Figure 1. Hearing loss in males with Norrie disease. Percent of males enrolled in the Norrie Disease Registry (n=56) by age group with hearing loss [Sims, unpublished data]
Disease characteristics. NDP-related retinopathies are characterized by a spectrum of fibrous and vascular changes of the retina at birth that progress through childhood or adolescence to cause varying degrees of visual impairment. The most severe phenotype is described as Norrie disease (ND) and includes greyish-yellow fibrovascular masses (pseudogliomas), which appear in the first few months of life and result in total blindness. About 30-50% of males with ND have developmental delay/mental retardation, behavioral abnormalities, or psychotic-like features. The majority of males with ND develop sensorineural hearing loss. Less severe phenotypes include: persistent hyperplastic primary vitreous (PHPV), characterized by a fibrotic white stalk from the optic disk to the lens; X-linked familial exudative vitreoretinopathy (XL-FEVR), characterized by peripheral retinal vascular anomalies with or without fibrotic changes; retinopathy of prematurity (ROP); and Coats disease, an exudative proliferative vasculopathy. Phenotypes can vary within families.
Diagnosis/testing. The diagnosis of NDP-related retinopathies relies upon a combination of clinical findings and molecular genetic testing of NDP, the only gene known to be associated with NDP-related retinopathies, which identifies disease-causing mutations in about 85% of affected males. Such testing is clinically available.
Management. Treatment for individuals with complete retinal detachment includes surgery and/or laser therapy. Surgery may also be required for those who develop increased intraocular pressure. Rarely, enucleation of the eye is required to control pain. Treatment for hearing loss may include hearing aids and cochlear implantation. Behavioral issues and/ cognitive impairment involve supportive intervention and therapy. Surveillance includes routine monitoring of vision and hearing.
Genetic counseling. NDP-related retinopathies are inherited in an X-linked recessive manner. Affected males transmit the disease-causing mutation to all their daughters, who will be carriers, and none of their sons. Carrier females have a 50% chance of transmitting the disease-causing mutation to each child; males who inherit the mutation will be affected and females who inherit the mutation will be carriers and will generally not be affected. Carrier testing of at-risk female relatives and prenatal testing for pregnancies of women who are carriers are possible if the NDP mutation has been identified in a family member.
Mutations in the NDP gene are associated with a spectrum of retinal findings ranging from Norrie disease (ND) to X-linked familial exudative vitreoretinopathy (FEVR), including some cases of persistent hyperplastic primary vitreous (PHPV), Coats disease, and advanced retinopathy of prematurity (ROP). These phenotypes appear to be a continuum of retinal findings with considerable overlap (Table 1). The ocular findings that permit a presumptive diagnosis of an NDP-related retinopathy include the following:
Bilateral, often symmetric, involvement of the eyes
Normal-sized eyes, with normal anterior chambers and usually clear lenses at birth
Vitreous abnormalities (hemorrhage, membranes, detachment, and/or vitreoretinal attachments)
Presence of fibrous and vascular retinal changes at birth with progressive changes through childhood or adolescence
Phenotype | Ocular | Progression | Vision | ||
---|---|---|---|---|---|
Findings | Age | Findings | Age | ||
Norrie disease (ND) | Greyish-yellow fibrovascular masses ("pseudoglioma") behind the lens (i.e., retrolental) | Birth to 3 months | Cataract, posterior synechiae (iris to lens), anterior synechiae (iris to cornea), iris atrophy, shallowing of anterior chamber, corneal opacification, band keratopathy, loss of intraocular pressure, shrinking of the globe (phthisis bulbi) | 3 months to 8-10 years | Light perception impaired or non-existent |
Persistent hyperplastic primary vitreous (PHPV) | Fibrotic white stalk with hyaloid vessels extending from optic disk to posterior lens capsule | Birth | Unknown | Unknown | Varying impairment |
Familial exudative vitreoretinopathy (FEVR) | Peripheral temporal retinal avascular zone ± congenital retinal folds, macular ectopia, fibrous tissue band at ora serrata | Birth | ± Retinal detachment (tractional and/or exudative) (may be unilateral) | Up to 20 years | Normal to impaired |
Retinopathy of prematurity (ROP) stage 4B/5 1 | Retinal neovascularization, fibrous proliferation, end-stage retrolental fibroplasia | Premature birth | Partial or complete retinal detachment | Impaired to blind | |
Coats disease 2 | Unilateral retinal telangiectasia, exudative fibrosis | Progressive vascular leakage, subretinal exudation and fibrosis, retinal detachment | Normal to impaired |
1. Rare NDP mutations have been seen in those with an ROP phenotype [Shastry, Pendergast et al 1997]. Subsequent studies have identified DNA changes outside of the coding region that may be polymorphisms and/or possible modifiers of NDP gene expression [Kenyon & Craig 1999; Hiraoka, Berinstein et al 2001; Talks et al 2001; Haider et al 2002; Hutcheson et al 2005].
