Information on the following diseases can be found in the Related Disorders section of this report:

• Coats Syndrome
• Familial Exudatie Vitreoretinopathy
• Retinal Dysplasia, Primary
• Retinoblastoma
• Retinopathy of Prematurity
• Usher syndrome

The specific symptoms and physical findings associated with Norrie disease vary greatly from case to case. Infants with Norrie disease experience blindness in both eyes at birth (bilateral congenital blindness). A white mass develops in the pupil area behind the lenses of the eyes so that the pupil appears white, a condition known as leukokoria or "cat’s eye" reflex. In addition, the eyes may be abnormally small (micropthalmia) at birth.

The lenses of the eyes of an affected infant are initially clear. Eventually, clouding (opacity) of the front, clear portion of the eye through which light passes (cornea) may develop, a condition known as a cataract. In addition, as the disorder progresses, shrinking of the eyeballs (phthisis bulbi) may occur and is often apparent by ten years of age. By the age of 50, the lenses are often completely covered by cataracts.

Affected infants may also experience degeneration of the colored portion of the eye (iris atrophy), underdevelopment (hypoplasia) of the iris, abnormal adhesion of the iris to the lens or cornea (iris synechia), and/or disorders of the nerve-rich membrane lining the eyes (retinopathy) such as abnormal retinal folds and detachment of the retina. In some cases, affected infants may have an abnormally small head (microcephaly).

In approximately 25-40 percent of cases, affected individuals exhibit mild to moderate mental retardation. In approximately 33 percent of cases, individuals eventually develop hearing loss (late-onset deafness). Hearing loss may occur during childhood or later during adult life. Hearing loss usually becomes more profound as an affected individual ages.

In rare cases, affected individuals may exhibit failure of one or both testes to descend into the scrotum (cryptorchidism) and unusual placement of the urinary opening (meatus) on the underside of the penis (hypospadias). In rare cases, affected infants may display episodes of sudden muscle weakness (cataplexy).
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Norrie disease is inherited as a recessive X-linked trait. Human traits including the classic genetic diseases, are the product of the interaction of two genes for that condition, one received from the father and one from the mother.

X-linked recessive disorders are conditions that are coded on the X chromosome. Females have two X chromosomes, but males have one X chromosome and one Y chromosome. Therefore, in females, disease traits on the X chromosome can be masked by the normal gene on the other X chromosome. Since males only have one X chromosome, if they inherit a gene for a disease present on the X, it will be expressed. Men with X-linked disorders transmit the gene to all their daughters, who are carriers, but never to their sons. Women who are carriers of an X-linked disorder have a 50 percent risk of transmitting the carrier condition to both their daughters and their sons.

In some females who inherit a single copy of the disease gene for Norrie disease (heterozygotes), disease traits on the affected X chromosome may not always be masked by the normal gene on the other X chromosome. As a result, these females may exhibit some of the symptoms (e.g., detached retinas) associated with the disorder.

Investigators have determined that Norrie disease may be caused by disruptions or changes (mutations) of a gene located on the short arm (p) of the X chromosome (Xp11.4). Chromosomes are found in the nucleus of all body cells. They carry the genetic characteristics of each individual. Pairs of human chromosomes are numbered from 1 through 22, with an unequal 23rd pair of X and Y chromosomes for males, and two X chromosomes for females. Each chromosome has a short arm designated as "p" and a long arm identified by the letter "q."

It has been suggested that abnormal monoamine oxidase (MAO) activity or an imbalance between serotonin and other neurotransmitter levels may be involved in the development of cataplexy. Some individuals with Norrie disease have exhibited decreased levels of these substances.
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Norrie disease is a rare inherited disorder fully expressed in males only. In rare cases, heterozygous females will exhibit some of the symptoms associated with the disorder. More than 100 cases of Norrie disease have been reported in the medical literature.
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Symptoms of the following disorders can be similar to those of Norrie disease. Comparisons may be useful for a differential diagnosis:

Primary retinal dysplasia is a rare inherited condition characterized by an elevated retinal fold arising from the optic disc covering the macular area inside the eye, and widening toward the temporal fundus, which may cause blindness. This condition is thought to be inherited as an X-linked trait. Some researchers believe that primary retinal dysplasia may be caused by mutations to a gene located in the same area of the X chromosome as the Norrie disease gene (allelic disorders).

Usher syndrome is characterized by hearing loss as well as retinitis pigmentosa, a degeneration of the eye’s retina leading to progressive loss of vision. Hearing loss may be complete or mild, and usually does not worsen (progress). Retinitis pigmentosa can begin during childhood or later in life. Studies show that clear central vision may be maintained for many years even while peripheral vision decreases. In some cases, the hearing and vision problems may be accompanied by mental retardation, psychosis, disturbances in walking related to inner ear problems, or clouding (opacity) of the front, clear portion of the eye (cornea) through which light passes (cataracts). (For more information on this disorder, choose "Usher" as your search terms in the Rare Disease Database.)

Retinoblastoma is an extremely rare malignant tumor that develops in the nerve-rich layers of one eye or both eyes (retinas), most commonly in children under the age of three years. The most typical finding associated with retinoblastoma is the appearance of a distinctive white mass in the pupil area behind the lens of the eye, the so called "cat’s eye reflex" (leukokoria). In addition, the eyes may appear crossed (strabismus). In some affected children, the eye(s) may become red and/or painful. The presence of the tumor may cause a rise in the pressure in the eyeball (glaucoma). In most cases, retinoblastomas occur spontaneously for no apparent reason (sporadic); however, approximately 20 percent of cases are transmitted as an autosomal dominant trait. (For more information on this disorder, choose "Retinoblastoma" as your search terms in the Rare Disease Database.)

