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Norrie Disease: for patients

Overview

Norrie disease is a rare genetic condition that causes severe visual impairment or blindness from birth. Most affected individuals later suffer from progressive hearing loss, which is usually noticeable during teenage years. Less than 1 in 1,000,000 people are affected by this condition.[1]

Norrie disease is caused by changes in the NDP gene, which leads to insufficient development of the blood vessels in the retina and the inner ear when we are still developing in the womb. The lack of an adequate blood supply to the retina results in retinal detachment while hearing loss usually occurs around late childhood or during teenage years. There is currently no treatment for Norrie disease but various measures can be taken to help affected children achieve independence. Hearing loss can be addressed with hearing aids, while eye surgery may rarely be helpful in preserving any remaining vision in some less severe cases.

The NDP gene is found on the X chromosome. Females have two X chromosomes whereas males have just one. As only one functioning copy of the NDP gene is required for normal retinal and inner ear development, males are therefore affected by Norrie disease while females do not display any associated features. Norrie disease can be inherited but usually arises from a sporadic genetic mutation in the affected child. This means that the mutation in the NDP gene occurred by chance instead of being inherited from either parent. The affected child can then pass the faulty NDP gene copy to his offspring in an X-linked recessive manner.

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The condition

Symptoms

1) Visual

Children with Norrie disease are born with severe visual impairment. Most children are only able to detect light at best. The first sign that parents usually notice is that the pupil may appear white on photographs/when light is shone in the eye instead of red. This is known as leukocoria and is mainly due to the appearance of the immature retina. Abnormal development of the retinal blood vessels can also lead to retinal detachment.[2] Visual impairment in Norrie disease is mainly caused by the retina not being able to work properly. As the condition progresses, retinal detachments become more advanced and eventually causing any remaining vision to be lost. Cataract is also commonly detected in patients with Norrie disease. In some individuals, progression of the condition causes phthisis bulbi (shrinking and softening of the eyeball).

The pupil appears white due to an opaque lens.
Cataract

Credit: Prof Chris Lloyd, consultant paediatric ophthalmologist, Great Ormond Street Hospital for Children (GOSH), London

2) Systemic (other body systems)

  • Most patients are born with normal hearing but later suffer from progressive hearing loss, usually from around late childhood or teenage years[3]
  • Visual impairment at such an early age in children can lead to delays in achieving certain milestones (developmental delays) compared to normal-sighted children
  • About 30-50% of patients may have intellectual disability and behavioural difficulties[4]
  • Some patients report problems with their circulation such as varicose veins and leg ulcers
  • Some also report erectile dysfunction due to poor circulation to the penis
  • Reduced growth (short stature) and delayed puberty may occur; most affected males eventually develop puberty naturally without any medical interventions[1]

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Cause

Norrie disease is caused by changes in the NDP gene, which provides instruction to cells in the retina and the inner ear to produce a protein called Norrin. Norrie is crucial in the normal development of blood vessels in these organs when we are still developing in the womb.[5-7] Mutations in the NDP gene causes a lack of Norrin protein being produced, which subsequently leads to abnormal development of the blood vessels in the retina. As a result, the retina does not function properly and ultimately detaches.[8]

Similarly, the lack of Norrin protein in the inner ear causes insufficient blood flow to support the cochlea, which is the part of the inner ear responsible for converting sound into electrical activity that the brain can understand.[3]

Less is known about why some children additionally have intellectual disability and problems with blood circulation in the lower extremities (e.g legs and feet). One theory is that this is due to deletion of a section of the X-chromosome that not only contains the NDP gene, but also the adjacent MAOA and MAOB genes.[9-11]

How is it diagnosed?

1) Eye examination

An ophthalmologist is able to diagnose Norrie disease based on the presenting features. Specifically, the ophthalmologist will examine the retina after applying some eye drops to dilate the pupil and look for the characteristic type of retinal detachments seen in Norrie disease. They may then confirm their findings with an ultrasound examination of the eye. This is not an invasive procedure and does not usually cause any discomfort to the child. The examination involves applying some gel on an ultrasound probe, which is then placed on the eye when it is closed. The test is similar to how pregnant ladies get their tummy scans.

Genetic testing can help confirm the diagnosis by identifying mutations in the NDP gene.

2) General medical assessment

Apart from retinal detachment, progressive hearing loss is one of the most common features associated with Norrie disease, and can cause significant disability if not detected and addressed. Hence, hearing tests should be performed at birth, during early childhood, at school entry and annually thereafter. Follow-up with an audiologist should be lifelong.[1]

As Norrie disease can affect childhood development, it is pertinent that children should be looked after by a paediatrician as well, so that their physical and mental wellbeing can be monitored.

