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Prions (Spongiform encephalopathy)

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Prions (Spongiform encephalopathy)

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Prions (Spongiform encephalopathy)

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encephalopathy is characterized by dementia, ataxia and death.

Questions

USMLE® Step 1 style questions USMLE

3 questions
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A 62-year-old man is brought to the clinic by his partner for evaluation of worsening confusion and changes in personality. Symptoms began three months ago. The patient has had multiple falls over this same time period, which the partner attributes to his “unsteady gait.” He has not had urinary incontinence, fevers, or hallucinations. He has smoked a pack of cigarettes daily for the past 10 years. He has never consumed alcohol. Vital signs are within normal limits. The patient demonstrates nystagmus at rest. He is unable to perform rapidly alternating pronation and supination movements with his hands. The patient scores 17/30 on the Mini-Mental State Examination (normal: ≥24). Brain biopsy from a deceased patient with the same condition is shown below:  


Image reproduced from Wikimedia Commons  

Which of the following additional physical exam findings is likely to be seen in this patient?  

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Transcript

Spongiform encephalopathy can be broken down. Spongiform means sponge like, encephalo- refers to the brain, and -path refers to a disease process.

So spongiform encephalopathy is a disease where the brain tissue degenerates and healthy tissue gets replaced by clusters of tiny liquid filled, thin-walled cavities called cysts, making the brain look like a sponge.

The underlying cause of spongiform encephalopathy is the accumulation of misfolded proteins called prions.

First, let’s review a bit. Proteins are made up of a long string of amino acids, and the exact sequence of these amino acids is called the primary structure.

These long chains of amino acids can fold to form different shapes, like an α-helix which is a right-handed coiled strand and a ß pleated-sheet which is when the chain folds so that segments line up alongside one another.

Each protein can contain multiple α-helices or ß pleated-sheets.

Now, there’s a protein called Prion protein, or Prp, which is encoded by the PrNP gene.

This protein is 253 amino acid long and is made up of mostly α-helices.

It’s most commonly found on the cell membrane of neurons.

Although the function of Prp is unknown, it’s thought that it might play a role in synapses between neurons and the uptake of copper into the cell.

When a prion protein is misfolded, it changes from mostly having α-helices to having a lot of ß pleated-sheets.

This new abnormal protein is called a “prion”.

When the misfolded protein enters the cells of the nervous system and interact with the normal prion protein, it acts as a template and induces misfolding in the normal prion proteins.

These prions are also highly resistant to being broken down by proteases, which are the enzymes that break down abnormal proteins.

As a result, these misfolded prion proteins cannot be easily broken down, they cause normally folded proteins to misfold and become like them, and they have an affinity for the brain - they’re basically like little ß-sheet filled zombies.

The misfolded prions accumulate within the cell and they trigger apoptosis, which is programed cell death. This is done with the help of 14-3-3 protein which is an intracellular protein that promotes apoptosis.

When large numbers of cells start to die off, cysts begin to form in the brain, and over time, this gives the brain it’s spongy appearance.

Additionally, the prions aggregate together on the membrane of the neurons, forming large plaques that are toxic to brain tissue.

Now, the most common cause of spongiform encephalopathy is Creutzfeldt-Jakob disease or CJD.

And there are actually four types of CJD; familial or fCJD, variant or vCJD, iatrogenic or iCJD, and sporadic or sCJD.

All four types cause spongiform degeneration of the cerebral cortex and cerebellum.

Familial Creutzfeldt-Jakob’s disease occurs when there’s a mutation in the PRNP gene.

The most common mutation occurs at the 200th codon and causes the amino acid glutamic acid to be replaced by a lysine, and that’s enough to make the entire protein misfold.

Variant Creutzfeldt-Jakob’s disease is caused by eating the meat of cows with prions in the muscle tissue.

In cows, these prions cause bovine spongiform encephalopathy, which is more commonly called “Mad cow disease.”

When sheep are fed cow meat, the prion causes the disease Scrapie.

If a person eats the meat of affected cows or sheep, the prions get absorbed through the intestines and get absorbed into the bloodstream.

After that things get a bit unclear. It’s thought that the protein can somehow get through the blood brain barrier and then enters neurons by a process called adsorptive endocytosis.

Adsorptive endocytosis is a process where the plasma membrane of nerve cells folds inwards to bring in substances that otherwise would not be able to cross the plasma membrane by themselves.