Fatal familial insomnia: what is it, causes, symptoms, treatment

What is Fatal Familial Insomnia?

Fatal familial insomnia - a rare genetic degenerative brain disease. It is characterized by an inability to sleep (insomnia), which may be mild at first, but gradually deteriorate, leading to significant physical and mental impairment. Affected people may also develop dysfunction of the autonomic nervous system, the part of the nervous system that controls involuntary or automatic body processes - processes that occur without human intervention, such as regulating body temperature, sweating, breathing, or regulating frequency heartbeat.

The specific symptoms observed depend on the part of the autonomic nervous system affected by the disease. In all cases, fatal familial insomnia is caused by an abnormal variant of a prion-related protein (PRPN), although sometimes the disorder occurs randomly, with no gene variant PRPN (sporadic fatal insomnia). Gene

PRNP regulates the production of human prion protein. Changes in this gene lead to the formation of an irregularly shaped prion protein that is toxic to the body.

In fatal familial insomnia, prions accumulate mainly in the thalamus of the brain. This leads to the progressive loss of nerve cells (neurons) and various symptoms associated with this disorder. There is no cure, but researchers are exploring ways to best treat and manage the disease.

The disease is classified as transmissible spongiform encephalopathy (TSE) or prion disease. Prion diseases are caused by the accumulation of misfolded prion proteins in the brain. Two other prion diseases Creutzfeldt-Jakob disease and Gerstmann-Straussler-Scheinker syndrome, can also result from gene variations PRNPalthough some prion diseases occur in the absence of genetic variation. Typically, prion disorders are characterized by long incubation periods and short clinical duration, which means that abnormal prions can accumulate over many years (long incubation period), but once symptoms begin, the disorder quickly worsens.

Signs and symptoms

The characteristic symptom of the disease is progressive insomnia. Insomnia often starts in middle age, but it can happen sooner or later in life. Insomnia may be mild at first, but then it gets worse, the sick person begins to sleep less and less. Insomnia usually starts suddenly and can quickly worsen over the next few months. When sleep is achieved, vivid dreams can occur. Lack of sleep leads to physical and mental deterioration, and the disease eventually progresses to coma and death.

Although insomnia is usually the first symptom, some people may have progressive dementia, which causes problems with thinking, cognition, memory, language, and behavior. Signs may be subtle initially and include:

• unintentional weight loss;
• forgetfulness;
• inattention;
• trouble concentrating;
• problems with speech.

Eventually, episodes of confusion or hallucinations occur.

Some patients may have double vision (diplopia) or abnormal sharp eye movements (nystagmus). There may be problems with swallowing (dysphagia) or slurred speech (dysarthria). Some people have trouble coordinating voluntary movements (ataxia) over time. Abnormal movements may also develop, including tremors or twitching, involuntary short-term (up to 0.1 s) contractions of certain muscles (myoclonus) or Parkinson's symptoms.

Additional symptoms often appear associated with dysfunction of the autonomic nervous system. Specific symptoms can vary from one person to another depending on the specific part of the autonomic nervous system. Common symptoms may include;

• fever;
• heart palpitations (tachycardia);
• high blood pressure (arterial hypertension);
• increased sweating (hyperhidrosis);
• increased production of tears;
• constipation;
• fluctuations in body temperature;
• sexual dysfunction, including erectile dysfunction.

Anxiety and depression are also common finds.

Causes

The disease is caused by an abnormal variant (gene mutation) of a gene PRNP. Genes provide instructions for making proteins that play important roles in many bodily functions. When a gene mutation occurs, the protein product may be defective, ineffective, missing, or overproducible. Depending on the function of a particular protein, it can affect many systems in the body, including the brain.

In rare cases, a change (variation) in a gene PRPN in people with fatal familial insomnia, it occurs spontaneously without a family history of the disorder. This is called de novo or new mutation. The gene changes only occur during the formation of an egg or sperm in a particular child, and no other family member will be affected. The disorder is usually not inherited or "carried" by a healthy parent. However, a person who has this de novo variant could pass on the variant gene to their offspring in an autosomal dominant manner.

Genetic diseases are defined by a combination of genes for a specific trait, which are found on chromosomes received from the father and mother. Dominant inherited disorders occur when only one copy of the abnormal gene is needed for the disorder to occur. The abnormal gene can be inherited from either parent, or it can be the result of a new mutation (gene change) in the affected person. The risk of passing the abnormal gene from the affected parent to the offspring is 50% with every pregnancy, regardless of the sex of the child.

Some people develop fatal insomnia without gene change PRPN. These individuals are said to have sporadic fatal insomnia, and although this is a nongenetic form of fatal familial insomnia, the underlying factor in its development is unknown. Thus, sporadic fatal insomnia occurs by chance, much less frequently than fatal insomnia.

