Mobile Menu

A well camouflaged zebra

For my undergraduate research project, I studied a rare neurological disease known as Landau-Kleffner Syndrome. It was then that I first came across the phrase – a diagnostic odyssey. In this context, ‘odyssey’ refers to the time from initial disease recognition to the final diagnosis for a patient. For me personally, I associate this word with how long and painful I found it to read Homer’s ‘The Odyssey’ when I was at school. I was only 14 at the time and until now, I hadn’t appreciated the true value of this story.

For those who don’t know, the story follows the Greek hero Odysseus and his journey home after the Trojan War. The war itself lasted ten years, but then Odysseus’ journey home lasted another ten years. During this time, Odysseus encounters many perils. In the context of rare diseases, this phrase for me personally is so apt. For many rare disease patients (and their families), the time to diagnosis is lengthy and emotionally draining. On top of being unwell, these patients face endless doctor appointments, endless hours of school/work lost, endless frustration and tears because they feel hopeless and alone. They are in a constant battle. A simple diagnosis, regardless of whether anything can be done to help, provides reassurance for these patients that their invisible is actually visible

Foal play

My auntie was first diagnosed with hypermobile-Ehlers-Danlos Syndrome (hEDS) – a rare connective tissue disorder – at 38. When she looks back at her childhood she realises now that all her pain was because she had this rare disease that she never knew existed. It gave her some clarity, it empowered her to play a more active role in her disease and it made her feel less isolated.

The only reason she found out about hEDS was because both my younger cousins presented with symptoms during childhood, and she fought tirelessly to get to the bottom of it. To this day, despite a diagnosis, she has to fight for recognition – not just for herself, but her children. hEDS, like many other rare diseases, often does not present with visible symptoms or the symptoms overlap with many other conditions. This not only impacts time to diagnosis, but it also impacts care once a diagnosis has been made. Management of rare diseases can often require multiple specialists due to the disorder’s pleiotropic effects. Consequently, the battle for people with rare diseases extends beyond diagnosis – in the fight for better coordinated care and against stigma. 

Black with white stripes, or white with black stripes

The zebra is often used as a symbol of rare diseases (and also EDS). It can represent different things to different people, but it emphasises the uniqueness of every rare disease. It also highlights to clinicians that sometimes clinical presentation isn’t always as simple as it seems. The rare disease community often hear the saying ‘when you hear hoofbeats sometimes it’s a zebra’.

Every rare disease is different. Some affect a few thousand people, whereas others can affect a couple – each with its own unique set of symptoms. Although individually rare, these disorders collectively pose a huge economic and emotional burden on society and families. In fact, there are over 7,000 KNOWN rare diseases, affecting over 400 million people worldwide. Shockingly, I recently read that for these 7,000 diseases, there are only treatments available for 5%.

Equus to happiness

Earlier this year, the UK Department of Health and Social Care released the Rare Diseases Framework which sets out the priorities for the next five years to help improve the lives of rare disease patients and their families. Despite the endless challenges that exist for the rare disease community, which are likely to be personal to each individual, below are just some of the key challenges and how they are currently being addressed.

Reducing time to diagnosis

Patients like my auntie can wait years for a diagnosis. In many circumstances, early detection can be the difference between life and death. The UK’s 100,000 Genomes Project emphasised the value of harnessing whole-genome sequencing (WGS) data to identify causative variants in individuals with rare diseases. One example of the value of these results was seen in a four-year old child named Jessica. The study found that Jessica had a mutation in the SLC2A1 gene which resulted in Glut1 deficiency syndrome (Jessica’s diagnosis). Fortunately, this syndrome can be treated with a ‘ketogenic diet’ that can help reduce the number of seizures patients experience. This study provided peace of mind for many families and will continue to benefit others with similar conditions going forward.

