What Is Norrie Disease?
Norrie disease is a congenital genetically inherited eye condition that typically leads to blindness at birth or severe sight impairment. It is an X-linked recessive condition, caused by a mutation of the NDP gene on the X-chromosome. A recessive condition is a condition where two copies of each chromosome need to be present for the disease to occur. However, as Norrie is an X-linked condition, it would occur in every boy born with a faulty X-chromosome. Norrie disease therefore usually occurs in boys, because boys only have one X-chromosome. A girl with one abnormal X-chromosome will be a carrier but will not be affected if the other X-chromosome does not have the abnormal gene. Carrier females have a 50% chance of passing the gene unto the unborn male.
Around 25 cases in the UK are known and 500 globally. However, the Norrie community feel there are probably many more people with Norrie who have not been diagnosed.
Norrie disease causes abnormal development of the blood vessels and tissues at the backs of the eyes. This affects the retina and; causing abnormal development to this sensitive part of the eye that detects light and colour, leading to retinal detachment. As a result, the irises (the coloured part of the eye) appear white when they have light shone on them; a symptom called leukocoria. Cataracts often develop. The irises and the entire eyeball may shrink during the first few months of life, causing profound visual impairment.
Visual impairment of any cause can create developmental challenges in some individuals which may result in developmental delay and later on, learning disability. Communication and behaviour can also be affected. Some (approximately 30%-50%) of boys with Norrie disease have developmental delay, learning disability or behavioural issues.
Progressive sensorineural hearing loss (hearing loss of nerve origin) is a secondary symptom of Norrie disease and in many patients can start in early childhood. The hearing loss may be significant enough for hearing aids to be prescribed and in some cases, cochlear implants. More research is needed to gain a better understanding of how individuals with Norrie disease may be affected by hearing loss.
Norrie disease has been associated with peripheral venous insufficiency where the flow of blood through the veins is inadequate, causing blood to pool in the legs. Varicose veins and leg ulcers can develop.
Norrie disease has also been associated with short stature, delayed or arrested puberty, and sexual dysfunction. To date, the pathophysiological basis underlying the growth and pubertal issues remains largely unknown.
Norrie disease is diagnosed on the basis of clinical eye findings if the individual presents with congenital blindness. Clinical genetic testing is available to help confirm the diagnosis.
The management of Norrie disease is targeted towards establishing the extent of the disease. This determines the needs of the individual and is likely to require the coordinated efforts of a team of specialists:
The role of the Ophthalmologist would be to examine the eyes and decide on appropriate treatment. This could include removal of cataracts, treatment for glaucoma, laser treatment, shells for the eyes (for structural and cosmetic purposes) or prosthesis. Those who have not completely lost their vision have been treated with surgery or laser therapy in infancy in the US. Children in the UK are rarely offered eye surgery. If surgery is offered, it would be to prolong light perception vision. However, there is no good data available yet as to whether this surgery achieves this aim, and there are significant risks associated with surgery.
The role of the Clinical Geneticist is to establish the genetic origin of the disease and to provide genetic counselling to the family.
The role of the Paediatrician is to assess development in early childhood and to coordinate medical care and educational support as required.
The role of the Audiologist is to carry out regular hearing tests and to advise on hearing aids or cochlear implants if required.
Paediatric endocrinologists who work within the multidisciplinary team will ensure that any growth and pubertal issues are dealt with promptly, and growth of children and young people with Norrie disease is optimised. Growth must be monitored carefully by the local team, and children must be referred to a paediatric endocrinologist if there are concerns with respect to growth, and certainly, all children must be referred by the age of 11-12 years so that puberty can be monitored carefully. Management of growth and pubertal disorders may include the use of hormones such as growth hormone and testosterone. However each child must be carefully evaluated and the most appropriate investigations performed. Treatment must then be directed appropriately.
Therapy support (may include)
Speech and Language Therapist
Specialist Educational Support
Specialist Education Support will be required with key professionals being:
Rehabilitation Officer for sensory impairment
Qualified Teacher of the visually impaired
Qualified Teacher for the hearing impaired
Other healthcare professionals may also be needed to systematically and comprehensively plan the treatment and management of the condition on a case by case basis.
Genetics And Inheritance
Norrie disease is caused by a genetic misprint (mutation) in the ND pseudoglioma (NDP) gene which is located on the X-chromosome. Norrie disease is passed on in families in an X-linked recessive pattern of inheritance.
Females (XX) have two copies of the NDP gene, one on each of their two X-chromosomes. Males (XY) have only one copy on their single X-chromosome. Norrie disease occurs in males when there is a misprint in their single copy of the NDP gene. Otherwise healthy females can carry an altered NDP gene with the working copy on their other X-chromosome usually being enough to compensate for this, preventing them from developing the condition. Women who are carriers of Norrie disease have a 1 in 2 (50%) chance of passing the condition on to each son they have. Each of their daughters has a 1 in 2 (50%) chance of being a carrier of the condition. When a man with Norrie disease has children he will pass on his X-chromosome to all his daughters and so all (100%) daughters will be carriers of Norrie disease. None of the sons of a father with Norrie disease will inherit the condition from him as they will get their single X- chromosome from their mother.
The vast majority of mothers of a boy with Norrie disease are carriers of the condition. Very occasionally Norrie disease can occur due to a new spontaneous (de novo) mutation, without the mother actually being a carrier of the condition. If the mother has had carrier testing for Norrie disease and has not been found to be a carrier then the chance of her having another child with a Norrie gene alteration is low but still slightly higher than that of the general population. This is because of the very small possibility of there being a few egg cells in her ovaries that have a Norrie gene alteration (a situation known as germline mosaicism).
Genetic Services And Testing
Genetic testing methods change over time. A genetic doctor from an NHS genetic clinic (www.bsgm.org.uk/information-education/genetics-centres) can arrange testing of the NDP gene where appropriate, review the inheritance pattern and provide up-to-date management advice. Families are welcome to seek advice at various times of life from the genetic service or paediatrician. For example, when a child growing up with Norrie disease or their siblings want more details, they could attend the genetic clinic to ask about the condition for themselves.
The information on these pages represents current understanding of Norrie disease and has been taken from research to date and clinical findings of patients with Norrie disease. However, much more research is needed to get a better picture of how Norrie disease affects each individual. As and when new research reveals more information, these pages will be updated.