FRMD7: How the study of a gene shed new light on infantile nystagmus.

Dr Mervyn Thomas and Dr Frank Proudlock from the University of Leicester’s Ophthalmology Group updated us on how a PhD project, funded by Sight Research UK in 2008, has helped to advance research in infantile nystagmus and to transform diagnosis of this condition in young children.

What is nystagmus?

Nystagmus – sometimes known as “wobbly eyes” or “dancing eyes” - is a complex condition that causes rapid involuntary movements of the eye from side to side, up and down, or round and round. Congenital, or infantile nystagmus, usually becomes apparent in the first few weeks or months of life. Acquired nystagmus can occur at any time as the result of a neurological condition such as stroke, or following a head injury. Nystagmus affects people in different ways, and to varying degrees, but it can reduce vision significantly and cause problems with depth perception, making it difficult to judge distances or movement. Children with nystagmus may take a longer to walk, or find it difficult to read.

What was the aim of the project?

In 2008, Irene Gottlob, now Emeritus Professor of Ophthalmology at the University of Leicester, approached Sight Research UK for a grant to develop her research into infantile nystagmus. Having recently discovered that a specific gene, FRMD7, was linked to the condition, Professor Gottlob and her team wanted to better understand the gene’s function, and how different mutations of FRMD7 relate to different types of nystagmus. It was hoped that this knowledge could help improve clinical diagnosis of the condition and that ultimately, the research findings could also help to advance genetic treatments.

Funding from Sight Research UK allowed Mervyn Thomas, then an undergraduate with ambition to become an academic Ophthalmologist, to undertake the research as a PhD project. To facilitate the work, the Leicester team recruited 59 families and 72 single people to participate in what was then largest study cohort for infantile nystagmus in the world to date.

What did the study achieve?

The use of both genetic sequencing and advanced clinical imaging techniques were key to the project’s success, helping to progress research in two important areas. Firstly, these technologies enabled the team to make further discoveries about the nature and function of FRMD7, which provided a new understanding of the causes and development of infantile nystagmus. Secondly, the technologies facilitated huge improvements in diagnosis of the condition.

A new understanding of nystagmus

In the course of his PhD research, Dr Thomas made some significant new discoveries about the underlying mechanisms of infantile nystagmus. Notably, he found that mutations of the FRMD7 gene are linked to abnormal development of the afferent system: the structures within the eye that are responsible for receiving, transmitting, and processing visual information. In particular, he found that FRMD7 protein is produced quite heavily in specific layers of the retina during foetal development. This was a pivotal discovery that has since sparked many further studies by research groups across the world, who are working to understand how nystagmus develops in children, and how the condition might be prevented. As Dr Proudlock explained:

We appreciate now that infantile nystagmus is almost always associated with problems with information going into the eyes – so it’s changed our understanding of the disease itself.

Another new finding to come out of the project concerned a particular type of nystagmus known as periodic alternating nystagmus, or PAN. While PAN can be acquired in later life, generally through neurological disease or damage, very little was known about the cause of infantile PAN. Using both eye movement recordings and genetic information from participants in the study cohort, Dr Thomas showed that infantile PAN can be associated with mutations of the FRMD7 gene. This discovery has helped to improve the diagnosis of PAN – a significant achievement because PAN requires different therapeutic approaches from other forms of nystagmus. As the name “periodic alternating nystagmus” suggests, patients with this type of the condition have nystagmus movements that change direction periodically and so the clinical examination findings and symptoms can vary from day to day.

PAN can be associated with abnormal head postures, which can also alternate between each clinic visit. Therefore, standard corrective head posture surgery is not recommended due to unpredictable outcomes. Confirming diagnosis of the underlying nature of nystagmus enables clinicians to prescribe the correct treatment.

Improving diagnosis of nystagmus in young children

Finding the link between PAN and specific mutations of FRMD7 was just one of several similar discoveries made through this project. The team carried out a large scale genotyping study that enabled them to characterise the entire range of genetic mutations of FRMD7. This work revealed that 64% of families with infantile nystagmus had some variant of FRMD7 mutation, and it formed the basis for establishing the first clinical single gene test for infantile nystagmus, not only in the NHS but worldwide.

