Tag Archive for: diagnosis

Two sides to the story

LEES ARTIKEL IN NEDERLANDS

When your world turns dark

Joyce de Ruiter was sixteen years old when her parents had to tell her that she’d been diagnosed with Usher syndrome: an inherited dis- order which deteriorates hearing and especially vision during life, often resulting in people becoming deaf and blind. “Finally, the puzzle pieces of hearing loss and night blindness had been named, but at the same time your whole future outlook wavers.” Joyce tells us about the impact this diagnosis had on her life and how it gradually turned into something she now draws strength and courage from.

Joyce and her brother were hearing impaired from birth and started to experience initial symptoms of night blindness around puberty, which was strange, as it didn’t run in the family. A diagnosis was lacking until her then 18-year-old brother’s vision deteriorated even further and an ophthalmologist diagnosed Usher syndrome. Joyce was diagnosed with the same disorder when she was just sixteen years old, radically changing her life and future plans. “I wanted to study, work, get married, and have a family. Would that still be possible? When I discovered the study Visual Marketing the fire started burning again, even though the name of the study didn’t sound very useful when you have a visual handicap. But I always kept making choices that made me happy and I’m convinced this enables me to do the things I want to do – despite all the limitations.”

Rushing life no longer
Joyce has worked in HR, Communications, and Events. “I crossed my own limits for too long, because I felt like I had to cram a whole life into half. After my third burnout at age 30, I was declared incapacitated, also because my vision kept deteriorating. It was another one of those moments: what can I still do, what do I want? My eyes and ears didn’t work so well anymore, but there was nothing wrong with my brain.”

INVESTING IN A POSSIBLE TREATMENT IS CHEAPER THAN LIVING WITH THE LIMITATIONS

She decides to tell her personal story in the newspaper, on radio, and on TV as an ambassador for the Dutch Usher Syndrome Foundation, in order to underline the importance of scientific research and development of treatments. This is how the speaking profession came on her path and she has been working hard on her business for 6 years, with success: “As an independent entrepreneur, I now speak at conferences and events about change and agility. Usher constantly confronts you with problems and changes that you have to learn to deal with. I link my personal story to insights in psychology about how to develop an agile mindset. With that, I try to be of value to other people. I think that is the most meaningful thing you can do in a human life.”

Tunnel vision, literally
Joyce is now 38. Her hearing loss is 70 decibels, but with advanced hearing aids she can still function reasonably well. Her vision is greatly reduced, though. “Last year I still had 18 degrees of vision, which is less than a toilet roll I can see through. My orientation on the street is becoming more and more difficult, I haven’t been able to ride a bicycle for years and I feel unsafe in crowded environments; all because of my reduced vision. This is why scientific research is so important. Investing in a possible treatment is ultimately cheaper than living with the limitations. It would be fantastic if a treatment can be found that stops the deterioration and that children do not have to experience any hearingor sight restrictions at all. Of course, we hope that all patients with Ushers syndrome will recover.

That is why the volunteers of the Usher Syndrome Foundation are putting their heart and soul into continuing to make research into a treatment such as that at the Radboud university medical center possible.”

 

 

Bringing light to the dark

From discovering the gene to, hopefully, developing a therapy which will give patients a positive outlook. Erwin Van Wijk has been involved with Usher syndrome research from start to finish, which is quite unique in this field of work as it shows how rapidly developments are following up on each other. “In the most severe form of Usher, children are born deaf and slowly start to lose their vision before puberty. We developed a genetic patch that may be able to limit the damage to vision, our data and the results of the trials look positive.”

 “The hearing problems in Usher are not easy to treat because the underlying cause already arose during development in utero”, says Erwin. “With my research group, I have focused mainly on the visual problems. These arise during life, so there are more opportunities to do something about them at an early stage. The goal of the research was therefore to slow down or even prevent the deterioration of vision. First of all, we need to know which and how genetic defects lead to problems. Mutations in the USH2A gene are the most common, so we took that gene as the primary starting point for developing a therapy.”

Restoring the function of light-sensitive cells
Usher syndrome arises from a genetic mutation which causes the loss or malfunctioning of the corresponding protein usherin. Slowly but surely, the light-sensitive cells in the eye progressively die as a result, and people become vision impaired or at a later stage even completely blind.

