Auditory Neuropathy (Auditory Neuropathy Spectrum Disorder, ANSD): Disease Characteristics Research Report

Executive summary

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).

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.

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.

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.

1. Disease information

1.1 What is the disease?

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).

1.2 Key identifiers

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).

1.3 Synonyms/alternative names

Commonly used names include auditory neuropathy (AN) and auditory neuropathy spectrum disorder (ANSD). (wu2023outcomesofcochlear pages 1-2, wang2024clinicalandgenetic pages 1-3).

1.4 Evidence sources

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)

2. Etiology

2.1 Disease causal factors

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).

2.2 Risk factors

Genetic risk factors

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).

Environmental/perinatal risk factors

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).

2.3 Protective factors

No protective genetic or environmental factors were identified in the retrieved sources.

2.4 Gene–environment interaction

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).

3. Phenotypes

3.1 Core auditory phenotypes

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

3.2 Age of onset and course

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).

3.3 Frequency and variability

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)

3.4 Quality-of-life impact

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).

4. Genetic / molecular information

4.1 Causal genes (selected, from retrieved evidence)

Recent cohort evidence supports a multi-gene Mendelian architecture with strong dependence on onset age and laterality.

• Wang et al. 2024 (311 cases): 23 genes with pathogenic/likely pathogenic variants in 31.5% overall; OTOF and AIFM1 are the top two genes and show striking age dependence (OTOF mostly infant; AIFM1 non-infant). (wang2024clinicalandgenetic pages 1-3).
• Buianova et al. 2024 (20 clinically confirmed pediatric ANSD): variants identified in 60% (12/20); OTOF 25% (5/20) with additional genes including PRPS1 and HOMER2, among others. (buianova2024heterogeneousgroupof pages 2-3).

(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).

4.2 Pathogenic variants and variant classes (OTOF example)

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).

4.3 Modifier genes

No modifier-gene evidence was identified in the retrieved sources.

4.4 Epigenetic information

No disease-specific epigenetic mechanisms were identified in the retrieved sources.

5. Environmental information

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.

6. Mechanism / pathophysiology

6.1 Lesion-site framework (current understanding)

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).

6.2 Mechanistic causal chains (examples)

(A) OTOF-related presynaptic auditory synaptopathy

• Trigger: biallelic OTOF pathogenic variants impair otoferlin, a key IHC synaptic protein involved in vesicle exocytosis/rapid replenishment. (saidia2023currentadvancesin pages 3-4, stalmann2021otoferlinisrequired pages 1-2).
• Primary defect: impaired neurotransmitter release at the IHC ribbon synapse → absent/abnormal ABR with preserved outer hair cell measures (OAEs/CM). (saidia2023currentadvancesin pages 1-3, lin2020anintegrativeapproach pages 2-3).
• Downstream biology (mouse natural history): in Otof−/− mice, synapse counts drop from ~15/IHC at P14 to ~7 at 8 weeks and ~6 at 48 weeks, accompanied by SGN decline and progressive IHC loss (~75% of WT IHCs) plus later OHC dysfunction (DPOAE high-frequency decay by ~24 weeks). (stalmann2021otoferlinisrequired pages 1-2).

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).

(B) AIFM1-related postsynaptic/nerve auditory neuropathy (mitochondrial-neurodegeneration axis)

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.

(C) PJVK-related cochlear/neuronal vulnerability and gene therapy in mice

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).

6.3 Advanced technologies highlighted in recent work

• Patient-derived iPSC neurons + isogenic CRISPR correction to define ANSD mitochondrial mechanisms (AIFM1). (qiu2023impairedaifchchd4interaction pages 1-2)
• Large-cohort sequencing (WGS/panels) with subgroup stratification by onset age/laterality and ACMG classification workflows. (wang2024clinicalandgenetic pages 3-4, wang2024clinicalandgenetic pages 1-3)

7. Anatomical structures affected

7.1 Organ, tissue, and cell types

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.

8. Temporal development

8.1 Onset patterns

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).

8.2 Progression

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).

8.3 Critical periods

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).

9. Inheritance and population

9.1 Epidemiology (recent/quantitative)

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)

9.2 Inheritance patterns

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).

9.3 Population genetics / variant distribution

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).

10. Diagnostics

10.1 Clinical diagnostic criteria

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).

10.2 Genetic testing

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).

10.3 Differential diagnosis considerations

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).

10.4 Screening and implementation

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).

11. Outcome / prognosis

11.1 Prognostic factors

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).

11.2 Functional outcomes

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).

12. Treatment

12.1 Standard clinical management

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).

12.2 Cochlear implantation: outcomes and predictors (recent data)

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.

12.3 Emerging / experimental: OTOF gene therapy and enabling natural history

Multiple OTOF-targeted intracochlear AAV programs are in Phase 1/2 clinical development:

• Akouos/Lilly AAVAnc80-hOTOF trial (NCT05821959): first posted 2023-04-20; start 2023-09-15; primary endpoint safety (AEs) through ~1 year; secondary endpoints include ABR threshold change; includes participants with ≥2 OTOF mutations, profound bilateral SNHL by ABR, and preserved DPOAEs. (NCT05821959 chunk 1)
• Regeneron (Decibel-origin) DB-OTO CHORD trial (NCT05788536): first posted 2023-03-29; start 2023-06-27; primary endpoints include TEAEs and achievement of PTA ≤70 dB (up to week 104); secondary endpoints include ABR to click and early speech perception milestones. (NCT05788536 chunk 1)
• Long-term follow-up after AAVAnc80-hOTOF (NCT06696456): first posted 2024-11-20; monitors delayed safety and durability up to ~5 years post dosing. (NCT06696456 chunk 1)
• OTOF natural history study (NCT05572073): first posted 2022-10-07; longitudinal ABR/OAE outcomes; excludes cochlear nerve deficiency/dysplasia and requires OTOF mutations; prospective phase requires OAE/CM present with absent/abnormal ABR in at least one non-implanted ear. (NCT05572073 chunk 1)

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).

13. Prevention

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).

14. Other species / natural disease

The retrieved sources did not provide naturally occurring non-human (e.g., veterinary) disease evidence for ANSD.

15. Model organisms

15.1 Mouse models

• OTOF/DFNB9 models: Otof−/− mice show progressive synapse loss (from ~15 synapses/IHC at P14 to ~6 by 48 weeks) plus SGN decline and progressive hair-cell degeneration, with high-frequency DPOAE amplitude decay first observed at ~24 weeks. (stalmann2021otoferlinisrequired pages 1-2)
• AIFM1/AUNX1 model: Aifm1 p.R450Q KI mice recapitulate progressive auditory neuropathy with onset around P30, ribbon loss (P60), later demyelination, and mitochondrial pathology. (shi2024aiftranslocationinto pages 1-3)
• PJVK models and gene transfer: Pjvk mutant mice show cochlear and vestibular pathology; Anc80L65-mediated PJVK gene transfer partially restores hearing and normalizes vestibular function in mice. (lu2022genetherapywith pages 1-2)

15.2 Cellular models

• Patient iPSC-derived neurons (AIFM1): mechanism implicates mitochondrial Ca2+ overload, ROS elevation, and caspase-independent apoptosis; correction rescues phenotypes. (qiu2023impairedaifchchd4interaction pages 1-2)

Direct abstract quotes supporting key claims (selected)

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).

Limitations of this evidence set

• Formal ontology identifiers (MONDO, Orphanet, ICD, MeSH) were not present in the retrieved documents and were not inferred. (wang2024clinicalandgenetic pages 3-4).
• Variant-level population frequencies (gnomAD allele frequencies per variant) and penetrance/expressivity estimates by gene were not available in the retrieved texts.
• Some 2023–2024 high-impact ANSD management/outcomes papers were flagged as “unobtainable” by the paper retrieval system; therefore, this report prioritizes the accessible primary evidence and trial registry entries.

