Clinical Diagnosis

Mutations in NDP 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

Molecular Genetic Testing

Gene. NDP is the only gene known to be associated with NDP-related retinopathies.

Clinical testing

• Sequence analysis. Sequence analysis of both the coding and non-coding exons along with flanking intronic regions detects missense and splice mutations and small deletions and insertions in NDP and partial or whole NDP gene deletions in approximately 95% of males.
  
  Note: (1) Exon 1 insertions and deletions have been seen in a number of controls [Sims, unpublished data], suggesting that these may be benign polymorphisms or may possibly play a role in phenotype modulation. (2) Recently, three of 31 cases of ROP were reported with a 14-bp deletion in NDP exon 1, although the same deletion was identified in an unaffected ex-premature female [Dickinson et al 2006]. In 109 individuals with diverse vitreoretinopathies, this 14-bp deletion in exon 1 was identified in one person with clinical ROP [Wu et al 2007]. It is possible that these exon 1 variations may be polymorphisms which predispose to ROP.

• Deletion/duplication analysis. Approximately 15% of mutations are submicroscopic deletions involving all or part of NDP and adjacent genomic segments. NDP exonic and multiexonic deletions have also been identified [Berger & Ropers 2001; Sims, unpublished]. A variety of methods can be used to detect submicroscopic deletions of NDP and adjacent DNA in males and possibly in carrier females (see Table 2).

• Linkage analysis. When sequence analysis and deletion/duplication analysis are not an option 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 on 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.

Table 2. Summary of Molecular Genetic Testing Used in NDP-Related Retinopathies

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Gene Symbol	Test Method	Mutations Detected	Mutation Detection Frequency by Test Method 1		Test Availability
			Affected males	Carrier females
NDP	Sequence analysis	Sequence variants 2	80%	80%	Clinical
		Exonic, multiexonic, and whole-gene deletions	15%	0% 3
	Deletion / duplication analysis 4	Exonic, multiexonic, and whole-gene deletions	Not needed 5	15%

Test Availability refers to availability in the GeneTests™ Laboratory Directory. 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.

1. The ability of the test method used to detect a mutation that is present in the indicated gene

2. Examples of mutations detected by sequence analysis may include small intragenic deletions/insertions and missense, nonsense, and splice site mutations.

3. Sequence analysis of genomic DNA cannot detect exonic, multiexonic, or whole-gene deletions on the X chromosome in carrier females.

4. Testing that detects deletions/duplications not readily detectable by sequence analysis of genomic DNA; a variety of methods including quantitative PCR, real-time PCR, multiplex ligation-dependent probe amplification (MLPA), or array GH may be used.

5. Putative exonic, multiexonic, and whole-gene deletions on the X chromosome, in affected males, can be suspected when there is failure of amplification by PCR.

Interpretation of test results. For issues to consider in interpretation of sequence analysis results, click here.

Testing Strategy

To confirm the diagnosis in a proband. NDP sequence analysis

Identification of female carriers requires:

• Prior identification of the disease-causing mutation in the family
  OR

• If an affected male is not available for testing, molecular genetic testing first by sequence analysis, and if no mutation is identified, then by methods to detect gross structural abnormalities (most likely deletion)
  OR

• 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

Note: Carriers are heterozygotes for this X-linked disorder and rarely develop clinical findings related to the disorder.

Prenatal diagnosis and preimplantation genetic diagnosis (PGD) for at-risk pregnancies require prior identification of the disease-causing mutation in the family.

Note: It is the policy of GeneReviews to include in GeneReviews™ chapters any clinical uses of testing available from laboratories listed in the GeneTests™ Laboratory Directory; inclusion does not necessarily reflect the endorsement of such uses by the author(s), editor(s), or reviewer(s).

Genetically Related (Allelic) Disorders

No other phenotype is associated with mutations in NDP; however, an NDP mutation cosegregating with an RS mutation has been identified in one family with X-linked juvenile retinoschisis [Hiraoka et al 2001b] but not in other retinoschisis cases, either familial or non-familial [Shastry et al 2000].

