Classic Creutzfeldt-Jakob disease
Classic Creutzfeldt-Jakob disease (or sporadic CJD) is a fatal degenerative neurological disorder which is part of a group of diseases called transmissible spongiform encephalopaties (TSEs). These other diseases include bovine spongiform encephalopathy, Gerstmann-Straussler-Scheinker syndrome, kuru, and fatal familial insomnia, and they are caused by prions. Spongiform refers to the characteristic appearance of infected brains, which become filled with holes until they resemble sponges under a microscope. These human prion diseases can be inherited, acquired, or sporadic: hereditary CJD represents 10- 15% of all cases, and is associated with coding mutations in the PRNP gene. The most common form however is the sporadic CJD, which accounts to 80-85% of cases.
Other types of Creutzfeldt-Jakob disease include:
variant CJD (vCJD)
familial CJD (fCJD)
The term “prion” refers to abnormal pathogenenetic agents that are transmissible and are able to induce abnormal folding in normal specific proteins called prion proteins that are found most abundantly in the brain. The most common form of Creutzfeldt-Jakob disease is thought to be caused by a spontaneous transformation from normal prion proteins into abnormal prions.
These two isoforms are the normal PrpC which is expressed mostly in the nervous system, and the pathological PrpSC. PrpC is a protein found on cell membranes. In the human form, it is formed by 209 amino acids and has a structure which is mainly alpha-helical. Its function is complex, although it has been discovered to bind copper ions with high affinity, and has been reported to play important roles in cell to cell signaling in vivo- and therefore may be involved in cell-cell communication in the brain. What is important is that this isoform can be readily digested by proteinase K and can be liberated from the cell surface ph phospholypase C (PI-PLC) which cleaves the glycophosphatidylinositol (GPI) glycolipid anchor.
The infectious isoform, PrpSC, is able to convert normal prion proteins into a mutated state by changing their conformation, with a higher percentage of beta-sheets rather than alpha-helical structure. What is interesting is that this modified protein has an identical aminoacid sequence to the normal protein but has different secondary and tertiary conformation. The modified protein is extremely resistant to proteolysis and accumulates forming plaques.
This protein is codified by a gene (PNRP gene) which is located on the short arm of chromosome 20. It has been seen that the prion protein is highly conserved among mammals, with a 92.9-99.6% similarity in amino acid sequences among primates. The human protein structure consists of a globular domain with three α-helices and a two-stranded antiparallel β-sheet, an NH2-terminal tail, and a short COOH-terminal tail.A glycosylphosphatidylinositol (GPI) membrane anchor at the COOH-terminal tethers PrP to cell membranes, and this proves to be integral to the transmission of conformation change; secreted PrP lacking the anchor component is unaffected by the infectious isoform 1
Classic Creutzfeldt-Jakob disease is the most frequent disease of the TSE group, but is classified as a rare disease by the Office of Rare Deseases of the National Institute of Health. The prevalence is 0.6 - 1.5 / 1,000,000 wordwide per year. It usually affects people aged 45-75, most commonly between 60-65 years of age. The exception to this is the more recently recognized variant CJD (vCJD), which occurs in younger people. About 85% of cases are sporadic, 10% are genetic, while 5% are iatrogenic. 2,3
CJD is characterized by rapidly progressive dementia. Initially, the individuals experience problems with personality changes, including impaired memory, judgment, thinking and vision; problems muscular coordination (myoclonus and athaxia). Patients may also experience depression, insomnia, or unusual sensations, and difficulty swallowing and aphasia, and ultimately dementia.
The symptoms may be present for awhile before coming to a correct diagnosis, but as the illness progresses, mental impairment becomes evident, bringing the patient rapidly into a coma with successive death by pneumonia and other infections, heart failure, and respiratory failure. In more than 85% of cases, the duration of CJD is less than 1 year (median: four months) after the onset of symptoms. 4
Age. Sporadic Creutzfeldt- Jakob disease tends to appear later in life, usually around the age of 60. Familial CJD and variant CJD appear earlier in life.
Genetics. In those 10-15% of cases where the disease is hereditary, it is caused by a mutation in the PRNP gene, and is inherited in an autosomal dominant fashion. In cases of sporadic CJD, no mutations have been observed in the PrP gene but homozygous genotype (methionine/methionine or valine/valine) at codon 129 are more frequent than in the general population and represent a risk factor.
Exposure to contaminated tissues. People who've received human growth hormone derived from human pituitary glands or who've had dura mater grafts may be at risk of iatrogenic CJD. The risk of contracting vCJD from eating contaminated beef is difficult to determine. Generally, the risk is very low if countries are implementing sufficient security measures.
