Alport Syndrome

Definition and epidemiology

Alport syndrome is an inherited disorder of the network formed by the α3, α4 and α5 chains of type IV collagen, a major building block of basement membranes. This network is found in the glomerular basement membrane of the kidney, in the inner ear and in the eye, and pathogenic variants in COL4A3, COL4A4 and COL4A5 disrupt its structure. Current classification treats the condition as a single spectrum with X-linked, autosomal recessive and autosomal dominant forms (Kashtan et al., 2018). About 80-85% of cases are due to COL4A5 on the X chromosome, 12-15% to COL4A3 and 5-8% to COL4A4 (Nozu et al., 2025).

Older estimates based on the clinical picture put the frequency of the X-linked and autosomal recessive forms at between 1 in 5,000 and 1 in 50,000. Population genome data suggest that likely pathogenic COL4A5 variants occur in at least 1 in 2,320 people and heterozygous COL4A3 or COL4A4 variants in about 1 in 106; because some carriers have no symptoms, the true frequency of disease is lower (Nozu et al., 2025). Hearing loss affects 50-60% of males with X-linked disease and of people with the autosomal recessive form, but is rare in heterozygous carriers (Nozu et al., 2025; Savige et al., 2022).

Symptoms and signs

The first sign is usually blood in the urine (haematuria). Almost all males with the X-linked form and about 95% of females have haematuria, and proteinuria, hypertension and progressive kidney failure follow over time. About 90% of males with a pathogenic COL4A5 variant reach kidney failure by the age of 40 (Savige et al., 2022). The eyes may show anterior lenticonus, perimacular fleck retinopathy, temporal retinal thinning and recurrent corneal erosion; anterior lenticonus is almost pathognomonic (Savige et al., 2022; Nozu et al., 2025).

The hearing loss is not congenital. In boys it usually begins in late childhood or early adolescence as a bilateral, symmetrical sensorineural loss that at first can be detected only on audiometry, and later spreads to the speech frequencies (Nozu et al., 2025). In 87 males with X-linked Alport syndrome, hearing was normal before school age, loss began around school age and reached a plateau of about 50-60 dB HL in the teenage years; in 28 of 49 patients followed for more than two years, thresholds worsened by about 5 dB per year (Zhang et al., 2018).

In childhood the loss is concentrated in the mid frequencies. In the EARLY PRO-TECT trial, 18% of 51 children had hearing loss; the greatest loss was usually at 1-3 kHz, no ear had its greatest loss in the low frequencies (125-500 Hz), and in the 14-20-year group the loss also extended to 6 and 8 kHz (Boeckhaus et al., 2020). In female carriers, hearing loss is less common and appears later (Nozu et al., 2025). Hearing loss is always accompanied by kidney involvement (Alves and Ribeiro, 2008; Nozu et al., 2025).

Causes and risk factors

The type IV collagen network gives basement membranes their strength. When one of its three chains is missing or faulty, the glomerular basement membrane thins and splits, and similar structural changes occur in the cochlea and eye. Temporal bone studies have not found enough hair cell, stria vascularis or neuronal loss to explain the hearing loss; instead, they show separation between the basilar membrane and the cells of the organ of Corti and filling of the tunnel of Corti with cells. These findings suggest that the loss arises from altered cochlear micromechanics (Merchant et al., 2004).

X-linked Alport syndrome, due to COL4A5 variants, is severe in males; in heterozygous females the picture ranges from mild haematuria to kidney failure. The autosomal recessive form results from biallelic COL4A3 or COL4A4 variants and is severe in both sexes. People with a single pathogenic variant in one of these genes are now classed as having autosomal dominant Alport syndrome, in which hearing and eye features are rare (Kashtan et al., 2018; Savige et al., 2022).

The type of variant influences when hearing loss appears. In X-linked males with large rearrangements, nonsense, frameshift or splice-site variants, the risk of hearing loss reaches about 50% by age 10, whereas with missense variants this point is reached only around age 20 (Nozu et al., 2025). In the series by Zhang and colleagues, hearing loss was found in 83.9% of those with indel, splicing or nonsense variants and in 28.1% of those with missense variants (Zhang et al., 2018).

Audiological and clinical assessment

Audiological assessment has two aims: to pick up hearing loss early in a child already known to have Alport syndrome, and to point towards the diagnosis when sensorineural loss is found in a family with haematuria. Sensorineural hearing loss together with haematuria and a family history of haematuria or kidney failure is a strong reason for genetic testing (Savige et al., 2022).