Natural History

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 NDP 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, Dickinson et al 2006, Kondo et al 2007] (Table 1).

The 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 ages three to four years 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 development of a shallow anterior chamber with occlusion of the outflow tracts which may result in increased intraocular pressure and pain.
  
  These changes are followed by corneal opacification and band keratopathy, loss of intraocular pressure, and shrinkage of the globe (phthisis bulbi). In the end stage of ND, the corneas appear milky and opacified; and the globes appear small and sunken in the orbits [Dresner et al 2007].

• Cognitive/behavioral findings. Approximately 30%-50% of males with the ND phenotype have developmental delay/intellectual disability 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. A severe neurologic phenotype including infantile spasms has been reported [Lev et al 2007].

• Auditory findings. The majority of males with the ND phenotype develop progressive sensorineural hearing loss starting in early childhood (Figure 1). Onset of hearing loss can be insidious.
  
  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.

• Other. Peripheral vascular disease (Figure 2) appears to be an associated clinical finding in a number of affected males [Rehm et al 1997].
  
  General health is normal. Life span may be shortened by general risks associated with intellectual disability, blindness, and/or hearing loss, such as increased risk of trauma, aspiration pneumonia, and complications of seizure disorder.

Figure

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]

Figure

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]

PHPV is characterized by a fibrotic white stalk with vessels extending from the optic disk to the temporal posterior lens capsule [OMIM 611311]. 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 [Wu et al 2007]. PHPV is usually unilateral; therefore, bilateral presentation should suggest ND.

X-linked FEVR [OMIM 305390] 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 NDP have been identified in individuals with X-linked familial and sporadic exudative vitreoretinopathy [Shastry 1998, Dickinson et al 2006, Kondo et al 2007].

Retinopathy of prematurity (ROP) involves retinal changes similar to those found in FEVR. Mutations in NDP were identified in four of 16 premature infants with advanced ROP [Hiraoka et al 2001a], 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) [OMIM 300216] 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.

Genotype-Phenotype Correlations

Males with NDP deletions exhibit a more severe phenotype than those with non-deletion mutations [Suarez-Merino et al 2001, Wu et al 2007]. In addition to the ocular manifestations of ND, individuals with a deletion may have microcephaly, severe-to-profound intellectual disability, seizures, myoclonus, somatic growth failure, and/or delayed puberty.

Unique point mutations, identified in four individuals with severe retinal dysplasia, affected a Cys allele and presumably altered important structural aspects of the protein [Dresner et al 2007].

Although it has been suggested that missense mutations in the C-terminus region may be associated with the milder FEVR phenotype [Allen et al 2006], a number of individuals with severe ocular phenotypes with or without intellectual disability have had mutations in the C-terminus region.

Recently, one individual with a point mutation (C.134T>A) has been reported with a severe neurologic phenotype including profound intellectual disability and infantile spasms [Lev et al 2007].

No specific correlations have been identified between single base-pair mutations and cognitive dysfunction or hearing impairment.

Penetrance

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.

Nomenclature

The following are outdated terms for Norrie disease:

• Atrophia bulborum hereditaria

• Pseudoglioma

• Episkopi blindness

Prevalence

No incidence or prevalence figures are available.

Norrie disease has been reported in all ethnic groups, including northern and central European, Americans of European descent, 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.

Evaluations Following Initial Diagnosis

To establish the extent of disease in an individual diagnosed with NDP-related retinopathies, the following evaluations are recommended:

• 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

Treatment of Manifestations

Ocular manifestations

• The majority of males with the classic ND phenotype have complete retinal detachment at the time of birth; therefore, interventional therapy may not offer much with regard to preservation of sight. Ophthalmologic evaluation is warranted.

• 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 intellectual disability 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 for treatment of ND.

Surveillance

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-related spectrum of retinopathies are blind, hearing should be monitored routinely so that hearing loss can be detected early and managed appropriately.

Agents/Circumstances to Avoid

Given the increased risk of hearing loss, exposure to loud noises should be avoided.

