To coincide with Rare Disease Day 2023 and publication of the second Rare Diseases Action Plan for England, we spoke to Chloe, Tom, their parents Derrolyn and Dave, and Chloe’s husband Adrian (with input from Albert, 18 months) about the impact of LHON on their family. With several members of the family involved in research through the NIHR BioResource, we also discussed their motivations for taking part and the value of research in helping families like theirs impacted by rare conditions such as LHON.
Leber Hereditary Optic Neuropathy (LHON)
LHON is a maternally inherited genetic disease caused by a mutation in the mitochondrial DNA (the part of cells that creates the energy needed for them to function), affecting approximately 2,000 people in England. It is the most common of a number of conditions called inherited mitochondrial diseases and affects cells in the retina and the optic nerve that connects your brain to your eyes.
LHON is one of the conditions included in the Inherited Optic Neuropathies (ION) patient cohort at the NIHR Rare Diseases BioResource, led by Professor Patrick Yu Wai Man, Professor of Ophthalmology at the University of Cambridge. Professor Yu Wai Man’s study is one of seventeen comprising the first phase of our Rare Diseases RNA Phenotyping project.
Rare Diseases RNA Phenotyping project at the BioResource
Chloe is one of approximately 1,000 early participants in our Rare Diseases RNA Phenotyping (RNA) project, one of the case studies featured in the Rare Diseases Action Plan published today by the Department for Health and Social Care (DHSC).
The project aims to drive forward diagnosis and gene discovery for patients with rare genetic diseases to ultimately improve patient outcomes. Seventeen different rare disease areas are now involved in the RNA project, including bleeding, thrombotic and platelet disorders, inherited neurological disorders, stem cell and myeloid disorders, and giant cell arteritis.
The RNA project follows on from an initial study published in 2020 from the NIHR Rare Diseases BioResource to undertake whole genome sequencing (WGS) of approximately 8,000 volunteers. The study helped to provide a diagnosis for between 10-20% of rare disease patients, depending on disease profile and patient background, and was fundamental to the 100,000 Genomes Project from Genomics England that followed.
In May last year, Chloe donated a 50mL blood sample from which white blood cells were isolated. From these cells RNA is extracted. The RNA is then sequenced, along with her DNA, and combined with extensive clinical data to provide a large dataset. This detailed genetic and clinical picture can be studied to look for patterns between patients, relatives and those without the condition (controls) to help us accelerate diagnosis, develop new treatments and improve patient care.
Highlighting the role of the NIHR BioResource in his research, Professor Yu Wai Man commented:
“The major advances that have been made in the field of genetic eye diseases would not have been possible without the huge contribution of patient-led organisations. They have helped me and my team to recruit participants into a broad range of studies to better understand disease and also ground-breaking gene therapy trials that we hope will prevent people from going blind.”
Chloe’s journey
Chloe asked her mum to check if something was in her eye after her shift at a supermarket, aged 18, when she noticed an issue with the vision in her left eye. Several visits to the GP and Eastbourne hospital later, Chloe went through the “horrific” reality of vision in her right eye also starting to deteriorate.
What followed were several shocking clinical and social experiences – including one consultant proposing a psychosomatic assessment because he didn’t believe Chloe’s vision was as bad as she claimed, or having to conduct a fitness-to-work assessment in the public café at work – that left her feeling degraded, lacking confidence and scared for what the future would hold.
Only when Chloe was admitted to the National Hospital for Neurology & Neurosurgery at Queen's Square in London, part of University College Hospitals London (UCLH) after starting to collapse frequently – later diagnosed to be Postural Orthostatic Tachycardia Syndrome (POTS) - did the severity and explanation for her vision problems become apparent.
According to the LHON Society: ‘you can carry a mitochondrial DNA mutation without experiencing any signs or symptoms of vision loss. This makes it hard to predict which members of a family who carry a mutation will eventually become affected.’
Derrolyn, Chloe’s mother, is a carrier for the genetic variant but is not currently affected. It was when Derrolyn’s aunt called the hospital to explain the history of visual impairment in her family that doctors began to piece together the ancestry that supported a diagnosis of LHON.
Chloe explains that period in 2011:
She is now registered blind, with hardly any peripheral and no central vision in her left eye. The right, her ‘good eye’, with no central vision but ‘OK peripheral vision’, is Chloe’s go-to for using her phone and her tablet, which she describes as her ‘best friend’ (someone Chloe actually lost soon after her diagnosis).
