- The condition
- Current research in LCA
- Practical advice
- Referral to a specialist centre
- Further information and support
- A patient’s perspective
- LCA: for professionals
Leber congenital amaurosis (LCA) is a term used to describe a group of inherited retinal conditions that cause severe sight impairment or blindness from birth. It affects 1 in 33,000 to 81,000 people and accounts for 20% of blindness among school children. In LCA, the specialised light-sensing photoreceptor cells of the retina are not functioning properly, causing these cells to degenerate over time and eventually die, leading to sight loss.
In addition, patients may also experience other symptoms such as involuntary movement of the eyes (known as nystagmus), night blindness, light sensitivity, blind spots in the peripheral vision and extreme long sightedness (hypemetropia). Other eye conditions such as cataract and keratoconus may be present as well causing further sight deterioration.
So far, changes in 25 genes have been identified to cause LCA. The symptoms, visual function and progression of sight loss vary depending on the causative gene. As of 2019, gene therapy has been approved for the treatment of LCA caused by changes in the RPE65 gene under the UK National Health Service (NHS).
Children affected by LCA usually have very poor sight from birth. Parents will often notice that they are not responding to visual cues along with the presence of nystagmus within the first few months of life. Frequently, this is accompanied by the habitual poking, pressing and rubbing of their eyes with a knuckle or finger called the Franceschetti sign.
Other symptoms include:
- Night blindness
- Severe light sensitivity
- Blind spots at the peripheral vision which can worsen, leading to “tunnel vision”
- Long-sightedness or rarely short-sightedness which require glasses to improve
- Deep sunken eyes as a result of the Franceschetti sign
- Strabismus (abnormal alignment of the eyes when looking at an object)
- Keratoconus (affects focusing of light into the retina, causing vision to be blurry and distorted)
The retina may appear normal or show abnormal pigment changes due to the death of the photoreceptor cells over time.
The severity of sight impairment, accompanying symptoms, appearance of the retina and progression of the condition vary between patients depending on the causative gene. In most patients (75%), visual function remains stable over time while 15% of patients may experience deterioration.
For example, children with LCA caused by mutations in the RPE65 gene tend to have severe night blindness from birth but relatively preserved vision in well-lit situations during their early childhood years. However, their visual function tend to worsen progressively after this period leading to blindness in middle-age. On the contrary, those caused by mutations in the GUCY2D gene have very poor vision from birth along with severe light sensitivity but their visual function usually remains stable over a long period of time.
2) Systemic (other body systems)
In some cases, other parts of the body might be affected as well resulting in the following symptoms:
- Kidney failure
- Low muscle tone
- Poor co-ordination
- Hearing loss
- Developmental delay
- Learning difficulties
- Behavioural disorders
If these symptoms are present together with early sight loss, it might indicate that there is a related syndrome (group of symptoms consistently occurring together that characterise a particular condition) rather than LCA alone. This is because certain genes known to cause LCA, namely CEP290 and IQCB1 can also cause conditions such as Joubert syndrome and Senior-Loken syndrome. Often in these conditions, visual loss is one of the first symptoms noticed by parents.
However, children with LCA may still experience developmental delays, learning difficulties and/or behavioural disorders due to such early onset of such profound sight impairment.
The retina is a complex structure comprised of different type of cells working smoothly together to help us see. 25 genes so far have been identified causing LCA, accounting for 80-90% of the cases. This means that more genes are yet to be identified.
The genes associated with LCA provide instructions to make proteins vital to the healthy development and functioning of the retinal cells. For example, some genes are involved in the signalling pathway of retinal photoreceptor cells while others are involved in the process of converting light to electrical signals so that our brain can generate images for us to see. A defect in any of these genes disrupt the smooth working of the retina and lead to sight loss.
How is it diagnosed?
An eye doctor is able to diagnose LCA based on the onset of symptoms, examination and performing an electro-diagnostic test of the retina called electroretinogram (ERG). The ERG is used to assess the overall function of the photoreceptor cells in the retina. Patients with LCA typically have abnormally low or no electrical activity on ERG.
Genetic testing can help confirm the diagnosis by identifying mutations in one of the 25 genes associated with LCA.
How is it inherited?