Evaluation of Relatives at Risk

See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes

Therapies Under Investigation

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.

Registries

Contact information for voluntary patient registries is provided by GeneReviews staff.

Norrie Disease Registry
Massachusetts General Hospital
Phone: 617-726-5718
Fax: 617-724-9620
Email: ksims@partners.org

Other

Genetics clinics, staffed by genetics professionals, provide information for individuals and families regarding the natural history, treatment, mode of inheritance, and genetic risks to other family members as well as information about available consumer-oriented resources. See the GeneTests Clinic Directory.

See Consumer Resources for disease-specific and/or umbrella support organizations for this disorder. These organizations have been established for individuals and families to provide information, support, and contact with other affected individuals.

Mode of Inheritance

NDP-related retinopathies are inherited in an X-linked manner.

Risk to Family Members

Parents of a male proband

• The father of a male proband is neither affected nor is he 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 on 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.

Other family members of a male proband. The proband's maternal aunts may be at risk of being carriers and the aunts’ offspring, depending on their gender, may be at risk of being carriers or of being affected.

Carrier Detection

Carrier testing of at-risk female relatives is possible if the mutation has been identified in the family.

Related Genetic Counseling Issues

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.

• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers.

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. See for a list of laboratories offering DNA banking.

Prenatal Testing

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 approximately ten to 12 weeks' gestation or by amniocentesis usually performed at approximately 15 to 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. For laboratories offering PGD, see .

Note: It is the policy of GeneReviews to include in GeneReviews™ chapters any clinical uses of testing available from laboratories listed in the GeneTests™ Laboratory Directory; inclusion does not necessarily reflect the endorsement of such uses by the author(s), editor(s), or reviewer(s).

Molecular Genetic Pathogenesis

Studies of mouse models suggest that norrin deficiency may play a critical role in the retinal vasculopathy and visual failure of human Norrie disease (ND).

Some studies of the knockout mouse (Ndp y/-) showed failure of retinal angiogenesis with complete lack of the deep capillary layers of the retina and progressive loss of vessels in the stria vascularis of the cochlea [Rehm et al 2002]. Late involvement of photoreceptor cells was documented by gene expression analysis in an ND mouse model [Lenzner et al 2002]. NDP may have role in developmental sprouting angiogenesis [Luhmann et al 2005]. 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.

Studies in mouse models led to the hypothesis that the Norrin-Fzd4 signaling system may play a central role in vascular development of the eye and ear [Xu et al 2004, Hendrickx & Leyns 2008]. 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 LRP5-dependent activation of the classic Wnt pathway, which is thought to play a role in endothelial proliferation and survival. Defects in the Wnt signaling cascade affect ocular growth and development, and presumably are important in the pathobiologic processes underlying both ND and FEVR [Warden et al 2007]. Recent differential gene expression study in the Ndph-knockout mouse suggested significantly altered expression of Plvap and Slc38a5 as well as ectopic Plvap expression in the retina [Schafer et al 2009], but further study is needed to understand the potential biologic role of these changes.

The pathobiology of the intellectual disability and behavioral dysfunction seen in some individuals with ND is not yet understood.

In the mouse model, clinical features including abnormal gait and progressive cerebellar ataxia and the documented dramatic loss of cerebellar granular and Purkinje cells in the Fzd4 knockout mouse [Wang et al 2001] suggest the possible requirement of the Wnt-receptor Fzd4 in normal neuronal development. Luhmann et al [2008] have explored possible central nervous system pathology and document cerebellar vascular abnormalities in the Ndph knockout mouse.

Normal allelic variants. NDP 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 [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. 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].

The majority of mutations are single base-pair changes identified in the coding region of NDP [Schuback et al 1995, Shastry 1998, Zaremba et al 1998, Black et al 1999, Hiraoka et al 2001b, Yamada et al 2001, Dickinson et al 2006, Dresner et al 2007, Kondo et al 2007, Lev et al 2007, Wu et al 2007, Khan et al 2008].

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.

Approximately 15% of mutations are submicroscopic deletions involving all or part of NDP [Berger & Ropers 2001; Sims, unpublished data].

