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Understanding Leber Congenital Amaurosis : Causes, Symptoms, and Prevalence

  1. Introduction

    1. Definition of Leber Congenital Amaurosis

      Leber Congenital Amaurosis (LCA) is a group of inherited retinal diseases that can lead to severe vision loss or even blindness at birth or in early childhood. It is also associated with other vision problems, such as photophobia (increased sensitivity to light), nystagmus (involuntary movements of the eyes), and hyperopia (extreme farsightedness).
      Leber Congenital Amaurosis : Causes, Symptoms, and Prevalence

    2. Historical Background of Leber Congenital Amaurosis

      Theodor Leber, a German ophthalmologist, first described the disease in 1869 in a blind child who had amaurotic pupils, wandering nystagmus, and congenital retinitis pigmentosa.(1, 2)

      In 1995, a non-recordable electroretinogram (ERG) was identified to be a common feature required for the diagnosis of Leber Congenital Amaurosis. At this time the disease was named. At the same time, a Swedish study has identified the disease to be an autosomal recessive inheritance. This condition affects one in thirty thousand to one in eighty-one thousand subjects. It is a genetically heterogeneous recessive disease.(3)

    3. Prevalence of Leber Congenital Amaurosis

      Leber Congenital Amaurosis (LCA) appears at birth or in the first few months of life. However, it is a rare inherited eye disease.(4) This eye disease affects about 1 in 40, 000 newborns.(5) It is a rare disease and fewer than 50, 000 individuals in the United States are living with Leber Congenital Amaurosis. Even though LCA is a rare disease, it is one of the most common causes of blindness in children.

  2. Causes and Risk Factors of Leber Congenital Amaurosis

    Some retinal experts consider Leber Congenital Amaurosis is a severe form of retinitis pigmentosa (RP). This condition is caused by degeneration or dysfunction of photoreceptors (the cells in our retina due to which vision is possible). Mutations in one of more than 24 genes can result in Leber Congenital Amaurosis (LCA).

    1. Genetics and Inheritance

      Leber congenital amaurosis (LCA) can occur due to variants or mutations in at least more than 20 genes, all of which are required for the proper function of the retina and normal vision. These genes play a crucial role in the development and function of our retina. For instance, some of these genes which are linked with Leber congenital amaurosis are essential for the normal development of light-detecting cells known as photoreceptors. Other genes are involved in phototransduction, which is the process by which light that enters the eye gets converted into electrical signals that are transmitted to the brain. Some other genes are essential for the proper functioning of cilia that are found in the retina’s photoreceptors and required for vision.

      Leber Congenital Amaurosis generally has an autosomal recessive pattern of inheritance. This means both copies of the gene in each cell have mutations or variants. The parents of a person with an autosomal recessive condition each carry only one copy of the mutated or altered gene, and thus they usually do not show any symptoms of the disease.

      When variants in the CRX and IMPDH1 genes cause Leber congenital amaurosis, the disorder has an autosomal dominant pattern of inheritance. An autosomal dominant inheritance means only one copy of the altered gene in each cell can cause Leber congenital amaurosis. In the majority of such cases, an affected individual inherits a gene mutation from one affected parent. However, in other cases, new variants cause the disorder and these occur in individuals with no family history of the disorder.

    2. Types of Genetic Mutations

      Various types of genetic mutations can result in Leber congenital amaurosis. Genetic mutations are any changes that occur in the DNA of your biological parent’s reproductive cells during conception. We know mutations or variants in any of the genes associated with Leber congenital amaurosis (LCA) disrupt the function and development of the retina and thus result in early vision loss.

      Mutations in more than 20 different genes can result in the disorder. The most common genetic mutations that cause Leber congenital amaurosis to happen to genes that develop and form your retina, which include CEP290, GUCY2D, CRB1, and RPE65. Mutations in the other genes account only for a smaller percentage of cases. The cause of Leber congenital amaurosis is unknown in about 30% of all people with Leber congenital amaurosis and research in this regard is going on.

    3. Other Risk Factors for Leber Congenital Amaurosis

      Leber congenital amaurosis is passed down from parents through their genes. At least 19 different gene mutations can be passed down and result in the spectrum of this disorder. The affected genes instruct our body to prepare proteins required for vision. However, in Leber congenital amaurosis (LCA), the abnormal genes are passed down usually in an autosomal recessive pattern, which means the child needs two abnormal genes (one from each biological parent) to have the disease. The main risk in this is that both parents are basically unaware that they carry the mutation as they do not suffer from vision loss.

