In auditory neuropathy, MRI alone may miss the treatment-defining diagnosis
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A documented diagnosis of two OTOF-causing mutations gives the family an explanation of why their child has hearing loss and provides the opportunity for counseling on how the condition was inherited in the family and what testing may be done on relatives in the future.
—Scott Nass, MD
Auditory neuropathy spectrum disorder (ANSD) refers to a range of hearing disorders characterized by abnormal or absent auditory brainstem responses despite evidence of preserved cochlear outer hair cell function.[] Speech understanding, particularly in background noise, is often much worse than their pure-tone thresholds would suggest.
Variants in the otoferlin gene (OTOF) are identified as the most common genetic cause.[]
Related: 4 major shifts in genetic pediatric hearing loss care: A historical look-backPathogenesis
OTOF-related disease is a presynaptic form of ANSD. Otoferlin is required for synaptic vesicle fusion and neurotransmitter release from inner hair cells.[]
Biallelic pathogenic OTOF variants cause a synaptic transmission defect.
“Testing of OTOF (otoferlin) is especially important if it can be demonstrated that cochlear outer hair cells are functioning appropriately, yet there is no ABR (Auditory Brainstem Response), or that the ABR is either significantly abnormal or absent,” says Scott Nass, MD, a board-certified family medicine physician.
“This suggests that although sound may reach the inner ear, it does not appear to be transmitted properly across the synapse,” he adds.
Other genetic causes of ANSD include variants affecting synaptic and neural function.
Acquired causes include prematurity, hyperbilirubinemia, hypoxia, infection, and ototoxic exposure.[][]
Related: The sequencing dilemma in OTOF-related hearing lossHow to establish a differential diagnosis
Cochlear nerve deficiency is the most important differential diagnosis. The following investigations are useful:
MRI
MRI is important when the phenotype is unilateral or when cochlear nerve hypoplasia or aplasia is suspected.
A 2024 systematic review found cochlear nerve deficiency to be the most prevalent imaging abnormality reported among ANSD cohorts and identified MRI as the preferred imaging modality in most studies.[]
“MRI is particularly useful for distinguishing among the various possible reasons that the same type of test results (auditory neuropathy) could be produced by such distinctly different underlying causes. This is primarily due to the fact that an MRI allows clinicians to identify whether or not the cochlear nerve exists and, if so, whether it has developed properly,” Dr. Nass says.
Related: A new gene therapy makes delayed OTOF diagnosis harder to defendGenetic testing
“I would consider conducting a genetic test as soon as possible after the presence of an auditory neuropathy phenotype has been identified,” says Dr. Nass.
“It is highly valuable to have an idea of what may be causing this, for the child and their family to make informed choices regarding their hearing support system and future long-term needs,” he adds.
A 2026 systematic review of 29 studies involving 441 individuals with auditory neuropathy identified the following:[]
Twenty-one genes were identified to be causative of auditory neuropathy.
Variants in OTOF accounted for 59% of genetic diagnoses.
Among 362 individuals who underwent genetic testing, the reported diagnostic yield was 54%, although adjustment for study bias reduced the estimate to 31%.
The authors argue for considering genetic testing early in the diagnostic pathway.
This is clinically relevant because OTOF-directed treatment has moved into clinical practice.
Related: Hearing gains are not the endpoint: What should clinicians watch after OTOF gene therapy?Management
In April 2026, the FDA approved Otarmeni (lunsotogene parvec-cwha) for pediatric and adult patients with severe-to-profound or profound sensorineural hearing loss associated with molecularly confirmed biallelic OTOF variants, preserved outer hair cell function, and no previous cochlear implant in the treated ear.[] The therapy delivers a functional OTOF sequence to the cochlea using a dual AAV vector.
In the registrational DB-OTO study published in The New England Journal of Medicine, 9 of 12 treated children reached the prespecified hearing threshold at week 24.[] Six could hear soft speech without assistive devices, and 3 achieved average hearing sensitivity within the normal range.
Longer follow-up is also encouraging.
A multicenter nature study involving 42 participants reported hearing recovery in 90% of patients after AAV1-hOTOF treatment, with benefits sustained through 2.5 years.[]
Younger participants showed greater improvement than adults.
Baseline otoacoustic emissions and biallelic nontruncated OTOF variants were associated with better recovery.
Clinicians involved in the field have stressed the importance of the biological target. Daniel Choo, MD, professor and director of pediatric otolaryngology at the University of Cincinnati College of Medicine and Cincinnati Children’s Hospital Medical Center, described otoferlin as having an “unusually high safety profile.”[]
“The practical impact is increasing as molecular confirmation may be a requirement to determine if a family will qualify for OTOF-related gene therapy trials or treatment programs,” Dr. Nass says.
However, he warns, “Having the mutations doesn’t mean that a child will qualify. Other clinical requirements are used by each program individually.”
“A documented diagnosis of two OTOF-causing mutations gives the family an explanation of why their child has hearing loss and provides the opportunity for counseling on how the condition was inherited in the family and what testing may be done on relatives in the future,” he concludes.
Related: Physicians share a 'wish list' for treating pediatric genetic hearing loss