Affected individuals with insertions [Hiraoka et al 2001a], 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 [Sims 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 families have a short repeat segment expansion in the non-coding region of NDP (exon 1) that co.segregates with the disease phenotype; more recently, both insertion and deletion mutations in exon 1 associated with advanced ROP have been described [Hiraoka et al 2001a, Dickinson et al 2006, Wu et al 2007]. Exon 1 insertions and deletions, however, have been seen in a number of controls [Dickinson et al 2006; Sims, unpublished data], suggesting that these may be benign polymorphisms or may possibly play a role in phenotype modulation.

Normal gene product. Norrin comprises 133 amino acids. The predicted protein sequence and computer modeling 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 [Vitt et al 2001], which includes transforming growth factor (TGF-beta).

Messenger RNA localization by in situ hybridization to 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, Luhmann et al 2005], as well as the identification of an NDP mutation in a mosaic human 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 knockout (Ndp y/-) mouse model with ectopic norrin expression, Ohlmann et al [2005] showed restoration of the normal retinal vascular network. They also documented a direct neurotrophic effect of norrin.

Abnormal gene product. 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] and abnormal vessels in the inner ear were described [Rehm et al 2002, Ohlmann et al 2005]. Retinal vascular malformation and persistence of vitreal hyaloid in the 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]. By further examination of retinal vascular development in the mouse model, norrin deficiency was felt to lead to decreased retinal angiogenesis, lack of deep retinal capillary networks, and presumed retinal hypoxia [Luhmann et al 2005].

