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Norrie Disease: for professionals


Overview

Prevalence
  • Less than 1: 1,000,000[1]
Inheritance
  • X-linked recessive
  • De novo sporadic
Genes involved (OMIM No.)
Main features
  • Severe sight impairment from birth due to bilateral retinal detachments
  • Retinal detachment/ retrolental mass
  • Progressive sensorineural hearing loss from teenage years
  • Developmental delays
Key investigationsOcular
  • Dilated fundus examination
  • Ultrasound B-Scan
Systemic
  • Systemic assessment with a paediatrician
  • Audiometry
Molecular diagnosisNext generation sequencing
  • Targeted gene panels (Retinal)
  • Whole exome sequencing
  • Whole genome sequencing
ManagementOcular
  • Most cases are offered supportive management only given the poor baseline visual function
  • Interventions are rarely offered and decisions are made on a case-by-case basis
  • Laser to areas of peripheral non-perfusion may be indicated in eyes with visual potential
  • An encircling buckle or vitrectomy may be appropriate to treat sub-total retinal detachment (rare)
Systemic
  • Multidisciplinary approach
  • Referral to paediatricians for management of systemic manifestations and co-morbidities
  • Early involvement of practitioners familiar with developmental surveillance and intervention for children with visual impairment and hearing loss
  • Referral to dual sensory clinic (if available)
Therapies under research
  • Gene therapy (pre-clinical)

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Clinical phenotype

Norrie disease is a rare disorder caused by pathogenic variants in the NDP gene that affect normal vascular development of the retina and the inner ear. It is mainly characterised by severe visual impairment (bare perception of light at best) from birth or shortly after, and progressive sensorineural hearing loss. Other less common features include developmental delays, neurodevelopmental disorders (autism), endocrine dysfunction and peripheral vascular dysfunction.

Main features

1) Bilateral retinal detachments

Pathogenic variants in the NDP gene cause dysfunction of the WNT signalling pathway, leading to incomplete retinal vascularisation and persistence of the foetal vasculature. As a result, most children present with leukocoria due to the dysplastic and primitive retinal tissue situated behind the lens (often termed as pseudogliomas). As the immature retina has poorly developed blood-retinal barrier, bilateral mixed tractional/ exudative total retinal detachments are commonly detected on initial presentation. In addition, cataract and microphthalmia are also commonly reported associated ocular features.[2] Band keratopathy may occur over time.

2) Sensorineural hearing loss

Bilateral progressive sensorineural hearing loss is a common feature due to drop out of the vascular network supplying the striae vascularis of the cochlea with loss of Norrin protein maintenance. It usually develops in the second or third decade of life.[3]

Other features

1) Developmental delays and neurological deficits

Due to such early-onset of visual impairment, children affected by Norrie disease can experience delays in achieving developmental milestones compared to normal-sighted children. A proportion of patients (30% to 50%) may also have associated intellectual disability.[4] This is likely due to continuous deletion of the adjacent Monoamine Oxidase genes (MAOA and MAOB), which are found at the same locus as the NDP gene.[4] Norrie disease patients with MAOA and MAOB deletions have also been reported to have a more severe neurological involvement with profound psychomotor and verbal deficits, underpinning the importance of these genes in normal brain development and function.[5-7]

2) Autonomic and endocrine dysfunction

Norrie disease has been associated with delayed puberty, short stature and sexual dysfunction. Approximately one-third of patients experience delayed puberty, but it eventually develops naturally in all cases and no medical interventions are required.[1]

3) Peripheral vascular dysfunction

Patients with Norrie disease have reported peripheral venous insufficiency, resulting in varicose veins and rarely leg ulceration.[1]

The list of features provided here are not exhaustive. Please refer to the information leaflet written by the Norrie Disease Foundation for more information.

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Genetics

The NDP gene encodes the Norrin protein, a 133 amino acid cysteine-rich secreted growth factor. The absence of functioning Norrin is the cause of Norrie disease.[8] Norrin is secreted by the muller cells in the retina and binds to the FZD4/ LRP5-6/ TSPAN12 receptor complex on the developing vascular endothelium.[9,10] This promotes beta catenin stabilisation and hence gene expression required for normal development of the retinal vasculature and formation of the blood-retinal barrier.

Norrin also performs analogous functions in the cochlea, cerebellum and wider brain, and in the female reproductive organs.[11]

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Key investigations

Ocular

1) Ultrasound B-scan

Ocular ultrasound helps to establish the diagnosis and differentiate dysplastic retina from retinoblastoma; i.e. the retrolental mass in Norrie disease is NOT calcified, whereas calcification is a key feature of retinoblastoma.