PRNP the gene makes a protein called prion protein, or PrP. The exact function of PrP in the body is not fully understood. However, due to the gene variant, the PrP produced develops an abnormal three-dimensional shape, which is described simply as "incorrectly folded". Collapsed PrP is toxic to the body, especially to the cells of the nervous system. In disease, misfolded PrP is mainly found in the thalamus, a structure deep inside the brain, which helps regulate many bodily functions, including sleep, appetite, and temperature body. As misfolded PrP accumulates in the thalamus, it leads to progressive destruction of nerve cells (neurons), leading to symptoms of the disorder. Damage to the brain tissue may appear as spongy holes or slits when examined under a microscope.

The term "prion" was coined to refer to a "proteinaceous infectious agent" to explain the transmissible nature of prion diseases. Extensive research has shown that a prion is, in fact, an improperly folded PrP. However, it is important to know that fatal familial insomnia is not contagious in the traditional sense, as the only way transmitting prion disease to a healthy person - through direct exposure to diseased brain tissue, possibly by ingestion or injections. If a person without an underlying genetic defect develops prion disease, they are said to have an "acquired" form. For example, a variant of Creutzfeldt-Jakob disease originated in the United Kingdom when people ate prion-contaminated beef. A lesser known example is kuru. Kuru is an almost extinct prion disease that originated in the inhabitants of Papua New Guinea.

Affected populations

Fatal familial insomnia is an extremely rare condition. The exact frequency and prevalence of the disorder is unknown. The sporadic form of the disease, known as sporadic fatal insomnia, is extremely rare and has been reported in the medical literature in only two dozen people. Overall, prion disorders affect about 1 in 1,000,000 million people in the total population per year. It is believed that genetic prion diseases account for about 15% of all people with prion diseases. Because rare diseases are often misdiagnosed or misdiagnosed, it is difficult to determine their true frequency in the general population. The disease affects men and women equally. The average age at onset of the disease is 45-50 years, although the described disease occurs in adolescents and over the age of 70. The disease has been described in populations around the world.

Diagnostics

Diagnosis is based on the identification of characteristic symptoms, a detailed medical history, careful clinical evaluation, and a variety of specialized tests.

- Clinical testing and examination.

In some cases, molecular genetic testing can confirm the diagnosis. Molecular genetic testing can detect an abnormal variant in a gene PRPN, which is known to cause the disorder, but such testing is only available as a diagnostic service in specialized laboratories. In all cases of the disease, a pathological variant will be detected PRNP.

Polysomnography, also called sleep testing, can be performed on affected individuals to look for decreased sleep times and difficulties in getting through the various stages of sleep.

Positron emission tomography or PET scan is an advanced imaging technique useful in diagnosing fatal familial insomnia. PET scans create 3D images of metabolic activity brain and showing a decrease in activity in the thalamus (thalamic hypometabolism), as a characteristic peculiarity.

Other advanced imaging techniques include computed tomography (CT) and magnetic resonance imaging (MRI). CT scans are of no use in diagnosing prion diseases, while MRIs can show some abnormalities on scans. which can confirm prion disease, although its use in diagnosing fatal insomnia is not good enough characterized. However, MRI and CT scans can help rule out other conditions that may mimic prion disease.

Doctors may also run tests to detect the presence of the 14-3-3 protein. It is a normal protein made when nerve cells die. Sometimes, in people with fatal insomnia, levels of this protein are significantly elevated in the cerebrospinal fluid (CSF). CSF is a colorless fluid that surrounds the brain and spinal cord and provides them with protection and support. Elevated levels of 14-3-3 in CSF are not always found, and normal levels of this protein do not rule out disease. Tau protein is also frequently elevated in CSF in prion disease, although due to the rarity of fatal familial insomnia, the usefulness of tau testing in disease is not fully understood. More recently, a test called RTQuIC (second generation vibration-induced real-time conversion method) time), which helps detect low levels of prions in cerebrospinal fluid, is now used in diagnostics prion diseases

Standard treatments

There is no cure for fatal familial insomnia. Treatment focuses on treating the specific symptoms that each person experiences. Treatment may require the coordinated efforts of a team of specialists. Neurologists, psychiatrists, psychologists, pain specialists, social workers, and other health care providers may need systematic and comprehensive treatment planning. Psychosocial support for the entire family is also needed. Genetic counseling is recommended for affected individuals and their families.

There are no standardized treatment protocols or guidelines for sick people. Due to the rarity of the disease, there are no treatment trials that have been tested in a large group of patients. Various treatments have been described in the medical literature as part of individual cases or small groups of patients.

Symptomatic treatment includes anticonvulsant (antiepileptic) drugs to treat epilepsy or clonazepam for myoclonus therapy. Affected people may be advised to stop taking any medications that worsen confusion, memory, or insomnia.