Literature Cited

1. Allen RC, Russell SR, Streb LM, Alsheikheh A, Stone EM. Phenotypic heterogeneity associated with a novel mutation (Gly112Glu) in the Norrie disease protein. Eye. 2006;20:234–41. [PubMed: 15776010]
2. Berger W. Molecular dissection of Norrie disease. Acta Anat (Basel). 1998;162:95–100. [PubMed: 9831755]
3. Berger W, Ropers H-H. Norrie disease. In: Scriver CR, Beaudet AL, Sly WS, Valle D, Vogelstein B, eds. The Metabolic and Molecular Bases of Inherited Disease. 8 ed. New York, NY: McGraw-Hill; 2001:5977-85.
4. Berger W, van de Pol D, Bachner D, Oerlemans F, Winkens H, Hameister H, Wieringa B, Hendriks W, Ropers HH. An animal model for Norrie disease (ND): gene targeting of the mouse ND gene. Hum Mol Genet. 1996;5:51–9. [PubMed: 8789439]
5. Black GC, Perveen R, Bonshek R, Cahill M, Clayton-Smith J, Lloyd IC, McLeod D. Coats' disease of the retina (unilateral retinal telangiectasis) caused by somatic mutation in the NDP gene: a role for norrin in retinal angiogenesis. Hum Mol Genet. 1999;8:2031–5. [PubMed: 10484772]
6. Dickinson JL, Sale MM, Passmore A, Fitzgerald LM, Wheatley CM, Burdon KP, Craig JE, Tengtrisorn S, Carden SM, Maclean H, Mackey DA. Mutations in the NDP gene: contribution to Norrie disease, familial exudative vitreoretinopathy and retinopathy of prematurity. Clinical and Experimental Ophthalmology. 2006;34:682–688. [PubMed: 16970763]
7. Dresner KA, Fecko A, Dailey W, Trese MT. A characteristic phenotypic retinal appearance in Norrie disease. Retina. 2007;27:243–246. [PubMed: 17290208]
8. Haider MZ, Devarajan LV, Al-Essa M, Kumar H. A C597-->A polymorphism in the Norrie disease gene is associated with advanced retinopathy of prematurity in premature Kuwaiti infants. J Biomed Sci. 2002;9:365–70. [PubMed: 12145535]
9. Haider MZ, Devarajan LV, Al-Essa M, Srivastva BS, Kumar H, Azad R, Rashwan N. Retinopathy of prematurity: mutations in the Norrie disease gene and the risk of progression to advanced stages. Pediatr Int. 2001;43:120–3. [PubMed: 11285060]
10. Halpin C, Owen G, Gutierrez-Espeleta GA, Sims K, Rehm HL. Audiologic features of Norrie disease. Ann Otol Rhinol Laryngol. 2005;114:533–8. [PubMed: 16134349]
11. Hartzer MK, Cheng M, Liu X, Shastry BS. Localization of the Norrie disease gene mRNA by in situ hybridization. Brain Res Bull. 1999;49:355–8. [PubMed: 10452356]
12. Hendrickx M, Leyns L. Non-conventional Frizzled ligands and Wnt receptors. Dev Growth Differ. 2008;50:229–43. [PubMed: 18366384]
13. Hiraoka M, Berinstein DM, Trese MT, Shastry BS. Insertion and deletion mutations in the dinucleotide repeat region of the Norrie disease gene in patients with advanced retinopathy of prematurity. J Hum Genet. 2001a;46:178–81. [PubMed: 11322656]
14. Hiraoka M, Rossi F, Trese MT, Shastry BS. X-linked juvenile retinoschisis: mutations at the retinoschisis and Norrie disease gene loci? J Hum Genet. 2001b;46:53–6. [PubMed: 11281412]
15. Hutcheson KA, Paluru PC, Bernstein SL, Koh J, Rappaport EF, Leach RA, Young TL. Norrie disease gene sequence variants in an ethnically diverse population with retinopathy of prematurity. Mol Vis. 2005;11:501–8. [PubMed: 16052165]
16. Kenyon JR, Craig IW. Analysis of the 5' regulatory region of the human Norrie's disease gene: evidence that a non-translated CT dinucleotide repeat in exon one has a role in controlling expression. Gene. 1999;227:181–8. [PubMed: 10023053]
17. Khan AO, Aldahmesh MA, Meyer B. Correlation of ophthalmic examination in carrier status in females potentially harboring a severe Norrie disease gene mutations. Ophthalmology. 2008;115:730–733. [PubMed: 18387409]
18. Khan AO, Shamsi FA, Al-Saif A, Kambouris M. A novel missense Norrie disease mutation associated with a severe ocular phenotype. J Pediatr Ophthalmol Strabismus. 2004;41:361–3. [PubMed: 15609522]
