Leber congenital amaurosis (LCA) appears at birth or in very young children. It is an inherited disease that can have quite severe vision loss. The level of loss varies between individuals; some affected individuals can have little or no light perception. Leber congenital amaurosis was first described in 1869 by the German ophthalmologist Theodor Karl Gustav von Leber, which is where the disease gets its name.
What is LCA?
The term congenital means that the condition is present from birth and not acquired. Amaurosis refers to a loss of vision that is not associated with a lesion. While LCA is a rare form of retinitis pigmentosa (RP), it is unique in several ways. Symptoms are often noticed when a child is a few weeks or months old, and vision loss is more rapid and severe than other forms of RP. The disease is less prevalent than RP as well, affecting approximately 1 in 33,330 to 1 in 50,000 individuals.
LCA accounts for 5% of all retinal dystrophies and 20% of blindness in school age children. LCA is the result of a mutation in one of at least 17 different genes, which is why it is called a “genetic” or “inherited” disorder. Both rod and cone cells can be affected by the mutations and therefore can degenerate and die. In all cases, the retina’s ability to develop and function properly is impaired, resulting in visual impairment.
Symptoms of LCA
While LCA can manifest differently in affected individuals and there are different classes of LCA, there are some symptoms that are classically linked to LCA and appear very early in life. Parents may notice that the child does not focus on things around them or they may notice nystagmus, which is involuntary jerky rhythmic eye movement. Photophobia (sensitivity to light), slow pupillary response to light and eye-pressing or rubbing with fingers or knuckles are also common early symptoms. Eye pressing or rubbing can cause damage to the outer parts of the eye and affect the fatty tissue a is common in young children and babies with low vision.
Children with LCA usually have severe vision loss of 20/400 or worse, meaning that they can see at 20 feet what a person with “normal” vision can see at 400 feet. Some children may have only light/dark perception, and in fewer cases no vision at all. Children with some vision may have other symptoms such as night blindness, light sensitivity, and far-sightedness. There are rare genetic syndromes that mimic LCA vision loss in young children, including Alström syndrome, Batten disease, Joubert syndrome, and peroxisomal diseases (Zellweger syndrome or Refsum disease).
Children with these conditions have vision loss similar to LCA, as well as other physical or mental disabilities. A child diagnosed with true LCA (not one of the syndromes listed above) may, in rare cases, be more vulnerable to kidney disease than other children. Compared to the general population, however, they do not have a greater risk of either intellectual disabilities or autism.
LCA may be suspected on the basis of a child’s symptoms and the findings of a simple eye examination. The diagnosis of LCA can be confirmed with the following tests:
ERG (electroretinography): this is a test that measures the electrical responses of the retina to light, evaluating responses of both rod and cone photoreceptors. The ERG test involves staying in a darkened room for 30 minutes, with drops put into the eye or eyes being tested. A special contact lens or gold-foil electrode is then placed on the eye or lower eyelid, and the eye is exposed to flashes of light.
OCT (optical coherence tomography): this is an imaging technique that involves taking digital images of the various layers of the retina. The process is uses light rather than sound or radio waves, which is why the images are in high resolution.
Genetic counselling: while not a test in the traditional diagnostic sense, genetic counselling is an important part of the diagnostic process. It can help determine the gene or genes that have been mutated, as well as the hereditary factors that are involved. See our section on genetic testing fr more information: http://www.retina-international.org/toolkit-redalert
Some forms of LCA do not show a change in vision over time, while others progress. The type of LCA determines the amount of visual loss. LCA can be caused by mutations in different genes. While it can be sometimes inherited in an autosomal dominant pattern, it is usually inherited in an autosomal recessive pattern.
This short video from the National Eye Institute/National Institutes of Health (NEI/NIH) looks at vision in families:
Genetic Basis of LCA
IRDs are caused by a gene mutation that is inherited from a parent. This led to the title of “Inherited Retinal Disease”. In the case of IRDs, the mutation affects genes that play an essential role in normal retinal development and functioning, leading to the degeneration of photoreceptors and other retinal cells and associated vision loss.
LCA is the result of a mutation in one of at least 17 different genes, which is why it is called a “genetic” or “inherited” disorder. Both rod and cone cells can be affected by the mutations and therefore can degenerate and die. In all cases, the retina’s ability to develop and function properly is impaired, resulting in visual impairment. LCA is a very rare condition which is estimated to affect around 1 in 80,000 in the population. Forms of LCA are caused by a mutation in one of up to 18 genes that are important for retinal function. Both rod and cone cells can be affected by the mutations and therefore can degenerate and die.
