Creutzfeldt–Jakob disease causes

Creutzfeldt–Jakob disease (CJD) is a rare and fatal neurodegenerative disorder that affects the brain and nervous system. It is caused by abnormal, misfolded proteins known as prions, which lead to the destruction of brain tissue and progressive neurological deterioration. CJD belongs to a group of conditions called transmissible spongiform encephalopathies (TSEs), which also include variant CJD (vCJD), Gerstmann–Sträussler–Scheinker syndrome (GSS), fatal familial insomnia (FFI), and kuru. The disease occurs worldwide, typically in adults between 55 and 75 years of age, and progresses rapidly once symptoms appear.

Nature of the Causative Agent

The causative agent of CJD is the prion protein (PrP), a naturally occurring cell-surface protein found in the brain and other tissues. In normal form, it is designated PrP^C (cellular prion protein). However, in CJD, this protein undergoes a conformational change into an abnormal isoform known as PrP^Sc (scrapie prion protein).
The PrP^Sc protein is misfolded and resistant to protease degradation, which allows it to accumulate within neural tissue. This misfolded form can also induce normal PrP^C molecules to adopt the same abnormal configuration, triggering a self-propagating chain reaction. The resulting accumulation of prion aggregates leads to neuronal death, spongiform changes, and astrocytosis, giving the brain a sponge-like appearance under the microscope.
Prions are unique in that they lack nucleic acids (DNA or RNA), distinguishing them from viruses, bacteria, fungi, or parasites. They are extremely resistant to conventional sterilisation methods, including heat, radiation, and formaldehyde, which makes CJD particularly challenging to control in clinical environments.

Types and Causal Mechanisms

CJD can arise through several different mechanisms. These forms include sporadic, genetic (familial), and acquired types, each associated with distinct causes and modes of transmission.
1. Sporadic Creutzfeldt–Jakob Disease (sCJD)

• The most common form, accounting for about 85–90% of all cases.
• Occurs spontaneously without known risk factors or external exposure.
• Thought to result from a random mutation or spontaneous misfolding of the normal PrP^C protein into the pathogenic PrP^Sc form.
• The reason for this spontaneous conversion is not fully understood, but age-related changes in protein structure or oxidative stress may contribute.
• Typically affects individuals between 60 and 70 years of age and progresses rapidly, leading to death within months.

2. Familial (Genetic) Creutzfeldt–Jakob Disease (fCJD)

• Caused by inherited mutations in the PRNP gene, which encodes the prion protein.
• These mutations make the PrP^C protein more prone to abnormal folding.
• Accounts for approximately 10–15% of CJD cases worldwide.
• Inheritance follows an autosomal dominant pattern, meaning that a single copy of the defective gene from one parent can cause the disease.
• Several PRNP mutations have been identified, including E200K, D178N, and V210I, each associated with differing clinical presentations and disease duration.
• Family history of CJD or related prion disorders is often present.

3. Acquired Creutzfeldt–Jakob DiseaseThis rare form results from exposure to infectious prions from external sources. Transmission occurs when PrP^Sc from an infected individual or animal enters the human body, leading to conversion of normal prion proteins. There are several recognised routes:

• Iatrogenic CJD (iCJD):
  • Caused by medical procedures involving contaminated surgical instruments, corneal transplants, dura mater grafts, or the use of human-derived growth hormones extracted from infected pituitary glands.
  • Prions can survive standard sterilisation procedures, leading to inadvertent transmission.
  • The incubation period can range from years to decades.
• Variant CJD (vCJD):
  • Linked to consumption of beef or beef products contaminated with bovine spongiform encephalopathy (BSE), commonly known as mad cow disease.
  • The prions responsible for BSE are believed to cross the species barrier and induce disease in humans.
  • Affects younger individuals (average onset around 30 years) and often presents with psychiatric and sensory symptoms before neurological decline.
• Kuru:
  • A historically important form seen among the Fore people of Papua New Guinea, caused by ritualistic cannibalism.
  • Infection occurred through ingestion of brain tissue containing prions.
  • The cessation of these practices led to the disappearance of kuru, but it provided key evidence that prion diseases could be transmitted between humans.

Molecular Mechanism of Pathogenesis

Once PrP^Sc enters the body or is generated endogenously, it interacts with normal PrP^C molecules, promoting their transformation into the misfolded isoform. The abnormal proteins aggregate into amyloid-like fibrils, which accumulate in neurons and glial cells. This aggregation:

• Disrupts normal synaptic transmission.
• Causes neuronal apoptosis (cell death).
• Leads to vacuolation (formation of holes) in the grey matter, producing the characteristic spongiform appearance.
• Triggers astroglial proliferation, a sign of brain tissue response to damage.

Over time, these processes lead to extensive neurodegeneration, resulting in the classic symptoms of CJD, such as rapid dementia, myoclonus, ataxia, visual disturbances, and mutism.

Factors Influencing Susceptibility

Certain genetic and biological factors influence susceptibility to CJD:

• Polymorphism at codon 129 of the PRNP gene, where either methionine (M) or valine (V) may be present, affects disease risk and incubation time. Homozygosity (MM or VV) increases susceptibility to both sporadic and variant forms.
• Age is a critical factor; sporadic CJD typically affects older adults, while variant CJD occurs in younger individuals.
• Route and dose of exposure in acquired forms influence disease incubation and progression.

Resistance and Transmission Barriers

Although prions are highly resistant to degradation, species barriers reduce the likelihood of transmission between animals and humans. Differences in amino acid sequences of PrP proteins among species limit cross-species conversion efficiency. However, the BSE outbreak demonstrated that under certain conditions, these barriers can be overcome, posing a risk for zoonotic transmission.