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How Fatal Familial Insomnia affects Parts of the Nervous System

Fatal Familial Insomnia (FFI) is a rare type of degenerative brain disorder that presents as mild insomnia at first but progressively becomes worse and eventually leads to physical and mental deterioration. FFI can also affect the autonomic nervous system. The autonomic nervous system controls involuntary body processes such as sweating and breathing; processes that happen without you thinking about them. FFI affects different parts of the autonomic nervous system in different ways, so it is useful to look at what part of the nervous system is most affected by fatal familial insomnia. 

FFI is caused by an abnormal variant in the prion-related protein (PRPN) gene and sometimes without this variant, it happens randomly and is then called sporadic fatal insomnia, or SFI. The PRPN gene regulates the production of the human prion protein. If the PRPN gene is altered, it can lead to the formation of abnormally shaped or misfolded prion protein, which is toxic to the body. This is how FFI occurs, because when abnormal prions accumulate in the brain’s thalamus, it leads to a loss of neurons. 

Although it has no cure, investigators are researching ways to best treat and manage FFI.

Introduction

Creutzfeldt-Jakob disease and Gerstmann-Straussler-Scheinker syndrome are two other diseases that are caused by variations in the PRNP gene. These diseases, along with FFI can be classified as transmissible spongiform encephalopathy TSE or simply as prion diseases. Prion diseases usually have long incubation periods and a short clinical duration, which means the disease can be present and get progressively worse over a long period with no symptoms and then once symptoms begin to appear, it rapidly worsens.

Signs & Symptoms

The main notable symptom in FFI is progressive insomnia, which can manifest either during middle age or later in life. Insomnia can be mild at first and get progressively worse until sleep is almost impossible. Even when the person affected manages to sleep. It is usually interrupted by vivid dreams. The overall effect is that it eventually leads to physical and mental deterioration which progresses to coma and death. 

With FFI, insomnia is usually the first symptom but some individuals may experience dementia and challenges with thought, cognition, memory, language and behaviour. Other symptoms include weight loss, forgetfulness, inattentiveness, inability to concentrate and speech problems. The affected individual may also experience episodes of confusion or even hallucinations.

The possible symptoms do not end there. Some individuals experience double vision (diplopia) or abnormal, jerky eye movements (nystagmus). Other symptoms include: difficulty swallowing (dysphagia), slurred speech (dysarthria), trouble coordinating voluntary movements (ataxia), abnormal tremors, twitches or muscle spasms (myoclonus). Some of the symptoms may resemble those that are associated with Parkinson’s disease.

There are other symptoms that may present because of a dysfunction of the autonomic nervous system. Based on which specific part of the nervous system is affected, different individuals will experience different symptoms. These symptoms include fever, rapid heart rate (tachycardia), high blood pressure (hypertension), increased sweating (hyperhidrosis), increased production of tears, constipation, variations in body temperature, anxiety, depression and sexual dysfunction.   

Causes

An abnormal mutation of the PRNP gene causes FFI. Since these genes are responsible for providing instructions for creating proteins to carry out various roles in the body, when a mutation occurs, the protein can no longer carry out its functions effectively. They either become faulty, inefficient, absent or overproduced and this can affect relevant organ systems of the body, including the brain. 

Most cases of FFI occur where there is a family history of the disease but some rare spontaneous cases do occur. In these rare instances, it is called a new or de novo variant and usually means the variation happened when the egg or sperm for that child was formed. In these cases, no other family member will be affected and it was not inherited, but it can be passed on to the offspring of the person with the de novo variant in an autosomal dominant manner.

Disorders passed on in a dominant pattern happen when only one copy of the abnormal gene needs to be present for the appearance of the disorder. The affected gene can be inherited from either parent and the risk of passing it on from parent to child is 50% regardless of the sex of the child.

Individuals who develop FFI without a variation in the PRPN gene are said to have sporadic fatal insomnia (SFI). The trigger for SFI is not known and is not genetic. It is very rare compared to FFI.

The PRNP gene produces prion proteins or PrP and although its exact function in the body is not fully understood, the way that it is affected by the variant gene means it starts manifesting in an abnormal, misfolded, 3-dimensional shape. When they take on this misfolded shape, they are toxic to the body and especially to the cells in the nervous system. With FFI, toxic PrP is found in the thalamus of the brain. The thalamus regulates functions in the body such as sleep, appetite and body temperature. The progressive build up of the affected PrP destroys nerve cells and results in the symptoms of the disorder. Through a microscope, the effect on the brain resembles sponge-like holes or gaps, and diseases that adopt this appearance are called transmissible spongiform encephalopathies.

The term “prion” refers to a “proteinaceous infectious agent” and explains the transmissible nature of prion diseases. In FFI, the prion would be the misfolded PrP. It is not transmitted in a traditional sense. The only way to transmit prion disease to a healthy person is through direct exposure to the disease-affected brain tissue through injection or ingestion. Since the person acquires the disease without having a genetic defect, they are said to have an “acquired” form. For instance, prion-contaminated beef in the United Kingdom caused a spread of variant Creutzfeldt-Jakob disease. Kuru is another lesser-known example. This variant occurred in the Fore people of Papua New Guinea because the villagers practiced ritualistic cannibalism and ate the brains of deceased kuru-affected tribesmen.

Affected Populations

In the medical community, rare diseases often go undiagnosed or misdiagnosed and their true frequency in the general population is usually difficult to determine. FFI is so rare that the exact incidence and prevalence of the disorder is not really known. The sporadic form of FFI, (SFI) is even more rare and medical literature has only acknowledged cases in about two dozen people. Prion disorders in general only affect about 1 person per million people in the general population per year and genetic prion diseases make up about 15% of all individuals with prion diseases. The known data shows that FFI affects men and women equally and the average age of onset is 45-50 years old. It has been seen in different populations over the world and there are some cases where it has occurred in teenagers and individuals as old as 70 years old. 

