Fatal familial insomnia: symptom, cause, what is it?

Definition: what is fatal familial insomnia?

Fatal familial insomnia is a rare prion disease. “It’s a hereditary and genetic disease, linked to an anomaly of the PRNP gene, says Professor Christine Tranchant, neurologist at the Strasbourg University Hospital and specialist in rare prion genetic diseases. VShe gene codes for a protein called the prions. We have diseases affecting the prion, but which are not genetic. We are then talking about sporadic pathologyas the Creutzfeldt-Jakob disease. Others, such as fatal familial insomnia, are of genetic origin, linked to a mutation of the PRNP gene. The role of the prion protein is still poorly understood, but it is said to be ubiquitous. It is omnipresent in the organic environments (tissues, cells) of our body. She would have a role in the cell renewal of neural cells, essential for the development of the central nervous system. As a reminder, this system regulates many functions, such as the movement, memory, speech, thoughts and perception. Proteins are normally soluble in cell fluid. But in certain circumstances, when the prion protein has an abnormal conformation, it loses its solubility. “It aggregates and deposits at the level of certain cells, which promotes the degeneration and death of neuronal cells.explains Professor Tranchant.

How many cases in France?

Fatal familial insomnia is an exceptional disease. “In 2003, 27 families were known in the world. In France, maybe 2 or 3 families are affected”. The prevalence of rare prion diseases is less than 1 case per 1,000,000, “of which fatal familial insomnia represents only a very small proportion“. According to Inserm, every year in France, 100 to 150 cases of prion diseases are diagnosed, knowing that Creutzfeldt-Jakob disease accounts for 85% of cases. The average age of patients with fatal familial insomnia is 50 years. “The disease can occur earlier or later, between the ages of 20 and 61, with an average age of 50“, continues Dr. Catherine Tranchant.

What are the symptoms ?

We call it Fatal Familial Insomnia because:

• insomnia is the first and main symptom. It is very severe, since it involves a disappearance of the circadian cycles, regulating the biological rhythm of the body;
• Fatal : death is inevitable and occurs between 9 and 30 months after the declaration of the disease;
• family : she is hereditarytransmitted by one of the parents.

“Insomnia gradually sets in until it becomes disabling. It’s not just difficulty falling asleep: it’s a gradual loss of sleep. Moreover, we realize during the sleep recording examination that he is totally disorganized. 3 days of insomnia or chronic insomnia does not mean that one suffers from fatal insomnia.“, details the specialist. The picture of fatal familial insomnia is more complex“. Following this total disorganization of sleep, dysautonomic disorders set in. The autonomic nervous system is affected, followed by:

• Change in heart rate;
• Excessive sweating;
• Increased blood pressure;
• Weightloss.

“These disorders are fairly constant during the course of the disease and this clinical picture sets in gradually”. Cognitive functions are impaired, causing memory and attention problems that affect the daily life of the patient. “There confusion is also present, sometimes with hallucinations. In some patients, motor and balance disorders appear.” The patient loses his autonomy, he becomes bedridden. His condition worsened over the months. Mobility and contact with the environment decrease until they disappear. The disease is fatal, “after a period of insomnia, the patient falls into a form of coma, as in other rare prion diseases, due to significant damage to the structure of the central nervous system.” In summary, fatal familial insomnia evolves in 3 main stages:
► Rapid appearance of a insomnia that worsens over a few months, sometimes accompanied by psychiatric disorders (anxiety, hallucinations, etc.);
► Obvious presence of dysautonomic signs;
► Last stage of the disease: rapid onset of cognitive disordersthe patient is unable to speak, to walk (akinetic mutism), then falls into the coma leading to death.

You can get tested to find out your genetic status

What are the causes of fatal familial insomnia?

Familial insomnia is a autosomal dominant genetic disease. “It is enough for a parent to be a carrier of the anomaly to risk transmitting it to their child. Each individual has two copies of each gene: one copy comes from the father and another from the mother. If one of the two genes is abnormal, there is a risk of developing the disease. In other words, each time the parent concerned has a child, he transmits half of his genetic heritage to him: he has a 50% risk of transmitting the abnormal gene and a 50% chance of transmitting the healthy gene.“, explains Professor Tranchant. As for the origin of the anomaly in the gene encoding the prion protein remains unknown to this day.

What are the treatments ?

► The diagnostic is essential. First, the diagnosis must be confirmed by a sleep recording, to highlight his disappearance. In the event of very suggestive symptoms or strong arguments (case of fatal family insomnia already known in the family), a genetic analysis is carried out. “In most cases, the MRI is normal and shows no specific signs. Sometimes, the electroencephalogram guides this diagnosis.
► The palliative treatment. “We don’t have medicine for fatal familial insomnia and we don’t prescribe sleeping pills because they are ineffective. The treatment is mainly palliative. In case of confusion or agitation, we can help the patient. In case of swallowing disorders, we place a gastric tube. We ensure that the patient remains adequately hydrated. Physiotherapy can also be offered. Anything that can improve patient comfort is set up by the healthcare team”.

Genetic counseling

Professor Cyril Goizet, clinical geneticist of the Reference Center for Rare “Neurogenetic” Diseases of the Bordeaux University Hospital, specifies that he is “possible for the descendants of a person ill with get tested to find out their genetic status. This is the presymptomatic test, which is part of the bioethics law which governs predictive medicine. The presymptomatic test protocol is quite cumbersome and includes numerous support and preparation meetings with a multidisciplinary team. At a minimum, at the Bordeaux University Hospital we use the skills of 4 different professionals (neurogeneticist, psychologist, psychiatrist, genetic counsellor). The objective is not to say yes or no to the patient to perform the test, but to say yes, in good conditions. Fatal familial insomnia is already a heavy pathology, and we do not want to add difficulties to the patient”. Patients must be adults. The test is carried out in genetic services by teams that must be declared to the Biomedicine Agency. “The benefit is not medical, but it can be psychological, family, related to a design project, or even social. It is then possible, for those who have inherited the family transfer, to have preventive approaches for future pregnancies, through prenatal diagnosis or preimplantation diagnosis, offering the technological possibility of stopping the transmission of fatal familial insomnia”.

► As Professor Goizet points out, the first choice is prenatal diagnosis. Embryonic cells are collected and then analyzed. If the mutation is present, termination of pregnancy for medical reasons can be offered. If the mutation is absent, the pregnancy continues.

► Pre-implantation diagnosis is the second possibility. “Pregnancy goes through MAP with IVF. We take 1 or 2 cells from the embryo to do the genetic test. If it does not carry the anomaly, the embryo is reimplanted into the mother’s uterus. This protocol represents enormous constraints, but it makes it possible to avoid resorting to voluntary termination of pregnancy. The success rate of this technique is around 25%.

Thanks to Professor Christine Tranchant, neurologist at the Strasbourg University Hospital and specialist in rare prion genetic diseases, and Professor Cyril Goizet, clinical geneticist at the Reference Center for Rare “Neurogenetic” Diseases at the Bordeaux University Hospital.