“I’m stronger now, more opinionated (her family laughs in unison), more life experience”
By training her eyes, she feels her vision has improved, or at least ‘the deterioration has plateaued’, allowing her to get on with daily tasks, ably supported by her ‘incredible family support network’. She has also used the power of time to come to terms with her condition – Chloe does not feel like she has a ‘disease’ and prefers not to use the word – and has grown into a confident 30-year-old woman, wife to Adrian and mother to Albert.
Chloe’s son, Albert, is too young to be tested for the condition and until he shows symptoms, nothing can be done, but Chloe is not going to let any time go to waste when the opportunity to have him checked out arises. The family had been through a lengthy process to take part in a CRISPR gene editing trial to prevent their future child from carrying the mutation, but Chloe’s health prevented them from eventually taking part, and Albert came along a few months later.
The bond between Chloe and Albert is something special, according to Tom - “it’s like he just knows!’.
Albert seems to know not to put small things in his mouth, but hand them to Chloe instead. Not something most toddlers are renowned for...
“It’s not going to be easy, Tom. It’s going to be hard. You’re going to have a really tough time before it gets better”
Chloe says she never cried as much during her own diagnosis or anytime in the 12 years since, as she did when her older brother, hair stylist Tom, was diagnosed with LHON just four months ago. Chloe knew the journey Tom was about to embark on when he was formally diagnosed in October 2022, after first experiencing vision issues at work in August and having a regular eye test.
Derrolyn also knew, so with that in mind, they skipped the GP and local hospital and immediately called Professor Yu Wai Man, Chloe’s specialist.
On his emotions at that time, Tom explained:
“As soon as I had the results from the eye test, there was that initial ‘oh ****’, and then it got confirmed when we came up to see Patrick for the first time. I’m not going to lie; it was terrifying. Especially for someone in my job, one that is visual. It has become increasingly more challenging as time has gone on.”
Even in the short period between onset of symptoms and diagnosis, Tom’s vision deteriorated significantly, starting with central vision in the left eye, as with Chloe. By October, he’d lost most of the vision in his right eye too.
A bit of laughter goes a long way
Tom, by his own admission, is trying to take a more humorous approach to his recent diagnosis, often dismissing his new reality as “oh, that’s blind life” to which Chloe quickly interjects “hey - I have a blind life, and I do pretty well!”
The family all laugh when explaining that Chloe is sometimes the one to step in and find a missing item in the house for one of them.
One early bit of advice from Chloe to her older brother Tom:
That can be put to the test of course. Mum inadvertently tidying things away, or when dad, Dave, had beautifully redecorated the bedroom in preparation for the arrival of baby Albert, with Chloe, heavily pregnant, ‘stressing out’ about having to rearrange her clothes exactly as they were so she knows what is where.
“Through research, things are changing”
For years Chloe held on, literally and metaphorically, to a necklace bearing the word ‘believe’, gifted to her by her mum. Derrolyn sat with Chloe soon after her diagnosis and was told by her clinician that there would be change. It would take time, but in 10-15 years there would be advances in research to support patients like Chloe.
One such development is the drug Idebenone, something Tom has been taking since his diagnosis in October, with early signs of improvement to his vision. It works by activating viable-but-inactive retinal ganglion cells, which can enable recovery of vision in people who have experienced vision loss and help prevent people from becoming blind.
Idebenone is currently available on prescription in Scotland, Wales and Northern Ireland but not in England. For a recent BBC News article on a patient in Devon with LHON, an NHS England spokesperson is quoted as saying:
"We've carefully reviewed the evidence prepared by NICE to treat visual impairment in people with LHON. We've concluded that there's currently not enough evidence to consider making the treatment available, but it is open for a patient's doctor to ask for a review of the policy."
There is a growing body of evidence for the efficacy of the drug in slowing the progression of the condition, with support from Professor Yu Wai Man. There is currently a petition collecting signatures for the decision by NHS England to be reviewed.
In just two weeks, the family crowd-funded the £3,000 required to buy Tom a two-year supply of Idebenone from America, something that still brings Derrolyn almost to tears just thinking about.
