NORD gratefully acknowledges 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 Sofia Sees Hope, 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 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 (Franceschetti’s oculo-digital sign).This activity may cause the eyes to become sunken or deep set (enophthalmos).
Other symptoms may include strabismus; nystagmus; photophobia; cataracts; and/or keratoconus. In addition, some infants may exhibit hearing loss, intellectual disability, and/or developmental delay.
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).
LCA is a monogenic disease and at least 27 genes are implicated. Changes (mutations) in these genes can account for about 80-90% of diagnosed cases of LCA. The genes responsible for the remaining 10-20% of diagnoses are not known. LCA is usually inherited as an autosomal recessive genetic condition. Twenty-four of the genes associated with LCA cause only recessive disease. 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 mutation.
Recessive genetic disorders occur when an individual inherits two copies of an abnormal gene for the same trait, one from each parent. If an individual receives one normal gene and one gene for the disease, 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 defective gene and have an affected child is 25% with each pregnancy. The risk to have 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 and be genetically normal for that particular trait is 25%. The risk is the same for males and females.
There are about 20,000 different genes in a human and all individuals carry one copy of several abnormal genes. Parents who are close relatives (consanguineous) have a higher chance than unrelated parents to both carry the same abnormal gene, which increases the risk to have children with a recessive genetic disorder.
In rare cases, LCA is inherited as an autosomal dominant genetic disorder. Mutations in three genes, CRX, IMPDH1, and OTX2 are currently known to be associated with this type of LCA.
Dominant genetic disorders occur when only a single copy of an abnormal gene is necessary to cause a particular disease. The abnormal gene can be inherited from either parent or can be the result of a new mutation in the affected individual. The risk of passing the abnormal gene from affected parent to offspring 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.
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 for mutations in the genes associated with LCA. Clinical signs and symptoms can be helpful in determining which genes to test for, and in what order.
Treatment for LCA is symptomatic and supportive. Genetic counseling is recommended for families of affected children.
In 2017, the gene therapy Luxturna (voretigene neparvovec-rzyl) was approved by the U.S. Food and Drug Administration (FDA) to treat children and adults with two mutations in the RPE65 gene which includes a type of LCA called LCA2. Luxturna is manufactured by Spark Therapeutics, Inc.
A small molecule drug therapy for LCA due to mutations in the RPE65 or LRAT genes has completed phase II clinical trials and shown improvement in vision without harmful effects.
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:
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Some current clinical trials also are posted on the following page on the NORD website:
For information about clinical trials sponsored by private sources, contact:
For information about clinical trials conducted in Europe, contact:
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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.
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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.
Weleber RG, Francis PJ, Trzupek KM, et al. Leber Congenital Amaurosis – ARCHIVED CHAPTER, FOR HISTORICAL REFERENCE ONLY. 2004 Jul 7 [Updated 2013 May 2]. In: Adam MP, Ardinger HH, Pagon RA, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2020. Available from: https://www.ncbi.nlm.nih.gov/books/NBK1298/ Accessed June 10, 2020.
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