{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,18]],"date-time":"2026-05-18T13:17:59Z","timestamp":1779110279326,"version":"3.51.4"},"reference-count":58,"publisher":"MDPI AG","issue":"4","license":[{"start":{"date-parts":[[2021,11,26]],"date-time":"2021-11-26T00:00:00Z","timestamp":1637884800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Audiology Research"],"abstract":"<jats:p>Auditory Neuropathy (AN) is characterized by disruption of temporal coding of acoustic signals in auditory nerve fibers resulting in alterations of auditory perceptions. Mutations in several genes have been associated to the most forms of AN. Underlying mechanisms include both pre-synaptic and post-synaptic damage involving inner hair cell (IHC) depolarization, neurotransmitter release, spike initiation in auditory nerve terminals, loss of auditory fibers and impaired conduction. In contrast, outer hair cell (OHC) activities (otoacoustic emissions [OAEs] and cochlear microphonic [CM]) are normal. Disordered synchrony of auditory nerve activity has been suggested as the basis of both the alterations of auditory brainstem responses (ABRs) and reduction of speech perception. We will review how electrocochleography (ECochG) recordings provide detailed information to help objectively define the sites of auditory neural dysfunction and their effect on receptor summating potential (SP) and neural compound action potential (CAP), the latter reflecting disorders of ribbon synapses and auditory nerve fibers.<\/jats:p>","DOI":"10.3390\/audiolres11040059","type":"journal-article","created":{"date-parts":[[2021,11,28]],"date-time":"2021-11-28T22:19:16Z","timestamp":1638137956000},"page":"639-652","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":15,"title":["Electrocochleography in Auditory Neuropathy Related to Mutations in the OTOF or OPA1 Gene"],"prefix":"10.3390","volume":"11","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-7730-3446","authenticated-orcid":false,"given":"Rosamaria","family":"Santarelli","sequence":"first","affiliation":[{"name":"Department of Neurosciences, University of Padova, Via Belzoni 160, 35121 Padova, Italy"},{"name":"Audiology Service, Santi Giovanni e Paolo Hospital, Campo Santi Giovanni e Paolo, Castello 6777, 30122 Venezia, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5273-1938","authenticated-orcid":false,"given":"Pietro","family":"Scimemi","sequence":"additional","affiliation":[{"name":"Department of Neurosciences, University of Padova, Via Belzoni 160, 35121 Padova, Italy"},{"name":"Audiology Service, Santi Giovanni e Paolo Hospital, Campo Santi Giovanni e Paolo, Castello 6777, 30122 Venezia, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Chiara","family":"La Morgia","sequence":"additional","affiliation":[{"name":"Department of Biomedical and Neuromotor Sciences (DIBINEM), University of Bologna, Via Ugo Foscolo 7, 40123 Bologna, Italy"},{"name":"IRCCS Institute of Neurological Sciences of Bologna, Bellaria Hospital, Via Altura 3, 40139 Bologna, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1010-0024","authenticated-orcid":false,"given":"Elona","family":"Cama","sequence":"additional","affiliation":[{"name":"Department of Neurosciences, University of Padova, Via Belzoni 160, 35121 Padova, Italy"},{"name":"Audiology Service, Santi Giovanni e Paolo Hospital, Campo Santi Giovanni e Paolo, Castello 6777, 30122 Venezia, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1188-3665","authenticated-orcid":false,"given":"Ignacio","family":"del Castillo","sequence":"additional","affiliation":[{"name":"Servicio de Gen\u00e9tica, Hospital Universitario Ram\u00f3n y Cajal, IRYCIS, 28034 Madrid, Spain"},{"name":"Centro de Investigaci\u00f3n Biom\u00e9dica en Red de Enfermedades Raras (CIBERER), 28034 Madrid, Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4923-6404","authenticated-orcid":false,"given":"Valerio","family":"Carelli","sequence":"additional","affiliation":[{"name":"Department of Biomedical and Neuromotor Sciences (DIBINEM), University of Bologna, Via Ugo Foscolo 7, 40123 Bologna, Italy"},{"name":"IRCCS Institute of Neurological Sciences of Bologna, Bellaria Hospital, Via Altura 3, 40139 