, severe loss was defined as 61– 90 dB loss, and profound loss was defined as greater than 90 dB loss. Genomic DNA was extracted from blood samples. For both sequencing and genotyping, samples were amplified by the polymerase chain reaction and loaded on a Beckman – Coulter CEQ 8000 Genetic Analysis System using established methods [Yang et al., 2005]. Each exon of OPA1 was sequenced directly Grant sponsor: NIH ; Grant numbers: RO1 EY14438, RO1 EY14448, K23 RR16427; Grant sponsor: American Health Assistance Foundation; Grant sponsor: Karl Kirchgessner Foun- dation; Grant sponsor: Ruth and Milton Steinbach Fund; Grant sponsor: Ronald McDonald House Charities; Grant sponsor: Val and Edith Green Foundation; Grant sponsor: Research to Prevent Blindness, Inc. *Correspondence to: Dr. Elias I. Traboulsi, i32, 9500 Euclid Avenue, Cleveland, OH 44195. E-mail: kideyes1@yahoo.com **Correspondence to: Dr. Kang Zhang, Eccles Institute of Human Genetics, University of Utah, 15 N, 2030 East, Salt Lake City, UT 84132. E-mail: kang.zhang@hmbg.utah.edu Received 3 February 2005; Accepted 13 April 2005 DOI 10.1002/ajmg.a.30794 ß 2005 Wiley-Liss, Inc.