Introduction

Insomnia is hard, no question about it. Even missing a few hours of sleep a day usually has disastrous effects on our daily lives. Imagine if this went for not just for a few hours or a few days. This is the unfortunate reality that people with Fatal Familial Insomnia (FFI) have to endure. 

FFI is an extremely rare condition that affects only a small number of families in the world.^1,2,3,4 This condition robs them of their ability to sleep, eventually leading to their unfortunate demise. In this article we will cover the basics of FFI and dive into the genetic component of it.

Overview of fatal familial insomnia

Fatal Familial Insomnia is an extremely rare genetic disorder with only about a 100 reported cases. The disease's effects on the body start with the brain, leading to insomnia which then leads to rapid decline in both physical and mental health.^1,2,3,4 Unfortunately as the name suggests, FFI is fatal and while there is the option of palliative (supportive) care, there is no cure. 

Onset age of FFI can vary vastly but the median is around 30 to 60 years old, although there are reported cases earlier and later than that. Once the disease starts showing symptoms, it progresses very quickly which eventually leads to death within 6 to 36 months.⁴

FFI is a prion disease, which are misfolded proteins that cause further problems in the nervous system. The name prions may be familiar to some as it is the same misfolded protein (with the genetic component which we will get to below) that causes bovine spongiform encephalopathy (aka mad cow disease), Creutzfeldt–Jakob disease and Gerstmann Sträussler Scheinker syndrome. In FFI, these prions primarily affect a part of the brain called the thalamus, which plays a crucial role in regulating sleep and consciousness.⁶

While this article is focused on the genetic component of FFI, for further reading into signs, symptoms and progression we recommend this article from Klarity.

Genetic basis of FFI

The genetic basis of FFI revolves around understanding the PRNP gene and prions further. While these topics can sound quite complicated we will do our best to simplify it. 

PRNP gene, which is also known as the CD230, is responsible for coding the major prion protein (PrP). PrP is mostly found in the nervous system but it can be expressed in other tissues as well.⁷

The function of PrP is still unclear but researchers have proposed that it has strong associations in the nervous system including sleep, circadian rhythm, memory, learning, neuronal development as well as some functions in the immune system.

The PrP can exist in isoforms, which means proteins that are similar to each other but serve different functions due to genetic differences. For further reading on this we would suggest looking at how genes are translated into proteins. For this article, we will be focusing on the misfolded variant of PrP that causes FFI.

The mutation that causes this change is called a D178N mutation where the amino acid aspartic acid gets replaced with asparagine at position 178 of the prion protein. When this miniscule change in amino acid change is coupled with the methionine on position 129, it has a huge impact on how the protein functions.⁴

In a simplified manner, these misfolded proteins which are now called the prions cause the thalamus part of the brain to use less glucose. Because thalamus is highly involved in regulation of sleep, alertness and consciousness, this hypo-metabolism is considered as the cause of FFI.^1,2,3,4 Over time, the build-up of these prions lead to including the inability to sleep, loss of motor control, hallucinations, and eventually death.

Inheritance pattern

As the name suggests, fatal familial insomnia is hereditary, meaning it is passed down to the children from parents. The FFI follows an autosomal dominant trait, which means that the mutation it carries is dominant.^1,2,3,4 And if either one of the parents passes it down, whether the mother or the father, the recipient will inherit the mutation and eventually develop FFI. 

In other words, even if one parent carries the mutated PRNP gene, there is a 50% chance that their offspring will have it too. In rare cases FFI is known to occur sporadically, meaning although there isn’t a family history of the mutation, it occurs in an individual which is then passed onto their offspring.⁵

It is possible for a person to inherit the PRNP mutation but never develop the disease. This can happen due to what is known as an incomplete penetrance, where even though the genetic mutation is present, the individual does not present with the disease. However, this is rare with FFI and unfortunately most people who inherit the mutation will eventually develop the disease.⁶

Genetic counselling is crucial for approximately 50 families that have the PRNP gene. This can help these families understand the risk associated with inheriting or passing down the genes in order to support them make informed decisions.^1,2,3,4 Although extremely rare, since FFI can present with incomplete penetrance, individuals with matching symptoms should consider genetic counselling as well.

Current research and future directions

As we mentioned above, our knowledge about the mechanism of FFI and the role of the PRNP gene is clouded, and further research is needed to fully understand the forces at play. 

Understanding the PRNP gene mutations and prion diseases better are some of the areas that the researchers are focusing on. Prions cause other disorders as well so understanding how they misfold and how they spread in the brain will shine a light on how to stop or slow down the progression of FFI and other prion related illnesses.^1,2,3,7

Current treatment for FFI is just supportive, which means it focuses on managing the symptoms rather than a cure. This is why there are also drug development researches focused on stabilising prion proteins and preventing them from folding. Gene therapy and immunotherapy, which are specific treatments aiming to the immune system to target prion proteins are also other approaches that are being pursued.⁷

Summary

Fatal Familial Insomnia is a rare, hereditary disorder that gradually robs people of their ability to sleep, leading to severe mental and physical decline and, inevitably, death. 

FFI is a prion disease, caused by misfolded proteins that damage the brain, specifically the thalamus—a crucial area for sleep regulation. FFI is extremely rare, with only around 100 reported cases globally. 

People suffering from FFI usually start experiencing symptoms between the ages of 30 and 60 and once symptoms begin, the decline is swift, with life expectancy of 6 to 36 months after that.

FFI is a result of a mutation in the PRNP gene, which normally produces the prion protein PrP. This mutation however causes the protein to misfold, leading to brain damage. FFI is an autosomal dominant condition, meaning that a child has a 50% chance of inheriting the disease if one parent carries the mutation.

Research on FFI is still in its infancy. Currently, there is only palliative care for FFI, focusing on symptom management rather than a cure. Researchers are focusing on understanding the mechanisms of prion diseases in order to develop treatments that might stabilise prion proteins or prevent their misfolding in the first place.