Creutzfeldt-Jakob Disease (CJD) TAU Prion and Gene PRNP Overview

Creutzfeldt-Jakob disease (CJD) is a rare, degenerative, and fatal brain disorder caused by abnormal prion proteins that damage brain cells.

Diagnosing Creutzfeldt-Jakob disease (CJD) involves ruling out other conditions and identifying typical signs of the disease through various tests, as there is no single test for definitive diagnosis during life.

Creutzfeldt-Jakob disease (CJD) is triggered by misfolded prion proteins, which cause a chain reaction of abnormal folding in healthy prion proteins in the brain, leading to brain damage and rapid neurological decline. The exact cause of prion misfolding is not entirely understood, but CJD can arise in different ways:

• Definition: CJD is a rare, degenerative, and fatal brain disorder caused by abnormal prion proteins that damage brain cells.
• Trigger: Triggered by misfolded prion proteins, which cause a chain reaction of abnormal folding in healthy prion proteins in the brain, leading to brain damage and rapid neurological decline.
• Types of CJD:
  • Sporadic CJD (sCJD): The most common form, accounting for about 85% of cases. It arises spontaneously with no known cause.
  • Genetic or Familial CJD (fCJD): Inherited and caused by mutations in the PRNP gene, making up about 10–15% of cases.
  • Acquired CJD:
    • Variant CJD (vCJD): Linked to eating prion-contaminated meat (e.g., from cattle with Bovine Spongiform Encephalopathy, "mad cow disease").
    • Iatrogenic CJD: Caused by exposure to contaminated medical equipment or tissues (e.g., corneal transplants, dura mater grafts, or growth hormone from infected tissue).

Symptoms of CJD

• Early Stage: Memory loss, personality changes, impaired thinking, and blurred vision.
• Progression: Rapid mental decline, muscle stiffness, involuntary movements, difficulty speaking and swallowing, and coordination problems.
• Late Stage: Severe dementia, coma, and often death within a year of onset.

Diagnostic Methods for CJD

1. Clinical Evaluation:

   • Assessment of rapid cognitive decline, coordination issues, and muscle stiffness.
   • Review of medical history, focusing on rapid onset of dementia and neurological symptoms.

2. Electroencephalogram (EEG):

   • May show a unique brainwave pattern called periodic sharp wave complexes, though this is not always present in CJD.

3. MRI (Magnetic Resonance Imaging):

   • Certain MRI sequences, especially diffusion-weighted imaging (DWI), reveal specific changes in the basal ganglia and cerebral cortex, which are characteristic of CJD.

4. Cerebrospinal Fluid (CSF) Testing:

   • 14-3-3 Protein: Elevated in CJD due to rapid brain cell death, though not exclusive to CJD.
   • Tau Protein: High total tau levels support a CJD diagnosis when combined with elevated 14-3-3 protein.
   • RT-QuIC (Real-Time Quaking-Induced Conversion): Highly sensitive and specific for prion diseases, detecting misfolded prion proteins directly and providing a strong indication of CJD.
   • S100B Protein (less common): Elevated as a marker of brain injury but not specific to CJD.

5. Genetic Testing:

   • Useful for familial CJD, with genetic testing for mutations in the PRNP gene associated with inherited prion diseases.

6. Brain Biopsy:

   • Rarely performed due to invasiveness and risk, reserved for cases where other tests are inconclusive. A definitive diagnosis is typically confirmed through postmortem brain tissue examination.

Key Cerebrospinal Fluid (CSF) Markers for CJD

• 14-3-3 Protein: Elevated levels support a CJD diagnosis, indicating rapid brain cell death.
• Tau Protein: High levels specific to CJD when combined with other supportive markers.
• RT-QuIC: Detects misfolded prions with high specificity and sensitivity, making it a key tool in diagnosing prion diseases.
• S100B Protein: Indicates brain injury but is less specific to CJD.

Treatment and Management

• No Cure: Treatment is supportive, focusing on relieving symptoms such as pain, muscle spasms, and agitation.
• Supportive Care: Physical and occupational therapy, along with supportive care, help manage symptoms and improve comfort.
• Quality of Life: Since CJD progresses quickly, care focuses on enhancing quality of life for patients and supporting families.

Genetics of CJD

• The PRNP gene encodes the prion protein and plays a significant role in prion diseases. Certain SNPs (e.g., rs1799990, also known as M129V polymorphism) are associated with susceptibility to CJD and other prion diseases.

For familial CJD (fCJD), genetic testing may identify mutations in the PRNP gene that are linked to inherited forms of the disease.

