Transmissible Spongiform Encephalopathies

Transmissible spongiform encephalopathies are diseases caused by prions Prions Small proteinaceous infectious particles which resist inactivation by procedures that modify nucleic acids and contain an abnormal isoform of a cellular protein which is a major and necessary component. The abnormal (scrapie) isoform is prpsc (prpsc proteins) and the cellular isoform prpc (prpc proteins). The primary amino acid sequence of the two isoforms is identical. Human diseases caused by prions include creutzfeldt-jakob syndrome; gerstmann-straussler syndrome; and insomnia, fatal familial. Virology. Prions Prions Small proteinaceous infectious particles which resist inactivation by procedures that modify nucleic acids and contain an abnormal isoform of a cellular protein which is a major and necessary component. The abnormal (scrapie) isoform is prpsc (prpsc proteins) and the cellular isoform prpc (prpc proteins). The primary amino acid sequence of the two isoforms is identical. Human diseases caused by prions include creutzfeldt-jakob syndrome; gerstmann-straussler syndrome; and insomnia, fatal familial. Virology differ from viruses Viruses Minute infectious agents whose genomes are composed of DNA or RNA, but not both. They are characterized by a lack of independent metabolism and the inability to replicate outside living host cells. Virology in that they are small, infectious pathogens that do not contain nucleic acid. Recognized spongiform encephalopathies include Creutzfeldt-Jakob Disease (CJD), variant Creutzfeldt-Jakob Disease (vCJD), Kuru, fatal familial insomnia Insomnia Insomnia is a sleep disorder characterized by difficulty in the initiation, maintenance, and consolidation of sleep, leading to impairment of function. Patients may exhibit symptoms such as difficulty falling asleep, disrupted sleep, trouble going back to sleep, early awakenings, and feeling tired upon waking. Insomnia (FFI), and Gerstmann-Straussler syndrome (GSS). Common characteristics of these diseases include dementia Dementia Major neurocognitive disorders (NCD), also known as dementia, are a group of diseases characterized by decline in a person's memory and executive function. These disorders are progressive and persistent diseases that are the leading cause of disability among elderly people worldwide. Major Neurocognitive Disorders, ataxia Ataxia Impairment of the ability to perform smoothly coordinated voluntary movements. This condition may affect the limbs, trunk, eyes, pharynx, larynx, and other structures. Ataxia may result from impaired sensory or motor function. Sensory ataxia may result from posterior column injury or peripheral nerve diseases. Motor ataxia may be associated with cerebellar diseases; cerebral cortex diseases; thalamic diseases; basal ganglia diseases; injury to the red nucleus; and other conditions. Ataxia-telangiectasia, and myoclonus Myoclonus Involuntary shock-like contractions, irregular in rhythm and amplitude, followed by relaxation, of a muscle or a group of muscles. This condition may be a feature of some central nervous system diseases; (e.g., epilepsy-myoclonic). Nocturnal myoclonus is the principal feature of the nocturnal myoclonus syndrome. Neurological Examination. Unfortunately, these diseases are associated with long incubation Incubation The amount time between exposure to an infectious agent and becoming symptomatic. Rabies Virus periods (20+ years) and once symptoms occur, rapidly progress to death.

Last updated: Jan 20, 2025

Editorial responsibility: Stanley Oiseth, Lindsay Jones, Evelin Maza

Contents

Epidemiology and Etiology

Pathophysiology

Clinical Presentation and Diagnosis

Differential Diagnosis

References

Epidemiology and Etiology

Epidemiology

Spongiform encephalopathies are extremely rare.