2. In a family with an NDP mutation, a female carrier had a mosaic phenotype (Coats disease) and her sons had classic ocular findings of ND [Black et al 1999].
GeneReviews designates a molecular genetic test as clinically available only if the test is listed in the GeneTests Laboratory Directory by either a US CLIA-licensed laboratory or a non-US clinical laboratory. GeneTests does not verify laboratory-submitted information or warrant any aspect of a laboratory's licensure or performance. Clinicians must communicate directly with the laboratories to verify information.—ED.
Gene. NDP is the only gene known to be associated with NDP-related retinopathies.
Molecular genetic testing: Clinical uses
Confirmatory diagnostic testing
Carrier testing in females
Preimplantation genetic diagnosis
Molecular genetic testing: Clinical method
Sequence analysis. Sequence analysis of both the coding and non-coding exons detects missense and splice mutations in the NDP gene and partial or whole gene deletions in approximately 85% of males.
Deletion/duplication analysis. About 15% of mutations are submicroscopic deletions involving all or part of the NDP gene and adjacent genomic segments. Entirely intragenic NDP deletions have also been identified [Sims, unpublished]. MLPA (multiple ligation probe analysis) can be used to detect submicroscopic deletions of the NDP gene and adjacent DNA in males and possibly in carrier females.
Linkage analysis. When sequence analysis and deletion/duplication analysis is not available or a known disease causing mutation is not identified in a family, linkage analysis can be considered in families with more than one affected family member. Linkage studies are based upon accurate clinical diagnosis of NDP-related retinopathies in the affected family members and accurate understanding of the genetic relationships in the family. Linkage analysis is dependent on the availability and willingness of family members to be tested. The markers used for NDP linkage are highly informative and very tightly linked to the NDP locus; thus, they can be used in many families with NDP-related retinopathies with greater than 95% accuracy. In informative families, linkage analysis can be used to determine the carrier status of an at-risk female.
Linkage analysis may be considered in families with only one affected male; however, the possibly of a new mutation in the affected family member makes interpretation challenging.
Table 2 summarizes molecular genetic testing for this disorder.
Test Methods | Mutations Detected | Mutation Detection Rate | Test Availability |
---|---|---|---|
Sequence analysis | NDP sequence alterations | ~85% | Clinical |
Deletion/duplication analysis | Submicroscopic NDP deletions in males | 10-15% |
Interpretation of test results. For issues to consider in interpretation of sequence analysis results, click here.
NDP deletion analysis if a mutation is not found on sequence analysis
Linkage analysis if sequence analysis and deletion analysis do not identify a mutation and if the family structure is appropriate for linkage studies and the necessary family members are available for testing
No other phenotype is associated with mutations in the NDP gene; however, an NDP mutation co-segregating with an RS mutation has been identified in one family with X-linked juvenile retinoschisis [Hiraoka, Rossi et al 2001], but not in other retinoschisis cases, either familial or non-familial [Shastry et al 2000].
