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NDP-Related Retinopathies

Includes: Norrie Disease (ND), Persistent Hyperplastic Primary Vitreous (PHPV), Retinopathy of Prematurity (ROP), Coats Disease, X-Linked Familial Exudative Vitreoretinopathy (X-Linked FEVR)
, MD
Director, Developmental Neurogenetics Clinic
Director, Neurogenetics DNA Diagnostic Lab
Associate Professor, Neurology
Massachusetts General Hospital / Harvard Medical School
Boston, Massachusetts

Initial Posting: ; Last Update: July 23, 2009.

Summary

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), characterized by greyish-yellow fibrovascular masses (pseudogliomas) secondary to retinal vascular dysgenesis and detachment. Congenital blindness is almost always present. Approximately 30%-50% of males with ND have developmental delay/intellectual disability, 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 and retinal detachment; 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 on a combination of clinical findings and molecular genetic testing of NDP, which identifies disease-causing mutations in approximately 95% of affected males.

Management. Treatment of manifestations: Treatment for less than complete retinal detachment includes surgery and/or laser therapy. Surgery may be required for 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/or cognitive impairment involve supportive intervention and therapy.

Surveillance: Routine monitoring of vision and hearing.

Genetic counseling. NDP-related retinopathies are inherited in an X-linked 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 for at-risk female relatives and prenatal testing for pregnancies at increased risk are possible if the disease-causing mutation has been identified in the family.

Diagnosis

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

Table 1. Classification of Ocular Phenotypes Observed in Individuals with an NDP Mutation

Phenotype Ocular Findings /
Age
Progression /
Age
Vision
Norrie disease (ND)Greyish-yellow fibrovascular masses ("pseudoglioma") behind the lens (i.e., retrolental), retinal detachment (frequently) /
Birth – 3 mos
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 mos to 8-10 yrs
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
X-linked familial exudative vitreoretinopathy (FEVR)Peripheral temporal retinal avascular zone ± congenital retinal folds, macular ectopia, fibrous tissue band at ora serrate /
Birth
± Retinal detachment (tractional and/or exudative; may be unilateral) /
≤ age 20 yrs
Normal to impaired
Retinopathy of prematurity (ROP) stage 4B/5 1Retinal neovascularization, fibrous proliferation, end-stage retrolental fibroplasia /
Premature birth
Partial or complete retinal detachmentImpaired to blind
Coats disease 2Unilateral retinal telangiectasia, exudative fibrosisProgressive vascular leakage, subretinal exudation and fibrosis, retinal detachmentNormal to impaired

1. Rare NDP mutations have been seen in those with an ROP phenotype [Shastry 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 et al 2001a, 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].

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

Gene SymbolTest MethodMutations DetectedMutation Detection Frequency by Test Method 1
Affected malesCarrier females
NDPSequence analysisSequence variants 280%80%
Exonic, multiexonic, and whole-gene deletions15%0% 3
Deletion / duplication analysis 4Exonic, multiexonic, and whole-gene deletionsNot needed 515%

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:

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.

Clinical Description

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 1

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 2

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.

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 [Richter et al 1998, Schafer et al 2009]. 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. A differential gene expression study has identified candidate genes for retinal (photoreceptor) phenotype in the Ndp knockout mouse [Lenzner et al 2002]. Cerebellar vascular changes have also been documented in the Ndph knockout mouse [Luhmann et al 2008].

Heterozygotes

In rare instances, females who are carriers may have some retinal findings (retinal detachment, abnormal retinal vasculature) and associated vision loss [Yamada et al 2001]. A severe ocular phenotype has been described in multiple females in one family [Khan et al 2008].

Some carrier females may show a mild sensorineural hearing loss [Halpin et al 2005; Sims, unpublished data].

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 and is rare

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.

Differential Diagnosis

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), and familial exudative vitreoretinopathy (FEVR) [Dickinson et al 2006]. NDP is a frizzled-4 (Fzd-4) ligand and activates the canonical Wnt signaling pathway [Xu et al 2004, Hendrickx & Leyns 2008]. Mutations in Fzd4, and in another Wnt ligand, LRP5, have been identified in autosomal dominant FEVR [Robitaille et al 2002, Toomes et al 2004a, Toomes et al 2004b]. 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 intellectual disability and/or progressive sensorineural hearing loss (see Deafness and Hereditary Hearing Loss Overview) in the absence of the characteristic ocular features.

Management

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.

Genetic Counseling

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. —ED.

Mode of Inheritance

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

Risk to Family Members

Parents of a male proband

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.

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 (usually performed at ~10-12 weeks' gestation) or by amniocentesis (usually performed at ~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 an option for some families in which the disease-causing mutation has been identified.

Resources

GeneReviews staff has selected the following disease-specific and/or umbrella support organizations and/or registries for the benefit of individuals with this disorder and their families. GeneReviews is not responsible for the information provided by other organizations. For information on selection criteria, click here.

  • National Library of Medicine Genetics Home Reference
  • Norrie Disease Association (NDA)
    PO Box 3244
    Munster IN 46321
    Email: joinnda@gmail.com
  • 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.
  • American Council of the Blind (ACB)
    2200 Wilson Boulevard
    Suite 650
    Arlington VA 22201
    Phone: 800-424-8666 (toll-free); 202-467-5081
    Fax: 202-467-5085
    Email: info@acb.org
  • American Society for Deaf Children (ASDC)
    800 Florida Avenue Northeast
    #2047
    Washington DC 20002-3695
    Phone: 800-942-2732 (Toll-free Parent Hotline); 866-895-4206 (toll free voice/TTY)
    Fax: 410-795-0965
    Email: info@deafchildren.org; asdc@deafchildren.org
  • National Association of the Deaf (NAD)
    8630 Fenton Street
    Suite 820
    Silver Spring MD 20910
    Phone: 301-587-1788; 301-587-1789 (TTY)
    Fax: 301-587-1791
    Email: nad.info@nad.org
  • National Federation of the Blind (NFB)
    200 East Wells Street
    (at Jerigan Place)
    Baltimore MD 21230
    Phone: 410-659-9314
    Fax: 410-685-5653
    Email: pmaurer@nfb.org
  • Norrie Disease Registry
    Massachusetts General Hospital
    185 Cambridge Street
    CRP Building North, 5th Floor, Suite 5300
    Boston MA 02114
    Phone: 617-726-5718
    Fax: 617-724-9620
    Email: ksims@partners.org

Molecular Genetics

Information in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED.

Table A. NDP-Related Retinopathies: Genes and Databases

Data are compiled from the following standard references: gene symbol from HGNC; chromosomal locus, locus name, critical region, complementation group from OMIM; protein name from UniProt. For a description of databases (Locus Specific, HGMD) to which links are provided, click here.

Table B. OMIM Entries for NDP-Related Retinopathies (View All in OMIM)

300216COATS DISEASE
300658NDP GENE; NDP
305390EXUDATIVE VITREORETINOPATHY 2, X-LINKED; EVR2
310600NORRIE DISEASE; ND

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].

References

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Suggested Reading

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

Chapter Notes

Author Notes

Web: 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
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