Regardless of the mutation involved, visual impairment is due to impairments in the retina’s ability to develop and function properly. It is usually inherited in an autosomal recessive manner. However, there are rare incidences where the inheritance pattern may be autosomal dominant. You can learn more about inheritance patterns here: http://www.retina-international.org/patients/your-eyes/inheritance-patterns. Some genes that are implicated in LCA can also be connected to other IRDs. For example, different mutations in the GUCY2D gene can result in either cone-rod dystrophy or in LCA. You can see the list of genes currently known to be associated with LCA here.
Genetic testing is of utmost importance for many IRDs due to their genetic origin. Genetic testing can aid in diagnosis and, critically, it can determine if individuals have a specific mutation that may mean they are eligible for a clinical trial or even treatable by specific gene therapies. You can learn more about how genetic testing works, and what it can do, at our toolkit ‘SENDING A RED ALERT!’, intended to inform those with rare eye diseases about genetic testing services: http://www.retina-international.org/toolkit-redalert
Watch this short video from the National Eye Institute/National Institutes of Health (NEI/NIH) about vision in families:
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.
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.
It can be difficult to explain the complexities of vision and vision loss to children. However, there are useful videos designed to introduce children to some of the concepts. Some of these are listed here:
The Visual System: How Your Eyes Work
Ask a Scientist: Eyes at Night
Ask a Scientist: Eye Myths and Facts
Some people with sight loss can experience visual hallucinations, or see things that are not there. This can be very frightening for people and some fear that they are having mental health problems. However, it is a common condition in people who have recently lost their sight where the brain is adjusting to the loss of visual information. It is called Charles Bonnet syndrome and while it can be distressing, the hallucinations can get less frequent as time passes.
Vision rehabilitation is one of the supports that ensure you have the right information, training, skills and aids to transition to living with sight loss. Your local sight loss charity will have information on local supports http://www.retina-international.org/our-members
Simple adjustments such as reviewing the lighting in your home can make helpful improvements. A low vision service can advise you on the use of aids such as magnifiers and specialist lighting. Vision rehabilitation support is not just for physical adjustments but also takes into account a person’s communication needs and how they keep in touch with others. This can be aided with help with reading, writing, talking books and newspapers, telling the time, using technology such as smartphones, tablets and speech software. Most smartphones or computers have accessible features built in while there are many packages available that enable everyone to use a computer. ViaOpta is a recently developed suite of mobile applications to assist visually impaired people with their daily lives. These apps allow individuals to maintain their independence by assisting with daily activities, navigating their local region and recognising people and places using image analysis technology. See https://www.viaopta-apps.com for more details.
A visual impairment does not preclude an individual from education or employment. Appropriate vision rehabilitation can ensure access to training, education and learning opportunities as well as advice about disability employment.
Daily Life with LCA
THE KEY ELEMENT THAT IGNITED MY BLIND SONS TO ACHIEVE GREATNESS
In the year 2000 I met a blind person for the first time. I was 28 years old. Until then I had had only two “experiences” with blind people: First, there was a blind woman at my childhood church that sat alone in the front pew, entering and exiting the service through a side door with her guide dog. The second was a favorite childhood television show, “Little House on the Prairie”, that had a character, Mary, who completely lost her sight on an episode and was then shipped off to a school for the blind.
Knowing my lack of education or experience, imagine how I felt when I actually met a blind person for the first time. With my extremely skewed perspective, I saw this person as I saw blindness: scared, lonely and sad. There is a problem with this on many levels, but the worst of all is that the first blind person I ever met was my first born child.
It was the summer of 2000 when I noticed something was “not right” with our perfect first baby’s eyes. I smiled and laughed as I played with him… assuming he was seeing his toys. I cooed and giggled with him… thinking he was seeing our faces. I was shocked to learn at five months old that he was seeing just about nothing due to Leber’s Congenital Amaurosis. I was told in a tiny exam room by a retina specialist “I am sorry. I know how devastating this is. You are going to have to learn how to raise a blind child. The dreams you had for him are gone. Good luck.”
I fell on the floor.
Eventually I got up, dusted myself off, and met professionals in the field of blindness to learn the tools my son would need to survive school and life. Even after a second diagnosis of LCA (my second son was diagnosed in 2003) I managed to survive as the boys were happily adapting to a world they could not see. They were surviving blindness, but I was still devastated. I was still depressed. I was still angry.
I am typically a forever optimist but I could not shake the depression, sadness and anger. And then I figured out why: When friends would send my boys cute little Eagles jerseys (we are Philadelphia football fans) all I would think was: They are never going to play football. When preschool teachers showed us the dress up area on the tour of the classroom all I could think of was: They will never be a fireman, or a doctor, or an airplane pilot. I had absolutely no expectation of my children being able to have big dreams for big lives. That is, until I heard about a man that not only had great expectations for his life, he shattered my perception of what a person could accomplish – with or without sight.
