An upper arm that swells to twice its normal size. A stomach that inexplicably swells up causing colic pain, vomiting or diarrhoea. Or a life-threatening variant with severe swelling of the face, lips, tongue and larynx, bringing the risk of obstructed airways and death by suffocation.
This is how the mysterious and rare disease hereditary angioedema - a hereditary form of acute swelling - appears. The swelling happens because the patients lack a specific protein substance in their blood - called C1-inhibitor - which causes the blood vessels to leak fluid. When an attack that can happen daily, weekly or monthly occurs, patients must be quickly given the correct medicine, though they still face a dangerous and irksome way of life. Now, more than a half century after the first molecular details of the disease were described, there is pivotal new knowledge about the disease's biology:
"We have succeeded in identifying what takes place in the liver cells which produce the protein that the patients lack. This is the crucial first step towards having the ability to treat these patients with gene therapy, which is the interesting long-term perspective of our study," says Professor Jacob Giehm Mikkelsen from the Department of Biomedicine at Aarhus University, Denmark.
The research project documents that the hereditary genetic mutations which the patients have from one of their parents - and which express the C1-inhibitor protein - have a negative effect on the healthy gene from the other parent. Or, as it is put in the research article, which has just been published in JCI, the Journal of Clinical Investigation: Dominant negative SERPING1 variants cause intracellular retention of C1-inhibitor in hereditary angioedema.
"One of the mysteries about this disease has been the question of why the patients produce so little of the protein," says MSc Didde Haslund, who is a PhD student and the article's first author.
"Because with two hereditary genes - a defect from one of the parents and a normal one from the other - you would think that the production will be around half the normal dose. Yet these patients produce only 10-20 per cent of a normal level. But now we have, for the first time, an explanation at cellular level and this is crucial for the continuing work on gene therapy as a future treatment option," she says.
One of the difficulties related to the disease is that it only affects 1 in 10,000-50,000 people. This corresponds to fewer than 330 people in the whole of Scandinavia being diagnosed, which in turn has the unfortunate consequence that medical doctors regularly mistake it for allergy, even though allergy medicine has no effect in the event of an attack.
"The diagnosis is made with a blood test that measures the concentration and function of C1-inhibitor in the blood. However, this requires that the medical doctor is aware of the disease," says Jacob Giehm Mikkelsen as he directs attention to a thought-provoking aspect of researching a rare disease.
"You might sometimes think that with so few patients, perhaps we ought to concentrate on something that can help more people. But on the other hand, we actually have a national strategy for rare diseases, because as a whole this is a large patient group. The individual rare diseases don't affect many people but taken together there are between 30,000 and 50,000 Danes with rare diagnoses," he says.
Hereditary angioedema is characterised by attacks occurring suddenly and unexpectedly. They may be provoked by a range of factors ranging from physical exertion and other forms of physical stress to infections, hormonal factors and individual drugs.
Generally, the diagnosed patients are assigned to Odense University Hospital, as this is the national competence centre for treatment. It was also Anette Bygum, professor and research director at the hospital, who initially contacted Jacob Giehm Mikkelsen to hear more about the possibilities of gene therapy, thereby arousing his curiosity.
"For the whole team, Annette Bygum's enquiry turned out to be the beginning of a journey into a world that we who normally work on basic research are not part of on a daily basis. We have discussed our research with practitioners, presented the results for patients and international patient associations and shared our experiences with the medicinal industry. We were invited to join the club, and this has led to both an interdisciplinary project and a crucial research result," says Jacob Giehm Mikkelsen.