Bologna, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2021,11,26]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"741","DOI":"10.1093\/brain\/119.3.741","article-title":"Auditory neuropathy","volume":"119","author":"Starr","year":"1996","journal-title":"Brain"},{"key":"ref_2","first-page":"397","article-title":"Perspectives on auditory neuropathy: Disorders of inner hair cell, auditory nerve, and their synapse","volume":"Volume 3: Audition","author":"Basbaum","year":"2008","journal-title":"The Senses: A Comprehensive Reference"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"3050","DOI":"10.1152\/jn.00985.2004","article-title":"Perceptual Consequences of Disrupted Auditory Nerve Activity","volume":"93","author":"Zeng","year":"2005","journal-title":"J. Neurophysiol."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"135","DOI":"10.1038\/nrneurol.2016.10","article-title":"Auditory neuropathy\u2014Neural and synaptic mechanisms","volume":"12","author":"Moser","year":"2016","journal-title":"Nat. Rev. Neurol."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"215","DOI":"10.1016\/0010-0277(91)90054-8","article-title":"Critical period effects on universal properties of language: The status of subjacency in the acquisition of a second language","volume":"39","author":"Johnson","year":"1991","journal-title":"Cognition"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"36","DOI":"10.1002\/1531-8249(199907)46:1<36::AID-ANA7>3.0.CO;2-J","article-title":"Hereditary auditory, vestibular, motor, and sensory neuropathy in a Slovenian Roma (Gypsy) kindred","volume":"46","author":"Butinar","year":"1999","journal-title":"Ann. Neurol."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"91","DOI":"10.1186\/gm212","article-title":"Information from cochlear potentials and genetic mutations helps localize the lesion site in auditory neuropathy","volume":"2","author":"Santarelli","year":"2010","journal-title":"Genome Med."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"501","DOI":"10.3389\/fnins.2019.00501","article-title":"Hearing Dysfunction in a Large Family Affected by Dominant Optic Atrophy (OPA8-Related DOA): A Human Model of Hidden Auditory Neuropathy","volume":"13","author":"Santarelli","year":"2019","journal-title":"Front. Neurosci."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"200","DOI":"10.1016\/j.heares.2015.07.007","article-title":"Audibility, speech perception and processing of temporal cues in ribbon synaptic disorders due to OTOF mutations","volume":"330","author":"Santarelli","year":"2015","journal-title":"Hear. Res."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"1627","DOI":"10.1097\/AUD.0000000000001052","article-title":"Cochlear Synaptopathy due to Mutations in OTOF Gene May Result in Stable Mild Hearing Loss and Severe Impairment of Speech Perception","volume":"42","author":"Santarelli","year":"2021","journal-title":"Ear Hear."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"97","DOI":"10.1016\/j.brainres.2009.08.083","article-title":"Mutation of OPA1 gene causes deafness by affecting function of auditory nerve terminals","volume":"1300","author":"Huang","year":"2009","journal-title":"Brain Res."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"563","DOI":"10.1093\/brain\/awu378","article-title":"OPA1-related auditory neuropathy: Site of lesion and outcome of cochlear implantation","volume":"138","author":"Santarelli","year":"2015","journal-title":"Brain"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"451","DOI":"10.1002\/humu.10274","article-title":"Auditory neuropathy in patients carrying mutations in the otoferlin gene (OTOF)","volume":"22","author":"Morera","year":"2003","journal-title":"Hum. Mutat."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"770","DOI":"10.1038\/ng1829","article-title":"Mutations in the gene encoding pejvakin, a newly identified protein of the afferent auditory pathway, cause DFNB59 auditory neuropathy","volume":"38","author":"Delmaghani","year":"2006","journal-title":"Nat. Genet."