Course:MEDG550/Student Activities/Usher Syndrome

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Usher syndrome, a genetic condition, is the world-wide leading cause of deaf-blindness[1]. A syndrome describes a condition involving multiple co-occurring symptoms, and, in the case of Usher Syndrome, this includes hearing loss, vision loss, and balance issues[2][3]. There are three clinical types of Usher Syndrome, type 1 (USH1), type 2 (USH2), and type 3 (USH3), that all affect hearing and vision to varying degrees and are sometimes accompanied by balance issues.

Usher Syndrome is typically diagnosed during childhood, either through genetic testing spurred by the discovery of hearing loss or after the onset of vision loss[4]. As a parent who is finding out that their child has Usher Syndrome, it can be very distressing to learn about the condition and the effect it may have on their child's life. Though someone with Usher Syndrome will face unique obstacles, with proper management and support, they can go on to live fulfilling lives―potentially completing post-secondary education, building meaningful relationships, and succeeding in their careers.

Genetics

Genetic Cause

There are 14 genes that have been found to be associated with the three types of Usher Syndrome[2]. Though there are many different subtypes of Usher Syndrome caused by variants in these genes, USH1B, associated with variants in the MYO7A (myosin-VIIa) gene, and USH2A, associated with variants in the USH2A (usherin) gene, are responsible for 80% of Usher Syndrome cases[3].

The other genes that are associated with Usher Syndrome are:

  • USH1: MYO7A/USH1B (myosin VIIa), USH1C (harmonin), CDH23 /USH1D (cadherin 23), USH1E, PCDH15/USH1F (protocadherin 15), SANS/USH1G (scaffold protein containing ankyrin repeats and sam domain), USH1H, CIB2/USH1J (calcium- and integrin-binding protein 2), USH1K[2][3]
  • USH2: USH2A (usherin), ADGRV1/GPR98/USH2C (G-protein-coupled receptor 98), WHRN/USH2D (whirlin)[2][3]
  • USH3: CLRN1/USH3A (Clarin-1), HARS/USH3B (Histidyl-tRNA synthetase)[2][3]

The functions of these genes, which can cause Usher Syndrome when they are not functioning properly, are not well known within the eye, but some of the genes listed above are known to be required for the development and function of hair bundles in the inner ear which move in response to sound waves, gravity, and movement. This movement initiates the transmission of a signal to our brains which is decoded to detect the sound that we hear and to permit balance[2].

Inheritance

Autosomal recessive inheritance in a family with two carrier parents. Each child has a 25% chance of being affects, a 50% chance of being an unaffected carrier, and a 25% chance of being unaffected.

All three types of Usher Syndrome are inherited in an autosomal recessive manner[3]. Humans typically carry two copies of each of their genes which are like sets of instructions for the body; one copy comes from the egg and one from the sperm[5]. In autosomal recessive conditions, both copies of a particular gene must carry a variant, or "spelling mistake", which causes the gene not to function properly[5]. Those who have one normal copy of the gene and one copy that is not functioning properly are called carriers of a genetic condition[5]. It is completely normal to be a carrier of a genetic condition, and Usher Syndrome carriers would not be expected to have any symptoms indicative of Usher Syndrome[2]. When two carriers of variants that lead to Usher Syndrome have a child together, they have a 25% chance of both passing down their gene that is not functioning properly to their child, and this child would then have Usher Syndrome[5]. Because Usher Syndrome is inherited in an autosomal recessive manner, there may not necessarily be anyone else in the family with Usher Syndrome, which can result in this diagnosis coming as a surprise.

Prevalence

Usher Syndrome is found in the range of 1-4 out of every 25,000 people[2]. It is estimated to represent around 5% of all deafness and 18% of all cases of retinitis pigmentosa, which is the degeneration of the retina in the eye that leads to vision loss in Usher Syndrome[1]. The three types of Usher Syndrome are characterized by their clinical presentation, age of onset, and the severity of the condition. These types are further classified into subtypes based on the gene that is affected[2].  USH1 is the most severe form of Usher Syndrome and accounts for 25-44% of all cases[1]. This type is especially common in people with Ashkenazi Jewish descent (USH1F) and those of French-Acadian and Quebecois descent (USH1C)[6]. USH2 is the most common form of this condition, representing over half of the cases[3]. This type is also more common in people with French-Acadian and Quebecois decent (USH2A)[6]. USH3 is by far the rarest form of Usher Syndrome, only accounting for 2-4% of all cases[1]. This is not true, however, for people of Ashkenazi Jewish and Finnish descent, as USH3A accounts for 40% of Usher Syndrome cases in these populations[7].

