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Norrie disease is a rare X-linked recessive genetic disorder that primarily affects the human eye and almost always leads to blindness. It is caused by mutations in the Norrin gene, also referred to as Norrie Disease Pseudoglioma (NDP) gene. Norrie disease manifests with vision impairment either at birth, or within a few weeks of life, following an ocular event like retinal detachment and is progressive through childhood and adolescence. It generally begins with retinal degeneration, which occurs before birth and results in blindness at birth (congenital) or early infancy, usually by 3 months of age.
Patients with Norrie disease may develop , leukocoria (where the appear white when light is shone on them), along with other developmental issues in the eye, such as shrinking of the globe and the wasting away of the iris.
In addition to the congenital ocular symptoms, the majority of individuals afflicted by this disease develop progressive hearing loss caused by vascular abnormalities in the cochlea. Hearing loss usually begins in early childhood and may be mild at first before becoming more progressive by the third or forth decade of life.
Roughly 30–50% of those affected by the disease might encounter cognitive challenges, learning difficulties, incoordination of movements or behavioral abnormalities. These developmental delays often surpass those expected from their visual impairment alone. Additionally, behavioral issues such as psychosis, aggression, and cognitive decline may manifest in patients. Intellectual disabilities have been observed in 20–30% of cases, while dementia, though uncommon, can emerge in late adulthood. About 15% of patients are estimated to develop all the features of the disease.
Due to the X-linked recessive pattern of inheritance, Norrie disease affects almost entirely males. Only in very rare cases, females have been diagnosed with Norrie disease; cases of symptomatic female carriers have been reported. It is a very rare disorder that is not associated with any specific ethnic or racial groups, with cases reported worldwide (including cases in North America, South America, Europe, Asia and Australasia). While more than 400 cases have been described, the prevalence and incidence of the disease still remains unknown.
Auditory symptoms are common with Norrie disease. Progressive hearing loss has been reported to occur in 85–90% of patients and onset is generally in childhood and before the patient reaches their mid-20s. Early hearing loss is sensorineural, mild and asymmetric. By adolescence, high-frequency hearing loss begins to appear. Hearing loss is severe, symmetric, and broad-spectrum by the age of 35 years. However, studies show that while hearing deteriorates, the ability to speak well is highly preserved. The slowly progressing hearing loss is more problematic to adjust to than the congenital blindness for most people with Norrie disease.
Additionally, children with visual impairment have been shown to struggle establishing regular sleep/wake cycles due to reduced light perception impacting on their understanding of night and day; this can impact on the individual's behavior, mood and cognitive ability. Consistent with this, some case reports of Norrie disease patients have reported the presence of sleep disorders.
Peripheral vascular disease (PVD) has also been associated with Norrie disease. In a study of 56 patients with Norrie disease, 21 patients (38%) reported PVD (including varicose veins, peripheral venous stasis ulcers and erectile dysfunction). Due to the known role of the protein norrin in the vascular development of the eye and inner ear, as well as the association with PVD, norrin is thought to have an important angiogenic role in the body.
Females are very unlikely to express clinical signs. However, there have been a few rare cases where females have shown symptoms associated with Norrie disease such as retinal abnormalities and mild hearing loss. Additionally, cases of symptomatic female carriers have been reported. One possible scenario that could lead to a female case of Norrie disease is if both of their copies of the NDP gene bear mutations, which could be the case in consanguineous families or due to a spontaneous mutation. Another explanation for affected females could be skewed X-inactivation. In this latter case, carrier females with one mutated NDP allele could have a higher proportion of defective norrin being expressed, leading to the presentation of symptoms of Norrie disease.
Norrin is not only important in the development of the eye. The mutation of the NDP gene can affect other systems of the body as well. The most severe problems are caused by chromosomal deletions in the region of the NDP gene, causing the prevention of the gene product, or even that of the neighboring MAO genes. When the mutations simply change a single amino acid in norrin, the effects are less widespread and severe. However, the location and type of the NDP mutation does not necessarily determine the degree of severity of the disease, since highly varying clinical signs have been diagnosed in patients carrying exactly the same mutation. Therefore, the involvement of other modifying genes is very likely. On the other hand, if certain structurally important amino acids are changed (e.g. the forming the putative cystine knot), the clinical outcome has been shown to be more serious.
In addition to its use for initial diagnosis, molecular genetic testing is used to confirm diagnostic testing (such as diagnosis by ocular examination), for carrier testing females, prenatal diagnosis, and preimplantation genetic diagnosis. There are three types of clinical molecular genetic testing. In approximately 95% of males, mis-sense and splice mutations of the NDP gene and partial or whole gene deletions are detected using sequence analysis. Deletion/duplication analysis can be used to detect the 15% of mutations that are submicroscopic deletions. This is also used when testing for carrier females. The last testing used is linkage analysis, which is used when the first two types are unavailable. Linkage analysis is also recommended for those families who have more than one member affected by the disease.
MRI is often used to diagnose the retinal dysplasia that occurs with the Norrie disease. However, the retinal dysplasia can be indistinguishable on MRI from persistent fetal vasculature, or the dysplasia of trisomy 13 and Walker–Warburg syndrome. (2025). 9781451111750, Wolters Kluwer Health/Lippincott Williams & Wilkins. ISBN 9781451111750
For families with an existing history of Norrie disease, genetic counselling and in utero diagnosis of Norrie disease may be considered. In utero diagnosis has been reported to include genetic testing by amniocentesis and ultrasonography to examine fetal eyes. Confirmation of diagnosis on the first day of life by ophthalmological examination under anesthesia has also been reported in some cases.
A high proportion (85–90%) of individuals with Norrie disease experience progressive hearing loss in their second decade of life. In most cases, use of hearing aids has been shown to be effective into middle or late adulthood. For more significantly impaired hearing, may also be considered.
30–50% of individuals with Norrie disease have been reported to present with developmental delay or cognitive impairment. Additionally, behavioral issues have also been reported. Supportive intervention and therapy, for example working with speech and language therapists and occupational therapists, can be used to maximize educational opportunities for these individuals.
Routine monitoring of individuals with Norrie disease is recommended to best manage the disease. This includes regular follow-up with an ophthalmologist, even when vision is severely compromised. Additionally, due to the high proportion of individuals with Norrie disease who develop hearing loss, regular monitoring of hearing loss is beneficial to allow any hearing loss to be detected early and then correctly managed. More recently, the use of dual sensory clinics has been proposed to provide improved care to patients living with conditions such as Norrie disease. For example, Great Ormond Street Hospital (GOSH), London are building a new Sight and Sound center, with the aim of improving the patient experience for individuals with conditions such as Norrie disease.
Individuals with Norrie disease can often feel isolated from society due to difficulties in communication. In cases where hearing loss is also experienced, this psychological burden has been shown to increase. For example, a number of Norrie disease patients have been reported to experience transient depression correlating with the onset of hearing loss. Because of this, the provision of emotional support to individuals with Norrie disease can be as important as clinical treatment strategies in terms of improving their quality of life and reducing disease burden.
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