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"13396","DOI":"10.1073\/pnas.1003027107","article-title":"Increased activity of Diaphanous homolog 3 (DIAPH3)\/diaphanous causes hearing defects in humans with auditory neuropathy and in Drosophila","volume":"107","author":"Schoen","year":"2010","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"e33","DOI":"10.1136\/jmg.2005.037929","article-title":"AUNX1, a novel locus responsible for X linked recessive auditory and peripheral neuropathy, maps to Xq23-27.3","volume":"43","author":"Wang","year":"2005","journal-title":"J. Med. Genet."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"830","DOI":"10.1001\/archotol.129.8.830","article-title":"Phenotypic Characterization of Hereditary Hearing Impairment Linked to DFNA25","volume":"129","author":"Thirlwall","year":"2003","journal-title":"Arch. Otolaryngol.-Head Neck Surg."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"e2019681118","DOI":"10.1073\/pnas.2019681118","article-title":"A nonsense TMEM43 variant leads to disruption of connexin-linked function and autosomal dominant auditory neuropathy spectrum disorder","volume":"118","author":"Jang","year":"2021","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"295","DOI":"10.1002\/ajmg.10223","article-title":"Anticipation in a unique family with Charcot-Marie-Tooth syndrome and deafness: Delineation of the clinical features and review of the literature","volume":"108","author":"Kovach","year":"2002","journal-title":"Am. J. Med. Genet."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"1604","DOI":"10.1093\/brain\/awg156","article-title":"Pathology and physiology of auditory neuropathy with a novel mutation in the MPZ gene (Tyr145->Ser)","volume":"126","author":"Starr","year":"2003","journal-title":"Brain"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"367","DOI":"10.1016\/j.clinph.2007.10.004","article-title":"Auditory nerve is affected in one of two different point mutations of the neurofilament light gene","volume":"119","author":"Butinar","year":"2008","journal-title":"Clin. Neurophysiol."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"47","DOI":"10.1086\/302978","article-title":"N-myc Downstream-Regulated Gene 1 Is Mutated in Hereditary Motor and Sensory Neuropathy\u2013Lom","volume":"67","author":"Kalaydjieva","year":"2000","journal-title":"Am. J. Hum. Genet."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"947","DOI":"10.1093\/hmg\/10.9.947","article-title":"Connexin 31 (GJB3) is expressed in the peripheral and auditory nerves and causes neuropathy and hearing impairment","volume":"10","author":"Olive","year":"2001","journal-title":"Hum. Mol. Genet."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"202","DOI":"10.1136\/jnnp.66.2.202","article-title":"Central visual, acoustic, and motor pathway involvement in a Charcot-Marie-Tooth family with an Asn205Ser mutation in the connexin 32 gene","volume":"66","author":"Andres","year":"1999","journal-title":"J. Neurol. Neurosurg. Psychiatry"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"958","DOI":"10.1002\/ana.20681","article-title":"OPA1 R445H mutation in optic atrophy associated with sensorineural deafness","volume":"58","author":"Guichet","year":"2005","journal-title":"Ann. Neurol."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"1893","DOI":"10.1093\/hmg\/ddr071","article-title":"A clinically complex form of dominant optic atrophy (OPA8) maps on chromosome 16","volume":"20","author":"Carelli","year":"2011","journal-title":"Hum. Mol. Genet."},{"key":"ref_27","first-page":"650","article-title":"Nonsense mutation in TMEM126A causing autosomal recessive optic atrophy and auditory neuropathy","volume":"16","author":"Meyer","year":"2010","journal-title":"Mol. Vis."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"2002","DOI":"10.1093\/brain\/awn104","article-title":"Speech perception ability in individuals with Friedreich ataxia","volume":"131","author":"Rance","year":"2008","journal-title":"Brain"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"27","DOI":"10.1002\/ajmg.a.30424","article-title":"Clinical and molecular characterization of a Chinese patient with auditory neuropathy associated with mitochondrial 12S rRNA T1095C mutation","volume":"133A","author":"Wang","year":"2005","journal-title":"Am. J. Med. Genet. Part A"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"1202","DOI":"10.1097\/MLG.0b013e3180581944","article-title":"Otopathology in Mohr-Tranebjaerg syndrome","volume":"117","author":"Bahmad","year":"2007","journal-title":"Laryngoscope"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"626","DOI":"10.1136\/jnnp.2003.017673","article-title":"Progressive auditory neuropathy in patients with Leber\u2019s hereditary optic neuropathy","volume":"75","author":"Luxon","year":"2004","journal-title":"J. Neurol. Neurosurg. Psychiatr."