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NORD is very grateful to Peter Francis, MD, PhD, Associate Professor, Director Translational Clinical Trials Center, Casey Eye Institute/OHSU, 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 with LCA are born with an absence of functioning light-gathering cells (rods and cones) of the retina. 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 crossed eyes (strabismus); rapid, involuntary eye movements (nystagmus); unusual sensitivity to light (photophobia); clouding of the lenses of the eyes (cataracts); and/or abnormal protrusion of the front (anterior), clear portion of the eye through which light passes (cornea) (keratoconus). In addition, some infants may exhibit hearing loss, mental retardation, 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) while others become more severe over time (progressive).
Mutations in twelve genes are thought to be responsible for 40-50% of all LCA. LCA is usually inherited as an autosomal recessive genetic condition. Mutations in 11 genes are associated with this type of LCA: GUCY2D, RPE65, SPATA7, AIPL1, LCA5, RPGRIP1, CRB1, CEP290, IMPDH1, RD3 and RDH12.
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.
All individuals carry 4-5 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.
Rarely, LCA is inherited as an autosomal dominant genetic disorder. Mutations in the CRX gene are 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 (gene change) 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 2-3/100,000 births. This disorder affects males and females in equal numbers.
Symptoms of the following disorders can be similar to those of Leber congenital amaurosis. Comparisons may be useful for a differential diagnosis:
Loken-Senior Syndrome is a rare autosomal recessive genetic disorder characterized by progressive wasting of the filtering unit of the kidney (nephronophthisis), with or without medullary cystic renal disease, and progressive eye disease. Typically this disorder becomes apparent during the first year of life. (For more information on this disorder, choose "Loken-Senior" as your search term in the Rare Disease Database.)
Joubert syndrome is an autosomal recessive genetic disorder that affects the area of the brain that controls balance and coordination. This condition is characterized by a specific finding on an MRI called a "molar tooth sign" in which the cerebellar vermis of the brain is absent or underdeveloped and the brain stem is abnormal. The most common features of Joubert syndrome are lack of muscle control (ataxia), abnormal breathing patterns (hyperpnea), sleep apnea, abnormal eye and tongue movements and low muscle tone. (For more information on this disorder, choose "Joubert" as your search term in the Rare Disease Database.)
Zellweger spectrum disorders are a group of rare, autosomal recessive genetic, multisystem disorders that were once thought to be separate entities. These disorders are also known as peroxisome biogenesis disorders (PBDs), a group of disorders characterized by the failure of the body to produce peroxisomes that function properly. Zellweger syndrome is the most severe form; neonatal adrenoleukodystrophy is the intermediate form; and infantile Refsum disease is the mildest form. Zellweger spectrum disorders can affect most organs of the body. Neurological deficits, loss of muscle tone (hypotonia), hearing loss, vision problems, liver dysfunction, and kidney abnormalities are common findings. Zellweger spectrum disorders often result in severe, life-threatening complications early during infancy. Some individuals with milder forms have lived into adulthood. (For more information on this disorder, choose "Zellweger" as your search term in the Rare Disease Database.)
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 the 12 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.
Clinical trials of gene replacement therapy for LCA caused by RPE65 mutations have shown potential 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:
Tollfree: (800) 411-1222
TTY: (866) 411-1010
For information about clinical trials sponsored by private sources, contact:
Contacts for additional information about Leber congenital amaurosis:
Peter Francis, MD, PhD
Director Translational Clinical Trials Center
Casey Eye Institute/OHSU
3375 SW Terwilliger Blvd.
Portland, Oregon 97239
Richard Alan Lewis M.D., M.S.
Professor, Departments of Ophthalmology, Medicine,
Pediatrics, and Molecular and Human Genetics
Faculty Associate, Huffington Center on Aging
Cullen Eye Institute NC-206
Baylor College of Medicine
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Home page: http://www.rpinternational.org
Bainbridge JW, Smith AJ, Barker SS, et al. Effect of gene therapy on visual function in Leber's congenital amaurosis. N Engl J Med. 2008; 358: 2231, 9.
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: 979, 90.
Maguire AM, Simonelli F, Pierce EA, et al. Safety and efficacy of gene transfer for Leber's congenital amaurosis. N Engl J Med. 2008; 358: 2240, 8.
Simonelli F, Ziviello C, Testa F, et al. Clinical and molecular genetics of Leber's congenital amaurosis: a multicenter study of Italian patients. Invest Ophthalmol Vis Sci. 2007 Sep;48(9):4284-90.
Apushkin MA, Fishman GA. Attainment of educational levels in patients with Leber's congenital amaurosis. Ophthalmology. 2006 Mar;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: 639, 46.
Cremers FP, van den Hurk JA, den Hollander AI. Molecular genetics of Leber congenital amaurosis. Hum Mol Genet. 2002; 11: 1169, 76.
Huber A. Genetic diseases of vision. Curr Opin Neurol. 1994;7:65-68.
Kanski JJ, ed. Clinical Ophthalmology, 2nd ed. Butterworth-Heinemann. 1990:375.
FROM THE INTERNET
Weleber RG, Francis PJ and Trzupek KM. Leber Congenital Amaurosis. In: GeneReviews at GeneTests: Medical Genetics Information Resource (database online). Copyright, University of Washington, Seattle. 1997-2010. Last Updated: 3/30/10. Available at http://www.genetests.org. Accessed 5/10
Report last updated: 2010/11/10 00:00:00 GMT+0