Elsewhere, there have been several efforts focussed on incorporating WGS into clinical care for critically ill infants and children. For example, the All-Wales Medical Genomics Service last year launched a new service known as WINGS which aims to provide rapid diagnostic testing for critically ill babies and children with unexplained rare disorders. Meanwhile, the team at Rady Children’s Hospital are also focussing on reducing the time-to-results of WGS and utilising this technology to rapidly diagnose infants and children in intensive care. Check out our recent interview with AWMGS where members of the team discussed their ground-breaking new service. Additionally, read more about Rady’s efforts with Stephen F. Kingsmore (President and CEO, Rady Children’s Hospital) who recently joined us at the Festival of Genomics and Biodata 2021 to discuss how Rady are harnessing whole-genome sequencing technologies.

While all of this is exciting, actually implementing these technologies into clinical practice – and making sure there is equity of access – is a different story. Continued research into how best to implement these technologies as well as efforts to reduce costs and make these technologies more accessible will be critical.

Raising awareness

A patients’ diagnostic odyssey entails multiple referrals with multiple physicians – who in many cases are equally as dumbfounded. Even after a diagnosis, many patients mainly interact with their GPs who often do not have a detailed understanding of the disorder (and often knowledge of the disorder across the world is limited in itself). Raising awareness of rare diseases is a multifaceted issue.

Many rare disease patients present with heterogenous clinical symptoms that overlap with many other genetic and non-genetic conditions. Therefore, for a physician to immediately diagnose a patient with a genetic disorder that affects potentially five people in the entire world is unrealistic. But then again, I don’t think that’s what rare disease patients expect. I think they want acknowledgement and not just to be dismissed. Educating the healthcare workforce on the complexities of disease is important but developing skills in sensitivity and communication are particularly relevant. Listening and actively engaging in these patients lives can have a massive impact on patients’ trust towards healthcare systems.

I recently spoke to Dr Edward Miller (Senior Education & Development Officer) and Dr Michelle Bishop (Education Development Lead) from Health Education England’s Genomics Education Programme, who are attempting to address this by providing a wide range of resources to help healthcare professionals identify and communicate about rare disease with their patients. In addition to containing expert advice, all their resources are extensively reviewed by patients and the public to help shape their structure. Additionally, the team use a multi-pronged approach to ensure the accessibility of their resources. For example, they have developed, in conjunction with the Royal College of General Practitioners (RCGP), a ‘Genomics toolkit’ which the RCGP have made available on their website. The programme also offers a range of other support, including funding a Master’s programme in Genomic Medicine for NHS professionals and various online learning activities and resources. This includes a range of short films that put into perspective the value of a genetic diagnosis as well as advice for healthcare professionals to recognise and appropriately refer suspected rare disease patients to relevant specialists. The team are continuously supporting the ongoing workforce transformation and align their work with the expanding services offered under NHS England. Dr Bishop explained that while most of their resources are proactive, they are working on generating reactive resources that will help healthcare professionals respond more appropriately to situations they may face.

But who knows more about rare diseases than the patients themselves? Patient voice, particularly for a community who often feel ignored, is vital. Many rare disease patients or family members of those with rare diseases, become activists and fundraisers to help raise awareness. A particularly inspirational individual is Jillian Hastings Ward, the Chair of the Participant Panel at Genomics England and a mother to a child with a very rare disease. Ward’s child joined the 100,000 Genomes Project in 2015 where her son was discovered to have a variant in the GRIN1 gene. At the time, only three articles were published that described this gene. Since then, Ward has connected with other GRIN children all around the world and set up the charity – CureGRIN Foundation – which is dedicated to improving the lives of patients with this gene disorder. This is just one example that demonstrates not just the power of genomics but the power of patient voices striving for change and recognition. Check out our interview with Jillian Hastings Ward as she discusses her experiences as well as her involvement with Genomics England.

