Norrie disease

Definition

Norrie disease (ND) is a severe form of blindness that is evident at birth or within the first few months of life and may involve deafness, mental retardation, and behavioral problems.

Description

ND was first described in the 1920s and 1930s as an inherited form of blindness affecting only males. Recognizable changes in certain parts of the eye were identified that lead to a wasting away or shrinking of the eye over time.

At birth, a grayish yellow, tumor-like mass is observed to cover or replace the retina of the eye, whereas the remainder of the eye is usually of normal shape, size and form. Over time, changes in this mass and progressive deterioration of the lens, iris, and cornea cause the eye to appear milky in color and to become very small and shrunken. ND is always present in both eyes and although some abnormalities in the eye develop later, blindness is often present at birth. Some degree of mental retardation, behavior problems, and deafness may also occur.

ND is inherited in an X-linked recessive manner and so it affects only males. The gene for ND was found in the 1990s and genetic testing is available.

ND has also been referred to as:

• Norrie-Warburg syndrome
• Atrophia bulborum hereditaria
• Congenital progressive oculo-acoustico-cerebral degeneration
• Episkopi blindness
• Pseudoglioma congenita

Genetic profile

It has been known for several years by the analysis of many large families, that ND is an inherited condition that affects primarily males. Mothers of affected males do not show any symptoms of the disease. From this observation it was suspected that a gene on the X chromosome was responsible for the occurrence of ND. Genetic studies of many families led to the identification of a gene, named NDP (Norrie Disease Protein), located at Xp11. This means the gene is found on the shorter or upper arm of the X chromosome. NDP, a very small gene, was determined to produce a protein named norrin. The function of the norrin protein is not well understood. Preliminary evidence suggests that norrin plays a role in directing how cells interact and grow to become more specialized (differentiation).

Many different kinds of mistakes have been described in the NDP gene that are thought to lead to ND. The majority of these genetic mistakes or mutations alter a single unit of the genetic code and are called point mutations. Most of the identified point mutations are unique to the family studied. Few associations between the type of point mutation and severity of disease have been described. Other occasional errors in the NDP gene are called deletions, which permanently remove a portion of the genetic code from the gene. Individuals with deletions in the NDP gene are thought to have a more severe form of ND that usually includes profound mental retardation, seizures, small head size, and growth delays.

The X chromosome is one of the human sex chromosomes. A human being has 23 pairs of chromosomes in nearly every cell of their body. One of each kind (23) is inherited from the mother and another of each kind (23) is inherited from the father, which makes a total of 46. The twenty-third pair is the sex chromosome pair. Females have two X chromosomes and males have an X and a Y chromosome. Females therefore have two copies of all the genes on the X chromosome but males have only one copy. The genes on the Y chromosome are different than those on the X chromosome. Mothers pass on either one of their X chromosomes to all of their children and fathers pass on their X chromosome to their daughters and their Y to their sons.

Males affected with ND have a mutation in their only copy of the NDP gene on their X chromosome and therefore do not make any normal norrin protein. Mothers of such affected males are usually carriers of ND; they have one NDP gene with a mutation and one that is normal. As they have one normal copy of the NDP gene, they usually have a sufficient amount of the norrin protein so that they do not show signs of ND. Women that are carriers for ND have a 50% chance of passing the disease gene onto each of their children. If that child is male, he will be affected with ND. If that child is female, she will be a carrier of ND but not affected. Affected males that have children would pass on their disease gene to all of their daughters who would therefore be carriers of ND. Their sons inherit their Y chromosome and, therefore, would not inherit the gene for ND.

Genetic testing for mutations in the NDP gene is clinically available to help confirm a diagnosis of ND. This testing is able to identify gene mutations in about 70% of affected males. If such a mutation were found in an affected individual, accurate carrier testing would be available for females in that family. Additionally, diagnosis of a pregnancy could be offered to women who are at risk for having sons with ND.

Demographics

ND has been observed to affect males of many ethnic backgrounds and no ethnic group appears to predominate. The incidence is unknown, however.

