Auditory neuropathy spectrum disorder (ANSD) is a heterogeneous hearing disorder in which cochlear outer hair cell activity is often preserved while neural transmission from inner hair cells, ribbon synapses, spiral ganglion neurons, or the auditory nerve is impaired. This produces abnormal or absent auditory brainstem responses, variable hearing thresholds, and speech perception that is often worse than expected from the pure-tone audiogram.
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name: Auditory Neuropathy
creation_date: "2026-05-08T16:19:19Z"
updated_date: "2026-05-08T17:39:11Z"
category: Genetic
description: >-
Auditory neuropathy spectrum disorder (ANSD) is a heterogeneous hearing
disorder in which cochlear outer hair cell activity is often preserved while
neural transmission from inner hair cells, ribbon synapses, spiral ganglion
neurons, or the auditory nerve is impaired. This produces abnormal or absent
auditory brainstem responses, variable hearing thresholds, and speech
perception that is often worse than expected from the pure-tone audiogram.
synonyms:
- auditory neuropathy spectrum disorder
- ANSD
- auditory dys-synchrony
- auditory neuropathy
disease_term:
preferred_term: auditory neuropathy
term:
id: MONDO:0021944
label: auditory neuropathy
parents:
- hearing loss disorder
- inherited auditory system disease
has_subtypes:
- name: AUNA1
display_name: Autosomal Dominant Auditory Neuropathy 1
subtype_term:
preferred_term: autosomal dominant auditory neuropathy 1
term:
id: MONDO:0012196
label: autosomal dominant auditory neuropathy 1
description: >-
DIAPH3-associated autosomal dominant auditory neuropathy caused by increased
DIAPH3 activity and associated with progressive neural hearing dysfunction.
evidence:
- reference: PMID:20624953
reference_title: "Increased activity of Diaphanous homolog 3 (DIAPH3)/diaphanous causes hearing defects in humans with auditory neuropathy and in Drosophila."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "We have identified Diaphanous homolog 3 (DIAPH3) as the gene responsible for autosomal dominant nonsyndromic auditory neuropathy (AUNA1), which we previously mapped to chromosome 13q21-q24."
explanation: Establishes DIAPH3 as the causative gene for the AUNA1 subtype.
- name: AUNA2
display_name: Auditory Neuropathy, Autosomal Dominant 2
subtype_term:
preferred_term: auditory neuropathy, autosomal dominant 2
term:
id: MONDO:0957279
label: auditory neuropathy, autosomal dominant 2
description: >-
ATP11A-associated autosomal dominant auditory neuropathy characterized by
slowly progressive postlingual auditory synaptopathy/neuropathy.
evidence:
- reference: PMID:36300302
reference_title: A mutation in ATP11A causes autosomal-dominant auditory neuropathy type 2.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "By combining whole-genome sequencing, immunohistochemistry, in vitro functional assays and generation of a mouse model, we could thus identify a partial deletion of ATP11A as the genetic cause of AUNA2."
explanation: Supports ATP11A as the genetic cause of the AUNA2 subtype.
- name: AUNA3
display_name: Auditory Neuropathy, Autosomal Dominant 3
subtype_term:
preferred_term: auditory neuropathy, autosomal dominant 3
term:
id: MONDO:0859235
label: auditory neuropathy, autosomal dominant 3
description: >-
TMEM43-associated autosomal dominant auditory neuropathy subtype listed
under the MONDO auditory neuropathy branch.
evidence:
- reference: PMID:39834515
reference_title: Modeling of auditory neuropathy spectrum disorders associated with the TEME43 variant reveals impaired gap junction function of iPSC-derived glia-like support cells.
supports: SUPPORT
evidence_source: IN_VITRO
snippet: "TMEM43 mutation is identified as a causative factor in ANSD."
explanation: Supports TMEM43 as a causative gene for an auditory neuropathy spectrum disorder subtype.
pathophysiology:
- name: Lesion-Site Spectrum
description: >-
ANSD is not a single lesion but a spectrum spanning inner hair cells, ribbon
synapses, postsynaptic spiral ganglion terminals, and auditory nerve
demyelination or axonal loss.
cell_types:
- preferred_term: cochlear inner hair cell
term:
id: CL:0000589
label: cochlear inner hair cell
- preferred_term: spiral ganglion neuron
term:
id: CL:0011113
label: spiral ganglion neuron
- preferred_term: Schwann cell
term:
id: CL:0002573
label: Schwann cell
evidence:
- reference: PMID:36769387
reference_title: Current Advances in Gene Therapies of Genetic Auditory Neuropathy Spectrum Disorder.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "This defect can be due to a lesion or defect in the inner hair cell (IHC), IHC ribbon synapse (e.g., pre-synaptic release of glutamate), postsynaptic terminals of the spiral ganglion neurons, or demyelination and axonal loss within the auditory nerve."
explanation: Defines the cellular lesion-site spectrum underlying ANSD.
downstream:
- target: Abnormal Auditory Brainstem Response
description: >-
Impaired neural transmission disrupts synchronized brainstem responses
despite preserved peripheral cochlear receptor activity.
- name: Presynaptic Inner Hair Cell Synaptopathy
description: >-
Biallelic OTOF variants impair otoferlin-dependent vesicle release and
synapse maturation at inner hair cell ribbon synapses, producing a
presynaptic auditory synaptopathy.
cell_types:
- preferred_term: cochlear inner hair cell
term:
id: CL:0000589
label: cochlear inner hair cell
- preferred_term: spiral ganglion neuron
term:
id: CL:0011113
label: spiral ganglion neuron
biological_processes:
- preferred_term: chemical synaptic transmission
term:
id: GO:0007268
label: chemical synaptic transmission
modifier: DECREASED
evidence:
- reference: PMID:34335185
reference_title: Otoferlin Is Required for Proper Synapse Maturation and for Maintenance of Inner and Outer Hair Cells in Mouse Models for DFNB9.
supports: SUPPORT
evidence_source: MODEL_ORGANISM
snippet: "We found otoferlin to be required for proper synapse development in the immature rodent cochlea: In absence of otoferlin, synaptic pruning was delayed, and postsynaptic boutons appeared enlarged at 2 weeks of age."
explanation: Mouse data support otoferlin loss as a synaptic maturation defect at cochlear inner hair cell synapses.
- reference: PMID:23562982
reference_title: Genetic analysis of auditory neuropathy spectrum disorder in the Korean population.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "A novel nonsense mutation (p.Y1064X) and a known pathogenic mutation (p.R1939Q) of the OTOF gene were identified in a patient as compound heterozygote."
explanation: Human genetic evidence supports OTOF as a causative gene for recessive ANSD.
downstream:
- target: Poor Speech Perception
description: >-
Impaired synaptic release reduces temporal precision of auditory coding,
which degrades speech discrimination.
- name: Auditory Nerve Dyssynchrony
description: >-
Postsynaptic ANSD involves spiral ganglion terminals or auditory nerve
fibers; impaired spike initiation, demyelination, axonal loss, or distal
dendritic dysfunction reduce temporal precision of auditory nerve discharge.
cell_types:
- preferred_term: spiral ganglion neuron
term:
id: CL:0011113
label: spiral ganglion neuron
- preferred_term: Schwann cell
term:
id: CL:0002573
label: Schwann cell
biological_processes:
- preferred_term: axon ensheathment
term:
id: GO:0008366
label: axon ensheathment
modifier: DECREASED
evidence:
- reference: PMID:21176122
reference_title: Information from cochlear potentials and genetic mutations helps localize the lesion site in auditory neuropathy.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Abnormal discharge of auditory fibers results from lesions involving the nerve fibers themselves (postsynaptic AN), the inner hair cells (IHCs) or their synapses with auditory nerve terminals (presynaptic AN) [1]."
explanation: Supports separation of presynaptic and postsynaptic lesion classes in auditory neuropathy.
- reference: PMID:21176122
reference_title: Information from cochlear potentials and genetic mutations helps localize the lesion site in auditory neuropathy.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "The demyelination of auditory nerve fibers observed in demyelinating neuropathies is expected to result in slowed conduction velocity with consequent disruption of temporal coding of acoustic signals (desynchrony)"
explanation: Links auditory nerve demyelination to temporal dyssynchrony.
downstream:
- target: Poor Speech Perception
description: >-
Temporal coding impairment causes speech perception to be reduced out of
proportion to hearing threshold elevation.
- name: AIFM1-Associated Mitochondrial Neuronal Injury
description: >-
AIFM1 variants can impair AIF dimerization and CHCHD4 interaction, producing
mitochondrial dysfunction, mitochondrial calcium overload, ROS elevation,
and caspase-independent apoptosis in patient-derived neurons.
cell_types:
- preferred_term: spiral ganglion neuron
term:
id: CL:0011113
label: spiral ganglion neuron
evidence:
- reference: PMID:37365177
reference_title: Impaired AIF-CHCHD4 interaction and mitochondrial calcium overload contribute to auditory neuropathy spectrum disorder in patient-iPSC-derived neurons with AIFM1 variant.
supports: SUPPORT
evidence_source: IN_VITRO
snippet: "On the one hand, the mitochondrial import of ETC complex subunits was inhibited, subsequently leading to an increased ADP/ATP ratio and elevated ROS levels."
explanation: Patient iPSC-derived neuronal evidence supports mitochondrial energy and oxidative-stress mechanisms.