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"25","DOI":"10.1186\/s12967-017-1129-4","article-title":"Novel neuro-audiological findings and further evidence for TWNK involvement in Perrault syndrome","volume":"15","author":"Pollak","year":"2017","journal-title":"J. Transl. Med."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"3382","DOI":"10.1172\/JCI94351","article-title":"Clarin-1 gene transfer rescues auditory synaptopathy in model of Usher syndrome","volume":"128","author":"Dulon","year":"2018","journal-title":"J. Clin. Investig."},{"key":"ref_34","first-page":"111","article-title":"The CAPOS mutation in ATP1A3 alters Na\/K-ATPase function and results in auditory neuropathy which has implications for management","volume":"137","author":"Strenzke","year":"2018","journal-title":"Qual. Life Res."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"1028","DOI":"10.1016\/j.clinph.2008.01.018","article-title":"Neural and receptor cochlear potentials obtained by transtympanic electrocochleography in auditory neuropathy","volume":"119","author":"Santarelli","year":"2008","journal-title":"Clin. Neurophysiol."},{"key":"ref_36","unstructured":"Celesia, G.G. (2013). Electrocochleography. Handbook of Clinical Neurophysiology, Elsevier. Disorders of Peripheral and Central Auditory Processing."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"510","DOI":"10.1121\/1.381086","article-title":"Production of cochlear potentials by inner and outer hair cells","volume":"60","author":"Dallos","year":"1976","journal-title":"J. Acoust. Soc. Am."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"370","DOI":"10.1121\/1.423293","article-title":"Are inner or outer hair cells the source of summating potentials recorded from the round wi\u2018ndow?","volume":"104","author":"Durrant","year":"1998","journal-title":"J. Acoust. Soc. Am."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"2163","DOI":"10.1152\/jn.00006.2019","article-title":"Hair cell and neural contributions to the cochlear summating potential","volume":"121","author":"Pappa","year":"2019","journal-title":"J. Neurophysiol."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"107","DOI":"10.1121\/1.1909497","article-title":"Synchrony of Neural Activity in Electric Responses Evoked by Transient Acoustic Stimuli","volume":"30","author":"Goldstein","year":"1958","journal-title":"J. Acoust. Soc. Am."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"1025","DOI":"10.1152\/jn.00738.2013","article-title":"Contribution of auditory nerve fibers to compound action potential of the auditory nerve","volume":"112","author":"Bourien","year":"2014","journal-title":"J. Neurophysiol."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"53","DOI":"10.1016\/j.preteyeres.2003.10.003","article-title":"Mitochondrial dysfunction as a cause of optic neuropathies","volume":"23","author":"Carelli","year":"2004","journal-title":"Prog. Retin. Eye Res."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"500","DOI":"10.1016\/j.bbamcr.2006.04.003","article-title":"Mitochondrial dynamics and disease, OPA1","volume":"1763","author":"Olichon","year":"2006","journal-title":"Biochim. Biophys. Acta"},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"177","DOI":"10.1016\/j.cell.2006.06.025","article-title":"OPA1 Controls Apoptotic Cristae Remodeling Independently from Mitochondrial Fusion","volume":"126","author":"Frezza","year":"2006","journal-title":"Cell"},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"719","DOI":"10.1002\/ana.20278","article-title":"Deficit of in vivo mitochondrial ATP production in OPA1-related dominant optic atrophy","volume":"56","author":"Lodi","year":"2004","journal-title":"Ann. Neurol."