Norrie disease
Norrie disease, also known as Norrie syndrome, is a rare X-linked recessive disorder primarily affecting males, characterized by congenital blindness, which typically presents at birth or in the early months of life. The condition is caused by mutations in the NDP gene located on the X chromosome, which plays a role in retinal and vascular development. In addition to blindness, individuals may experience progressive sensorineural hearing loss, developmental delays, and various cognitive impairments. While female carriers may exhibit mild symptoms, most affected individuals are male, as the disease is transmitted from father to daughter and can affect sons of carrier mothers.
Diagnosis of Norrie disease involves clinical evaluations alongside genetic testing to identify mutations in the NDP gene. Symptoms can include grayish-yellow fibrovascular masses in the eyes and progressive deterioration of hearing and cognitive function. Unfortunately, there is currently no cure for Norrie disease, but management strategies include supportive therapies, hearing aids, and potential surgical interventions for eye-related issues. Ongoing research is exploring gene therapy possibilities, which may offer hope for future symptom prevention. Genetic counseling is recommended for families affected by Norrie disease to discuss inheritance patterns and implications for future generations.
Norrie disease
ALSO KNOWN AS: Norrie syndrome; oculoacousticocerebral dysplasia; congenital progressive oculo-acoustico-cerebral degeneration; Norrie-Warburg syndrome; fetal iritis syndrome; atrophia bulborum hereditaria; episkopi blindness; pseudoglioma
DEFINITION Norrie disease is a rare X-linked recessive disorder that is caused by mutations in the NDP gene on the X chromosome. It is characterized by blindness at birth or in the first months of life. Common additional features are hearing loss, developmental delay, and mental retardation.
Risk Factors
Norrie disease affects predominantly males. Carriers are heterozygotes and rarely develop clinical manifestations. Occasionally, female carriers may show mild vision impairment and hearing loss. The exact of Norrie disease is unknown. Approximately three hundred cases from all ethnic groups have been reported.
Etiology and Genetics
Norrie disease is caused by mutations in the NDP gene, which maps to the short arm of chromosome Xp11.4. Mutations in the NDP gene have been associated with a spectrum of pediatric vitreoretinopathies including Norrie disease (the most severe phenotype), X-linked familial exudative vitreoretinopathy, persistent hypertrophic primary vitreous, Coats disease, and retinopathy of prematurity. NDP-related retinopathies are characterized by retinal dysgenesis during embryogenesis, and a spectrum of fibrous and vascular changes of the retina at birth (peripheral avascular retina, abnormal vascularization with retinal neovascularization, subretinal exudation, abnormal vitreous composition and vitreoretinal interface, and retinal detachment) that progress through childhood and adolescence.
NDP is a three exon gene that encodes for the 133 amino acids protein norrin, a member of the mucin-like subgroup of 10-membered cysteine-knot proteins. The cysteine-knot motif is highly conserved in many growth factors (such as transforming growth factor beta, human chorionic gonadotropin, nerve growth factor, and platelet-derived growth factor). Though the exact function of norrin remains not fully understood, involvement in blood vessel formation, development and regulation of the neuroectoderm, and regulation of neural cell proliferation has been suggested.
A large number of mutations in the NDP gene have been described: more than 80 point mutations, frame shift and truncating mutations, and intragenic and submicroscopic deletions. About 15 percent of the mutations are larger deletions that involve most of the NDP. Males with NDP deletions seem to exhibit more severe than those with nondeletion mutations. However, the phenotype-genotype correlations and the functional relevance of each mutation still remain to be understood and further explored.
Males with Norrie disease transmit the disease-causing mutation to all their daughters (who will be carriers), but not sons. Carrier females have a 50 percent chance of transmitting the disease-causing mutation to each child: males who inherit the mutation will be affected and females will be carriers. Rarely, affected males have a de novo mutation.
Symptoms
Ocular findings in newborns and infants with Norrie disease include grayish-yellow fibrovascular masses (pseudogliomas) that replace the retina and are visible through a clear lens. Congenital blindness is almost always present. Light perception is severely impaired. Cataract, atrophy of the iris, increased intraocular pressure and pain develop progressively. The end stage is characterized by corneal opacification and band keratopathy, loss of intraocular pressure, and shrinking of the globe.
In early childhood, the majority of males with Norrie disease develop progressive sensorineural hearing loss that can be mild, insidious, and asymmetric. In the second to third decade of life, hearing loss is severe, symmetric, and broad-spectrum. Speech discrimination is relatively preserved.
Developmental delay, progressive mental retardation, and behavioral or psychotic-like abnormalities occur in approximately 30 to 50 percent of males. Seizures, growth failure, myoclonus, and peripheral vascular disease have been described in patients with a more severe and extended phenotype.
Screening and Diagnosis
The diagnosis of Norrie disease relies on a combination of clinical findings and molecular of NDP that identifies disease-causing mutations in approximately 95 percent of affected males. Molecular test methods are clinically available and include sequence analysis, deletion/duplication analysis, and linkage analysis.
Prenatal testing by (at approximately ten to twelve weeks of gestation) or (at approximately fifteen to eighteen weeks of gestation) is possible for pregnancies at increased risk, if the disease-causing mutation has been identified in the family. Preimplantation genetic diagnosis is feasible.
Differential diagnosis includes retinoblastoma and the other pediatric vitreoretinopathies.
Treatment and Therapy
As of 2024, there was no treatment for Norrie disease that could stop or reverse the symptoms. In cases with incomplete retinal detachment, management includes surgery and/or laser therapy. Surgery may be required for increased intraocular pressure. Occasionally, enucleation of the eye is required to control pain. Treatment for hearing loss includes hearing aids and cochlear implantation. Routine monitoring of vision and hearing should be offered to all patients with Norrie disease, even when the vision and hearing are severely reduced. Behavioral and cognitive impairment involve supportive care and therapy. Children with Norrie disease need special education comprising language pathologists, school with special orientation, mobility services, and parent education.
Researchers working on a treatment for Norrie disease tested a neonatal gene therapy on a mouse in 2023. It prevented the death of sensory cochlear hair cells, protecting the mouse from hearing loss. The treatment also used a neonatal gene therapy to restore retinal dysfunction. This gave experts hope that some symptoms of Norrie disease may be preventable in the future.
Prevention and Outcomes
Genetic counseling should be offered to all individuals with Norrie disease and their families. The natural course of the disease, treatment, mode of inheritance, and genetic risks should be discussed.
Patients with Norrie disease may have normal general health and life expectancy. Lifespan may be shortened by general risks associated with blindness, hearing loss, and intellectual deficit, such as increased risk of trauma, aspiration pneumonia, and complications of seizure disorder.
Bibliography
Pauzuolyte, Valda, et al. "Systemic Gene Therapy Rescues Retinal Dysfunction and Hearing Loss in Model of Norrie Disease." EMBO Molecular Medicine, vol. 15, no. 10, 29 Aug. 2023, doi.org/10.15252%2Femmm.202317393. Accessed 9 Sept. 2024.
Scriver, Charles R., et al. “Norrie Disease.” In The Metabolic and Molecular Bases of Inherited Disease. 8th ed. New York: McGraw-Hill, 2001.