- reference: PMID:37365177
reference_title: Impaired AIF-CHCHD4 interaction and mitochondrial calcium overload contribute to auditory neuropathy spectrum disorder in patient-iPSC-derived neurons with AIFM1 variant.
supports: SUPPORT
evidence_source: IN_VITRO
snippet: "Mitochondrial dysfunction, especially mCa2+ overload, plays a prominent role in ANSD associated with AIFM1."
explanation: Directly supports mitochondrial calcium overload as an AIFM1-associated ANSD mechanism.
downstream:
- target: Poor Speech Perception
description: >-
AIFM1-driven spiral ganglion neuronal injury can reduce temporal
precision of auditory nerve discharge, impairing speech perception
disproportionately to threshold elevation.
- name: TMEM43-Associated Gap Junction Dysfunction
description: >-
TMEM43 variants impair gap-junction intercellular communication in
patient-derived iPSC glia-like support cells, reducing the cochlear
support-cell coupling needed for temporally precise auditory signaling.
cell_types:
- preferred_term: cochlear glia-like support cell
term:
id: CL:0000630
label: supporting cell
cellular_components:
- preferred_term: gap junction
term:
id: GO:0005921
label: gap junction
molecular_functions:
- preferred_term: gap junction channel activity
term:
id: GO:0005243
label: gap junction channel activity
modifier: DECREASED
evidence:
- reference: PMID:39834515
reference_title: Modeling of auditory neuropathy spectrum disorders associated with the TEME43 variant reveals impaired gap junction function of iPSC-derived glia-like support cells.
supports: SUPPORT
evidence_source: IN_VITRO
snippet: "Reduced expression of genes associated with GLSs characteristics and reduced gap junction intercellular communication in TMEM43 mutant cell lines were observed compared to controls."
explanation: >-
Patient-derived iPSC glia-like support-cell evidence supports TMEM43
mutation as a gap-junction communication defect.
downstream:
- target: Poor Speech Perception
description: >-
Reduced gap-junction communication in cochlear support cells can disrupt
neural synchrony and degrade speech discrimination in TMEM43-associated
auditory neuropathy.
phenotypes:
- category: Clinical
name: Hearing Impairment
description: >-
Hearing thresholds are variable, ranging from mild to profound impairment,
and may improve, remain stable, fluctuate, or deteriorate depending on
etiology and lesion site.
phenotype_term:
preferred_term: Hearing impairment
term:
id: HP:0000365
label: Hearing impairment
evidence:
- reference: PMID:38456936
reference_title: Clinical and genetic architecture of a large cohort with auditory neuropathy.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Auditory neuropathy (AN) is a unique type of language developmental disorder, with no precise rate of genetic contribution that has been deciphered in a large cohort."
explanation: Supports auditory neuropathy as a hearing-related developmental disorder evaluated in a large human cohort.
- reference: PMID:36769387
reference_title: Current Advances in Gene Therapies of Genetic Auditory Neuropathy Spectrum Disorder.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Auditory neuropathy spectrum disorder (ANSD) refers to a range of hearing impairments characterized by an impaired transmission of sound from the cochlea to the brain."
explanation: Defines ANSD as a hearing-impairment spectrum.
- category: Clinical
name: Poor Speech Perception
description: >-
Speech perception is often disproportionately poor relative to pure-tone
thresholds because temporal neural coding is impaired.
phenotype_term:
preferred_term: poor speech perception
term:
id: HP:0001963
label: Abnormal speech discrimination
evidence:
- reference: PMID:21176122
reference_title: Information from cochlear potentials and genetic mutations helps localize the lesion site in auditory neuropathy.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "The disruption of auditory nerve discharge underlies both the absence of or profound alterations in auditory brainstem responses and the severe impairment of speech perception."
explanation: Links auditory nerve discharge disruption to severe speech-perception impairment.
- reference: PMID:21176122
reference_title: Information from cochlear potentials and genetic mutations helps localize the lesion site in auditory neuropathy.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "some patients with AN may have normal hearing thresholds and an impairment of speech perception that is only apparent in the presence of noise"
explanation: Supports speech-in-noise impairment as an important clinical feature that may be missed by threshold testing.
- category: Diagnostic
name: Abnormal Auditory Brainstem Response
description: >-
Absent or markedly abnormal auditory brainstem responses are a core
diagnostic hallmark of ANSD.
phenotype_term:
preferred_term: abnormal auditory brainstem response
term:
id: HP:0006958
label: Abnormal auditory evoked potentials
evidence:
- reference: PMID:20624953
reference_title: "Increased activity of Diaphanous homolog 3 (DIAPH3)/diaphanous causes hearing defects in humans with auditory neuropathy and in Drosophila."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Auditory neuropathy is a rare form of deafness characterized by an absent or abnormal auditory brainstem response with preservation of outer hair cell function."
explanation: Provides the classic ABR/OHC diagnostic contrast.
- reference: PMID:38016438
reference_title: "Cochlear Implantation in Children with Auditory Neuropathy: Meta-Analysis."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Its diagnosis is based on presence of otoacoustic emissions and lack of, or abnormal, brainstem auditory evoked potential."
explanation: Meta-analysis abstract restates the diagnostic requirement.
- category: Diagnostic
name: Preserved Otoacoustic Emissions or Cochlear Microphonics
description: >-
Outer hair cell activity is often preserved, particularly early, as shown by
otoacoustic emissions or cochlear microphonics despite abnormal ABR.
evidence:
- reference: PMID:21176122
reference_title: Information from cochlear potentials and genetic mutations helps localize the lesion site in auditory neuropathy.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Affected subjects show impairment of speech perception beyond that expected for the hearing loss, abnormality of auditory brainstem potentials and preserved outer hair-cell activities."
explanation: Supports preserved outer hair cell activity as part of the diagnostic pattern.
genetic:
- name: DIAPH3
gene_term:
preferred_term: DIAPH3
term:
id: hgnc:15480
label: DIAPH3
association: Causative
inheritance:
- name: Autosomal dominant
notes: >-
DIAPH3 overexpression causes AUNA1, an autosomal dominant nonsyndromic
auditory neuropathy subtype.
evidence:
- reference: PMID:20624953
reference_title: "Increased activity of Diaphanous homolog 3 (DIAPH3)/diaphanous causes hearing defects in humans with auditory neuropathy and in Drosophila."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "We have identified Diaphanous homolog 3 (DIAPH3) as the gene responsible for autosomal dominant nonsyndromic auditory neuropathy (AUNA1), which we previously mapped to chromosome 13q21-q24."
explanation: Establishes DIAPH3 as the causative gene for autosomal dominant nonsyndromic auditory neuropathy.
- reference: PMID:20624953
reference_title: "Increased activity of Diaphanous homolog 3 (DIAPH3)/diaphanous causes hearing defects in humans with auditory neuropathy and in Drosophila."
supports: SUPPORT
evidence_source: IN_VITRO
snippet: "Using genome-wide expression arrays and quantitative RT-PCR, we demonstrate a 2- to 3-fold overexpression of DIAPH3 mRNA in lymphoblastoid cell lines from affected individuals."
explanation: Supports gain-of-expression DIAPH3 mechanism in affected humans.
- reference: CGGV:assertion_fc54aaf6-8e1b-4c98-bcbe-e1f337f6eadc-2020-02-06T170000.000Z
reference_title: "DIAPH3 / auditory neuropathy (Limited)"
supports: SUPPORT
evidence_source: OTHER
snippet: "DIAPH3 | HGNC:15480 | auditory neuropathy | MONDO:0021944 | AD | Limited"
explanation: ClinGen classifies the DIAPH3-auditory neuropathy gene-disease relationship as limited with autosomal dominant inheritance.
- name: ATP11A
gene_term:
preferred_term: ATP11A
term:
id: hgnc:13552
label: ATP11A
association: Causative
inheritance:
- name: Autosomal dominant
notes: >-
ATP11A partial deletion causes AUNA2 through loss of phosphatidylserine
flippase activity and progressive auditory nerve dysfunction.
evidence:
- reference: PMID:36300302
reference_title: A mutation in ATP11A causes autosomal-dominant auditory neuropathy type 2.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "By whole-genome sequencing, we now detected a 5500 bp deletion in ATP11A on chromosome 13q34 segregating with the phenotype in this family."
explanation: Supports ATP11A as a causative autosomal dominant auditory neuropathy gene.
- name: OTOF
gene_term:
preferred_term: OTOF
term:
id: hgnc:8515
label: OTOF
association: Causative
inheritance:
- name: Autosomal recessive
notes: >-
OTOF is a major infant-onset ANSD gene, with biallelic variants causing
presynaptic otoferlin-related synaptopathy.
evidence:
- reference: PMID:38456936
reference_title: Clinical and genetic architecture of a large cohort with auditory neuropathy.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Most of the OTOF gene (96.6%, 28/29) could only be identified in the infant group, while the AIFM1 gene could only be identified in the non-infant group"
explanation: Large cohort evidence supports OTOF as the major infant-onset AN gene.
