Key Chronology

1976: Meeting of first patient by two researchers

Until 1976, the diagnosis of patients with CADASIL was attributed to other brain diseases such as multiple sclerosis, dementia, etc.

The discovery of the disease began in 1976 during hospitalization in the Neurology Department of “La Pitié Salpêtrière” Hospital in Paris of a patient aged 50, following a stroke (CVA) of unknown origin, despite with no previous cardiac risk factor.

The patient suffered of right hemiparesis (weakness of one side of the body) and dysarthria (motor speech disorder). The patient recovered quickly, but the brain scan was abnormal, showing multiple small deep infarcts and leukoencephalopathy of unidentified origin, later confirmed by MRI. The case intrigued researchers. This man died in 1995, suffering from a long period of dementia with pseudo bulbar symptoms (outburst of uncontrollable crying and laughing).

1986: Family hypothesis – Beginning of study

Ten years later, the daughter of the man sought treatment for ophthalmic migraines, transient ischemic attacks and a minor heart attack. She was then 35 years old. Her MRI looked exactly like that of her father. It pointed to a family pathology. The case began to captivate two female researchers: a neurologist, Marie-Germaine BOUSSER and a geneticist, Elisabeth Tournier-LASSERVE.

 At first, the genetic hypothesis was uncertain and the two researchers sought to prove the family origin of the disease.

They began the systematic study of this first large family from Loire Atlantique region (western France). Overall, fifty-seven members of this family agreed to be interviewed and examined by the researchers.

Their research led to a conclusion that the disease exhibited an autosomal dominant transmission mode. They also discovered that a cousin in this family suffered and died from Pick's disease. Her autopsy revealed that it was due to the same family illness. Under optical microscopy, the researchers observed a thickening of the wall of small vessels. Under electronic microscopy, they discovered a major alteration of the tissue media revealing the presence of unidentified deposits and serious lesions of vascular smooth muscle cells.

1993: Chromosome carrying the disease was identified

In 1993, the mutation was located on chromosome 19.

1996:  The gene was identified and the disease was named

In 1996, the NOTCH3 gene was identified as responsible for the disease. The disease was then named very descriptively by the acronym CADASIL (Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leucoencephalopathy) meaning it reaches the cerebral arteries, it is autosomal dominant and results in subcortical infarcts and leucoencephalopathy.

A genetic test was developed to insure an accurate diagnosis. The Neurology Department under Professor Bousser at Lariboisière hospital was in charge of clinical diagnosis of the disease. Genetic tests were performed by the laboratory of Professor Tournier-Lasserve. The collaboration between both researchers did not stop there. They continued to work together for better understanding of the disease. Many families were eventually diagnosed in France, then in Germany, England and the United States.

1999: Creation of the CADASIL France Association

See the link: "History of CADASIL Association".

2003: Launch of patients monitoring protocol

The objective of this protocol was to monitor 200 patients at the Lariboisière hospital for a period of three years for better understanding of the disease. In 2008, this study received a supplement budget to allow for an additional two years extension.

In parallel, the same monitoring program was being conducted in Germany.

Although this program had ended, the monitoring of patients, both old and new, is still carried on and the collected data is integrated into the CERVCO database created for this project. This work allows for better understanding the characteristics of the disease and predictive symptoms of aggravation. These data will be useful for future establishment of experimental treatment protocols.

2005: Drug treatment protocol

150 patients from different countries received Donepezil or placebo for a period of 18 weeks. The results were published in 2008. They showed no significant improvement for the majority of patients. 

2005: Establishment of CERVCO Reference Center

CERVCO, acronym for “CEntre de Référence des maladies Vasculaires rares du Cerveau et de l'Oeil” (Center of Reference for Rare Vascular Diseases of Brain and Eye), was set up in 2005 as part of the French Rare Diseases policy. Its missionis to improve care of patients andcollect data on the evolution of their illness with the goal of better understandingCADASIL.

2011:  Publication of CADASIL PNDS

The Haute Autorité de Santé (HAS) or French National Authority for Health has developed a National Protocol for Diagnosis and Treatment (PNDS- Protocole National de Diagnostic et de Soins) for CADASIL.

2012: Constitution of an international network

Thanks to a grant from the American Leducq Foundation, an international collaboration network links different research teams in Europe and the United States.

2013:  International conference

In commemoration of the 20th anniversary of the identification of chromosome carrier of CADASIL, a 2-days conference in Paris reunited Professor Bousser with many international experts to share their knowledge on the disease and build momentum for future research.

More than four hundred families affected by CADASIL are registered in Europe today, in addition to a few sporadic cases.

2015: Conference in Paris

Conference in Paris, 10 years after setting up the CERVCO, national reference center for CADASIL and a few other rare diseases affecting the brain or the eyes.

Thank you!  ♦