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.
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   . 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  . For this reason, the clinical presentation of Norrie disease is focused on ocular manifestations . 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     . 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)  . 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)     . Although rare, seizures have been described in a subset of patients .
Entire Body System
- Increased Susceptibility to Infections
We have examined a three-generation family in which ND is part of a complex X-linked syndrome with severe mental retardation, hypogonadism, growth disturbances, and increased susceptibility to infections as additional features. [ncbi.nlm.nih.gov]
Among the plethora of roles that Wnt signaling plays, its canonical branch regulates eye organogenesis and angiogenesis. [ncbi.nlm.nih.gov]
- Recurrent Infection
This complex syndrome is apparently segregating through three generations: four other male relatives of the patient were blind from birth and died from recurrent infections between the ages of three to 15 months. [ncbi.nlm.nih.gov]
Other studies suggest that epileptic seizures or growth retardation that is associated with ND is the consequence of loss of contiguous genes, because most such patients had deletions extending beyond the Norrie locus. [ncbi.nlm.nih.gov]
An MAOA deficiency state has been described in one family to date, with features of altered amine and amine metabolite levels, low normal intelligence, apparent difficulty in impulse control and cardiovascular difficulty in affected males. [ncbi.nlm.nih.gov]
The signs and symptoms of Norrie Disease may include the following: Degeneration of the retina during fetal development, which can leave the child blind from birth The retina is responsible for converting light signals to nerve impulses to be relayed [dovemed.com]
- Loss of Initiative
The loss was initially high frequency and asymmetric in adolescence and became more severe, more symmetric and affected practically all frequencies by the end of childhood. [ncbi.nlm.nih.gov]
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) , 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 , 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 .
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]
Management and treatment Many patients have complete retinal detachment at birth making treatment for preservation of sight difficult. Those that do not have complete retinal detachment may benefit from surgery or laser therapy. [orpha.net]
Treatment The treatment of ND is directed towards the specific symptoms that are apparent in each individual. [geneticdisordersuk.org]
To describe disease progression and treatment outcomes over a 20-year period (ages 5-25) in a young man with Norrie disease (occuloacousticocerebral dysplasia), ND; OMIM #310600. [ncbi.nlm.nih.gov]
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]
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]
Prognosis Overall health is generally good in patients with ND. Life expectancy may however be reduced due to general risks associated with the disabling manifestations of the disease. [orpha.net]
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]
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]
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]
In our lab, we focus on the investigation of the molecular pathophysiology of the disease phenotype, which is similar in different vasoproliferative blindness diseases, especially with regard to abnormalities in the retinal vasculature ( angiogenesis [medmolgen.uzh.ch]
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]
In the special case of Norrie disease, we recommend early screening for mental retardation and related psychotic disorders and, depending on the patient's level of understanding, preventive information on the benefits and limits of cochlear implants before [ncbi.nlm.nih.gov]
Norrie Disease is a genetic disorder, and currently, there are no methods or guidelines available to prevent its occurrence. [dovemed.com]
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]
With 30,000 we can fund the following: 20,000 towards pioneering gene therapy research to prevent Norrie disease hearing loss. Two NDF family days – these provide essential peer and emotional support to the whole family affected by Norrie disease. [norriedisease.org.uk]
Mutations in the NDP gene can prevent the norrin protein from working correctly, resulting in the signs and symptoms of Norrie disease.   Last updated: 3/11/2016 Making a diagnosis for a genetic or rare disease can often be challenging. [rarediseases.info.nih.gov]
- 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.
- 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.
- 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.
- 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.
- 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.
- Walsh MK, Drenser KA, Capone A Jr, Trese MT. Early vitrectomy effective for Norrie disease. Arch Ophthalmol. 2010 Apr;128(4):456-460.
- 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.