Fatal familial insomnia: causes, symptoms and treatment.

We review the characteristics of this serious neurodegenerative disease.

Not all forms of insomnia are psychologically caused. Fatal Familial Insomnia is far from resembling a typical sleep disorder.. It is a neurodegenerative prion disease, which, as the name implies, is genetically transmitted and ends with the death of the patient in a relatively short period of time, usually lasting less than two years.

Fortunately, it is not a frequent disease, but as soon as it appears it is synonymous with lethality.. It is one of the few diseases known to end life through sleep deprivation, which is why it is so fascinating to neurologists.

What is fatal familial insomnia?

Fatal familial insomnia is an autosomal dominant hereditary prion disease.. A mutation in the PRNP gene on chromosome 20 results in an overproduction of prion proteins, which accumulate and have the ability to convert other proteins into prions, leading to neurodegeneration in the area where they are located.

Localization of the lesions

The main neuropathological manifestation found in fatal familial insomnia is degeneration of the thalamus, which is responsible for sleep, with selective involvement in the ventral anterior and dorsal medial region of the thalamic nucleus. In addition, there is involvement of the olivary nucleus and changes in the cerebellum, as well as spongiform changes in the cerebral cortex. The most affected areas of the cortex are mainly frontal, parietal and temporal.

There is no clear relationship between neuronal dysfunction and prion distribution.. Moreover, even the number of prions is not indicative of the degree of disease severity or neuronal death. All patients show similar levels of prions in the thalamus and subcortical structures. Only in those in whom the disease has progressed sufficiently we find prions in the cortex to the extent that there is a higher concentration than in the inner areas of the brain.

Given these data, two hypotheses arise: either prions are not toxic and only appear at the same time as the disease and what causes neuronal death is the mutation of the PRNP gene, or prions are toxic but the different brain tissues have different degrees of resistance to this toxicity. Be that as it may, we know that the neurons of these patients do not simply die, but undergo apoptosis, i.e. they program their own death guided by a signal.

How does it manifest itself? Frequent symptoms

It is a disease that usually manifests itself around the age of 50. Its onset is abrupt and continues to progress until it causes the death of the patient. The sufferer begins to lose the ability to fall asleep. Not in the same way as insomniacs, who due to psychophysiological factors may sleep little or poorly. It is an absolute inability to fall asleep or to do so in an extremely superficial way..

The disease progresses to hallucinations, alterations of the autonomic nervous system such as tachycardia, hypertension, hyperhidrosis and hyperthermia, an increase in the levels of catecholamines in the brain, cognitive changes such as attentional and short-term memory problems, ataxia and endocrine manifestations.

Does insomnia cause death?

The exact cause of death in fatal familial insomnia is unknown.. Although any neurodegenerative process ends in death, it is possible that in this disease death comes earlier due to the deregulation of other functions due to insomnia.

We know that sleep is a fundamental part of health since it is restorative at a physical and psychic level, allowing the purification of toxins in the brain. In animals, for example, sleep deprivation over a long period causes death. Thus, it is possible that the insomnia of this disease, if not the direct cause of death, probably influences the rapid worsening of brain structures. Thus, an intervention aimed directly at alleviating insomnia may greatly extend the life expectancy of someone with fatal familial insomnia.

Sleep in fatal familial insomnia

In some cases, insomnia itself does not occur. Instead, sleep can be impaired in its architecture when we measure it through a polysomnogram, without the need for the patient to be unable to fall asleep. This patient's EEG shows predominantly delta wave activity, which is present during wakefulness, with brief instances of microsleeps in which slow waves and K-complexes, characteristic of stage 2 sleep, are triggered.

The observed rhythms are neither typical of someone awake nor of someone asleep, but look like someone who is in sleep.The rhythms observed are neither typical of someone awake nor asleep, but look like someone who is in limbo, halfway between one side and the other. As the disease progresses, microsleeps become less and less frequent, and the slow waves and K-complexes that mark these periods of rest progressively disappear.

There is less and less metabolic activity in the thalamus, epileptic seizures begin to occur, autonomic system disturbances worsen and cortisol levels increase. Finally, the production of growth hormone, produced during the night, which allows the body to inhibit glucose utilization, is stopped, causing the rapid Weight loss and premature aging characteristic of the disease.

Treatment

For the time being, only symptomatological treatments are available, i.e. treatments that attack the symptomatology, but do not stop the cause of the disease.but do not stop the cause of neuronal deterioration. In fact, in many cases the treatment is not even symptomatic, but palliative. Worse still, patients with fatal familial insomnia respond poorly to conventional hypnotics and sedatives. In order to enable these people to sleep, a drug that stimulates slow-wave sleep is needed.

Apparently some drugs still under investigation seem to be able to do this, although they have not been tested in people with thalamic damage, only in normal insomniac patients. To date all attempts to find an effective drug or drug cocktail have been in a trial-and-error context. More clinical trials with compounds specifically targeted to induce sleep are needed taking into account the barriers posed by thalamic impairment.