A friend told me about a book called Touch the Top of the World. The author, Erik Weihenmayer, tells his story of going blind as a young teenager and eventually becoming a mountain climber that ultimately went on to climb all seven summits of the world. It was just the story I needed to begin the shift in my thinking. Erik’s tale of growing into acceptance of blindness and creatively chasing his dreams ignited a new perspective for me – and my expectations for my sons began to change.
I read that book over and over again and sent it to family and friends. I wanted everyone to know that great things were still possible for my boys – we just were going to have to expect the best from them, help them access tools and strategies, and we were likely going to have to be very creative on our journey. I started making them do chores like I would a sighted child. I made them learn Braille so they could read like a sighted child. They went to playgroups and gym classes to socialize with other children. I learned all the tools they would need and I went into our first Individualized Education Plan (IEP) meeting at our local Kindergarten with high energy and a positive attitude that my son was going to do well with school. I rattled off terms like “inclusion” and “direct braille instruction” and “mobility lessons”. I was on fire!
And then it was the school’s turn to speak. They rattled off their “goals” and “service time” which included things like Braille instruction one time per week and occupational therapy thirty minutes per week. I thought to myself, in the twelve and a half hours per week that my son would be in that building, he’d only be taught how to read and write Braille for an hour? I knew from my teaching background that there would be sight word and words-read-per-minute goals for the sighted kids, but although Michael was highly intelligent, his goals were more like “master one to two Braille contractions per week.” There were no goals for learning how to socialize with the other children. There was no plan to address finding friends at recess. And the item that would end up changing our entire course of direction in educating our son: Michael will find his cubby and hang up his jacket 70% of the time. It turns out the vision support and special education staff were only “allowed” to put 70% as the highest percentage achievable “for evaluation purposes” “After all Kristin”, they said, “we can’t set him up to fail. If you say he should do it 100% of the time and he doesn’t, that would make him a failure.”
My stance was that if the sighted children were expected to find their cubby 100% of the time, then the same was to be expected of my Michael. Since that moment I have never settled for 70% or 80% or even 90% as the expectation for any of the tools my sons need to learn.
That “conversation” back in Kindergarten opened my eyes to something so many others had already known and unfortunately experienced then and still now: expectations of blind children and adults are entirely too low and not in line with expectations of sighted people. And the most unfortunate, devastating part about that: blind children, just like sighted children, that grow up knowing there is no expectation of greatness rarely achieve it.
It was time to change perceptions and raise the level of expectations of what my sons could do, would do, and should do.
As luck would have it, at the same time I was trying to convince that IEP team to raise their expectations of our son, Erik Weihenmayer was receiving an award near my home at the Associated Services for the Blind of Philadelphia – and I was able to convince Michael’s entire IEP team to attend and hear Erik speak. Erik talked enthusiastically about climbing Everest and the other mountains, about getting married and writing books. He was funny. He was smart. He talked about how he used his adversity to his advantage (see Erik’s second book The Adversity Advantage) and encouraged the audience to never set limits on people, especially blind people. That speech changed the perceptions of Michael’s educators, which completely changed how they went about educating Michael and later Mitchell. From that point on everyone was on the high expectations bus for my boys.
Ever since that experience with Erik, my boys have attended the ASB’s annual awards ceremony to meet the blind people receiving the awards and thereby growing our list of role models. I believe these encounters with people that are chasing their dreams and accomplishing their personal greatness are what ignited my sons to dream big and create a path to their own greatness. Michael is in his first year of college and Mitch in 10th grade and they have been elected to student government, started clubs when there was no club for their interests, and are social butterflies. They are also award winning Braille students, musicians and athletes. Michael dreams of being a mover and shaker in the music industry and Mitchell dreams of being the most watched weather anchor on tv. They talk about the college life, traveling Europe with friends, the lists of dreams are endless. With every successful blind person they meet, their expectation of greatness grows and it has been beautiful to watch them follow their passions.
My boys are not surviving blindness, they are thriving.
I believe every single child has greatness. It is our job as parents and educators to guide them on their path, help them gather the tools they need, and assist them in building a team of supportive resources so that every single child, blind and sighted, chases their dreams and achieves their personal greatness.
Kristin Smedley lives in Bucks County, PA, USA with her three children Michael (LCA-CRB1) Mitchell (LCA-CRB1) and Karissa (sighted). She is President and Co-Founder of the Curing Retinal Blindness Foundation that funds vision research for CRB1, LCA, and RP and provides resources for families of blind children. Kristin speaks around the USA about raising expectations of blind children and guiding them to greatness. She delivered a TEDx talk in New York City about changing perceptions of blindness and her first book, Thriving Blind, Stories of Real People Succeeding Without Sight, is coming soon! Connect with all of her writing, speaking and philanthropy at http://kristinsmedley.com/ and on Twitter @KristinSmedley
Where Are We Now?
