Prion Diseases

Fatal Familial Insomnia: Symptoms, Causes, and Treatment

Prion Diseases | Johns Hopkins Medicine

Fatal familial insomnia (FFI) is a very rare sleep disorder that runs in families. It affects the thalamus. This brain structure controls many important things, including emotional expression and sleep. While the main symptom is insomnia, FFI can also cause a range of other symptoms, such as speech problems and dementia.

There’s an even rarer variant called sporadic fatal insomnia. However, there have only been 24 documented cases as of 2016. Researchers know very little about sporadic fatal insomnia, except that it doesn’t seem to be genetic.

FFI gets its name partly from the fact that it often causes death within a year of two of symptoms starting. However, this timeline can vary from person to person.

It’s part of a family of conditions known as prion diseases. These are rare conditions that cause a loss of nerve cells in the brain. Other prion diseases include kuru and Creutzfeldt-Jakob disease. There are only about 300 reported cases of prion diseases each year in the United States, according to Johns Hopkins Medicine. FFI is considered one of the rarest prion diseases.

The symptoms of FFI vary from person to person. They tend to show up between the ages of 32 and 62. However, it’s possible for them to start at a younger or older age.

Possible symptoms of early stage FFI include:

  • trouble falling asleep
  • trouble staying asleep
  • muscle twitching and spasms
  • muscle stiffness
  • movement and kicking when sleeping
  • loss of appetite
  • rapidly progressing dementia

Symptoms of more advanced FFI include:

  • inability to sleep
  • deteriorating cognitive and mental function
  • loss of coordination, or ataxia
  • increased blood pressure and heart rate
  • excessive sweating
  • trouble speaking or swallowing
  • unexplained weight loss
  • fever

FFI is caused by a mutation of the PRNP gene. This mutation causes an attack on the thalamus, which controls your sleep cycles and allows different parts of your brain to communicate with each other.

It’s considered a progressive neurodegenerative disease. This means it causes your thalamus to gradually lose nerve cells. It’s this loss of cells that lead to FFI’s range of symptoms.

The genetic mutation responsible for FFI is passed down through families. A parent with the mutation has a 50 percent chance of passing on the mutation to their child.

If you think you might have FFI, your doctor will ly start by asking you to keep detailed notes about your sleeping habits for a period of time. They might also have you do a sleep study.

This involves sleeping in a hospital or sleep center while your doctor records data about things such as your brain activity and heart rate.

This can also help rule out any other causes of your sleep problems, such as sleep apnea or narcolepsy.

Next, you may need a PET scan. This type of imaging test will give your doctor a better idea about how well your thalamus is functioning.

Genetic testing can also help your doctor confirm a diagnosis. However, in the United States, you must have a family history of FFI or be able to show that previous tests strongly suggest FFI in order to do this. If you have a confirmed case of FFI in your family, you’re also eligible for prenatal genetic testing.

There’s no cure for FFI. Few treatments can effectively help manage symptoms. Sleep medications, for example, may provide temporary relief for some people, but they don’t work long term.

However, researchers are actively working toward effective treatments and preventive measures.

A 2016 animal study suggests that immunotherapy may help, but additional research, including human studies, are needed. There’s also an ongoing human study involving the use of doxycycline, an antibiotic.

Researches think it may be an effective way to prevent FFI in people who carry the genetic mutation that causes it.

Many people with rare diseases find it helpful to connect with others who are in a similar situation, either online or in a local support group. The Creutzfeldt-Jakob Disease Foundation is one example. It’s a nonprofit that provides several resources about prion diseases.

It can be years before the symptoms of FFI start to appear. However, once they start, they tend to get rapidly worse over the course of a year or two. While there’s ongoing research about potential cures, there’s no known treatment for FFI, though sleep aids may provide temporary relief.


The proper handling of CJD-infected patient samples in the pathology laboratory

Prion Diseases | Johns Hopkins Medicine

The term prion was introduced in 1982 by neurologist Stanley B. Prusiner1 to describe a proteinaceous infectious particle that was associated with the disease scrapie.