Coats disease is an extremely rare disorder characterized by abnormal enlargement or widening (dilation) of the ends of the blood vessels in the retina that may result in blood leaking from the vessel. In some cases, the retina may become detached. A white membrane or mass may develop in the pupil area behind the lens of the eyes (leukokoria). The exact cause of Coats disease is unknown. The disorder may result from mutations of the Norrie disease gene on the X chromsome. (For more information on this disorder, choose "Coats" as your search terms in the Rare Disease Database.)

Retinopathy of prematurity (ROP) is a multifactorial disorder that occurs in premature infants. The disorder is characterized by abnormalities affecting the retina that may lead to vision loss and potentially blindness. In rare cases, advanced ROP may be clinically similar to Norrie disease. Researchers believe that in these rare cases ROP and Norrie disease are caused by different mutations of the same gene on the X chromosome (allelic disorders). Further research is necessary to determine the link, if any, between mutations in the Norrie disease gene and advanced ROP.

Familial exudative vitreoretinopathy is a rare disorder characterized by abnormalities affecting certain structures of the eyes (i.e., retina and vitreous body). The retina is the nerve-rich membrane lining the eye and the vitreous body is the structure that fills the area between the lens and the retina. Some cases of X-linked recessive familial exudative vitreoretinopathy result from mutations to the same gene that is linked to Norrie disease (allelic disorders).

Persistent hyperplastic primary vitreous (PHPV) is a developmental disorder affecting the eye that is present at birth (congenital). The disorder is characterized by abnormalities of certain eye structures and loss of vision. Specific symptoms include abnormally small eyes (microphthalmia), cataracts, and/or the formation of a white membrane or mass in the pupil area behind the lens of the eyes (leuokokoria).
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Diagnosis
A diagnosis of Norrie disease may be made at birth by the identification of characteristic physical findings. Prenatal diagnosis is possible through a test called chorionic villus sampling (CVS). During chorionic villus sampling, a tissue sample is removed from a portion of the placenta and studied.

Treatment
The treatment of Norrie disease may require the coordinated efforts of a team of specialists. Pediatricians, specialists who assess and treat eye (ocular) abnormalities (ophthalmologists), specialists who assess and treat hearing loss (audiologists), and other health care professionals may need to systematically and comprehensively plan an affected child's treatment.

The treatment of individuals with Norrie disease is directed toward the specific symptoms that are apparent in each individual. Surgery may be necessary to remove cataracts and reattach retinas. These efforts may prevent shrinkage of the eyeballs, but will not improve vision. Hearing aids may be of benefit for individuals with hearing loss.

Genetic counseling may be of benefit for affected individuals and their families. Other treatment is symptomatic and supportive.
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Research on genetic disorders and their causes is ongoing. The National Institutes of Health (NIH) is sponsoring the Human Genome Project, which is aimed at mapping every gene in the human body and learning why they sometimes malfunction. It is hoped that this new knowledge will lead to prevention and treatment of genetic and familial disorders in the future.
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McKusick VA., ed. Online Mendelian Inheritance in Man (OMIM). Baltimore. MD: The Johns Hopkins University; Entry No:310600; Last Update:11/14/99. Entry No:305390; Last Update:10/14/97. Entry No:312550; Last Update:6/11/99.

TEXTBOOKS
Magalini SI, et al., eds. Dictionary of Medical Syndromes. 4th ed.New York, NY: Lippincott-Raven Publishers; 1997:

Buyce ML, ed. Birth Defects Encyclopedia. Dover, MA: Blackwell Scientific Publications; For: The Center for Birth Defects Information Services Inc; 1990:1258-9.

JOURNAL ARTICLES
Hiraoka M. Insertion and deletion mutations in the dinucleotide repeat region of the Norrie disease gene in patients with advanced retinopathy of prematurity. J Hum Genet. 2001;46:178-81.

Ott S, et al. A novel mutation in the Norrie disease gene. J AAPOS. 2000;4:125-26.

Silbert M, et al. Persistent hyperplastic primary vitreous. Clin Eye Vis Care. 2000;12:131-37.

Shastry BS, et al. Norrie disease and exudative vitreoretinopathy in families with affected female carriers. Eur J Ophthalmol. 1999;9:238-42.

Berger W. Molecular dissection of Norrie disease. Acta Anat (Basel). 1998;162:95-100.

Sims KB, et al. Norrie disease in a family with a manifesting female carrier. Arch Ophthalmol. 1997;115:517-19.

Caballero M, et al. Two novel mutations in the Norrie disease gene associated with the classical ocular phenotype. Ophthalmic Genet. 1996;17:187-91.

Vossler DG, et al. Cataplexy and monoamine oxidase deficiency in Norrie disease. Neurology. 1996;46:1258-61.

Ohba N, et al. A literature review of Norrie disease. Nippon Ganka Gakkai Zasshi. 1996;100:101-10.

Wolff G, et al. Clinical reinvestigation and linkage analysis in the family with Episkopi blindness (Norrie disease). J Med Genet. 1992;29:816-19.

Sims KB, et al. The Norrie disease gene maps to a 150 KB region on chromosome Xp11.3. Hum Mol Genet. 1992;1:83-89.

Sims KB, et al. Norrie disease gene is distinct from the monoamine oxidase genes. Am J Hum Genet. 1989;45:424-34.

de la Chapello A, et al. Norrie disease caused by a gene deletion allowing carrier detection and prenatal diagnosis. Clin Genet. 1985;28:317-20.

Liberfarb RM, et al. Norrie's disease: a study of two families. Ophthalmology. 1985;92:1445-51.