Known human diseases:

Creutzfeldt-Jakob Disease (CJD)
Kuru
Fatal familial insomnia Insomnia Insomnia is a sleep disorder characterized by difficulty in the initiation, maintenance, and consolidation of sleep, leading to impairment of function. Patients may exhibit symptoms such as difficulty falling asleep, disrupted sleep, trouble going back to sleep, early awakenings, and feeling tired upon waking. Insomnia (FFI)
Gerstmann-Straussler syndrome (GSS) ( incidence Incidence The number of new cases of a given disease during a given period in a specified population. It also is used for the rate at which new events occur in a defined population. It is differentiated from prevalence, which refers to all cases in the population at a given time. Measures of Disease Frequency: 1 per 100 million new cases per year)

The most common spongiform encephalopathy Encephalopathy Hyper-IgM Syndrome is Creutzfeldt-Jakob disease. The variations are:

Sporadic Sporadic Selective IgA Deficiency Creutzfeldt-Jakob disease (sCJD):
- Incidence Incidence The number of new cases of a given disease during a given period in a specified population. It also is used for the rate at which new events occur in a defined population. It is differentiated from prevalence, which refers to all cases in the population at a given time. Measures of Disease Frequency: 1 per 1,000,000 cases per year (90% of cases)
- Mean age of onset is 62 years of age
Variant Creutzfeldt-Jakob disease (vCJD) and iatrogenic Iatrogenic Any adverse condition in a patient occurring as the result of treatment by a physician, surgeon, or other health professional, especially infections acquired by a patient during the course of treatment. Anterior Cord Syndrome Creutzfeldt-Jakob disease (iCJD): younger age of onset (not clearly defined)
Genetic Creutzfeldt-Jakob disease (gCJD): clusters exist in North Africa, Israel, and Italy

Etiology

High-risk factors are:

Cannibalism (Kuru)
Family history Family History Adult Health Maintenance of gCJD, GSS, or FFI

Pathophysiology

Prion diseases occur when a normal, ⍺-helical protein known as PrPc is converted into an abnormal, β-pleated protein known as PrPsc.

Can be thought of as a “protein-misfolding” disease
Abnormal PrP PRP Raynaud Phenomenon^sc is resistant to protease Protease Enzyme of the human immunodeficiency virus that is required for post-translational cleavage of gag and gag-pol precursor polyproteins into functional products needed for viral assembly. HIV protease is an aspartic protease encoded by the amino terminus of the pol gene. HIV Infection and AIDS degradation, which facilitates conversion of PrP PRP Raynaud Phenomenon^c into abnormal PrP PRP Raynaud Phenomenon^sc. This constant conversion slowly replaces normal proteins Proteins Linear polypeptides that are synthesized on ribosomes and may be further modified, crosslinked, cleaved, or assembled into complex proteins with several subunits. The specific sequence of amino acids determines the shape the polypeptide will take, during protein folding, and the function of the protein. Energy Homeostasis.
PrP PRP Raynaud Phenomenon^sc accumulates in lymphoreticular and secretory organs
- Spreads to the central nervous system Central nervous system The main information-processing organs of the nervous system, consisting of the brain, spinal cord, and meninges. Nervous System: Anatomy, Structure, and Classification (CNS) → astrocytosis → loss of neurons Neurons The basic cellular units of nervous tissue. Each neuron consists of a body, an axon, and dendrites. Their purpose is to receive, conduct, and transmit impulses in the nervous system. Nervous System: Histology → vacuolation of the brain Brain The part of central nervous system that is contained within the skull (cranium). Arising from the neural tube, the embryonic brain is comprised of three major parts including prosencephalon (the forebrain); mesencephalon (the midbrain); and rhombencephalon (the hindbrain). The developed brain consists of cerebrum; cerebellum; and other structures in the brain stem. Nervous System: Anatomy, Structure, and Classification
- This process causes the classic symptoms of spongiform encephalopathy Encephalopathy Hyper-IgM Syndrome:
  - Cerebellar ataxia Cerebellar ataxia Incoordination of voluntary movements that occur as a manifestation of cerebellar diseases. Characteristic features include a tendency for limb movements to overshoot or undershoot a target (dysmetria), a tremor that occurs during attempted movements (intention tremor), impaired force and rhythm of diadochokinesis (rapidly alternating movements), and gait ataxia. Cerebellar Disorders
  - Dementia Dementia Major neurocognitive disorders (NCD), also known as dementia, are a group of diseases characterized by decline in a person’s memory and executive function. These disorders are progressive and persistent diseases that are the leading cause of disability among elderly people worldwide. Major Neurocognitive Disorders
  - Death

