Норри ауруы: Көздің генетикалық бұзылысы және соқырлыққа әкелуі

Genetic disorder that primarily affects the eye and almost always leads to blindness

Norrie disease is a rare X linked recessive genetic disorder that primarily affects the eyes and almost always leads to blindness. It is caused by mutations in the Norrin cystine knot growth factor gene, also referred to as Norrie Disease Pseudoglioma (NDP) gene. Patients with Norrie disease may develop cataracts, leukocoria (where the pupils 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 percent of those affected by the disease might encounter cognitive challenges, learning difficulties, incoordination of movements or behavioral abnormalities. 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.

The most prominent symptoms initially observed in Norrie disease are ocular. Initial characteristics are usually identified at birth or in early infancy, with parents often noticing abnormal eye features or that their child fails to show a response to light. The first visible finding is leukocoria, a grayish yellow pupillary reflection that originates from a mass of disorganized tissue behind the lens. This material, which possibly includes an already detached retina, may be confused with a tumor and thus is termed pseudoglioma. Early hearing loss is sensorineural, mild and asymmetric. 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).

Norrie disease is a rare genetic disorder caused by mutations in the NDP gene, located on Xp11.4 (GeneID: 4693). It is inherited in an X linked recessive manner. This means that almost only males are affected. Sons of affected men will not have the mutation, while all of their daughters will be genetic carriers of the mutation. Female carriers usually show no clinical symptoms, but will pass the mutation to 50% of their offspring. Daughters with the mutated gene will also be, like their mother, asymptomatic carriers, but 50% of their sons will express clinical symptoms. 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. Norrin also appears to be crucial in the specialization of the cells of the retina and the establishment of a blood supply to the inner ear and the tissues of the retina. The role of norrin in the specialization of retinal cells for their unique sensory function is impeded by the mutation of NDP.

Norrie disease and other NDP related diseases are diagnosed with the combination of clinical findings and molecular genetic testing. Molecular genetic testing identifies the mutations that cause the disease in about 95% of affected males. 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.

Ocular, auditory and behavioral management are the most common areas of intervention and treatment for patients with Norrie disease. For ocular (eye) management, often patients already have complete retinal detachment at birth, or by the time of diagnosis, so surgical intervention is often not offered. However, there is some evidence for the benefit of early surgery or laser therapy for cases where retinal detachment is incomplete. Surgery may also be used to treat increased intraocular pressure and in rare cases enucleation (removal) of the eye is considered to control pain. The benefits of dual sensory clinics include improved communication between the different health care professionals (HCPs) involved in management of Norrie disease (e. g. ophthalmologists and audiologists) as well as allowing more consistent training of staff on best practices for managing and interacting with individuals with sensory impairment. 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. The group at UCL GOSICH is focusing particularly on the hearing loss aspect of the disease, and whether it might be possible to treat by gene therapy.

In 1961, a Danish ophthalmologist named Mette Warburg reported on a Danish family that showed seven cases of a hereditary degenerative disease throughout seven generations. The first member of the family to be thoroughly studied was a 12 month old boy. At the child's examination at three months, it was noticed that he was normal except that his lens appeared to be opaque and his irises were deteriorating. The area behind his lens was filled with a growing yellowish mass. Five months later, his left eye was removed due to suspicion of retinoblastoma, a cancerous tumor on the retina. A histologic examination showed a hemorrhagic necrotic mass in the posterior chamber, surrounded by undifferentiated (immature, undeveloped) glial tissue. The diagnosis included a pseudotumor of the retina, hyperplasia of retinal, ciliary, and iris pigment epithelium, hypoplasia and necrosis of the inner layer of the retina, cataract, and phthisis bulbi. The physician had suspected a tumor, although it emerged that it was a developmental defect that led to the malformation of inner parts of the eye. Because the eye was not functional, cells had already begun to die (necrosis) and the eye globe began to shrink due to its dysfunction (phthisi bulbi). In this Danish family, five of the seven people in these cases developed deafness later in life. Also, in four of the seven, mental capacity was determined to be low. After Warburg researched literature under various medical categories, she discovered 48 similar cases which she believed were caused by this disease as well. The NDP gene was previously named the “Norrie disease (pseudoglioma)” gene, which is still used widely when referring to NDP. However, the current approved name for NDP is “Norrin cystine knot growth factor”.

There are two patient organizations for people affected by Norrie disease. The Norrie Disease Association (NDA) was founded in 1994 and is a US based non profit organization aiming to provide information and support to people living with Norrie disease and their families. The NDA holds a conference on Norrie disease every three years in Boston, US. The Norrie Disease Foundation (NDF) is a UK based charity established in 2016. The main aims of NDF are to provide support for families and promote pioneering research into Norrie disease. They organize two family days a year where families with Norrie disease can come together to share experiences, meet each other and build relationships and supportive networks. The websites for both patient organizations contain useful information for patients and their families about the disease.