The question is: How can this disease process be stopped? Erwin: “Replacing the mutated gene was technically almost impossible because the USH2A gene is extremely large. Instead, we taped the region of the gene with the mutation with a genetic patch. As a result, a slightly shorter protein is produced, lacking the mutation. When carefully selecting the region to skip, the resulting ‘shortened protein’ could work almost as well as the original protein. In principle, this would then solve the problem. In cells we saw that the genetic patch indeed masked the region of the hereditary error. Next, we had to demonstrate that the shortened protein is also functional in the eye.”

Zebrafish as part of the solution
Erwin stumbled upon an unexpected animal to establish whether the genetic patch could preserve visual function. “Zebrafish happen to have an USH2A gene and protein that’s very similar to those of humans. If a mutation is introduced into this gene, the visual function of the zebrafish is also significantly reduced. They are an excellent model for studying USH2A-related visual dysfunction and for determining the effect of a therapeutic intervention. Indeed, visual function of USH2A mutant zebrafish treated with the genetic patch was highly improved.”

INITIAL RESULTS FROM A CLINICAL STUDY IN PATIENTS ARE HIGHLY PROMISING

 After this, the first careful steps towards the translation of the results into a use in humans could be taken. First tests in Usher patients with a mutation in the specific region of the USH2A gene showed promising outcomes, resulting in the design of a large multicenter follow-up study in which the results of the initial clinical trial will hopefully be corroborated in a large cohort of patients. If results hold up, a request for market introduction can be submitted to the American FDA and the European EMA.”

Source: PULSE Magazine #1 2022

Sleep problems Usher patient appears to be a hallmark feature of the disease

LEES ARTIKEL IN NEDERLANDS

Vision impairment is not the driver of fatigue and sleep problems

It was always thought that fatigue and sleep problems in patients with Usher syndrome are the result of increased efforts to compensate for their dual sensory impairment: limited vision combined with hearing loss. Researchers from Radboudumc show in Ophthalmology Science that this idea is incomplete. Besides severe problems with hearing and vision, sleep problems also seem to be a hallmark feature of the disease.

Patients with Usher syndrome experience major problems with vision and hearing. They are born profound deaf or hearing impaired and around puberty they also start to slowly lose their eyesight. These are the central features of the disease. The large individual differences in disease severity and progression are closely related to the underlying genetic defect and the type of Usher syndrome. “Besides hearing and vision loss, patients occasionally also encounter some other problems, like balance deficits, but these have been recognized as part of the disease,” says researcher Erwin van Wijk. “In addition, sleep problems and excessive fatigue are also regularly reported in the consulting room. The fatigue has always been regarded as a result of the dual sensory impairment that patients have to deal with. It’s generally assumed that the sleep problems often reported by patients are the result of their impaired light perception. After all, individuals with poor light perception gradually lose visual day and night rhythms, having a significant impact on their sleep quality.”

Poor sleep
Researchers at Radboudumc are in close contact with patients, mainly via the Dutch Ushersyndrome Foundation. “At one point we noticed that very many patients complained about sleep problems and fatigue”, says Van Wijk. “That intrigued us. Was perhaps something else going on than we always anticipated? Under supervision of Erik de Vrieze, Juriaan Metz, Rob Collin and myself, PhD student Jessie Hendricks started a survey to further investigate this. Fifty-six Usher syndrome type 2A (USH2A) patients and 120 healthy controls were subjected to a set of five validated questionnaires to assess sleep quality, sleep disorders, fatigue, daytime sleepiness and chronotype.” The results indicated that USH2A patients indeed experienced a strongly reduced sleep quality and that they were more often sleepy and tired during the day as compared to controls. But most strikingly, their sleep problems were not related to the severity of their visual impairment. Van Wijk: “These findings perfectly matched the reports of several parents of young USH2A patients, but that were never given a proper follow-up.”

Hallmark feature of Usher syndrome
At a first glance, it may seem only a gradual difference, but the finding is much more significant. Van Wijk: “Actually, it means that the ubiquitously reported sleep problems by USH2A patients are not primarily due to impaired light perception, but that these problems already exist in patients who still have a near normal eyesight. Sleep problems should therefore probably be considered as an additional hallmark feature of Usher syndrome, and not as a consequence of poor or deteriorating eyesight.” Of course, this conclusion based on questionnaires, needs further substantiation. This can be done, for example, through research in an existing zebrafish model for Usher syndrome. Zebrafish also have a distinct sleep pattern. Is it also disturbed? And is there evidence in the brain that Usher syndrome-associated proteins are somehow involved in regulating sleep? These research questions are currently being followed-up.