Key URLs (access points)

• Wang et al. 2024 (Human Genetics): https://doi.org/10.1007/s00439-024-02652-7 (Published online 2024-03-08) (wang2024clinicalandgenetic pages 1-3)
• Wu et al. 2023 (Frontiers in Neuroscience): https://doi.org/10.3389/fnins.2023.1281884 (2023-11-13) (wu2023outcomesofcochlear pages 1-2)
• Jafari et al. 2024 (PLOS ONE): https://doi.org/10.1371/journal.pone.0304316 (2024-05-29) (jafari2024predictorsofcochlear pages 1-2)
• Saidia et al. 2023 (J Clin Med): https://doi.org/10.3390/jcm12030738 (2023-01) (saidia2023currentadvancesin pages 1-3)
• Forli et al. 2023 (Medicina): https://doi.org/10.3390/medicina59020352 (2023-02-13) (forli2023temperaturesensitiveauditoryneuropathy pages 1-2)
• Qiu et al. 2023 (Cell Death & Disease): https://doi.org/10.1038/s41419-023-05899-6 (2023-06) (qiu2023impairedaifchchd4interaction pages 1-2)
• Shi et al. 2024 (Hum Mol Genet): https://doi.org/10.1093/hmg/ddae010 (2024-03) (shi2024aiftranslocationinto pages 1-3)
• ClinicalTrials.gov NCT05821959: https://clinicaltrials.gov/study/NCT05821959 (First posted 2023-04-20) (NCT05821959 chunk 1)
• ClinicalTrials.gov NCT05788536: https://clinicaltrials.gov/study/NCT05788536 (First posted 2023-03-29) (NCT05788536 chunk 1)
• ClinicalTrials.gov NCT06696456: https://clinicaltrials.gov/study/NCT06696456 (First posted 2024-11-20) (NCT06696456 chunk 1)
• ClinicalTrials.gov NCT05572073: https://clinicaltrials.gov/study/NCT05572073 (First posted 2022-10-07) (NCT05572073 chunk 1)

References

1. (wang2024clinicalandgenetic pages 3-4): Hongyang Wang, Liping Guan, Xiaonan Wu, Jing Guan, Jin Li, Nan Li, Kaili Wu, Ya Gao, Dan Bing, Jianguo Zhang, Lan Lan, Tao Shi, Danyang Li, Wenjia Wang, Linyi Xie, Fen Xiong, Wei Shi, Lijian Zhao, Dayong Wang, Ye Yin, and Qiuju Wang. Clinical and genetic architecture of a large cohort with auditory neuropathy. Human Genetics, 143:293-309, Mar 2024. URL: https://doi.org/10.1007/s00439-024-02652-7, doi:10.1007/s00439-024-02652-7. This article has 19 citations and is from a peer-reviewed journal.

2. (wu2023outcomesofcochlear pages 1-2): Jie Wu, Jiyue Chen, Zhiwei Ding, Jialin Fan, Qiuquan Wang, Pu Dai, and Dongyi Han. Outcomes of cochlear implantation in 75 patients with auditory neuropathy. Frontiers in Neuroscience, Nov 2023. URL: https://doi.org/10.3389/fnins.2023.1281884, doi:10.3389/fnins.2023.1281884. This article has 7 citations and is from a peer-reviewed journal.

3. (saidia2023currentadvancesin pages 1-3): Anissa Rym Saidia, Jérôme Ruel, Amel Bahloul, Benjamin Chaix, Frédéric Venail, and Jing Wang. Current advances in gene therapies of genetic auditory neuropathy spectrum disorder. Journal of Clinical Medicine, 12:738, Jan 2023. URL: https://doi.org/10.3390/jcm12030738, doi:10.3390/jcm12030738. This article has 32 citations.

