Overview of Fatal Familial Insomnia

Fatal familial insomnia is a hereditary sleep disorder that currently affects about 30 families throughout the world, making it extremely uncommon. Insomnia is a decreased ability to fall asleep or stay asleep, and it does tend to run in families. Fatal familial insomnia is characterized by a severely impaired ability to reach a state of deep sleep—it is accompanied by dementia, psychosis, abnormal movements, and alterations of physical functions such as heart rhythm.

Diagnostic sleep studies may show an altered pattern, and some brain imaging abnormalities may be identified with the disease. A genetic test can verify the condition. While there is no effective treatment that can reverse or prevent fatal familial insomnia, ongoing research may point to some progress in the future.

Symptoms

Symptoms of FFI generally begin at an average age of 56 (range 18 to 73 years). Despite the name, insomnia may not be the first symptom of the disease. Neuropsychiatric issues, movement problems, and physiological effects can be the earliest symptoms as well.

The symptoms of fatal familial insomnia include:

• Sleeping problems: Difficulty falling asleep and staying asleep are the hallmark features of this condition. This can result in daytime fatigue, irritability, and anxiety. Excessive physical movements or vocal noises may occur whenever a person with fatal familial insomnia falls asleep. When insomnia does occur, it usually comes on suddenly and steadily worsens over a period of a few months.
• Behavioral symptoms: Mental status and behavioral changes include inattention, impaired concentration and memory, confusion, and hallucinations, but overt dementia is rare or occurs late in the illness course.
• Movement disorder: Muscle twitching and erratic jerking movements often occur in fatal familial insomnia. These are called myoclonus. Ataxia (balance and coordination problems) and uncoordinated eye movements can develop. As the disease progresses, motor disturbances such as myoclonus, ataxia, parkinsonism, and spasticity can occur along with dysarthria and dysphagia. In the terminal stages of the disease, patients become unable to walk and talk.
• Autonomic dysfunction: The body regulates many physical functions through the autonomic nervous system, which is controlled by the brain. Autonomic dysregulation occurs with this condition, resulting in high blood pressure, hyperventilation (fast, shallow breathing), a rapid and irregular heart rhythm, increased sweating, and fevers or fluctuations in body temperature. In addition, patients develop a lack of appetite, which leads to weight loss. Impotence may develop due to erectile dysfunction.

The prognosis for fatal familial insomnia is not good. It is a rapidly fatal disease with a mean duration of 13 months.

Causes

This is usually a hereditary disease carried from parent to child through an autosomal dominant pattern. This means that a person who has one parent with the disease has a 50% chance of inheriting the genetic trait.

It can occur sporadically as well, which means that a person can develop the condition without having inherited it, although sporadic cases are even less common than familial cases.

Affected Areas of the Brain

Several regions of the brain are affected by fatal familial insomnia. The area most commonly affected is the thalamus, which moderates communication between different regions of the brain. It is believed that damage to the thalamus interferes with a person’s sleep-wake cycle, preventing progression past a sleep stage described as stage 1 sleep. This makes it impossible to achieve restful sleep.

The disease causes damage to the inferior olives in the medulla oblongata part of brain, which leads to the patient losing control of their muscles. Involvement of the cingulate cortex, an area near the middle of the cerebral cortex (the largest part of the brain, which controls planning and thinking), causes emotional, psychiatric, and cognitive (thinking) problems.

Fatal Familial Insomnia Is a Prion Disease

Fatal familial insomnia is a prion disease.

A prion is a protein called PrPc, and its function is not known. When it is folded in an abnormal shape, as in fatal familial insomnia, it is called PrPSc. These abnormal prions build up in several areas of the brain, and their presence is toxic, causing damage. Experts say that the toxic proteins may build up over years, and then suddenly cause symptoms when the brain’s functions become severely impaired.

Chromosomal Mutation

The abnormally folded prions of fatal familial insomnia are caused by a genetic mutation (abnormality) in the PRNP gene that codes for prion protein. This gene is located on chromosome 20 in codons 178 and 129.

