Fatal Familial Insomnia

Condition 101

What is the definition of Fatal Familial Insomnia?

Fatal familial insomnia (FFI) is an inherited prion disease that mainly affects the thalamus. The thalamus is the part of the brain that controls the sleep-wake cycle, but is also known as the "relay center" of the brain because it helps the different parts of t ...

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What are the alternative names for Fatal Familial Insomnia?

  • Familial fatal insomnia
  • Insomnia familial fatal

What are the causes for Fatal Familial Insomnia?

Fatal familial insomnia (FFI) is a very rare form of genetic prion disease. In almost every case it is caused by a very specific mutation in the PRNP gene. This mutation causes the prion protein (PrP) that is made from this gene to be a different shape (fold incorrectly). Since the protein has a different shape, it cannot work correctly. 

The abnormally shaped PrP (prion protein) causes changes in the thalamus including the progressive loss of neurons (nerve cells). The thalamus relays messages between different parts of the brain. It manages our sleep/wake cycle; the flow of visual, auditory, and motor information; our sense of balance; how we experience pain; aspects of learning, memory, speech and understanding language; and even emotional experiences, expression, and our personalities. Losing neurons in the thalamus causes many of the symptoms of FFI because the thalamus can no longer do all of its jobs well.

Although the main target of FFI is the thalamus, other parts of the brain are affected as well including the inferior olives. The inferior olives are part of the medulla oblongata and are important for coordinating our movements (motor control). Losing neurons in the inferior olives can make it harder for a person to control their movements as seen in later stages of FFI. Medical researchers are still working to understand how the abnormally folded PrP causes the progressive changes in the thalamus and other affected brain areas.

In very rare cases of FFI, the cause is sporadic, meaning there is not a change in the PRNP gene. As of 2016, there have only been 24 reported cases of sporadic FFI. Sporadic FFI occurs when some of a person's normal PrP (prion protein) spontaneously changes into the abnormal shape which causes FFI, and then somehow changes the shape of PrP in other neurons in a chain reaction. 

What are the symptoms for Fatal Familial Insomnia?

The first symptoms of fatal familial insomnia (FFI) usually begin between the ages of 32 and 62 (mean average 51 years), but have been reported to begin as early as 18 to as late as 72. It is important to note that insomnia is not always the first symptom of FFI; sometimes the first symptom is progressive dementia. When insomnia begins, it usually comes on suddenly and steadily worsens over a period of a few months. Other symptoms may include panic attacks, phobias, weight loss, lack of appetite, and having a body temperature which is too low or too high (hypothermia; hyperthermia). Autonomic disorders such as high blood pressure, episodes of hyperventilation, excessive sweating and salivation, and/or erectile dysfunction may occur.

As the disease progresses, most people with FFI develop abnormal, uncoordinated movements (ataxia), hallucinations, severe confusion (delerium), and muscle twitches and jerks (myoclonus). Although the dementia may begin as forgetfulness and confusion, it leads eventually to the inability to walk and talk. Total inability to sleep is common towards the end of the course of the disease.

What are the current treatments for Fatal Familial Insomnia?

There is currently no cure for fatal familial insomnia (FFI) or treatment that can slow the disease progression. The management goal is to ease symptoms and keep the person with FFI as comfortable as possible. However research is ongoing and a number of potential treatments are being developed.

As of 2016, a number of treatments have had some success in slowing disease progression in animal models, including pentosan polysulfate, quinacrine (mepacrine), and amphotericin B. Sadly, the results have been less clear in clinical trials in humans. In Italy, a clinical trial trying to prevent symptoms in people known to have the genetic changes for FFI but have not yet developed symptoms is underway using doxyclycline. Most promisingly, several forms of immunotherapy have reported success. The three main research areas focus on antibody vaccines, dendritic cell vaccines, and adoptive transfer of physiological prion protein-specific CD4+ T-lymphocytes. More research is being done to study how well these treatments work (effectiveness) and if the treatments are safe, but medical researchers believe that these or similar immunotherapies may offer hope for those with FFI in the future.

What is the outlook (prognosis) for Fatal Familial Insomnia?

Presently, after symptoms of fatal familial insomnia (FFI) begin, the disease usually causes death within 12 to 18 months, with a range of a few months to several years. As research continues however, it is hoped a treatment or even a cure will be developed that will dramatically change the outlook for people who have FFI. 

Is Fatal Familial Insomnia an inherited disorder?

In most cases, a  person with fatal familial insomnia (FFI) has inherited the genetic change from a parent with FFI. In order to have FFI, a person only needs one copy of their PRNP gene to carry the specific genetic change (mutation) that causes FFI.  In other words, a person only needs to inherit the genetic change from one parent. In genetic terms, this is called autosomal dominant inheritance.  In rare cases, FFI may result from a new (de novo) change in the PRNP gene, however it is not known how often a new mutation is the cause of FFI. New mutations can happen during the making of the egg or the sperm.

A person that has the genetic change that causes FFI has a 50% chance with each pregnancy of passing along the changed gene to his or her child.

In the rare sporadic cases of FFI, the disease is not inherited from either parent and cannot be passed down to their children.

Data Source : GARD