Clinical Features

USH1

USH1 is the most severe form of Usher Syndrome characterized by the onset of vision loss occurring within the first ten years of life, severe to profound deafness in both ears, and constant balance issues[2][3]. Hearing loss is present at birth and typically remains stable throughout life, not getting increasingly worse or better[7]. Because there is severe-profound deafness at birth, people with USH1 are not typically able to use verbal language[7]. Vision loss begins as night blindness and a loss of peripheral vision during childhood. Children will then lose their visual acuity which rapidly progresses to full blindness[3]. Children with USH1 may also develop gait disturbances as a result of disrupted balance and vision loss[2]. Problems with balance will initially present as delayed motor development. Children would be expected to begin sitting independently and walking later than usual[7].

USH2

USH2, the most common type of Usher Syndrome, is known for less severe hearing loss in the moderate-severe range, which is present at birth[8]. Hearing loss remains stable throughout life; it would not be expected to get progressively worse over time[7]. Because people with USH2 have some hearing that may be amplified through the use of hearing aids or cochlear implants, they may be able to use intelligible verbal language[7] Vision loss typically begins during of after puberty, in the second decade of life, and progresses along the same course as described in USH1[3]. Balance issues are not typically observed in this type of Usher Syndrome[3].

USH3

USH3, the rarest form of Usher Syndrome, is characterized by progressive, post-lingual (after the development of speech) hearing loss, occasional balance issues, and vision loss that begins around puberty or some time within the second decade of life[3]. The progression and age of onset of hearing loss is variable, usually beginning in the second or third decade of life, but in most cases it progresses to profound hearing loss[7]. Hearing loss begins after the child has started talking, which permits well-developed speech[7]. Balance issues are variable and affect around half of people with USH3[7].

Table 1. Clinical features in the three types of Usher Syndrome[7][8]
USH1 USH2 USH3
Hearing Severe-profound; Congenital Moderate-severe; Congenital Moderate-Severe; Progressive
Onset of Vision Loss First decade Second decade Variable, but within three decades
Balance Affected Unaffected Variable
Language Typically unintelligible Intelligible Intelligible

Diagnosis

Depending on the type of Usher Syndrome, it may present and be diagnosed in early life through the initial detection of hearing loss and balance issues, followed by genetic testing. In some cases, especially in USH3, the diagnosis may follow the later onset of vision and hearing loss in the second or third decade of life[8]. In USH1 and USH2, infants are typically found to have hearing loss in their newborn hearing screen, or else it may be suspected by their parents where hearing screening is not offered[1]. USH1 also involves balance issues that delay motor development[1][3]. Children may not walk until they are 18 months old, which could initiate the parents’ concerns[1].

In USH2, hearing loss is typically also detected in newborn screening. If screening is not available, USH2 hearing loss will more often be missed in infancy due to the less severe nature of the hearing loss and the fact that high frequency hearing is mostly affected[1]. If hearing loss is not caught in infancy, it will likely be detected within the first decade of life[1][3].

Hearing loss in USH3 is progressive and begins in the second decade of life, so this delays the diagnosis when compared to the other two types, unless there is a family history or if parents are aware of their carrier status[1][2].

The onset of vision loss occurs later in life, in comparison to hearing loss, in all three types of Usher Syndrome. Though retinal anomalies can be caught in some USH1 cases through electroretinography at 2-3 years of age, many times retinitis pigmentosa is not suspected prior to initiation of vision loss[7].

Management and Treatment

Diagram of a surgically implanted cochlear implant.

Management and treatment for Usher Syndrome typically involves the use of hearing aids or cochlear implants to improve hearing when hearing loss is not profound[2][3]. Due to the profound nature of the deafness experienced in those with USH1, hearing aids are not typically helpful, and children will turn to sign language to communicate[1]. Cochlear implants in children with USH1 may be recommended in the first two years of life in order to provide the highest chance of achieving speech acquisition[1]. In USH2 and USH3, hearing aids are more commonly used, and, in USH2, they can help with speech acquisition[1]. Speech is already developed in USH3, but hearing aids may be beneficial in the early course of the condition. As hearing loss progresses, people may opt for cochlear implants later on in life[1].

There are no approved and commonly recommended treatments available for retinitis pigmentosa, so management and treatment is usually focused on hearing[1]. Vestibular and retinal implants are also increasingly available as options for treating balance and vision problems, respectively; however, these have not been quite as successful as cochlear implants[2]. There are some clinical trials which are available for Usher Syndrome, so that is an option for patients aiming to also improve their vision. Some clinical trials involve the use of gene replacement, gene editing, small molecule drugs, and antisense oligonucleotides[1][2].

