What Is Fatal Familial Insomnia?

“Fatal Familial Insomnia”- the name probably does not strike a bell for most people, as it is an extremely rare condition affecting one in a million people. As the name suggests, it is a condition marked by progressive and chronic insomnia that eventually results in death. 

• Fatal Familial Insomnia is an extremely rare condition, affecting only 50 families worldwide.
• It is a neurodegenerative genetic disorder.
• The main symptom is progressive insomnia, which leads to coma and later death throughout the disease. 
• There is currently no cure; however, research is ongoing.

This condition is not caused by a virus, bacteria, or a typical disorder- a unique agent called a prion. Read on to learn more about prions, Fatal Familial Insomnia, and how it’s diagnosed, treated, and managed. 

Introduction

Fatal Familial Insomnia is a genetic autosomal dominant neurodegenerative prion disease. The autosomal dominant nature of inheritance is one where the disease is not passed down via the sex chromosomes, and even one faulty copy of the gene (out of two) is enough to express the condition.¹ 

A prion disease is one caused by a protein called a prion. This prion can cause other proteins present in the brain called prion proteins to fold abnormally, resulting in various diseases. For example, they may cause Fatal Familial Insomnia and Creutzfeldt-Jakob Disease (CJD).

The characteristic feature of this disorder is a chronic inability to sleep that progressively worsens. This is accompanied by other symptoms like hypertension, cognitive decline, physical and mental distress, and dysfunction of the nervous system regulating involuntary processes (for example sweating, breathing, or heart rate regulation). Fatal Familial Insomnia is abbreviated as FFI.

FFI is a rare disorder, with around 1 to 1.5 cases per one million people. The FFI causative allele is even rarer, as it has only been found in 50 families worldwide.¹ 

Causes

Fatal Familial Insomnia is caused by a mutation in the Prion Protein Gene, also known as the PRNP Gene. This mutation may be passed on by an inherited parent or be spontaneous. Due to the mutated PRNP Gene, the protein produced from the instructions given by this gene is faulty. This is called the Prion Protein or PrP. 

The exact function of this gene and protein is unknown at the moment. The mutation in the PRNP Gene causes an abnormal 3-D structure of the PrP that is described as a “misfolded protein”. This misfolded variation of the protein is harmful to the brain. 

As the misfolded toxic PrP builds up in regions of the brain, particularly the thalamus, the processes regulated by the thalamus suffer, including involuntary actions like temperature regulation, sleep, and appetite regulation. This also destroys neurons, leading to neurodegenerative action and loss of cognitive ability. 

Prion diseases are not usually contagious. The only way of spreading a prion disease to an otherwise healthy person is through direct exposure to infected brain tissue. 

In rarer variations of this already rare disorder, the genetic mutation occurs spontaneously and not in an inherited form. This form of fatal insomnia is known as a de novo variant of Fatal Familial Insomnia and can be passed down to children from that point onward.

There is also a non-genetic form of the condition with unknown inherited pattern. 

It is Sporadic Fatal Insomnia, and its trigger is unknown at the moment.³ 

Symptoms

Owning to the rarity of the condition, diagnosis of Fatal Familial Insomnia is not straightforward. The course of the disease after the onset of symptoms is 7 to 36 months. 

It should be noted that none of the symptoms by themselves are indicative of Fatal Familial Insomnia. Due to the rarity and drastic nature of the condition, common diagnosis should be ruled out first. It is much more likely for the average person to show some collection of symptoms listed here, like insomnia and variable blood pressure for other common conditions like stress.  The following symptoms are observed in patients interviewed for studies:

• Insomnia- A person suffering from Fatal Familial Insomnia faces a decrease in total sleep time. This lack of sleep grows as the disease progresses. A sleep history is essential for the general practitioner to form a pattern. Vivid dreaming during sleeping is common among patients.
• Another hallmark of the condition is autonomic dysfunction, also called dysautonomia- The inability of the body to perform involuntary activities properly. This includes high blood pressure, abnormal respiratory rate (tachypnoea), excessive sweating, and constipation of highly variable body temperature²
• Dysfunction relating to abnormal cranial nerves- This can include double vision in the early stages of the disease, progressing to speech abnormalities called dysarthria and difficulties in swallowing.
• Cognitive symptoms like delirium, abnormal thought processing, and short-term memory loss. However, intellectual capacity and behaviour remain normal in most patients, even in late Fatal Familial Insomnia. 
• Abnormal gait
• Depression or apathy as a side effect of insomnia¹ 