19. Kondo H, Qin M, Kusaka S, Tahira T, Hasebe H, Hayashi H, Uchio E, Hayashi K. Novel mutations in Norrie disease gene in Japanese patients with Norrie disease and Familial Exudative Vitreoretinopathy. Invest. Ophthalmol. Vis. Sci. 2007;48:1276–82. [PubMed: 17325173]
20. Lenzner S, Prietz S, Feil S, Nuber UA, Ropers H-H, Berger W. Global gene expression analysis in a mouse model for Norrie disease: late involvement of photoreceptor cells. Invest. Ophthalmol. Vis. Sci. 2002;43:2825–2833. [PubMed: 12202498]
21. Lev D, Weigl Y, Hasan M, Gak E, Davidovich M, Vinkler C, Leshinsky-Silver E, Lerman-Sagie T, Watemberg N. A novel missense mutation in the NDP gene in a child with Norrie disease and severe neurological involvement including infantile spasms. Am J Med Genet A. 2007;143A:921–4. [PubMed: 17334993]
22. Luhmann UF, Lin J, Acar N, Lammel S, Feil S, Grimm C, Seeliger MW, Hammes HP, Berger W. Role of the Norrie disease pseudoglioma gene in sprouting angiogenesis during development of the retinal vasculature. Invest Ophthalmol Vis Sci. 2005;46:3372–82. [PubMed: 16123442]
23. Luhmann UFO, Neidhardt J, Kloeckener-Gruissem B, Schafer NF, Glaus E, Feil S, Berger W. Vascular changes in the cerebellum of Norrin/Ndph knockout mice correlate with high expression of Norrin and Frizzled-4. Eur. J Neurosci. 2008;27:2619–28. [PubMed: 18547247]
24. Meire FM, Lafaut BA, Speleman F, Hanssens M. Isolated Norrie disease in a female caused by a balanced translocation t(X,6). Ophthalmic Genet. 1998;19:203–7. [PubMed: 9895245]
25. Ohlmann A, Scholz M, Goldwich A, Chauhan BK, Hudl K, Ohlmann AV, Zrenner E, Berger W, Cvekl A, Seeliger MW, Tamm ER. Ectopic norrin induces growth of ocular capillaries and restores normal retinal angiogenesis in Norrie disease mutant mice. J Neurosci. 2005;25:1701–10. [PubMed: 15716406]
26. Rehm HL, Gutierrez-Espeleta GA, Garcia R, Jimenez G, Khetarpal U, Priest JM, Sims KB, Keats BJ, Morton CC. Norrie disease gene mutation in a large Costa Rican kindred with a novel phenotype including venous insufficiency. Hum Mutat. 1997;9:402–8. [PubMed: 9143918]
27. Rehm HL, Zhang DS, Brown MC, Burgess B, Halpin C, Berger W, Morton CC, Corey DP, Chen ZY. Vascular defects and sensorineural deafness in a mouse model of Norrie disease. J Neurosci. 2002;22:4286–92. [PubMed: 12040033]
28. Richter M, Gottanka J, May CA, Welge-Lussen U, Berger W, Lutjen-Drecoll E. Retinal vasculature changes in Norrie disease mice. Invest Ophthalmol Vis Sci. 1998;39:2450–7. [PubMed: 9804153]
29. Riveiro-Alvarez R, Trujillo-Tiebas MJ, Gimenez-Pardo A, Garcia-Hoyos M, Cantalapiedra D, Lorda-Sanchez I, Rodriguez de Alba M, Ramos C, Ayuso C. Genotype-phenotype variations in five Spanish families with Norrie disease or X-linked FEVR. Mol Vis. 2005;11:705–12. [PubMed: 16163268]
30. Robitaille J, MacDonald ML, Kaykas A, Sheldahl LC, Zeisler J, Dube MP, Zhang LH, Singaraja RR, Guernsey DL, Zheng B, Siebert LF, Hoskin-Mott A, Trese MT, Pimstone SN, Shastry BS, Moon RT, Hayden MR, Goldberg YP, Samuels ME. Mutant frizzled-4 disrupts retinal angiogenesis in familial exudative vitreoretinopathy. Nat Genet. 2002;32:326–30. [PubMed: 12172548]
31. Schafer NF, Luhmann UFO, Feil S, Berger W. Differential gene expression in Ndph-knockout mice in retinal development. Invest. Ophthalmol. Vis. Sci. 2009;50:906–16. [PubMed: 18978344]
32. Schuback DE, Chen ZY, Craig IW, Breakefield XO, Sims KB. Mutations in the Norrie disease gene. Hum Mutat. 1995;5:285–92. [PubMed: 7627181]
33. Shastry BS. Identification of a recurrent missense mutation in the Norrie disease gene associated with a simplex case of exudative vitreoretinopathy. Biochem Biophys Res Commun. 1998;246:35–8. [PubMed: 9618247]
34. Shastry BS, Hiraoka M, Trese MT. Lack of association of the Norrie disease gene with retinoschisis phenotype. Jpn J Ophthalmol. 2000;44:627–9. [PubMed: 11094177]