Prions are pathologic infectious agents composed of bits of misfolded protein that cause other proteins to fold in multiple, structurally abstract ways.

Prion diseases are rare neurodegenerative disorders identified as transmissible spongiform enchephalopathies (TSEs).

History of prion diseases

Several hundred years ago, sheep herders noted that some of their sheep became ill, appeared to be deranged, and started scraping their hindquarters. This sheep disease became known as scrapie.

For many years this disease was not well understood, with the causative agent remaining elusive.

Un most bacteria and viruses, prion protein (PrP) is hearty and is not susceptible to high temperatures and many common disinfectants.2

In the mid-20th century, while scientists were studying kuru, another neurological disease found in the people of Papua New Guinea, it was shown that this disease could be transmitted to chimpanzees, as could a third neurological disease, Creutzfeldt-Jakob Disease (CJD).

Further studies showed that scrapie, kuru, and CJD all acted in similar ways, creating severe neurologic abnormalities within the brain. Prusiner demonstrated that this (scrapie) agent was not a bacteria or virus because it lacked DNA and RNA, but was actually a protein.


Prion protein (PrP)

Over the years, other prion diseases have been identified in both humans and animals (Table 1). In humans, cases of CJD and kuru (attributed to cannibalistic practices) have been seen.

While scrapies was well known, “mad cow disease” (bovine spongiform encephalopathy) became relevant when individuals contracted a form of it (known as variant CJD, or vCJD) when ingesting contaminated beef.


Table 1. Prion diseases (

Studies have shown that the prion protein can be found in healthy individuals due to a gene found on chromosome 20(p13).5 This prion protein gene (PRNP) in its healthy state causes no symptoms or disease. However, it can misfold and can further “teach” other proteins to misfold.6 These misfolded proteins lead to TSEs.7

In the United States, about 300 cases of TSEs are reported each year and have been associated with fatal degenerative brain diseases. TSEs are characterized by microscopic vacuoles and amyloid deposition in the brain, similar to those deposits seen in Alzheimer’s disease and Parkinson’s disease.2

TSEs: types and symptoms

There are three types of TSEs seen in humans. The infectious form (less than one percent incidence) is spread by consuming infected foods, iatrogenic spread of infected tissues (organ transplant, contaminated human growth hormone, etc.), and transfusion. The sporadic form is the most common and is responsible for 85 percent to 90 percent of all classic CJD cases.

One or two people a million die every year from sporadic CJD, which appears later in life, between the ages of 55 and 75. The familial form occurs due to an autosomal, dominant gene mutation of PrP. About 10 percent to 15 percent of the total human TSEs are inherited.

Fatal familial insomnia interferes with sleep and eventually leads to the deterioration of mental and motor brain functions.8,9

Symptoms of TSEs are progressive and can include headaches, joint pain, difficulty in walking/talking, seizures, paralysis, and loss of bodily and cognitive functions.

These neurodegenerative disorders have a long incubation period, estimated to be about 11 years up to 40 years, depending on the type.

10 Various treatment modalities have been tried with no success, as death is always imminent once symptoms appear.

Guidelines for handling known or suspected tissues/fluids from patients with or at risk for CJD/vCJD

Infectivity is most often found in the central nervous system, specifically the brain, spinal cord, and eye. Table 2 identifies tissues that are proven or assumed to have medium to high infectivity for TSEs. Dura mater/anterior eye/cornea are considered high-risk tissue sources even though PrPTSE (disease-associated form of the prion protein) may not be detected.

Table 2. Tissues assumed or proven to have medium or high infectivity for TSEs

Peripheral tissues have been found to carry low levels of prion protein and are considered low-risk. Cerebrospinal fluid (CSF) and blood are also classified as having low-risk infectivity. However, vCJD has been transmitted via contaminated blood transfusions. The most recent TSE described is variably protease-sensitive prionopathy (VPSPr).11

Decontamination of infected materials12,13

Agents of TSEs are generally resistant to routine disinfectants as well as common sterilizing methods used in the laboratory.

Ineffective disinfectants include alcohol, ammonia, chlorine dioxide, formalin, glutaraldehyde, hydrogen peroxide, and iodine.

