Cadasil disease, a rare vascular brain disease

Cadasil disease, a rare vascular brain disease

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Referred to by an acronym, CADASIL disease is a rare genetic disorder that affects the small blood vessels in the brain. Little known to the general public, this cerebrovascular disease was discovered by French doctors in 1993, which 24 years later earned them the greatest prize in neuroscience, the Brain Prize 2019. Professor Hugues Chabriat (Reference Center for rare vascular diseases of the central nervous system and the retina, Lariboisière Hospital, Paris), who participated in this discovery, describes the symptoms of CADASIL disease, reviews the origin of this pathology, and tells us how to diagnose it and how to care for the sick.

What is CADASIL disease?

A serious disease of the brain vessels

Cadasil disease is a rare and serious genetic disease which affects the tiny blood vessels in the brain. The term CADASIL is an acronym to designate this disease, indicates in the preamble Professor Hugues Chabriat. “In English, this means Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy.. And the specialist clarifies each of the terms:

  • “Cerebral arteriopathy” means that it is damage to the vessels that bring blood to the brain;
  • “Autosomal dominant” refers to the way in which this genetic disease is transmitted from one generation to the next: in this case, the children of an affected parent will have a one in two risk of inheriting the mutated gene responsible for the disease;
  • The term “Subcortical” means that the infarcts reach the deep areas of the brain, where the white matter and gray nuclei are located.
  • Finally, “leucoencéphalopathie“designates the type of most extensive lesions caused by Cadasil disease”.

We owe the discovery of Cadasil disease first to Professors Marie-Germaine Bousser and Elizabeth Tournier-Lasserve who described it for the first time in 1993. This first step made it possible to identify, three years later, the responsible gene, with Professor Anne Joutel, and to better understand, with Professor Hugues Chabriat, the entire clinical and brain imaging spectrum of the disease. The discovery of the gene then allowed the development of diagnostic tests and the development of mouse models used today to research treatment. All of this work was recognized around the world by awarding the four researchers with the Brain Prize in 2019 – a major international prize which rewards scientists for the importance of their research in neuroscience.

How many people suffer from this disease in Europe?

Cadasil disease is considered a rare disease because its prevalence is less than 1/2000. The number of people affected was initially estimated at around 1 to 3/100,000, or between 2000 and 7000 cases in Europe.but this prevalence could in reality be largely underestimated.. And Professor Chabriat added: “A Dutch study shows that the prevalence of the mutation responsible for Cadasil is actually close to 1/300 in the general population; and in England, a comparable study carried out using data from the United Kingdom biobank (around 500,000 individuals) estimated it to be around 1/400. It therefore seems that the NOCHT3 genetic mutation is very common but that Cadasil disease with its suite of symptoms is rare. This would depend on the location of the mutation on the NOCHT3 gene but also on other factors, possibly genetic, which still remain unknown today..

Who can get Cadasil disease?

There is no particular profile of people affected by Cadasil disease: everyone can therefore be affected, both women and men, provided they inherit the disease. genetic mutation responsible for the disease. Since the transmission of the mutated gene is autosomal dominant, the children of a person carrying this gene have a 50% risk of inheriting it.

What causes CADASIL disease?

Cadasil disease is caused by a mutation in the NOTCH3 gene, carried on chromosome 19.”This gene encodes the NOCHT3 protein, a receptor on the surface of contractile cells present in the wall of small cerebral blood vessels, arterioles and capillaries.“, specifies Professor Chabriat. This genetic mutation leads to an abnormal thickening of the walls of the arterioles and capillaries of the brain (vessels whose diameter is less than 500µ) and an alteration of their tone, thus reducing blood flow to certain parts of the brain .

This poor irrigation causes lesions in the white matter, an area located deep in the brain, composed of axons surrounded by a myelin sheath of neurons – these “cables” which ensure the rapid propagation of information in the system nervous, in the form of an electrical signal. In summary, “Cadasil disease results from the accumulation of fragments of the NOTCH3 protein in the wall of small vessels, this accumulation leads to the death of muscle cells in the wall, which causes their loss of elasticity and tone; ultimately, the blood pressure is weakened and no longer allows the blood to be brought to the end..

What are the symptoms of CADASIL disease?

If the disease is present from birth, the first symptoms, which correspond to lesions of the white matter, appear in adulthood, between 20 and 35 years old. Symptoms which vary greatly from one person to another, both in their presentation and in their severity or in the age of their onset. “The particularity of people suffering from Cadasil disease is that they do not necessarily presenthigh blood pressure ni de diabetestwo major risk factors for stroke and heart attack.specifies Professor Chabriat.

Migraine attacks with aura, first symptoms of Cadasil disease

The first symptoms of Cadasil disease generally appear between the ages of 20 and 40, and manifest in the form of migraine with aura in a third to half of patients. These are acute, intense headaches, often predominating on one side of the head, sometimes accompanied by nausea and vomiting and intolerance to noise and light.

These headaches can be very severe. They are always preceded for 20 to 30 minutes by abnormal sensations, always regressive (most often visual disturbances but also sometimes temporary disturbances in the sensitivity or motor skills of a part of the body, language disturbances, balance disturbances) which we call “auras”. Their frequency varies extremely from one patient to another, ranging from two episodes per week to one every 3 or 4 years, we can read on the Orphanet website. They can be very painful. However, these migraine attacks with aura are very rare after the age of 50.

Behavioral disorders followed by cognitive decline

As the disease progresses, the accumulation of small infarcts in the brain can cause strokes around the age of 50-60. These strokes are manifested by various symptoms whose sudden appearance should alert and lead to urgent consultation: paralysis of one side of the body (hemiplegia), difficulty speaking, visual disturbances, loss of sensitivity of a part of the body. .”Most of the time, patients recover. But the accumulation of brain damage ends up causing irreversible cognitive and motor disorders around the age of 70., indicates Professor Chabriat. These cognitive disorders result in problems with concentration, attention, or memory problems of varying importance. People affected often have difficulty organizing an activity, planning things, taking initiatives… “This common symptom of Cadasil’s disease is called apathy: the patient finds it impossible to achieve a goal by himself, he necessarily needs to receive an order. This symptom is particularly confusing and poorly experienced by those around you.”specifies the neurologist.

This cognitive decline is often associated with motor disorders characterized by loss of balance, slow walking, and falls. In approximately 20% of cases, patients may also have neuropsychiatric disorders such as severe depression, irritability, and in some cases, manic episodes – these neuropsychiatric disorders could be favored by the accumulation of substance damage. cerebral white.

How does CADASIL disease progress?

Increasingly severe cognitive disorders

Gradually, cognitive disorders become more and more severe, particularly memory disorders, and can progress to dementia, leading to a loss of autonomy which considerably alters the lives of patients. “In the terminal stage of Cadasil disease, patients are demented, bedridden and paralyzed., describes Professor Chabriat. The neurologist points out, however, that there is great variability in the clinical presentation of the disease and that it evolves over several decades: “It can be serious from the start or only in old age. Some patients only have migraines with aura and…