- name: AIFM1
gene_term:
preferred_term: AIFM1
term:
id: hgnc:8768
label: AIFM1
association: Causative
inheritance:
- name: X-linked
notes: >-
AIFM1 variants contribute especially to later-onset auditory neuropathy and
can act through mitochondrial neuronal injury.
evidence:
- reference: PMID:38456936
reference_title: Clinical and genetic architecture of a large cohort with auditory neuropathy.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "In conclusion, genes distribution of AN, with the most common genes being OTOF and AIFM1, is totally different from other sensorineural hearing loss."
explanation: Large cohort evidence identifies AIFM1 as one of the two most common AN genes.
- reference: PMID:37365177
reference_title: Impaired AIF-CHCHD4 interaction and mitochondrial calcium overload contribute to auditory neuropathy spectrum disorder in patient-iPSC-derived neurons with AIFM1 variant.
supports: SUPPORT
evidence_source: IN_VITRO
snippet: "This study demonstrates that the AIFM1 variant is one of the molecular bases of ANSD."
explanation: Patient-derived iPSC neuronal evidence supports AIFM1 as a molecular basis of ANSD.
- name: OPA1
gene_term:
preferred_term: OPA1
term:
id: hgnc:8140
label: OPA1
association: Causative
inheritance:
- name: Autosomal dominant
notes: >-
OPA1 was identified in both infant and non-infant auditory neuropathy
subgroups in a large sequencing cohort.
evidence:
- reference: PMID:38456936
reference_title: Clinical and genetic architecture of a large cohort with auditory neuropathy.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "other genes such as ATP1A3 and OPA1 were identified in both infant and non-infant groups."
explanation: Supports OPA1 as a recurring auditory neuropathy gene across onset-age groups.
- name: ATP1A3
gene_term:
preferred_term: ATP1A3
term:
id: hgnc:801
label: ATP1A3
association: Causative
inheritance:
- name: Autosomal dominant
notes: >-
ATP1A3 was identified in both infant and non-infant auditory neuropathy
subgroups in a large sequencing cohort.
evidence:
- reference: PMID:38456936
reference_title: Clinical and genetic architecture of a large cohort with auditory neuropathy.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "other genes such as ATP1A3 and OPA1 were identified in both infant and non-infant groups."
explanation: Supports ATP1A3 as a recurring auditory neuropathy gene across onset-age groups.
- name: TMEM43
gene_term:
preferred_term: TMEM43
term:
id: hgnc:28472
label: TMEM43
association: Causative
inheritance:
- name: Autosomal dominant
notes: >-
TMEM43 mutations can impair gap-junction function in cochlear glia-like
support cells in patient-derived iPSC models.
evidence:
- reference: PMID:39834515
reference_title: Modeling of auditory neuropathy spectrum disorders associated with the TEME43 variant reveals impaired gap junction function of iPSC-derived glia-like support cells.
supports: SUPPORT
evidence_source: IN_VITRO
snippet: "Reduced expression of genes associated with GLSs characteristics and reduced gap junction intercellular communication in TMEM43 mutant cell lines were observed compared to controls."
explanation: Supports a TMEM43-associated cellular mechanism in patient-derived glia-like support cells.
diagnosis:
- name: Audiologic Electrophysiology
description: >-
Diagnosis depends on demonstrating preserved OAE or cochlear microphonics
with absent or abnormal ABR, alongside behavioral speech perception testing
when developmentally possible.
results: Present OAE or cochlear microphonics with absent/abnormal ABR supports ANSD.
evidence:
- reference: PMID:38016438
reference_title: "Cochlear Implantation in Children with Auditory Neuropathy: Meta-Analysis."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Its diagnosis is based on presence of otoacoustic emissions and lack of, or abnormal, brainstem auditory evoked potential."
explanation: Supports the diagnostic electrophysiology pattern.
- name: Molecular Genetic Testing
diagnosis_term:
preferred_term: genetic testing
term:
id: MAXO:0000127
label: genetic testing
description: >-
Sequencing panels, exome sequencing, or genome sequencing help identify
causal genes and localize lesion site, especially in infant, bilateral, or
familial cases.
results: Pathogenic or likely pathogenic variants in ANSD genes support molecular diagnosis.
evidence:
- reference: PMID:38456936
reference_title: Clinical and genetic architecture of a large cohort with auditory neuropathy.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "In a retrospective cohort of 311 patients with AN, pathogenic and likely pathogenic variants of 23 genes were identified in 98 patients (31.5% in 311 patients)"
explanation: Supports molecular testing yield in a large AN cohort.
treatments:
- name: Hearing Aid Use
description: >-
Hearing aids may be trialed as part of hearing rehabilitation, but benefit
is variable because ANSD primarily disrupts neural timing and speech
perception.
treatment_term:
preferred_term: hearing aid usage
term:
id: MAXO:0009030
label: hearing aid usage
target_phenotypes:
- preferred_term: Hearing impairment
term:
id: HP:0000365
label: Hearing impairment
evidence:
- reference: PMID:36769387
reference_title: Current Advances in Gene Therapies of Genetic Auditory Neuropathy Spectrum Disorder.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "To date, the only clinical treatment options for ANSD are hearing aids and cochlear implantation."
explanation: Review identifies hearing aids as one of the current clinical treatment options.
- name: Cochlear Implantation
description: >-
Cochlear implantation is a major rehabilitative option for selected ANSD
patients, with outcomes influenced by lesion site and cochlear nerve
integrity.
treatment_term:
preferred_term: surgical procedure
term:
id: MAXO:0000004
label: surgical procedure
target_phenotypes:
- preferred_term: Hearing impairment
term:
id: HP:0000365
label: Hearing impairment
evidence:
- reference: PMID:38027523
reference_title: Outcomes of cochlear implantation in 75 patients with auditory neuropathy.
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "CI is a viable therapy option for patients with AN; CN deficiency might impact outcomes of CI."
explanation: Directly supports cochlear implantation while noting cochlear nerve deficiency as an outcome modifier.
- reference: PMID:38809896
reference_title: "Predictors of cochlear implant outcomes in pediatric auditory neuropathy: A matched case-control study."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Children with ANSD can achieve similar open-set speech perception outcomes as children with SNHL."
explanation: Supports pediatric cochlear implantation outcomes comparable to matched SNHL controls.
- reference: PMID:38016438
reference_title: "Cochlear Implantation in Children with Auditory Neuropathy: Meta-Analysis."
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "CI provides the comparable benefit to children with ANSD in comparison to children with neurosensory hearing loss associated with other causes in their speech development."
explanation: Meta-analysis supports cochlear implantation benefit for speech development in children with ANSD.
- name: OTOF-Targeted Gene Therapy
description: >-
Gene-replacement or gene-editing approaches for genetic ANSD, particularly
OTOF-related presynaptic synaptopathy, remain emerging rather than standard
clinical care.
treatment_term:
preferred_term: gene therapy
term:
id: MAXO:0001001
label: gene therapy
target_phenotypes:
- preferred_term: Hearing impairment
term:
id: HP:0000365
label: Hearing impairment
evidence:
- reference: PMID:36769387
reference_title: Current Advances in Gene Therapies of Genetic Auditory Neuropathy Spectrum Disorder.
supports: PARTIAL
evidence_source: OTHER
snippet: "genetic routes involving the replacement or corrective editing of mutant sequences or defected genes to repair damaged cells for the future restoration of hearing in deaf people are showing promise."
explanation: Review supports gene therapy as a promising emerging approach, but not established standard therapy.
notes: >-
Falcon deep research completed on 2026-05-08 and emphasized recent 2023-2024
ANSD literature: large-cohort genetic architecture, cochlear-implant outcome
predictors, lesion-site classification, and emerging OTOF-targeted gene
therapy. Clinical trial registry entries from the report were not cited in
this page to keep the initial curation focused on PMID-backed literature.
