What Is Norrie's Disease?

Norrie disease is characterised by the loss of vision at birth or within a few weeks of an eye lesion. Typically, this disease occurs in individuals assigned to males at birth (AMAB), though milder symptoms can appear in individuals assigned to females at birth (AFAB). It can also cause auditory impairment alongside neurological features and developmental delays. Patients are born blind or lose their sight in infancy. However, hearing loss progresses in the second decade of life. The combination of hearing and sight loss has a physical, psychosocial, and financial impact on patients with this condition. The condition should be routinely monitored so that it can be identified and treated and the patients can receive the support they need.¹

The nature of norrie's disease

This disease is very rare, with only 400 cases known. It is a derivative of mutations in the ND pseudo glioma (NDP) gene on the X chromosome. This is why the majority of the patients are AMAB, as they only possess 1 X chromosome. Ocular signs of the disease can be observed at birth or develop in very early life. On clinical examination, abnormally small eyes can be observed (microphthalmia), as well as corneal opacity, leakage of blood into the eye, cataracts and retinal detachment. Children may fail to respond to light. Patients typically pass the newborn hearing test, but most will have progressive hearing loss. Severe hearing loss typically presents by 35 years of age. Patients reported intermittent hearing loss, with deterioration over time.¹

Norrie disease is also linked to cognitive impairment, neurodevelopmental disorders, peripheral vascular disease and seizures. The presentation of Norrie disease can widely vary, with different patients having different experiences. These differences could be due to genetic, epigenetic, or environmental factors. In some cases, the same mutation has been found in patients with partial sight and patients with blindness.¹

There are few facilities suitable for patients with dual sensory impairments, and the variability of the disease can be hard for patients and caregivers. Diagnosis and monitoring means patients must attend specialist clinics where they can be given the best treatment for their condition. A holistic approach may be good for patients, where ocular and extraocular symptoms can be reviewed.¹

Causes of norrie disease

Norrie disease is an X-linked recessive disorder where retinal detachment can occur in the early postnatal period. 25-50% of patients have additional symptoms, including deafness and intellectual disability. The Norrie disease gene is on chromosome Xp11.³ Which is the gene code for amino acids that make up the Norrie protein.² 

Research shows that Norrie's disease is caused by variations in the NDP gene. There are over 140 point mutations, chromosomal rearrangements, nucleotide insertions, deletions, splicing variations, and frame-shift variants associated with the NDP gene. Variation in the NDP gene is not just linked to Norrie disease, as they are linked to multiple retinopathy-related diseases. When the eyes were examined in people with Norrie disease, it showed bilateral retinal detachment and a reduction in retinal nerve cells. The disease is complex, with more than 60% of patients thought to have point mutations and 20% thought to have NDP gene deletions. Yet, the majority of NDP variants have missense, deletion and nonsense variations. It has been found that a Norrie disease-associated variant in the NDP gene causes a change in splicing. This could be a potential route to explore in relation to the treatment of the disease.² 

The timing of auditory sensory deficits and how it can affect therapeutic intervention

Whilst the congenital nature of blindness may not be a window for intervention, the childhood/early adulthood onset of hearing loss is a potential opportunity for therapeutic intervention. However, as the disease is rare, it has been hard to study the nature of hearing loss in Norrie disease patients. In one patient who was studied in a postmortem, there was a loss of sensory hair cells, deposits of tissue around neurons, and other conditions affecting the whole cochlea. Studies have shown the first impacts of hearing loss influence hearing high frequencies, alongside only mild hearing loss.³ 

Mice with a loss of function in the gene involved in Norrie disease show a phenotype similar to human patients with Norrie disease, though it is less severe. Mice have shown progressive hearing loss and pathological changes in the cochlea. This suggests that there is a common mechanism responsible for both hearing and sight loss. This could be something to consider when looking at therapeutic options. Yet, it is still unclear as to how these mutations cause hearing loss. NDP is a protein which can join with certain receptors and proteins to control important processes in the retina. When there are mutations in the things the NDP proteins bind to, it can disrupt blood vessel development in the retina. This has been identified as a potential target for therapeutic interventions.³ 

Before interventions can target hearing loss in Norrie disease, the timing and onset of cochlear pathology need to be understood. According to a study, hearing loss in the disease is likely to be of trial or metabolic defect, which causes neural defects. This enhances our understanding of the disease and can help in therapeutic approaches hoping to prevent hearing loss in Norrie disease patients. The study also found that hearing loss had a mild to moderate onset. However, in one patient, moderate to profound hearing loss was observed. This shows that in some patients, hearing loss can occur faster than in others.³ 

Diagnosis of norrie disease

The diagnosis of Norrie's disease can take some time. Often, there is a referral to an ophthalmologist, as the disease is rare and there is delayed diagnosis. Patients are then typically sent to a specialist ophthalmologist, where they are diagnosed using ophthalmic investigation and then gene testing. Whilst not normally done, the disease can be diagnosed in utero if the mother is a suspected or known carrier of the disease. Genetic testing can be done to identify the NDP gene.¹

Management of norrie disease

Patients with Norrie disease are given a team of specialists and healthcare professionals. These can include speech, language and hearing specialists, as well as an educational team, social workers and psychologists. This helps patients with Norrie disease get the support and help they need to maximise their quality of life. Some surgical interventions can be offered to try to retain light perception. When blindness is detected in an infant, they are referred to a developmental paediatrician. This should happen as early as possible. If a hearing impairment is detected, clinicians can discuss how to best manage dual sensory loss. Management can include hearing aids for the patients, and there are multiple to choose from. Patients can also use assistive hearing devices. Some patients with Norrie disease use cochlear implants, which have been reported to have a positive impact on their quality of life.¹

Dual sensory clinics

Dual sensory clinics are a suggested way of decreasing the impact of sensory disorders on patients. They could provide a range of benefits to patients and clinicians when dealing with diseases such as Norrie disease. It is known that multidisciplinary care helps patients with a range of conditions. In the dual sensory clinic, there should be clinicians who are trained to communicate treatment for patients with Norrie disease.¹

Summary

Norrie disease is a complex condition where the patient has visual and auditory impairment. These symptoms can occur alongside developmental delays. Patients are born blind or lose their vision in infancy and go on to typically lose their hearing in the second decade of life. The disease is thought to be caused by variations in the NDP gene. Diagnosis of the disease can take some time, with it often being misdiagnosed. In terms of management, patients are given a team of specialists, and hearing aids can be used.