Usher Syndrome
By: Swaminathan Sivakumar & Gayathri Sivakumar, Dublin High School
Introduction
Usher syndrome is a rare genetic disorder characterized by a combination of hearing loss and vision impairment, often leading to deafness and blindness over time. It is classified into three major types, each with varying degrees of severity. Type 1 is the most severe, typically causing profound hearing loss from birth and progressive vision loss in childhood. Type 2 results in moderate to severe hearing loss from birth but slower vision deterioration. Type 3, the rarest form, manifests as progressive hearing and vision loss during late childhood or adolescence. Usher syndrome is caused by mutations in specific genes and currently has no cure, although early intervention and support can improve the quality of life for affected individuals.
Usher Syndrome and the regions it affects (Source)
Disease information
Usher syndrome is a complex genetic disorder characterized by a combination of hearing loss and vision impairment. It is classified into three major types (1, 2, and 3) based on the severity of these impairments. This condition typically manifests in childhood or adolescence, with varying ages of onset depending on the Usher syndrome type. One of the hallmark features of Usher syndrome is its progressive nature, where both hearing and vision loss worsen over time. Individuals may experience moderate to profound hearing impairment, which can be congenital or develop early in life, leading to communication difficulties. Vision loss in Usher syndrome progresses gradually, starting with night blindness and tunnel vision, eventually culminating in complete blindness in some cases. Balance and coordination difficulties may also arise due to the combined effects of sensory impairment.
Usher syndrome is genetically heterogeneous, involving mutations in specific genes associated with sensory cell development and function. While there is currently no cure for Usher syndrome, early diagnosis and intervention are crucial for improving the quality of life for affected individuals. Treatments such as hearing aids, cochlear implants, communication training, and orientation and mobility training can help mitigate the impact of the condition. Ongoing research is focused on potential treatments and gene therapies aimed at slowing down or halting the progression of Usher syndrome, offering hope for the future. Despite the challenges it presents, individuals with Usher syndrome can lead fulfilling lives with appropriate support from healthcare professionals and support networks.
Diagnosis
The most common way to diagnose the disease is through its symptoms, which tend to worsen with age. Anyone born with low-impacted vision, mild to severe deafness, or Vestibular Dysfunction could have Usher Syndrome. Vestibular Dysfunction results from reduced reliance on the eyes and ears, weakening the body's ability to coordinate with its surroundings, thus impeding bodily function. There are three types of Usher Syndrome, each with its own set of symptoms. Another, more reliable diagnostic method is genetic testing, performed through a simple blood test collected in a doctor's office, with a 99% accuracy rate. Testing involves examining the patient's blood for nine genes associated with Usher Syndrome.
Blindness, Deafness, and Vestibular Dysfunction are three prominent Usher Syndrome symptoms, subject to extensive research. Regular hearing and vision tests are used for diagnosis.
Tests for diagnosis
Additional tests include Electroretinography (ERG), Optical coherence tomography (OCT), Videonystagmography (VNG), Fundus autofluorescence (FAF) imaging, and DNA testing. ERG assesses retinal function based on its response to light, while OCT captures a detailed image of the retina using light waves. VNG checks for involuntary eye movements indicating Vestibular Dysfunction. FAF imaging employs blue light to capture a retinal image, and DNA testing, conducted by a Genetic Counselor, examines DNA for the disease.
Genetic Characteristics of Usher Syndrome
Usher Syndrome is a recessive trait, meaning the parents would at least have to be carriers of the disease to pass it on to their child. The information collected by researchers so far has led to the discovery that there are 3 types of Usher Syndrome, each with its own set of symptoms. Mutations in at least 10 genes are the identified causes of Usher Syndrome. The USH proteins consist of a set of proteins that are linked with one another so a modulation in any of those proteins results in some type of Usher syndrome.
Implications of genetic mutations in Usher Syndrome (Source)
Usher Syndrome type 1 (USH1)
Patients are completely deaf and do not get any use out of hearing aids. Their night vision decreases when they're young and it becomes a severe vision loss at any time of day by the middle of their life and they have Vestibular Dysfunction from birth. The genes involved are MYO7A, USH1C, CDH23, PCDH15, USH1G and CIB2. MYO7A is the most common gene among USH1 cases
Usher Syndrome type 2 (USH2)
Patients have mild to moderate hearing loss and their vision is the same as in type 1 of the condition because there is no Vestibular Dysfunction. The genes involved are USH2A, ADGRV1 and WHEN.
Usher Syndrome Type 3 (USH3)
The hearing loss begins in childhood in Type 3 (USH3) and the vision loss starts from adolescence but it worsens with age and there will be a severe loss by midlife. There will be little to no balance issues but there might be a possibility for it to occur later in life. The only mutation associated with this type so far is CLRN1.