Auditory neuropathy spectrum disorder (ANSD) is a heterogeneous hearing disorder defined physiologically by evidence of preserved cochlear outer hair cell function (otoacoustic emissions and/or cochlear microphonics) with impaired neural transmission as reflected by abnormal or absent auditory brainstem responses (ABR). (wang2024clinicalandgenetic pages 3-4, wu2023outcomesofcochlear pages 1-2). Contemporary work frames ANSD as a spectrum of lesion sites (inner hair cell, ribbon synapse, spiral ganglion neuron terminals, demyelinating/axonal auditory nerve processes), which has direct implications for prognosis, cochlear implant outcomes, and emerging gene therapy—especially for presynaptic “auditory synaptopathy” due to biallelic OTOF variants. (saidia2023currentadvancesin pages 1-3, lin2020anintegrativeapproach pages 2-3, wang2024clinicalandgenetic pages 1-3).
| Concept | Details | Source (with DOI/URL and year) |
|---|---|---|
| Disease name | Auditory neuropathy; auditory neuropathy spectrum disorder (ANSD) | Wang et al., Human Genetics (2024), DOI: https://doi.org/10.1007/s00439-024-02652-7 (wang2024clinicalandgenetic pages 1-3) |
| Common synonym(s) | “Auditory neuropathy (AN) or auditory neuropathy spectrum disorder (ANSD)” | Wu et al., Frontiers in Neuroscience (2023), DOI: https://doi.org/10.3389/fnins.2023.1281884 (wu2023outcomesofcochlear pages 1-2) |
| Concise disease definition | Hearing impairment caused by impaired transmission of sound from the cochlea to the brain; lesion may involve inner hair cells, IHC ribbon synapse, postsynaptic spiral ganglion terminals, or auditory nerve demyelination/axonal loss | Saidia et al., Journal of Clinical Medicine (2023), DOI: https://doi.org/10.3390/jcm12030738 (saidia2023currentadvancesin pages 1-3) |
| Key diagnostic definition | Presence of otoacoustic emissions (OAE) and/or cochlear microphonics (CM) with absent or abnormal auditory brainstem responses (ABR) | Wang et al., Human Genetics (2024), DOI: https://doi.org/10.1007/s00439-024-02652-7; Wu et al., Frontiers in Neuroscience (2023), DOI: https://doi.org/10.3389/fnins.2023.1281884 (wang2024clinicalandgenetic pages 3-4, wu2023outcomesofcochlear pages 1-2) |
| Additional audiologic hallmarks | Poor speech perception despite relatively preserved pure-tone thresholds; absent stapedial reflex and absent contralateral OAE suppression are often observed | Saidia et al., Journal of Clinical Medicine (2023), DOI: https://doi.org/10.3390/jcm12030738 (saidia2023currentadvancesin pages 1-3) |
| MeSH identifier | not found in retrieved sources | not found in retrieved sources |
| ICD-10 identifier | not found in retrieved sources | not found in retrieved sources |
| ICD-11 identifier | not found in retrieved sources | not found in retrieved sources |
| MONDO identifier | not found in retrieved sources | not found in retrieved sources |
| Epidemiology: share among people with hearing loss | ANSD affects between 1.2% and 10% of people with hearing loss | Saidia et al., Journal of Clinical Medicine (2023), DOI: https://doi.org/10.3390/jcm12030738 (saidia2023currentadvancesin pages 1-3) |
| Epidemiology: share among hearing-loss cases in one cohort/reviewed populations | Auditory neuropathy affects 1.2%–8.4% of cases with hearing loss from different populations | Wang et al., Human Genetics (2024), DOI: https://doi.org/10.1007/s00439-024-02652-7 (wang2024clinicalandgenetic pages 1-3) |
| Epidemiology: school-age/severe-profound pediatric hearing loss | ANSD is observed in 4%–5% of all degrees of hearing loss and 10%–15% of school-age children with severe to profound SNHL | Jafari et al., PLOS ONE (2024), DOI: https://doi.org/10.1371/journal.pone.0304316 (jafari2024predictorsofcochlear pages 1-2) |
| Epidemiology: children with SNHL | Nearly 9.85% of 1,025 children with sensorineural hearing loss were identified to have ANSD | Wu et al., Frontiers in Neuroscience (2023), DOI: https://doi.org/10.3389/fnins.2023.1281884 (wu2023outcomesofcochlear pages 1-2) |
| Epidemiology: newborn prevalence | 0.006%–0.039% in low-risk newborn population | Wang et al., Human Genetics (2024), DOI: https://doi.org/10.1007/s00439-024-02652-7 (wang2024clinicalandgenetic pages 1-3) |
| Epidemiology: birth incidence and hearing-loss proportion | Incidence ~1–3 per 10,000 births; 8.4%–11% of children with permanent hearing loss | Smith thesis/excerpt (2018), DOI: https://doi.org/10.14288/1.0372052 (smith2018cochlearmicrophonicsfrom pages 17-21) |
| Screening limitation statistic | Newborn hearing screening may miss 30%–50% of ANSD cases | Smith thesis/excerpt (2018), DOI: https://doi.org/10.14288/1.0372052 (smith2018cochlearmicrophonicsfrom pages 17-21) |
Table: This table summarizes core disease naming, diagnostic hallmarks, identifier availability in the retrieved sources, and key epidemiology statistics for auditory neuropathy spectrum disorder. It is useful as a quick-reference artifact for disease knowledge-base population.
| Item | Population/Model | Key quantitative results | Publication date/Trial post date | URL/DOI/NCT | Notes |
|---|---|---|---|---|---|
| Wang 2024: large AN genetic cohort | Retrospective human cohort; 311 patients with auditory neuropathy (AN) | Pathogenic/likely pathogenic variants identified in 98/311 (31.5%); subgroup yields: trios 54.4%, families 56.2%, proband-only 22.9%; infants 45.7% vs non-infants 25.6%; bilateral AN 33.7% vs unilateral 0%; OTOF accounted for 96.6% (28/29) of OTOF-positive cases in infants; cohort was 93.6% bilateral AN; MRI auditory nerve abnormalities in 26.3%; CM recorded in 241 ears (77.5%); only 7.6% of ears elicited at least one ABR wave (wang2024clinicalandgenetic pages 1-3, wang2024clinicalandgenetic pages 12-14) | Published online 2024-03-08 | https://doi.org/10.1007/s00439-024-02652-7 | Identified OTOF and AIFM1 as the top two genes; study emphasizes different genetic spectra by age at onset and laterality (wang2024clinicalandgenetic pages 1-3, wang2024clinicalandgenetic pages 12-14) |
| Wu 2023: CI outcomes in AN | Human cohort; 75 AN patients receiving cochlear implantation; genetic testing in 46 | After CI, average aided thresholds: prelingual 38.25 ± 6.63 dB, post-lingual 32.58 ± 9.26 dB; CAP improved to 5.52 ± 1.64 (prelingual) and 6.00 ± 0.96 (post-lingual), both p < 0.001; SIR improved to 3.57 ± 1.22 and 4.15 ± 0.95, both p < 0.001; maximum speech recognition ranged 58–93% (prelingual) and 43–98% (post-lingual); CN deficiency associated with poorer CI speech outcomes (p = 0.008) (wu2023outcomesofcochlear pages 1-2, wu2023outcomesofcochlear pages 3-5) | 2023-11-13 | https://doi.org/10.3389/fnins.2023.1281884 | Included molecular etiologies such as TWIST1, ACTG1, m.A7445G, and ACTB CNV; OTOF subgroup showed CAP improvement from 0.10 ± 0.32 to 6.20 ± 1.32 and SIR from 1.00 to 3.83 ± 1.10 (wu2023outcomesofcochlear pages 3-5) |
| Jafari 2024: predictors of pediatric CI outcome | Matched case-control study; 66 implanted children, including 22 ANSD and 44 SNHL controls | No significant between-group differences across five open-set speech tests; average outcome scores ranged 88.40% to 95.65%; predictors of better post-CI speech perception were longer CI follow-up, younger age at CI activation, younger age at hearing-aid fitting, and use of two CIs (jafari2024predictorsofcochlear pages 1-2, jafari2024predictorsofcochlear pages 2-4) | 2024-05-29 | https://doi.org/10.1371/journal.pone.0304316 | ANSD cases had bilateral disease and no cochlear nerve deficiency on MRI; supports that children with ANSD can achieve outcomes similar to matched SNHL peers (jafari2024predictorsofcochlear pages 1-2, jafari2024predictorsofcochlear pages 2-4) |
| Buianova 2024: genetically determined ANSD in children | Human pediatric cohort; 20 children with clinically confirmed ANSD within a larger hearing-loss study | Variants found in 12/20 ANSD cases (60%); OTOF was the most frequent ANSD gene in 5/20 (25%); genetically determined hearing loss identified in 55.74% of children treated at center; among SNHL controls, GJB2 accounted for 56/102 (54.90%); parent-reported rehabilitation outcomes were poorer in ANSD vs SNHL; device-use months 14.35 ± 13.1 (ANSD) vs 20.37 ± 16.4 (SNHL); median satisfaction/QoL score 6 vs 7, p = 0.0026 (buianova2024heterogeneousgroupof pages 7-9, buianova2024heterogeneousgroupof pages 2-3) | 2024-11 | https://doi.org/10.3390/ijms252312554 | Report also cites early human AAV1-hOTOF experience in 5 children: no serious adverse effects; ABR thresholds improved from >95 dB to 50–85 dB with recovery of speech perception and sound localization (as summarized in paper) (buianova2024heterogeneousgroupof pages 7-9) |
