(ربنا الذي اعطى كلَّ شئ خلقه ثم هدى) سورة طه: الآية رقم 50

1. (ربنا الذي اعطى كلَّ شئ خلقه ثم هدى) سورة طه: الآية رقم 50

2. Prion Diseases Transmissible Spongiform Encephalopathies (TSE)

3. Dr.Mohammad Jamil Al-Habbal MRCP (UK),FRCP (London),FRCP (Edin.) Consultant Internal Medicine King Fahad Specialist Hospital-Dammam

4. DEFINITION • Family of progressive neurodegenerative disorders. • Affect both humans and animals. • Long incubation periods. • A unique feature of these diseases is that they can be inherited, arise spontaneously or may be acquired through infection. • Characteristic neuropathologic feature of multifocal spongiform changes in brain with astrogliosis & neuronal loss. • No inflammatory response. • The causative agent is an abnormal prion protein (PrPsc) which induce abnormal folding of normal prion proteins (PrPc) in the neurons. • Usually rapidly progressive and always fatal. • No effective therapy.

5. The following diseases are caused by prions In animals: • Scrapie in sheep • Bovine spongiform encephalopathy (BSE) in cattle (known as mad cow disease) • Transmissible mink encephalopathy (TME) in mink • Chronic wasting disease (CWD) in elk and mule deer • Feline spongiform encephalopathy in cats • Exotic ungulate encephalopathy (EUE) in nyala, oryx and greater kudu

6. In humans : • Creutzfeldt-Jakob disease (CJD) and its varieties: 1:iatrogenic Creutzfeldt-Jakob disease (iCJD), 2:familial Creutzfeldt-Jakob disease (fCJD), 3:sporadic Creutzfeldt-Jakob disease (sCJD) 4:variant Creutzfeldt-Jakob disease (vCJD), • Gerstmann-Sträussler-Scheinker syndrome (GSS) • Fatal familial insomnia (fFI) • Sporadic fatal insomnia (sFI) • Kuru • Alpers syndrome

7. Humans might be infected by prions in 2 ways: 1: Acquired infection (diet and following medical procedures such as surgery, growth hormone injections, corneal transplants) i.e. infectious agent implicated. 2: Apparent hereditary mendelian transmission where it is an autosomal and dominant trait.

8. WHY PRION DISEASE? • Transmissible (animals & humans) • Causative agent is a protein! • Iatrogenic – CJD • Fatal and no therapy. • Outbreak of BSE in UK during 1986 & its human type (vCJD) in1996 • Caused by feeding cattles animal protein. • Islamic Teaching!

9. What is the Prion ? Professor Stanley Prusiner discovered prions • To date, the evidence indicates that the infectious agent in the TSEs is a protein discovered by: Stanley Prusiner (in 1996) who: 1. Pioneered in the study of these proteins. 2. Awarded the Nobel Prize in 1997. 3. Named them prion proteins (designated PrP) or simply prions.

10. PrPc • The normal protein. • Called PrPc (for cellular). • A transmembraneglycoprotein normally found at the surface of certain cells (e.g., neural and hematopoietic stem cells). • Has its secondary structure dominated by alpha helices (probably 3 of them). • Easily soluble. • Easily digested by proteases. • Encoded by a gene designated (in humans) PRNP located on chromosome 20.

11. PrPsc • The abnormal, disease-producing protein (infectious). • Called PrPsc (for scrapie). • Has the same amino acid sequence and number as the normal protein; that is, their primary structures are identical but: - its secondary structure is dominated by beta conformation - Insoluble in all solvents. - Highly resistant to digestion by proteases. - When PrPsc comes in contact with PrPc, it converts the PrPc into PrPsc (even in the test tube).