Improvement in quality of life
Van Wijk points out another aspect of the research. If sleep problems indeed turn out to be part of the disease, there might be a possibility to treat these problems. “Currently, sleep problems are not included in the daily care for Usher syndrome patients, because it is not yet being recognized as a hallmark feature of the disorder. As a result, the visit to a sleep clinic is often not reimbursed by health insurance companies. This hopefully changes based on the study published in Ophthalmology Science and the follow-up studies that are currently being conducted. Treatment of sleep problems will be a major step forward in improving the quality of life of Usher syndrome patients.”

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Paper in Ophthalmology Science: Evaluation of sleep quality and fatigue in patients with Usher syndrome type 2a – Jessie M. Hendricks, MSc, Juriaan R. Metz, Hedwig M. Velde, Jack Weeda, Franca Hartgers, Suzanne Yzer, Carel B. Hoyng, Ronald J.E. Pennings, Rob W.J. Collin, H. Myrthe Boss, Erik de Vrieze, Erwin van Wijk

Does this mutation cause blindness? It does, doesn’t, does!

LEES ARTIKEL IN NEDERLANDS

Janine Reurink ends long lasted controversy with major implications for healthcare


Initially there was no doubt a specific mutation in the USH2A gene caused the eye disease retinitis pigmentosa. Spanish research undermined that clarity and left patients in limbo. Until new research by PhD candidate Janine Reurink made it abundantly clear that the cause is indeed to be found in that USH2A gene. A textbook example of science in action.

We know of ten different genes that can cause Usher syndrome if they contain a mutation. Mutations in these genes eventually lead to deafness and blindness in patients with Usher syndrome. Mutations in Usher genes sometimes ‘generate’ other disorders as well. For example, a specific mutation in the Usher2A gene (USH2A) causes the eye disease retinitis pigmentosa (RP) when inherited from both father and mother. This mutation causes one spot in the USH2A protein to change the amino acid cysteine to phenylalanine, another amino acid. All this was genetically and clinically fine-tuned at the end of the last century. If you had such a specific double mutation in the USH2A gene, you didn’t have Usher syndrome but RP and the clinical problems were limited to blindness.

Smoldering controversy
Then suddenly a publication appeared about a Spanish family with RP. It wrote that researchers had found two individuals with exactly those specific USH2A mutations. But without any vision problem, which after all is an essential characteristic of RP! Erwin van Wijk, who has been researching Usher syndrome at the Radboudumc for over more than ten years: “That caused rather a lot of commotion among researchers and patients, because it meant this specific mutation could not be the cause of RP! Everyone who had previously received this diagnosis had apparently been misdiagnosed. So the real cause had to be found somewhere else in the genes.”
The publication causes many clinical genetics centers around the world to stop diagnosing RP on the basis of this USH2A mutation and all these patients should actually be re-screened. This also applies to Nijmegen. In the meantime, doubts continued. Was the screening in this Spanish family complete and reliable enough? – the results were never confirmed in any other study. Requests from different research groups to check the DNA of those families were not granted. Thus, a smoldering controversy about the value of the Spanish research ensued..

No alternatives mutations found
In recent years, Van Wijk and colleagues developed a promising therapy for a number of mutations in Usher genes. This therapy is based on a technique in which a piece of the RNA is ‘taped off’ (exon skipping). This prevents the mutation from being read and creates a protein that once again functions properly. These therapeutic ‘genetic patches’ can also be used for the specific USH2A mutation, but based on the Spanish family research the causal link with the eye disease is being questioned. As long as it’s unclear whether or not this mutation causes RP, no health insurance company will ever reimburse such a therapy. So a conclusive answer is needed. That proof was exactly what Janine Reurink set out to provide as part of her doctoral research.
Reurink: “First of all, we looked at several patients with the USH2A mutation to see if another explanation could be found for the disorder. To do this, we mapped their entire genome and examined it on all sides. The result? We did not find any alternative genetic explanation. Based on our research, the USH2A mutation remains the only possible explanation.”

