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Norrie Disease

Norrie disease is an X-linked recessive genetic disorder that primarily affects the retina and causes a number of ocular complaints in the first several months of life. Leukocoria, atrophy of the iris, cataracts, and irreversible blindness are common features. Several extraocular features have been identified, including sensorineural hearing loss, mental retardation, and seizures. The diagnosis is made by observing typical clinical findings, a thorough examination, and genetic testing to confirm specific mutations.


Presentation

Norrie disease is a rare X-linked recessive disorder that stems from mutations in the Norrie disease gene (NDP) that is located on chromosome X [1] [2] [3]. Although the exact pathogenesis remains unknown, mutations of NDP lead to an improper synthesis of the protein norrin, responsible for the formation of blood vessels and neural networks, and one of the most important sites of NDP expression is the retina [1] [4]. For this reason, the clinical presentation of Norrie disease is focused on ocular manifestations [5]. One of the hallmarks of this X-linked recessive disorder is a very early (congenital) onset of blindness, usually in a bilateral and symmetrical fashion [1] [2] [5] [6] [7]. By 3 months of age, the majority of boys have no light perception, while other notable signs are leukocoria (fibrosis of the retina that causes whitish discoloration in the presence of light), retinal dysplasia or detachment (developing within the first few months of life), atrophy of the iris, cataracts, and a retrolental fibrovascular mass that is yellow-to-gray in color (termed pseudoglioma) [1] [6]. In addition to ocular manifestations, which follow a progressive course, a substantial proportion of patients suffering from Norrie disease present with extraocular symptoms, most important being sensorineural hearing loss (encountered in approximately a third of cases) and mental retardation (seen in two-thirds) [1] [2] [4] [6] [7]. Although rare, seizures have been described in a subset of patients [5].

Workup

Clinical suspicion must be present in order to make the diagnosis of Norrie disease, but because of its rare occurrence in clinical practice (approximately 300 cases are documented in the literature up to 2005) [4], its recognition might not be easy. For this reason, the physician must obtain a complete patient history and perform a thorough physical examination in the presence of bilateral progressive blindness in boys without an apparent cause. Given the X-linked recessive nature of the disease, a complete family history (particularly from the mother) must be obtained [1], whereas the course of symptoms, as well as its progression, must be assessed (either with the patient or parents in the case of neonates, infants, or small children) as well. A close inspection of the eye can be crucial for identifying leukocoria, hemorrhagic insults from retinal detachments, cataracts, or pseudogliomas, after which a meticulous ophthalmological examination need to be conducted. Extraocular findings such as mental retardation and sensorineural hearing loss should also be evaluated using appropriate neurological testing. To confirm the diagnosis of Norrie disease, however, genetic testing that will be able to identify specific mutations in the NDP gene (a pathogenic variant) is necessary [1].

Hypsarrhythmia
  • At the age of 8 months he developed infantile spasms, which were diagnosed at 11 months as his EEG demonstrated hypsarrhythmia.[ncbi.nlm.nih.gov]

Treatment

  • Treatment Is there a treatment for Norrie disease? Unfortunately there is currently no cure for Norrie disease or treatment that can take away the symptoms.[thinkgenetic.com]
  • Treatment The treatment of ND is directed towards the specific symptoms that are apparent in each individual.[geneticdisordersuk.org]
  • Treatment There is no specific treatment for Norrie disease and no way to stop or reverse the loss of vision and possibly hearing. Medical treatment may be needed for other problems the disease may cause, such as with breathing or digestion.[verywell.com]
  • Make informed clinical choices for each patient , from diagnosis and treatment selection through post-treatment strategies and management of complications, with new evidence-based criteria throughout.[books.google.com]
  • You may also want to contact a university or tertiary medical center in your area, because these centers tend to see more complex cases and have the latest technology and treatments.[rarediseases.info.nih.gov]

Prognosis

  • Norrie disease is a rare, but devastating cause of pediatric retinal detachment, universally portending a poor visual prognosis.[ncbi.nlm.nih.gov]
  • (Outcomes/Resolutions) The prognosis for Norrie Disease is generally good.[dovemed.com]
  • The data generated could have broad implications in genetic counseling, disease management, and early intervention for a better prognosis in FEVR.[ncbi.nlm.nih.gov]
  • Diagnosis and Prognosis: The diagnosis is usually made by an ophthalmologist in cooperation with neurologists and pediatricians. Life expectancy is usually not shortened but the blindness and deafness create challenges for caregivers.[disorders.eyes.arizona.edu]
  • Communication options, hearing aids, cochlear implants, and aural rehabilitation can be explored in relation to the patient's current needs and prognosis.[audiologyonline.com]