12. Proposed mechanism of prion propagation

13. PrPc and PrPsc

14. Infection

15. Infection

16. Infection

17. Infection

18. Human Prion Diseases • Creutzfeldt-Jakob Disease (CJD) • Variant Creutzfeldt-Jakob Disease (vCJD) • Gerstmann-Straussler-Scheinker Syndrome (GSS) • Fatal Familial Insomnia (FFI) • Kuru

19. CREUTZFELDT-JAKOB DISEASE (CJD)1.SPORADIC • Firstly reported by the German neurologists Creutzfeldt and Jakob in 1920s . • It accounts for »85% of all CJD cases. • Estimated incidence of one case/1 million population per year with equal sex ratio. • A peak age of onset between 55 and 75 yrs (mean:61.5yrs). • Induced by somatic mutation or spontaneous conversion of PrPc into PrPsc.

20. Clinical Features • Dementia: rapidly progressive, visual abnormalities. • Ataxia: cerebellar dysfunction, including muscle incoordination,gait and speech abnormalities. • Most patients develop pyramidal and extrapyramidal dysfunction with abnormal reflexes, spasticity, tremors, and rigidity. • Psychaitric manifestations:some patients may also show behavioral changes with agitation, depression, or confusion. • Myoclonus: most constant physical sign,present in > 90% pts. • Invariably fatal, with a median illness duration of 4 months & death occurs within 12 months of illness onset in 85–90% of pts.

22. Diagnosis 1. EEG: two cycles per second triphasic sharp-wave discharges. 2. CSF: presence of 14-3-3 protein, 3. Histopathology:Biopsy or Autopsy (confirmatory diagnosis): The typical neuropathology consists of a microscopic picture of spongiform changes, gliosis, and neuronal loss in the absence of inflammatory reaction. Amyloid plaques demonstrated in >>10% of patients. 4. PrPsc :The presence of PrPsc in biopsy or autopsy of brain samples can be demonstrated by immunodiagnostic tests, such as: a) immunohistochemical staining. b) Histoblot c) Western blot techniques d) Conformation-dependent immunoassay(CDI) 5. Genetic test:sequencing the PRNP gene Prion diseases damage the brain

23. This tissue slide shows sponge-like lesions in the brain tissue of a classic CJD patient. This lesion is typical of many prion diseases.

24. CREUTZFELDT-JAKOB DISEASE 2.FAMILIAL • It accounts for 5–15% of CJD patients. • Autosomal dominant inheritance pattern with a family history of CJD. • Most patients presented with personality changes followed by progressive dementia and a Parkinsonian syndrome. • The mean age at onset was 44.8 years, and the mean duration of illness was 4.2 years. • spongiform changes, neuronal loss, and mild gliosis were predominantly seen in frontal and temporal lobes .

25. CREUTZFELDT-JAKOB DISEASE 3.IATROGENIC ● The transmissible nature of CJD was first described in 1968, after intracerebral inoculation of a brain biopsy tissue from a CJD patient into a chimpanzee. • Person-to-person transmission of the CJD agent was reported in: 1.Corneal transplant 2.Contaminated EEG depth electrodes 3.Neurosurgical instruments 4.Cadaveric pituitary-derived gonadotropin 5.Human growth hormone (hGH) 6.Dura mater grafts 7.Blood transfusion?

26. Bloodborne Transmission • Experimental transmission of CJD to laboratory animals intracerebrally inoculated with blood obtained from CJD patients indicated the possible presence of the CJD agent in human blood in low concentrations . • Three studies have clearly confirmed the infectivity of blood derived from experimentally infected guinea pigs or mice after intracerebral inoculation of healthy animals • Whether the results of these animal studies provide any knowledge on blood-borne transmission of the CJD agent in humans?

27. Bloodborne Transmission • The FDA, on recommendation from its TSB Advisory Committee and with support from the CDC and the National Institutes of Health,had recommended a blood donor deferral policy to exclude donors who have spent specific periods of time in UK and other European countries.

