Norrie Disease

Disease Overview

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.

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Synonyms

• atrophia bulborum hereditaria
• Episkopi blindness
• ND
• NDP (Norrie disease pseudoglioma)
• Norrie syndrome
• Norrie-Warburg disease

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Signs & Symptoms

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.

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Causes

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.

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Affected populations

The incidence and prevalence rates for Norrie disease are unknown. The disorder has been reported in all ethnic groups.

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Disorders with Similar Symptoms

Symptoms of the following disorders can be similar to those of Norrie disease. Comparisons may be useful for a differential diagnosis. Common differential diagnoses include retinoblastoma with unilateral pseudoglioma, retinopathy as a result of prematurity, persistent hyperplastic primary vitreous and familial exudative vitreoretinopathy.

Retinoblastoma is an extremely rare malignant tumor that develops in the nerve-rich layers that line the back of the eyes (retina). It occurs most commonly in children under the age of three. The most suggestive and earliest clinical sign associated with retinoblastoma is the reflection of light off a tumor behind the lens of the eye, which causes the pupil to appear white, the so called “cat’s eye reflex” (leukocoria). In addition, the eyes may be crossed (strabismus). In some affected children, the eye(s) may become red and/or painful. The presence of a retinoblastoma may cause a rise in the pressure in the eyeball (glaucoma). Retinoblastoma may affect one eye (unilateral) or both eyes (bilateral). In most cases, retinoblastoma occurs as a sporadic disease but familial forms with autosomal dominant inheritance account for about 40% of cases. (For more information on this disorder, choose “retinoblastoma” as your search term in the Rare Disease Database).

Retinopathy of prematurity (ROP) is a potentially blinding disease affecting the retinas in premature infants. The retinas are the light-sensitive linings of the insides of the eyes. In infants born prematurely, the blood vessels that supply the retina are not yet completely developed. ROP may cause blood vessels to develop in an abnormal, disorganized pattern. In some affected infants, the changes associated with ROP spontaneously subside. However, in others, ROP may lead to bleeding, scarring of the retina, retinal detachment and visual loss. Even in cases in which ROP changes cease or regress spontaneously, affected children may have an increased risk of certain eye (ocular) abnormalities, including nearsightedness (myopia), misalignment of the eyes (strabismus), and/or future retinal detachment. The two major risk factors for ROP are a low birth weight and premature delivery. (For more information on this disorder, choose “retinopathy of prematurity” as your search term in the Rare Disease Database.)

Persistent hyperplastic primary vitreous (PHPV) is a developmental disorder affecting the eye that is present at birth (congenital). The disorder is characterized by abnormalities of certain eye structures and loss of vision. Specific symptoms may include abnormally small eyes (microphthalmia), cataracts, and the formation of a white membrane or mass in the pupil area behind the lens of the eyes (leukocoria). This later feature causes the pupil to appear white when light reflects off it. In a limited number of some cases of bilateral PHPV, gene mutations have been identified including mutations of the NDP gene.

Familial exudative vitreoretinopathy (FEVR) is a genetic disorder involving retinal detachment caused by retinal dysfunction or dysfunction of the blood vessel bearing tissue of the eye (choroids). These conditions disturb the outer blood-retinal barrier – known as the retinal pigment epithelium (RPE) – or inner blood-retinal barrier. The X-linked form of this disorder (X-linked FEVR) may be caused by mutations in the NDP gene.

Coats disease is a rare disorder characterized by abnormal development of the blood vessels of the nerve-rich membrane lining the eyes (retina). Affected individuals may experience loss of vision and detachment of the retina. In most patients, only one eye is affected (unilateral).Rarely, both eyes (bilateral) may be affected. In these bilateral cases, one eye may be affected more than the other (asymmetric Coats disease). Some cases of Coats disease have occurred due to mutations of the NDP gene. (For more information on this disorder, choose “Coats” as your search term in the Rare Disease Database.)

Lenz microphthalmia is a rare X-linked disorder with multisystem involvement. This includes bilateral microphthalmia and missing eyes (anophthalmia), anomalies of the digits, ear, skeleton and genitourinary tract. Mild to severe intellectual disability and other neurological impairment are often present. Lenz microphthalmia is inherited in an X-linked recessive pattern and caused by mutations in the NAA10 gene. (For more information on this disorder, choose “Lenz microphthalmia” as your search term in the Rare Disease Database).

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Diagnosis

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.

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Standard Therapies

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.

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Clinical Trials and Studies

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: prpl@cc.nih.gov

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/

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References

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.

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