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]
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]
In particular, we expand our understanding of the neurologic manifestations in ND and identify a chronic seizure disorder in approximately 10% of all patients. [ncbi.nlm.nih.gov]
Profound Mental Retardation
We report on a novel mutation identified in a patient with ND and profound mental retardation. The patient was diagnosed at the age of 6 months due to congenital blindness. [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 .
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- 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.
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- 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.