Creutzfeldt-Jakob Disease (CJD) is an extremely rare, fatal neurodegenerative disorder that belongs to a group of conditions known as transmissible spongiform encephalopathies (TSEs). CJD is characterized by rapidly progressive dementia and the loss of muscle coordination, leading to death typically within one year of symptom onset. The fundamental cause across all forms of this disease is the accumulation of an abnormal infectious protein in the brain.
The Underlying Cause: Prions
The mechanism behind Creutzfeldt-Jakob Disease centers on a unique infectious agent called a prion, which is an acronym for proteinaceous infectious particle. Prions are distinct from viruses or bacteria because they contain no genetic material like DNA or RNA, existing solely as a misfolded protein. The disease starts when the normal cellular prion protein (PrPC) changes its three-dimensional shape into the infectious, disease-causing form (PrPSc).
This misfolded PrPSc acts as a template, triggering a chain reaction that forces surrounding normal PrPC molecules to also change their structure. The transformation involves the normal alpha-helical structure shifting to a beta-pleated sheet conformation, which is highly stable and resistant to the body’s normal mechanisms for protein breakdown. As these abnormal proteins accumulate, they form insoluble aggregates and plaques within the central nervous system, leading to the death of nerve cells.
The resulting damage causes the brain tissue to develop numerous microscopic holes, giving it a sponge-like appearance, which is why CJD is classified as a spongiform encephalopathy. This progressive neuronal destruction accounts for the rapid decline in mental and physical functions observed in affected individuals.
Sporadic Creutzfeldt-Jakob Disease
The majority of Creutzfeldt-Jakob Disease cases, approximately 85%, are classified as sporadic CJD (sCJD). The term “sporadic” indicates that the disease develops spontaneously without a known cause, a genetic mutation, or any external source of infection. The prevailing theory suggests that the normal prion protein spontaneously misfolds into the abnormal PrPSc form due to an error in the cell’s protein quality control machinery.
This spontaneous misfolding is thought to be a chance event, and it is more likely to occur with advancing age. Most people diagnosed with sporadic CJD are between 60 and 65 years old, and the incidence increases with age. The rapid progression of this form means that about 70% of those affected die within one year of the onset of symptoms.
Sporadic CJD is considered an endemic disease, occurring at a rate of about one to two cases per million people globally each year. The lack of a family history or a clear external exposure distinguishes this most common form from the others.
Inherited Creutzfeldt-Jakob Disease
The inherited or familial form of CJD accounts for a smaller but significant proportion of cases, ranging from 5% to 15%. This type is directly caused by a mutation in the PRNP gene, which provides the instructions for making the normal prion protein (PrPC). Over 20 different pathogenic mutations have been identified in the PRNP gene, located on chromosome 20.
These specific genetic alterations make the PrPC protein structurally unstable and highly susceptible to spontaneously misfolding into the infectious PrPSc form. Inherited CJD typically follows an autosomal dominant pattern of inheritance, meaning a child has a 50% chance of inheriting the mutation if one parent carries it. The presence of the mutation is highly penetrant, meaning it almost guarantees the eventual development of the disease.
Familial CJD often manifests at a younger age than the sporadic form, with some types appearing as early as ages 20 to 40. Related hereditary prion diseases also caused by PRNP gene mutations include Gerstmann-Sträussler-Scheinker syndrome (GSS) and Fatal Familial Insomnia (FFI).
Acquired Creutzfeldt-Jakob Disease
The rarest form of CJD is acquired CJD, accounting for less than 1% of all cases, where the disease is contracted through external exposure to the infectious prion. This category is divided primarily into two types: iatrogenic CJD and variant CJD. Iatrogenic CJD results from the accidental transmission of prions during medical or surgical procedures.
Historically, this has included recipients of contaminated human-derived pituitary growth hormone, dura mater grafts used in brain surgery, and, very rarely, corneal transplants. Because prions are highly resistant to standard sterilization methods like heat and chemicals, contaminated surgical instruments have also been a source of transmission. Modern medical practices have significantly reduced these risks by discontinuing the use of human-derived hormones and implementing stringent sterilization protocols.
Variant CJD (vCJD) is strongly linked to consuming products from cattle infected with Bovine Spongiform Encephalopathy (BSE), commonly known as “mad cow disease.” This is considered a zoonotic transmission, where the infectious agent jumps from an animal species to humans. Variant CJD differs from the sporadic form by affecting younger individuals and often presenting initially with psychiatric symptoms rather than memory loss.