Prion Diseases

                                     Prion Diseases

                                               P.K. Ghatak, MD

Draft CJD:

Creutzfel

1. Creutzfeldt-Jakob Disease.

In 1922, a German neurologist Hans Gerhard Creutzfeldt described a patient with a neurodegenerative disease. Alfon Maria Jakob described 4 more cases of rapidly progressive neurodegenerative disease, just as Creutzfeldt described. Dr. Jacob credited this new disease to Dr. Creutzfeldt. This rare but an important infectious disease is known as Creutzfeldt-Jakob disease (CJD).

What causes CJD.

It is a Prion (PrP)

These are several ways people can be infected.

1. Spontaneously evolved – spPrP.

2. Consuming beef of animal suffering from Mad-Cow-Disease.

3. PNRP (gene controlling Prion generation) mutated gene inherited in Autosomal dominant manner.

4. Receiving contaminated Corneal transplants, and injections of Pituitary Growth Hormone extracted from cadavers.

The CJD is a very rare disease, the incidence is about 1 in 1 million in the general population worldwide and inherited CJD is only 7.5% of cases of CJD, the remaining 85 % cases arise sporadically from an unknown cause.

Symptoms:

In the majority of cases, the initial symptoms are progressive dementia, ataxia and behavioral abnormalities, beginning at the age of 55 to 75. Soon patients have dysarthria, myoclonus and mutism. There is rapid deterioration of condition and the majority of the patients are dead within 6 months, rarely a few survive for 2 years.

Diagnosis:

EEG shows triphasic sharp waves.

CSF :

Recently, a new laboratory method has been used, called QUIC or RC QUIC to multiply PrP sc protein in the CSF or other tissues in sufficient amount for a positive identification of CJD disease.

MRI of the brain typically shows punctate holes in the caudate nuclei.

Histopathology:

A combination of neuronal gliosis of Astrocytes and spongiform lesions.

Diagnostic test is Western blot detecting PrP sc protein. QUIC is a preferred test nowadays.

2. Variant CJD.

In 1996, the first human case of mad-cow disease was described. It is called Variant CJD (vCJD) to distinguish from non-animal source of Prion disease. Clinically and pathologically, both forms of CJD are the same. Prion particles are concentrated in the brain and nervous tissue of cows, once the practice of adding nerve tissue of dead animals to animal feeds was discontinued, the Mad cow disease and vCJD disappeared.

3. Gerstmann-Straussler-Scheinker syndrome (GSS) is a very rare disease.

Symptoms develop with dysarthria followed by cerebellar truncal ataxia and progressive dementia. GSS is also a highly progressive and fatal disease.

The defective gene in GSS is not the same as CJD. The P102L gene mutation on chromosome 20 is present in GSS.

4. Fatal Familiar Insomnia.

Initially, symptoms include hallucinations and panic attacks. A few months later, patients are unable to fall asleep, rapidly lose weight, and develop dementia and die. Mutation of the PRNP gene is responsible for this disease.

5. Kuru.

Headhunters of Papua New Guinea used to be cannibals. They ate the brain of their victims and cooked the brain of their deceased relatives and consumed it during funeral ceremonies. They suffered a terrible neurodegenerative disease involving muscles of the trunk and extremities.

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Prion

 

                                                        Prion

                                P.K.Ghatak,MD

Dr. Daniel Carleton Gajdusek in 1957, while studying a spongiform encephalitis called Kuru, in the local population of Papua New Guinea who were cannibals, proved that Kuru was an infectious disease when he successfully reproduced the disease by injecting the brain extract of Kuru victims in chimpanzees. He theorized Kuru was due to a slow growing unknown virus. It became evident that it was not a virus because Ultraviolet radiation did not kill the infective agent, on the other hand, was sterilized by a protein alerting chemical, bleach.

 In 1982, Stanley Prusiner of UC at SF called the infective agent "a proteinaceous particle and named it  Prion.

Prion is simply a protein molecule made up of 259 amino acids. All living animals and plants, including yeast, have prions in the cell membrane and in the cytoplasm. Neurons have the highest concentration of normal Prion molecules.

Chemical compounds like toxins, snake poison, etc., are also compounds of proteins but Prions differ from toxins in that Prions multiply in huge numbers in the victim's body, whereas, poison and toxins do not. The Medical community was naturally skeptical that an inert protein molecule could multiply in a victim without having Nucleic acids or DNA or RNA.

Dr. Prusiner proved that the infectious Prion (PrP sc), once introduced into the living cells it induces a change of configuration of normal similar protein molecules to adopt the shape and appearance of the PrPsc. The newly formed PrPsc, in turn, makes changes to more protein molecules and the chain reaction follows.

Normal protein molecule is alpha helical in their molecular foldings but abnormal Prion takes beta helical foldings. Misfolded protein molecules prevent cells from carrying out normal cell functions, including elimination of metabolic wastes. Accumulated wastes clog the cells to death. The brain cells (neurons) have a high concentration of Prion molecules. As the misfolded cells die, they leave behind many small voids in the brain matter. Loss of vital functions of the brain cells results in progressive dementia, a movement disorder, and other symptoms, leading to premature end of life. The pathological process is called spongiform encephalopathy because of the resemblance with a sponge.

In the normal individual, the nature has provided a gene called the PRNP gene, that regulates the rate of conversion of misfolded proteins. When a mutation occurs in the PRNP gene, the mutation is passed to the next generation by an Autosomal Dominant fashion. Normal prion protein PRNP codon 129 also exists in polymorphic forms in association with variants Type 1 and Type 2 genes, which arise out of coding errors for amino acid methionine and valine respectively. The combination of these mutations results in 6 subtypes. This explains the variable penetration and low frequency of disease despite dominant inheritance.

Daniel Carleton Gajdusek and Stanley Prusiner received the Nobel Prize in medicine in 1976 and 1999 respectively.

These are the notations used when referring to a particular Prion and a prion disease.

Normal- PrP.  Scrapi - PrPsc.  Creutzfeldt-Jackob disease - CJD.  Variant CJD - vCJD, Familial - f CJD, Spontaneous -sp CJD.

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Diseases caused by prions in humans are

CJD Creutzfeldt-Jacob Disease.

vCJD (variant CJD).

Kuru.

Gerstmann Straussler -Scheinker syndrome (GSSS),

Fatal Familial insomnia,

In mammals prion causes Scrapie in sheep,

Mad-cow-disease in cattle.

Chronic wasting disease in deer, elk, moose, reindeer and caribou.

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