What is Fatal Familial Insomnia?

Fatal familial insomnia (FFI) is an extremely rare and deadly disease that is passed down through families. This disease is a type of illness that causes the brain cells to waste away and eventually leads to severe sleep problems. This disease is hereditary, meaning that it’s passed down from parents to children. It is caused by a fault in the gene known to produce prion protein (PRNP), leading to damage in a part of the brain called the thalamic nucleus.

The main signs of FFI include severe sleep issues that progress quickly, followed by problems with bodily functions like fast heartbeat, excessive sweating, high blood pressure, memory loss, difficulty focusing, balance problems, and issues related to the body’s hormone system. Unfortunately, the disease can’t be cured at present, and the average duration of the disease is 18 months, usually resulting in death.

The first known case of this disease dates back to 1765, when an Italian man showed symptoms similar to FFI. It was officially recognized and described scientifically in 1986. Further studies were conducted to understand the inner workings, causes, and progression of the disease. Since the disease is typically diagnosed based on the symptoms and a careful examination of the nervous system, knowing the patient’s detailed health history is crucial.

Because there is no cure for FFI at the moment, the treatments aim to provide relief from symptoms and improve the quality of life as much as possible. This means that the goal of treatment is to help manage symptoms and make the patient as comfortable as possible.

What Causes Fatal Familial Insomnia?

Fatal familial insomnia (FFI) belongs to a group of genetic disorders known as human prion diseases. Similar conditions include familial Creutzfeldt-Jakob disease, prion protein amyloidosis, Gerstmann-Straussler-Scheinker syndrome, and Huntington disease-like 1.

FFI is caused by a genetic change or mutation in a specific part of the PRNP gene located at a position on chromosome 20 known as 20p13. This area of the gene is responsible for making a type of prion protein. Prion proteins are normal substances our bodies produce, but when they are shaped in a wrong way due to mutations, they can cause diseases. The mutation that causes FFI goes by the name D178N and is linked to a specific version (or genotype) of the prion gene known as M129.

While it’s not certain when FFI first appears, researchers think it could depend on how much of the normal prion protein gets converted into the wrongly shaped version due to this mutation. Approximately 10% to 15% of all diagnosed prion disease cases are inherited, caused by similar genetic changes in the PRNP gene.

Risk Factors and Frequency for Fatal Familial Insomnia

Fatal Familial Insomnia (FFI) is a rare condition that affects people across the globe, primarily in Europe and Asia, and its occurrence has been increasing, especially in China. Over 100 cases of FFI have been reported, involving both males and females, with the average age of symptom onset being around 47.5 years. Many of these patients unfortunately passed away within an average of 13.2 months from the onset of the disease. It’s interesting to note that the characteristics may vary depending on geographical regions and genetic variations. A specific genetic difference is thought to be linked to the specifics of FFI. Symptoms of FFI differ among various populations. For instance, some people in Asia may experience movement troubles, sleep-related breathing issues, and laryngeal stridor, while others may suffer from high blood pressure, sweating excessively, and weight loss. It has also been noted that Asians experience double vision and myoclonus at different rates compared to other ethnicities.

However, it’s important to note that genetic prion diseases like FFI are extremely rare, with only 1 to 1.5 new cases occurring per 1 million people every year. In fact, hereditary forms of prion diseases account for only about 10% of all the prion disease cases.