4. (lin2020anintegrativeapproach pages 2-3): Pei-Hsuan Lin, Chuan-Jen Hsu, Yin-Hung Lin, Yi-Hsin Lin, Shu-Yu Yang, Ting-Hua Yang, Pei-Lung Chen, Chen-Chi Wu, and Tien-Chen Liu. An integrative approach for pediatric auditory neuropathy spectrum disorders: revisiting etiologies and exploring the prognostic utility of auditory steady-state response. Scientific Reports, Jun 2020. URL: https://doi.org/10.1038/s41598-020-66877-y, doi:10.1038/s41598-020-66877-y. This article has 23 citations and is from a peer-reviewed journal.

5. (wang2024clinicalandgenetic pages 1-3): Hongyang Wang, Liping Guan, Xiaonan Wu, Jing Guan, Jin Li, Nan Li, Kaili Wu, Ya Gao, Dan Bing, Jianguo Zhang, Lan Lan, Tao Shi, Danyang Li, Wenjia Wang, Linyi Xie, Fen Xiong, Wei Shi, Lijian Zhao, Dayong Wang, Ye Yin, and Qiuju Wang. Clinical and genetic architecture of a large cohort with auditory neuropathy. Human Genetics, 143:293-309, Mar 2024. URL: https://doi.org/10.1007/s00439-024-02652-7, doi:10.1007/s00439-024-02652-7. This article has 19 citations and is from a peer-reviewed journal.

6. (jafari2024predictorsofcochlear pages 1-2): Zahra Jafari, Elizabeth M. Fitzpatrick, David R. Schramm, Isabelle Rouillon, and Amineh Koravand. Predictors of cochlear implant outcomes in pediatric auditory neuropathy: a matched case-control study. PLOS ONE, 19:e0304316, May 2024. URL: https://doi.org/10.1371/journal.pone.0304316, doi:10.1371/journal.pone.0304316. This article has 7 citations and is from a peer-reviewed journal.

7. (smith2018cochlearmicrophonicsfrom pages 17-21): Kyle Smith. Cochlear microphonics from auditory brainstem responses of infants with auditory neuropathy spectrum disorder. ArXiv, Jan 2018. URL: https://doi.org/10.14288/1.0372052, doi:10.14288/1.0372052. This article has 1 citations.

8. (wang2024clinicalandgenetic pages 12-14): Hongyang Wang, Liping Guan, Xiaonan Wu, Jing Guan, Jin Li, Nan Li, Kaili Wu, Ya Gao, Dan Bing, Jianguo Zhang, Lan Lan, Tao Shi, Danyang Li, Wenjia Wang, Linyi Xie, Fen Xiong, Wei Shi, Lijian Zhao, Dayong Wang, Ye Yin, and Qiuju Wang. Clinical and genetic architecture of a large cohort with auditory neuropathy. Human Genetics, 143:293-309, Mar 2024. URL: https://doi.org/10.1007/s00439-024-02652-7, doi:10.1007/s00439-024-02652-7. This article has 19 citations and is from a peer-reviewed journal.

9. (wu2023outcomesofcochlear pages 3-5): Jie Wu, Jiyue Chen, Zhiwei Ding, Jialin Fan, Qiuquan Wang, Pu Dai, and Dongyi Han. Outcomes of cochlear implantation in 75 patients with auditory neuropathy. Frontiers in Neuroscience, Nov 2023. URL: https://doi.org/10.3389/fnins.2023.1281884, doi:10.3389/fnins.2023.1281884. This article has 7 citations and is from a peer-reviewed journal.

10. (jafari2024predictorsofcochlear pages 2-4): Zahra Jafari, Elizabeth M. Fitzpatrick, David R. Schramm, Isabelle Rouillon, and Amineh Koravand. Predictors of cochlear implant outcomes in pediatric auditory neuropathy: a matched case-control study. PLOS ONE, 19:e0304316, May 2024. URL: https://doi.org/10.1371/journal.pone.0304316, doi:10.1371/journal.pone.0304316. This article has 7 citations and is from a peer-reviewed journal.