The family are no strangers to rallying round and raising awareness and funds to support research into the condition. ‘Chloe’s Fight for Sight’ was set up soon after her diagnosis and has raised about £19,000, with funds for Chloe’s welfare but also for research into LHON and related conditions.
Taking part in research
Early diagnosis and access to treatment is fundamental to a LHON patient’s prospects. Idebenone was only a talking point back in 2011 but through research, something Chloe has taken part in at every opportunity, it has progressed to a viable therapeutic intervention that Tom is now able to access, albeit currently at great expense.
Tom added:
“I know it is down to those before me, people like Chloe, and everyone who helped fundraise for Chloe’s Fight for Sight, that I am in the ‘lucky’ position of having something like Idebenone available to help me.”
Chloe joined the Inherited Optic Neuropathies patient cohort at the NIHR Rare Diseases BioResource in 2018, via her clinician at Moorfields Eye Hospital, one of 18 BioResource Centres across England. Derrolyn has been a BioResource volunteer since 2016 and Tom signed consent forms to join the BioResource after our interview last week and before meeting Professor Yu Wai Man in Cambridge for a check-up. We’ve subsequently heard from the family some excellent news from that check-up regarding progress of Idebenone in treating Tom’s vision.
Support networks
Chloe is visibly emotional when talking about the role of her family in accepting and now embracing her blindness.
“I’ve only become who am I today because of the support of my family, and the time that has passed. I’ve had a wonderful support system. My family are incredible, and I don’t think I’d be the way I am if I didn’t have them.”
The LHON Society – a registered charity and patient-led support group for patients, family members and medical professionals – also provided Chloe and her family with advice, understanding and a sense of community after her diagnosis.
Chloe added:
“Before we knew of them and actually knew other people with the condition, I felt very alone. I don't know anyone else that's got this condition. I can't speak to someone else and ask ‘oh, how are you getting on with it?’”
Chloe and Tom both feel acutely aware of the stigma that exists for people with hidden disabilities. By their own admission, they don’t look blind.
Chloe explains some of her frustrations, and her hopes for the future:
“It’s a visual impairment but you’re still a person. You’re the same person within. People talk to my mum when they hear I am blind. I can understand. Talk to both of us!
“I’d love them to find it, cure it, and nobody else to go through it.”
The road ahead
Annual awareness days, getting their story out there - it’s all helping to educate the public on the reality of daily life for people living with a visual impairment, and the need for research to continue at pace.
With Tom’s diagnosis, he has been invited to also join the RNA project as a LHON patient, with Derrolyn, as a carrier, also set to take part this year. It is valuable to have relatives taking part in rare disease research to further our understanding of the genetic variations contributing to the onset and progression of inherited conditions such as LHON and many others like it.
Derrolyn knows patience is required:
“We feel change is coming, but it takes time. Research takes time, and funding!”
We are incredibly grateful to the whole family for spending their morning talking to us. There is no greater motivation to press on with the research we are doing at the NIHR BioResource and with our partners to further our understanding of the links between our genes, the environment, health and disease. Without research volunteers such as Chloe, Tom, Derrolyn and the hundreds of thousands like them at the BioResource, research cannot take place.
Professor Yu Wai Man added:
“We are very fortunate to have access to the Rare Disease BioResource in this country. By capitalising on this unique resource, we are recruiting participants with genetic eyes diseases and using the latest technology to give us a clearer insight into how genetic changes can affect different parts of the eye and cause visual loss.”
To sign the petition calling for Idebenone to be made available on the NHS in England, visit change.org.
The LHON Society can provide support for patients, families and researchers in Leber Hereditary Optic Neuropathy.
Find out more about the newly published second Rare Diseases Action Plan for England, which features two NIHR BioResource case studies on how our work is supporting rare disease research: this story on our RNA project and a review of a collaboration between patient-group Ring20 Research and Support UK, Illumina and the NIHR BioResource to understand ring chromosomes.
If you are interested in learning more about becoming an NIHR BioResource volunteer, please visit our website or get in contact on nbr@bioresource.nihr.ac.uk or call 0800 090 2233
If you are a researcher interested in working with us to facilitate your experimental research or early phase clinical trials, including provision of data, samples and recall from over 200,000 participants by genotype and or phenotype, please head to our website or contact us on nbr@bioresource.nihr.ac.uk
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