How is it inherited?

1) X-linked recessive inheritance

The genetic changes causing Norrie disease is inherited in this manner. The NDP gene is located on the X chromosome. The X chromosome determines our gender together with the Y chromosome. Females have two X chromosomes whereas males have one X and one Y chromosome. Only one functioning copy of the NDP gene is required for normal blood vessel development of the retina and the inner ear.

As a result, males are affected in Norrie disease while females do not display any features as they have another functioning copy of the NDP gene. They are hence termed carriers.  

If the mother is a “carrier” and the father is healthy: 

  • Each son has a 50% chance of being affected
  • Each daughter has a 50% chance of being a carrier like the mother

If the father is affected and the mother is healthy: 

  • None of his sons will be affected
  • All of his daughters will be carriers
If a mother has 1 copy of the faulty gene in her X chromosome (a carrier) while the father is unaffected, there is 50% chance that a daughter is a carrier and a 50% chance that a son is affected by the condition.
X-linked recessive inheritance

2) Sporadic

Some affected individuals do not know of any other family members affected by Norrie disease. This is because mutations in the NDP gene can also arise sporadically (“by chance”) and the child is the first in the family to be affected by this condition.[12] The faulty gene copy is then passed down to subsequent generations in an X-linked recessive manner.

If you or your child is affected by Norrie disease, families can seek a genetic counsellor to obtain more information and advice on inheritance and family planning options.

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Treatment

Is there any treatment?

1) Supportive visual measures

There is no treatment at present that can correct the genetic changes associated with Norrie disease or restore vision. Treatment is mainly focused on optimising and preserving remaining sight. These include:

  • Referral to low vision services
  • Utilising visual aids and assistive technology to improve quality of life
  • Having a healthy diet consisting of fresh fruit and green leafy vegetables 

Laser procedures or surgery to repair the retinal detachments may be helpful in a small number of less severe cases, but the decision for intervention is made on a case-by-case basis.

2) Monitoring for hearing loss

Hearing loss is one of the most consistent features in Norrie disease which can present at any age, but it tends to become apparent around late childhood or during teenage years. Therefore, regular hearing tests should be conducted so that hearing loss can be detected and addressed with hearing aids to avoid significant disability.

3) Optimisation of development and educational support

Children with Norrie disease are affected by severe visual impairment from birth and progressive hearing loss. As hearing and vision are equally important in normal childhood development and education, children affected by Norrie disease should be referred to developmental paediatricians and advisory teaching services for children/adolescents with hearing loss and visual impairment (e.g. sensory support services within local authority). This will enable provisions to be made within the educational and home settings so that the child can reach his/her developmental potential and develop skills to achieve independence.

Dual sensory clinics are now being established in some centres to improve the clinical experience of children with hearing and sight impairment. Patients are able to access the relevant specialists in one clinic visit, hence reducing the stress and burden associated with numerous, separate medical appointments. Such specialist clinics will promote faster and more accurate diagnosis through extensive genetic testing and detection of visual symptoms at an earlier stage.

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Current research in Norrie disease

Current research is focused on investigating and understanding the mechanism of Norrin in the normal development of blood vessels, especially in the inner ear and how mutations in the NDP gene cause progressive hearing loss. Improved understanding of the protein will then enable researchers to find new therapeutic strategies. A group at the University College London (UCL) Great Ormond Street Institute of Child Health is currently working on finding a therapy to prevent or slow down hearing loss in Norrie disease. In terms of visual impairment, another UCL group headed by Mr Robert Henderson, a consultant ophthalmologist at Great Ormond Street Hospital for Children, London is investigating if gene therapy is a safe and effective treatment option using animal models of Norrie disease. This still in the very early stages of development.

Another aspect of Norrie disease research is recruiting patients into natural history studies. It is important to understand how the condition usually develops over time with no treatment, and therefore help researchers identify what are the best outcome measures to assess treatment response when clinical trials begin. If you are interested in taking part, you can ask your GP to refer your child to the Great Ormond Street Hospital for Children (GOSH) or contact the Norrie Disease Foundation.