| Forli 2023: temperature-sensitive ANSD | Single-patient case report; 7-year-old boy with TS-ANSD | Baseline mild-to-moderate hearing loss at low/mid frequencies worsening to severe-to-profound with fever/exercise; OAEs present, click/tone-burst ABRs generally absent; identified OTOF c.2521G>A missense variant plus 7.4 kb deletion; phenotype returned toward baseline after temperature normalized (forli2023temperaturesensitiveauditoryneuropathy pages 1-2) | 2023-02-13 | https://doi.org/10.3390/medicina59020352 | Illustrates OTOF-related temperature-sensitive phenotype; no inner-ear malformation on CT/MRI (forli2023temperaturesensitiveauditoryneuropathy pages 1-2) |
| Dmitriev 2023: OTOF missense prediction | Computational variant-classification study using OTOF missense variants linked to ANSD | Dataset included 270 annotated single amino-acid substitutions; random-forest ConStruct model achieved balanced accuracy 0.866 and AUC 0.903 by 5-fold cross-validation; evaluated 1302 OTOF VUS and prioritized 16 as most probable pathogenic variants (dmitriev2023predictingtheimpact pages 1-2) | 2023-12-07 | https://doi.org/10.3390/ijms242417240 | Useful for variant interpretation in OTOF-associated ANSD, especially early diagnosis and panel/WES interpretation (dmitriev2023predictingtheimpact pages 1-2) |
| NCT05821959: AAVAnc80-hOTOF interventional trial | Phase 1/2, non-randomized interventional trial; estimated n = 22 | Start date 2023-09-15; primary completion estimated 2028-10; dose levels up to 4.1E11 and 8.1E11 vg/cochlea; primary endpoint: frequency of adverse events through ~1 year; secondary endpoints include ABR threshold change; key inclusion: at least two OTOF mutations, profound bilateral SNHL by ABR, preserved DPOAEs, no cochlear implant in study ear(s) (NCT05821959 chunk 1) | First posted 2023-04-20 | NCT05821959; https://clinicaltrials.gov/study/NCT05821959 | Intracochlear AAVAnc80-hOTOF via Akouos delivery device; includes unilateral cohorts and bilateral expansion (NCT05821959 chunk 1) |
| NCT05788536 (CHORD): DB-OTO interventional trial | Phase 1/2, open-label multicenter trial; estimated n = 30 children/infants | Start date 2023-06-27; primary completion estimated 2032-02-28; primary endpoints: TEAEs up to week 104 and achievement of PTA threshold ≤70 dB; secondary endpoints include ABR to click up to week 48, ESP ≥3, PTA ≤45 dB and ≤25 dB, SAT milestones, speech perception and language measures; key inclusion: age <18 years, biallelic likely pathogenic/pathogenic OTOF variants, profound SNHL >90 dB HL, OAE or CM evidence of outer hair cell function, exclusion of non-OTOF AN risk factors (NCT05788536 chunk 1, NCT05788536 chunk 2) | First posted 2023-03-29 | NCT05788536; https://clinicaltrials.gov/study/NCT05788536 | Unilateral dose-escalation followed by bilateral expansion; registry record cites later derived publication on DB-OTO gene therapy (NCT05788536 chunk 1, NCT05788536 chunk 2) |
| NCT06696456: long-term follow-up after AAVAnc80-hOTOF | Observational post-intervention long-term follow-up study; estimated n = 30 | Start date 2024-11-11; completion estimated 2033-04; follows prior AK-OTOF-101 participants for ~4 additional years (total ~5 years after dosing); primary outcome: late-occurring adverse events; secondary outcome: ABR threshold change (NCT06696456 chunk 1) | First posted 2024-11-20 | NCT06696456; https://clinicaltrials.gov/study/NCT06696456 | Includes only individuals previously dosed with AAVAnc80-hOTOF in AK-OTOF-101; designed to assess durability and delayed safety signals (NCT06696456 chunk 1) |
| NCT05572073: OTOF natural history study | Observational retrospective/prospective natural history study; estimated n = 150 | Start date 2022-07-14; completion estimated 2029-02; primary outcome ABR from first audiologic data through 5-year prospective follow-up; secondary outcome OAE; inclusion requires bilateral SNHL with OTOF mutation(s), including AN/ANSD phenotype or history; prospective phase requires OAE/CM present and absent/abnormal ABR in at least one non-implanted ear; excludes cochlear nerve deficiency/dysplasia (NCT05572073 chunk 1) | First posted 2022-10-07 | NCT05572073; https://clinicaltrials.gov/study/NCT05572073 | Important enabling study for defining progression, candidate selection, and trial-readout baselines in otoferlin-mediated ANSD (NCT05572073 chunk 1) |
Table: This table compiles the most decision-relevant recent quantitative findings from human ANSD cohorts, cochlear implantation studies, variant-interpretation work, and current OTOF gene therapy trials. It is useful as a compact evidence map for genetics, prognosis, rehabilitation outcomes, and translational trial design.
| Gene | Inheritance pattern (as stated) | Lesion site class (as stated) | Evidence type | Key notes/phenotype | Key citation (DOI/URL/year) |
|---|---|---|---|---|---|
| OTOF | Autosomal recessive; biallelic pathogenic/likely pathogenic variants; DFNB9 (saidia2023currentadvancesin pages 3-4, forli2023temperaturesensitiveauditoryneuropathy pages 1-2, stalmann2021otoferlinisrequired pages 1-2) | Presynaptic; inner hair cell/ribbon synapse; auditory synaptopathy (lin2020anintegrativeapproach pages 2-3, saidia2023currentadvancesin pages 3-4, stalmann2021otoferlinisrequired pages 1-2) | Human cohort, case report, mouse, review, computational | Most common infant AN gene in a 311-case cohort; 96.6% (28/29) of OTOF-positive cases were in infants. Causes congenital/prelingual ANSD and temperature-sensitive ANSD; ~220 pathogenic variants reported; Otof-/- mice show synapse loss and progressive SGN/IHC/OHC degeneration. Variant-modeling study used 270 missense SAVs and prioritized 16 likely pathogenic VUS (wang2024clinicalandgenetic pages 1-3, forli2023temperaturesensitiveauditoryneuropathy pages 1-2, dmitriev2023predictingtheimpact pages 1-2, stalmann2021otoferlinisrequired pages 1-2) | 10.1007/s00439-024-02652-7 / https://doi.org/10.1007/s00439-024-02652-7 / 2024; 10.3390/jcm12030738 / https://doi.org/10.3390/jcm12030738 / 2023; 10.3389/fncel.2021.677543 / https://doi.org/10.3389/fncel.2021.677543 / 2021 (wang2024clinicalandgenetic pages 1-3, saidia2023currentadvancesin pages 3-4, stalmann2021otoferlinisrequired pages 1-2) |
| AIFM1 | X-linked; AUNX1 (wang2024clinicalandgenetic pages 1-3, shi2024aiftranslocationinto pages 1-3) | Postsynaptic / auditory nerve-related; mitochondrial neuronal pathology affecting auditory pathway (wang2024clinicalandgenetic pages 1-3, qiu2023impairedaifchchd4interaction pages 1-2, shi2024aiftranslocationinto pages 1-3) | Human cohort, iPSC-derived neurons, mouse, review | Common non-infant AN gene in the large cohort; patient-iPSC neurons showed impaired AIF-CHCHD4 interaction, mitochondrial Ca2+ overload, ROS increase, and caspase-independent apoptosis. Knock-in mice developed progressive hearing loss from P30 with SGN loss and later demyelination (wang2024clinicalandgenetic pages 1-3, qiu2023impairedaifchchd4interaction pages 1-2, shi2024aiftranslocationinto pages 1-3) | 10.1007/s00439-024-02652-7 / https://doi.org/10.1007/s00439-024-02652-7 / 2024; 10.1038/s41419-023-05899-6 / https://doi.org/10.1038/s41419-023-05899-6 / 2023; 10.1093/hmg/ddae010 / https://doi.org/10.1093/hmg/ddae010 / 2024 (wang2024clinicalandgenetic pages 1-3, qiu2023impairedaifchchd4interaction pages 1-2, shi2024aiftranslocationinto pages 1-3) |
| PRPS1 | X-linked (jafari2024predictorsofcochlear pages 1-2) | Not clearly localized in retrieved primary sources; listed among genetic predispositions to ANSD (jafari2024predictorsofcochlear pages 1-2) | Review / clinical overview | Mentioned as an X-linked cause/predisposition in pediatric ANSD overview; also detected among genes in a pediatric ANSD cohort (buianova2024heterogeneousgroupof pages 2-3, jafari2024predictorsofcochlear pages 1-2) | https://doi.org/10.1371/journal.pone.0304316 / 2024 (jafari2024predictorsofcochlear pages 1-2); 10.3390/ijms252312554 / https://doi.org/10.3390/ijms252312554 / 2024 (buianova2024heterogeneousgroupof pages 2-3) |
