Fatal Familial Insomnia: Sleep and Mortality | Sporadic Overview

The phenomenon of Sporadic Fatal Insomnia further emphasizes the intricate interplay between sleep and mortality, shedding light on the profound impact sleep disorders can have on our well-being.

The Fatal Insomnia

When I was a kid, my father used to tell me a story about a man who died because he can’t sleep for a few months.

Sleep is one of the most important components of achieving a healthy life, hence, longevity.

In the few families which I have mentioned before which were having some problems with sleeping off at night, they were having some kind of disease which can be inherited causing problems with their sleeping arrangement, some symptoms resembling a neurocognitive disorder called dementia and finally death.

The mode of inheritance for this disease is autosomal dominant, which can simply be translated to if either one of the genes they inherited from either of their parents were defective, they will be affected by the disease.

Oh yeah, I forgot to tell you, the name of the disease is Fatal Familial Insomnia (FFI) and it is caused by an abnormal folding of proteins called the prion in the brain specifically in the region called the thalamus.

The thing about prion disease is, they are fatal and usually left people with a severe neurocognitive degeneration which will result in a significant deterioration of the physical and mental abilities to perform activities.

The causes of prion diseases were relatively unknown but the majority of them were thought to be caused by an infectious agent called prions or a bacterium species called the Spiroplasma.

In FFI, however, the cause can be attributed to a sporadic mutation which affects a gene called the PRNP gene which is thought to have important functions in several metabolic processes such as:

• Providing a set of specific instruction to create a protein in the brain and other tissues called the prion
• Providing cells with copper
• Providing a neuroprotective effect to the brain to prevent injury
• Plays an important role in cellular communication

One of the factors which would determine the kind of functionality a protein will carry out will depend on the way they were folded.

Incorrectly fold prion proteins were the consequences of the PRNP genes mutation causing them to perform an abnormal function thus affecting tissues in which they were a part of.

The abnormal PNRP gene consists of:

• Aspartic acid at the 178th codon instead of asparagine
• Methionine at the 129th codon.

When it affects a region of the brain called the thalamus, they will not only disrupt an individual’s sleep-wake cycle but also the ability for the other parts of the brain to communicate with each other.

People with FFI usually presented with a sleeping disorder (insomnia which is progressive in nature) along with disruptions in the function of the autonomic nervous system which we called the sympathetic overdrive.

People who were affected usually will have symptoms which indicate some sort of problems with their sympathetic nervous system such as palpitations, headache (related to hypertension), excessive sweating and an elevated core body temperature.

Most of the affected people were aged between 20 to 60 years old with 50 years old being the mean age of onset.

Back in the 1980s, when FFI was first discovered in Silvano’s family (one of the families which have been identified with FFI), they were reluctant at first to tell any physicians regarding their problems and kept the genetic disease (FFI) as a secret.

They were literally living out of fear of their own genetic material and as the mode of inheritance is autosomal dominant, it was unfortunate for most of the family members.

I mean won’t you be scared as well when the chances of you inheriting the defective gene to your child assuming your partner is unaffected and you hold one abnormal gene out of two is 50%?

People who were born with a defective PRNP gene will not show any signs of abnormality until they reach a specific age of onset which could not even be determined/predicted by the characteristic of the genetic mutation.

The only thing we know is that the course of the disease can be determined by the type of amino acids which bind with the methionine at the 129th codon.

If the binding is between two methionines, then the course of the disease could be short (around 12 months).

If the amino acid which is bounded to the methionine at the 129th codon is a valine, then the course of the disease could be longer (around 24 months).

People usually succumb to death after 7 to 36 months from the onset of the first symptom.

Can Insomnia Kill You?

So, as the most prominent symptom of this disease is insomnia, the most sought out question is, does insomnia kills or is it the other symptoms which cause the ultimate consequence of FFI (death)? Up to this point, most of the scientists and brain specialists out there have no idea what is the exact cause of death in patients with FFI.

Critical changes in the brain as a result of the prion gene mutation can be one of the factors but sometimes, the unbalanced physiological processes (disrupted autonomic nervous system) can kill a patient even before the critical changes took place.

Sleep is extremely important and a few studies have proved that sleep deprivation (less than 5 hours per day) is associated with an increased in the mortality rate.

However, a paper which has been published in the Journal of Sleep Research on May 22nd, 2018 has found that sleep deprivation during weekdays can be compensated by sleeping during the weekend.

Among individuals <65 years old, short sleep (≤5 hr) during weekends at baseline was associated with a 52% higher mortality rate (hazard ratios 1.52; 95% confidence intervals .15–2.02) compared with the reference group (7 hr), while no association was observed for long (≥9 hr) weekend sleep.

When, instead, different combinations of weekday and weekend sleep durations were analysed, we observed a detrimental association with consistently sleeping ≤5 hr (hazard ratios 1.65; 95% confidence intervals 1.22–2.23) or ≥8 hr (hazard ratios 1.25; 95% confidence intervals 1.05–1.50), compared with consistently sleeping 6–7 hr per day (reference).

The mortality rate among participants with short sleep during weekdays, but long sleep during weekends, did not differ from the rate of the reference group. Among individuals ≥65 years old, no association between weekend sleep or weekday/weekend sleep durations and mortality was observed.

This simply means that the relationship between sleep deprivation and mortality rate may no longer be a U-shaped.

In the past, it was hypothesized that sleeping less than 5 hours or more than 8 hours per day can lead to an increase in mortality rate but now, the statement might get a little bit flexible.

Unless people sleep 7-8 hours per day during the weekdays, sleeping longer during the weekend may actually do more good than harm (provided you are sleep deprived on the weekdays).

However, it’s worth noting that, this is one of the grey areas in health and medicine so more studies should be conducted to investigate the validity of the finding.

In a long-term study which has been conducted for 40 years to investigate the effect of insomnia on the overall health of an individual has found that, people who were experiencing chronic insomnia were 58% more likely to die prematurely.

The cause of death was usually related to cardiovascular or pulmonary problems in the general population. For people who are experiencing FFI, there will most likely to experience different symptoms related to sleep deprivation which include: