What is Usher syndrome?

What is Usher Syndrome?

Usher syndrome is a genetic disorder characterized by the combination of sensorineural hearing loss, progressive vision loss from retinitis pigmentosa, and in some cases vestibular dysfunction—making it the most common genetic cause of combined deafness and blindness. 1, 2

Clinical Classification

Usher syndrome is divided into three distinct clinical types based on severity and age of onset:

Type 1 (USH1) - Most Severe Form

• Profound congenital sensorineural hearing loss present at birth 3, 4
• Vestibular areflexia causing balance problems from infancy 4
• Prepubertal onset of progressive retinitis pigmentosa, typically beginning before age 10 4
• Patients require ophthalmologic evaluation due to early vision loss 1

Type 2 (USH2) - Most Common Form

• Moderate to severe hearing loss present at birth 5, 4
• No vestibular dysfunction 4
• Later onset of retinal degeneration, typically beginning in adolescence or early adulthood 4
• Accounts for approximately 50% of all Usher syndrome cases 5

Type 3 (USH3) - Progressive Form

• Progressive postlingual hearing loss that worsens over time 4
• Variable onset of retinitis pigmentosa 4
• Variable vestibular response 4
• Rare except in certain populations 4

Genetic Basis

Usher syndrome is inherited in an autosomal recessive pattern, meaning both parents must carry a mutation for a child to be affected 1, 2:

• Nine confirmed causative genes have been identified 1, 3, 2
• Type 1 genes: MYO7A, USH1C, CDH23, PCDH15, USH1G 2, 4
• Type 2 genes: USH2A (most frequently mutated, explaining 50% of all cases), ADGRV1, WHRN 5, 2
• Type 3 gene: CLRN1 2
• Additional loci including USH1H have been mapped to chromosome 15q22-23 6

Pathophysiology

The proteins encoded by Usher genes form complexes critical for development and maintenance of cellular structures in the inner ear and retina 3:

• In the cochlea: These proteins stabilize stereocilia tip links on hair cells that transduce sound waves into neural signals 3
• Mutations destabilize these structures, causing defects in protein trafficking, stereocilia bundle morphology, and mechanosensory transduction 3
• In the retina: The protein complex functions at the photoreceptor periciliary membrane, and dysfunction leads to progressive retinal degeneration 5

Clinical Management Implications

Early diagnosis enables implementation of personalized health maintenance strategies 1:

• Vitamin A therapy may slow retinal degeneration in Usher syndrome patients 1
• Ophthalmologic evaluation is required for patients suspected of having Usher syndrome 1
• Audiologic rehabilitation with hearing aids or cochlear implants addresses the hearing loss component 1
• Genetic counseling provides recurrence risk information for families 1

Additional Clinical Features

Emerging evidence suggests Usher syndrome may also involve 5:

• Sleep deprivation
• Olfactory dysfunction
• Deficits in tactile perception
• Reduced sperm motility

Current Treatment Landscape

There is currently no cure for Usher syndrome, but multiple therapeutic approaches are under development 3, 2:

• Genetic therapies are rapidly advancing, with some already in clinical trials 3, 5
• Treatment strategies focus primarily on preserving or partially restoring visual function 5
• Management remains supportive with amplification for hearing loss and visual aids for progressive blindness 2