Most cases of LCA are inherited in this manner. Both parents are usually unaffected carriers (only have one faulty gene copy) while the patient has two faulty gene copies (inherited one each from each parent). This means that every newborn has the following risks regardless of gender:
- 25% chance (one in four) of being affected by LCA
- 25% chance (one in four) of being unaffected and not a carrier
- 50% chance (one in two) of being a carrier with no symptoms
Only one copy of the faulty gene (inherited from either parent) is required to cause disease. This means that each newborn of the patient has a 50% chance of inheriting the condition regardless of gender.
If you or your child is affected by LCA, it is advisable to see a genetic counsellor to obtain more information and advice on inheritance and family planning options.
Is there any treatment?
1) Gene therapy
Gene therapy aims to halt retinal degeneration by replacing the mutated gene with a normal healthy copy. This enables the affected cells to regain some of their function and produce functioning proteins.
- Great Ormond Street Hospital for Children, London (for children below 10 years of age)
- Moorfields Eye Hospital, London (for children and adults)
- Manchester Royal Eye Hospital
- Oxford Eye Hospital
This followed the approval by the US Food and Drug Administration (FDA) in 2017 after the success of a phase 3 trial conducted by Russell and colleagues. Patients with RPE65 genetic mutations typically have significant night blindness from birth. The trial showed that those patients treated with Luxturna in both eyes (sequentially at different periods) have improved visual function and navigational abilities at low light levels compared to those who did not receive treatment.
In Luxturna, a normal copy of the mutated RPE65 gene is “packaged” into a harmless virus called the adeno associated virus (AAV) which is then surgically injected into the retina (subretinal injection). This way, the affected retinal cells are maximally exposed to the viruses containing the normal gene.
- Further information about retinal degeneration caused by changes in the RPE65 gene
- Safety of gene therapy
- NHS news on the first UK patients receiving Luxturna treatment
- Explanation of different phases of clinical trials
2) Supportive treatment
There is no approved treatment for other types of LCA at present but several clinical trials are ongoing. In the meantime, treatment is focused on alleviating symptoms and optimising remaining sight by treating the other eye conditions associated with LCA. These include:
- Regular monitoring of visual function and prescribing glasses (if required) to optimise development of remaining vision
- Visual aids and assistive technology
- Having a healthy diet consisting of fresh fruits and green leafy vegetables
- Using blue light screen protectors on mobile devices or computer screens*
- Wearing hats/UV protected sunglasses and placing sunlight diffusers at the back window of cars to ease light sensitivity
- Regular check-ups to monitor for other eye conditions frequently associated with LCA such as cataract and keratoconus
*Current available evidence shows that blue light emitted from screens do not damage the retina but it can disrupt our sleep cycle. The screen protectors are used as a precautionary measure.
3) Systemic treatment
As some children with LCA may suffer from conditions affecting other parts of the body (like in Joubert syndrome or Senior-Loken syndrome), they might need input from various specialists co-ordinated by the paediatrician.
Furthermore, visual impairment can have a negative impact on a child’s early general development. Therefore, timely referral to practitioners familiar with developmental surveillance and intervention for children with visual impairment (VI), such as developmental paediatricians as well as a Qualified Teacher of children and young people with Visual Impairment (QTVI) is crucial to optimise their developmental potential.
The Developmental Journal for babies and young children with visual impairment (DJVI), developed by Great Ormond Street Hospital Developmental Vision team is a structured early intervention programme designed to track developmental and vision progress in children from birth to three years of age. It is mainly used by qualified healthcare professionals working in services providing support to babies and young children with VI in conjunction with the child’s parents. Children with VI may be referred to specialist services such as the developmental vision clinic in the Great Ormond Street Hospital for Children or other specialist developmental services for further management.
1) Gene therapy
Although Luxturna has been approved for the treatment of LCA caused by mutations in the RPE65 gene, a second generation gene therapy called AAV2/5-OPTIRPE65 is being developed to increase the efficiency of transferring the normal RPE65 gene into the retinal cells. A phase 1/2 trial has been conducted and the interim results show that its safety profile was consistent with gene therapies under research for other eye conditions.