Genetic Counselling

Because around 50% of congenital (present at birth) or childhood hearing loss is genetic in origin, consultation with a geneticist and/or genetic counsellor may follow the diagnosis of sensorineural hearing loss[9]. This could facilitate genetic testing which can screen for many types of syndromic and non-syndromic hearing loss―Usher Syndrome being one of these. This conversation may also involve discussing the treatment, management, and testing options, the implications of the diagnosis for the affected person and their family members, and the psychological experience of the patient and/or their family members as they learn about this condition[10].

Family History

Family pedigree of a family with an autosomal recessive disorder. The squares show the men in the family, and the circles are the women. The "a" indicates that this individual carries a genetic variant for the genetic disorder. The "A" indicates that the individual carries a typically functioning copy of the gene associated with the disorder. Shapes that are filled in with black are affected

A family history is a critical part of a genetic counselling appointment where the genetic counsellor may be able to further focus in on the possible explanation for hearing loss. They may ask questions about other family members and medical concerns present in the family which could co-occur with some syndromic forms of hearing loss (e.g., structural abnormalities, pigmentation differences, vision loss, developmental delay, tumors)[3].

Genetic Testing

Gene Panels

Genetic variants that are known to cause Usher Syndrome are included on gene panels for hearing and vision loss, which are genetic tests that search for the more common genetic variants associated with certain clinical features[1]. When considering this kind of testing, it is important to ensure that those involved are aware of the implications of the results and the possible associated findings[3]. In the case of genetic testing for hearing loss, it is important that families are aware of syndromic causes of hearing loss, like Usher Syndrome, which could indicate that the patient will lose their vision along with their hearing. This can be very distressing to find out about, so it is imperative that the genetic counsellor prepares families for this possibility.

Carrier Testing

Some of the genes that are more commonly affected in certain ethnic populations may also be included on gene panels specific to certain ethnicities. This facilitates the screening of people who may carry variants for diseases that they could pass on to their future children, which is called carrier screening[4]. Usher Syndrome may then be diagnosed earlier if parents have already received carrier screening and are aware that they have a higher chance of having a child with Usher Syndrome. Carrier screening may be recommended for couples from ethnic backgrounds that are known to be at a higher risk for genetic conditions, like the Ashkenazi Jewish population, or for couples who are known to be biologically related (e.g., first cousins)[5]. As discussed in the section on inheritance, two people who both carry variants which are associated with Usher Syndrome are Usher Syndrome carriers, and they would be expected to have a 25% chance of having a child with Usher Syndrome[5].

Prenatal Genetic Testing

Diagram depicting the process of an amniocentesis

People who are at an increased risk of having a child with Usher Syndrome, due to a family history or positive carrier screen, may decide to test their unborn child for Usher Syndrome for the purpose of either early diagnosis or possible termination of the pregnancy[10]. Diagnostic options for prenatal testing include amniocentesis, in which a sample of amniotic fluid is collected by a needle inserted through the abdomen at around 15-18 weeks along in the pregnancy[5]. This fluid will contain skin cells from the fetus which can be tested for the genetic variants that cause Usher Syndrome[10]. The other options is chorionic villus sampling (CVS) which is offered for pregnancies that are 11-13 weeks along[5]. This involves the extraction of a small sample from the placenta with a needle inserted through the abdomen or cervix. Genetic tests for variants causing Usher Syndrome are then conducted on this sample. With each of these invasive tests, there is a 0.5% or 1% risk of miscarriage, so this must be considered by the family prior to testing[5]. The options for the pregnancy should also be considered prior to testing as there are no in utero interventions or extra preparations needed for a fetus with Usher Syndrome, and genetic testing can be offered after birth. Prenatal testing may be desired and beneficial when the family is potentially planning on using the test results to inform their decision about whether or not to continue with the pregnancy[10].

Preimplantation Genetic Diagnosis

For those who know their pregnancy or future child is at risk of having Usher Syndrome, testing an embryo conceived through in vitro fertilization (IVF) prior to implantation, pre-implantation genetic testing, may be an option[11]. In preimplantation genetic testing, an embryo can be tested by removing a few cells at the blastocyst stage and testing these cells for the genetic variant carried by the parents and/or the egg/sperm donor. The parent(s) may then choose to only move forward with the embryo(s) that are not at risk of developing Usher Syndrome[11].