  3. Symptoms and Diagnosis of Leber Congenital Amaurosis

    1. Early Onset Of Vision Loss

      Profound vision impairment or vision loss from birth are a major symptom of Leber congenital amaurosis. One-third of people with Leber congenital amaurosis have no perception of light. The visual impairment is usually stable or extremely slowly progressive. Sometimes, in the early stages, a mild degree of visual improvement can be observed, followed by progressive degradation. Leber congenital amaurosis has retinal, ocular, and extraocular features, and occasionally, systemic associations.(6)

    2. Other Ocular Symptoms

      Many children with Leber congenital amaurosis press their eyes with their fists or fingers quite often and it becomes habitual. This habitual pressing on the eyes is termed an oculodigital reflex. Apart from this, the eyes of people with this disorder can also appear sunken. Cataracts (clouding of the lens through which light passes) and Keratoconus (cone shape to the front of the eye) are other ocular symptoms that can occur with Leber congenital amaurosis.

      In certain cases, other body systems like kidneys can also be affected by the genetic defects that result in LCA.

    3. Diagnosis and Screening Methods

      If your doctor suspects Leber congenital amaurosis (LCA), they might use some of the tests and screening methods mentioned below.

      Electroretinogram (ERG)

      Electroretinogram (ERG) is a diagnosis that can confirm the visual function and activity of the retina. Patients with LCA usually have a ‘flat” electroretinogram, and this suggests virtually no retinal function. Later, these retinas get damaged and show thinning, usually with pigmentary changes, and the optic nerves turn pale.

      Molecular Genetic Test

      Genetic testing or a molecular genetic test will look for mutations among the specific genes that cause Leber congenital amaurosis. Some mutations can cause problems in other bodily organs, including developmental delay. Thus affected children should be evaluated properly by a pediatrician who must be experienced in treating inherited diseases.

  4. Management and Treatment of Leber Congenital Amaurosis

    1. Available Treatments for Leber Congenital Amaurosis

      The main treatment available for Leber congenital amaurosis is Gene therapy. Gene therapy is an advanced method for treating patients with LCA and it primarily focuses on altering a patient’s genetic makeup instead of using any medication or surgery.

      By gene transfer and genome editing, doctors can repair an altered gene, input a healthy gene to replace the mutated one, input a new gene and help fight a specific disease, shut down an impaired gene, activate a gene to help the body fight against a disorder or disease, and more.

      The US Food and Drug Administration (FDA) in 2017 approved voretigene neparvovecrysl (Luxturna Spark Terapeutics, Inc. Philadelphia, PA) or LUXTURNA for the treatment of biallelic RPE6 mutation-associated- LCA2. It was the first gene therapy product for the eye that has been approved by US Food and Drug Administration (FDA). RPE65 mutation accounts only for a minority of patients with Leber congenital amaurosis. There is no effective therapy till now for other mutations. However, it is recommended to reduce light exposure to avoid photophobia.

    2. Gene Therapy And Its Effectiveness

      The main theory behind gene therapy is that in an individual with known mutations of a coding region of a single gene, introducing a normal allele can return cells to function normally. The first attempt at gene therapy was conducted on the Briard dog, which was having similar clinical characteristics to humans of disease that resulted from mutation of the RPE65 gene.

      Several gene mutations in the RPE65 gene are linked with inherited retinal dystrophies in both dogs and human beings. The Briad dog was the first successful retinal gene therapy performed in animal models. Various studies have reported that by using recombinant adeno-associated virus vectors as effective gene delivery vehicles for treating retinal diseases, the restoration of vision in Briard dogs with RPE65 mutation was possible.(7) These breakthroughs in animal studies severed as the basis for clinical trials of gene therapy in human beings.

      The Food and Drug Administration (FDA) approved the sequential and bilateral injection of LUXTURNA or voretigene neparvovec-ryzl for treating visually impaired individuals who carry a mutation in the RPE65 gene, and this approval was based on one-year data from the only randomized controlled phase III clinical study to date, which demonstrated significant improvement in the vision because of the treatment.(8)

      Patients with LCA2 or a mutation of the gene RPE65 were treated with injections of an adenovirus vector that carried a normal copy of the RPE65 gene. However, multiyear follow-up evaluation of the patients from two different trials (ClinicalTrials.gov NCT00481546 and NCT00643747) revealed a progressive decline of clinical benefits, which included visual activity, retinal sensitivity, and functional gain, that followed an initial peak seen at six to twelve months post-treatment.(9)

      Several other gene therapy programs that target both inherited retinal diseases and other ocular diseases are underway with animal models including treatments for mutations in AIPL1, GUCY2D, and CEP290 genes found in other subtypes of Leber congenital amaurosis.

