Support. Overview. Auditory Dys-synchrony. Auditory Brainstem Response. Potential Causes

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1 Potential Role of Genetic Testing in Auditory Neuropathy/Dys-synchrony Christina Runge-Samuelson, Ph.D., CCC-A Associate Professor Co-Director, Koss Cochlear Implant Program Department of tolaryngology and Communication Sciences Medical College of Wisconsin, Milwaukee, WI Support Genotype-Phenotype Relationships in Auditory Neuropathy NIH/NIDCD K23DC8837 Mentors: P. Ashley Wackym, M.D. Anne Kwitek, Ph.D. verview Auditory Neuropathy/Dys-synchrony phenotypes Genetic testing study Results and conclusions Auditory Dys-synchrony Recently defined Present HC function AEs Cochlear microphonic Desynchronous neural activity Unusually poor speech perception Particularly in noise Auditory Brainstem Response Potential Causes Amplitude (.1 µv / div) I Normal Hearing III V Amplitude (.1 µv / div) Auditory Neuropathy/Dys-synchrony Cochlear microphonic present Absent neural response Possible sites of lesion IHC Synapse Nerve Time (ms) Time (ms) Encyclopedia Britannica, 24 1

2 Diagnosis and Intervention Several possible causes of AN/AD Subtypes (IHC, synapse, nerve) Range of impairment severity ften not reflected in audiogram Different responses to intervention Hearing aids Cochlear implant No auditory intervention 2 year-old boy Twin-to-twin transfusion 9 months +CM, -ABR Mild-moderate hearing loss Hearing aids at 11 months Didn t tolerate, no benefit Age-appropriate speech and language Repeat ABR at 1.8 years (NR) Difficulty in noise K 2K 4K Age 2 years Non-traditional cochlear implant candidate 6 year-old boy Hyperbilirubinemia, preemie 2 mos +AEs, -ABR Moderate hearing loss Hearing aids at 1 year Improved detection only Poor speech/language Cochlear implant at 2.9 years CI use of 2.5 years 7% GASP sent, 44% PBK K 2K 4K Age 2.5 years Traditional cochlear implant candidate 3 year-old girl Cystic fibrosis Diagnostic +AEs, -ABR Severe to profound loss Minimal progress with HAs Cochlear Implant at 18 mo. 1 year progress in 1 year s time Subsequent sister AN/AD K 2K 4K Age 1 year Clinical Questions Variety of clinical presentations of AN/AD ften unable to differentiate underlying causes What to do and when? Hearing aid trial Watch development of auditory skills, speech and language Behavioral testing Cochlear implantation Genetic Testing Study Genetic testing for early identification of AN/AD subtypes Appropriate, timely intervention Prevention 2

3 Specific Aims Aim 1 Phenotype To define the audiologic characteristics of the clinical AN/AD population Aim 2 Genotype To test for genetic mutations that may be associated with AN/AD in this population Candidate Mutation Approach Mutations Natural variants Cause disorders Mutations associated with AN/AD SNHL and peripheral neuropathy Risk factor for AN/AD Mutations associated with AN/AD toferlin (TF) TF is expressed in the inner hair cells Affects calcium binding and vesicle docking Mutations Associated with AN/AD PJVK (DFNB59) Expressed in afferent aud pathway SLC19A2 Thiamine-responsive megaloblastic anemia (TRMA) Selective IHC loss in mutant mice Pujol, 27 Encyclopedia Britannica, 24 Mutations Associated with SNHL & Peripheral Neuropathy PMP22 Charcot-Marie-Tooth type 1A, HNPP Demyelination and axonal loss MPZ CMT1B (myelin sheath) and CMT2 (axonal) FN Freidereich s ataxia Demyelination and axonal loss Mutations Associated with Risk Factor UGT1A1 Gilbert syndrome Chronic, mild hyperbilirubinemia Predisposition for AN/AD? 3

4 Candidate Mutation Summary Pheno Gene/Locus Mutation Codon Ex/Intr Pheno Gene/Locus Mutation Codon Ex/Intr Screen AN/AD TF 2p C>A P49Q Ex15 AN/AD MPZ 1q21.3-q23 434A>C Y145S Ex3 Cx26 35delG DFNB9 1544T>C I515T Ex15 371C>T T124M Ex3 M34T 1651 delg Ex16 38G>A G74E Ex3 167delT 1886_1887 K629fs Ex17 293G>C R98P Ex3 IVS+1G-A insa 2122 C>T R78 Ex19 293G>A R98H Ex3 235delC 2348 delg G783fs Ex21 292C>T R98C Ex3 Cx3 GJB6-D13S G>A R794H Ex21 29A>T E97V Ex3 2485C>T Q829 Ex22 242A>G H81R Ex3 332 T>C L111P Ex G>A W1425 Ex36 515G>A G172D Ex2 AN/AD aslc19a2 1q T>A Y1497 Ex37 animal 724delC del242fs/259 Ex C>G P1825A Ex44 75G>A W25 Ex2 586_5862delATC I1954de Ex48 484C>T R162 Ex2 614 G>A R1939Q Ex48 515G>C G172R Ex C>G P1987R Ex48 79C>T R237 Ex8 SNHL PMP22 17p Mb dup/del IVS 18+1 G>T In18 248G>C A67P Ex3 IVS 24+1 G>A In24 G94(insG) IVS 28-2 A>C In28 IVS 36+2T>G In36 SNHL FN 9q GAA rep Int1 IVS39+1G>C In39 IVS 8-2 A>G In8 HyperbiUGT1A1 2q37 A(TA)7TAA Promoter -3263T>G Promoter 2q C-T Ex4 211G>A Ex1 AN/AD PJVK R183W G71R DFNB59 161C-T T541I Ex2 Phenotype Health/family/birth history Neurologic evaluation and MRI Audiologic behavioral testing (longitudinal) Audiometric Speech perception in quiet and noise AEs ABR Candidate mutation analyses Samples: Buccal swabs or blood DNA extraction Amplification of desired region Sequencing Analyze sequence for mutation Research results to subjects Amplification of desired region PCR - polymerase chain reaction Sequence Chromatograph Bases: T=Thymine A=Adenine C=Cytosine G=Guanine 61 DNA samples obtained to date 21 children with AN/AD 4 sibling pairs Various family members A pair of siblings with AN/AD each have one copy of an otoferlin mutation Normal Mutation 2485C>T 4

5 Potential Role of Genetic Testing? S38 S39 Help identify subtypes of AN/AD Streamline intervention approach Counseling Background noise Expectations Supplement existing diagnostic findings Continue audio and speech/language testing Continue to follow closely over time Acknowledgements Christy Erbe, BS Jamie Jensen, AuD, CCC-A Sarah Drake, MS, CCC-A Scott Evans, BS David Friedland, MD, PhD Masters Family Speech and Hearing Center, Children s Hospital of Wisconsin Contact Information Christina Runge-Samuelson, Ph.D crunge@mcw.edu 5