The ocular findings in males with an NDP mutation are usually bilateral and symmetric. They are present at birth and are usually progressive. The classic ND phenotype after which the disorder is named was the first described eye finding and is the best characterized of the ocular manifestations. With the discovery of the NDP gene and the advent of clinically available molecular genetic testing, it has become evident that the ocular phenotypes observed in NDP-related retinopathies include Norrie disease (ND), X-linked familial exudative vitreoretinopathy (XL-FEVR), and persistent hyperplastic primary vitreous (PHPV) [Riveiro-Alvarez et al 2005] (Table 1).
Ocular phenotype can vary even within a family [Berger & Ropers 2001, Allen et al 2006]. In one family, the spectrum of ocular phenotypes in nine affected males included unilateral subtotal retinal detachment at three to four years of age that slowly progressed to a tractional detachment at the severe end to peripheral retinal pigmentary changes in a 79-year-old male at the mild end [Allen et al 2006].
Norrie disease
Ocular findings. At birth, the irises, anterior chambers, cornea, intraocular pressure, and size of the globe may be normal. In newborns and infants, the classic finding is a greyish-yellow, glistening, elevated mass that replaces the retina and is visible through a clear lens. These masses are referred to as "pseudogliomas" because they resemble tumors. Partial or complete retinal detachment evolves over the first few months.
From infancy throughout childhood, progressive changes typically include opacification of the lens (cataract), atrophy of the iris with adhesions forming between the lens and the iris (posterior synechiae) and between the iris and the cornea (anterior synechiae), and shallowing of the anterior chamber with occlusion of the outflow tracts, resulting in increased intraocular pressure that may be painful.
These changes are followed by corneal opacification and band keratopathy, loss of intraocular pressure, and shrinking of the globe (phthisis bulbi). In the end stage of ND, the corneas appear milky and the globes appear small and sunken in the orbits.
Cognitive/behavioral findings. About 30-50% of males with the ND phenotype have developmental delay/mental retardation and may show poorly characterized behavioral abnormalities or psychotic-like features. Intra- and interfamilial variability in the appearance and expression of the cognitive and behavioral difficulties is common.
Figure 1. Hearing loss in males with Norrie disease. Percent of males enrolled in the Norrie Disease Registry (n=56) by age group with hearing loss [Sims, unpublished data]
Audiologic data suggest that the pathology resides in the cochlea (specifically, the stria vascularis) and that retrocochlear and brain auditory system function is normal. Early hearing loss is sensorineural, mild and asymmetric. High-frequency hearing loss appears by adolescence. By age 35 years, hearing loss is severe, symmetric, and broad-spectrum. Speech discrimination is relatively well preserved even when the threshold loss is severe [Halpin et al 2005].
For most affected individuals, adaptation to the congenital blindness may be less problematic than adjustment to the later-onset, slowly progressive hearing loss.
Figure 2. Peripheral vascular disease in males with Norrie disease. Percent of males enrolled in the Norrie Disease Registry (n=56) with peripheral vascular disease by age group [Sims, unpublished data].
General health is normal. Life span may be shortened by general risks associated with mental retardation, blindness, and/or hearing loss, such as increased risk of trauma, aspiration pneumonia, and complications of seizure disorder.
PHPV is characterized by a fibrotic white stalk with vessels extending from the optic disk to the temporal posterior lens capsule [Chynn et al 1996, Walker et al 1997]. The retina may be in folds or detached; the lens may or may not be clear. Although progression to complete retinal detachment has been described, it is not clear if such progression always occurs.
FEVR is characterized by premature arrest of vascularization of the retina resulting in an avascular zone in the peripheral retina. This avascular zone may be the only retinal finding, or congenital falciform retinal folds or retinal detachment may be present. When falciform folds are present, the macula may be dragged temporally (so-called macular ectopia).