Progression

The main characteristic feature of FFI, progressive insomnia, usually shows onset during middle age, but it can also happen at other stages of life. Insomnia is mild at the beginning and progressively worsens over a few months to the point that an individual gets very little sleep. This lack of sleep is the principal reason behind the physical and mental deterioration and ultimately culminates in coma or death.³ 

The progressive insomnia may also be coupled with other progressive neurodegenerative symptoms like dementia. In the later stages, hallucinations may also occur. The progression of the disease takes an average of 18 months; however, it can last as little as 7 months or as long as 73 months. Sporadic Fatal Insomnia has a longer progression compared to Fatal Familial Insomnia. Four stages of the disorder have been marked by experts, as listed below:

1. Stage One (3-6 Months)

This is the onset of progressive insomnia. The overall amount of sleep reduces, and the little amount of sleep observed is often filled with vivid dreams. This phase also shows the onset of some psychological symptoms like paranoia and panic attacks.

2. Stage Two (5-9 Months)

Insomnia worsens and starts affecting other aspects of the person’s life. This predominantly affects the mood, and psychological conditions like anxiety and depression are observed due to the lack of sleep. Fatal Familial Insomnia starts affecting the nervous system at this stage and disrupts involuntary actions. For example, irregular heart rate, trouble regulating body temperature, and gait changes may be observed.

3. Stage Three (3 months)

The sleep cycle is severely damaged, and the patient struggles to get any sleep. 

4. Stage Four (6 months)

Neurodegenerative conditions like dementia, trouble speaking, and other conditions lead to coma and eventually death.⁴ 

Diagnosis

Scientists are developing clinical criteria for Fatal Familial Insomnia. It is a hard condition to identify based on only the symptoms, especially if there is no prior family history. As mentioned above, only 50 families in the world showcase Fatal Familial Insomnia. Doctors may recommend testing upon complaints of disrupted sleep, among other symptoms indicating neurodegeneracy.

Sleep Study or Polysomnography

This study tracks the sleep patterns of a patient, the duration of the REM period during sleep, the duration of the state of deep sleep, and brain activity levels. This can help to track patterns characteristic of Fatal Familial Insomnia or Sporadic Familial Insomnia.

Brain Scans and Imaging

Decreased activity in the thalamus region of the brain combined with atrophy in other regions of the brain may indicate Fatal Insomnia or other neurodegenerative conditions. 

Cerebrospinal Fluid (CSF) Analysis

Even though the most commonly analyzed features of CSF remain normal in patients with Fatal Familial Insomnia, certain abnormalities can act as indicators.⁴ 

Treatment and palliative care

As of now, Fatal Familial Insomnia and Sporadic Fatal Insomnia have no cures. Therefore, current treatments are focused on palliative care, providing relief to patients for the course of the disease till it culminates in death. These options are relief-focused and may vary with each person. These options include but are not limited to:

• Melatonin supplements- Melatonin is a sleep hormone, and certain dosages of melatonin may help to promote sleep in people suffering from FFI.
• Sedative use-certain sedatives may provide short-term relief for patients. Antianxiety drugs may also help. However, the effect of such medication differs from individual to individual.
• Gamma-Hydroxybutyrate- This is a drug that has prompted sleep in people suffering from Fatal Familial Insomnia. 
• Antipsychotic Drugs

Another important aspect is therapy for a person with a fatal familial insomnia diagnosis, as all the cases of this condition lead to death. A therapist can help the patient and their family process their emotions regarding the disease and learn to cope with strategies to support themselves and reduce the mental strain.⁴ 

Summary

Fatal Familial Insomnia is a rare inherited condition that affects 50 families worldwide and 1-1.5 people per million population. It is a condition that usually onsets in middle age and is fatal. The course of the disease is 18 months on average and culminates in death or coma. It is a neurodegenerative condition caused by a mutation in the PRNP Gene, which encodes Instructions for a protein called the Prion Protein or PrP. A faulty PrP protein is said to be misfolded and is toxic to the brain. It accumulates in the thalamus and is responsible for the symptoms of the disease. Fatal Familial Insomnia, as the name suggests, manifests as progressive insomnia. Initially, the person suffering from the disease shows a reduction in total sleep time, and vivid dreaming is observed. However, within a few months, the loss of sleep becomes more and more severe, and other symptoms set in due to this chronic lack of sleep- psychological ones like anxiety and paranoia, and this may eventually develop into dementia. As the thalamus is affected, the involuntary actions of the body (heart rate, temperature regulation) show disruptions. As there is no known treatment, palliative care and counselling are provided to the patient and their relatives so they can stably handle the diagnosis and prepare emotionally for the same.