Related Disorders

Outward indications of some of the disorders discussed below compare to indications seen in FFI. It is helpful to make these comparisons because they can be used for differential diagnosis. 

Four of these major prion diseases have been observed. They are Kuru, Creutzfeldt-Jakob disease, variant Creutzfeldt-Jakob disease, and Gerstmann-Straussler-Scheinker syndrome. The main indication of these diseases is usually nerve cell (neuron) loss and brain damage. Animals can also be affected by prion diseases. Bovine spongiform encephalopathy (mad cow disease) in cows can cause Variant Creutzfeldt-Jakob disease in humans if they consume beef contaminated with the unhealthy prions. Scrapie in sheep is another example of animals being affected. 

Another related disorder is frontotemporal degeneration. It is caused by progressive damage in the front and temporal lobes of the brain and can be observed by their degenerative impact. Medically, the disease can present in a variety of ways because apart from affecting an individual’s behaviour and personality, it can also impair their thinking and communication capabilities. Different people will be affected in different ways but clinical symptoms are grouped into three main categories. They are separated according to which changes are observed, that is whether it is behavioral, language-related or related to changes in motor function. The degenerative effects are usually seen in addition to the build up of either the tau or TDP -43 protein, or both. In FTD, the characteristic misfolded feature of the protein is present which leads to their eventual disruption and negative effects. The FTD medical subtypes may also be categorized as ‘tauopathies’or TDP43-opathies, based on where the misfolded proteins come together in the brain. In some instances, a third protein, FUS, accumulates instead. Tau protein and TDP-43 protein is sometimes seen in other neurological disorders. (If you want more information about this condition, pick “frontotemporal dementia” as your search phrase in the Rare Disease Database.)

Alzheimer’s, another progressive condition is a related disorder. It affects memory, thought and language. Some of the changes associated with this disease causes plaques or clumps of the (neurofibrillary tangles). When the changes start happening, it causes memory loss and even behavioral changes. However, it usually progresses slowly and the symptoms usually occur in individuals over the age of 65. On the other hand, symptoms that affect the frontotemporal lobe are more common in middle-age and below 65. With Alzheimer’s, the first sign is usually difficulty with short-term memory. Progressively, it begins to affect personality, mood and behavior. It can cause impairment of concentration, confusion and even restlessness. However, the progression of the disease can be more unique in different individuals in terms of type, severity and sequence.  (You can search the Rare Disease Database for more information on this disorder.) 

Other diseases that display similar symptoms include: Huntington disease, progressive supranuclear palsy, dementia with Lewy Bodies, corticobasal degeneration, Hashimoto encephalopathy, paraneoplastic syndromes, and multiple system atrophy. (The Rare Disease Database has more information on these disorders.)

Diagnosis

When diagnosing FFI, the usual symptoms and the patient history is taken into consideration. A clinical evaluation is also done along with specialized tests.

Clinical Testing and Workup

There are several different types of testing processes that may be used to diagnose FFI. 

The genetic testing available for FFI is usually available as a diagnostic service at specialized laboratories. The type of molecular testing can confirm the presence of FFI but, if the test is negative, it does not mean that there is no SFI.

A sleep study called polysomnography may also be used on individuals to show how their sleep is being affected as they transition through the different stages. 

Advanced imaging technology in the form of a Positron emission tomography or PET scan can also be used. The three dimensional images produced from this scan will show the brain’s metabolic activity or any reduced activity in the thalamus (thalamic hypometabolism).

Other imaging techniques that can be used include computerized tomography (CT) scanning and magnetic resonance imaging (MRI). These scans on their own may not be able to confirm a final diagnosis of FFI but they can rule out other conditions that may mimic FFI or other prion diseases. 

Another way to try and diagnose FFI includes testing for the 14-3-3 protein. This protein is produced when nerve cells die so individuals with FFI might have this protein accumulated in their cerebrospinal fluid (CSF). However, this is not the case for every single case of FFI 

Standard Therapies

Treatment

FFI has no cure, neither have there been any treatment trials or standard treatment protocols since the disease is so rare. Instead, the treatment is mainly managing the symptoms based on the individual. Affected individuals should stay away from any form of medication that can affect memory, cause confusion of insomnia. Some symptomatic treatments include anti-seizure (anti-epileptics) or clonazepam for myoclonus.  The treatment would require specialists such as neurologists, psychiatrists, psychologists, pain specialists, social workers and other professionals. They all have to work in tandem in order to come up with the best treatment plan. Throughout the treatment process, the affected individual and their families may also need psychosocial support and counseling.

Frequently Asked Questions FAQ

How do you die from fatal insomnia?

Fatal insomnia can cause death anywhere within a range of a few months to a few years. It is a prion disease of the brain caused when the gene that encodes the protein PrPC mutates. It usually appears in two forms, either fatal familial insomnia FFI which is autosomal dominant or sporadic fatal insomnia, which is not inherited at all and is caused by a mutation. 

Is it possible to lose the ability to sleep?

Insomnia, or the inability to fall and stay asleep at night is a common problem that can affect one’s energy, mood and ability to function during the day. It can lead to serious health problems if it becomes chronic. 

What part of the brain is affected by fatal familial insomnia?

Since FFI affects different people in different ways, a very important question is what part of the nervous system is most affected by fatal familial insomnia. Fatal familial insomnia (FFI) affects the thalamus, which is the part of the brain that controls the sleep-wake cycle. It is also known as the ‘relay center’ since it acts as a connector for other parts of the brain to communicate with each other.

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