What is Choroideremia?

Choroideremia (CHM) is a rare inherited disorder that causes progressive vision loss, ultimately leading to complete blindness. It is also known as choroidal sclerosis, progressive choroidal atrophy or progressive tapetochoroidal dystrophy. Choroideremia is designated as a rare disease as it affects an estimated 1 in 50,000 to 1 in 100,000 people.

 

The disease affects the retina, which is the area at the back of the eye that gives us vision. The disease is caused by a genetic defect of the X chromosome. Males suffer the full effects of the condition while females experience less severe symptoms and can be carriers.

 

Choroideremia is sometimes misdiagnosed as other retinal conditions such as retinitis pigmentosa (RP) due to the similarity of symptoms. The family inheritance pattern of mainly males being affected and the characteristic pattern of the back of the eye can help with diagnosis. However, choroideremia is a prime example of where genetic diagnosis can be crucial to receiving the correct diagnosis. You can find more information on genetic testing for IRDs in our Genetic Testing Toolkit http://www.retina-international.org/genetics/

Symptoms of Choroideremia

Night-blindness is often the first symptom of choroideremia, like many IRDs, and is usually first noticed in childhood. This can be followed by variable loss of side vision, known as the mid-periphery. These “blind spots” are initially experienced in an irregular circle, while central vision is still maintained. As time passes, the vision loss spreads around the whole periphery of the eye leading to “tunnel vision”. Central vision is usually maintained until late adulthood but, eventually, complete loss of sight occurs in late adulthood. The symptoms of choroideremia may vary greatly between affected individuals. Female carriers usually have very mild symptoms with night blindness or sensitivity to glare occurring late in life.

 

Choroideremia is characterized by extensive loss of all the layers in the eyes. Choroideremia usually begins during childhood with loss of the retina, the pigmented retinal epithelium (RPE) and choroid. The retina is a thin layer at the back of the eye composed of different types of light-sensitive nerve cells that detect light and give us colour vision and night vision. The RPE is a single layer of pigmented cells that lies on the outside of the retina. The choroid is the next layer and is also called the choroidea or choroid coat. It contains connective tissues and small blood vessels (vasculature) of the eye. It is the layer between the retina and the white part of the eye (the sclera).  The thickness of the human choroid layer varies, with the area right at the back of the eye being approximately twice as thick as that at the periphery. You can read in more detail about parts of the eye here http://retina-ird.org/menu/introduction/#howeyeswork

 

The symptoms of choroideremia can be very similar to several different disorders. This can lead to difficulties in determining which exact condition a person has. Differential diagnosis (the process of differentiating between two or more conditions which share similar signs or symptoms) can be useful. As choroideremia is a genetic or inherited condition with a known gene, a genetic diagnosis can determine a specific diagnosis of choroideremia and potentially exclude other conditions. Some of the other conditions that have similar symptoms include:

  • X linked retinitis pigmentosa (RP) – symptoms include poor night vision that progresses to loss of peripheral vision and tunnel vision. As it is X linked, it has a similar inheritance pattern to choroideremia

Gyrate atrophy of the choroid and retina – symptoms include vision loss due to circular loss of the choroid and retina. It can be diagnosed due to elevated blood levels of ornithine and people with this condition have other symptoms such as muscle weakness

Genetic Basis of Choroideremia

IRDs are characterised by the fact that they are genetic conditions that can be inherited. Some IRDs, such as Leber’s congenital amaurosis (LCA), can be due to mutations in many different genes. However, choroirderemia is unlike most other forms of IRDs as it is mainly due to mutations in just one gene, called CHM. The CHM gene (OMIM 303390) encodes a protein call Rab escort protein 1 (REP1). REP1 is involved in transporting small sacs (vesicles) containing proteins, molecules and cell components to different locations within cells. The exact mechanism and origin of the degradation of the different parts of the retina is still not fully clear and may differ between people affected. So far, there have been 280 mutations in the CHM gene that can result in the choroideremia condition. Most of these mutations result in a non-functional copy of the gene, known as a null allele. This means that the mutation can result in the production of a protein that doesn’t work properly or lack of production of any protein.  There has been a second gene connected with some cases of choroideremia. The CHM-like (CHML) gene encodes the REP2 protein, which is very similar to REP1. As they are so similar, the two proteins may be able to compensate for the loss of the each other.

 

The CHM gene is located on the X chromosome. As males have one X chromosome and one Y chromosome, they are vulnerable to diseases that are caused by mutations in their single x chromosome. Therefore, only males suffer the full effects of complete blindness of choroideremia. Females have two X chromosomes, one inherited from each parent. If one of their X chromosomes carries a mutation, the other unmutated X chromosome may be able to compensate for the loss. In females, only one of the two X chromosomes is used, while the other is inactivated. This occurs randomly in individual cells and so in the whole retina, approximately 50% of the cells will use one of the X chromosomes and 50% will use the other X chromosome. Thus, females can be carriers of the disease and show no symptoms or they can have below normal sensitivity of vision, pigment changes in the back of the eye and problems with seeing in dim light.