• Pure-tone audiometry: a bilateral, symmetrical sensorineural loss. In children the greatest loss is usually at 1-3 kHz. A common configuration is the U-shaped (cookie-bite) pattern, with poorer thresholds in the mid frequencies than in the low and high frequencies. In EARLY PRO-TECT, 9 of 22 affected ears showed a cookie-bite curve and 10 a flat (plateau) curve (Boeckhaus et al., 2020). Among 55 males with X-linked Alport syndrome and hearing loss, 51 (92.7%) had a groove-type curve with the poorest thresholds in the mid frequencies (Zhang et al., 2018). With age the high frequencies are also affected. In a series that also included adults, the most common curve was a mild high-frequency slope, with flat curves less frequent (Alves and Ribeiro, 2008).
• Speech audiometry: word recognition scores are in keeping with a cochlear loss; as the loss reaches the speech frequencies, listening in noise becomes harder.
• Tympanometry and acoustic reflexes: the middle ear is normal; reflex thresholds match the degree of cochlear loss.
• Otoacoustic emissions (OAE): reduced or absent in affected frequency regions, supporting a cochlear site of lesion.
• Auditory brainstem response (ABR): used for threshold estimation when behavioural testing is not possible; wave latencies are consistent with a cochlear loss.
• Multidisciplinary work-up: urinalysis and kidney function, eye examination with retinal photography and optical coherence tomography, and genetic analysis of COL4A3, COL4A4 and COL4A5, which is the main diagnostic tool (Savige et al., 2022).

The differential diagnosis includes other inherited kidney disorders that can combine haematuria and hearing loss (Savige et al., 2022). BOR syndrome, which also links kidney and ear findings, is distinguished by pinna anomalies, preauricular pits and branchial cysts or fistulae in the neck. For genetic hearing loss without systemic features, see non-syndromic hearing loss.

Treatment and audiological rehabilitation

No treatment stops or reverses the hearing loss of Alport syndrome. Angiotensin-converting enzyme inhibitors or angiotensin receptor blockers are used to slow kidney disease, and the nephrologist decides when to start them according to genotype and albuminuria (Nozu et al., 2025). Dialysis and kidney transplantation are used for kidney failure. After transplantation, close monitoring during the first year is advised for anti-GBM nephritis against the new kidney, especially in males with truncating COL4A5 variants and in autosomal recessive disease (Nozu et al., 2025). Studies on whether transplantation changes the course of hearing loss are lacking, so audiological monitoring should continue after transplantation. Drug choice and dosing in kidney disease are decided by the physician; for drugs that can harm hearing, see ototoxicity.

For monitoring, audiological assessment every 1-2 years from age 6-7, protection from noise and hearing aids when needed are recommended (Nozu et al., 2025). A recommendation based on EARLY PRO-TECT data is that checks should start before primary school and be repeated every three years in children with normal hearing, with closer follow-up for those with a four-frequency average of 16-25 dB, who are at higher risk of progression. Children with hearing loss should be fitted with bilateral hearing aids and reviewed at least yearly; rehabilitation with hearing aids is usually successful and marked language delay is uncommon (Boeckhaus et al., 2020).

When the loss becomes severe or profound and hearing aids no longer give enough benefit, a cochlear implant (CI) is considered. For transplant recipients on immunosuppression, evidence is limited to case reports. In a case from Istanbul, a 60-year-old woman taking tacrolimus and prednisolone after kidney transplantation received a CI without stopping these drugs and with infection precautions; cochlear fibrosis required a split electrode array, there were no complications, and closed-set test scores were clearly improved at three months. The authors stress that this is a single case (Sarı et al., 2008).

Impact on quality of life and advice

Alport syndrome affects the child and family for many years, through both the kidneys and hearing. Hearing loss often becomes noticeable during the school years, when listening demands in class increase; even a mild loss can raise listening effort in a noisy classroom and lead to fatigue and attention difficulties. In adolescence and early adulthood, dialysis, transplantation, frequent hospital visits and medication can limit social participation, and psychosocial support becomes important when hearing difficulty adds to this burden.

Practical advice:

• Link hearing checks to the kidney and eye review schedule; because the loss progresses slowly, families and teachers may notice changes late.
• Avoid noisy settings and loud music; for the additional harm of long-term noise, see noise-induced hearing loss.
• Inform the school; sitting near the front and using a remote microphone system make it easier to follow lessons.
• Seek genetic counselling: in X-linked inheritance a carrier mother has a 50% chance of passing the variant to each child, and daughters also need kidney and hearing monitoring.
• You can track hearing aid use and everyday listening difficulties with the questionnaires below.