11. (buianova2024heterogeneousgroupof pages 7-9): Anastasiia A. Buianova, Marina V. Bazanova, Vera A. Belova, Galit A. Ilyina, Alina F. Samitova, Anna O. Shmitko, Anna V. Balakina, Anna S. Pavlova, Oleg N. Suchalko, Dmitriy O. Korostin, Anton S. Machalov, Nikolai A. Daikhes, and Denis V. Rebrikov. Heterogeneous group of genetically determined auditory neuropathy spectrum disorders. International Journal of Molecular Sciences, 25:12554, Nov 2024. URL: https://doi.org/10.3390/ijms252312554, doi:10.3390/ijms252312554. This article has 2 citations.

12. (buianova2024heterogeneousgroupof pages 2-3): Anastasiia A. Buianova, Marina V. Bazanova, Vera A. Belova, Galit A. Ilyina, Alina F. Samitova, Anna O. Shmitko, Anna V. Balakina, Anna S. Pavlova, Oleg N. Suchalko, Dmitriy O. Korostin, Anton S. Machalov, Nikolai A. Daikhes, and Denis V. Rebrikov. Heterogeneous group of genetically determined auditory neuropathy spectrum disorders. International Journal of Molecular Sciences, 25:12554, Nov 2024. URL: https://doi.org/10.3390/ijms252312554, doi:10.3390/ijms252312554. This article has 2 citations.

13. (forli2023temperaturesensitiveauditoryneuropathy pages 1-2): Francesca Forli, Silvia Capobianco, Stefano Berrettini, Luca Bruschini, Silvia Romano, Antonella Fogli, Veronica Bertini, and Francesco Lazzerini. Temperature-sensitive auditory neuropathy: report of a novel variant of otof gene and review of current literature. Medicina, 59:352, Feb 2023. URL: https://doi.org/10.3390/medicina59020352, doi:10.3390/medicina59020352. This article has 8 citations.

14. (dmitriev2023predictingtheimpact pages 1-2): Dmitry A. Dmitriev, Boris V. Shilov, Michail M. Polunin, Anton D. Zadorozhny, and Alexey A. Lagunin. Predicting the impact of otof gene missense variants on auditory neuropathy spectrum disorder. International Journal of Molecular Sciences, 24:17240, Dec 2023. URL: https://doi.org/10.3390/ijms242417240, doi:10.3390/ijms242417240. This article has 6 citations.

15. (NCT05821959 chunk 1): Gene Therapy Trial for Otoferlin Gene-mediated Hearing Loss. Akouos, Inc.. 2023. ClinicalTrials.gov Identifier: NCT05821959

16. (NCT05788536 chunk 1): A Study of DB-OTO, an Adeno-Associated Virus (AAV) Based Gene Therapy, in Children/Infants With Hearing Loss Due to Otoferlin Mutations. Regeneron Pharmaceuticals. 2023. ClinicalTrials.gov Identifier: NCT05788536

17. (NCT05788536 chunk 2): A Study of DB-OTO, an Adeno-Associated Virus (AAV) Based Gene Therapy, in Children/Infants With Hearing Loss Due to Otoferlin Mutations. Regeneron Pharmaceuticals. 2023. ClinicalTrials.gov Identifier: NCT05788536

18. (NCT06696456 chunk 1): Long Term Follow-up Study of AAVAnc80-hOTOF Gene Therapy. Akouos, Inc.. 2024. ClinicalTrials.gov Identifier: NCT06696456

19. (NCT05572073 chunk 1): Otoferlin Gene-mediated Hearing Loss Natural History Study. Akouos, Inc.. 2022. ClinicalTrials.gov Identifier: NCT05572073

20. (saidia2023currentadvancesin pages 3-4): Anissa Rym Saidia, Jérôme Ruel, Amel Bahloul, Benjamin Chaix, Frédéric Venail, and Jing Wang. Current advances in gene therapies of genetic auditory neuropathy spectrum disorder. Journal of Clinical Medicine, 12:738, Jan 2023. URL: https://doi.org/10.3390/jcm12030738, doi:10.3390/jcm12030738. This article has 32 citations.

