Creutzfeldt–Jakob disease

Creutzfeldt–Jakob disease (CJD) is a fatal and incurable neurodegenerative condition, part of a group known as transmissible spongiform encephalopathies, or prion diseases. It is caused by a prion—an infectious, abnormally folded version of a protein called the prion protein. The disease affects roughly one person in every million each year.

Early signs often include memory loss, behavioral changes, poor coordination, and problems with vision or hearing. As it progresses, symptoms can develop into dementia, involuntary jerking movements, blindness, deafness, weakness, and eventually coma. About 70% of those diagnosed die within a year. The first symptom is usually rapidly advancing dementia, which brings memory loss, personality shifts, and hallucinations. Involuntary jerking (myoclonus) occurs in about 90% of cases, though it may not be present at the start. Other common features include anxiety, depression, paranoia, obsessive-compulsive symptoms, and psychosis. Physical problems such as speech difficulties, balance and coordination issues (ataxia), changes in walking, and rigid posture also appear. In rare instances, unusual symptoms like the alien limb phenomenon have been reported. Most people die within six months of the first symptoms, often from pneumonia due to a weakened cough reflex. About 15% survive for two years or more.

The symptoms result from the progressive death of nerve cells in the brain, linked to the buildup of abnormal prion proteins. When brain tissue from a person with CJD is examined under a microscope, many tiny holes are visible where nerve cells have died, giving parts of the brain a sponge-like appearance.

CJD is caused by prions, which are misfolded proteins found in neurons of the central nervous system. The CJD prion is dangerous because it encourages normal prion proteins to refold into the diseased form. This leads to an exponential increase in misfolded proteins, creating large amounts of insoluble proteins that disrupt cell function and cause cell death. Mutations in the gene for the prion protein can trigger misfolding, changing the protein’s shape from alpha helices to beta-pleated sheets, which makes it resistant to digestion. Once transmitted, the defective proteins invade the brain and cause other prion proteins to misfold in a self-sustaining loop. Current research suggests that small, highly toxic aggregates of misfolded proteins (called PrPSc) interact with cell surfaces, disrupting neuronal function—similar to how amyloid aggregates damage synapses in Alzheimer’s disease. Different conformations of these prion aggregates, known as strains, are thought to cause distinct subtypes of prion disease, explaining variations in symptoms and progression. Other human prion diseases include Gerstmann–Sträussler–Scheinker syndrome, fatal familial insomnia, kuru, and variably protease-sensitive prionopathy. Susceptibility and disease course are influenced by a common genetic variation at codon 129 of the PRNP gene (methionine or valine). People who are homozygous at this codon are overrepresented in sporadic CJD cases and tend to have shorter incubation periods.

About 85% of CJD cases occur for unknown reasons (sporadic CJD), while 10–15% are inherited in an autosomal dominant pattern. In rare instances, the disease has been transmitted through exposure to brain or spinal tissue from an infected person, such as from contaminated human brain products, corneal grafts, dural grafts, electrode implants, or pituitary growth hormone (now replaced by a safe recombinant version). A variant form of CJD was caused by eating meat from cows with bovine spongiform encephalopathy (“mad cow disease”). There is no evidence that sporadic CJD spreads through normal contact or blood transfusions, though this is possible in the variant form.

Diagnosis involves ruling out other causes. Tests such as an electroencephalogram, spinal tap, or MRI may support the diagnosis. A newer technique, the real-time quaking-induced conversion assay, can detect the disease in its early stages. There is no specific treatment for CJD. Opioids may help with pain, and medications like clonazepam or sodium valproate can reduce involuntary movements. Onset of sporadic CJD typically occurs around age 60. The condition was first described in 1920, and the name “Creutzfeldt–Jakob disease” was introduced by Walther Spielmeyer in 1922, after German neurologists Hans Gerhard Creutzfeldt and Alfons Maria Jakob.