These eye findings may progress to retinal detachment either through increasing traction on the retina from progressive fibrovascular changes in the temporal retinal periphery or through exudation of serous fluid by the fragile capillaries in the abnormal peripheral retinal vasculature. Retinal detachment is usually accompanied by a decrease in central visual acuity because of macular involvement.
Mutations in the NDP gene have been identified in individuals with X-linked familial and sporadic exudative vitreoretinopathy [Johnson et al 1996; Shastry 1998].
Retinopathy of maturity is similar to the retinal changes found in FEVR. Mutations in NDP were identified in four of 16 premature infants with advanced ROP [Shastry, Pendergast et al 1997; Hiraoka, Berinstein et al 2001], raising the question whether NDP mutations may predispose to the ND ocular phenotype in some premature infants. A study of 102 Kuwaiti Arab premature infants, however, identified only polymorphisms and no phenotype-associated NDP mutations [Haider et al 2001]. Hutcheson et al (2005) studied 54 infants with severe ROP (≥ stage 3) of different ethnic backgrounds and identified five sequence variations in untranslated regions (UTR) of NDP. No clear role for these NDP polymorphisms in the pathogenesis of ROP was established.
Coats disease (exudative retinitis) is an exudative proliferative vasculopathy with onset typically before age 20 years, and usually in infancy or childhood. Male to female ratio is 10:1. Retinal vascular changes include telangiectasias, venous and capillary fusiform dilatation, and microaneurysms. Subretinal lipid exudate and retinal hemorrhage are observed, usually in the macula and/or supertemporal regions. Exudative retinal detachment and decreased retinal capillary perfusion may occur. Other complications can include iridocyclitis, cataract, or neovascular glaucoma. More than 90% of reported cases appear to be unilateral.
Histopathology. A retinal vasculopathy appears to be the primary pathophysiologic ocular change underlying the secondary, fibrotic reaction and associated vitreous hemorrhage. Retinal ganglion cell loss may also occur.
Abnormalities of retinal vasculature have been described in the mouse model [Berger et al 1996, Richter et al 1998]. In the ND mouse model, Rehm et al (2002) documented a progressive loss of vessels in the stria vascularis of the cochlea and an associated hearing loss.
Heterozygotes. In rare instances, females who are carriers may have some retinal findings (retinal detachment, abnormal retinal vasculature) and associated vision loss [Sims et al 1997; Yamada et al 2001]. Some carrier females may show a mild sensorineural hearing loss [Sims, unpublished data; Halpin et al 2005].
Phenotypic expression has been reported in two females with an X;autosome translocation [Meire et al 1998]; however, carrier expression is usually presumed to be secondary to non-random X-chromosome inactivation.
Males with NDP deletions exhibit a more severe phenotype than those with non-deletion mutations [Donnai et al 1988; Sims, de la Chapelle et al 1989; Collins et al 1992; Suarez-Merino et al 2001]. In addition to the ocular manifestations of ND, affected individuals with a deletion may have microcephaly, severe-to-profound mental retardation, seizures, myoclonus, somatic growth failure, and/or delayed puberty.
No specific correlations have been identified between single base pair mutations and cognitive dysfunction or hearing impairment.
Although it has been suggested that missense mutations in the C-terminus region may be associated with the milder FEVR phenotype [Meindl et al 1995, Walker et al 1997, Allen et al 2006], a number of individuals with severe ocular phenotypes with or without mental retardation have had mutations in the C-terminus region [Fuchs et al 1996].
Penetrance is complete in affected males.
Rarely, a partial or mild ocular phenotype occurs in carrier females, presumably secondary to non-random X-chromosome inactivation.
The following are outdated terms for Norrie disease:
Atrophia bulborum hereditaria
Pseudoglioma
Episkopi blindness
No incidence or prevalence figures are available.