35. Shastry BS, Pendergast SD, Hartzer MK, Liu X, Trese MT. Identification of missense mutations in the Norrie disease gene associated with advanced retinopathy of prematurity. Arch Ophthalmol. 1997;115:651–5. [PubMed: 9152134]
36. Sims KB, de la Chapelle A, Norio R, Sankila EM, Hsu YP, Rinehart WB, Corey TJ, Ozelius L, Powell JF, Bruns G. et al. Monoamine oxidase deficiency in males with an X chromosome deletion. Neuron. 1989;2:1069–76. [PubMed: 2483108]
37. Suarez-Merino B, Bye J, McDowall J, Ross M, Craig IW. Sequence analysis and transcript identification within 1.5 mB of DNA deleted together with the NDP and MAO genes in atypical Norrie disease patients presenting with a profound phenotype. Hum Mutat. 2001;17:523. [PubMed: 11385715]
38. Talks SJ, Ebenezer N, Hykin P, Adams G, Yang F, Schulenberg E, Gregory-Evans K, Gregory-Evans CY. De novo mutations in the 5' regulatory region of the Norrie disease gene in retinopathy of prematurity. J Med Genet. 2001;38:E46. [PMC free article: PMC1734786] [PubMed: 11748312]
39. Toomes C, Bottomley HM, Jackson RM, Towns KV, Scott S, Mackey DA, Craig JE, Jiang L, Yang Z, Trembath R, Woodruff G, Gregory-Evans CY, Gregory-Evans K, Parker MJ, Black GC, Downey LM, Zhang K, Inglehearn CF. Mutations in LRP5 or FZD4 underlie the common familial exudative vitreoretinopathy locus on chromosome 11q. Am J Hum Genet. 2004a;74:721–30. [PMC free article: PMC1181948] [PubMed: 15024691]
40. Toomes C, Bottomley HM, Scott S, Mackey DA, Craig JE, Appukuttan B, Stout JT, Flaxel CJ, Zhang K, Black GC, Fryer A, Downey LM, Inglehearn CF. Spectrum and frequency of FZD4 mutations in familial exudative vitreoretinopathy. Invest Ophthalmol Vis Sci. 2004b;45:2083–90. [PubMed: 15223780]
41. Vitt UA, Hsu SY, Hsueh AJ. Evolution and classification of cystine knot-containing hormones and related extracellular signaling molecules. Mol Endocrinol. 2001;15:681–94. [PubMed: 11328851]
42. Wang Y, Huso D, Cahill H, Ryugo D, Nathans J. Progressive cerebellar, auditory and esophageal dysfunction caused by targeted disruption of the frizzled-4 gene. J Neurosci. 2001;21:4761–71. [PubMed: 11425903]
43. Warden SM, Andreoli CM, Mukai S. The Wnt signaling pathway in familial exudative vitreoretinopathy and Norrie disease. Semin Ophthalmol. 2007;22:211–7. [PubMed: 18097984]
44. Wu W-C, Drenser K, Trese M. Retinal phenotype-genotype correlation of pediatric patients expressing mutations in the Norrie disease gene. Arch. Ophthalmol. 2007;125:225–30. [PubMed: 17296899]
45. Xu Q, Wang Y, Dabdoub A, Smallwood PM, Williams J, Woods C, Kelley MW, Jiang L, Tasman W, Zhang K, Nathans J. Vascular development in the retina and inner ear: control by Norrin and Frizzled-4, a high-affinity ligand-receptor pair. Cell. 2004;116:883–95. [PubMed: 15035989]
46. Yamada K, Limprasert P, Ratanasukon M, Tengtrisorn S, Yingchareonpukdee J, Vasiknanonte P, Kitaoka T, Ghadami M, Niikawa N, Kishino T. Two Thai families with Norrie disease (ND): association of two novel missense mutations with severe ND phenotype, seizures, and a manifesting carrier. Am J Med Genet. 2001;100:52–5. [PubMed: 11337749]
47. Zaremba J, Feil S, Juszko J, Myga W, van Duijnhoven G, Berger W. Intrafamilial variability of the ocular phenotype in a Polish family with a missense mutation (A63D) in the Norrie disease gene. Ophthalmic Genet. 1998;19:157–64. [PubMed: 9810571]

Suggested Reading

1. Berger W, Ropers HH. Norrie disease. In: Scriver CR, Beaudet AL, Sly WS, Valle D, Vogelstein B, eds. The Metabolic and Molecular Bases of Inherited Disease (OMMBID). New York, NY: McGraw-Hill. Chap 239. Available at www.ommbid.com. Accessed 1-12-12.

Author Notes

Web site: www.DNAlab.org

Revision History

• 23 July 2009 (me) Comprehensive update posted live

• 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