Prions abnormal proteins — Prions are usually located at the outer surfaces of neurons. When the PrP^sc (abnormal protein) is acquired in the organism, it will approach the mucosal surface of the intestine and cause normal prion proteins to convert into pathogenic form.
Image by Lecturio.

Prions are usually located at the outer surfaces of neurons. When the PrP^sc (abnormal protein) is acquired in the organism, it will approach the mucosal surface of the intestine and cause normal prion proteins to convert into pathogenic form.
Image by Lecturio.

Transmission

There are 3 primary ways of developing spongiform encephalopathies:

Acquired or infectious:
- Direct exposure to CNS-infected tissues, such as in a corneal transplant (iCJD)
- Administration of cadaveric human pituitary Pituitary A small, unpaired gland situated in the sella turcica. It is connected to the hypothalamus by a short stalk which is called the infundibulum. Hormones: Overview and Types hormones Hormones Hormones are messenger molecules that are synthesized in one part of the body and move through the bloodstream to exert specific regulatory effects on another part of the body. Hormones play critical roles in coordinating cellular activities throughout the body in response to the constant changes in both the internal and external environments. Hormones: Overview and Types (iCJD)
- Ingestion of food contaminated by bovine spongiform encephalopathy Encephalopathy Hyper-IgM Syndrome (BSE)-infected (“mad cow”) animal products (vCJD)
- Cannibalism of CNS-infected tissues (Kuru)
Genetics Genetics Genetics is the study of genes and their functions and behaviors. Basic Terms of Genetics:
- Mutation Mutation Genetic mutations are errors in DNA that can cause protein misfolding and dysfunction. There are various types of mutations, including chromosomal, point, frameshift, and expansion mutations. Types of Mutations from parental PrP PRP Raynaud Phenomenon^c into abnormal PrP PRP Raynaud Phenomenon^sc (gCJD, FFI, GSS)
Spontaneous:
- Sudden misfolding of PrP PRP Raynaud Phenomenon^c into abnormal PrP PRP Raynaud Phenomenon^sc (sCJD)

Mad cow disease transmission — Origins of prion diseases
Image by Lecturio.

Clinical Presentation and Diagnosis

Transmissible spongiform encephalopathies are associated with extremely long incubation Incubation The amount time between exposure to an infectious agent and becoming symptomatic. Rabies Virus times (20–50 years) and once symptoms appear, the disease rapidly progresses to death.

No curative measures exist and the diseases are universally fatal.

**Clinical presentation and diagnosis of transmissible spongiform encephalopathies**
	Symptoms	Diagnosis
Creutzfeldt-Jakob disease	Rapidly progressive dementia Dementia Major neurocognitive disorders (NCD), also known as dementia, are a group of diseases characterized by decline in a person’s memory and executive function. These disorders are progressive and persistent diseases that are the leading cause of disability among elderly people worldwide. Major Neurocognitive Disorders (over weeks to months) Startle myoclonus Myoclonus Involuntary shock-like contractions, irregular in rhythm and amplitude, followed by relaxation, of a muscle or a group of muscles. This condition may be a feature of some central nervous system diseases; (e.g., epilepsy-myoclonic). Nocturnal myoclonus is the principal feature of the nocturnal myoclonus syndrome. Neurological Examination Ataxia Ataxia Impairment of the ability to perform smoothly coordinated voluntary movements. This condition may affect the limbs, trunk, eyes, pharynx, larynx, and other structures. Ataxia may result from impaired sensory or motor function. Sensory ataxia may result from posterior column injury or peripheral nerve diseases. Motor ataxia may be associated with cerebellar diseases; cerebral cortex diseases; thalamic diseases; basal ganglia diseases; injury to the red nucleus; and other conditions. Ataxia-telangiectasia Death within 1 year of symptom onset	Head CT/MRI (magnetic resonance imaging): normal appearance Cerebrospinal fluid Cerebrospinal Fluid A watery fluid that is continuously produced in the choroid plexus and circulates around the surface of the brain; spinal cord; and in the cerebral ventricles. Ventricular System: Anatomy (CSF): ↑ in 14-3-3 protein Electroencephalogram ( EEG EEG Seizures): periodic sharp wave complexes Post-mortem brain biopsy Brain biopsy JC Virus and BK Virus: Intracytoplasmic vacuoles in the spongiform cortex Accumulation of PrP PRP Raynaud Phenomenon^sc on histopathology Neuronal loss
Kuru	First stage: tremors ( shivering Shivering Involuntary contraction or twitching of the muscles. It is a physiologic method of heat production in man and other mammals. Body Temperature Regulation), ataxia Ataxia Impairment of the ability to perform smoothly coordinated voluntary movements. This condition may affect the limbs, trunk, eyes, pharynx, larynx, and other structures. Ataxia may result from impaired sensory or motor function. Sensory ataxia may result from posterior column injury or peripheral nerve diseases. Motor ataxia may be associated with cerebellar diseases; cerebral cortex diseases; thalamic diseases; basal ganglia diseases; injury to the red nucleus; and other conditions. Ataxia-telangiectasia, postural instability Second stage: loss of ambulation, myoclonus Myoclonus Involuntary shock-like contractions, irregular in rhythm and amplitude, followed by relaxation, of a muscle or a group of muscles. This condition may be a feature of some central nervous system diseases; (e.g., epilepsy-myoclonic). Nocturnal myoclonus is the principal feature of the nocturnal myoclonus syndrome. Neurological Examination Late stage: dementia Dementia Major neurocognitive disorders (NCD), also known as dementia, are a group of diseases characterized by decline in a person’s memory and executive function. These disorders are progressive and persistent diseases that are the leading cause of disability among elderly people worldwide. Major Neurocognitive Disorders Death within 1 year of symptom onset	Unknown; few studies have been performed due to limited cases (mostly isolated to Papua New Guinea in the 1950s)