There is also ongoing research for LCA associated with the GUCY2D gene. A phase 1/2 trial is currently underway to investigate the safety of injecting harmless AAV viruses carrying the normal GUCY2D gene into the human retina.
2) Antisense oligonucleotides (AON)
AONs are small molecules genetically engineered to correct a disease-causing genetic mutation. It is being investigated as a therapeutic option for a specific type of mutation in the CEP290 gene that is very common in Europe and USA.
The AON under research for this type of LCA, Sepofarsen, is introduced into the retina through a common outpatient procedure called intravitreal injections. A phase 1/2 trial has been conducted and the interim results showed that not only Sepofarsen was safe, most patients also experienced some visual improvement. Due to such promising results, a phase 2/3 trial (ILLUMINATE) is currently underway.
3) CRISPR/Cas9 genome editing system
CRISPR/Cas9 (pronounced as “crisper”) stands for clustered regularly interspaced short palindromic repeats and CRISPR-associated protein 9. This system is a relatively new gene editing technique based on the immune system of bacteria.
It works like a pair of molecular “scissors”, where guided by specially designed markers, it can cut the abnormal section of a specific gene out and introduce the correct section. As a result, the affected cells will be able to produce the appropriate protein and function normally.
The system is a potential treatment for the same common CEP290 gene mutation targeted by antisense oligonucleotides. Labelled as EDIT-101, it is packaged into harmless AAV viruses and surgically injected into the retina (similar technique to gene therapy). A phase 1/2 trial for EDIT-101 is currently being conducted.
- Research Opportunities at Moorfields Eye Hospital UK
- Searching for current clinical research or trials
Living with LCA
Patients are still able to lead fairly independent lives through maximising their available vision and having access to social support. Here are some ideas:
- Attending the low vision clinic which provides access to low vision specialists, Eye Clinic Liaison Officers (ECLOs), visual aids and visual rehabilitation services
- Utilising assistive technologies that can improve quality of life
- Getting in touch with the local education authority for access to qualified teachers for children with visual impairment (QTVI) and special educational needs co-ordinator (SENCO)
- Registering your child as sight impaired (SI) or severely sight impaired (SSI) if eligible for access to social support and financial concessions
- Getting in touch with national or local charities for advice and peer support
If you are based in the UK and would like to be seen in the nearest specialist centre for your eye condition, either to receive a more comprehensive genetic management or just to find out more about current research, you can approach your GP to make a referral or alternatively arrange for a private appointment.
More information can be found in our “How to see a genetic eye specialist?” page.
Further information and support
A patient’s perspective
- Lorenz B, Preising M. Leber congenital amaurosis. https://www.orpha.net/consor/cgi-bin/OC_Exp.php?Lng=EN&Expert=65. Updated July 2015. Accessed 12 March 2020
- Daiger SP. RetNet: Summaries of Genes and Loci Causing Retinal Diseases. https://sph.uth.edu/retnet/sum-dis.htm#B-diseases. Published 2019. Updated 14 February 2020. Accessed 12 March 2020
- den Hollander AI, Roepman R, Koenekoop RK, Cremers FP. Leber congenital amaurosis: genes, proteins and disease mechanisms. Prog Retin Eye Res. 2008;27(4):391-419
- Kumaran N, Moore AT, Weleber RG, Michaelides M. Leber congenital amaurosis/early-onset severe retinal dystrophy: clinical features, molecular genetics and therapeutic interventions. Br J Ophthalmol. 2017;101(9):1147-1154
- Thompson JA, De Roach JN, McLaren TL, et al. The genetic profile of Leber congenital amaurosis in an Australian cohort. Mol Genet Genomic Med. 2017;5(6):652-667
- Bernardis I, Chiesi L, Tenedini E, et al. Unravelling the Complexity of Inherited Retinal Dystrophies Molecular Testing: Added Value of Targeted Next-Generation Sequencing. Biomed Res Int. 2016;2016:6341870-6341870
- Russell S, Bennett J, Wellman JA, et al. Efficacy and safety of voretigene neparvovec (AAV2-hRPE65v2) in patients with RPE65-mediated inherited retinal dystrophy: a randomised, controlled, open-label, phase 3 trial. Lancet. 2017;390(10097):849-860