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Norrie Disease is a genetic disorder that primarily affects the eye and almost always leads to blindness. In addition to the congenital ocular symptoms, some patients suffer from a progressive hearing loss starting mostly in their 2nd decade of life, while another portion may be mentally challenged.
Patients with Norrie Disease may develop cataracts, Leukocoria (a condition 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.[1] Around 30-50% of them will also have developmental delay/mental retardation, psychotic-like features, incoordination of movements or behavioral abnormalities.[1] Most patients are born with normal hearing; however, the onset of hearing loss is very common in early adolescence.[2] About 15% of the patients are estimated to develop all the features of the disease. [3]
The disease affects almost only male infants at birth or soon after birth, because the disease is inherited X-linked recessive. Only in very rare cases, females have been diagnosed with Norrie Disease as well. The exact incidence number is unknown; only a few hundred cases have been reported so far. It is a very rare disorder that is not associated with any specific ethnic or racial groups.[4]
In 1961, a Danish ophthalmologist named Mette Warburg reported that a Danish family showed seven different 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 for his lens appeared to be opaque and his irises were deteriorating.[5] The area behind his lens was filled with a growing yellowish mass. Five months later, his left eye was removed due to the suspicion of retinoblastoma, a cancerous tumor on the retina. An 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. This means his eye was removed because the physician suspected a tumor, although it emerged that it was a developmental defect that lead to the malformation of inner parts of the eye. Because the eye was not functional, cells already began 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 low. After Warburg researched literature under various medical categories, she discovered 48 similar cases which she believed were cause by this disease as well.[5] She then suggested this disease be named after another famous Danish ophthalmologist, Gordon Norrie (1855-1941). Norrie was greatly recognized for his work with the blind and for being a surgeon at the Danish Institute for the Blind for 35 years.[6]
Norrie Disease is a genetic disorder caused by mutations in the NDP gene, located on Xp11.4 (GeneID: 4693). It is inherited in an X-linked recessive way from usually one of your parents. 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. They also usually show no clinical symptoms, but will inherit the mutation to 50% of their offspring. Daughters receiving 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. One possible scenario leading to this (unlikely) case would be if both of their copies of the NDP gene bear mutations, which could be the case in consanguineous families or due to a spontaneous somatic mutation. Another explanation for affected females could be skewed X-Chromosome inactivation.
However, throughout history, there have been a few rare cases where females have shown symptoms associated with Norrie Disease such as retinal abnormalities and mild hearing loss.[7]
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