Crystal clear evidence
In Nijmegen, much Usher research is done in zebrafish. This time it was also used for additional research, looking for as much evidence as possible. Reurink: “With the CRISPR/Cas9 system, a molecular scissors with which pieces of DNA can be very precisely cut away and replaced, we made a zebrafish with exactly the same mutation as in humans. Analysis of retinal cells in the eye of these fish showed that the corresponding proteins are then no longer or hardly produced. Normal production is really very thoroughly disturbed by the mutation. What’s more: as a result, other essential proteins for vision no longer end up in the right places. We also made an ERG, a kind of brain film for the eye. It demonstrated with crystal clarity that vision is really affected in zebrafish with this mutation. In short, extensive genetic bio-molecular and functional research clearly shows that the USH2A mutation is indeed the underlying cause of this form of retinitis pigmentosa. In terms of a detective novel, we now really have tracked down the culprit.”

Impact on healthcare
The research by Reurink and colleagues has been published in NPJ Genomic Medicine. For people with RP with a USH2A mutation, it’s clear now that this is the real causative, pathogenic mutation. Further search for a (non-existent) cause is no longer necessary. Meanwhile, the clinical genetics laboratories at Radboudumc have adjusted their diagnostics accordingly. Something that many more laboratories worldwide are likely to do in the near future. Moreover, patients are now eligible for therapy as soon one is available. A nice example of PhD research with impact on healthcare.

Radboudumc
Promotion Janine Reurink – USH2A-associated disease. Genetics, pathogenesis and treatment
Thursday April 6, 2023 at 12.30 pm

New type of Usher Syndrome discovered: USH IV   

LEES ARTIKEL IN HET NEDERLANDS

The team of the Hearing & Genes Expert Centre of Radboudumc lately made a discovery: Usher Syndrome includes four different clinical types. The researchers, with Hedwig Velde as principal author, recently published their study and findings in the leading Human Genetics. With the identification of minor faults (mutations) in the ARSG gene and the description of a new clinical picture, they confirm the discovery of a fourth type of Usher Syndrome.  

This really is an important discovery, which gives more clarity about a number of patients with atypical Usher complaints without a genetic diagnosis. In the meantime, following the identification of ARSG as Usher gene, globally fifteen people have still been diagnosed, now that they all appear to have mutations in the ARSG gene. As it has been demonstrated that these patients have a common pattern of symptoms, this is no longer an atypical picture, but it makes up a new clinical type.       

A patient with an atypical clinical picture  
Very rarely a patients visits the outpatients’ clinic showing symptoms that correspond with the clinical picture of Usher Syndrome (loss of hearing combined with retinitis pigmentosa), but which picture deviates from the familiar Usher types. This is called an atypical clinical picture. In some cases no generic cause is found in the Usher genes that are known so far. Consequentially, these patients are unfortunately sent home again without having been diagnosed (and without any clarity). 

Hedwig velde

 Hedwig Velde is researcher and doctoral candidate at the ENT section Hearing & Genes of the Radboudumc. She is studying patients who suffer from loss of hearing but who have not been genetically diagnosed. With her research team she confirmed a new Usher Syndrome type, which is caused by minor faults in the ARSG gene.  

A publication from the year 2018 written by a group of scientists in Israel described the discovery of the ARSG gene with Arylsulfatase G as a protein that might be involved with Usher Syndrome. The researchers from Israel described five persons from three families who all had the same minor fault in the ARSG gene. Such a publication may give other researchers ideas for their studies.  

Studying the DNA of several people within one family sharing the same symptoms is a big help for scientists. Hedwig Velde: “There is a big chance that all patients within the family share the same genetic cause. When outside the family that has been studied another patient is found with the same atypical clinical picture and a minor fault in the same gene, this may confirm the relation between the gene and the clinical picture. Of course, the chance of coming across this patient is really small. Usher Syndrome is very rare.”  

Until the national Expert Centre in the Radboud UMC saw a patient with this atypical clinical picture of Usher Syndrome and Hedwig Velde and other researchers in the Radboud UMC continued the study that was started by the team in Israel in 2018.    

New type now confirmed  
With the publication of Hedwig Velde c.s. the researchers confirmed this new type. The researchers found minor faults in the same gene (the ARSG gene), which creates the codes for the Arylsulfatase G protein. This protein is involved in the degradation of another protein and the idea is that malfunctioning of Arylsulfatase G will lead to an adverse accumulation of the protein that normally should be destroyed. With this study the research team also demonstrated that the minor faults in the ARSG gene that have been found really result in a non-functioning protein.  