    3. Assistive Devices and Interventions

      There is no significant cure for Leber congenital amaurosis. However, an ophthalmologist will treat the symptoms of LCA to improve any sight the affected children have. Treatments supporting their vision general include eyeglasses and other low-vision aids, such as magnifying glasses or reading prisms.

  5. Research and Current Developments for Diagnosing and Treating Leber Congenital Amaurosis

    1. Advances in Genetic Testing and Diagnosis

      Genetic testing is an essential method of identifying abnormal genes. The genomic revolution has had a huge impact on our understanding of various genetic defects and disease mechanisms that cause different ophthalmic diseases.

      With significant advances in next-generation genetic technologies, huge progress has been achieved over the last few decades in discovering genes and genetic defects that result in retinal dystrophies. Currently, in the pathogenesis of Leber congenital amaurosis, twenty-eight genes have been implicated, and with initial successful reports in management with targeted gene therapy, in recent times, LCA has attracted much research attention.

    2. Clinical Trials and Potential Therapies

      Twp decades ago, the genetic causes of Leber congenital amaurosis were unknown. However, not more than twenty LCA genes have been identified, and genetic testing can now identify the genetic defects in around 75% of all the cases of Leber congenital amaurosis. Now, gene-specific treatments have entered the clinical trial phase for three LCA genes, and gene-specific therapies have been tested in model systems for seven LCA genes.(10)

      Advances in gene therapy provide hope for some patients with Leber congenital amaurosis. Gene therapy has become available recently for LCA patients with mutations in both copies of the RPE65 gene. Voretigene neparvovec-rzyl (Luxturna) is the gene therapy product that is injected underneath the retina, thus allowing a new and functional copy of the gene to pass into the appropriate cells. This gene therapy has been approved by the US. FDA. It requires a common retina surgery procedure known as Vitrectomy. This must be performed by an experienced ophthalmologist.

      This treatment has shown an improvement in the patient’s vision. Though Luxturna does not restore vision, the improvement noted in clinical trials can be effective in patients with extreme vision loss. This improvement in vision remains stable over a few years after the treatment.(11)

    3. Future Directions For Research and Treatment

      Molecular diagnosis of Leber congenital amaurosis is extremely important to complement clinical diagnosis and genetic counseling in patients with LCA, but also important in identifying the eligibility of the patients for future treatments using gene therapy.

      With recent success using the RPE65 gene therapy approach, gene-specific pharmacogenetic modalities offer hope in the treatment or management of these patients.(12)

  6. Living with Leber Congenital Amaurosis

    1. Coping Strategies For Patients and Families

      Using Eyeglasses and Other Supportive Devices To Cope With The Condition

      An eye care specialist will treat the symptoms of Leber congenital amaurosis to improve any sight that your child has. Usually, treatments to support vision include eyeglasses and some other low-vision aids, such as reading prisms and magnifying glasses. Children having Leber will have to undergo regular eye examinations to track any changes in their eyes.

      Genetic Counseling For Parents and Other Family Members

      Family members of children or people with Leber congenital amaurosis should go for genetic counseling. LCA being prominently autosomal recessive, family members of affected individuals might not be aware that they are carriers. Genetic counseling offers families appropriate information regarding inheritance, implications, and Leber congenital amaurosis. Moreover, it also empowers families to make correct decisions regarding personal and medical decisions.

    2. Support Groups And Resources

      If your child has been diagnosed with Leber congenital amaurosis, you might be worried about how it would affect them and must be looking for the best support groups or resources for them. Various support groups and teams of experienced social workers help LCA patients and their families in several ways.

      Various free services, activity sheets, rhyme books, screen reader software, voice recognition applications, and programs are available for children with Leber congenital amaurosis. Moreover, visual aids like magnifiers are also beneficial for patients with Leber congenital amaurosis.

      Having the right support from support groups and families will make all the difference in people living with LCA and vision or sight loss. Right support services will provide a range of practical advice and services that include home adaptations where required, respite care, play schemes, and advice about financial help.

    3. Impact on Quality of Life

      Patients with Leber congenital amaurosis suffer from vision loss. Apart from this, they also experience symptoms of nystagmus (involuntary movements of the eyes), light sensitivity, night blindness, and hypermetropia (extremely long-sightedness). Cataracts and Keratoconus are also present in LCA-affected individuals.

      Children who have Leber congenital amaurosis usually have extremely poor sight from birth, and they usually press and rub their eyes with fingers or a knuckle. This is known as the Franceschetti sign.

      Apart from all these symptoms, there might be other problems like low muscle tone, kidney failure, hearing loss, poor coordination, developmental delay, behavioral disorders, and learning difficulties. All these could impact the quality of life in patients with Leber congenital amaurosis. A lot of things should be considered while planning for your children’s school.