Signs and Symptoms of Fatal Familial Insomnia

People with a condition known as Fatal Familial Insomnia, or FFI, typically start showing symptoms between the ages of 20 and 61, with the average onset occurring at the age of 50. This condition can show itself in diverse ways and is often associated with neuron loss and an increase in non-neuronal cells, especially in a region of the brain known as the thalamus. It’s important to thoroughly examine and question patients suspected of having FFI. Here are some of the aspects to consider:

  • Sleep disturbance: People with FFI often struggle with insomnia in the early stages, finding it difficult to fall asleep and not sleeping much overall. These sleep disturbances can become worse over time. It’s also common for these patients to experience vivid dreaming during the little sleep they do get. In some cases, nearly half to over half of FFI patients exhibit disrupted sleep patterns, involuntary leg movements, and sleep apnea. As FFI gets worse, it can ruin the natural sleep-wake cycle leading to a state of confusion while awake.
  • Autonomic dysfunction: Patients may deal with various degrees of abnormal functionality in this system, such as high blood pressure, episodes of fast breathing, an increase in tears and sweating, constipation, sexual dysfunction, and changes in body temperature.
  • Neurological impairments: To include symptoms such as double vision, difficulties swallowing, abnormal gaze, movement disorders, difficulties with speech, balance issues, involuntary muscle jerks, and others. After about 12 weeks, patients usually start losing a sense of time and space. As the disease progresses, various symptoms appear, with some only revealing themselves much later in the disease’s progression like hallucinations and slowness in thought processing, attention issues, and short-term memory loss. As FFI gets worse, it can deteriorate into a state of delirium.
  • Mental health disease: Mood changes can be observed as patients with FFI may become more depressed or indifferent as their insomnia worsens. However, FFI patients’ intellectual abilities typically remain mostly untouched even in the later stages of disease progression.
  • Systemic and endocrine changes: Most patients with FFI will experience signs of weight loss and weakening. Also, reported hormonal dysfunctions include decreased secretion of ACTH (a hormone involved in stress response) and increased secretion of cortisol (a steroid hormone). Other changes can include the loss of normal daily variations in levels of growth hormone, melatonin, and prolactin.

In 2022, a global group set up a list of clinical diagnostic criteria for identifying FFI from other conditions with similar symptoms and for recognizing FFI earlier on. They determined that the core symptoms that usually last for less than 2 years include the following:

  • Specific sleep disturbances such as severe insomnia, agrypnia excitata (complete or almost complete lack of sleep) with or without a whistling noise during breathing or sleep apnea, or unintentional movements like sudden muscle contractions or restless sleep with frequent changes in body position
  • Neurological and mental health impairments that progress quickly, including dementia, balance issues, muscle twitches, hallucinations, delusions, or changes in personality including depression, anxiety, apathy, and confusion
  • Increasing autonomic and systemic abnormalities, including high blood pressure, fast heartbeat, irregular breathing, high body temperature, sweating, or weight loss of more than 10 kg (22 lbs) in the last 6 months.

Alongside these core clinical symptoms, it could support a diagnosis of FFI if the patient also has a family history of insomnia-related symptoms or shows evidence of organic insomnia—like a disrupted sleep-wake cycle or fragmented sleep and reduced total sleep time—with or without unintentional movements during a sleep study.

Testing for Fatal Familial Insomnia

When it comes to diagnosing FFI, while doctors rely primarily on clinical diagnostics, they also use various diagnostic studies to confirm the diagnosis and rule out other conditions.

Some common diagnostic studies include a complete blood count (CBC), which checks the number of red cells, white cells and platelets in your body, erythrocyte sedimentation rate (ESR) test, which monitors inflammation responses in the body, and serum chemistry, which assesses the overall health functioning. Liver function tests (LFT), assess the health of your liver by measuring the levels of proteins, liver enzymes, and bilirubin in your blood. Ammonia level tests and blood cultures could also be performed if bacterial infections are suspected.

Tests to exclude reversible cognitive decline like thyroid function tests (TFT), vitamin B-12 and folate levels, testing for neurosyphilis and human immunodeficiency virus (HIV) may be conducted as well.

Polysomnography (PSG), a sleep study used to diagnose sleep disorders, can also be used to identify reduced sleep times, less REM sleep and sleep efficiency, and slow wave sleep.

An electroencephalogram (EEG), which tracks and records brain wave patterns, can help suggest the presence of prion disease, a rare and usual fatal disease that affects the brain. However, this is only seen in a small percentage of patients.

