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Last updated: 9/10/2024
Years published: 1986, 1987, 1990, 1996, 1997, 2001, 2010, 2017, 2020. 2024
NORD gratefully acknowledges Gioconda Alyea, MD (FMG), MS, National Organization for Rare Disorders, Peter Francis, MD, PhD, Chief Scientific Officer and Retina Therapeutic Area Head, 4D Molecular Therapeutics; Brian Mansfield, PhD, Deputy Chief Research Officer, Foundation Fighting Blindness; and Hope in Focus, for assistance in the preparation of this report.
Leber congenital amaurosis (LCA) is a rare genetic eye disorder. Affected infants are often blind at birth. Other symptoms may include crossed eyes (strabismus); rapid, involuntary eye movements (nystagmus); unusual sensitivity to light (photophobia); clouding of the lenses of the eyes (cataracts) and/or a cone shape to the front of the eye (keratoconus). LCA is usually inherited as an autosomal recessive genetic condition.
Children born with Leber congenital amaurosis (LCA) have light-gathering cells (rods and cones) of the retina that do not function properly. Absence or reduction of the electrical activity of the retina is always observed and is necessary for the diagnosis of LCA.
A decrease in visual responsiveness at birth is the first sign of the disease. Often the child will poke, press and rub the eyes to stimulate the retina to produce light (Franceschettiโs oculo-digital sign). This activity may cause the eyes to become sunken or deep set (enophthalmos).
Other symptoms may include:
Specific types of LCA have been defined based on the causative gene. Some types are associated with little change in vision over time (stationary disease) while others become more severe over time (progressive disease).
Leber congenital amaurosis (LCA) can be caused by changes (variants) in at least 29 different genes. There are several types of LCA classified from 1-19. The most frequent genetic causes of LCA are variants in the CEP290 (15%), GUCY2D (12%), CRB1 (10%) and RPE65 (8%) genes and account for 70%-80% of known cases.
LCA is usually inherited as an autosomal recessive genetic condition. Two genes (IMPDH1 and OTX2) are known to cause dominant disease. One gene (CRX) is known to cause either dominant or recessive disease, depending on the specific variant.
Recessive genetic disorders occur when an individual inherits a disease-causing gene variant from each parent. If an individual receives one normal gene and one disease-causing gene variant, the person will be a carrier for the disease, but usually will not show symptoms. The risk for two carrier parents to both pass the gene variant and have an affected child is 25% with each pregnancy. The risk of having a child who is a carrier like the parents is 50% with each pregnancy. The chance for a child to receive normal genes from both parents is 25%. The risk is the same for males and females.
Dominant genetic disorders occur when only a single copy of a disease-causing gene variant is necessary to cause the disease. The gene variant can be inherited from either parent or can be the result of a new (de novo) changed gene in the affected individual that is not inherited. The risk of passing the gene variant from an affected parent to a child is 50% for each pregnancy. The risk is the same for males and females.
The prevalence of LCA has been estimated to be 1-2/100,000 births. This disorder affects males and females in equal numbers. LCA accounts for about 20% of legal blindness in children.
Electroretinography (ERG) is used to assess visual function by measuring activity in the retina. Infants with LCA have absent or reduced electrical activity of the retina.
Molecular genetic testing is available to look for variants in the genes associated with LCA and can confirm the diagnosis. Clinical signs and symptoms can be helpful in determining which genes to test for, and in what order.
Treatment
Currently there is no way to prevent or stop vision loss in LCA in most patients. However, there are new treatments being tested in clinical trials, including gene therapy, oral medications and eye injections, that show great promise.
The first step in managing LCA is getting an accurate clinical and genetic diagnosis. A team approach involving eye specialists, genetic counselors and support groups is crucial for helping patients navigate the many aspects of this disease, including planning for work, education and family life. Itโs also important to monitor and treat any related health issues, like kidney problems or hearing loss, to ensure the best possible quality of life.
In 2017, the gene therapy voretigene neparvovec-rzyl (Luxturna) was approved by the U.S. Food and Drug Administration (FDA) to treat children and adults with two variants in the RPE65 gene which includes a type of LCA called LCA2. Luxturna is injected underneath the retina, allowing a new, functional copy of the gene to pass into the appropriate cells. It is the first gene therapy approved by the US Food and Drug Administration (FDA) to treat a disease. Luxturna requires a common retina surgery procedure called a vitrectomy and must be done by an ophthalmologist with experience in injecting genes under the retina. This treatment has been shown to improve vision in patients who have received it.
The basic idea behind gene therapy is that if someone has a variant in a specific gene, introducing a normal version of that gene can help the cells work correctly again. Gene therapy was first tested in Briard dogs, which were found to have similar eye problems to humans caused by a variant in the RPE65 gene. Interestingly, both humans and dogs can have inherited retinal dystrophies linked to variants in this gene.
The Briard dog became well-known as the first animal model to successfully undergo retinal gene therapy. Multiple studies have shown that using a special virus to deliver the normal gene into the eyes of these dogs restored their vision. These important discoveries paved the way for testing gene therapy in humans.
Once the diagnosis is made, a retina specialist who is an expert in inherited retinal diseases can refer the patient to a treatment center. Eventually, through further research, it is expected that gene therapy could help individuals with other gene variants.
Other therapies targeting genes, including RPGR and CEP290, are currently under investigation.
There have been major advances in treatments for inherited retinal diseases, such as gene replacement, stem cell therapy and drug therapies, offering hope for the future.