Related links

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Practical advice

Living with Norrie disease

Patients are still able to lead independent lives through addressing the hearing loss, maximising their available vision and having access to social support. Here are some ideas:

  • Attending the low vision clinic which provides access to low vision specialists, Eye Clinic Liaison Officers (ECLOs), visual aids and visual rehabilitation services
  • Getting in touch with the local education authority for access to qualified teachers for children with visual impairment (QTVI), teachers for children with hearing loss (Teachers of the Deaf) and special educational needs co-ordinator (SENCO)
  • Utilising assistive technologies to improve quality of life and aid independence
  • Registering your child as sight impaired (SI) or severely sight impaired (SSI) if eligible for access to social support and financial concessions
  • Getting in touch with national or local charities for advice and peer support

Related links

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Referral to a specialist centre

If you are based in the UK and would like to be seen in the nearest specialist centre for your condition, either to receive a more comprehensive genetic management or just to find out more about current research, you can approach your GP to make a referral or alternatively arrange for a private appointment. 

In addition, a referral to a dual sensory clinic (if available) such as the one in Great Ormond Street Hospital for Children in London can be very helpful as hearing, visual and vestibular issues can be addressed simultaneously by the relevant specialists in one clinic visit.

More information can be found in our “How to see a genetic eye specialist?” page.

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Further information and support

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References

  1.  The Norrie Disease Foundation. Norrie Disease. Accessed 25 November 2020, https://norriedisease.org.uk/wp-content/uploads/2019/02/Unique-NDF-Norrie-Disease-Information-Leaflet-.pdf
  2.  Apple DJ, Fishman GA, Goldberg MF. Ocular histopathology of Norrie’s disease. Am J Ophthalmol. Aug 1974;78(2):196-203. doi:10.1016/0002-9394(74)90076-2
  3.  Halpin C, Owen G, Gutiérrez-Espeleta GA, Sims K, Rehm HL. Audiologic features of Norrie disease. Ann Otol Rhinol Laryngol. Jul 2005;114(7):533-8. doi:10.1177/000348940511400707
  4.  Smith SE, Mullen TE, Graham D, Sims KB, Rehm HL. Norrie disease: extraocular clinical manifestations in 56 patients. Am J Med Genet A. Aug 2012;158a(8):1909-17. doi:10.1002/ajmg.a.35469
  5.  Ye X, Smallwood P, Nathans J. Expression of the Norrie disease gene (Ndp) in developing and adult mouse eye, ear, and brain. Gene Expr Patterns. Jan-Feb 2011;11(1-2):151-5. doi:10.1016/j.gep.2010.10.007
  6.  Ye X, Wang Y, Nathans J. The Norrin/Frizzled4 signaling pathway in retinal vascular development and disease. Trends Mol Med. Sep 2010;16(9):417-25. doi:10.1016/j.molmed.2010.07.003
  7.  Ke J, Harikumar KG, Erice C, et al. Structure and function of Norrin in assembly and activation of a Frizzled 4-Lrp5/6 complex. Genes Dev. Nov 1 2013;27(21):2305-19. doi:10.1101/gad.228544.113
  8.  Berger W, Meindl A, van de Pol TJ, et al. Isolation of a candidate gene for Norrie disease by positional cloning. Nat Genet. Jun 1992;1(3):199-203. doi:10.1038/ng0692-199
  9.  Collins FA, Murphy DL, Reiss AL, et al. Clinical, biochemical, and neuropsychiatric evaluation of a patient with a contiguous gene syndrome due to a microdeletion Xp11.3 including the Norrie disease locus and monoamine oxidase (MAOA and MAOB) genes. Am J Med Genet. Jan 1 1992;42(1):127-34. doi:10.1002/ajmg.1320420126
  10.  Rodriguez-Revenga L, Madrigal I, Alkhalidi LS, et al. Contiguous deletion of the NDP, MAOA, MAOB, and EFHC2 genes in a patient with Norrie disease, severe psychomotor retardation and myoclonic epilepsy. Am J Med Genet A. May 1 2007;143a(9):916-20. doi:10.1002/ajmg.a.31521
  11.  Whibley A, Urquhart J, Dore J, et al. Deletion of MAOA and MAOB in a male patient causes severe developmental delay, intermittent hypotonia and stereotypical hand movements. European journal of human genetics : EJHG. 2010;18(10):1095-1099. doi:10.1038/ejhg.2010.41
  12.  Han S, Sun J, Yang L, Qi M. Role of NDP- and FZD4-Related Novel Mutations Identified in Patients with FEVR in Norrin/β-Catenin Signaling Pathway. Biomed Res Int. 2020;2020:7681926. doi:10.1155/2020/7681926

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Updated on November 30, 2020
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