However, in the majority of cases, patients with sporadic CJD did not present other significant risk factors. These symptoms are similar to those experiences in other neurodegenerative diseases, but the diagnosis is quite clear because in the case of CJD the symptoms tend to progress much more quickly. 5
A diagnosis can be reached by evaluating varying combinations of neurological symptoms with a late onset age, such as dementia, psychiatric symptoms, athaxia, dysarthria, myoclonus, muscle weakness, chorea, stroke-like episodes, and seizures. It is also necessary to gain specific family history with the anamnesis to single out the cases of familial CJD. The only way to confirm a diagnosis of CJD is by brain biopsy or autopsy. In a brain biopsy, a neurosurgeon removes a small piece of tissue from the patient's brain so that it can be examined by a neuropathologist. This procedure may be dangerous for the individual, and the operation does not always obtain tissue from the affected part of the brain. Because a correct diagnosis of CJD does not help the person, a brain biopsy is discouraged unless it is needed to rule out a treatable disorder.6 Other tests include:
Brain imaging. Magnetic resonance imaging (MRI) may show mild to moderate generalized atrophy at the time of presentation or within a short interval after presentation. T2-weighted images may demonstrate hyperintensity of the basal ganglia. Neuropathologic findings in CAT scans include spongiform degeneration and astrogliosis diffusely distributed throughout the cortex and deep nuclei of the brain (fCJD); multiple amyloid plaques to which anti-prion protein (PrP) antibodies bind.
Diffusion-weighted MRI (DWI) appears to be more sensitive and specific in this regard. In some reports, signal hyperintensity appears within the cortical ribbon before it appears in the deeper structures in sCJD. A small number of reports suggest similar findings in genetic prion disease, especially those with CJD-like phenotypes.
Electroencephalogram (EEG)- Characteristic EEG findings of periodic sharp wave complexes (PSWCs), consisting of triphasic or sharp wave bursts every 0.5 to 2.0 seconds, can suggest the diagnosis of prion disease. Although PSWCs are observed in a relatively small percentage of individuals with genetic prion disease, their presence appears to be more specific to the classical variant of the disease. Initially, the PSWCs may be unilateral, but with disease progression, they typically spread to both brain hemispheres. In late stages of the disease, the periodic activity may disappear.
CSF (cerebrospinal fluid). An elevation of CSF protein concentration by approximately 10% is common, and may be attributed at least in part to release of the normal neuronal 14-3-3 protein into the CSF following neuronal death; however, this finding is not specific for prion disease. This is because the protein can be released in varying amounts based on the progression of the disease (for example, it will be elevated mostly in sporadic cases). It is also release in cases of herpes encephalitis, hypoxic events resulting from a stroke, or in case of Alzheimer's.
Molecular genetic testing. The PRNP gene is the only gene in which the mutation is known t o cause the genetically transmissible disease. However, this gene is also involved in the disease Familial Fatal Insomnia: for alleles with the p.Asp178Asn mutation, the presence of p.Met129 vs p.Val129 modifies the phenotype of disease. If Val is encoded, the phenotype is almost always typical fCJD. If Met is encoded, the phenotype is almost always FFI.Tests that can be run are:
Sequence Analysis, which goes on to detect sequence variations such as small non-sense, missense, splice-site mutations, and small insertions or deletions.
Targeted Mutation Analysis, which looks for a specific mutation. In this case it looks for the Duplication of one to nine additional octapeptide repeats (Pro-His-Gly-Gly-Gly-Trp-Gly-Gln), where normally only 5 are present.
These tests may be carried out in the forms of predictive testing for at-risk asymptomatic adult family members and prenatal diagnosis and preimplantation genetic diagnosis (PGD) for at-risk pregnancies, but both require prior identification of the disease-causing mutation in the family. 7,8
To this day, no effective treatment exists for Creutzfeldt-Jakob disease or any of its variants. A number of drugs have been tested — including steroids, antibiotics and antiviral agents — and have not shown benefits. For that reason, doctors focus on alleviating pain and other symptoms and on making people with these diseases as comfortable as possible.
Interleukins and other medications may help slow the disease and some medications may be needed to control aggressive behaviors. Generally, psychological symptoms of CJD such as anxiety and depression, can be treated with sedatives and antidepressants. Other medicines, such as clonazepam and sodium valproate, can be used to treat muscle jerks and tremors, and opiate-based painkillers can provide effective pain relief.
Providing a safe environment, controlling aggressive or agitated behavior, and meeting the person's needs may require monitoring and assistance in the home or in a care facility. Family counseling may help the family cope with the changes needed for home care of the patient. It may be necessary to have visiting nurses or volunteer services and other community resources. This may be especially important in case of unacceptable or dangerous behaviours.
These measures have included:
- Exclusive use of synthetic human growth hormone, rather than the kind derived from human pituitary glands
- Destruction of surgical instruments used on the brain or nervous tissue of someone with known or suspected CJD
- Single-use kits for spinal taps (lumbar punctures)
To help ensure the safety of the blood supply, people with a risk of exposure to CJD or vCJD aren't eligible to donate blood. This includes people who have a biological relative who has been diagnosed with CJD, have received a dura mater brain graft or human growth hormone, or have injected bovine insulin at any time since 1980. The risk of contracting vCJD remains extremely low. In the United Kingdom, where the majority of vCJD cases have occurred, fewer than 200 cases have been reported. After its first appearance in 1995, CJD incidence peaked between 1999 and 2000, and has been declining since.
Bosque PJ. Prion diseases. In: Goldman L, Schafer AI, eds. Cecil Medicine. 24th ed. Philadelphia, Pa: Saunders Elsevier; 2011:chap 424.
DeKosky ST, Kaufer DI, Hamilton RL, Wolk DA, Lopez OL. The dementias. In: Bradley WG, Daroff RB, Fenichel GM, Jankovic J, eds. Neurology in Clinical Practice. 5th ed. Philadelphia, Pa: Butterworth-Heinemann Elsevier; 2008:chap 70.