Enabling faster diagnosis of rare diseases: Interview with HBA Support’s Rebecca Middleton

As global research and the understanding of genomics grows, the view on familial brain aneurysm syndrome continues to develop. Determining whether there is a genetic foundation to this rare disease can bring answers to the families affected by, and at risk of, this condition.

We speak with Rebecca Middleton, chief executive and founder of the Hereditary Brain Aneurysm (HBA) Support, and vice-chair of the participant panel at Genomics England in the second of a two-part interview on the work at HBA Support.

Globally, what are governments and healthcare systems doing to screen people who may be at risk for Hereditary Brain Aneurysm (HBA)?

When we launched HBA Support in 2022, we published our first piece of global research. Up until this point, people affected by HBA often found themselves trying to piece together information from multiple sources, which was difficult to understand and navigate. Our Targeted Literature Review (TLR), looked at hundreds of reports and sources to create an accessible and reliable single source of information on this rare disease. We looked at three core areas including ‘prevalence and incidence’, the ‘genomics’ of the disease and ‘national and international guidelines’.

We found there are few national and international guidelines available covering the management and treatment of HBA. This indicates that the current clinical approach may be variable. Where guidance is specific to HBA, it is mostly focused on the screening of high-risk individuals. Just seven guidelines suggested a screening test for asymptomatic individuals with two or more first-degree relatives with an intracranial aneurysm or who have suffered a brain aneurysm rupture and haemorrhage.

Only one specific guideline is available that considers treatment recommendations for those with the familial disease. There is evidence that people with the familial disease have a higher risk of rupture than those who suffer a sporadic intercranial aneurysm and may therefore require a more rigorous treatment regimen to avoid rupture from occurring. We’re also not aware of any research to better track and understand the natural history of the familial disease. 

Tailored guidelines would be valuable globally. We’re keen to explore this further, in addition to the screening advice available. We have seen many examples of patients who don’t follow the strict ‘two or more first-degree relatives’ pattern but there is a familial cluster that is worthy of exploration and possible screening. We want to explore the analytical approach to screening for this rare condition where the standard of evidence is not attainable as it is for common diseases. We would like to see the patient experience brought in and reflected and monitored through screening and surveillance pathways. It is only through a better understanding of the natural history and genomics foundations of the disease can we implement the right policy framework and support tailored care pathways for patients.

Given current technology, what more do you think can be done to improve diagnosis of HBA patients?

Simply put, we need greater awareness and more data. Awareness of the condition is critical, both in a clinical and community setting. The more the condition is understood, the better the possible outcomes for patients and their families. In some cases, we have seen this disease explained away as ‘bad luck’. As generations become more curious, they are putting together pieces of their family puzzle and asking valid questions about this hereditary condition.

According to information from NHS Scotland, 3% of adults in the UK have a brain aneurysm.   That means that unruptured brain aneurysms affect around 3,000 people in every 100,000. We do not know how many of these 3,000 have the familial disease and should be undergoing screening that could potentially save their lives.  But we do know this familial patient cohort is at a greater risk of a life-changing haemorrhage.

Studies have shown that individuals with a family history of brain aneurysms are more likely to have one themselves. However, no studies have reported the prevalence and incidence of familial disease within the general population. This data would give valuable insight into the predicted number of total individuals affected by the rare condition.

Globally, from our research, we found that if you have a strong family history of brain aneurysms there is a 2.3% to 29.4% chance of having an unruptured brain aneurysm, compared with 0.2% – 8.8% of the general population.

At the moment, screening and diagnosis of the familial disease are confirmed through MRI or CT scans and then through exploration of the family history to confirm the pattern. We hope eventually that a genetic test will be able to pick up the disease but first, we need to better understand the genetic foundations of the condition. Until then, we are reliant on investigations of family histories, often supported by dedicated genetic counsellors, and brain scans.

Global prevalence and incidence data at the moment are very limited. We’re talking to the NHS in England and its National Congenital Anomaly and Rare Disease Registration Service to better understand and explore how we can monitor the prevalence of this rare disease. With better data and tracking, we can learn more about its natural history, support more families, enable a faster diagnosis for patients and save lives – as well as better direct and enable much-needed scientific research.

Could you comment on the availability and future of genetic testing for HBA?

Through our research, we found that variants in more than 30 genes have been suggested to increase susceptibility to familial brain aneurysm development. Six of these genes, all involved in the blood vessel wall strength, were implicated in the familial disease across two or more studies: NOTCH3, CDKN2BAS, SOX17, ARHGEF17, ANGPTL6 and LOXL2.

Despite multiple genetic variants suggested to contribute to susceptibility, there is no ‘confirmed’ list of genetic candidates that cause the familial disease. Further research is needed to consolidate a list of genetic candidates and allow for genetic screening measures to be explored and developed. Eventually, these could identify high-risk individuals so that preventative treatments could be offered to avoid rupture and the catastrophic impact on individuals and their families.

How much impact will the availability of genetic screening have on the early diagnosis of those at risk and preventative measures?

Sadly, I know first-hand the devastating impact of familial brain aneurysm syndrome on individuals and their families.  I lost my mother and grandmother to brain aneurysms, and it has had a profound impact on my life.  I was diagnosed with an aneurysm and underwent successful surgery to treat it nearly five years ago. My daughters, when they are over 18, and my two young nieces will undergo regular brain scans, and the rounds of anxiety that accompany the screening, to look out for signs of this disease. In the future, with a genetic test, we can look for susceptibility and support individuals with better personalised care plans and pathways, reduce anxiety and do away with unneeded, costly brain scans.

With more research and funding, we can better understand the genetic foundations of the disease and save families and family members going through years of worry. This would be life-changing for family members and save considerable resources. Until that time, HBA Support is on hand to support those affected through a network of support and information to reduce fear and improve knowledge.

Hear more from Rebecca Middleton at the Cell and Gene Therapy Summit by the Economist Impact on 24-25 April 2023 in Brussels.

For more global data and analysis on the state of clinical NGS, explore our IVD Gateway solution.

IVD Gateway

The go-to source for tracking and understanding market size, share and trends in IVD. Granular break-out of data and comprehensive coverage of international and domestic suppliers’ brand share across Asia, Europe, Latin America and the Middle East.