Norrie disease

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Norrie disease
Classification & external resources
OMIM 310600
DiseasesDB 31165

Norrie Disease is a genetic disorder that infects the eye and almost always leads to blindness. Patients with Norrie Disease may also 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, and behavioral abnormalities.[1] Most patients are born with normal hearing; however, the onset of hearing loss is very common in early adolescence.[2] This disease infects mainly male infants at birth or soon after birth. In a few very rare cases, a female has been diagnosed with Norrie Disease as well. The exact incidence number is unknown. It is a very rare disorder that is not associated with any specific ethnic or racial groups.[3]

Contents

[edit] History

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.[4] 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 examination using histology showed that in the posterior chamber there was a hemorrhagic necrotic mass. This mass was surrounded by undifferentiated glial tissue, which is tissue that has not separated. According to Victor MsKusich, the author to publish the findings of this case, “The histologic diagnosis included a pseudotumor of the retina, retinal hyperplasia, ciliary, and iris pigment epithelium, hypoplasia and necrosis of the inner layer of the retina, cataract, and Phthisis bulbi.”[5] This means he had a tumor, an overproduction of cells in his retina, his irises were not the normal color, the cells in his inner layer of the retina were dying, he had cataracts, and his eye was shrinking. 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.[6] 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.[7]

[edit] Causes

Norrie Disease is a genetic disorder caused by mutations in the NDP gene. It is an X-linked recessive pattern inherited from one of your parents. It is considered an X-linked condition because the mutated gene that causes the disorder is located on the X chromosome. It is much more difficult for a female to inherit the disease.[8] This is because males only have one X chromosome, meaning the condition can be created from only one altered copy of the gene in each cell. However, females have two X chromosomes; therefore both copies of the gene must have mutations in order for the disease to occur. As a result, males are affected much more frequently than females by Norrie Disease and other X-linked disorders.[9]

As any in any genetic disorder, Norrie Disease is passed to the offspring through a carrier parent. Surprisingly, fathers who carry an X-linked trait cannot pass it on to their sons. A female who has one altered copy of the gene in each cell is known as a carrier. In general she does not have any symptoms or signs of the disorder, but she can pass it on. Throughout history, there have been a few rare cases where females have shown of the symptoms associated with Norrie Disease such as retinal abnormalities and mild hearing loss.[10]

[edit] The NDP Gene

NDP is the mutated gene causing Norrie disease. The official name of the gene is “Norrie disease (pseudoglioma)”. The gene’s official symbol is NDP. The normal function of the NDP gene is to produce the instructions for creating a protein called norrin. For the normal development of the eye and other body systems, norrin is believed too be crucial.[11] 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 is interfered by the mutation of NDP.[12] This results in an accumulation of immature retinal cells in the back of the eye. When norrin’s role in the establishment of blood vessels supplying the eye is disrupted, eventually the tissues will break down.[13]

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 location of the NDP mutation determines the specific abnormalities and how severe they will be. The most severe problems affecting many body systems as well as the eyes occur when the mutations delete portions of the NDP gene causing the prevention of the production of norrin. When the mutations simply change a single amino acid in the NDP, the effects are less widespread and severe.[14]

[edit] Diagnosis

As of right now, 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 85% of affected males.[1] Clinical diagnoses rely on ocular findings. Norrie Disease is diagnosed when grayish-yellow fibrovascular masses are found behind the eye from birth through three months. Doctors also look for progression of the disease from three months through eight-ten years of age. Some of these progressions include cataracts, iris atrophy, shallowing of anterior chamber, and shrinking of the globe.[1] By this point, the vision is light perception impaired or non-existent.

Molecular genetic testing is used for more than an initial diagnosis. It is used to confirm diagnostic testing, for carrier testing females, prenatal diagnosis, and preimplantion genetic diagnosis. There are three types of clinical molecular genetic testing. In approximately 85% of males, mis-sense and splice mutations of the NDP gene and partial or whole gene deletions are detected using sequence analysis.[1] 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 are unavailable. Linkage analysis is also recommended for those families who have more than one member affected by the disease.[1]

Graph of percentage of hearing loss according to age
Graph of percentage of hearing loss according to age[1]