      Most individuals with LCA usually have a significant level of visual impairment from an early age, and this makes it difficult for them to drive. Though it could be difficult for people with Leber congenital amaurosis, they can still work with some support and adjustments.

  7. Conclusion

  1. Summary of Key Points

    Leber congenital amaurosis (LCA) makes the affected children’s cells in the retinas malfunction. It would also result in the loss of their vision. This condition is caused due to genetic mutation. Genetic testing can help in identifying the condition and gene therapy is the main treatment for correcting or improving the symptoms of Leber congenital amaurosis.

    Being born with Leber congenital amaurosis does not mean that your child will not be healthy. You should see an eye care specialist who will help you understand what to expect and what all treatment and coping strategies are available.

  2. Importance of Continued Research and Treatment Options

    To have a clearer idea about the causes of Leber congenital amaurosis and have better treatment options, the research in this field shall continue. Genes like CEP290, GUCY2D, CRB1, and RPE65 have been identified as the most common genetic mutations that result in LCA. However, in at least 30% of all cases of Leber congenital amaurosis, the cause is unknown and research is continuing. This shall continue so that we can get more information about other genetic mutations or the cause of LCA.

    Apart from this, there should also be continuous research in the field of gene therapy or possible treatments for the condition. Now, we know that LUXTURNA is the gene therapy product available for LCA caused due to RPE65 gene mutation. But, there is no effective therapy available for other mutations. Continued research in this field can help us know about such mutations and best treatments for those mutations.

  3. Hope For the Future of Leber Congenital Amaurosis Patients

    Leber congenital amaurosis is a heterogeneous group of genetic disorders and the diagnosis could be quite challenging. However, advances in both genetic and clinical technologies together have improved greatly and we have understood the causes, symptoms, and treatments of the disease.

    But again, clinical phenotyping remains the stepping stone in LCA diagnosis, and genetic testing can be utilized as a complementary tool. With the continuous advances made in the field of Leber congenital amaurosis research, there is a growing hope for the future of patients with the condition.


  1. Leber’s congenital amaurosis at Who Named It?
  2. ^ Leber T (1869). “Über Retinitis pigmentosa und angeborene Amaurose”. Archiv für Ophthalmologie (in German). 15 (3): 1–25. doi:10.1007/BF02721213. S2CID 543893.
  3. Chung DC, Traboulsi EI. Leber congenital amaurosis: clinical correlations with genotypes, gene therapy trials update, and future directions. J AAPOS. 2009;13(6):587-592. doi:10.1016/j.jaapos.2009.10.004
  4. ^ Stone EM (December 2007). “Leber congenital amaurosis – a model for efficient genetic testing of heterogeneous disorders: LXIV Edward Jackson Memorial Lecture”. American Journal of Ophthalmology. 144 (6): 791–811. doi:10.1016/j.ajo.2007.08.022. PMID 17964524.
  5. “Leber congenital amaurosis”. Genetics Home Reference. August 2010. Retrieved 14 May 2017.
  6. Daiger SP, S.L., Bowne SJ. Available from: http: // www.retnet.org.
  7. Le Meur G, Stieger K, Smith AJ, et al. Restoration of vision in RPE65-deficient Briard dogs using an AAV serotype 4 vector that specifically targets the retinal pigmented epithelium. Gene Ther. 2007;14(4):292-303. doi:10.1038/sj.gt.3302861
  8. ↑ Russell S, Bennett J, Wellman JA, Chung DC, Yu ZF, Tillman A, 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):849–60
  9. Bainbridge JW, Mehat MS, Sundaram V, Robbie SJ, Barker SE, Ripamonti C, et al. Long-term effect of gene therapy on Leber’s congenital amaurosis. N Engl J Med. 2015;372(20):1887–97. 13.
  10. den Hollander AI. Omics in Ophthalmology: Advances in Genomics and Precision Medicine for Leber Congenital Amaurosis and Age-Related Macular Degeneration. Invest Ophthalmol Vis Sci. 2016 Mar;57(3):1378-87. doi: 10.1167/iovs.15-18167. PMID: 27010695.
  11. Leber Congenital Amaurosis (LCA) – Patients – The American Society of Retina Specialists (asrs.org)
  12. Kondkar A, Abu Amero K K ( 2019 December), ‘Leber congenital amaurosis: Current genetic basis, scope for genetic testing, and personalized medicine’. Exprimental Eye Research. Science Direct. V 189, Dec 2019, 107834
Team PainAssist
Team PainAssist
Written, Edited or Reviewed By: Team PainAssist, Pain Assist Inc. This article does not provide medical advice. See disclaimer
Last Modified On:July 22, 2023

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