Norrie disease has been reported in all ethnic groups, including northern and central European, Caucasian American, African American, French-Canadian, Hispanic, and Japanese. No ethnic group appears to predominate, although most of the individuals reported in the first decades after the original description of Norrie disease were from Scandinavia.
For current information on availability of genetic testing for disorders included in this section, see GeneTests Laboratory Directory. —ED.
Retinoblastoma (RB) is often considered in index cases of Norrie disease (ND) if the ocular pathology is predominantly that of unilateral pseudoglioma; because the usual presentation of ND is bilateral, diagnosis of RB is not usually a consideration. Fundoscopic examination by an ophthalmologist familiar with retinal diseases can distinguish between the two disorders.
Retinal findings of ND can mimic PHPV, retinopathy of prematurity (ROP), which occurs in preterm low birth-weight infants who have been treated with supplemental oxygen, familial exudative vitreoretinopathy (FEVR), which can be inherited in an autosomal dominant manner (see Autosomal Dominant Familial Exudative Vitreoretinopathy). Mutations in FZD4, encoding the protein frizzled-4, have been identified in autosomal dominant FEVR [Robitaille et al 2002, Toomes et al 2004]. Because the phenotype of FEVR may overlap with that of ND, FZD4 mutations may underlie some instances of ND in which the mode of inheritance is not clear.
Retinal dysplasia with PHPV-type changes can be associated with lissencephaly in Walker-Warburg syndrome, an autosomal recessive disorder, and with multiple anomalies in trisomy 13. However, neither of these should be confused clinically with Norrie disease.
ND is not considered in the differential diagnosis of mental retardation and/or progressive sensorineural hearing loss in the absence of the characteristic ocular features.
Complete ophthalmologic examination
Audiologic evaluation if the affected individual is older than age three to four years
Developmental assessment in early childhood if developmental milestones are not met
Behavioral evaluation as needed
Ocular manifestations
The majority of males with the classic ND phenotype have complete retinal detachment at the time of birth; therefore, interventional therapy cannot offer much with regard to preservation of sight.
Individuals without complete retinal detachment may benefit from surgery and/or laser therapy.
In the progressive stage of the ND phenotype, development of increased intraocular pressure may require surgery. Rarely, enucleation of the eye is required to control pain.
Sensorineural hearing loss
Hearing aid augmentation is usually successful well into middle or late adulthood.
Cochlear implantation should be considered when hearing-assisted audiologic function is significantly impaired.
Behavioral issues are a lifelong challenge to many individuals with Norrie disease and to their guardians/caretakers, whether or not mental retardation or cognitive impairment is present. Intervention and therapy are supportive and aimed at maximizing educational opportunities.
An empiric trial of psychotropic medications may be warranted, although no studies have addressed or supported the use of specific medications in ND.
Routine follow-up with an ophthalmologist is recommended in all individuals with ND even when vision is severely reduced.
Given that most individuals with the NDP-rleated spectrum of retinopathies are blind, hearing should be monitored routinely so that hearing loss can be detected early and managed appropriately.
Ohlmann et al (2005) have elaborated in the mouse knockout a failure of retinal angiogenesis and documented correction of the ocular-vascular phenotype by transgenic ectopic lens expression of norrin. These authors also noted a potential effect of norrin on retinal ganglion cell proliferation.
Search ClinicalTrials.gov for access to information on clinical studies for a wide range of diseases and conditions.
Genetic counseling is the process of providing individuals and families with information on the nature, inheritance, and implications of genetic disorders to help them make informed medical and personal decisions. The following section deals with genetic risk assessment and the use of family history and genetic testing to clarify genetic status for family members. This section is not meant to address all personal, cultural, or ethical issues that individuals may face or to substitute for consultation with a genetics professional. To find a genetics or prenatal diagnosis clinic, see the GeneTests Clinic Directory.
NDP-related retinopathies are inherited in an X-linked recessive manner.
Parents of a male proband
The father of a male proband is not affected and is not a carrier.