This test, which is still available on the NHS today, has helped to transform the diagnosis of infantile nystagmus and has been of great benefit to patients. Previously, when a very young child was brought into the clinic with suspected nystagmus, they would undergo a battery of investigations, requiring multiple hospital appointments, in order for a diagnosis to be confirmed. The process would entail a series of invasive and distressing eye examinations, some of which would need to be administered under anaesthesia or sedation. The availability of genetic testing for infantile nystagmus removes, or reduces, the need for babies and young children to have such unpleasant tests, and it also provides prospective parents with the opportunity for genetic counselling.

A further achievement of the project was that it demonstrated, for the first time, that a hand-held optical coherence tomography (OCT) scanner can be used as a reliable tool for diagnosing infantile nystagmus. This non-invasive, high resolution imaging device uses light waves to take cross-section pictures of the layers of the retina, in much the same way that an MRI scanner is used to take images of the brain.

Using the OCT scanner, the Leicester team discovered that certain changes or abnormalities in the retina, such as those found in children with colour blindness or albinism, are also associated with different types of infantile nystagmus.

In addition, the OCT imaging helped to confirm foveal hypoplasia –the developmental arrest of the retina - as a cause of infantile nystagmus. If the retina stops developing at an early stage, the child’s vision is likely to be worse than if the arrest happens when the retina is more fully developed. Using the OCT images, the team was able to document and categorise different stages of developmental arrest of the retina. This allowed them to create a grading system that has since been used not only as a diagnostic tool, but also to provide a prognosis of a child’s visual health. Again, this achievement has been greatly beneficial for patients.

It is hugely helpful for parents to know, at a very early stage, what impact infantile nystagmus is likely to have on their child’s vision. A prognosis helps to reduce doubt and anxiety, and crucially, it gives parents an understanding of what difficulties their child might experience, for example with co-ordination or reading, and what support they might need as they grow up with nystagmus.

How has this research developed and what further impact has the study had?

Not only did Dr Thomas’s PhD project achieve its goals in terms of furthering understanding of the fundamental nature and causes of nystagmus, but it laid the ground for subsequent studies that have helped to drive further improvements in diagnosis.

Since Dr Thomas developed his single gene test for FRMD7 in 2011, huge advances have been made in gene sequencing technology, enabling an entire human genome to be sequenced in a single day. The Leicester team took advantage of these next-generation sequencing (NGS) techniques to develop a panel test for infantile nystagmus, based on over 300 genes associated with the condition, including FRMD7. This test has since become the mainstream strategy for genetic testing for infantile nystagmus.

Furthermore, the proof of concept work that the group undertook in developing and trialling their panel test led to them being successful in nominating infantile nystagmus as a condition for inclusion in the 100,000 Genomes Project. This flagship initiative, established by the UK Government in 2012, was set up to sequence 100,000 whole genomes - a complete set of DNA - from volunteer NHS patients with cancer or with rare diseases, and from family members of people with rare conditions. As most rare diseases are inherited, the genomes of patients with a rare condition, in addition to those from two close blood relatives, can help to pinpoint the exact cause of the disease and reveal how personalised treatments might be developed.

The Leicester team has continued to develop the work in OCT imaging too. Recently, Dr Thomas has been creating a system using artificial intelligence to interpret paediatric OCT images, in order to improve the accuracy of diagnosis of infantile nystagmus, and to make the OCT technology more widely available to other clinical colleagues.

As he explained: interpreting paediatric OCT scans requires a good understanding of the normal developmental sequence of the retina - so it’s not something that any ophthalmologist would be able to do. By having an AI system, it opens up the technology to other clinicians as well, and it augments or assists the clinical decision making process.

Reflecting back on his PhD project and its impact on nystagmus research, Dr Thomas told us, “I am very grateful for that initial funding I received from Sight Research UK - which formed a huge stimulus for me personally, and for our group”.

For our part, we are hugely proud that the findings from a PhD project have led to such considerable improvements in diagnosing infantile nystagmus, and have given clinicians the tools to provide reliable visual prognoses for children with the condition. Of course, we are delighted too that Dr Thomas’s achievements have led to his appointment as academic clinical lecturer, with patients and students as the ultimate beneficiaries of his knowledge and expertise.

The ground-work from Dr Thomas’s PhD project has since enabled him and his colleagues to secure over £2 million in research investment from funders including the Wellcome Trust, the Academy of Medical Science, and The Ulverscroft Foundation, and the Medical Research Council. All of this funding has helped to establish the Leicester Ophthalmology Group as the leading centre for diagnosis and treatment of nystagmus in the UK, seeing over 600 patients a year from all over the country.

If you would like to find out more about living with nystagmus, including what support may be available for people with the condition, please visit the Nystagmus Network.