Etiology

  • Etiology Norrie disease is caused by mutations in the Norrie disease (pseudoglioma) NDP gene (Xp11.4-p11.3). A large number of disease-causing mutations have been identified.[orpha.net]
  • (Etiology) Norrie Disease may be caused by an inherited genetic mutation affecting the NDP gene on the X-chromosome.[dovemed.com]
  • These characteristics help to clearly identify ROP as a causative etiology. The classic finding in FEVR is peripheral retinal capillary nonperfusion.[reviewofophthalmology.com]

Epidemiology

  • Chapters on epidemiology, embryology, non-syndromic hearing loss, and syndromic forms of hearing loss have all been updated with particular attention to the vast amount of new information on molecular mechanisms, and chapters on clinical and molecular[books.google.com]
  • Summary Epidemiology The prevalence and annual incidence of ND are not known but more than 400 cases have been described. No ethnic predilection has been found. Affected patients are almost always male, while females are carriers.[orpha.net]
  • Epidemiology of hereditary ocular disorders. Dev Ophthalmol 2003 ;37: 16 - 33 3. Gokgoz N, Wunder JS, Mousses S, Eskandarian S, Bell RS, Andrulis IL. Comparison of p53 mutations in patients with localized osteosarcoma and metastatic osteosarcoma.[nejm.org]
Sex distribution
Age distribution

Pathophysiology

  • The objective of this study was to characterize the audiologic phenotype of Norrie disease for comparison with the pathophysiologic mechanism.[ncbi.nlm.nih.gov]
  • Because abnormalities of biogenic amines, particularly serotonin, have been implicated in the pathophysiology of pulmonary hypertension, we propose that presumed MAO deficiency in these patients may represent a novel risk factor for pulmonary hypertension[ncbi.nlm.nih.gov]
  • Comprehensively updated to reflect everything you need to know regarding retinal diagnosis, treatment, development, structure, function, and pathophysiology, this monumental ophthalmology reference work equips you with expert answers to virtually any[books.google.de]
  • Such an association would contribute to developing a better understanding of ROP pathophysiology and would provide paediatric ophthalmologists with an adjunctive diagnostic test for predicting likely progression of disease.[jmg.bmj.com]

Prevention

  • The fundamental advances in recent years have identified a number of genes involved in the groups of diseases which hopefully will lead to discoveries that may, in the not too distant future, allow the prevention and possible cure of some of these blinding[books.google.com]
  • Norrie Disease is a genetic disorder, and currently, there are no methods or guidelines available to prevent its occurrence.[dovemed.com]
  • Mutations in the NDP gene can prevent the norrin protein from working correctly, resulting in the signs and symptoms of Norrie disease. [1] [3] Last updated: 3/11/2016 Making a diagnosis for a genetic or rare disease can often be challenging.[rarediseases.info.nih.gov]
  • Otherwise healthy females can carry an altered NDP gene with the working copy on their other X chromosome usually being enough to compensate for this, preventing them from developing the condition.[geneticdisordersuk.org]
  • Laser photocoagulation at birth prevents blindness in Norrie’s disease diagnosed using amniocentesis. Ophthalmology. 2010 Dec;117(12):2402-6. PubMed PMID: 20619898. Walsh MK, Drenser KA, Capone A Jr, Trese MT.[rarediseases.org]

References

Article

  1. Sims KB. NDP-Related Retinopathies. 1999 Jul 30 [Updated 2014 Sep 18]. In: Pagon RA, Adam MP, Ardinger HH, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2017.
  2. Lev D, Weigl Y, Hasan M, et al. 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:921–924.
  3. Sims KB, Lebo RV, Benson G, et al. The Norrie disease gene maps to a 150 kb region on chromosome Xp11.3. Hum Mol Genet 1992; 1:83-89.
  4. Hutcheson KA, Paluru PC, Bernstein SL, et al. Norrie disease gene sequence variants in an ethnically diverse population with retinopathy of prematurity. Mol Vis. 2005;11:501-508.
  5. 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.
  6. Walsh MK, Drenser KA, Capone A Jr, Trese MT. Early vitrectomy effective for Norrie disease. Arch Ophthalmol. 2010 Apr;128(4):456-460.
  7. Zhang X-Y, Jiang W-Y, Chen L-M, Chen S-Q. A novel Norrie disease pseudoglioma gene mutation, c.-1_2delAAT, responsible for Norrie disease in a Chinese family. Int J Ophthalmol. 2013;6(6):739-743.

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