2) Fundus fluorescein angiography

Fluorescein angiography is rarely required in Norrie disease but may be relevant if total retinal detachment has not yet occurred.

Systemic

Patients are often seen in the eye clinic initially as the ocular phenotype is one of the earliest manifestations. If a child is suspected of having Norrie disease, he/she should be referred to a dual sensory clinic (if available) as well as a paediatrician, who can then co-ordinate onward referrals to other relevant specialists for further assessment and investigations. The assessments may include but not limited to:

  • General physical examination including assessment of height, weight (BMI), head circumference and plotting of growth chart
  • Blood tests (haematology and biochemistry profiles including renal and liver function, plasma glucose level, bone chemistry, cholesterol, triglycerides and other endocrine bloods if indicated)
  • Audiology
  • Developmental assessment

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Diagnosis

Clinical diagnosis of Norrie disease is based initially on the ocular phenotype, clinical history and any supportive family history suggesting X-linked inheritance.

Genetic testing should be undertaken to confirm the diagnosis, directing further clinical management, aid in genetic counselling and providing accurate advice on future family planning. Pathogenic variants in the NDP gene can be identified through a variety of next generation sequencing (NGS) methods:

  • Targeted gene panels (retinal/vitreoretinopathy and deafness)
  • Whole exome sequencing (WES)
  • Whole genome sequencing (WGS)
  • Targeted exome sequencing

Related links

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Management

There is currently no specific medical treatment for Norrie disease. Patients are usually managed symptomatically within a multidisciplinary setting.

Ocular

Management is mainly supportive which include:

  • Referral to low vision services
  • Directing patients and families to supporting organisations
  • Encourage the use of assistive technology that may improve quality of life
  • Encourage a healthy diet consisting of fresh fruit and green leafy vegetables

Interventions are rarely recommended due to the advanced stage of retinal detachment at presentation. In selected less advanced cases without a total retinal detachment, laser photocoagulation may preserve perception of light.[12] For the treatment of sub-total retinal detachment, vitrectomy surgery or an encircling buckle may also be appropriate.[13]

Systemic

1) Hearing loss management

Early audiological assessment in children is advised to maintain educational and social development. Audiology testing should be performed at birth, during early childhood, at school entry and annually thereafter.[1] Hearing aids can help if hearing loss is detected. Audiological follow-up should be lifelong.

2) Optimisation of development

Children with Norrie disease are affected by severe visual impairment from birth and progressive hearing loss. As vision and hearing loss 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 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 a multidisciplinary clinic in one 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.

Family management and counselling

Norrie disease can be inherited in an X-linked recessive manner, but some mutations arise de novo and therefore there is no family history.[14]

Patients and families require genetic counselling and can seek advice for family planning including prenatal testing and preimplantation genetic diagnosis. Norrie disease is on the UK’s Human Fertilisation and Embryology Authority’s approved list for pre-implantation genetic diagnosis.

Emotional and social support

Eye Clinic Liaison Officers (ECLOs) act as an initial point of contact for newly diagnosed patients and their parents in clinic. They provide emotional and practical support to help patients and parents deal with the diagnosis and maintain independence. They work closely with the local council’s sensory support team and are able to advise on the broad range of services provided, such as visual rehabilitation, home assessment, work and access to qualified teachers for children with visual impairment (QTVI) among other services.

Related links

Referral to a specialist centre

In the UK, patients should be referred to their local genomic ophthalmology (if available) or clinical genetics services to receive a more comprehensive genetic management of their conditions (genetic testing and genetic counselling) and having the opportunity to participate in clinical research.

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 in optimising patient management where both visual and audio-vestibular issues can be addressed simultaneously.

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Current research in Norrie disease

Current research is mainly focused on the natural history and pathophysiology of hearing loss in Norrie disease, the spectrum of disease caused by variants in the NDP gene and therapeutic interventions to prevent hearing loss. 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 have patients interested in taking part, you can refer him/her to the Great Ormond Street Hospital for Children (GOSH) or contact the Norrie Disease Foundation.

Related links

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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.  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
  6.  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
  7.  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
  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.  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
  10.  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
  11.  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
  12.  Chow CC, Kiernan DF, Chau FY, et al. Laser photocoagulation at birth prevents blindness in Norrie’s disease diagnosed using amniocentesis. Ophthalmology. Dec 2010;117(12):2402-6. doi:10.1016/j.ophtha.2010.03.057
  13.  Walsh MK, Drenser KA, Capone A, Jr., Trese MT. Early vitrectomy effective for Norrie disease. Arch Ophthalmol. Apr 2010;128(4):456-60. doi:10.1001/archophthalmol.2009.403
  14.  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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