Dario S. and his older brother, Matteo, were both born with severe hearing difficulties. Hearing aids improved their ability to distinguish sound and the growing boys took comfort in knowing that those aids would help them through life. But when puberty hit, Dario and Matteo realized that something else was wrong: they couldn’t see well in the dark and they some- times tripped over objects.
In 1995, doctors suspected that the brothers had Usher syndrome, a rare genetic condition that affects both hearing and vision, and they ordered analysis of the boys’ DNA. But only in 2021 was the diagnosis of Usher syndrome confirmed at the molecular level, thanks to genetic analyses done at IOB.
The journey begins
Arriving at a correct diagnosis sometimes follows a short and simple journey. At other times, the journey can take years, even decades. At IOB, clinicians and researchers work together to overcome diagnostic challenges. This close collaboration allows them to solve about 6 in 10 ‘tough’ cases – instances where people with eye condi- tions struggle to have their genetic mutations identified.
With a correct diagnosis, Dario and Matteo will now have access to potential treatments – including some that are being developed at IOB. “It rekindles the hope that vision loss in people with Usher syndrome may be stopped or even reversed during the course of my lifetime,” says Dario, who is an advocate for people with the syndrome through his non-profit association NoisyVision.
Genetic detectives
Nearly 30 years after the first signs of vision loss, Dario’s sight has significantly worsened: he can no longer drive a car or a bicycle, he has difficulties seeing in dimly lit environments such as bars or churches, and has trouble moving around in crowded places such as airports or train stations. He can’t read printed books and he uses phone apps that work like a magnifying glass to get a closer look at menus or small objects. In the evening, he needs a flashlight to locate things like keys in drawers and cupboards.
Previous tests on Dario’s and Matteo’s DNA identified one mutation in a gene called USH2A, which can cause Usher syndrome type 2. To confirm this diagnosis, it was necessary to find a second mutation – but a series of follow-up genetic tests didn’t succeed. Then, in 2020, Dario’s ophthalmologist, Giacomo Calzetti, suggested that he get tested at IOB. Giacomo had started to work at IOB a few months before and knew that the Institute had expertise in genetic testing and the identification of disease-associated genes.
Discovery of second mutation at IOB
Karolina Kaminska and her colleagues in the Ophthalmic Genetics Group led by Carlo Rivolta conducted advanced analyses on Dario’s DNA. They confirmed the first genetic mutation in the USH2A gene and discovered a second mutation that affects the same gene in one of its non- coding segments. The same mutation was identified in the DNA of Dario’s brother.
These so-called intronic mutations are not evaluated in conventional genetic tests, which explains why they were not found before, Giacomo says. “IOB is at the cutting edge of making diagnoses for patients with rare eye conditions that had not been diagnosed by other centers.”
New opportunities
A correct diagnosis can pave the way for treatment. Although currently there is no cure for Usher syndrome, Dario and his brother now have the opportunity to enroll in a clinical trial that is currently being conducted to test the efficacy of a therapy to stop vision loss in people with Usher syndrome.
IOB researchers are also working on therapies that could help people with the disease to regain some sight. One is called “optogenetic therapy” and it functions by sensitizing the eyes of a blind person to light, allowing them to see again. The therapy has already succeeded in partially restoring vision in a blind man with retinitis pigmentosa.
Another therapy that is being developed at IOB relies on an efficient and precise gene-editing technique called prime editing, which replaces one DNA base with an- other without completely breaking the DNA backbone. Using this approach, IOB researchers hope to correct the most common mutations found in people with Usher syndrome. According to Giacomo: “This therapy is in the preclinical stage, but in the future it will be another promising option for Dario.”
What is Usher syndrome
Usher syndrome is caused by genetic mutations in any one of at least 12 known genes, resulting in a combination of variably severe deafness and an eye disease called retinitis pigmentosa. Some people with Usher syndrome may also experience balance problems. Retinitis pigmentosa causes breakdown and loss of cells in the retina – the light-sensitive tissue at the back of the eye. Common symptoms include difficulty seeing in the dark and loss of side vision. There are four main types of Usher syndrome, each with different symptoms, but everyone with the condition develops retinitis pigmentosa, which worsens over time.