In XLAS, COL4A5 Mutations Determine Progression of Hearing Loss, Study Finds

Hearing loss in male patients with X-linked Alport syndrome (XLAS) is caused by sensorineural deafness that becomes worse with age. Also, the more serious the mutations carried by patients, the higher the degree of their hearing loss and the poorer their kidney function, a study reports.

The study, “X-linked Alport syndrome: pathogenic variant features and further auditory genotype-phenotype correlations in males,” was published in the Orphanet Journal of Rare Diseases.

Mutations in the COL4A5 gene, the underlying cause of XLAS, lead to defects in collagen type IV protein, resulting in injury to the basement membranes within the cochlea, the part of the inner ear responsible for hearing.

Collagen type IV is a major component of basement membranes, which separate the lining of organs or body surfaces (epithelial cells) from the underlying tissue.

Alterations to this membrane may also impair the work of other organs including the kidneys and retina — two other signs of AS.

In XLAS, hearing loss occurs mostly in male patients, appearing at the end of childhood or the beginning of adolescence.

Most studies have shown that this type of deafness is progressive, symmetrical (same severity and pattern of hearing loss) and sensorineural, caused by damage to the inner ear or cochlea, the auditory nerve or the brain.

Different types of mutations of COL4A5 can cause XLAS and the risk of developing hearing loss has been reported to vary with the type of mutation involved.

However, few studies have examined the relationship between the type of genetic defect and the hearing changes or the hearing level of patients.

A team of researchers analyzed the hearing characteristics of 87 male patients (ages 2 to 33) with XLAS and examined the relationship of such features to the type of mutations those patients carried.

Researchers reviewed the results of hearing tests used to evaluate the patients. The tests included  pure tone audiometry (PTA), or audiogram, acoustic immittance, and otoacoustic emissions (OAE).

Results indicated that most patients (63.2%) had some degree of hearing loss, mostly mild to moderate in severity.

In all cases, this loss was characterized by bilateral (both ears) and symmetrical sensorineural deafness.

Usually patients began to stop hearing middle frequency sounds at school age and gradually lost the ability to hear high frequencies as they aged.

However, the range of sounds that patients were able to hear reached a steady level during the teenage years, and were maintained through adulthood.

A total of 60 different pathogenic (disease-causing) COL4A5 mutations were identified in the patient population studied.

Researchers noted that the degree of hearing loss was influenced by the severity of gene mutations.

For carriers of mild mutations, hearing loss began at school age and increased with age, whereas for severe mutations, there was already a mild hearing loss at preschool age.

“The more serious the mutation type was, the greater the hearing loss was,” researchers said.

The results also showed a correlation with kidney function. The more severe the mutation, the worse the kidney function and the poorer a patient’s hearing.

Based on this preliminary study, researchers suggest that the gradual hearing loss patients experience as they age is rooted in the increasing damage to the cochlea over time.

“The results of this study might be useful in predicting the trends in hearing changes and in providing timely interventions for such patients,” researched stated.

Researchers saw that the configuration, or shape, of the hearing loss of XLAS patients (the audiometric curve) was mainly a groove-type curve, which is clinically rare.

This means that if a child presents with this type of hearing loss, it may be possible that “a preliminary diagnosis of AS can be made in children with hematuria (blood in urine) or proteinuria (protein in urine) before kidney puncture, skin biopsy pathology, or genetic diagnosis,” researchers said.