The potential of gene augmentation therapy for the treatment of IRDs is highlighted by the recent approval in the United States of voretigene neparvovec (tradename: Luxturna) for the treatment of RPE65 mutation-associated inherited retinal diseases.
Luxturna (voretigene neparvovec)
The first commercialized gene therapy for the treatment of an IRD, voretigene neparvovec (tradename: Luxturna, Spark Therapeutics), received approval from the United States Food and Drugs Administration (FDA) in December 2017. Luxturna is approved for use in children and adults who have vision loss due to inherited retinal diseases caused by mutations in both copies (bialleic) of the RPE65 gene and have sufficient viable retinal cells.
The RPE65 gene provides instructions for making an enzyme (a protein that facilitates chemical reactions) that is essential for normal vision. Mutations in the RPE65 gene lead to reduced or absent levels of RPE65 activity, blocking the visual cycle and resulting in impaired vision. Individuals with biallelic RPE65 mutation-associated retinal dystrophy experience progressive deterioration of vision over time. Mutations in RPE65 account for approximately 2% of cases of recessive retinitis pigmentosa and between 6–16% cases of Leber congenital amaurosis.
Luxturna works by delivering a normal copy of the RPE65 gene directly to retinal cells. These retinal cells then produce the normal protein that converts light to an electrical signal in the retina to restore patient’s vision loss. Luxturna is administered via subretinal injection in both eyes separately and on separate days. This procedure performed is a specialist eye surgeon. It is given as a one-time treatment.
NEI/NIH have produced a short video to explain Leber Congenital Amaurosis (LCA) and potential treatments for specific forms of LCA (note that this was produced prior to approval of Luxturna):
The approval of Luxturna in the United States was based on the results of a clinical trial programme that enrolled a total 41 people between the ages of 4 and 44 years, all of whom had had confirmed biallelic RPE65 mutations. The effectiveness (efficacy) of Luxturna was demonstrated by a Phase 3 clinical trial that enrolled 31 participants. The study found that at 1 year after the treatment, participants who received Luxturna had significantly improved light sensitivity, visual fields, and navigational ability under dim lighting conditions, compared with the control group (participants who were not treated Luxturna). Furthermore, no product-related serious side effects were observed among patients treated with Luxturna during the study.
In Europe, Luxturna received a positive opinion from the Committee for Medicinal Products for Human Use (CHMP) on 20 September 2018) who recommended granting of marketing authorisation. However, that is just one step on the road to access to treatments; the next hurdle is recommendation for reimbursement. This means that the treatment will need to be assessed via Health Technology Assessment (HTA) and other decision-making procedures in each country in order to be recommended to be made available in that country and for a price to be agreed with health care providers, public health systems or health insurance companies.
Where Are We Going?
While the gene therapy Luxturna has been recently approved by regulatory bodies, it is designed to treat only one subtype of LCA – people with specific biallelic mutations in the RPE65 gene. Other forms of LCA that are due to other gene mutations therefore would not benefit from Luxturna. However, the success of this first ocular gene therapy paves the way for other forms of inherited retinal disease to be treated with a similar technology of gene replacement.
Promising human clinical trials investigating an oral drug are also underway in forms of LCA caused by alterations in the RPE65 gene or the LRAT gene. These therapies aim to improve vision by bypassing the biochemical effects of lack of RPE65 or LRAT and thus “reawakening” dormant or sleeping retinal cells in order to allow the patient to see. It is extraordinary that this very uncommon, and severe, inherited retinal degeneration is the subject of several different clinical trials, which have shown early evidence of success. This gives justifiable hope that less severe inherited retinal degenerations might also be treatable in the foreseeable future.
While action is needed to maintain momentum in research and clinical trials to find these treatments, it is also of great importance to advocate for access to these treatments for all. Please see our Advocacy section for helpful information.
Access to Treatments
Luxturna has been approved as safe and effective by the American Food and Drug Administration (FDA) and is currently on the market in the USA. It was approved by the European Committee for Medicinal Products for Human Use (CHMP) in September 2018 and the European Medicines Agency (EMA) is expected to release its opinion by the end of 2018 on approval in Europe.
Pending such approval,the next stages in the access journey will be at a local level where individual countries will decide whether to approve the therapy for reimbursement in their country. It is of utmost importance 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(link)
- 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 firstname.lastname@example.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 LCA. While we await new treatments, individuals with LCA 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 LCA for more information.