The Laryngoscope Lippincott Williams & Wilkins, Inc. © 2004 The American Laryngological, Rhinological and Otological Society, Inc. Deafness Due to A1555G Mitochondrial Mutation Without Use of Aminoglycoside Tatsuo Matsunaga, MD, PhD; Hiroshi Kumanomido, MD; Masae Shiroma, PhD; Akihiro Ohtsuka, MD; Kenji Asamura, MD; Shin-ichi Usami, MD, PhD Objectives/Hypothesis: The objective was to clar- ify the characteristics of deafness associated with the A1555G mutation within mitochondrial 12S ribo- somal RNA gene in the absence of aminoglycoside exposure. Study Design: Clinical and genetic studies in family members with the A1555G mitochondrial mutation were performed. Methods: The subjects were 123 maternally related members of a large Jap- anese family with the A1555G mutation. All subjects had no previous history of exposure to aminoglyco- sides. Hearing disability and handicap, tinnitus, and medical histories were analyzed by interviews in all of the subjects, genetic testing was performed in 41 subjects, and pure-tone audiometry was conducted in 26 subjects with hearing disability and handicap. Re- sults: The A1555G mutation was detected in a ho- moplasmic form (meaning that all the mitochondrial DNA carries the mutation) in all 41 subjects who were screened. The risk for developing postlingual hearing loss was likely to be much higher in the present sub- jects than in the general population. Both the severity and age at onset of the phenotype were similar in affected subjects within the same sibling group. Pure- tone averages were significantly worse in subjects who developed hearing loss before age 10 years than in those who developed hearing loss later. Conclu- sion: The present study demonstrated that the preva- lence of deafness in individuals with the A1555G mi- tochondrial mutation was likely to be high even in the absence of aminoglycoside exposure and clearly showed the association of severe to profound hearing loss with the onset of hearing loss before age 10 years. Key Words: Hereditary hearing loss, nonsyndromic, cochlea, mitochondria. Laryngoscope, 114:1085–1091, 2004 INTRODUCTION The A1555G mutation (i.e., A to G substitution at position 1555) in the mitochondrial 12S ribosomal RNA (rRNA) gene contributes to nonsyndromic sensorineural hearing loss and is prevalent in Japanese 1 and other pop- ulations. 2 This mutation is homoplasmic, indicating that all the mitochondrial DNA in different cells and tissues of the subject harbors the mutation. The A1555G mutation was first identified in family members who exhibited aminoglycoside-induced deafness, 3,4 and this ototoxic sus- ceptibility has its basis in the increased binding affinity of aminoglycosides for A1555G rRNA. 5 In addition, this mu- tation may also induce hearing loss in the absence of aminoglycosides. 3,6 –12 The expressivity of the A1555G mutation varies even within the same family and is not strictly associated with aminoglycoside exposure. Preva- lence, onset, and severity of the A1555G mutation–asso- ciated hearing loss in the absence of aminoglycoside expo- sure have not been characterized. Furthermore, what modulates the expressivity of this mutation is not clear. We identified a large Japanese family in which the A1555G mutation was prevalent. All the family members were not previously exposed to aminoglycosides. We con- ducted genetic tests, interviews, and pure-tone audiome- try in maternally related members of this family and elucidated the prevalence, characteristics, and intrafamil- ial patterns of the auditory dysfunction associated with the A1555G mutation in the absence of aminoglycoside exposure. PATIENTS AND METHODS Subjects Subjects were maternally related members of a large Japa- nese family in which hearing loss was common in a pattern that was compatible with maternal inheritance (Fig. 1). Because of the inheritance pattern, mutations in the mitochondrial DNA was suspected and the following genetic analysis in the proband (V- 10) revealed homoplasmic A1555G mutation in the mitochondrial 12S rRNA gene. There were 124 maternally related family mem- bers in all (57 male and 67 female family members) comprising Presented at the Meeting of the Association for Research in Otolar- yngology, Daytona Beach, FL, February 24, 2003. From the Department of Otolaryngology (T.M.), National Tokyo Med- ical Center, Tokyo, Japan; the Department of Speech-Language Pathology and Audiology (T.M., H.K., M.S.), School of Health Science, International University of Health and Welfare, Tochigi, Japan; and the Department of Otorhinolaryngology (A.O., K.A., S-I.U.), Shinshu University School of Medi- cine, Matsumoto, Japan. Supported by a Health Science Research Grant from the Ministry of Health Labor and Welfare of Japan (T.M.). Editor’s Note: This Manuscript was accepted for publication Decem- ber 15, 2003. Send Correspondence to Tatsuo Matsunaga, MD, PhD, Department of Otolaryngology, National Tokyo Medical Center, Higashigaoka 2-5-1, Meguro-ku, Tokyo 152-8902, Japan. E-mail: tmatsuna@ntmc.hosp.go.jp Laryngoscope 114: June 2004 Matsunaga et al.: A1555G Mitochondrial Mutation 1085