Molecular bases of hearing loss in multi-systemic mitochondrial cytopathy Fernando Scaglia, MD 1,2 , Chang-Hung Hsu, MD 3 , Haeyoung Kwon, PhD 4 , Ren-Kui Bai, MD, PhD 1 , Cherng-Lih Perng, MD 3 , Hua-Mei Chang, PhD 5 , Pu Dai, MD 6 , E. O’Brian Smith, PhD 7 , David A. H. Whiteman, MD 8 , Annette Feigenbaum, MD 9 , Andrea Gropman, MD 10 , and Lee-Jun C. Wong, PhD 1 Purpose: Hearing loss is a common clinical feature in classic mitochondrial syndromes. The purpose of this study was to evaluate the diverse molecular etiologies and natural history of hearing loss in multi-systemic mitochondrial cytopathies and the possible correlation between degree of hearing loss and neurological phenotype. Methods: In this retrospective study we evaluated the clinical features and molecular bases of hearing loss associated with multi-systemic mitochondrial cytopathy. Forty-five patients with sensorineural hearing loss and definite diagnosis of mitochondrial cytopathy according to the published diagnostic criteria were studied. Results: The sensorineural hearing loss was progressive and for the most part symmetrical with involvement of the higher frequencies. Both cochlear and retrocochlear involvement were found in this cohort. No correlation was found between the degree of hearing loss and the number and severity of neurological manifestations. Deleterious mtDNA point mutations of undisputed pathogenicity were identified in 18 patients. The A3243G mutation was the most frequently encoun- tered among this group. MtDNA depletion, over-replication, and multiple deletions were found in further 11 cases. Conclusion: This study reveals an expanding spectrum of mtDNA abnormalities associated with hearing loss. No correlation was found between the degrees of hearing loss and the severity of neurological manifestations. Genet Med 2006:8(10):641–652. Key Words: mtDNA mutation, deafness, maternal inheritance, maternally inherited hearing loss, mitochondrial syndrome Hearing loss is the most common neurosensory disorder in humans 1,2 with an incidence of approximately 1 in 1,000 children. 1 Hereditary deafness is extremely genetically hetero- geneous with more than 40 autosomal dominant (DFNA), 30 autosomal recessive (DNFB), and 6 X-linked (DFN) genes for non-syndromic deafness that account for 60 –70% of inherited hearing impairment. 3 The most common cause for non-syn- dromic autosomal recessive hearing loss is caused by muta- tions in Connexin 26, a gap junction protein encoded by the GJB2 gene. 4–6 However, about 30 – 40% of hereditary deafness is syndromic presenting with other clinical features in addition to hearing impairment. More than 30 nuclear genes, including those encoding transcription factors and gap junction proteins in Waardenburg syndrome and Usher syndrome, have been identified as responsible for syndromic hearing loss. 3 Although the majority of cases with hereditary hearing loss are caused by nuclear gene defects, in recent years, it has become clear that mitochondrial genes and nuclear genes that affect mitochon- drial biogenesis and function also play an important role. Sensorineural hearing loss (SNHL) is one of the most prev- alent and recognized clinical features of mitochondrial cytopathies. 2,7 Mutations in mitochondrial DNA (mtDNA) can cause non-syndromic hearing loss. 2,8,9 The most well-stud- ied mutation is the (A1555G) mutation in the mitochondrial 12S rRNA gene causing the non-syndromic hypersensitivity to ototoxic effects of aminoglycosides by increased binding of aminoglycosides to mitochondrial ribosomes, leading to the disruption of mitochondrial protein synthesis. 10,11 Another re- cently identified mutation in the mitochondrial 12S rRNA gene is the T1494C in the conserved stem structure of 12S From the 1 Department of Molecular and Human Genetics, Baylor College of Medicine, Hous- ton, Texas; 2 Department of Genetics, Texas Children’s Hospital, Houston, Texas; 3 Depart- ment of Neurology (C-HH) and Division of Clinical Pathology (C-LP), Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan; 4 Department of Applied Chem- istry, Dong-duk Women’s University, Seoul, Korea; 5 Vita Genomics, Inc., Taipei, Taiwan; 6 Department of Otolaryngology, 301 General Hospital, Beijing, People’s Republic of China; 7 Department of Pediatrics, Baylor College of Medicine, Houston, Texas; 8 Shire Human Ge- netic Therapies, Inc., Cambridge, Massachusetts; 9 Division of Clinical and Metabolic Dis- eases, The Hospital for Sick Children and University of Toronto, Toronto, Ontario, Canada; and the 10 Department of Pediatrics, Georgetown University Medical Center, Washington DC, and Medical Genetics Branch, National Human Genome Research Institute, NIH, Be- thesda, MD. Lee-Jun C. Wong, PhD, Department of Molecular and Human Genetics, Baylor College of Medicine, One Baylor Plaza, NAB2015, Houston, Texas 77030. Supplementary Table 1 is available via the Article Plus feature at www.geneticsinmedicine. org. Please go to the October issue and click on the Article Plus link posted with the article in the Table of Contents to view this table. Submitted for publication April 20, 2006. Accepted for publication July 10, 2006. FS and C-HH contributed equally to this article. DOI: 10.1097/01.gim.0000237781.10594.d1 October 2006  Vol. 8  No. 10 article Genetics IN Medicine 641