28. DECONTAMINATION OF CJD PRIONS • Prions are extremely resistant to common inactivation procedures, and there is some disagreement about the optimal conditions for sterilization. • Autoclaving at 132°C for 5 h or treatment with 2 N NaOH for several hours is recommended for sterilization of prions. • The term "sterilization" implies complete destruction of prions; any residual infectivity can be hazardous.

29. Creutzfeldt-Jakob Disease 4.Variant (vCJD) -Variant CJD was first described in 1996 in UK. -Has different clinical and pathologic characteristics from other types of CJD. -Till Feb 2006,159 cases of vCJD were diagnosed in UK and 153 have died. -? Begening of a growing epidemic,unclear.

30. Evidence for Relationship between BSE and vCJD • Since 1996, evidence has been increasing for a causal relationship between ongoing outbreaks of BSE and vCJD. • Strong scientific evidences: agent responsible for BSE(in cattle) and vCJD (in humans), is the same (PrPsc).

32. Histopathology of vCJD (A) Section from frontal cortex stained by the periodic acid-Schiff (PAS) method,showing a field with aggregates of plaques surrounded by spongiform degeneration (B) Multiple plaques and amorphous deposits are PrP- immunopositive. Scale bar, 50 µm.

33. Bloodborne Transmission • A highly probable bloodborne, person-to-person transmission of vCJD was reported in the UK in a 69-year-old man who had vCJD onset in late 2002, 6.5 years after receipt of 5 units of packed red blood cells. One of the red blood cell units was obtained from a 24-year-old donor who developed vCJD >3 years after donation. • Both the donor and recipient died of pathologically confirmed vCJD. • The reports of bloodborne spread of vCJD in the UK appear to justify the precautionary deferral policy recommended by FDA (USA).

34. GERSTMANN-STR¨AUSSLER-SCHEINKER SYNDROME(GSS) • A familial disease with autosomal dominant inheritance, • First described in1936 by Gerstmann, Str¨aussler, & Scheinker. • It occurs at an estimated annual incidence of 5 cases/100 million population. • Neurologic signs and symptoms: cerebellar ataxia, gait abnormalities, dementia, dysarthria, ocular dysmetria, and hyporeflexia or areflexia in the lower extremities with infrequent myoclonus and diagnostic EEG, and a neuropathologic feature of numerous amyloid plaques. • GSS is considered a variant of the familial form of CJD, but it is primarily associated with mutations at codon 102 of the prion protein gene.

35. FATAL FAMILIAL INSOMNIA (FFI) • A familial disease with autosomal dominant inheritance, have been reported since 1939. • Patients with severe dementia and bilateral symmetrical degeneration of the thalamus • Progressive insomnia and autonomic dysfunction, followed by dysarthria, tremor, and myoclonus. • Neuropathologic examination showed neuronal degeneration and reactive astrocytosis confined to the anterior and dorsomedial nuclei of the thalamus; no spongiform changes or inflammatory infiltrates were noted. • Rare sporadic cases of FFI were reported. • FFI is primarily associated with a mutation at codon 178 of the prion protein gene.

36. Kuru • Kuru was once found among the Fore tribe in Papua New Guinea in 1957. • Ingesting brain tissue of dead relatives for religious reasons was the route of transmission whose rituals included eating the brain tissue of their recently deceased members of the tribe. • Since this practice (ritualistic cannibalism ) was halted, the disease has disappeared. • Clinically, the disease resembles CJD.

37. Disappearance of kuru Number of biannual cases of kuru in Papua New Guinea.

38. Animal Prion Diseases • Scrapie • Bovine Spongiform Encephalopathy (BSE) • Chronic Wasting Disaese (CWD) • Transmissible mink encephalopathy • Feline spongiform encephalopathy • Ungulate spongiform encephalopathy

39. Spongiform Encephalopathies (in animals) • BSE in Cattle • Scrapie in sheep

40. Scrapie:داء الحكه (قعاص الغنم) • This disease of sheep (and goats) • The first TSE to be studied. • Known for several hundreds yrs • Transmitted from animal to animal in feed contaminated with nerve tissue. • Loss of motor control,paralysis wasting and death.