The majority of mothers of a male proband are carriers of an NDP disease-causing mutation, even when the family history is negative. Rarely, affected males have a de novo mutation. Women who are carriers may have a de novo mutation or may have inherited the mutant gene.
Women who have an affected child and one other affected relative are obligate heterozygotes (carriers).
Sibs of a male proband
The risk to sibs depends upon the carrier status of the mother.
If the mother of the proband has a disease-causing mutation, the chance of transmitting it in each pregnancy is 50%. Male sibs who inherit the mutation will be affected; female sibs who inherit the mutation will be carriers and will generally not be affected.
If the disease-causing mutation has not been identified in DNA extracted from the mother's leukocytes, the risk to sibs is low but greater than that of the general population because of the possibility of germline mosaicism.
Offspring of a male proband. Males with an NDP-related retinopathy will pass the disease-causing mutation to all of their daughters, who will be carriers, and to none of their sons.
Carrier testing of at-risk female relatives is available on a clinical basis if the mutation has been identified in the proband.
Family planning. The optimal time for determination of genetic risk, clarification of carrier status, and discussion of the availability of prenatal testing is before pregnancy.
DNA banking. DNA banking is the storage of DNA (typically extracted from white blood cells) for possible future use. Because it is likely that testing methodology and our understanding of genes, mutations, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals. DNA banking is particularly relevant in situations in which the sensitivity of currently available testing is less than 100%. See DNA Banking for a list of laboratories offering this service.
Prenatal testing is possible for pregnancies of women who are carriers if the NDP mutation has been identified in a family member. The usual procedure is to determine the fetal sex by performing chromosome analysis on fetal cells obtained by chorionic villus sampling (CVS) at about 10-12 weeks' gestation or by amniocentesis usually performed at about 15-18 weeks' gestation. If the karyotype is 46,XY, DNA from fetal cells can be analyzed for the known disease-causing mutation.
Note: Gestational age is expressed as menstrual weeks calculated either from the first day of the last normal menstrual period or by ultrasound measurements.
Preimplantation genetic diagnosis (PGD) may be available for families in which the disease-causing mutation has been identified in an affected family member in a research or clinical laboratory. For laboratories offering PGD, see .
Information in the Molecular Genetics tables is current as of initial posting or most recent update. —ED.
Gene Symbol | Chromosomal Locus | Protein Name |
---|---|---|
NDP | Xp11.4 | Norrin |
Data are compiled from the following standard references: Gene symbol from HUGO; chromosomal locus, locus name, critical region, complementation group from OMIM; protein name from Swiss-Prot.
257910 | OCULOPALATOCEREBRAL SYNDROME |
300216 | COATS DISEASE |
305390 | EXUDATIVE VITREORETINOPATHY, FAMILIAL, X-LINKED RECESSIVE; EVR2 |
310600 | NORRIE DISEASE; ND |
Gene Symbol | Locus Specific | Entrez Gene | HGMD |
---|---|---|---|
NDP | NDP | 4693 (MIM No. 310600) | NDP |
For a description of the genomic databases listed, click here.
Some studies of the knockout mouse (Ndp y/-) showed failure of retinal angiogenesis with complete lack of the deep capillary layers of the retina [Ruether et al 1997] and progressive loss of vessels in the stria vascularis of the cochlea [Rehm et al 2002]. Recent study of the knockout mouse (Ndp y/-) documented complete reversal of this pathophysiology by the transgenic ectopic norrin secretion using a lens-specific promoter [Ohlmann et al 2005]. These authors also found Norrin to have a direct stimulatory effect on the proliferation of retinal ganglion cells that was dose dependent. Thus Norrin deficiency may play a critical role in the retinal vasculopathy and visual failure of human Norrie disease (ND).