Fatal familial insomnia Insomnia Insomnia is a sleep disorder characterized by difficulty in the initiation, maintenance, and consolidation of sleep, leading to impairment of function. Patients may exhibit symptoms such as difficulty falling asleep, disrupted sleep, trouble going back to sleep, early awakenings, and feeling tired upon waking. Insomnia	In patients Patients Individuals participating in the health care system for the purpose of receiving therapeutic, diagnostic, or preventive procedures. Clinician–Patient Relationship aged 23–73: Progressive insomnia Insomnia Insomnia is a sleep disorder characterized by difficulty in the initiation, maintenance, and consolidation of sleep, leading to impairment of function. Patients may exhibit symptoms such as difficulty falling asleep, disrupted sleep, trouble going back to sleep, early awakenings, and feeling tired upon waking. Insomnia Loss of normal circadian sleep-activity pattern Myoclonus Myoclonus Involuntary shock-like contractions, irregular in rhythm and amplitude, followed by relaxation, of a muscle or a group of muscles. This condition may be a feature of some central nervous system diseases; (e.g., epilepsy-myoclonic). Nocturnal myoclonus is the principal feature of the nocturnal myoclonus syndrome. Neurological Examination Ataxia Ataxia Impairment of the ability to perform smoothly coordinated voluntary movements. This condition may affect the limbs, trunk, eyes, pharynx, larynx, and other structures. Ataxia may result from impaired sensory or motor function. Sensory ataxia may result from posterior column injury or peripheral nerve diseases. Motor ataxia may be associated with cerebellar diseases; cerebral cortex diseases; thalamic diseases; basal ganglia diseases; injury to the red nucleus; and other conditions. Ataxia-telangiectasia Dysautonomia Death within 1 year of symptom onset	Unclear; post-mortem brain biopsy Brain biopsy JC Virus and BK Virus
Gerstmann-Straussler-Scheinker syndrome	In patients Patients Individuals participating in the health care system for the purpose of receiving therapeutic, diagnostic, or preventive procedures. Clinician–Patient Relationship mid-to-late 40s: Progressive cerebellar degeneration (clumsiness, incoordination, ataxia Ataxia Impairment of the ability to perform smoothly coordinated voluntary movements. This condition may affect the limbs, trunk, eyes, pharynx, larynx, and other structures. Ataxia may result from impaired sensory or motor function. Sensory ataxia may result from posterior column injury or peripheral nerve diseases. Motor ataxia may be associated with cerebellar diseases; cerebral cortex diseases; thalamic diseases; basal ganglia diseases; injury to the red nucleus; and other conditions. Ataxia-telangiectasia) Dementia Dementia Major neurocognitive disorders (NCD), also known as dementia, are a group of diseases characterized by decline in a person’s memory and executive function. These disorders are progressive and persistent diseases that are the leading cause of disability among elderly people worldwide. Major Neurocognitive Disorders Death within 5 years of symptom onset	Post-mortem brain biopsy Brain biopsy JC Virus and BK Virus