As for imaging studies, computed tomography (CT) and magnetic resonance imaging (MRI) may not necessarily help in diagnosing FFI, but they can help rule out other neurological conditions. These might identify reduced diffusion in the thalamus (a part of the brain) due to gliosis (a form of scarring in the central nervous system), and atrophic changes (wasting away or decrease in size of an organ or tissue) as the disease progresses. PET imaging might show reduced metabolism in certain parts of the brain.

Genetic testing is also recommended as part of the diagnosis process, particularly testing for the pathogenic variant of PRNP or full gene sequencing, which could identify changes in FFI’s underlying genetic cause.

Brain biopsies, while not ruling in FFI, may help exclude other neurological diseases.

The diagnosis process also involves Polysomnography and genetic testing, conducted after comprehensive genetic counselling. Also, checking for the D178N mutation of the PRNP gene can help in diagnosing FFI at an early stage.

The international group’s 2022 diagnostic criteria establish the likelihood of FFI. This includes identifying clinical and supportive features, checking for positive genetic test results, and ruling out any potential alternative explanations.

Treatment Options for Fatal Familial Insomnia

Fatal familial insomnia (FFI) is a rare genetic condition for which there is currently no known cure. The main focus of treatment for this disease is to manage the symptoms and make the patient as comfortable as possible, which is often referred to as palliative care.

One method of handling FFI is to stop using any medications that might intensify the patient’s confusion, memory issues, or sleeplessness. Unfortunately, medications traditionally used to induce sleep, such as barbiturates or benzodiazepines, have been proven ineffective in FFI patients.

As FFI progresses, more serious symptoms may develop, such as difficulty swallowing. This sometimes requires the insertion of a feeding tube to ensure proper nutrition. Certain drugs, such as gamma-hydroxybutyrate, have been clinically observed to induce sleep in some cases, but this is not a standard treatment. Other compounds have also been tested, but the results have been inconclusive so far.

In Italy, a clinical trial is currently underway to prevent the onset of prion disease (a category of illnesses that includes FFI) in individuals who are known carriers of a specific genetic mutation associated with FFI. This study is investigating the effects of a daily antibiotic taken orally by a group of carriers over a span of 10 years, but the results have not been determined yet.

Recently, a form of treatment known as immunotherapy has shown some promise in laboratory settings, with three primary areas of research – antibody vaccines, dendritic cell vaccines, and adoptive transfer of physiological prion protein-specific T cells. These treatments are designed to target and fight against the misshapen proteins that cause prion diseases.

Apart from these potential treatments, counseling or therapy can be very beneficial to both the patients and their families in managing the complex emotional facets of this disease. Hospice care can also be greatly beneficial to provide comfort and support.

When looking at cases of Fatal Familial Insomnia (FFI), it’s crucial for doctors to also ponder other diseases that may share common symptoms. These include:

  • Sporadic Creutzfeldt-Jakob disease (sCJD) and familial Creutzfeldt-Jakob disease (fCJD), both of which can cause memory issues and confusion, and eventually muscle spasms and difficulty with coordination.
  • Sporadic familial insomnia (sFI), a condition with features similar to FFI, but without a related genetic mutation.
  • Gerstmann-Straussler-Scheinker syndrome (GSS), typically showing problems with cerebellar function and minimal cognitive dysfunction, especially in the later stages of the disorder.
  • Variably protease-sensitive prionopathy, demonstrated by variable degrees of speech problems and aberrant behavior.
  • Other conditions that can cause dementia, such as Diffuse Lewy body disease, chronic meningitis, motor neuron disease, and various paraneoplastic syndromes.

Doctors should also rule out other reversible dementia causes, such as herpes encephalitis, limbic encephalitis, Hashimoto’s encephalitis, lithium poisoning, chronic meningitis, HIV-related brain disease, and hydrocephalus.

