It all started with the patient ‘Mr. C ‘. Read the whole story about the groundbreaking research that led to the discovery of CADASIL, the most common hereditary form of stroke. The four French scientists in charge of the research have just been awarded the world’s largest brain research award, The Brain Prize.
In 1976, a middle-aged man – ‘Mr C’ as he is known in scientific literature – was referred for neurological assessment at Salpêtrière Hospital in Paris.
The examination he underwent would prove to have vital consequences for medical science’s understanding of a specific type of recurrent strokes.
The neurologist who performed the examination was Professor Marie-Germaine Bousser. Together with three of her colleagues from Lariboisière Hospital – Hugues Chabriat, Anne Joutel and Elisabeth Tournier-Lasserve – Professor Bousser is receiving the 2019 Brain Prize.
The Brain Prize is the world’s largest and most prestigious prize for brain research and has been awarded by the Lundbeck Foundation for ground-breaking neuroscience research since 2011. The prize is accompanied by a monetary award of EUR 1 million – about DKK 7.5 million – and will be shared equally by the four French scientists.
Anders Björklund, Chair of the Lundbeck Foundation Selection Committee, explains that the prize should be considered as a recognition of the fact that, during more than 30 years of clinical and laboratory work, these four scientists ‘have produced scientific results with far-reaching consequences for our understanding of strokes and dementia disorders’.
The children were to come a few years later
When Marie-Germaine Bousser examined ‘Mr C’ in 1976, she discovered that he had suffered several minor strokes. He also suffered from migraine and showed clear signs of rapidly progressive dementia.
However, it was not yet clear what was wrong with ‘Mr C’ – his disease presentation did not fit any known diagnosis. The answer gradually began to dawn in 1985 when his children visited Marie-Germaine Bousser at Lariboisière Hospital. They had exactly the same symptoms and signs as their father presented nine years earlier.
It was immediately obvious to Professor Bousser that this had to be a hereditary disorder, as yet undescribed in scientific literature – and in collaboration with the three other Brain Prize winners, she began systematically to examine almost 50 members of Mr C’s family.
An underdiagnosed disease
As a result of the examination of this family, the four French researchers were the first to gain a scientific grasp of a broad range of the characteristics of Mr C’s disease. Among other things, they were able to prove:
* That the disease known as CADASIL is hereditary and attributable to mutations in the so-called NOTCH3 gene on chromosome 19.
*That carriers of this mutation will most certainly develop the disease – sooner or later.
*And that there is a 50% chance that carriers will pass the disease on to their children.
The mutation is characterised by an accumulation of protein in the walls of the small blood vessels. In CADASIL this occurs throughout the body, but the protein accumulation only produces pronounced symptoms in the brain, recurrent strokes – due to obliteration of the small vessels.
The “mini” strokes result in recurrent transient muscle weakness, numbness and impairment of coordination, and symptoms are often accompanied or preceeded by migraine with aura.
Patients will typically experience difficulties in concentration and develop depression, and in most cases also dementia.
CADASIL is the most prevalent hereditary disease of the cerebral small vessels. There is currently no treatment for this disease, which can lead to severe disability and premature death.
The prevalence is usually estimated to 2-5 per 100,000; that is between 120 and 300 CADASIL patients in Denmark.
‘But there’s much to suggest that CADASIL is underdiagnosed, and that the prevalence is higher than 2-5 cases per 100,000. There’s a tremendous need to strengthen this field of brain research, and this award for the four French scientists is very much a recognition of a pioneering achievement,’ says Dr Kim Krogsgaard, Director of The Brain Prize.
The first signs of CADASIL may appear as early as at 25 to 30 years of age, in the form of migraine. However, cognitive difficulties and dementia usually present at a later stage. Jørgen Erik Nielsen, professor of clinical neurology at Rigshospitalet, University of Copenhagen explains:
‘It’s important to understand that CADASIL is not just one disease. There are different clinical variants, all attributable to mutations in the NOTCH3 gene. Many families have their own ‘personal’ mutation and there are very pronounced clinical variations in terms of age at onset of the disease, symptoms and progression – both within a specific family and between families. However, the common denominator is that, in almost all cases, the disease results in significant cognitive impairment and dementia.’ Jørgen Erik Nielsen also believes that CADASIL is underdiagnosed.
Marie-Germaine Bousser, Hugues Chabriat, Anne Joutel and Elisabeth Tournier-Lasserve will receive The Brain Prize 2019 at a ceremony on 9 May at the Black Diamond in Copenhagen.
As part of the Brain Prize activities, prizewinners will participate at a number of events for Danish and international neuroscientists and university students during the coming year.