NORD gratefully acknowledges Katherine B. Sims, MD, Director, Developmental Neurogenetics Clinic, Massachusetts General Hospital and Associate Professor of Neurology, Harvard Medical School, for assistance in the preparation of this report.
Norrie disease is a rare X-linked disorder that occurs due to errors or disruption (mutations) of the NDP gene.
All males are affected by loss of vision present at birth or shortly thereafter. Additional symptoms may occur in some cases, although this varies even among individuals in the same family. Most affected individuals develop hearing (auditory) loss which is progressive of many years and some may exhibit cognitive abnormalities such as developmental delays or behavioral issues. Mental retardation may occur in some cases.
Several disorders can occur due to mutation of the NDP gene including persistent hyperplastic primary vitreous (PHPV), X-linked familial exudative vitreoretinopathy (X-linked-FEVR), and some cases of retinopathy of prematurity (ROP) and Coats disease. These disorders represent a spectrum of disease associated with the NDP gene. Each of these disorders can also occur secondary to mutations in other genes.
The main symptom of Norrie disease is a retinal degeneration which occurs in utero and results in blindness at birth (congenital) or early infancy. Visual failure in this disorder is characterized by the abnormal development of the retina, the thin layer of nerve cells that lines the back of the eyes (retina). The retina senses light and converts it into nerve signals, which are then relayed to brain through the optic nerve.
In Norrie disease, the retinas separate from the underlying, supporting tissue (retinal detachment). This causes a grayish-yellow mass to develop in the back of eye behind the lens that may be mistaken for a tumor (pseudoglioma). This mass consists of immature retinal cells and may be apparent a few days after birth or may not be noted until weeks or months later. This mass is located behind the pupils of the eyes so that the pupils appear white, a condition known as leukocoria or “cat’s eye” reflex.
The eyes of affected children go through additional progressive changes. The lenses of the eyes of an affected infant may be 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. Subsequently, the lenses are often completely covered by cataracts.
In addition, the eyes may be abnormally small (microphthalmia) at birth, the pupils may be widened (dilated) and the colored portion of the eyes (irises) may be underdeveloped (hypoplastic) and may stick to the lens (posterior synechiae) or may stick to the cornea (anterior synechiae). The space in the eye behind the cornea and in front of the iris (anterior chamber) may be abnormally shallow and the outflow tracts of the eye may be blocked (occluded), resulting in increased pressure with the eye (intraocular pressure) that may be extremely painful.
Most individuals with Norrie disease develop progressive hearing loss due to abnormalities in the vascular abnormalities in the cochlear (inner ear). Hearing loss usually begins in early childhood and may be mild at first and slowly progressive. By the third or fourth decade there may be significant functional loss but can usually be aide assisted. Speech discrimination is relatively well preserved. The development and severity of hearing loss varies greatly even among members of the same family. In some cases, hearing loss may not develop until adulthood.
Approximately 30-50 percent of individuals with Norrie disease may experience cognitive abnormalities including delays in reaching developmental milestones disproportional to vision loss. Some will show behavioral problems including psychosis, aggressive behavior and cognitive regression. Mental retardation has been reported in some cases. Dementia is rare but may occur in late adulthood.
Norrie disease has been associated with disease of the peripheral blood vessels in some cases. Patients have been reported with venous stasis ulcers. In more complex molecular genetic cases (NDP deletion), one can sometimes see other clinical features including seizures, growth failure, endocrine abnormalities or severe mental retardation.
Norrie disease is inherited as an X-linked recessive trait. X-linked recessive genetic disorders are conditions caused by an abnormal gene on the X chromosome. Females have two X chromosomes but one of the X chromosomes is “turned off” and all of the genes on that chromosome are inactivated. Females who have a disease gene present on one of their X chromosomes are carriers for that disorder. Carrier females usually do not display symptoms of the disorder because it is usually the X chromosome with the abnormal gene that is “turned off”. A male has one X chromosome and if he inherits an X chromosome that contains a disease gene, he will develop the disease. Males with X-linked disorders pass the disease gene to all of their daughters, who will be carriers. A male cannot pass an X-linked gene to his sons because males always pass their Y chromosome instead of their X chromosome to male offspring. Female carriers of an X-linked disorder have a 25 percent chance with each pregnancy to have a carrier daughter like themselves, a 25 percent chance to have a non-carrier daughter, a 25 percent chance to have a son affected with the disease, and a 25 percent chance to have an unaffected son.
Investigators have determined that Norrie disease occurs due to mutations of the NDP gene located on the X chromosome (Xp11.4). Chromosomes, which are present in the nucleus of human cells, carry the genetic information for each individual. Human body cells normally have 46 chromosomes. Pairs of human chromosomes are numbered from 1 through 22 and the sex chromosomes are designated X and Y. Males have one X and one Y chromosome and females have two X chromosomes. Each chromosome has a short arm designated “p” and a long arm designated “q”. Chromosomes are further sub-divided into many bands that are numbered. For example, “chromosome X” refers to band 11.4 on the short arm of the X chromosome. The numbered bands specify the location of the thousands of genes that are present on each chromosome.
The NDP gene contains instructions for the body’s cells to make (encode) a protein known as Norrin. The exact role or function of Norrin is unknown. It is believed to be essential for the proper development of blood vessels (angiogenesis), especially those that supply blood to the retina and the cochlear. .
In rare cases, females (heterozygotes) who inherit a single copy of the disease gene for Norrie disease, disease traits on the 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 associated with the disorder such as vision loss.
Norrie disease is a rare disorder that is fully expressed in males only. In rare cases, carrier females may display some symptoms of the disorder. The incidence and prevalence rates for Norrie disease are unknown. The disorder has been reported in all ethnic groups.
A diagnosis of Norrie disease is suspected based upon a detailed patient history, a thorough clinical evaluation, and identification of characteristic findings. There may be a family history supporting X-linked inheritance. A diagnosis may be confirmed by molecular genetic testing in which a mutation in the defective gene (NDP) is identified. Such testing is available through clinical testing labs (www.genetests.org).
The treatment of Norrie disease may require the coordinated efforts of a team of specialists. Pediatricians, specialists who assess and treat eye abnormalities (ophthalmologists), specialists who assess and treat hearing loss (audiologists), and other healthcare 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. Earlier in utero treatment has been reported as well as early vitrectomy in attempts to preserve vision.
Hearing aids may be of benefit for individuals with hearing loss and is usually successful into middle or late adulthood. When hearing is significantly impaired, a cochlear implant may be helpful . Other treatment is symptomatic and supportive.
Early intervention and appropriate specialized education is important in ensuring that children with Norrie disease reach their highest potential. Services that may be beneficia. include special remedial or personalized education, other medical, social, and/or vocational services.
Genetic counseling is important for genetic risk assessment in family members.
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