Prion diseases

Prion diseases and the impact on blood transfusion.

1. Prion diseases Dr. G.D.A. Samaranayaka

2. Introduction Pr oteinaceous - ion – infectious Particle No nucleic acid Prions are made up of prion proteins Discovered by Stanley Prusiner 1. Pioneered in the study of these proteins. 2. Awarded the Nobel Prize in 1997.

3. Prion Diseases Animals Scrapie (sheep) ‏ Bovine spongiform encephalopathy (BSE) ‏ Chronic wasting disease (CWD) (deer & elk) ‏ Humans Kuru Creutzfeldt-Jakob disease (CJD) Fatal familial insomnia Gerstmann-Sträussler-Scheinker disease Family of diseases known as the transmissible spongiform encephalopathies (TSEs) Prolonged incubation period of several years – depends on the disease Progressive debilitating neurologic syndrome - invariably fatal Pathological changes confined to the CNS with classic features - spongiosis , gliosis, and neuronal loss Transmissible agent does not elicit any specific immunologic response

4. Epidemilogy Believed to be rare in human, estimated to occur in about 1 out of every one million people every year Austria, Belgium, Canada, Czech Republic, Denmark, Finland, France, Germany, Greece, Ireland, Israel, Italy, Japan, Luxembourg, Liechtenstein, the Netherlands, Poland, Portugal, Slovakia, Slovenia, Switzerland, and Spain.

5. Pathophysiology Cause neurodegenerative disease by aggregating amyloid plaques the central nervous system Disrupt the normal tissue structure. "holes" in the tissue - spongy architecture due to the vacuole formation in the neurons. Astrogliosis Absence of an inflammatory reaction. Classical features - spongiosis , gliosis, and neuronal loss

6. PrPc PrP C is a normal protein found on the membranes of cells. Transmembrane glycoprotein normally found at the surface of certain cells ( e.g - neural and hematopoietic stem cells). Secondary structure - predominately alpha helices Encoded by a gene designated (in humans) PRNP located on chromosome 20. Play important roles in cell-cell adhesion and intracellular signaling in vivo - may therefore be involved in cell-cell communication in the brain

7. Physiological processes of the native prion protein ( PrP c ) ‏ PrP C + Cu (Copper)  Antioxidant activity  Resistance to oxidative stress  Prevent neuronal dysfunction

8. PrP sc Abnormal, disease-producing protein - PrPsc (for scrapie). Convert normal PrP C proteins into the infectious isoform by changing their conformation Has the same amino acid sequence and number as the normal protein - identical primary structures Aggregations of these abnormal isoforms form highly structured amyloid fibers, which accumulate to form plaques.

9. Polymerisation PrP C PrP* PrP Sc PrP Sc PrP* Dimerisation PrP Sc PrP Sc PrP C PrP* PrP Sc PrP* PrP Sc

10. PrP C PrP SC Solubility Soluble Non soluble Structure Alpha-helical Beta-sheeted Multimerisation state Monomeric Multimeric Infectivity Non infectious Infectious Susceptibility to Proteinase K Susceptible Resistant

11. Etiology Sporadic (85%) Most commonest Spontaneous PrP C to PrP Sc conversion or somatic mutation sporadic Creutzfeldt-Jakob disease ( sCJD ) Genetic/familial (15%)‏ caused by defects in the PrP gene - short arm of chromosome 20 ‏ autosomal dominant familial CJD ( fCJD ), fatal familial insomnia

12. Acquired/Infectious (<1%)‏ Kuru – Highlands of New Guinea, r itualistic c annibalism Iatrogenic CJD organ and tissue transplants, use of contaminated surgical instruments dura mater grafts human pituitary-derived gonadotrophins, and human-derived growth hormone. Blood transfusions – theoretical risk based on experimental studies in animals– no reported cases Variant CJD ingestion of beef products contaminated with BSE Small number of transfusion transmitted cases reported in uk

13. Clinical features Onset of signs and symptoms varies with the disease. Dysphoria, Withdrawal, Anxiety, Irritability, Insomnia, Loss of interest, Poor memory, Disorientation, Impaired concentration Hallucinations, Lack of emotion, Paranoid delusions, Acalculia , Impaired comprehension, Diurnal mood variation, suicidal thoughts Gait disturbance, Slurring of speech, Hyperreflexia, Impaired coordination, Myoclonus, Incontinence Paresthesia, Numbness, Chorea, Extensor plantars , Dysphagia , Clonus , Hypertonia

14. Investigations Initial workup includes - tests as for dementia. FBC, serum electrolytes, liver function test results, ESR, Thyroid functions MRI - hockey stick" sign, which refers to increased signal in the putamen and head of the caudate nucleus resembling a hockey stick

15. Investigations EEG with periodic/ pseudoperiodic paroxysms of sharp waves or spikes on a slow background. CSF - Protein 14-3-3, neuron-specific enolase (NSE), S-100b, and total tau protein (t-tau) Brain biopsy – gold standard - spongiform changes, gliosis, and neuronal loss in the absence of inflammatory reaction.

16. Management Rapidly progressive neurodegenerative diseases, and outcome is inexorably fatal. classic CJD - live less than 12 months after signs and symptoms appear. Death is usually due to heart failure, respiratory failure or pneumonia. vCJD - tend to live slightly longer – about 12 to 14 months after signs and symptoms appear No specific treatment Interlukins and some experimental drugs – slow the progression Supportive therapy – antiepileptics , physiotherapy ect

17. Prevention Protecting the food supply precautions when handling infected tissues and by using appropriate techniques to clean contaminated instruments Steam autoclaving materials at 132° C for 1 h Immersing them in Na hydroxide 1 N (normal) or 10% Na hypochlorite solution for 1 h Blood /Tissue donation No screening test to identify infected donor blood Residence in the UK (and, to a lesser extent, Ireland and France) is clearly a risk factor for variant CJD, and many countries exclude prospective donors who have lived in such countries. removing white blood cells, which may carry the greatest risk of transmitting CJD, from all blood used for transfusions

18. Thank you