| OPA1 | Autosomal dominant (listed among dominant predisposition genes) (jafari2024predictorsofcochlear pages 1-2) | Postsynaptic / spiral ganglion-related (wang2024clinicalandgenetic pages 1-3) | Human cohort, review | Identified in both infant and non-infant groups in the 311-case cohort; review literature places OPA1 among dominant ANSD genes and postsynaptic lesions (wang2024clinicalandgenetic pages 1-3, jafari2024predictorsofcochlear pages 1-2) | 10.1007/s00439-024-02652-7 / https://doi.org/10.1007/s00439-024-02652-7 / 2024; https://doi.org/10.1371/journal.pone.0304316 / 2024 (wang2024clinicalandgenetic pages 1-3, jafari2024predictorsofcochlear pages 1-2) |
| ATP1A3 | Autosomal dominant (listed among dominant predisposition genes) (jafari2024predictorsofcochlear pages 1-2) | Postsynaptic / spiral ganglion-related (wang2024clinicalandgenetic pages 1-3) | Human cohort, review | Found in both infant and non-infant subgroups in the large cohort; genotype-specific CI review summarized favorable CI outcomes for ATP1A3/CAPOS-associated ANSD (wang2024clinicalandgenetic pages 1-3, ismail2024systematicreviewof pages 2-4, jafari2024predictorsofcochlear pages 1-2) | 10.1007/s00439-024-02652-7 / https://doi.org/10.1007/s00439-024-02652-7 / 2024; 10.1186/s43163-024-00677-3 / https://doi.org/10.1186/s43163-024-00677-3 / 2024 (wang2024clinicalandgenetic pages 1-3, ismail2024systematicreviewof pages 2-4) |
| PJVK | Autosomal recessive / DFNB59 (jafari2024predictorsofcochlear pages 1-2, lu2022genetherapywith pages 1-2) | Variable; auditory hair cells and first-order neurons/SGNs implicated; sometimes described as auditory neuropathy, sometimes cochlear origin (lu2022genetherapywith pages 1-2) | Human cohort/review, mouse, gene therapy | Listed as recessive ANSD gene; patients may show limited CI benefit. Pjvk-mutant mice show increased hearing thresholds, SGN degeneration, and vestibular dysfunction; Anc80L65-PJVK gene transfer improved cochlear/vestibular phenotypes (jafari2024predictorsofcochlear pages 1-2, lu2022genetherapywith pages 1-2) | https://doi.org/10.1371/journal.pone.0304316 / 2024; 10.1172/jci.insight.152941 / https://doi.org/10.1172/jci.insight.152941 / 2022 (jafari2024predictorsofcochlear pages 1-2, lu2022genetherapywith pages 1-2) |
| DIAPH3 | Autosomal dominant (jafari2024predictorsofcochlear pages 1-2) | Postsynaptic / spiral ganglion-related (wang2024clinicalandgenetic pages 1-3) | Review | Listed among dominant ANSD genes and mapped in review/classification work to postsynaptic spiral ganglion lesion class (wang2024clinicalandgenetic pages 1-3, jafari2024predictorsofcochlear pages 1-2) | 10.1007/s00439-024-02652-7 / https://doi.org/10.1007/s00439-024-02652-7 / 2024; https://doi.org/10.1371/journal.pone.0304316 / 2024 (wang2024clinicalandgenetic pages 1-3, jafari2024predictorsofcochlear pages 1-2) |
| CACNA1D | Not stated in retrieved source set | Synaptic site (wang2024clinicalandgenetic pages 1-3) | Review | Named among genes affecting the synaptic site in AN classification reviews (wang2024clinicalandgenetic pages 1-3) | 10.1007/s00439-024-02652-7 / https://doi.org/10.1007/s00439-024-02652-7 / 2024 (wang2024clinicalandgenetic pages 1-3) |
| CABP2 | Not stated in retrieved source set | Synaptic site (wang2024clinicalandgenetic pages 1-3) | Review | Named among genes affecting the synaptic site in AN classification reviews; AAV approaches for Cabp2 are discussed in gene-therapy review (wang2024clinicalandgenetic pages 1-3, saidia2023currentadvancesin pages 11-12) | 10.1007/s00439-024-02652-7 / https://doi.org/10.1007/s00439-024-02652-7 / 2024; 10.3390/jcm12030738 / https://doi.org/10.3390/jcm12030738 / 2023 (wang2024clinicalandgenetic pages 1-3, saidia2023currentadvancesin pages 11-12) |
| SLC17A8 | Autosomal dominant (listed among dominant predisposition genes) (jafari2024predictorsofcochlear pages 1-2) | Synaptic site (wang2024clinicalandgenetic pages 1-3) | Review | Listed among dominant ANSD genes; review classifies it as synaptic-site gene (wang2024clinicalandgenetic pages 1-3, jafari2024predictorsofcochlear pages 1-2) | 10.1007/s00439-024-02652-7 / https://doi.org/10.1007/s00439-024-02652-7 / 2024; https://doi.org/10.1371/journal.pone.0304316 / 2024 (wang2024clinicalandgenetic pages 1-3, jafari2024predictorsofcochlear pages 1-2) |
| MPZ | Autosomal dominant (listed among dominant predisposition genes) (jafari2024predictorsofcochlear pages 1-2) | Auditory nerve / spiral ganglion cell bodies and proximal axons (wang2024clinicalandgenetic pages 1-3) | Review | Listed as dominant ANSD gene in pediatric overview and as nerve-level lesion gene in large-cohort mechanistic classification (wang2024clinicalandgenetic pages 1-3, jafari2024predictorsofcochlear pages 1-2) | 10.1007/s00439-024-02652-7 / https://doi.org/10.1007/s00439-024-02652-7 / 2024; https://doi.org/10.1371/journal.pone.0304316 / 2024 (wang2024clinicalandgenetic pages 1-3, jafari2024predictorsofcochlear pages 1-2) |
| PMP22 | Not stated in retrieved source set | Auditory nerve / spiral ganglion cell bodies and proximal axons (wang2024clinicalandgenetic pages 1-3) | Review | Included in lesion-site classification as an auditory-nerve gene for AN (wang2024clinicalandgenetic pages 1-3) | 10.1007/s00439-024-02652-7 / https://doi.org/10.1007/s00439-024-02652-7 / 2024 (wang2024clinicalandgenetic pages 1-3) |
| TIMM8A | Not stated in retrieved source set | Auditory nerve / spiral ganglion cell bodies and proximal axons (wang2024clinicalandgenetic pages 1-3) | Review | Included in lesion-site classification as an auditory-nerve gene for AN (wang2024clinicalandgenetic pages 1-3) | 10.1007/s00439-024-02652-7 / https://doi.org/10.1007/s00439-024-02652-7 / 2024 (wang2024clinicalandgenetic pages 1-3) |
| NARS2 | Not stated in retrieved source set | Auditory nerve / spiral ganglion cell bodies and proximal axons (wang2024clinicalandgenetic pages 1-3) | Review | Included in lesion-site classification as an auditory-nerve gene for AN (wang2024clinicalandgenetic pages 1-3) | 10.1007/s00439-024-02652-7 / https://doi.org/10.1007/s00439-024-02652-7 / 2024 (wang2024clinicalandgenetic pages 1-3) |
| WFS1 | Not stated in retrieved source set | Presynaptic in the pediatric etiologic/site-of-lesion cohort (lin2020anintegrativeapproach pages 2-3) | Human cohort | One syndromic/genetic pediatric AN case carried WFS1 p.A684V in the 101-child cohort; study grouped WFS1 among presynaptic/genetic causes (lin2020anintegrativeapproach pages 2-3) | 10.1038/s41598-020-66877-y / https://doi.org/10.1038/s41598-020-66877-y / 2020 (lin2020anintegrativeapproach pages 2-3) |
| PLP1 | Not stated in retrieved source set | Postsynaptic in the pediatric etiologic/site-of-lesion cohort (lin2020anintegrativeapproach pages 2-3) | Human cohort | One syndromic/genetic pediatric AN case carried PLP1 duplication; study grouped Pelizaeus-Merzbacher disease/PLP1 among postsynaptic causes (lin2020anintegrativeapproach pages 2-3) | 10.1038/s41598-020-66877-y / https://doi.org/10.1038/s41598-020-66877-y / 2020 (lin2020anintegrativeapproach pages 2-3) |
| m.1555A>G | Mitochondrial (maternal inheritance implied by mitochondrial variant class) (jafari2024predictorsofcochlear pages 1-2) | Presynaptic in pediatric etiologic/site-of-lesion cohort (lin2020anintegrativeapproach pages 2-3) | Human cohort | Identified as a genetic cause in pediatric auditory neuropathy; study classified mitochondrial mutation among presynaptic causes (lin2020anintegrativeapproach pages 2-3, jafari2024predictorsofcochlear pages 1-2) | 10.1038/s41598-020-66877-y / https://doi.org/10.1038/s41598-020-66877-y / 2020; https://doi.org/10.1371/journal.pone.0304316 / 2024 (lin2020anintegrativeapproach pages 2-3, jafari2024predictorsofcochlear pages 1-2) |
Table: This table maps Mendelian genes explicitly mentioned in the retrieved ANSD/auditory neuropathy sources to their reported inheritance patterns, mechanistic lesion-site classes, and evidence types. It is useful for connecting genotype to pathophysiology and for anticipating diagnosis, prognosis, and cochlear implant response.
ANSD is a hearing impairment in which sound detection thresholds may be variable (mild to profound), but speech perception is often disproportionately poor because neural timing/synchrony is disrupted despite evidence of intact outer hair cell function. (saidia2023currentadvancesin pages 1-3, wu2023outcomesofcochlear pages 1-2).
