NDP gene

Overview

Gene (OMIM No.)
Function of gene/protein
  • Protein: Norrin
  • Part of the Wnt signalling pathway
  • Ligand of FZD4 receptor
  • Involved in the normal development of vascular endothelium in the retina and inner ear
  • Dysfunction leads to poor blood-retinal barrier in the retina
Clinical phenotype
(OMIM phenotype no.)
Inheritance
  • X-linked recessive (Norrie disease and exudative vitreoretinopathy)
  • X-linked dominant (exudative vitreoretinopathy)
Ocular features
  • Familial exudative vitreoretinopathy (FEVR) of variable severity
  • Leukocoria
  • Retinal folds extending from temporally from the disc to the anterior periphery
  • Macula dragging
  • Retinal neovascularisation
  • Retinal detachments
  • Retrolental mass of dysplastic and primitive retinal tissues
  • Retinal detachments
  • More severe phenotype in Norrie disease
  • Cataract and microphthalmia common in Norrie disease
Systemic featuresNorrie disease
  • Progressive sensorineural hearing loss
  • Developmental delays
  • Neurological deficits (more common in chromosomal deletions involving the MAOA and MAOB genes
  • Autonomic and endocrine dysfunction (delayed puberty, short stature, sexual dysfunction)
  • Peripheral vascular dysfunction (varicose veins, leg ulcers)
Key investigations
  • Fluorescein angiography to determine areas of non-perfusion in the peripheral retina
  • Electrophysiology to determine visual potential
  • B-scan USS to identify any posterior segment abnormalities (e.g retinal detachment) if presence of retrolental mass prevents a detailed fundal examination
  • Developmental assessment
  • Audiometry
Molecular diagnosisNext generation sequencing
  • Targeted gene panels (retinal)
  • Whole exome sequencing
  • Whole genome sequencing
Management
  • Laser to all areas of non-perfusion especially in eyes with visual potential
  • Retinal detachments should be treated with an encircling buckle instead of a vitrectomy where possible; vitrectomy may be required for posterior breaks
  • Management is usually supportive in Norrie disease due to the advanced retinal detachment at initial presentation
  • Multidisciplinary approach in Norrie disease
  • Routine audiology testing and hearing aids if hearing loss is present
Therapies under research
Further information

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Additional information

NDP deletion and truncation mutations lead to Norrie disease, while missense variants are associated with Norrie disease or exudative vitreoretinopathy.[8]

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References

  1.  Berger W, Meindl A, van de Pol TJ, et al. Isolation of a candidate gene for Norrie disease by positional cloning [published correction appears in Nat Genet. 1992 Sep;2(1):84]. Nat Genet. 1992;1(3):199-203
  2.  Wang Z, Liu CH, Huang S, Chen J. Wnt Signaling in vascular eye diseases. Prog Retin Eye Res. 2019;70:110-133
  3.  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. 2011;11(1-2):151-155
  4.  Ye X, Wang Y, Nathans J. The Norrin/Frizzled4 signaling pathway in retinal vascular development and disease. Trends Mol Med. 2010;16(9):417-425
  5.  Fullwood P, Jones J, Bundey S, Dudgeon J, Fielder AR, Kilpatrick MW. X linked exudative vitreoretinopathy: clinical features and genetic linkage analysis. Br J Ophthalmol. 1993;77(3):168-170
  6.  Chen ZY, Battinelli EM, Fielder A, et al. A mutation in the Norrie disease gene (NDP) associated with X-linked familial exudative vitreoretinopathy. Nat Genet. 1993;5(2):180-183
  7.  Kondo H, Qin M, Kusaka S, et al. Novel mutations in Norrie disease gene in Japanese patients with Norrie disease and familial exudative vitreoretinopathy. Invest Ophthalmol Vis Sci. 2007;48(3):1276-1282
  8.  Sızmaz S, Yonekawa Y, T Trese M. Familial Exudative Vitreoretinopathy. Turk J Ophthalmol. 2015;45(4):164-168
  9.  Apple DJ, Fishman GA, Goldberg MF. Ocular histopathology of Norrie’s disease. Am J Ophthalmol. 1974 Aug;78(2):196-203
  10.  Halpin C, Owen G, Gutiérrez-Espeleta GA, Sims K, Rehm HL. Audiologic features of Norrie disease. Ann Otol Rhinol Laryngol. 2005;114(7):533-538
  11.  Smith SE, Mullen TE, Graham D, Sims KB, Rehm HL. Norrie disease: extraocular clinical manifestations in 56 patients. Am J Med Genet A. 2012 Aug;158A(8):1909-17
  12.  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. 1992;42(1):127-134

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Updated on January 18, 2021
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