Fatal Familial Insomnia (FFI)

Inside the gloomy world of people who cannot sleep

Not long ago, I came across a short story. Many of us will be familiar with the plot. A wealthy man, two wives, the usual rivalry, a promising first son, then the death of the first wife after several mysterious symptoms. After a few years, the first son developed the same symptoms. The doctors didn’t know what was wrong and he died a couple of years later. Accusations flew; the second wife must have been the culprit, the witch. She was cast out of her home and eventually, she committed suicide. Several years later, a relative of the late first wife spoke about a sort of family curse that rendered the victims unable to sleep. The late wife’s mother had died the same way. Research began and the true culprit was found; Fatal Familial Insomnia. Remorse, but it was too late. This story prompted me to research this rare disease and share what I found.

What is FFI?

Fatal familial insomnia is a rare neurodegenerative genetic disorder. FFI is part of a group of rare diseases called prion disorders which affect around 1 in 1 million people around the world each year. Generally, prion disorders are characterised by long incubation periods and short clinical duration. This means that the abnormal prions may accumulate for years without causing symptoms, but once symptoms appear, the disorder rapidly worsens.

Symptoms

Fatal familial insomnia affects the thalamus, the brain structure that controls many important activities including emotional expression and sleep. Consequently, the disease is characterised by insomnia and brain damage which worsens with time. While insomnia is the major symptom, FFI can cause a wide range of other symptoms including muscle spasms, problems with thinking and memory, and vivid dreams. The characteristic lack of sleep can cause other symptoms such as sweating, fever, high blood pressure, rapid heart rate, weight loss, loss of temperature control, slurred speech, double or jerky vision, anxiety disorders, trouble with swallowing(dysphagia), lack of coordination and rapidly progressing dementia. Miosis (pinpoint pupils), sudden entrance into menopause for women and impotence for men may also occur. People with severe symptoms may succumb to a coma which eventually leads to death. Symptoms usually appear around middle age but could appear earlier or later than that.

Cause

FFI develops due to an abnormal mutation of the prion-related protein (PRNP) gene which produces prion proteins.  While research has made it clear that these proteins are active in the brain, their exact function remains unknown. Mutation causes PRNP to produce misfolded prion proteins. These misfolded proteins harm the nervous system and brain, particularly the thalamus, the region of the brain that plays a role in regulating sleep, appetite and body temperature.  A build-up of the misfolded proteins in the thalamus results in progressive destruction of nerve cells (neurons), causing symptoms to develop and become increasingly severe. Because fatal familial insomnia is so rare, there is little information available about its risk factors. The risk of passing the abnormal gene from affected parent to offspring is 50%.

Diagnosis

The patient is asked to monitor his sleeping habits for a period of time. Polysomnography (a sleep study) may be used to monitor the various sleep stages, brain activity, heart rate, respiration and eye or leg movements while asleep. This helps to rule out any other causes of sleep problems such as sleep apnea and narcolepsy. If FFI is suspected, a PET scan may be used to detect abnormalities in the activity of the thalamus. Molecular genetic testing which can detect the abnormal variant in the PRNP gene is then used to confirm the diagnosis. Unfortunately, fatal familial insomnia is so rare that doctors may not be able to detect it in every case. Some patients with the disorder may receive a diagnosis of a more common condition, such as dementia.

Treatment

There is currently no cure or effective treatment for fatal familial insomnia. Symptoms are treated as they appear. Sleep medications may provide temporary relief but they do not work in the long term. Treatment may require the coordinated efforts of a team of specialists; neurologists, psychiatrists, psychologists, pain specialists, social workers and other healthcare professionals. Psychosocial support is also necessary for the family of the patient. Due to the rarity of the disease, there are no treatment trials that have been tested on a large group of people. However, researchers are actively working toward effective treatments and preventive measures. A 2016 animal study suggests that immunotherapy may help, but additional research and human studies are required. There is an ongoing human study involving the use of doxycycline, an antibiotic that may be an effective way to prevent FFI in people who carry the genetic mutation that causes it.

Life expectancy and outlook

Symptoms often appear around middle age although they can appear earlier or later than that. The symptoms are mild at first and may not impact daily activities. As insomnia worsens and other symptoms appear, daily activities may become challenging. During the later stages of the illness, the patient may require regular care. Death usually occurs between six to thirty-six months from onset of the symptoms

Conclusion

Fatal familial disorder is a very rare genetic disease. It causes sleep problems and brain damage together with other symptoms that becomes increasingly severe and lead to death. There is currently no cure for the disease but symptoms are treated as they appear. Patients with familial insomnia tend to live between six months to three years after the appearance of the symptoms.

A’isha Ibrahim
Preclinical Press