Mutant mice with a Wnt receptor, frizzled-4 (FZD4) defect were observed to have deficits in the retina and stria vascularis that resemble those of the Norrie knockout mice (NDP y/-) [Xu et al 2004]. These authors showed that Norrin and FZD4 function as a high-affinity ligand receptor pair and that Norrin induces FZD4 and lrp-dependent activation of the classic Wnt pathway, which is thought to play role in endothelial proliferation and survival. It has been hypothesized that the Norrin-FZD4 signaling system may play a central role in vascular development of the eye and ear [Xu et al 2004].
Normal allelic variants: The NDP gene spans 28 kb of genomic DNA. The cDNA comprises three exons and the coding portion spans the latter half of exon 2 and the first portion of exon 3. Exon 1 is untranslated and may function as a promoter region for gene transcription. ND-associated mutations have been identified in exon 1 [Isashiki, Ohba, Yanagita, Hokita, Doi et al 1995; Schuback et al 1995; Kenyon & Craig 1999]. A cysteine-rich region, presumed critical to secondary protein structure, exists in the carboxyl terminus of exon 3. It is here that the majority of mutations have been identified, although widely dispersed. This C-terminal, cysteine-rich domain shows homology to carboxyl regions of other extracellular proteins.
Pathologic allelic variants: The majority of mutations are single base pair changes identified in the coding region of NDP [Schuback et al 1995; Caballero et al 1996; Chynn et al 1996; Fuchs et al 1996; Johnson et al 1996; Rehm et al 1997; Shastry, Pendergast et al 1997; Torrente et al 1997; Walker et al 1997; Shastry 1998; Zaremba et al 1998; Black et al 1999; Hiraoka, Rossi et al 2001; Yamada et al 2001].
About 15% of mutations are submicroscopic deletions involving all or part of the NDP gene [Schuback et al 1995; Caballero et al 1996; Sims, unpublished data]. Affected individuals with insertions [Schuback et al 1995; Caballero et al 1996; Hiraoka, Berinstein et al 2001], complex rearrangements [Schuback et al 1995], and X;autosome translocations [Meire et al 1998] have been documented. A few of these individuals have deletions that have been identified as extending beyond the NDP locus. These individuals have more complex phenotypes suggestive of contiguous gene syndromes [Gal et al 1986; Sims, de la Chapelle et al 1989; Suarez-Merino et al 2001]. Intrafamilial phenotypic variability and the spectrum of the ocular phenotype are the subject of recent reports [Khan et al 2004, Allen et al 2006].
Two reported families carry a short repeat segment expansion in the non-coding region of NDP (exon 1) that co-segregates with the disease phenotype [Schuback et al 1995]; more recently, both insertion and deletion mutations in exon 1 associated with two cases of advanced ROP have been described [Hiraoka, Berinstein et al 2001]. Exon 1 insertions and deletions, however, have been seen in a number of control subjects, suggesting that these may be benign polymorphisms or may possibly play a role in phenotype modulation [Sims, unpublished data]. To date, more than 100 missense, null, and splice mutations have been identified, as well as more than 20 DNA rearrangements, intragenic (small) deletions, or submicroscopic ("NDPplus") deletions [Berger & Ropers 2001; Sims, unpublished data].
Most mutations are unique and have been identified in single individuals/families; a few mutations have been seen in multiple, apparently unrelated, families. Founder mutations have not been identified. The missense mutations all predict significant amino acid change and often affect one of the many cysteine residues immediately adjacent to a cysteine. These cysteine residues are presumed important for the maintenance of protein structure and mutations in these residues would be potentially deleterious to protein function.
Normal gene product: Norrin comprises 133 amino acids. The predicted protein sequence and computer modeling of the NDP gene protein (norrin) suggests a potential role for the cysteine residues and their disulfide bonds in the structural conformation of norrin and, presumably, in its function. Modeling suggests that the norrin protein is a member of the cysteine-knot growth factor family (see recent review in Vitt et al 2001), which includes transforming growth factor (TGF-beta).
