NORD gratefully acknowledges Margaret Doyle, Natalie Ingram and Elizabeth Pryor, NORD Editorial Interns from the University of Notre Dame, and Prof. Patrick Calvas, Department of Medical Genetics, Federative Institute of Biology, Toulouse University Hospital, France, for assistance in the preparation of this report.
Norrie disease is characterized by vision loss at birth or a few weeks after an eye lesion such as retinal detachment occurs which threatens vision and can lead to severe visual impairment or loss of vision. Norrie disease mostly occurs in males, but females can show milder symptoms. Norrie disease is progressive through childhood and adolescence. Additional symptoms may occur in some people, although this varies even among individuals in the same family. Most affected males develop hearing loss which is progressive over many years. Some may exhibit cognitive abnormalities such as developmental delays, intellectual disabilities or behavioral issues.
Norrie disease is a rare X-linked genetic disorder that occurs due to change (mutation) in the NDP gene. NDP gene mutations are associated with a spectrum of retinopathies and Norrie disease is the most severe. Less severe retinopathies that can be caused by NDP gene mutations include persistent hyperplastic primary vitreous (PHPV), X-linked familial exudative vitreoretinopathy (X-linked-FEVR), and some cases of retinopathy of prematurity (ROP) and Coats disease The ocular manifestations may vary between individuals even within a family.
Norrie Disease was thought to have first been reported in Denmark in 1927 when Norrie, a Danish ophthalmologist, surveyed the cause of blindness in Denmark and found a disease that only affected males and occurred in several generations. The records were later reviewed by Mete Warburg and the name Norrie was proposed.
The main symptom of Norrie disease is a retinal degeneration which occurs before birth and results in blindness at birth (congenital) or early infancy, usually by 3 months of age. Visual failure in this disorder is characterized by the abnormal development of the neuroretina, the thin layer of nerve cells that lines the back of the eyes. The neuroretina 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 the 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 lens of the eyes so that in some, instant illumination 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) lens through which light passes may develop, a condition known as a cataract. In addition, as the disorder progresses, shrinking of the eyeball (phthisis bulbi) may occur and is often apparent by ten years of age. Subsequently, the lenses are often completely obscured 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 (hypoplasia) and may stick to the lens (posterior synechiae) or 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 within the eye (intraocular pressure) which may be extremely painful. Other signs of Norrie disease that occur in 80%-99% of individuals with this condition can be found in the facial features. These include abnormally close eyes (hypotelorism), deeply set eyes, a narrow nasal bridge, and larger than normal ears (macrotia).
Most individuals with Norrie disease develop progressive hearing loss due to vascular abnormalities in the cochlea (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 patients, 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. Patients could also show behavioral problems including psychosis, aggressive behavior and cognitive regression. Intellectual disabilities have been reported in 20-30% of patients. Dementia is rare but may occur in late adulthood.
Norrie disease has been associated with disease of the peripheral blood vessels in some people. Patients have been reported with venous stasis ulcers. In more complex molecular genetic cases (NDP gene deletion), other clinical features may occur including seizures, growth failure and endocrine abnormalities.
Norrie disease occurs due to a mutation of the NDP gene located on the X chromosome. The NDP gene encodes a protein known as norrin which plays a role in cell and tissue development. It is believed to be essential for the proper development of blood vessels (angiogenesis), especially those that supply blood to the retina and the cochlea of the inner ear. Norrin is an essential ligand for the frizzled-4 receptor of the Wnt cascade pathway, which contributes to cell development and specialization. Mutations in the NDP gene can prevent the protein from working correctly.
Norrie disease is inherited in an X-linked recessive pattern. X-linked recessive genetic disorders are conditions caused by an abnormal gene on the X chromosome. Females who have a disease gene present on one of their X chromosomes are carriers for that disorder, meaning they can pass on the chromosome to their children. Carrier females usually do not display symptoms of the disorder because the functional X chromosome will mask the symptoms of the disease. Males have only one X chromosome inherited from their mothers. When the transmitted X chromosome they receive contains a disease gene, they will develop the disease. Males with X-linked disorders pass the disease gene to all of their daughters, who will be carriers, but cannot pass it to any of their sons. Female carriers of an X-linked disorder have a 25% chance with each pregnancy to have a carrier daughter like themselves, a 25% chance to have a non-carrier daughter, a 25% chance to have a son affected with the disease, and a 25% chance to have an unaffected son.
Heterozygous females who have a single copy of a mutated NDP gene may, rarely exhibit some of the symptoms of ND such as visual impairment.
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. There are no biochemical or functional assays available for diagnosis. A diagnosis may be confirmed by molecular genetic testing in which a mutation in the NDP gene is identified.
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. Regular follow-ups are necessary, even if there is no light perception, to prevent painful eye pressure.
The treatment of individuals with Norrie disease is directed toward the specific symptoms that are apparent in each individual. There is no standard of care yet, but early surgical intervention may preserve some vision. Surgery may be necessary to remove cataracts and reattach retinas. These efforts may prevent shrinkage of the eyeballs, but will not improve vision. Treatment for patients with less than complete retinal detachment includes surgery or laser surgery to preserve eyesight if done at an early age. Intraocular pressure, which is pressure in the eye, may require surgery to remove. Very rarely does the eye need to be removed. For patients who have complete retinal detachment at birth, surgery is not an option.
Hearing aids may be of benefit for individuals with hearing loss and is usually successful in 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 are important in ensuring that children with Norrie disease reach their highest potential. Services that may be beneficial include special remedial or personalized education, other medical, social, and/or vocational services. Individualized educational plans should also be implemented early in pre-schools.
Genetic counseling is recommended for affected individual and their family members.
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