Long-term brain diseases, including Alzheimer’s disease, Pick disease, corticobasal degeneration, multiple system atrophy, frontotemporal dementia, and familial myoclonic dementia should all be thought about during assessment, despite their typically slow progress.

What to expect with Fatal Familial Insomnia

The progression of the disease can extend from 7 to 36 months, ending up in an average period of 18 months before death. Patients who have a specific genetic mutation in both copies of their gene (referred to as ‘Met-Met’) tend to have a lower average survival time compared to patients having different versions of the gene (referred to as ‘Met-Val’).

Possible Complications When Diagnosed with Fatal Familial Insomnia

Fatal Familial Insomnia (FFI) is a disease that is always deadly, no matter the circumstances. It leads to multiple complications featuring the automatic body functions, brain function, muscle movements, and hormone regulation. To learn more about these complexities, see the History and Physical section.

Common Complications:

  • Problems with automatic body functions (autonomic)
  • Cognitive issues (thinking and memory)
  • Motor complications (movement and coordination)
  • Endocrine complications (hormonal imbalances)

Preventing Fatal Familial Insomnia

Patients and their families need to understand that Fatal Familial Insomnia (FFI) is a serious disease that can have life-threatening effects. Currently, there are only a few available treatments, but researchers are constantly working to develop new ones. Genes play a big role in this disease, so family members should consider getting genetic counseling. This helps them understand if they are at risk and what that means for their health.

Frequently asked questions

Fatal Familial Insomnia (FFI) is an extremely rare and deadly disease that is passed down through families. It causes brain cells to waste away and leads to severe sleep problems. FFI is hereditary and caused by a fault in the gene known to produce prion protein (PRNP).

Fatal Familial Insomnia is extremely rare, with only 1 to 1.5 new cases occurring per 1 million people every year.

The signs and symptoms of Fatal Familial Insomnia (FFI) include: - Sleep disturbance: FFI patients often struggle with insomnia, finding it difficult to fall asleep and not sleeping much overall. They may also experience vivid dreaming during the little sleep they do get. As the disease progresses, sleep disturbances can become worse, leading to disrupted sleep patterns, involuntary leg movements, and sleep apnea. FFI can eventually ruin the natural sleep-wake cycle, causing confusion while awake. - Autonomic dysfunction: FFI patients may experience abnormal functionality in the autonomic system. This can manifest as high blood pressure, episodes of fast breathing, increased tears and sweating, constipation, sexual dysfunction, and changes in body temperature. - Neurological impairments: FFI can cause various neurological impairments, including double vision, difficulties swallowing, abnormal gaze, movement disorders, difficulties with speech, balance issues, and involuntary muscle jerks. After about 12 weeks, patients may start losing a sense of time and space. As the disease progresses, additional symptoms may appear, such as hallucinations, slowness in thought processing, attention issues, and short-term memory loss. FFI can deteriorate into a state of delirium. - Mental health disease: Mood changes, such as increased depression or indifference, can be observed as FFI patients' insomnia worsens. However, their intellectual abilities typically remain mostly unaffected, even in the later stages of the disease. - Systemic and endocrine changes: FFI patients may experience weight loss and weakening. Hormonal dysfunctions can include decreased secretion of ACTH (a hormone involved in stress response) and increased secretion of cortisol (a steroid hormone). Other changes may include the loss of normal daily variations in levels of growth hormone, melatonin, and prolactin. In addition to these symptoms, a global group established clinical diagnostic criteria for identifying FFI. These criteria include specific sleep disturbances, neurological and mental health impairments that progress quickly, and increasing autonomic and systemic abnormalities. A family history of insomnia-related symptoms or evidence of organic insomnia can also support a diagnosis of FFI.

Fatal Familial Insomnia (FFI) is caused by a genetic change or mutation in a specific part of the PRNP gene located at a position on chromosome 20 known as 20p13. This mutation, known as D178N, is linked to a specific version of the prion gene called M129.