Messenger RNA localization by in situ hybridization in the outer nuclear layer, inner nuclear layer, and ganglion cell layer of the retina (mice, rabbit, human [Hartzer et al 1999]) suggests a role in retinal development. Retinal vascular changes identified in ND mice [Berger et al 1996, Richter et al 1998] as well as the identification of an NDP mutation in a mosaic female carrier with a Coats disease ocular phenotype suggest a possible critical role for norrin in retinal vascular development. It has been postulated that norrin may play a role in cellular or tissue differentiation and maintenance of cellular phenotype, and/or may function in intracellular communication critical to normal retinal, central nervous system, and cochlear development.
In a transgenic mouse model for ectopic expression of norrin, Ohlmann et al (2005) showed restoration of the normal retinal vascular network in knockout mice (Ndp y/-). In addition, they documented a direct neurotrophic effect of norrin.
Abnormal gene product: No neurobiologic information describing or explaining the pathophysiology of the mutant protein effect has been published. In early studies on Ndp knockout mice, the retinal phenotype was mild, with preserved vision and lack of pseudoglioma formation. Late-life hearing loss was associated with cochlear degeneration in these animals [Berger 1998]. Retinal vascular malformation and persistence of vitreal hyaloid in ND mice suggested a possible role for norrin in the normal vascularization of the inner retinal layers and/or the regression of hyaloid vessels [Richter et al 1998].
GeneReviews provides information about selected national organizations and resources for the benefit of the reader. GeneReviews is not responsible for information provided by other organizations. Information that appears in the Resources section of a GeneReview is current as of initial posting or most recent update of the GeneReview. Search GeneTests for this disorder and select for the most up-to-date Resources information.—ED.
National Library of Medicine Genetics Home Reference
Norrie disease
Norrie Disease Association
Massachusetts General Hospital
Simches Research Building CRP 5-238
185 Cambridge St.
Boston MA 02114
Phone: (617) 726-5718
Fax: (617) 724-9620
Email: ksims@partners.org
Norrie Disease Listserv
An online discussion group for individuals with Norrie disease and their families. Questions and comments regarding symptoms, research, psychosocial issues and Norrie disease in general are "posted" and sent to all members of the group. Listserv members include medical experts in the field of Norrie disease.
health.groups.yahoo.com/group/norries/
American Council of the Blind (ACB)
1155 15th Street NW Suite 1004
Washington DC 20005
Phone: 800-424-8666; 202-467-5081
Fax: 202-467-5085
Email: info@acb.org
www.acb.org
American Society for Deaf Children
3820 Hartzdale Drive
Camp Hill PA 17011
Phone: 800-942-2732 (parent hotline); 717-703-0073 (business V/TTY)
Fax: 717-909-5599
Email: asdc@deafchildren.org
www.deafchildren.org
National Association of the Deaf
814 Thayer Avenue
Silver Spring MD 20910
Phone: 301-587-1788 (voice); 301-587-1789 (TTY)
Fax: 301-587-1791
Email: NADinfo@nad.org
www.nad.org
National Federation of the Blind (NFB)
1800 Johnson Street
Baltimore MD 21230
Phone: 410-659-9314
Fax: 410-685-5653
Email: nfb@nfb.org
www.nfb.org
Norrie disease (ND) Registry
Massachusetts General Hospital
Center of Human Genetic Research Simches Research Building Suite 5-238
185 Cambridge Street
Boston MA 02114
Phone: 617—726-5718
Email: ksims@partners.org
Norrie disease Registry
Medical Genetic Searches: A specialized PubMed search designed for clinicians that is located on the PubMed Clinical Queries page.
No specific guidelines regarding genetic testing for this disorder have been developed.
Web site: www.DNAlab.org
8 August 2006 (me) Comprehensive update posted to live Web site
14 May 2004 (me) Comprehensive update posted to live Web site
11 June 2002 (me) Comprehensive update posted to live Web site
30 July 1999 (me) Review posted to live Web site
10 February 1999 (ks) Original submission