Current concept/definition (lesion-site spectrum): A 2023 gene therapy-focused review defines ANSD as “hearing impairments characterized by an impaired transmission of sound from the cochlea to the brain” and explicitly enumerates candidate lesion sites: inner hair cells (IHCs), IHC ribbon synapse (presynaptic glutamate release), postsynaptic spiral ganglion neuron terminals, and demyelination/axonal loss within the auditory nerve. (saidia2023currentadvancesin pages 1-3).
Within the retrieved source set, formal cross-ontology identifiers were not captured for MeSH/ICD-10/ICD-11/MONDO/Orphanet/OMIM as explicit IDs (artifact-00). (wang2024clinicalandgenetic pages 3-4).
OMIM usage in recent research: A 2024 large cohort study describes using OMIM “clinical synopsis advanced search” to find entries associated with “auditory neuropathy,” but the excerpted text does not list specific OMIM numbers for ANSD as a single entity. (wang2024clinicalandgenetic pages 3-4).
Commonly used names include auditory neuropathy (AN) and auditory neuropathy spectrum disorder (ANSD). (wu2023outcomesofcochlear pages 1-2, wang2024clinicalandgenetic pages 1-3).
Evidence in this report comes from: - Aggregated disease-level resources and reviews (e.g., Saidia et al. 2023) (saidia2023currentadvancesin pages 1-3) - Large and moderate human cohorts (Wang et al. 2024; Wu et al. 2023; Jafari et al. 2024) (wang2024clinicalandgenetic pages 1-3, wu2023outcomesofcochlear pages 1-2, jafari2024predictorsofcochlear pages 1-2) - Case report evidence for specific phenotypes (Forli et al. 2023 temperature-sensitive ANSD) (forli2023temperaturesensitiveauditoryneuropathy pages 1-2) - Mechanistic human cellular models (patient iPSC-derived neurons for AIFM1) (qiu2023impairedaifchchd4interaction pages 1-2) - Model organisms (OTOF and AIFM1 mouse models; PJVK mutant mouse and inner-ear gene transfer) (stalmann2021otoferlinisrequired pages 1-2, shi2024aiftranslocationinto pages 1-3, lu2022genetherapywith pages 1-2) - Clinical trial registry entries for OTOF gene therapy and natural history studies (clinicaltrials.gov) (NCT05821959 chunk 1, NCT05788536 chunk 1, NCT06696456 chunk 1, NCT05572073 chunk 1)
Genetic causes (Mendelian): Recent large-cohort sequencing shows a substantial Mendelian contribution, with pathogenic/likely pathogenic variants identified in 23 genes in 31.5% (98/311) of clinically diagnosed AN cases. (wang2024clinicalandgenetic pages 1-3). OTOF predominates in infant-onset AN, whereas AIFM1 is enriched in non-infant (later-onset) AN. (wang2024clinicalandgenetic pages 1-3).
Acquired/non-genetic factors: Contemporary clinical literature lists perinatal and environmental contributors such as hyperbilirubinemia, hypoxia/anoxia, infection, prematurity, ototoxic drug exposure, and cochlear nerve deficiency (CND) as risk factors/associations. (wu2023outcomesofcochlear pages 1-2).
A 2024 pediatric cochlear implant outcome paper summarizes genetic predisposition as >40% in some cohorts and lists representative inheritance modes (AR, AD, X-linked, mitochondrial), giving examples including OTOF, PJVK (AR), OPA1, MPZ, ATP1A3, SLC17A8, DIAPH3 (AD), AIFM1 (X-linked), and mitochondrial variants. (jafari2024predictorsofcochlear pages 1-2).
In a 2023 cochlear implantation cohort paper, risk factors “highly related to AN” included hyperbilirubinemia, infection, prematurity, ototoxic drug exposure, cochlear nerve deficiency, and congenital brain anomalies. (wu2023outcomesofcochlear pages 1-2).
No protective genetic or environmental factors were identified in the retrieved sources.
Direct gene–environment interaction analyses were not identified in the retrieved sources. However, the lesion-site spectrum framework implies that environmental insults (e.g., hyperbilirubinemia, hypoxia) may preferentially drive postsynaptic/nerve forms, whereas specific genes (e.g., OTOF) drive presynaptic synaptopathy—potentially interacting with developmental timing and intervention windows. (lin2020anintegrativeapproach pages 2-3, saidia2023currentadvancesin pages 1-3).
Key clinical/audiologic phenotype: A defining feature is the discrepancy between relatively preserved cochlear outer hair cell activity and impaired neural conduction, manifesting as present OAE/CM with absent/abnormal ABR and poor speech perception (often especially in noise). (saidia2023currentadvancesin pages 1-3, jafari2024predictorsofcochlear pages 1-2).
Suggested HPO terms (non-exhaustive): - Abnormal auditory brainstem response (suggest: Abnormal auditory brainstem response [HPO term exists]) - Sensorineural hearing impairment - Speech discrimination abnormality / impaired speech perception (esp. in noise) - Auditory neuropathy
A pediatric etiologic cohort study (n=101) reported that onset at birth was common (82/101; 81.2%), especially for acquired forms (46/48; 95.8%). (lin2020anintegrativeapproach pages 2-3).
A large 2024 AN cohort notes variability: hearing may improve, remain stable, or deteriorate; some cases showed progressive worsening with loss of OAEs and progressive decreases in speech recognition over follow-up. (wang2024clinicalandgenetic pages 12-14).
Population-level prevalence estimates vary by ascertainment: - 1.2–8.4% of hearing-loss cases (multiple populations) and 0.006–0.039% in low-risk newborns in one large review/citation summary embedded in a 2024 cohort introduction. (wang2024clinicalandgenetic pages 1-3) - 4–5% of all degrees of hearing loss and 10–15% of school-age children with severe-to-profound SNHL (clinical overview within a 2024 pediatric CI outcomes study). (jafari2024predictorsofcochlear pages 1-2)
A 2024 pediatric genetic cohort reported parent survey data suggesting rehabilitation satisfaction and QoL improvements were lower in ANSD than in SNHL comparators (median satisfaction/QoL score 6 vs 7; p=0.0026). (buianova2024heterogeneousgroupof pages 7-9).
Recent cohort evidence supports a multi-gene Mendelian architecture with strong dependence on onset age and laterality.
(See artifact-02 for gene-by-gene mapping to lesion site and evidence type.) (wang2024clinicalandgenetic pages 1-3, lin2020anintegrativeapproach pages 2-3, lu2022genetherapywith pages 1-2).
OTOF variant spectrum and interpretation challenges: A 2023 computational study constructed a dataset of 270 annotated OTOF single amino-acid substitutions related to ANSD and evaluated 1302 variants of uncertain significance (VUS), prioritizing 16 as “most probable pathogenic variants” based on predicted impact. The model achieved balanced accuracy 0.866 and AUC 0.903 (5-fold cross-validation). (dmitriev2023predictingtheimpact pages 1-2).
Temperature-sensitive ANSD: A 2023 case report identified OTOF c.2521G>A missense plus a 7.4 kb deletion, in a child whose hearing thresholds worsened with fever/exercise and improved after temperature normalized; OAEs were present and ABRs generally absent. (forli2023temperaturesensitiveauditoryneuropathy pages 1-2).
No modifier-gene evidence was identified in the retrieved sources.
No disease-specific epigenetic mechanisms were identified in the retrieved sources.
Non-genetic contributing factors are described mainly as perinatal and medical risk factors (e.g., hyperbilirubinemia, prematurity, infection, ototoxic drug exposure). (wu2023outcomesofcochlear pages 1-2). No toxin-specific or exposure-response analyses were identified in the retrieved sources.
ANSD is increasingly conceptualized as a spectrum spanning: - IHC dysfunction - IHC ribbon synapse (presynaptic) synaptopathy - Postsynaptic terminal / spiral ganglion neuron (SGN) dysfunction - Auditory nerve demyelination/axonal loss This framework is explicitly stated in recent reviews and is operationalized in cohort analyses that classify cases as presynaptic versus postsynaptic based on genetics and ancillary tests. (saidia2023currentadvancesin pages 1-3, lin2020anintegrativeapproach pages 2-3).
GO process suggestions: synaptic vesicle exocytosis; chemical synaptic transmission; glutamatergic synaptic transmission; auditory receptor cell synaptic transmission.
Cell type (CL) suggestions: cochlear inner hair cell; spiral ganglion neuron; Schwann cell (for neuropathic/demyelinating forms).
Human iPSC-neuron mechanism: A 2023 mechanistic study using patient PBMC→iPSC→neurons reports that an AIFM1 c.1265G>A variant caused a splicing deletion producing altered AIF proteins, impairing AIF dimerization and weakening AIF–CHCHD4 interaction. This led to inhibited mitochondrial import of ETC subunits, increased ADP/ATP ratio, elevated ROS, impaired MICU1–MICU2 heterodimerization causing mitochondrial Ca2+ overload, calpain activation, AIF cleavage and nuclear translocation, and caspase-independent apoptosis; CRISPR correction improved neuronal physiology. (qiu2023impairedaifchchd4interaction pages 1-2).
