Última actualización:
May 29, 2020
Años publicados: 1988, 1989, 1994, 1996, 2001, 2008, 2012, 2020
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.
Summary
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.
Introduction
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.
Treatment
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.
Information on current clinical trials is posted on the Internet at www.clinicaltrials.gov. All studies receiving U.S. government funding, and some supported by private industry, are posted on this government web site.
For information about clinical trials being conducted at the NIH Clinical Center in Bethesda, MD, contact the NIH Patient Recruitment Office:
Tollfree: (800) 411-1222
TTY: (866) 411-1010
Email: [email protected]
Some current clinical trials also are posted on the following page on the NORD website: https://rarediseases.org/living-with-a-rare-disease/find-clinical-trials/
For information about clinical trials sponsored by private sources, contact: www.centerwatch.com
For information about clinical trials conducted in Europe, contact:
https://www.clinicaltrialsregister.eu/
TEXTBOOKS
Spandau U., Kim S.J. Norrie Disease. In: Pediatric Retinal Vascular Diseases. 2019. Springer, Cham.
Traboulsi EI. Ed. A Compendium of Inherited Disorders and the Eye. Oxford University Press. New York, NY. 2006:125-126.
Lewis RA. Norrie Disease. NORD Guide to Rare Disorders. Lippincott Williams & Wilkins. Philadelphia, PA. 2003:655-656.
JOURNAL ARTICLES
Wu LH, Chen L-H, Xie H, Xie Y-J. Prenatal diagnosis of a case of Norrie disease with late development of bilateral ocular malformation. Fetal Pediatr Pathol. 2017 Jun;36(3):240-245.
Champneys, McLoone E, Willoughby CE. A mutation in the Norrie disease gene (NDP) associated with familial exudative vitreoretinopathy. Eye (Lond). 2011 Dec;25(12):1658. doi: 10.1038/eye.2011.226. Epub 2011 Sep 30. PubMed PMID:21960066.
Drenser KA, Walsh MK, Capone A Jr, Trese MT, Luo CK. Preterm treatment of Norrie disease. Ophthalmology. 2011 Aug;118(8):1694-5; author reply 1695,1695.e1. PubMed PMID: 21813101.
Walsh MK, Drenser KA, Capone A Jr, Trese MT. Norrie disease vs familial exudative vitreoretinopathy. Arch Ophthalmol. 2011 Jun;129(6):819-20. PubMed PMID: 21670366.
Chow CC, Kiernan DF, Chau FY, Blair MP, Ticho BH, Galasso JM, Shapiro MJ. Laser photocoagulation at birth prevents blindness in Norrie’s disease diagnosed using amniocentesis. Ophthalmology. 2010 Dec;117(12):2402-6. PubMed PMID: 20619898.
Kiernan DF, Blair MP, Shapiro MJ. In utero diagnosis of Norrie disease and early laser preserves visual acuity. Arch Ophthalmol. 2010 Oct;128(10):1382. PubMed PMID: 20938020.
Liu D, Hu Z, Peng Y, et al. A novel nonsense mutation in the NDP gene in a Chinese family with Norrie disease. Mol Vis. 2010 Dec 8;16:2653-8. PubMed PMID: 21179243; PubMed Central PMCID: PMC3002970.
Nikopoulos K, Venselaar H, Collin RW, et al. Overview of the mutation spectrum in familial exudative vitreoretinopathy and Norrie disease with identification of 21 novel variants in FZD4, LRP5, and NDP. Hum Mutat. 2010 Jun;31(6):656-66. PubMed PMID: 20340138.
Staopoli JF, Xinw, Sims KB. Co-segregation of Norrie disease and idiopathic pulmonary hypertension in a family with a microdeletion of the NDP region. J Med Genet 2010;47:786-790.
Walsh MK, Drenser KA, Capone A Jr, Trese MT. Early vitrectomy effective for Norrie disease. Arch Ophthalmol. 2010 Apr;128(4):456-60. PubMed PMID: 20385941.
Ye X, Smallwood P, Nathans J. Expression of the Norrie disease gene (Ndp) in developing and adult mouse eye, ear, and brain. Gene Expr Patterns. 2011 Jan-Feb;11(1-2):151-5. Epub 2010 Nov 3. PubMed PMID: 21055480; PubMed Central PMCID: PMC3061303.
Ye X, Wang Y, Nathans J. The Norrin/Frizzled4 signaling pathway in retinal vascular development and disease. Trends Mol Med. 2010;16(9):417–425. doi:10.1016/j.molmed.2010.07.003
Riveiro-Alvarez R, Trujillo-Tiebas MJ, Gimenez-Pardo A, et al. Genotype-phenotype variations in five Spanish families with Norrie disease. Mol Vis. 2005;11:705-711.