Ineffective sterilization processes include dry heat, UV light, microwaving, autoclaving (at 121oC for 15 minutes), glass bead sterilizers, and certain gases (ethylene oxide or formaldehyde). Effective disinfectants include 2M NaOH for one hour.

Precautions in handling infectious materials

Frozen section examination should not be performed on high-risk tissues for patients with or at risk for CJD or vCJD. Gross examination of tissues requires following routine universal precautions for blood-borne pathogens and wearing appropriate personal protective equipment (PPE).

Use of cut-resistant steel mesh gloves and disposable instruments is strongly advised. Gross examination can be performed on fresh or fixed tissue, preferably in a class I biological safety cabinet, using disposable paper lining over the base of the cabinet to absorb contaminated splashes.

Surgical instruments and the grossing area can be decontaminated with 2M NaOH for a minimum of one hour.

Disposable instruments and sharps can be decontaminated with 2M NaOH for one hour prior to placing them in a suitable biohazard container. All waste, including gowns, gloves, and aprons, should be incinerated.

Non-disposable instruments and cut resistant/steel gloves should be decontaminated with 2M NaOH for one hour.

Any contaminated glassware, including microscope slides, should be collected in a suitable container, double-bagged, and incinerated.

Work surfaces, including microtome for non-formic treated blocks and biohazard safety cabinet, should be washed with 2M NaOH.

Any contaminated fluids, fixatives, or solvents can be absorbed in sawdust in a combustible, stout container with lid, double-bagged, and incinerated. Blood and CSF samples can also be handled in a similar manner.

Tissue samples can be fixed in 10 percent neutral buffered formalin for 24 hours followed by a one-hour fixation in 96 percent formic acid.

Tissues can then be removed, washed thoroughly with tap water, and routinely processed other pathology specimens. Fluids used to process tissue samples can be disposed of as per routine protocols/precaution procedures.

Microtomy can be performed using disposable blades as per routine protocol.

Retrospective diagnoses and special circumstances

In cases where a retrospective diagnosis of CJD after normal tissue sample processing has occurred, follow-up is required. Take into account the following when considering what action to take:

  • The type of tissue(s) involved.
  • The type of CJD that has been diagnosed and how recently the diagnosis was made.
  • Whether the patient had clinical symptoms of CJD or was in one of the “at risk” groups.
  • Whether the case was reported to the National
  • Prion Disease Pathology Surveillance Center (NPDPSC) and whether any of the tissue should be referred for further special investigations.

The following are action steps under these circumstances:

  • Any samples taken from the patient should be traced, including stored specimens.
  • Fixed tissue should be double-bagged and sent for incineration after the statutory six weeks.
  • Any residual frozen tissue, including cryostat sections, should be fixed per CJD protocol, double-bagged, and sent for incineration.
  • The paraffin blocks should be removed from main store and filed separately, clearly labeled as form of CJD, and then stored separately. Reprocessing the blocks using formic acid is not required.
  • Unmounted slides should be sent for incineration. Mounted (cover-slipped) slides can be filed as per routine protocol.
  • Prior to incineration, the NCJDSC should be contacted to ascertain whether it has a use for fixed/frozen tissue(s).
  • If it is still in use, the microtome blade used to cut the sample should be placed in a sharps box and disposed of by incineration. The water bath should be changed and cleaned with 2M NaOH for 60 minutes.
  • For brain banking, identify the brass plates used for dissection of the CJD sample. They can no longer be used for the dissection or freezing of brain tissues. Prions are known to bind to metal surfaces, and washing with water will not guarantee the removal of prion infectivity. Frozen tissue from the next two cases received and cut fresh on the same brass plate following the CJD sample should be identified and withdrawn from research and either stored with appropriate biohazard labeling or transferred to NPDPSC.

Here’s where to send tissue samples for CJD testing: National Prion Disease Pathology Surveillance Center; Institute for Pathology; Case Western Reserve University; Cleveland, OH 44106. Email:

Occupational exposure guidelines

the World Health Organization (WHO) “Infection Control Guidelines for Transmissible Spongiform Encephalopathies (TSE or Creutzfeldt-Jacob Disease, CJD)” and the information received from Centers for Disease Control and Prevention (CDC), Prion and Public Health Office, there have been no confirmed cases of occupational transmission of TSEs to humans, but it is prudent to take a precautionary approach.

The highest potential risk from exposure to high or low infectivity tissues is through direct inoculation (for example, needle-sticks, puncture wounds, sharps, injuries, or contamination of broken skin). Exposure by splashing or unintentional ingestion may be considered a hypothetical risk and should be avoided.

CSF and blood are classified as low-risk tissues and do not require special precautions for biochemical or cytological testing. Regular precautions applied in the laboratory by following proper laboratory safety procedures and use of PPE for any blood or body fluid sample are protective against CJD as well.

CJD and other forms of TSEs are rare in occurrence. However, the presence of prion disease cannot be taken lightly.

Due to the lengthy incubation period, it becomes an extreme hazard that requires every effort to quickly identify.

Protocols for handling and processing contaminated specimens must be part of every laboratory manual. Treatment for prion disease is mainly supportive and no cure is available at this time.


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Nadine Pizzella, MT(ASCP), serves as the Anatomic Pathology Manager for NorDx Laboratories, Scarborough, ME.

Anthony Kurec, MS, H(ASCP)DLM, is Clinical Associate Professor, Emeritus, SUNY Upstate Medical University, Syracuse, NY, and a member of MLO’s Editorial Advisory Board.


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Prion Diseases | Johns Hopkins Medicine

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Mad Cow Disease (Bovine Spongiform Encephalopathy)

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Mad cow disease, or bovine spongiform encephalopathy (BSE), is a disease that was first found in cattle. It's related to a disease in humans called variant Creutzfeldt-Jakob disease (vCJD).

Both disorders are universally fatal brain diseases caused by a prion. A prion is a protein particle that lacks DNA (nucleic acid). It's believed to be the cause of various infectious diseases of the nervous system.

Eating infected cattle products, including beef, can cause a human to develop mad cow disease.

What is mad cow disease?

Mad cow disease is a progressive, fatal neurological disorder of cattle resulting from infection by a prion. It appears to be caused by contaminated cattle feed that contains the prion agent. Most mad cow disease has happened in cattle in the United Kingdom (U.K.), a few cases were found in cattle in the U.S. between 2003 and 2006. Feed regulations were then tightened.

In addition to the cases of mad cow reported in the U.K. (78% of all cases were reported there) and the U.S., cases have also been reported in other countries, including France, Spain, Netherlands, Portugal, Ireland, Italy, Japan, Saudi Arabia, and Canada.

Public health control measures have been implemented in many of the countries to prevent potentially infected tissues from entering the human food chain. These preventative measures appear to have been effective.

For instance, Canada believes its prevention measures will wipe out the disease from its cattle population by 2017.

What is variant Creutzfeldt-Jakob Disease (vCJD)?

Creutzfeldt-Jakob Disease (CJD) is a rare, fatal brain disorder. It causes a rapid, progressive dementia (deterioration of mental functions), as well as associated neuromuscular disturbances. The disease, which in some ways resembles mad cow disease, traditionally has affected men and women between the ages of 50 and 75.

The variant form, however, affects younger people (the average age of onset is 28) and has observed features that are not typical as compared with CJD. About 230 people with vCJD have been identified since 1996. Most are from the U.K. and other countries in Europe. It is rare in the U.S., with only 4 reported cases since 1996.

What is the current risk of acquiring vCJD from eating beef and beef products produced from cattle in Europe?

Currently this risk appears to be very small, perhaps fewer than 1 case per 10 billion servings–if the risk exists at all.

Travelers to Europe who are concerned about reducing any risk of exposure can avoid beef and beef products altogether, or can select beef or beef products, such as solid pieces of muscle meat, as opposed to ground beef and sausages.

Solid pieces of beef are less ly to be contaminated with tissues that may hide the mad cow agent. Milk and milk products are not believed to transmit the mad cow agent. You can't get vCJD or CJD by direct contact with a person who has the disease.

Three cases acquired during transfusion of blood from an infected donor have been reported in the U.K. Most human Creutzfeldt-Jakob disease is not vCJD and is not related to beef consumption but is also ly due to prion proteins


Prion Diseases

Prion Diseases | Johns Hopkins Medicine

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Prion diseases comprise several conditions.

A prion is a type of protein that can trigger normal proteins in the brain to fold abnormally. Prion diseases can affect both humans and animals and are sometimes spread to humans by infected meat products.

The most common form of prion disease that affects humans is Creutzfeldt-Jakob disease (CJD).

Prion diseases are rare. About 300 cases are reported each year in the U.S.

Types of prion diseases include:

  • CJD. A person can inherit this condition, in which case it's called familial CJD. Sporadic CJD, on the other hand, develops suddenly without any known risk factors. Most cases of CJD are sporadic and tend to strike people around age 60. Acquired CJD is caused by exposure to infected tissue during a medical procedure, such as a cornea transplant. Symptoms of CJD (see below) quickly lead to severe disability and death. In most cases, death occurs within a year.
  • Variant CJD. This is an infectious type of the disease that is related to “mad cow disease.” Eating diseased meat may cause the disease in humans. The meat may cause normal human prion protein to develop abnormally. This type of the disease usually affects younger people.
  • Variably protease-sensitive prionopathy (VPSPr). This is also extremely rare, it is similar to CJD but the protein is less sensitive to digestion. It is more ly to strike people around age 70 who have a family history of dementia.
  • Gerstmann-Sträussler-Scheinker disease (GSS). Extremely rare, but occurs at an earlier age, typically around age 40.
  • Kuru. This disease is seen in New Guinea. It's caused by eating human brain tissue contaminated with infectious prions. Because of increased awareness about the disease and how it is transmitted, kuru is now rare.
  • Fatal insomnia (FI). Rare hereditary disorder causing difficulty sleeping. There is also a sporadic form of the disease that is not inherited.

What causes prion disease?

Prion diseases occur when normal prion protein, found on the surface of many cells, becomes abnormal and clump in the brain, causing brain damage.

This abnormal accumulation of protein in the brain can cause memory impairment, personality changes, and difficulties with movement.

Experts still don't know a lot about prion diseases, but unfortunately, these disorders are generally fatal.

Who is at risk for prion diseases?

Risk factors for prion disease include:

  • Family history of prion disease
  • Eating meat infected by “mad cow disease”
  • Infection from receiving contaminated corneas or from contaminated medical equipment

What are the symptoms of prion diseases?

Symptoms of prion diseases include:

  • Rapidly developing dementia
  • Difficulty walking and changes in gait
  • Hallucinations
  • Muscle stiffness
  • Confusion
  • Fatigue
  • Difficulty speaking

Prion diseases are confirmed by taking a sample of brain tissue during a biopsy or after death. Healthcare providers, however, can do a number of tests before to help diagnose prion diseases such as CJD, or to rule out other diseases with similar symptoms. Prion diseases should be considered in all people with rapidly progressive dementia.

The tests include:

  • MRI (magnetic resonance imaging) scans of the brain
  • Samples of fluid from the spinal cord (spinal tap, also called lumbar puncture)
  • Electroencephalogram, which analyzes brain waves; this painless test requires placing electrodes on the scalp
  • Blood tests
  • Neurologic and visual exams to check for nerve damage and vision loss

How are prion diseases treated?

Prion diseases can't be cured, but certain medicines may help slow their progress. Medical management focuses on keeping people with these diseases as safe and comfortable as possible, despite progressive and debilitating symptoms.

Can prion diseases be prevented?

Properly cleaning and sterilizing medical equipment may prevent the spread of the disease. If you have or may have CJD, do not donate organs or tissue, including corneal tissue.
Newer regulations that govern the handling and feeding of cows may help prevent the spread of prion diseases.

Living with prion diseases

As prion diseases progress, people with these diseases generally need help taking care of themselves. In some cases they may be able to stay in their homes, but they eventually may need to move to a care facility.

Key points about prion diseases

  • Prion diseases are very rare.
  • Symptoms can progress rapidly requiring help with daily needs.
  • Prion diseases are always fatal.

Next steps

Tips to help you get the most from a visit to your healthcare provider:

  • Know the reason for your visit and what you want to happen.
  • Before your visit, write down questions you want answered.
  • Bring someone with you to help you ask questions and remember what your provider tells you.
  • At the visit, write down the name of a new diagnosis, and any new medicines, treatments, or tests. Also write down any new instructions your provider gives you.
  • Know why a new medicine or treatment is prescribed, and how it will help you. Also know what the side effects are.
  • Ask if your condition can be treated in other ways.
  • Know why a test or procedure is recommended and what the results could mean.
  • Know what to expect if you do not take the medicine or have the test or procedure.
  • If you have a follow-up appointment, write down the date, time, and purpose for that visit.
  • Know how you can contact your provider if you have questions.


Prion Disease | Johns Hopkins Psychiatry Guide

Prion Diseases | Johns Hopkins Medicine

— The first section of this topic is shown below —

  • Prion diseases are rare and invariably fatal neurodegenerative disorders caused by transmissible misfolded prion proteins.
    • The “prion protein” that causes all known mammalian prion diseases is a misfolded form of protease-resistant protein (PRP).
    • The endogenous, properly folded form is PRPc (for Common or Cellular), whereas the misfolded protein is PRPsc (for SCrapie).
  • Collectively these are known as transmissible spongiform encephalopathies.
    • They primarily affect the central nervous system of humans and other mammals.
    • Discussed here are Creutzfeldt-Jakob disease, variant Creutzfeldt-Jakob disease, kuru, Gerstmann-Sträussler-Scheinker syndrome, fatal familial insomnia.
  • The condition may be hereditary, idiopathic, or acquired through exposure to affected tissues or contaminated surgical instruments.
  • Cognitive impairment due to prion disease is classified under the neurocognitive disorders (NCDs) section of the Diagnostic and Statistical Manual of Mental Disorders, 5th Edition (DSM-5)[1].

— To view the remaining sections of this topic, please sign in or purchase a subscription —

  • Prion diseases are rare and invariably fatal neurodegenerative disorders caused by transmissible misfolded prion proteins.
    • The “prion protein” that causes all known mammalian prion diseases is a misfolded form of protease-resistant protein (PRP).
    • The endogenous, properly folded form is PRPc (for Common or Cellular), whereas the misfolded protein is PRPsc (for SCrapie).
  • Collectively these are known as transmissible spongiform encephalopathies.
    • They primarily affect the central nervous system of humans and other mammals.
    • Discussed here are Creutzfeldt-Jakob disease, variant Creutzfeldt-Jakob disease, kuru, Gerstmann-Sträussler-Scheinker syndrome, fatal familial insomnia.
  • The condition may be hereditary, idiopathic, or acquired through exposure to affected tissues or contaminated surgical instruments.
  • Cognitive impairment due to prion disease is classified under the neurocognitive disorders (NCDs) section of the Diagnostic and Statistical Manual of Mental Disorders, 5th Edition (DSM-5)[1].

There's more to see — the rest of this entry is available only to subscribers.

Yin, Ophelia, and Chiadi Onyike‎. “Prion Disease.” Johns Hopkins Psychiatry Guide, 2017. Johns Hopkins Guide, Yin O, Onyike‎ C. Prion Disease. Johns Hopkins Psychiatry Guide. 2017. Accessed May 18, 2020.Yin, O., & Onyike‎, C. (2017). Prion Disease. In Johns Hopkins Psychiatry Guide Retrieved May 18, 2020, from O, Onyike‎ C. Prion Disease [Internet]. In: Johns Hopkins Psychiatry Guide. ; 2017. [cited 2020 May 18]. Available from:* Article titles in AMA citation format should be in sentence-caseMLAAMAAPAVANCOUVERTY – ELECT1 – Prion DiseaseID – 787113A1 – Yin,Ophelia,AU – Onyike‎,Chiadi,M.D.Y1 – 2017/02/26/BT – Johns Hopkins Psychiatry GuideUR – – Johns Hopkins GuideDP – Unbound MedicineER –