Usher syndrome: Genetic diagnosis and current therapeutic approaches

Abstract

Usher Syndrome (USH) is the most common deaf-blind syndrome, affecting approximately 1 in 6000 people in the deaf population. This genetic condition is characterized by a combination of hearing loss (HL), retinitis pigmentosa, and, in some cases, vestibular areflexia. Among the subtypes of USH, USH type 1 is considered the most severe form, presenting profound bilateral congenital deafness, vestibular areflexia, and early onset RP. USH type 2 is the most common form, exhibiting congenital moderate to severe HL for low frequencies and severe to profound HL for high frequencies. Conversely, type 3 is the rarest, initially manifesting mild symptoms during childhood that become more prominent in the first decades of life. The dual impact of USH on both visual and auditory senses significantly impairs patients’ quality of life, restricting their daily activities and interactions with society. To date, 9 genes have been confirmed so far for USH: MYO7A, USH1C, CDH23, PCDH15, USH1G, USH2A, ADGRV1, WHRN and CLRN1. These genes are inherited in an autosomal recessive manner and encode proteins expressed in the inner ear and retina, leading to functional loss. Although non-genetic methods can assist in patient triage and disease extension evaluation, genetic and molecular tests play a pivotal role in providing genetic counseling, enabling appropriate gene therapy, and facilitating timely cochlear implantation (CI). The CRISPR/Cas9 system and viral-based gene replacement therapy have recently emerged as highly promising techniques for treating USH. Regarding drug therapy, PTC-124 and Nb54 have been identified as promising drug interventions for genetic HL in USH. Simultaneously, CI has proven to be critical in the restoration of hearing. This review aims to summarize the genetic and molecular diagnosis of USH and highlight the importance of early diagnosis in guiding appropriate treatment strategies and improving patient prognosis.

Keywords: Usher syndromes; Hearing loss; Retinitis pigmentosa; Diagnosis; Genetic therapies; Cochlear implantation; Quality of life

Core Tip: Usher syndrome (USH) is a genetically inherited condition characterized by both hearing loss and vision impairment, leading to restrictions in daily activities and social interactions. Therefore, gaining a comprehensive understanding of the genetic and molecular aspects of this syndrome is of utmost importance to facilitate early intervention and enhance the quality of life for affected individuals. This review aims to summarize the genetic and molecular diagnosis and current treatments of USH and underscore the significance of early diagnosis in guiding appropriate treatment approaches.