Additional LCA treatments involve artificial implants to bypass the non-functioning photoreceptor cells. A more detailed explanation of these implants can be found by visiting the Retinal Health Series portal (www.asrs.org/retinahealthseries) and clicking on the Retinitis Pigmentosa and Retinal Prosthesis tab.
Other current treatments for LCA are symptomatic and supportive. Low-vision specialists can work with patients to use tools and technology to improve quality of life and functioning. Individuals affected by this condition can benefit from correcting their vision with glasses or contact lenses, using low-vision aids when needed and having the best possible access to educational and work opportunities.
Genetic counseling is recommended for families of affected children.
Information on current clinical trials is posted on the Internet at www.clinicaltrials.gov . All studies receiving U.S. government funding, and some supported by private industry, are posted on this government web site.
For information about clinical trials being conducted at the NIH Clinical Center in Bethesda, MD, contact the NIH Patient Recruitment Office:
Tollfree: (800) 411-1222
TTY: (866) 411-1010
Email: [email protected]
Some current clinical trials also are posted on the following page on the NORD website:
https://rarediseases.org/living-with-a-rare-disease/find-clinical-trials/
For information about clinical trials sponsored by private sources, contact:
www.centerwatch.com
For information about clinical trials conducted in Europe, contact:
https://www.clinicaltrialsregister.eu/
JOURNAL ARTICLES
Sather R 3rd, Ihinger J, Simmons M, Lobo GP, Montezuma SR. The clinical findings, pathogenic variants, and gene therapy qualifications found in a Leber congenital amaurosis phenotypic spectrum patient cohort. Int J Mol Sci. 2024 Jan 19;25(2):1253. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10816538/
Zhou Y, Huang L, Xie Y, Liu W, Zhang S, Liu L, Lin P, Li N. Clinical and genetic studies for a cohort of patients with Leber congenital amaurosis. Graefes Arch Clin Exp Ophthalmol. 2024 Apr 25. https://pubmed.ncbi.nlm.nih.gov/38662103/
Wright AF. Long-term effects of retinal gene therapy in childhood blindness N Engl J Med. 2015;372:1954-955.
Scholl HP, Moore AT, Koenekoop RK, et al. Safety and proof-of-concept study of oral QLT091001 in retinitis pigmentosa due to inherited deficiencies of retinal pigment epithelial 65 protein (RPE65) or lecithin: retinol acyltransferase (LRAT). PLoS One 2015;10(12):e0143846.
Bennett J, Ashtari M, Wellman J, et al. AAV2 gene therapy readministration in three adults with congenital blindness. Science Translational Medicine 2012;4(120):120ra15.
Hauswirth WW, Aleman TS, Kaushal S, et al. Treatment of Leber congenital amaurosis due to RPE65 mutations by ocular subretinal injection of adeno-associated virus gene vector: short-term results of a phase I trial. Hum Gene Ther. 2008;19(10):979-90.
Simonelli F, Ziviello C, Testa F, et al. Clinical and molecular genetics of Leberโs congenital amaurosis: a multicenter study of Italian patients Invest Ophthalmol Vis Sci. 2007;48(9):4284-90.
Apushkin MA and Fishman GA. Attainment of educational levels in patients with Leberโs congenital amaurosis Ophthalmology 2006;113(3):481-2.
Perrault I, Hanein S, Gerber S, et al., Retinal dehydrogenase 12 (RDH12) mutations in leber congenital amaurosis Am J Hum Genet. 2004:75(4):639-46.
Mackay DS, Borman AD, , Sui R, et al. Screening of a large cohort of Leber congenital amaurosis and retinitis pigmentosa patients identifies novel LCA5 mutations and new genotype-phenotype correlations Human Mut. 2013;34(11):1537-46.
Hanein SI, Perrault S, Gerber G, et al. Leber congenital amaurosis: comprehensive survey of the genetic heterogeneity, refinement of the clinical definition, and genotype-phenotype correlations as a strategy for molecular diagnosis Hum Mutat. 2004;23(4):306-17.
INTERNET Weleber RG, Francis PJ, Trzupek KM, et al. Leber Congenital Amaurosis โ RETIRED CHAPTER, FOR HISTORICAL REFERENCE ONLY. 2004 Jul 7 [Updated 2013 May 2]. In: Adam MP, Feldman J, Mirzaa GM, et al., editors. GeneReviewsยฎ [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2024. Available from: https://www.ncbi.nlm.nih.gov/books/NBK1298/ Accessed Sept 10, 2024.
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Learn more https://rarediseases.org/patient-assistance-programs/caregiver-respite/The information provided on this page is for informational purposes only. The National Organization for Rare Disorders (NORD) does not endorse the information presented. The content has been gathered in partnership with the MONDO Disease Ontology. Please consult with a healthcare professional for medical advice and treatment.
The Genetic and Rare Diseases Information Center (GARD) has information and resources for patients, caregivers, and families that may be helpful before and after diagnosis of this condition. GARD is a program of the National Center for Advancing Translational Sciences (NCATS), part of the National Institutes of Health (NIH).
View reportOrphanet has a summary about this condition that may include information on the diagnosis, care, and treatment as well as other resources. Some of the information and resources are available in languages other than English. The summary may include medical terms, so we encourage you to share and discuss this information with your doctor. Orphanet is the French National Institute for Health and Medical Research and the Health Programme of the European Union.
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