41. Bovine Spongiform Encephalopathy (BSE) or "Mad Cow Disease”مرض جنون البقر • An epidemic of this disease began in UK in 1985 • Over 170,000 cattle were sickened by it. • Transmission of scrapie agent (PrPsc) to cattles by feeding the contaminated meat &bone meal. • The use of such food (MBM) was banned in 1988 and after peaking in 1992, the epidemic declined quickly.

42. BSE epidemic in UK Number of annual cases of BSE in cattle in UK

43. BSE • Although no. of cattles with BSE (UK) till 2003 is >180,000, the total estimated number is excess of 2 million. • Between 1980-996 ,about 750,000 BSE-infected cattles have been slaughtered and consumed by millions of U.K. residents. • The disease can pass along the food chain and the consumers may be infected by ingestion of prion-contaminated beef. • Milk from BSE Infected Cattle is Banned by the British government.

44. (ربنا الذي اعطى كلَّ شئ خلقه ثم هدى) سورة طه: الآية رقم 50

45. قال تعالى:(كلواوأرعوا أنعامكم , ان في ذلك لآيات لأوليالنهى) طه: 54 و قال تعالى: ( وفاكهة وأبا,متاعا لكم ولانعامكم) عبس:32,31 وتفسير أباما تأكله البهائم من الاعشاب وقيل التبن. وقال تعالى :(هو الذي انزل من السماء ماءً لكم منه شراب ومنه شجر فيه تسيمون) النحل: 10 وتفسير تسيمون اي ترعون بهائمكم من هذا الشجر

46. النهي عن تغيير فطرة المخلوقات التي خلقها الله عليها - ان الله سبحانه وتعالى خلق الانسان والحيوان والطير والاشياء جميعا كل على هيئته التي خلقه عليها بما يتناسب مع وظيفته في الحياة والطريقة التي يتعايش بها مع الطبيعة التي حوله لكي تقوم حياته على الوجه الصحيح. - فأذا ما تغيرت هذه الفطرة او الطريقة التي خلقه الله عليها تغير نمط حياة هذا المخلوق والوظيفة التي خلق من اجلها وكان هذا التغيير سببا في ضرره او ضرر الاخرين من حوله خاصة الانسان الذي كرمه الله على جميع المخلوقات .

47. النهي عن اكل لحوم الجلالة وشرب البانها وركوبها - الجلالة : هي الحيوانات كالابل والبقر والغنم والدجاج وغيرها التي تاكل العذرة او القاذورات - فعن ابن عباس رضي الله عنهما قال : (نهى رسول الله صلى الله عليه وسلم عن شرب لبن الجلالة واكل لحومها ) رواه الخمسة وصححه الترمذي. وفي رواية ابو داوود (نهى عن ركوب الجلالة ) - وعن عمرو بن شعيب عن ابيه عن جده رضي الله عنهم قال: (نهى رسول الله صلى الله عليه وسلم عن لحوم الحمر الاهلية . وعن الجلالة : عن ركوبها واكل لحومها ) رواه احمد والنسائي وابو داوود المصدر: سيد سابق (فقه السنة :ج1 ص26)

48. DECONTAMINATION OF CJD PRIONS • Prions are extremely resistant to common inactivation procedures, and there is some disagreement about the optimal conditions for sterilization. • Autoclaving at 132°C for 5 h or treatment with 2 N NaOH for several hours is recommended for sterilization of prions. • The term "sterilization" implies complete destruction of prions; any residual infectivity can be hazardous.

49. PREVENTION AND THERAPEUTICS • There is no known effective therapy for preventing or treating CJD. • The finding that phenothiazines and acridines inhibit PrPSc formation in cultured cells led to clinical studies of quinacrine in CJD patients. • Although quinacrine seems to slow the rate of decline in some CJD patients, no cure of the disease has been observed.

50. Prion Diseases: summary