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"338","DOI":"10.1093\/brain\/awm298","article-title":"OPA1 mutations induce mitochondrial DNA instability and optic atrophy \u2019plus\u2019 phenotypes","volume":"131","author":"Valentino","year":"2008","journal-title":"Brain"},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"771","DOI":"10.1093\/brain\/awq007","article-title":"Multi-system neurological disease is common in patients with OPA1 mutations","volume":"133","author":"Griffiths","year":"2010","journal-title":"Brain A J. Neurol."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"181","DOI":"10.1097\/00005537-199902000-00002","article-title":"Cochlear Implantation in Auditory Neuropathy","volume":"109","author":"Miyamoto","year":"1999","journal-title":"Laryngoscope"},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"287","DOI":"10.1179\/1754762813Y.0000000029","article-title":"Bilateral cochlear implantation in Friedreich\u2019s ataxia: A case study","volume":"14","author":"Frewin","year":"2013","journal-title":"Cochlear Implants Int."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"823","DOI":"10.1002\/humu.20708","article-title":"A multicenter study on the prevalence and spectrum of mutations in the otoferlin gene (OTOF) in subjects with nonsyndromic hearing impairment and auditory neuropathy","volume":"29","author":"Reynoso","year":"2008","journal-title":"Hum. Mutat."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"277","DOI":"10.1016\/j.cell.2006.08.040","article-title":"Otoferlin, Defective in a Human Deafness Form, Is Essential for Exocytosis at the Auditory Ribbon Synapse","volume":"127","author":"Roux","year":"2006","journal-title":"Cell"},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"869","DOI":"10.1038\/nn.2578","article-title":"Hearing requires otoferlin-dependent efficient replenishment of synaptic vesicles in hair cells","volume":"13","author":"Lasarow","year":"2010","journal-title":"Nat. Neurosci."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"545","DOI":"10.1007\/s10162-009-0181-z","article-title":"Abnormal Cochlear Potentials from Deaf Patients with Mutations in the Otoferlin Gene","volume":"10","author":"Santarelli","year":"2009","journal-title":"J. Assoc. Res. Otolaryngol."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"4496","DOI":"10.1073\/pnas.1817537116","article-title":"Dual AAV-mediated gene therapy restores hearing in a DFNB9 mouse model","volume":"116","author":"Akil","year":"2019","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"253","DOI":"10.3389\/fnmol.2020.600051","article-title":"Overloaded Adeno-Associated Virus as a Novel Gene Therapeutic Tool for Otoferlin-Related Deafness","volume":"13","author":"Rankovic","year":"2021","journal-title":"Front. Mol. Neurosci."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"13452","DOI":"10.1523\/JNEUROSCI.2156-11.2011","article-title":"Tinnitus with a Normal Audiogram: Physiological Evidence for Hidden Hearing Loss and Computational Model","volume":"31","author":"Schaette","year":"2011","journal-title":"J. Neurosci."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"138","DOI":"10.1016\/j.heares.2017.01.003","article-title":"Cochlear synaptopathy in acquired sensorineural hearing loss: Manifestations and mechanisms","volume":"349","author":"Liberman","year":"2017","journal-title":"Hear. Res."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"2492","DOI":"10.1121\/10.0006572","article-title":"The summating potential in human electrocochleography: Gaussian models and Fourier analysis","volume":"150","author":"Hancock","year":"2021","journal-title":"J. Acoust. Soc. Am."}],"container-title":["Audiology Research"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2039-4349\/11\/4\/59\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T07:36:06Z","timestamp":1760168166000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2039-4349\/11\/4\/59"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,11,26]]},"references-count":58,"journal-issue":{"issue":"4","published-online":{"date-parts":[[2021,12]]}},"alternative-id":["audiolres11040059"],"URL":"https:\/\/doi.org\/10.3390\/audiolres11040059","relation":{},"ISSN":["2039-4349"],"issn-type":[{"value":"2039-4349","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,11,26]]}}}