DFNB9 is a rare, congenital hearing loss. This form of hearing impairment is nonsyndromic, meaning it is not associated with other medical problems or abnormalities in other parts of the body. The hearing loss associated with DFNB9 is severe to profound.
The Genetic Cause of DFNB9
DFNB9 is caused by mutations in the OTOF gene. This gene provides the instructions for creating otoferlin, a protein with an important job in the inner ear. Otoferlin is found in the inner hair cells, which are the sensory cells that convert sound vibrations into electrical signals.
Otoferlin enables inner hair cells to communicate with the auditory nerve. It functions as a calcium sensor, detecting changes in calcium ion levels. This detection triggers the release of neurotransmitters, which are chemical signals that carry information from the hair cells to the nerve fibers. Without functional otoferlin, this signal transmission fails, and auditory information cannot effectively reach the brain.
DFNB9 is inherited in an autosomal recessive pattern. This means a child must inherit two non-working copies of the OTOF gene—one from each parent—to have the condition. The parents are carriers, having one functional and one non-working copy of the gene, which is why they have normal hearing. When both parents are carriers, there is a 25% chance with each pregnancy that their child will be affected by DFNB9.
Symptoms and Diagnosis
The primary symptom of DFNB9 is a severe to profound prelingual hearing loss in both ears that is stable and does not worsen over time. A defining characteristic is that it falls under Auditory Neuropathy Spectrum Disorder (ANSD). ANSD describes a hearing impairment where the cochlea functions properly, but the transmission of the sound signal to the brain is disrupted.
This mechanism leads to a unique set of diagnostic findings. Newborn hearing screenings using otoacoustic emissions (OAEs) may initially show a “pass” result. OAE tests measure the function of the outer hair cells in the cochlea, which are healthy in individuals with DFNB9. The normal activity of these cells can be misleading.
A more detailed test, the auditory brainstem response (ABR), is required for diagnosis. The ABR test measures the electrical activity of the auditory nerve and brain pathways for hearing. In a child with DFNB9, the ABR will be absent or severely abnormal, indicating the signal is not being relayed to the brain. The combination of present OAEs and an absent ABR is a strong indicator of ANSD, and genetic testing for OTOF mutations confirms the diagnosis.
Standard Intervention with Cochlear Implants
For children diagnosed with DFNB9, the primary intervention is the cochlear implant. A cochlear implant is an electronic device that provides a sense of sound to a profoundly deaf person. Unlike a hearing aid that only amplifies sound, a cochlear implant bypasses the core problem. Hearing aids are ineffective because amplifying sound does not fix the faulty signal transmission.
A cochlear implant bypasses the non-functional parts of the auditory system. The device has an external component behind the ear and a surgically placed internal component. The implant directly stimulates the auditory nerve, which is healthy in individuals with DFNB9. This stimulation circumvents the synapse where the missing otoferlin protein prevents communication.
This direct nerve stimulation allows the brain to perceive sound. Children with DFNB9 who receive cochlear implants at a young age often experience excellent outcomes in developing spoken language and speech understanding. Early implantation is beneficial as it takes advantage of the brain’s plasticity during the formative years of language acquisition.
Breakthroughs in Gene Therapy
Medical research is shifting the approach to DFNB9 from management to potential correction through gene therapy. This technique aims to fix the underlying genetic cause of the condition. The strategy involves delivering a healthy, functional copy of the OTOF gene directly to the inner hair cells of the cochlea.
To achieve this, scientists use a modified, harmless virus, a viral vector, as a delivery vehicle. An adeno-associated virus (AAV) is commonly used for this purpose. However, the OTOF gene is too large to fit inside a single AAV vector. Researchers overcame this by splitting the gene into two halves, placing each half into a separate AAV, and injecting the mixture into the inner ear. Once inside the cells, the two parts recombine to form a complete, functional copy.
Recent clinical trials have demonstrated success with this approach. Children with DFNB9 who received the gene therapy showed significant hearing recovery, with some able to recognize speech. In a trial where the therapy was administered to both ears, patients gained the ability to locate sound sources and perceive speech in noisy environments. This research offers the possibility of restoring natural hearing by correcting the disorder’s source. While still in early stages, gene therapy provides substantial optimism for treating this form of congenital deafness.