Symptoms of each type (Source)
Vestibular Dysfunction is caused by an abnormal formation of "Vestibular Hair Cells", which are cells that detect gravity and control head movements. These Vestibular hair cells normally depend on the eye's retina and ears since they aid in the body's coordination. Impacted sight and hearing will play an important factor in Vestibular Dysfunction. Since the retinas might not function in some types of Usher Syndrome, the Vestibular hair cells can't rely on the retina or the ears and the body's senses are not strong enough to be coordinated and perfectly balanced.
Researchers have identified 5 deep-intron mutations in the USH2A for USH2 and 1 intron mutation in the CLRN1 gene for USH3. These mutations affect the mRNA because the exon called pseudoexon (PE) doesn't get deleted in the splicing process but that
truncates the mRNA. Researchers expect to discover more such mutations.
CDH23 has been connected to HL even in non-usher syndrome cases. CDH23 surrounds a genomic sequence that has 69 exons as well as 2 microexons of 6 and 3 base pairs. The CDH23 codes three different isoforms: isoform A, B, and C. Isoform A has 27 calcium binding domains, Isoform B has seven, and Isoform C has none. Isoforms A and B play the role of binding the stereocilia in the ear. Sterocilia are tiny hair-like extensions that are on hair cells (sensory cells) and they are found in the cochlear region of the inner ear. Isoform C is a cytoplasmic protein that is in charge of the microtubule network.
Stereocilia structure with Usher Syndrome proteins (Source)
Treatment
While there is no perfect cure for Usher Syndrome, several treatment options are available. For those with hearing impairments, Cochlear implants, hearing aids, and auditory training are options. Auditory training involves associating sounds with speech to enhance comprehension. Those with low or no vision can receive vision support from optical aids. Mobility training benefits individuals with both hearing and vision impairments and helps counter Vestibular Dysfunction. Gene Therapy is also an option for Usher Syndrome patients.
Ongoing Research
Usher Syndrome is a heterogeneous condition characterized by both deafness and blindness, primarily inherited in an autosomal recessive manner. Researchers have been diligently working to identify the disease at earlier stages and develop more effective treatments. Some research endeavors are aimed at utilizing gene therapy for addressing common mutations, while others focus on slowing down and preventing retinitis pigmentosa (RP), the vision loss component of Usher Syndrome.
One noteworthy effort comes from Sparing Vision, a genomics medicine company based in France, which has dedicated the past year to researching RP in Usher syndrome. Their work has led to the development of RdCVF, a protein released by retinal rods that enhances night and peripheral vision. This drug has received FDA approval for further clinical trials involving RP patients.
Additionally, another research project aims to gather information about Usher Syndrome by employing CRISPR technology to correct mutations in the USH2A gene instead of delivering the entire gene. Diagrams have been created to explore this hypothesis further. While the results of these trials are yet to be documented, it is evident that scientists are actively experimenting with CRISPR technology in the context of Usher Syndrome.
DNA, RNA, and Cell Therapy model - future in usher Syndrome (Source)
Future directions
Future directions in Usher syndrome research are marked by a multifaceted approach aimed at comprehensively addressing the complexities of this genetic disorder. Researchers are actively exploring genetic therapies, including cutting-edge techniques like CRISPR gene editing, to correct the mutated genes responsible for Usher syndrome. Additionally, there is a strong focus on pharmacological treatments targeting specific disease pathways and mechanisms to preserve both hearing and vision. Early diagnosis methods are being refined, seeking reliable biomarkers and improved genetic testing for swift identification.
Efforts are also directed towards vision restoration through innovative approaches like retinal implants and optogenetics, as well as hearing restoration techniques, such as advanced cochlear implants. A deeper understanding of the molecular mechanisms driving disease progression is sought to identify new therapeutic targets. Moreover, comprehensive support programs and patient engagement initiatives are being developed to enhance the overall quality of life for individuals with Usher syndrome. Collaborations among researchers, clinicians, and advocacy groups, along with the expansion of clinical trials, are expected to accelerate progress and bring us closer to effective treatments for this rare genetic condition.
Conclusion
Usher Syndrome is a genetic disorder that involves 10 genes and has 3 types. It impacts hearing, vision, and the person's ability to balance.
Even though there is currently no cure, as technology advances, it should be incorporated into medicine to develop much more efficient treatments for disorders like Usher Syndrome and many more.
References
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A Review of Gene, Drug and Cell-Based Therapies for Usher Syndrome
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https://pubmed.ncbi.nlm.nih.gov/?term=usher+syndrome&filter=simsearch2.ffrft&filter=years.2023-2023
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https://www.nei.nih.gov/learn-about-eye-health/eye-conditions-and-diseases/usher-syndrome
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New CRISPR Tools to Correct Pathogenic Mutations in Usher Syndrome
_By: Swaminathan Sivakumar & Gayathri Sivakumar_
The opinions expressed here are the views of the writer and do not necessarily reflect the views and opinions of Elio Academy.