Signs and symptoms

The first sign of ND is usually the reflection of a white area from within the eye, which gives the appearance of a white pupil. This is caused by a mass or growth behind the lens of the eye that covers the retina. This mass tends to grow and cause total blindness. It may also develop blood vessels that may burst and further damage the eye. At birth the iris, lens, cornea and globe of the eye are generally otherwise normal. The problems in the retina evolve over the first few months and until about ten years of age progressive changes in other parts of the eye develop. Cataracts form and the iris is observed to stick or be attached to the cornea and/or the lens of the eye. The iris will also often decrease in size. Pressure in the fluid within the eye may increase, which can be painful. The retina often becomes detached and may become thickened. Toward the end stages of the disease, the eye globe is seen to shrink considerably in size and appear sunken within the eye socket. The above findings affect both eyes and the changes are usually the same in each eye.

Approximately 50% of affected males have some degree of developmental delay or mental retardation. Some may show behavioral problems or psychosis-like features. Hearing loss may develop in 30–40% of males with ND starting in early childhood. If speech is developed before the onset of deafness, it is usually preserved. Mental impairment and hearing loss do not necessarily occur together. The role that the norrin protein plays in causing mental impairment and hearing loss is unknown.

Much variability in the expression of ND within a family as well as between families has been observed. On rare occasion, carrier females may show some of the retinal problems, such as retinal detachment, and may have some degree of vision loss.

Diagnosis

The diagnosis of ND is usually made by clinical examination of the eye by an ophthalmologist. Gene testing can be pursued as well, keeping in mind that as many as 30% of affected males cannot be identified using current methods.

The symptoms of ND have considerable overlap with a few other eye diseases and ND must be distinguished from the following conditions:

• Persistent hyperplastic primary vitreous (PHPV)
• Familial exudative vitroeretinopathy (FEVR)
• Retinoblastoma (RB)
• Retinopathy of prematurity (ROP)
• Incontinentia pigmenti type 2 (IP2) The first two diseases have been shown to also be associated with mutations in the NDP gene and may represent a more mild condition in the broad spectrum of ND.

Treatment and management

Since the symptoms of ND are often present at birth, little can be done to change them or prevent the disease from progressing. If the retina is still attached to the back of the eye, surgery or laser therapy may be helpful. An ophthalmologist should follow all children with ND to monitor the changes in the disease, including the pressure within the eye. Occasionally, surgery may be necessary. Rarely, the eye is removed because of pain.

The child's hearing should also be monitored regularly so that deafness can be detected early. For individuals with hearing loss, hearing aids are usually quite successful. Cochlear implants may be considered when hearing aids are not helpful in restoring hearing.

Developmental delays or mental retardation as well as lifelong behavioral problems can be a continuous challenge. Educational intervention and therapies may be helpful and can maximize a person's educational potential.

Prognosis

The life span of an individual with ND may be within the normal range. Risks associated with deafness, blindness, and mental retardation, including injury or illness, might shorten the life span. General health, however, is normal.

Resources

ORGANIZATIONS

American Council of the Blind. 1155 15th St. NW, Suite 720, Washington, DC 20005. (202) 467-5081 or (800) 424-8666. <http://www.acb.org>.

American Society for Deaf Children. PO Box 3355, Gettysburg, PA 17325. (800) 942-ASDC or (717) 334-7922 v/tty. <http://www.deafchildren.org/asdc2k/home/home.shtml>.

National Association of the Deaf. 814 Thayer, Suite 250, Silver Spring, MD 20910-4500. (301) 587-1788. [email protected]. <http://www.nad.org>.

National Federation for the Blind. 1800 Johnson St., Baltimore, MD 21230. (410) 659-9314. [email protected]. <http://www.nfb.org>.

Norrie Disease Association. Massachusetts General Hospital, E #6217, 149 13th St., Charlestown, MA 02129. (617) 726-5718. [email protected].

WEBSITES

Sims, Katherine B., MD. "Norrie Disease." May 14, 2004 (June 24, 2005). GeneClinics. University of Washington, Seattle. <http://www.geneclinics.org/profiles/norrie/details.html>.

Jennifer Elizabeth Neil, MS, CGC