Biopsy brain of a cow with bovine spongiform encephalopathy — Section of the brain from a cow infected with bovine spongiform encephalopathy. The brown staining indicates the presence of the agent causing the disease.
Image: “Mad_Cow_Disease” by CSIRO. License: CC BY 3.0

Variant creutzfeldt jacob disease — Section of the brain from a cow infected with bovine spongiform encephalopathy. The brown staining indicates the presence of the agent causing the disease.
Image: “Mad_Cow_Disease” by CSIRO. License: CC BY 3.0

Differential Diagnosis

Differential diagnosis includes diseases that are associated with rapidly progressing dementia Dementia Major neurocognitive disorders (NCD), also known as dementia, are a group of diseases characterized by decline in a person’s memory and executive function. These disorders are progressive and persistent diseases that are the leading cause of disability among elderly people worldwide. Major Neurocognitive Disorders, including the following:

Dementia Dementia Major neurocognitive disorders (NCD), also known as dementia, are a group of diseases characterized by decline in a person’s memory and executive function. These disorders are progressive and persistent diseases that are the leading cause of disability among elderly people worldwide. Major Neurocognitive Disorders with Lewy bodies Lewy bodies Intracytoplasmic, eosinophilic, round to elongated inclusions found in vacuoles of injured or fragmented neurons. The presence of lewy bodies is the histological marker of the degenerative changes in lewy body disease and parkinson disease but they may be seen in other neurological conditions. They are typically found in the substantia nigra and locus coeruleus but they are also seen in the basal forebrain, hypothalamic nuclei, and neocortex. Parkinson’s Disease:
- Can be rapidly progressing
- Associated with dementia Dementia Major neurocognitive disorders (NCD), also known as dementia, are a group of diseases characterized by decline in a person’s memory and executive function. These disorders are progressive and persistent diseases that are the leading cause of disability among elderly people worldwide. Major Neurocognitive Disorders, visual hallucinations Hallucinations Subjectively experienced sensations in the absence of an appropriate stimulus, but which are regarded by the individual as real. They may be of organic origin or associated with mental disorders. Schizophrenia, and syncope Syncope Syncope is a short-term loss of consciousness and loss of postural stability followed by spontaneous return of consciousness to the previous neurologic baseline without the need for resuscitation. The condition is caused by transient interruption of cerebral blood flow that may be benign or related to a underlying life-threatening condition. Syncope
- Histologic findings: intracellular Lewy bodies Lewy bodies Intracytoplasmic, eosinophilic, round to elongated inclusions found in vacuoles of injured or fragmented neurons. The presence of lewy bodies is the histological marker of the degenerative changes in lewy body disease and parkinson disease but they may be seen in other neurological conditions. They are typically found in the substantia nigra and locus coeruleus but they are also seen in the basal forebrain, hypothalamic nuclei, and neocortex. Parkinson’s Disease (⍺-synuclein)
Frontotemporal dementia Dementia Major neurocognitive disorders (NCD), also known as dementia, are a group of diseases characterized by decline in a person’s memory and executive function. These disorders are progressive and persistent diseases that are the leading cause of disability among elderly people worldwide. Major Neurocognitive Disorders (Pick’s disease):
- Associated with early changes in personality and behavior that progress to parkinsonism-like movement
- MRI: frontotemporal lobe degeneration
Vascular dementia Dementia Major neurocognitive disorders (NCD), also known as dementia, are a group of diseases characterized by decline in a person’s memory and executive function. These disorders are progressive and persistent diseases that are the leading cause of disability among elderly people worldwide. Major Neurocognitive Disorders:
- Generally stepwise decline in neurological function with late-onset memory Memory Complex mental function having four distinct phases: (1) memorizing or learning, (2) retention, (3) recall, and (4) recognition. Clinically, it is usually subdivided into immediate, recent, and remote memory. Psychiatric Assessment impairment
- MRI: multiple cortical infarctions
Alzheimer’s disease:
- Most common cause of dementia Dementia Major neurocognitive disorders (NCD), also known as dementia, are a group of diseases characterized by decline in a person’s memory and executive function. These disorders are progressive and persistent diseases that are the leading cause of disability among elderly people worldwide. Major Neurocognitive Disorders in the elderly
- Symptoms often develop gradually
- MRI: cortical and hippocampal atrophy Atrophy Decrease in the size of a cell, tissue, organ, or multiple organs, associated with a variety of pathological conditions such as abnormal cellular changes, ischemia, malnutrition, or hormonal changes. Cellular Adaptation

References

Baiardi, S., Capellari, S., Bartoletti-Stella, A., & Parchi, P. (2023). Human Prion Disease: Molecular Pathogenesis, and Possible Therapeutic Targets and Strategies. Expert Opinion on Therapeutic Targets, 27(12), 1271–1284. https://doi.org/10.1080/14728222.2023.2199923
Geschwind M. D. (2015). Prion Diseases. Continuum (Minneapolis, Minn.), 21(6 Neuroinfectious Disease), 1612–1638. https://doi.org/10.1212/CON.0000000000000251
Ironside, J. W., Ritchie, D. L., & Head, M. W. (2017). Prion diseases. Handbook of clinical neurology, 145, 393–403. https://doi.org/10.1016/B978-0-12-802395-2.00028-6
Liu, F., Lü, W., & Liu, L. (2024). New implications for prion diseases therapy and prophylaxis. Frontiers in molecular neuroscience, 17, 1324702. https://doi.org/10.3389/fnmol.2024.1324702
Prusiner S. B. (2013). Biology and genetics of prions causing neurodegeneration. Annual review of genetics, 47, 601–623. https://doi.org/10.1146/annurev-genet-110711-155524
Appleby, B. S., & Cohen, M. L. (2024). Creutzfeldt-Jakob disease. UpToDate, Inc. Retrieved January 19, 2025, from https://www.uptodate.com/contents/creutzfeldt-jakob-disease
National Institute of Neurological Disorders and Stroke. (n.d.). Kuru. U.S. Department of Health and Human Services. Retrieved January 19, 2025, from https://www.ninds.nih.gov/health-information/disorders/kuru
World Health Organization. (2003). WHO guidelines on transmissible spongiform encephalopathies in relation to biological and pharmaceutical products. World Health Organization. Retrieved January 19, 2025, from https://www.who.int/publications/m/item/who-guidelines-on-transmissible-spongiform-encephalopathies

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