Diagnosis

This disease causes symptoms that are very noticeable. Initially, however, it can be confused with conditions such as dementia, movement disorders, or psychosis. Eventually, the unusual combination of symptoms along with a family history point to fatal familial insomnia. Sleep studies and imaging tests may support the diagnosis, while genetic testing can confirm it.

There are a number of different tests you may undergo during your evaluation.

Polysomnography (Sleep Study)

You may have a sleep study if you complain of sleeping problems. This is a non-invasive test that uses electrodes to measure electrical brain activity during sleep. The electrodes are held into place on the scalp with adhesive. The brain’s electrical activity produces a pattern of brain waves that can be seen on a paper or a computer.

An unusual fluctuation between sleep stages may be seen in fatal familial insomnia. People with this condition tend to have a decrease in slow waves and sleep spindles, which are normally present during deep sleep. The brain waves may have an altered shape as well.

This study also measures breathing and muscle activity (of the arms and legs) during sleep. Normally, people have almost no muscle movement during certain deep stages of sleep, but with fatal familial insomnia, a pattern described as agrypnia excitita is present. This pattern involves a lack of deep sleep, unusual muscle movements, and excessive sounds during sleep. These movements and sounds can also be seen with video monitoring.

Brain Imaging

A brain computerized tomography (CT) is not generally helpful in identifying fatal familial insomnia. It may show some abnormalities, including atrophy, which is shrinking of the brain. However, this finding is not specific for fatal familial insomnia and is found with many neurological conditions, especially dementia.

Brain MRI in fatal familial insomnia can show signs of disease in many brain regions. These are described as white matter leukoencephalopathy, which is not specific to fatal familial insomnia and can occur with other conditions as well, including vascular dementia and encephalopathy (brain inflammation or infection).

Functional Brain Imaging

A type of brain imaging study called positron emission testing (PET) measures the activity of the brain. With fatal familial insomnia, PET can show evidence of decreased metabolism in the thalamus. However, this test is not standard and is not available in most hospitals. Furthermore, this abnormality may or may not be detected, and most health insurers do not typically cover PET scans.

Treatment

There is no effective treatment that can reverse the disease or stop it from progressing. Treatment is directed toward managing a patient's individual symptoms and may require the coordinated efforts of a team of specialists.

Medication to help reduce fevers and to maintain normal blood pressure, heart function and breathing may temporarily help stabilize vital signs and physical functions. Antipsychotics and medications used for movement disorders may be effective for a few days at a time. Vitamins B6, B12, iron, and folic acid may be used to help optimize well-being, and while it is not clear whether or not they work, they don’t appear to be harmful.

Typical strategies used for insomnia, such as sleeping pills and anti-anxiety medications, do not induce deep sleep because this disease causes damage to the mechanisms that allow deep sleep to occur in the brain.

Quinacrine, an anti-parasitic medication, was thought at one point to hold potential in treating fatal familial insomnia, but it was not effective and caused toxic side effects.

Ongoing Research

Current research in Italy involves the use of an antibiotic, doxycycline, as a preventative treatment. Previously, it has been suggested that doxycycline may have anti-prion effects. Researchers have reported that at least 10 participants over the age of 42 who carry the mutation are enrolled in the study. All of the participants are receiving the medication and undergoing frequent assessment for early symptoms. Preliminary results are due to be reported in about 10 years.

Antibodies against the abnormal prion have also been studied as a way to potentially immunize (vaccinate) against the disease. So far, this strategy has not been used in humans, and preliminary results in the laboratory setting are emerging.

A Word From Verywell

Fatal familial insomnia is a devastating disease. Not only does it cause death, but in the years following diagnosis, life is very difficult for a person who has the disease as well as for loved ones. If you or a loved one is diagnosed with fatal familial insomnia, it is crucial that you seek professional emotional and psychological help and support as you cope with this overwhelming condition.

If you decide that you want to learn about ongoing clinical trials or if you are considering participating in a clinical trial yourself, be sure to discuss your interest with your healthcare provider. You can also find information about trials on government websites, patient support groups, and by contacting universities.