Halpin C, Owen G, Gutierrez-Espeleta GA, Sims K, Rehm HL. Audiologic features of Norrie disease. Ann Oto Rhinol Laryngol. 2005;114:533-538.
Royer G, Hanein S, Raclin V, et al. NDP gene mutations in 14 French families with Norrie disease. Hum Mutat. 2003;22:499.
Rehm HL, Gutierrez-Espeleta GA, Garcia R, et al. Norrie disease gene mutation in a large Costa Rican kindred with a novel phenotype including venous insufficiency. Hum Mutat. 1997;9:420-428.
Sims KB, Irvine AR, Good WV. Norrie disease in a family with a manifesting female carrier. Arch Ophthalmol. 1997;115:517-519.
Meindl A, Lorenz B, Achatz H, et al. Missense mutations in the Norrie disease gene (NDP) associated with X-linked familial vitreoretinopathy. Nat Genet. 1995;5:180-183
Chen ZY, Hendriks RW, Jobling MA, et al. Isolation and characterization of a candidate gene for Norrie disease. Nat Genet. 1992 Jun;1(3):204-8.
Berger W, Meindl A, van de Pol TJ, et al. Isolation of a candidate gene for Norrie disease by positional cloning. Nat Genet. 1992;: 199-203.
INTERNET
Norrie disease – Genetics Home Reference. Reviewed March 2020. https://ghr.nlm.nih.gov/condition/norrie-disease . Accessed April 30, 2020.
Norrie disease. Orphanet. Feb 2020. https://www.orpha.net/consor/cgi-bin/Disease_Search.php?lng=EN&data_id=190&Disease_Disease_Search_diseaseGroup=Norrie-disease&Disease_Disease_Search_diseaseType=Pat&Disease(s)/group%20of%20diseases=Norrie-disease&title=Norrie%20disease&search=Disease_Search_Simple Accessed April 30, 2020.
Sun J, Sisk RA, Traboulsi EI, Miraldi Utz V. Norrie Disease. American Academy of Ophthalmology. Published November 20, 2017. https://www.aao.org/disease-review/norrie-disease Accessed April 30, 2020.
McKusick VA., ed. Online Mendelian Inheritance in Man (OMIM). Baltimore. MD: The Johns Hopkins University; Entry No:310600; Last Update: 09/09/2016. Available at: https://omim.org/entry/310600 Accessed April 30, 2020.
Sims KB. NDP-Related Retinopathies. 1999 Jul 30 [Updated 2014 Sep 18]. In: Adam MP, Ardinger HH, Pagon RA, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2020. Available from: https://www.ncbi.nlm.nih.gov/books/NBK1331/ Accessed April 30, 2020.
NORD y la Fundación MedicAlert se han asociado en un nuevo programa para brindar protección a pacientes con enfermedades raras en situaciones de emergencia.
Aprende más https://rarediseases.org/patient-assistance-programs/medicalert-assistance-program/Asegurarse de que los pacientes y los cuidadores estén equipados con las herramientas que necesitan para vivir su mejor vida mientras manejan su condición rara es una parte vital de la misión de NORD.
Aprende más https://rarediseases.org/patient-assistance-programs/rare-disease-educational-support/Este programa de asistencia, primero en su tipo, está diseñado para los cuidadores de un niño o adulto diagnosticado con un trastorno raro.
Aprende más https://rarediseases.org/patient-assistance-programs/caregiver-respite/The information provided on this page is for informational purposes only. The National Organization for Rare Disorders (NORD) does not endorse the information presented. The content has been gathered in partnership with the MONDO Disease Ontology. Please consult with a healthcare professional for medical advice and treatment.
The Genetic and Rare Diseases Information Center (GARD) has information and resources for patients, caregivers, and families that may be helpful before and after diagnosis of this condition. GARD is a program of the National Center for Advancing Translational Sciences (NCATS), part of the National Institutes of Health (NIH).
View reportOrphanet has a summary about this condition that may include information on the diagnosis, care, and treatment as well as other resources. Some of the information and resources are available in languages other than English. The summary may include medical terms, so we encourage you to share and discuss this information with your doctor. Orphanet is the French National Institute for Health and Medical Research and the Health Programme of the European Union.
View reportOnline Mendelian Inheritance In Man (OMIM) has a summary of published research about this condition and includes references from the medical literature. The summary contains medical and scientific terms, so we encourage you to share and discuss this information with your doctor. OMIM is authored and edited at the McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine.
View report