The other conditions that a doctor needs to rule out when diagnosing Fatal Familial Insomnia include: - Sporadic Creutzfeldt-Jakob disease (sCJD) and familial Creutzfeldt-Jakob disease (fCJD) - Sporadic familial insomnia (sFI) - Gerstmann-Straussler-Scheinker syndrome (GSS) - Variably protease-sensitive prionopathy - Diffuse Lewy body disease - Chronic meningitis - Motor neuron disease - Paraneoplastic syndromes - Herpes encephalitis - Limbic encephalitis - Hashimoto's encephalitis - Lithium poisoning - HIV-related brain disease - Hydrocephalus - Alzheimer's disease - Pick disease - Corticobasal degeneration - Multiple system atrophy - Frontotemporal dementia - Familial myoclonic dementia

The types of tests that are needed for Fatal Familial Insomnia (FFI) include: 1. Clinical diagnostics: Doctors rely primarily on clinical diagnostics to diagnose FFI. 2. Diagnostic studies: Various diagnostic studies are used to confirm the diagnosis and rule out other conditions. These include: - Complete blood count (CBC): Checks the number of red cells, white cells, and platelets in the body. - Erythrocyte sedimentation rate (ESR) test: Monitors inflammation responses in the body. - Serum chemistry: Assesses overall health functioning. - Liver function tests (LFT): Measures the levels of proteins, liver enzymes, and bilirubin in the blood to assess liver health. - Ammonia level tests and blood cultures: Performed if bacterial infections are suspected. - Thyroid function tests (TFT): Tests to exclude reversible cognitive decline. - Vitamin B-12 and folate levels: Tests to exclude reversible cognitive decline. - Testing for neurosyphilis and human immunodeficiency virus (HIV): Tests to exclude reversible cognitive decline. - Polysomnography (PSG): A sleep study used to diagnose sleep disorders and identify sleep abnormalities. - Electroencephalogram (EEG): Tracks and records brain wave patterns to suggest the presence of prion disease. - Computed tomography (CT) and magnetic resonance imaging (MRI): Help rule out other neurological conditions. - PET imaging: Might show reduced metabolism in certain parts of the brain. - Genetic testing: Recommended to identify changes in FFI's underlying genetic cause. - Brain biopsies: Help exclude other neurological diseases. 3. Polysomnography and genetic testing: Conducted after comprehensive genetic counseling. 4. Checking for the D178N mutation of the PRNP gene: Can help in diagnosing FFI at an early stage. 5. International group's 2022 diagnostic criteria: Establish the likelihood of FFI by identifying clinical and supportive features, checking for positive genetic test results, and ruling out any potential alternative explanations.

Fatal Familial Insomnia (FFI) is currently incurable, so the main focus of treatment is to manage the symptoms and provide palliative care. This includes stopping the use of medications that may worsen confusion, memory issues, or sleeplessness. Medications traditionally used to induce sleep have been ineffective in FFI patients. In more advanced stages of FFI, a feeding tube may be necessary to ensure proper nutrition. Some drugs, like gamma-hydroxybutyrate, have been observed to induce sleep in some cases, but this is not a standard treatment. Clinical trials are also being conducted to prevent the onset of prion disease in carriers of the genetic mutation associated with FFI. Immunotherapy has shown promise in laboratory settings, targeting the misshapen proteins that cause prion diseases. Counseling, therapy, and hospice care can also provide support for patients and their families.

When treating Fatal Familial Insomnia (FFI), there can be side effects or complications that arise. These include: - Problems with automatic body functions (autonomic) - Cognitive issues, such as thinking and memory problems - Motor complications, affecting movement and coordination - Endocrine complications, resulting in hormonal imbalances

The prognosis for Fatal Familial Insomnia (FFI) is poor, as there is currently no cure for the disease. The average duration of the disease is 18 months, usually resulting in death. Patients with a specific genetic mutation in both copies of their gene tend to have a lower average survival time compared to patients with different versions of the gene.

A neurologist.

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