I also recently spoke to Carolyn Brathwaite, a mother of a child with Ogden syndrome (a rare neurodevelopmental disorder) and advocate who helped set up the patient organisation for Ogden syndrome alongside other parents. Carolyn’s daughter underwent six years of extensive tests and referrals, during which she was offered the opportunity to participate in the pioneering Deciphering Developmental Disorders (DDD) study. Here, after over four years on the study, Carolyn’s daughter finally received a diagnosis – a mutation in the NAA10 gene. At the time, only one other girl was known in the literature to have this condition – all other cases were males who died in early infancy. Despite a diagnosis, Carolyn expressed that she feels more alone than ever. Like many rare diseases, Ogden syndrome affects less than 100 people in the world, making it hard for families to build a community and get support. Most importantly, lack of funding and awareness of these organisations can make families feel forgotten and despair that their children may never get the help they need.  

Better care

The ultimate aim of scientific research is to improve patient care and lives. While some people can go throughout life and rarely have to step foot inside a doctor’s office, rare disease patients do not have this luxury. Rare diseases coincide with multiple co-morbidities that need to be managed in the context of their specific disease. As discussed above, awareness of these extremely rare diseases amongst first line physicians is limited. As a result, care often falls short. Coordination of care is essential to ensure that these patients’ conditions are effectively managed and the burden on them is minimised. This will require healthcare professionals to work together to provide the best possible joined up and high-quality care.

As demonstrated by the ongoing COVID-19 pandemic, digital tools are becoming essential within care. Advances in technology and digital tools are allowing patients to access services remotely. It is also enabling specialists from across systems and the world to easily share information and discuss tailored care plans. This leads me onto the value of data sharing. Many rare diseases as the name suggests are rare – not just affecting thousands of people, but sometimes a few. Connecting these communities and enabling open data sharing can support the diagnosis of patients, recruitment into trials, the development of precision diagnostics and therapies, and clinical trial transparency. Patients are becoming increasingly involved in data sharing, including the ‘Your DNA, Your Say’ survey. This survey explored public perspectives about the international sharing of genomic and health-related data and identified public fears and issues regarding trust towards certain organisations. Involving patients and their families in these discussions will be important to help inform policy and build trust.

The ultimate goal is the development of effective therapies that can help improve and save lives. Currently, very few rare diseases have well established treatments. However, like in Jessica’s case, where they do exist, they can be life changing. Ensuring patients have access to expertise in the treatment and care of their rare disease where available is important. In addition, international collaboration and the support of researchers to better understand rare diseases will be key to develop new affordable treatments and to establish their clinical and cost effectiveness. Another key area of focus will be increasing availability of funding to rare disease groups to ensure that the vital research needed to find treatments can be conducted. Governments and industry leaders, in particular, will be key in this process. 

Razzle Dazzle them

Despite adversity, the rare disease community is truly amazing. The community is full of activists, campaigners and fundraisers who endure hardship daily. Rare disease research unfortunately continues to be hindered by lack of academic and commercial incentives and practical barriers involving small, geographically dispersed populations. These barriers lead to limited understanding of rare disease, delayed diagnosis and a lack of therapeutic options. Improving our understanding of rare disease and developing new therapies can only succeed through global collaboration. We must continue to raise awareness and incorporate patient voices in order to help policymakers and service providers when creating services for rare disease patients.

We often forget why we do research, why we attend conferences, why we write articles like this. It’s about the patient. Research has and will continue to change lives. Unfortunately, rare disease patients are often neglected within academia and industry. It is our duty to give these patients a voice and make sure that the benefits of genomics reach all patients, regardless of how many people it impacts.

I mentioned earlier the plight of Odysseus. I want to emphasise that this story is a myth. But the reality that patients with rare diseases experience is not. These patients and their families have to continuously fight for recognition and for fair care. Odysseus faced a gruelling ten-year journey to get home, so when he eventually revealed himself to his family again, he was finally able to be at peace.  

  • Unique –
  • National Organisation for Rare Disorders (NORD) –
  • Rare Disease UK –
  • SWAN UK –
  • Findacure –
  • Cambridge Rare Disease Network –
  • Medics 4 Rare Disease –
  • Rare Disease Day –

Image credit: By wirestock – freepik