 

Segment of genomic data associated with the PRNP gene on chromosome 20.
The table lists specific SNP markers (single nucleotide polymorphisms), their positions in two genome assemblies (Build 37 and Build 38), the possible variants (alleles), and the individual’s genotype at each position.

For example: See graphic

    rs1799990 (M129V): The genotype A/G here corresponds to heterozygosity at this site, sometimes referred to as M/V (methionine/valine) heterozygosity, which is associated with different risks in prion disease susceptibility.

Here's a summary of what each row indicates:

    PRNP rs117575976

        Position: 4671835 (Build 37), 4691189 (Build 38)

        Variants: A or C

        Genotype: A/A

0 citations

     PRNP rs6107516

        Position: 4677092 (Build 37), 4696446 (Build 38)

        Variants: A or G

        Genotype: A/G
25918841          A genome wide association study links glutamate receptor pathway to sporadic Creutzfeldt-Jakob disease risk.          Sanchez-Juan P et al.   2014     PloS one

22137330          Genome-wide study links MTMR7 gene to variant Creutzfeldt-Jakob risk.                Sanchez-Juan P et al.   2012     Neurobiology of aging

22210626          Genome-wide association study in multiple human prion diseases suggests genetic risk factors additional to PRNP.         Mead S et al.    2012     Human molecular genetics

22988944          Network-based SNP meta-analysis identifies joint and disjoint genetic features across common human diseases.     Arnold M et al. 2012     BMC genomics

19081515          Genetic risk factors for variant Creutzfeldt-Jakob disease: a genome-wide association study.             Mead S et al.    2009     The Lancet. Neurology

    PRNP rs1799990

        Position: 4680251 (Build 37), 4699065 (Build 38)

        Variants: A or G

        Genotype: A/G

71 citations https://www.ncbi.nlm.nih.gov/snp/rs1799990#publications
ONE example: 16023289          Genetic influences on oxidative stress and their association with normal cognitive ageing.
Quote: “Reactive oxygen species produced during normal aerobic metabolism damage cellular macromolecules. The brain is particularly susceptible to oxidative stress due to its high rate of aerobic metabolism.”

     PRNP rs150351644

        Position: 4680290 (Build 37), 4699644 (Build 38)

        Variants: A or G

        Genotype: G/G
0 citations

    PRNP rs181348299

        Position: 4680309 (Build 37), 4699663 (Build 38)

        Variants: A or G

        Genotype: G/G

0 citations 

Medications That May Provide Symptom Relief

1. Pain Management:

   • Opioids (e.g., morphine): Can be used to manage severe pain, especially in later stages, to keep the patient comfortable.

2. Muscle Stiffness and Spasms:

   • Muscle Relaxants (e.g., baclofen, clonazepam): These can help reduce muscle rigidity and involuntary muscle spasms, improving mobility and reducing discomfort.

3. Agitation and Anxiety:

   • Antipsychotics (e.g., haloperidol, quetiapine): Sometimes used to manage agitation, aggression, or hallucinations, though doses should be low to prevent excessive sedation.
   • Benzodiazepines (e.g., lorazepam): May be used sparingly for acute agitation or severe anxiety but can cause drowsiness and confusion.

4. Seizure Control:

   • Antiepileptic drugs (e.g., valproate, levetiracetam): Used to control seizures, which can occur in advanced CJD.

Medications to Avoid or Use Cautiously

1. Anticholinergics:

   • Medications with strong anticholinergic effects (e.g., diphenhydramine, some antidepressants like amitriptyline) should generally be avoided, as they can exacerbate confusion and cognitive decline.

2. Sedatives and Hypnotics:

   • Excessive use of sedative medications (e.g., benzodiazepines in high doses, barbiturates) can worsen disorientation, increase fall risk, and further impair cognition. If used, they should be closely monitored.

3. Neuroleptics with Strong Side Effects:

   • Older antipsychotics like haloperidol can sometimes lead to excessive sedation, muscle stiffness, and movement problems, especially in the elderly. Newer antipsychotics like quetiapine may be preferred, though used in low doses.

General Recommendations

• Symptom-focused Approach: Since CJD progresses rapidly, medications should primarily target symptom relief and comfort rather than aggressive interventions.
• Monitoring for Side Effects: Many CJD patients are highly sensitive to medications, especially those affecting the central nervous system, so doses should be carefully adjusted to minimize side effects.
• Non-Pharmacologic Support: Supportive care, including physical and occupational therapy, is essential to help manage symptoms and maximize comfort.

 

 © 2000-2025 Sieglinde W. Alexander. All writings by Sieglinde W. Alexander have a fife year copy right.
Library of Congress Card Number: LCN 00-192742 ISBN: 0-9703195-0-9