Patient Resources

  • The Usher Syndrome Coalition: Provides support and information to individuals and families affected by Usher Syndrome, while accelerating research and raising awareness about Usher Syndrome.
  • Fighting Blindness Canada: Canada’s leading private funder of vision research. They have information about Usher syndrome, available treatment, clinical trials, and research developments.
  • FamilyConnect: a website for parents of children with vision loss; they provide a supportive place for sharing and finding resources on raising their children from birth to adulthood.

References

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  1. ↑ 1.00 1.01 1.02 1.03 1.04 1.05 1.06 1.07 1.08 1.09 1.10 1.11 1.12 1.13 1.14 1.15 1.16 Toms, M., Pagarkar, W., & Moosajee, M. (2020). Usher syndrome: clinical features, molecular genetics and advancing therapeutics. Therapeutic advances in ophthalmology, 12, 2515841420952194. https://doi.org/10.1177/2515841420952194
  2. ↑ 2.00 2.01 2.02 2.03 2.04 2.05 2.06 2.07 2.08 2.09 2.10 2.11 2.12 2.13 2.14 Mathur, P., & Yang, J. (2015). Usher syndrome: Hearing loss, retinal degeneration and associated abnormalities. Biochimica et biophysica acta, 1852(3), 406–420. https://doi.org/10.1016/j.bbadis.2014.11.020
  3. ↑ 3.00 3.01 3.02 3.03 3.04 3.05 3.06 3.07 3.08 3.09 3.10 3.11 3.12 3.13 3.14 3.15 3.16 Gettelfinger, J. D., & Dahl, J. P. (2018). Syndromic Hearing Loss: A Brief Review of Common Presentations and Genetics. Journal of pediatric genetics, 7(1), 1–8. https://doi.org/10.1055/s-0037-1617454
  4. ↑ 4.0 4.1 Brodie, K. D., Moore, A. T., Slavotinek, A. M., Meyer, A. K., Nadaraja, G. S., Conrad, D. E., Weinstein, J. E., & Chan, D. K. (2021). Genetic Testing Leading to Early Identification of Childhood Ocular Manifestations of Usher Syndrome. The Laryngoscope, 131(6), E2053–E2059. https://doi.org/10.1002/lary.29193
  5. ↑ 5.0 5.1 5.2 5.3 5.4 5.5 5.6 5.7 5.8 Nussbaum, R. L., McInnes, R. R., & Willard, H. F. (2015). Thompson & thompson genetics in medicine e-book. Elsevier.
  6. ↑ 6.0 6.1 Saihan, Z., Webster, A. R., Luxon, L., & Bitner-Glindzicz, M. (2009). Update on Usher syndrome. Current opinion in neurology, 22(1), 19–27. https://doi.org/10.1097/wco.0b013e3283218807
  7. ↑ 7.00 7.01 7.02 7.03 7.04 7.05 7.06 7.07 7.08 7.09 7.10 Millán, J. M., Aller, E., Jaijo, T., Blanco-Kelly, F., Gimenez-Pardo, A., & Ayuso, C. (2011). An update on the genetics of usher syndrome. Journal of ophthalmology, 2011, 417217. https://doi.org/10.1155/2011/417217
  8. ↑ 8.0 8.1 8.2 Lønborg-Møller, H., Subhi, Y., & Kessel, L. (2020). Living with Usher Syndrome: Patient and Physician Perspectives. Ophthalmology and therapy, 9(3), 1–6. https://doi.org/10.1007/s40123-020-00258-6
  9. ↑ Yang, T., Guo, L., Wang, L., & Yu, X. (2019). Diagnosis, Intervention, and Prevention of Genetic Hearing Loss. Advances in experimental medicine and biology, 1130, 73–92. https://doi.org/10.1007/978-981-13-6123-4_5
  10. ↑ 10.0 10.1 10.2 10.3 Koenekoop RK, Arriaga MA, Trzupek KM, et al. Usher Syndrome Type I. 1999 Dec 10 [Updated 2020 Oct 8]. In: Adam MP, Ardinger HH, Pagon RA, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2022. Available from: https://www.ncbi.nlm.nih.gov/books/NBK1265/
  11. ↑ 11.0 11.1 Luo, H., Chen, C., Yang, Y., Zhang, Y., Yuan, Y., Wang, W., Wu, R., Peng, Z., Han, Y., Jiang, L., Yao, R., An, X., Zhang, W., Le, Y., Xiang, J., Yi, N., Huang, H., Li, W., Zhang, Y., & Sun, J. (2019). Preimplantation genetic testing for a family with usher syndrome through targeted sequencing and haplotype analysis. BMC medical genomics, 12(1), 157. https://doi.org/10.1186/s12920-019-0600-x
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