The clinical picture of the type does not fit in with the already known Usher types I, II and III. Apart from a later starting age of both the loss of hearing and the retinitis pigmentosa, the ophthalmic defects are more centrally located. This means that the vision problems with these patients rather occur in the central part of the field of vision as opposed to the other Usher types, which usually show problems in the outer part of the field of vision (the periphery). As the clinical picture is consistent with all USH IV patients, researchers of the Radboud UMC are of the opinion that this is not atypical Usher, but a new clinical type: Usher Syndrome type 4.   

Hedwig: “By publishing these findings, we as researchers hope to start up a discussion in the scientific world. Various studies may together lead to the confirmation that the findings are correct or, in some cases, rebut these findings. In case of USH IV it is the accumulation of evidence in several publications that enables us to confirm that this clinical type really is a new Usher type.”    

By now, globally several patients have been diagnosed for this Usher Syndrome type and for minor faults in the same ARSG gene. Previously, these patients used to be categorised in the group ‘diagnosis unknown with atypical Usher symptoms’.    

The course of Usher Syndrome type IV  
Both the loss of hearing and the complaints related to retinitis pigmentosa start at a later age with people suffering from USH IV. Patients started to develop complaints concerning hardness of hearing between the ages of 20 and 40 and the retinitis pigmentosa between the ages of 40 and 60. Based on the audiograms of USH IV patients, the research team has been able to calculate that the loss of hearing starts about the age of 17.  

The course and the progressiveness are not necessarily milder than with the other Usher types. “We still have little insight into the course of USH IV, because only fifteen patients have been described and we therefore have to base our findings on this small group.” 

Genetic tests or not?  
With this discovery the researchers of the Radboudumc have managed to fit in yet another piece of the ‘Usher puzzle’.” Thanks to this, a part of the patients with an unknown diagnosis will eventually be given clarity and this is really important to this group of patients.  

Unfortunately, there still are people for whom the Usher-related symptoms cannot be confirmed by a diagnosis. This makes genetic tests so important!    

The physicians indicate that, of course, the choice is still to be made by the patient. One patient attaches a lot of value to a confirmation by means of genetic tests, while another does not.  
Hedwig: “There are various reasons to have genetic tests done or not. An advantage of a genetic diagnosis is that with this the development of a disorder can better be predicted and that this may help the patient to adapt to the situation. Imagine that you are hard of hearing at a young age and that there is a small chance of becoming visually impaired. However, if you know that you will be visually impaired, then you had better concentrate on the kind of care that will help you both early and later in life. For instance, in this case learning sign language will not be a long-term solution for your loss of hearing, but good hearing aids may make a substantial contribution.”  

Genetic tests will also help the scientific world to get further. For example, as scientific research allows for comparing the DNA of various patients, new genetic causes can be discovered. Besides, this offers a possibility for meticulously mapping out the relation between a minor fault in a gene and the corresponding complaints.
Hedwig: “Because of this, future patients can be better informed about their diagnoses. On the other hand, it is also important for any future genetic treatments to know the exact underlying deviations in the DNA.”    

Usher Syndrome: 4 types and 11 genes involved
In 2022, type IV and the ARSG gene will be added to the list of Usher types and genes involved in the development of Usher Syndrome. So at this moment, Usher Syndrome distinguishes 4 types with 11 different genes involved. [Ed.: This evidence is not entirely conclusive for USH1J (CIB2) yet]
For all these genes scientific evidence has been provided that minor faults (mutations) in these genes will result in Usher Syndrome.    

The Knowledge Portal of the Usher Syndrome Foundation provides a complete overview of the genes with the names of the ‘protein involved’.     

Here you can read the publication of the article by Hedwig Velde c.s. in Human Genetics.  

 

Trailer Silence in the night

The documentary Silence in the night, made by Lisanne van Spronsen and Milou op ten Berg, is ready. The premiere has been postponed due to the COVID-9 measures.

The trailer can already be viewed, with subtitles.

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Vader, Simon, Jet, moeder en zus Op 't Land naast elkaar op een bospad

Hear, see and feel

In ‘Hear, see and feel’ we see the Op ‘t Land family from Zevenhoven, the Netherlands. Daughter Jet (13) and son Simon (18) were recently told that they suffer from Usher Syndrome.

All family members live in the knowledge that both children will eventually become both deaf and blind. However, nobody knows when and how fast this will go.

This documentary was made by students of the Media, Information and Communication training at the Amsterdam University of Applied Sciences.

Automatically generated English subtitling available.