 

Choroideremia has a 50% chance of being passed onto the children of an affected parent. However, men with choroideremia cannot pass the gene onto their sons, as the mutation is on the X chromosome and sons get their single X chromosome from their mother. Daughters, however, will inherit their father’s X chromosome as well and their mother’s X chromosome. Daughters can therefore inherit the mutated chromosome and will be carriers but may not be affected. For a woman with a CHM mutation who is pregnant a female child, there is a 50% chance of passing the gene onto a daughter and 50% chance of passing on the normal gene to a daughter. For a male child, there is a 50% chance the son will inherit the mutated gene from his mother and a 50% chance the son will inherit the normal copy. You can read more about inheritance patterns of IRDs here http://www.retina-international.org/for-patients/your-eyes/inheritance-patterns/

Coping with a Diagnosis

The time of diagnosis can be difficult and many different emotions can arise. For some people, it may be quite distressing, upsetting or overwhelming. People often struggle to understand how this has happened and how they will cope now and in the future. If you feel like this, you are not alone. There is no need to feel guilty about these feelings. It is important to find support for your situation and to have a way to express your feelings and thoughts.

The initial feelings that people experience after a diagnosis can include shock, denial and despair. These feelings will lessen as time passes. While it is natural to feel like this after such a life-changing diagnosis, it could help you to talk to a healthcare professional or a counsellor. With the appropriate support and guidance it is possible to work through and overcome difficulties to find new and life-enhancing meaning and purpose in living.

For Parents

If your child has been diagnosed with a visual impairment, it is important to remember that, despite the diagnosis, your child has not changed. Your child is a person that is much more than the threat of blindness. Children are more aware of things than we give them credit for, and so it is important to be honest and answer their questions truthfully and compassionately. Ideally, a child should be told about their diagnosis in an age-appropriate way by a loving person who is close to them. If a child isn’t told about their diagnosis but then discovers information from sources other than the family, for example overhearing a doctor’s conversation, over time this can foster mistrust and resentment.

However, there are many supports and outside help available to parents, so that they don’t have to do everything alone. Parents can often feel that they must be the sole doctor and carer and nurse for their child. However, this can be an overwhelming and impossible task. Outside help can support those roles to allow parents to do the very important role of being parents to their child. Please see the member charities of Retina International for a local sight loss charity near you http://www.retina-international.org/our-members.

Daily Life with Choroideremia

My journey for a therapy for CHM – Michael Längsfeld

 

As my vision deteriorated, I could not accept that there was no therapy for my condition, choroideremia. I went on a journey to search for something or someone that could bring me closer to a treatment. My first hope arose when I was listening to a speech from Prof. Jean Bennet about a study for LCA at the Retina International conference in Italy. There, she announced that she will also start work on a gene therapy for choroideremia. Full of euphoria, I emailed her and offered to be a candidate for her study. Unfortunately, the study was only open to American patients and I am living in Germany. I didn’t let that stop me and I continued with my search. I found that Prof Robert Mac Laren from Oxford was also working on a study for gene therapy for choroideremia. He had published a study in the journal The Lancet with promising results. Unfortunately, my offer to Prof Mc Laren to be a candidate in his studies was again not successful as the study was only open to people within the UK.

At one point, Prof. Robert Mac Laren and Prof. Jean Bennet presented results of their studies at a conference in the Netherlands. A friend and I made our way there and we learned that studies for a gene therapy for choroideremia are working but are only accessible to patients in foreign countries, which did not help us in my home country of Germany. I made contact with and was invited to attend a conference on choroideremia organised by the American CHM Foundation CRF. There I met several of the lead researchers in the field, including Prof Bennet, Prof Mc Laren and Prof Ian McDonald. I learned a lot about the possibilities of gene therapy for choroideremia. I began to contact many clinicians and researchers in Germany in order to find studies I could take part in. I organised the first choroideremia conference in Frankfurt, Germany. I wanted to highlight gene therapy in the conference program so I invited Dr. Dominik Fischer to speak. At our conference, he announced that the University Eye Hospital in Tübingen would begin a study on gene therapy. We were delighted to support recruitment to the study and requested our members to take part on a screening, to find out if they are suitable for the study. The authorisation of the study was still outstanding, but we tried everything to support it in order for opportunity of gene therapy comig to Tübingen. I supported that approval procedure through a visit in London at the European Medicine Agency (EMA) and discussions at the Paul Ehrlich Institute in Germany. Around this time, Prof Issa from the University of Bonn in Germany was conducting a Natural History Study on choroideremia and contacted me to ask if our members would take part. We were delighted to support recruitment for this important study.

Thirteen months after this, I received a hugely important phone call. Prof Dominik Fischer called to say that the authorisation was granted for the gene therapy and he asked if I was ready to be the first patient to receive the treatment. In January 2018, I finally received gene therapy for choroideremia in one eye. I found in the clinic in Tübingen a great, competent and helpful team that was helpful at all times and kept me informed. Some days later I could leave the hospital. The vision of my operated eye had subsided after the operation, but since then it has again stabilized on the level which I had before. Prof. Fischer presented the first results on our first European CHM conference last year and they’re very promising. So far, there are six patients who have received the therapy in this study. For me it would be a great success if this therapy maintains the eyesight that I have. The next step, of course, will be that my eyesight of the second eye will be saved as well.