Mouse model (AUNX1): A 2024 Aifm1 p.R450Q knock-in mouse showed progressive hearing loss beginning around P30, worsening by P60, and stabilizing until P210, with progressive SGN reduction (P30), ribbon loss (P60), later demyelination and mitochondrial abnormalities, and muscle atrophy by P210. (shi2024aiftranslocationinto pages 1-3).
GO process suggestions: mitochondrial calcium ion homeostasis; oxidative phosphorylation; reactive oxygen species metabolic process; regulation of apoptotic process; axon ensheathment / myelination.
A 2022 preclinical study reports that recessive PJVK mutations cause pejvakin deficiency affecting hair cells and first-order neurons (SGNs), with limited benefit from cochlear implantation in some patients. In Pjvk mutant mice, Anc80L65-mediated PJVK transgene delivery led to robust pejvakin expression in cochlear/vestibular hair cells and neurons with morphologic restoration (including SGN density) and partial hearing recovery, plus vestibular recovery to WT levels. (lu2022genetherapywith pages 1-2).
Primary organ/system: inner ear (cochlea) and auditory nerve pathways. (saidia2023currentadvancesin pages 1-3, wang2024clinicalandgenetic pages 1-3).
Key tissues/cells implicated by the lesion-site framework and model/human genetics: - Cochlear inner hair cells (IHCs) and IHC ribbon synapses (OTOF synaptopathy). (stalmann2021otoferlinisrequired pages 1-2, saidia2023currentadvancesin pages 3-4) - Spiral ganglion neurons (SGNs) and their terminals (postsynaptic forms; AIFM1; PJVK). (shi2024aiftranslocationinto pages 1-3, lu2022genetherapywith pages 1-2) - Auditory nerve myelination/axons (demyelination/axonal loss described in AIFM1 model). (shi2024aiftranslocationinto pages 1-3)
UBERON suggestions: cochlea; organ of Corti; spiral ganglion; vestibulocochlear nerve.
GO cellular component suggestions: presynaptic active zone; synaptic ribbon; mitochondrion; myelin sheath.
ANSD can be congenital/infant-onset or later onset; a large cohort suggests genetic spectra differ by onset age, with OTOF predominating in infants and AIFM1 in non-infants. (wang2024clinicalandgenetic pages 1-3).
Natural history can include stability, improvement, or deterioration; in the large cohort, some cases showed progressive worsening and loss of OAEs over time, with progressive decline in speech recognition. (wang2024clinicalandgenetic pages 12-14).
Intervention timing is emphasized indirectly by evidence that early cochlear implantation and longer CI use predict better outcomes in pediatric ANSD. (jafari2024predictorsofcochlear pages 1-2).
Key statistics from recent cohorts are summarized in artifact-00. Notable points include: - AN affects 1.2–8.4% of hearing loss cases across populations and 0.006–0.039% in low-risk newborns (as cited in Wang et al. 2024). (wang2024clinicalandgenetic pages 1-3) - In one CI cohort, 9.85% (of 1,025 children with SNHL) were identified as ANSD (Almishaal et al. 2022 referenced in Wu et al. 2023). (wu2023outcomesofcochlear pages 1-2) - A 2024 pediatric CI paper reports ANSD is observed in 4–5% of all degrees of hearing loss and 10–15% of school-age children with severe-to-profound SNHL. (jafari2024predictorsofcochlear pages 1-2)
Inheritance patterns are diverse: autosomal recessive (e.g., OTOF, PJVK), autosomal dominant (e.g., OPA1, ATP1A3, DIAPH3), X-linked (AIFM1, PRPS1), and mitochondrial. (jafari2024predictorsofcochlear pages 1-2, wang2024clinicalandgenetic pages 1-3).
The retrieved sources did not provide gnomAD-based allele frequencies for specific variants; however, the Wang 2024 study documents filtering variants at population frequency <0.005 using gnomAD/1000G/ExAC in its sequencing pipeline. (wang2024clinicalandgenetic pages 3-4).
A large cohort study states inclusion criteria for AN as: (1) presence of OAE and/or CM and (2) abnormal or absent ABR. (wang2024clinicalandgenetic pages 3-4).
A 2023 gene therapy-focused review reiterates the hallmark profile: preserved OAE or CM with impaired/absent ABR, often with absent stapedial reflex and absent contralateral OAE suppression. (saidia2023currentadvancesin pages 1-3).
Large cohort sequencing using WGS/panels identified pathogenic/likely pathogenic variants in 31.5% overall, with higher yields in trios/families than proband-only cases, supporting family-based sequencing when feasible. (wang2024clinicalandgenetic pages 1-3).
Cochlear nerve deficiency (CND) is an important anatomic/etiologic subgroup and is associated with poorer CI speech outcomes in a CI cohort. (wu2023outcomesofcochlear pages 3-5).
Newborn screening limitation: ANSD may be missed by screening strategies that rely primarily on OAEs, because OAEs can be preserved in ANSD; a large cohort also highlights dependence on OAE/CM and ABR for diagnosis. (wang2024clinicalandgenetic pages 3-4, saidia2023currentadvancesin pages 1-3).
Cochlear nerve integrity: CI outcomes are poorer in AN cases with cochlear nerve deficiency (p=0.008). (wu2023outcomesofcochlear pages 1-2).
Intervention timing and exposure: In a matched case-control pediatric study, improved speech perception outcomes were predicted by longer follow-up with CI, lower age at CI activation, and use of bilateral CIs; younger hearing-aid fitting age also correlated with better improvement. (jafari2024predictorsofcochlear pages 1-2).
In a 2023 CI cohort of 75 AN patients, post-CI aided thresholds improved to ~32–38 dB and CAP/SIR scores improved significantly in both prelingual and post-lingual onset groups. (wu2023outcomesofcochlear pages 1-2).
Current clinical treatment options are commonly described as hearing aids and cochlear implantation, with outcomes depending on lesion site and cochlear nerve integrity. (saidia2023currentadvancesin pages 1-3, wu2023outcomesofcochlear pages 1-2).
Human cohort outcomes (Wu et al. 2023): - Aided thresholds after CI: prelingual 38.25 ± 6.63 dB; post-lingual 32.58 ± 9.26 dB. (wu2023outcomesofcochlear pages 1-2) - CAP and SIR improvements were significant (p<0.001). (wu2023outcomesofcochlear pages 1-2) - Maximum speech recognition ranged 58–93% (prelingual) and 43–98% (post-lingual). (wu2023outcomesofcochlear pages 1-2)
Predictors (Jafari et al. 2024): - Children with ANSD achieved similar open-set speech perception outcomes as matched SNHL peers (average scores ~88.40%–95.65%). (jafari2024predictorsofcochlear pages 1-2) - Predictors of optimal outcomes: longer CI follow-up, younger activation age, and two CIs. (jafari2024predictorsofcochlear pages 1-2)
MAXO suggestions: cochlear implantation; hearing aid therapy; audiologic rehabilitation; speech-language therapy.
Multiple OTOF-targeted intracochlear AAV programs are in Phase 1/2 clinical development:
Expert synthesis: Recent reviews emphasize that current care remains device-based (HA/CI) and that gene therapy approaches are motivated by the ability to precisely localize lesion site and target presynaptic synaptopathy; preclinical outcomes depend strongly on timing of delivery. (saidia2023currentadvancesin pages 1-3, saidia2023currentadvancesin pages 11-12).
No primary-prevention interventions specific to genetic ANSD are identified in the retrieved sources. Secondary prevention aligns with early detection (ABR-based components in newborn screening and early diagnostic workup) and early intervention (hearing technology, CI candidacy assessment), which are supported by evidence that younger intervention timing predicts better outcomes. (jafari2024predictorsofcochlear pages 1-2).
The retrieved sources did not provide naturally occurring non-human (e.g., veterinary) disease evidence for ANSD.
1) Lesion-site spectrum and definition: “Auditory neuropathy spectrum disorder (ANSD) refers to a range of hearing impairments characterized by an impaired transmission of sound from the cochlea to the brain.” (Saidia et al., 2023; abstract) (saidia2023currentadvancesin pages 3-4).
2) Large-cohort genetic yield: “In a retrospective cohort of 311 patients with AN, pathogenic and likely pathogenic variants of 23 genes were identified in 98 patients (31.5% in 311 patients)… Most of the OTOF gene (96.6%, 28/29) could only be identified in the infant group, while the AIFM1 gene could only be identified in the non-infant group.” (Wang et al., 2024; abstract) (wang2024clinicalandgenetic pages 1-3).
3) CI outcomes in AN: “After CI, the average aided hearing threshold for patients with prelingual and post-lingual onset was 38.25 ± 6.63 dB and 32.58 ± 9.26 dB, respectively… Speech outcomes of CI in cases with cochlear nerve (CN) deficiency were significantly poorer (p = 0.008).” (Wu et al., 2023; abstract) (wu2023outcomesofcochlear pages 1-2).
4) AIFM1 iPSC mechanism and conclusion: “This study demonstrates that the AIFM1 variant is one of the molecular bases of ANSD. Mitochondrial dysfunction, especially mCa2+ overload, plays a prominent role in ANSD associated with AIFM1.” (Qiu et al., 2023; abstract) (qiu2023impairedaifchchd4interaction pages 1-2).
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