21. (stalmann2021otoferlinisrequired pages 1-2): Ursula Stalmann, Albert Justin Franke, Hanan Al-Moyed, Nicola Strenzke, and Ellen Reisinger. Otoferlin is required for proper synapse maturation and for maintenance of inner and outer hair cells in mouse models for dfnb9. Frontiers in Cellular Neuroscience, Jul 2021. URL: https://doi.org/10.3389/fncel.2021.677543, doi:10.3389/fncel.2021.677543. This article has 45 citations.

22. (shi2024aiftranslocationinto pages 1-3): Tao Shi, Ziyi Chen, Jin Li, Hongyang Wang, and Qiuju Wang. Aif translocation into nucleus caused by aifm1 r450q mutation: generation and characterization of a mouse model for aunx1. Human Molecular Genetics, 33:905-918, Mar 2024. URL: https://doi.org/10.1093/hmg/ddae010, doi:10.1093/hmg/ddae010. This article has 3 citations and is from a domain leading peer-reviewed journal.

23. (qiu2023impairedaifchchd4interaction pages 1-2): Yue Qiu, Hongyang Wang, Mingjie Fan, Huaye Pan, J. Guan, Yangwei Jiang, Zexiao Jia, Kaiwen Wu, Hui Zhou, Qianqian Zhuang, Zhaoying Lei, Xue Ding, Huajian Cai, Yufei Dong, Le-Qin Yan, Aifu Lin, Yong Fu, Dong Zhang, Qingfeng Yan, and Qiuju Wang. Impaired aif-chchd4 interaction and mitochondrial calcium overload contribute to auditory neuropathy spectrum disorder in patient-ipsc-derived neurons with aifm1 variant. Cell Death & Disease, Jun 2023. URL: https://doi.org/10.1038/s41419-023-05899-6, doi:10.1038/s41419-023-05899-6. This article has 20 citations and is from a peer-reviewed journal.

24. (ismail2024systematicreviewof pages 2-4): Naema Mohamed Ismail, Salma Badreldin Galal, Reda Mohamed Behairy, and Rasha Mohamed Sabry. Systematic review of outcomes of cochlear implantation of different genotypes in patients with auditory neuropathy spectrum disorder. The Egyptian Journal of Otolaryngology, Sep 2024. URL: https://doi.org/10.1186/s43163-024-00677-3, doi:10.1186/s43163-024-00677-3. This article has 2 citations.

25. (lu2022genetherapywith pages 1-2): Ying-Chang Lu, Yi-Hsiu Tsai, Yen-Huei Chan, Chin-Ju Hu, Chun-Ying Huang, Ru Xiao, Chuan-Jen Hsu, Luk H. Vandenberghe, Chen-Chi Wu, and Yen-Fu Cheng. Gene therapy with a synthetic adeno-associated viral vector improves audiovestibular phenotypes in pjvk-mutant mice. JCI Insight, Oct 2022. URL: https://doi.org/10.1172/jci.insight.152941, doi:10.1172/jci.insight.152941. This article has 24 citations and is from a domain leading peer-reviewed journal.

26. (saidia2023currentadvancesin pages 11-12): Anissa Rym Saidia, Jérôme Ruel, Amel Bahloul, Benjamin Chaix, Frédéric Venail, and Jing Wang. Current advances in gene therapies of genetic auditory neuropathy spectrum disorder. Journal of Clinical Medicine, 12:738, Jan 2023. URL: https://doi.org/10.3390/jcm12030738, doi:10.3390/jcm12030738. This article has 32 citations.