[edit] Symptoms

The most prominent symptoms of Norrie Disease are ocular. A baby with Norrie Disease irises, anterior chambers, cornea, intraocular pressure, and the size of their globe may all be normal. The most common finding that indicates a problem is an elevated glistening grayish-yellow mass that replaces the retina and is visible through a clear lens. The masses resemble tumors and are given the name “pseudogliomas.”[1] Another indicator of problem is the condition called Leukocoria. Leukocoria results from abnormal development in the retina due to masses of retinal cells that accumulate in the back of the eye.[15]

Over the first few months of life, complete or partial retinal detachment evolves. From the time they’re a baby through childhood, the patient may undergo progressive changes in the disease.[1] These progressions include the formation of cataracts, deterioration of the iris with adhesions forming between the iris and the lens or the cornea, and shallowing of the anterior chamber which increases intraocular pressure that can become painful.[1] As the situation worsens, there is corneal opacification, where the cornea becomes opaque, and band keratopathy. Intraocular pressure is lost and the globe shrinks. In the last stage of Norrie disease, the globes appear small and sunken in and the cornea appears a milky color.[1]

Norrie disease can also have cognitive and behavioral symptoms. Developmental delay and mental retardation are present in about 30-50% of males who have Norrie disease.[1] Psychotic-like features and poorly characterized behavior abnormalities may also be present. Auditory symptoms are often common with Norrie disease. Progressive hearing loss starts in early childhood for a majority of males with the disease. Early hearing loss is sensorineural, mild and asymmetric.[1] By adolescence, high-frequency hearing loss begins to appear. Hearing loss is severe, symmetric, and broad-spectrum by the age of 35. However, studies show that while the hearing loss is deteriorating, the ability to speak well is highly preserved.[2] The slowly progressing hearing loss is more problematic in adjusting to than the congenital blindness for most people with Norrie disease.[1]

[edit] References

  1. ^ a b c d e f g h i j k l m n Sims , Katherine. "NDP-Related Retinopathies." Gene Reviews. 08 Aug 2006. 28 Jan 2007 <http://www.geneclinics.org/profiles/norrie/>
  2. ^ a b Halpin C, Owen G, Gutiérrez-Espeleta G, Sims K, Rehm H (2005). "Audiologic features of Norrie disease". Ann Otol Rhinol Laryngol 114 (7): 533-8. PMID 16134349. 
  3. ^ "Norrie Disease." Genetics Home Reference. 26 Jan 2007. 28 Jan 2007 <http://ghr.nlm.nih.gov>
  4. ^ McKusich, Victor. "Norrie Disease; ND." Online Mendelian Inheritance in Man. 02 June 2006. 31 Jan 2007 <http://www.ncbi.nlm.nih.gov>
  5. ^ McKusich, Victor. "Norrie Disease; ND." Online Mendelian Inheritance in Man. 02 June 2006. 31 Jan 2007 <http://www.ncbi.nlm.nih.gov>
  6. ^ McKusich, Victor. "Norrie Disease; ND." Online Mendelian Inheritance in Man. 02 June 2006. 31 Jan 2007 <http://www.ncbi.nlm.nih.gov>
  7. ^ "Gordon Norrie." Who Named It?. 1994-2007. 13 Feb 2007 <http://www.whonamedit.com>
  8. ^ "Norrie Disease." Genetics Home Reference. 26 Jan 2007. 28 Jan 2007 <http://ghr.nlm.nih.gov>
  9. ^ "Norrie Disease." Genetics Home Reference. 26 Jan 2007. 28 Jan 2007 <http://ghr.nlm.nih.gov>
  10. ^ "Norrie Disease." Genetics Home Reference. 26 Jan 2007. 28 Jan 2007 <http://ghr.nlm.nih.gov>
  11. ^ "NDP." Genetics Home Reference. 26 Jan 2007. 31 Jan 2007 <http://ghr.nlm.nih.gov/gene=ndp>
  12. ^ "NDP." Genetics Home Reference. 26 Jan 2007. 31 Jan 2007 <http://ghr.nlm.nih.gov/gene=ndp>
  13. ^ "NDP." Genetics Home Reference. 26 Jan 2007. 31 Jan 2007 <http://ghr.nlm.nih.gov/gene=ndp>
  14. ^ "NDP." Genetics Home Reference. 26 Jan 2007. 31 Jan 2007 <http://ghr.nlm.nih.gov/gene=ndp>
  15. ^ "Norrie Disease." Genetics Home Reference. 26 Jan 2007. 28 Jan 2007 <http://ghr.nlm.nih.gov>
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