 

Michael Längsfeld is the Working Group Head of PRO RETINA Germany, an organisation he has been a member of since 2013. Michael is also a member of Board of Directors of Choroideremia Research Foundation Inc, USA, a member of the Management Committee of Retina International and currently chair of Retina International’s new SIG on Choroideremia. 

Email: michael.laengsfeld@googlemail.com

Website: http://www.pro-retina.de/netzhauterkrankungen/chorioideremie

Internet community: www.rareconnect.org/en/community/choroideremia

Facebook: www.facebook.com/groups/1388456481446308/?fref=ts,

Where Are We Now?

For an individual affected by choroideremia, maximising the remaining vision that an individual has is a crucial first step to take, and there are many new low vision aids including telescopic and magnifying lenses. The wide range of assistive technologies for people with visual impairments provides plenty of choice for users at all stages of sight loss, and this technology has also removed many barriers to education and employment.

While there is no current treatment on the market for choroideremia, studies are underway to find potential treatments. As it is a genetic condition where (usually) only one gene is affected, choroideremia is a prime candidate for gene therapy. A genetic diagnosis is very important for affected individuals to access clinical trials for gene therapy. You can find out more about genetic testing in our toolkit on it here. There are clinical trials currently underway for choroideremia. You can search for clinical trials at www.clinicaltrials.gov or you can read about trials for IRDs here

Where Are We Going?

Gene Therapy

Identification of the specific gene mutations that cause choroideremia has provided the opportunity to develop novel therapies targeted towards addressing the genetic defect. Choroideremia is (usually) due to defects in only one gene and so is a prime candidate for gene therapy.

In gene therapy, genetic material is inserted into cells to compensate for abnormal genes or to make a beneficial protein in order to treat a disease. The most common type of gene therapy being investigated for the treatment of IRDs in clinical trials is gene augmentation therapy. Many IRDs including choroideremia are caused by specific gene mutations which lead to reduced production or loss of the function to the proteins they make (so-called “loss-of-function” mutations). With gene augmentation therapy, a normal functioning version of the disease-causing gene is inserted into the affected retinal cells helping them to produce sufficient levels of the protein, restoring its normal function and preventing cell death.

The potential of gene augmentation therapy for the treatment of IRDs is highlighted by the recent approval, by the FDA in the United States and the EMA of the EU, of voretigene neparvovec (tradename: Luxturna). Luxuturna is approved for the treatment of the RPE65 mutation-associated inherited retinal disease, LCA – click here for further details about Luxturna While this treatment will not directly be beneficial to people with choroideremia, the success of Luxturna gives hope that treatments for other IRDs such as choroideremia are possible.

Stem Cell Therapy

Choroideremia is characterised by the irreversible loss of retinal cells, including retinal pigment epithelium (RPE), photoreceptor cells (rods or cones) and choroidal cells, all which lead to vision loss.

Stem cells are undifferentiated immature cells that are capable of self-renewal and can differentiate into specialist cell types, including RPE and photoreceptor cells. The application of stem cells to replace or repair damaged cells in the diseased retina, potentially restoring visual function, is an important area of ongoing research in drug development.

There are different types of stem cells that are being evaluated as potential treatment of IRDs. You can read about them in detail here.

Drug Treatments

Choroideremia causes cells in the retina to gradually stop functioning and die, leading to vision loss.  One area of research is looking into drugs to keep these cells healthy and functional. Called neuroprotective agents, they are intended to slow the degeneration of the cells and to slow or halt the progressive loss of vision. You can read more about these agents here.

Access to Treatments

Access to treatments is a universal issue, with the reportedly high prices of many new treatments being a potential barrier globally. While treatments using new technologies such as gene therapy may have a high price tag at first look, the fact remains that some could result in a once-off treatment that will potentially prevent vision loss for at least 10 years, if not for life. It is of utmost importance, therefore, that patient groups in every country have the right information and the right advocacy tools to ensure that such life-changing treatments are made available in their countries.

Information that would help illuminate the benefits of such a treatment includes:

  • the number of potential patients in each country, which requires access to genetic diagnosis. Please see our Red Alert Toolkit for more information on genetic testing http://www.retina-international.org/toolkit-redalert
  • the impact of these conditions on the life of the patients and of their families
  • the impact of these conditions on society, including the everyday care needs of someone with visual impairment from young children to adults; the potential effect on the education and employment of the patient and their carers; the additional supports supplied by health care providers, health systems or charity groups.

Retina International see the need for such information to be gathered and we are actively engaged in projects to this end. If you would like to contribute information of this kind, we would love to hear from you. Please get in touch info@retina-international.org. and you can visit our section on Advocacy for more information on the need for data on impact.

While treatments such as gene replacement therapy are revolutionary, they are still quite a way from being universally available for all types of IRDs. While we await new treatments, individuals with Choroideremia and other IRDs can access appropriate visual supports to ensure they can live as fully and as independently as possible. Please see our sections on Coping with a diagnosis and Life with Choroideremia for more information.