ثم ) خلقه شئ كَّل اعطى الذي ربنا(هدى

: رقم اآلية طه 50سورة

Prion Diseases

Transmissible Spongiform Encephalopathies

(TSE)

Dr.Mohammad Jamil Al-Habbal

MRCP (UK),FRCP (London),FRCP (Edin.)

Consultant Internal Medicine

King Fahad Specialist Hospital-Dammam

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.

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

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

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.

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!

What is the Prion ?

• 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.

Professor Stanley Prusiner discovered prions

PrPc

• The normal protein. • Called PrPc (for cellular). • A transmembrane glycoprotein 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.

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).

Proposed mechanism of prion propagation

PrPc and PrPsc

Infection

Infection

Infection

Infection

Human Prion Diseases

• Creutzfeldt-Jakob Disease (CJD)

• Variant Creutzfeldt-Jakob Disease (vCJD)

• Gerstmann-Straussler-Scheinker Syndrome (GSS)

• Fatal Familial Insomnia (FFI)

• Kuru

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. 

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.

Diagnosis

1. EEG: two cycles per second triphasic sharp-wave discharges. 2. CSFCSF: presence of 14-3-3 protein, 3. HistopathologyHistopathology: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

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

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 .

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?

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?

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.

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.

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.

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).

Clinical and Pathologic CharacteristicsDistinguishing Classic CJD from Variant CJD

Characteristic Classic CJD Variant CJD

Median age at death 68 years 28 years

Median duration of illness 4-5 months 13-14 months

Clinical signs and symptoms Dementia; early neurologic signs

Prominent psychiatric/behavioral symptoms; painful dyesthesiasis; delayed neurologic signs

Periodic sharp waves on EEG Often present Often absent

Pulvinar sign on MRI Not reported Present in >75% of cases

Presence of "florid plaques" on neuropathology

Rare or absent

Present in large numbers

Immunohitochemical analysis of brain tissue

Variable accumulation

Marked accumulation of protease-resistance prion protein

Presence of agent in lymphoid tissue

Not readily detected

Readily detected

Increased glycoform ratio on immunoblot analysis of protease-resistance prion protein

Not reported Marked accumulation of protease-resistance prion protein

Histopathology of vCJD

(B) Multiple plaques and amorphous deposits are PrP- immunopositive. Scale bar, 50 µm.

(A) Section from frontal cortex stained by the periodic acid-Schiff (PAS) method,showing a field with aggregates of plaques surrounded by spongiform degeneration

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).

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.

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.

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.

Number of biannual cases of kuru in Papua New Guinea.

Disappearance of kuru

Animal Prion Diseases

• Scrapie

• Bovine Spongiform Encephalopathy (BSE)

• Chronic Wasting Disaese (CWD)

• Transmissible mink encephalopathy

• Feline spongiform encephalopathy

• Ungulate spongiform encephalopathy

Spongiform Encephalopathies (in animals)

• BSE in Cattle • Scrapie in sheep

Scrapie: ( الغنم ( قعاص الحكه داء

• 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.

Bovine Spongiform Encephalopathy (BSE) or "Mad Cow Disease” البقر جنون مرض

• 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.

Number of annual cases of BSE in cattle in UK

BSE epidemic in UK

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.

ثم ) خلقه شئ كَّل اعطى الذي ربنا(هدى

: رقم اآلية طه 50سورة

: تعالى ألولي ,نعامكمأوأرعوا اكلو( قال آليات ذلك في النهى) ان54طه:

تعالى و )وأباوفاكهة : ( قال والنعامكم, لكم متاعا32,31عبس:

وقيَّل أبا وتفسير االعشاب من البهائم تأكله التبن ما .

تعالى و ومنه( :قال شراب منه لكم ماًء? السماًء من انزل الذي هوفيه )تسيمونشجر

10النحَّل:

الشج تسيمونوتفسير هذا من بهائمكم ترعون راي

التي المخلوقات فطرة تغيير عن النهيعليها الله خلقها

والحيوان - االنسان خلق وتعالى سبحانه الله انخلقه التي هيئته على كَّل جميعا واالشياًء والطير

والطريقة الحياة في وظيفته مع يتناسب بما عليهاتقوم لكي حوله التي الطبيعة مع بها يتعايش التي

الصحيح الوجه على .حياته

خلقه - التي الطريقة او الفطرة هذه تغيرت ما فأذاوالوظيفة المخلوق هذا حياة نمط تغير عليها الله

في سببا التغيير هذا وكان اجلها من خلق التياالنسان خاصة حوله من االخرين ضرر او ضرره

المخلوقات جميع على الله كرمه . الذي

لحوم اكل عن البانها الجاللةالنهي وشربوركوبها

وغيرها :الجاللة - والدجاج والغنم والبقر كاالبَّل الحيوانات هيالقاذورات او العذرة تاكَّل التي

قال - عنهما الله رضي عباس ابن : فعن

لبن ) شرب عن وسلم عليه الله صلى الله رسول نهىلحومها واكل . ( الجاللة الترمذي وصححه الخمسة رواه

داوود ( ابو رواية عن وفي نهىالجاللة )ركوب

قال - عنهم الله رضي جده عن ابيه عن شعيب بن عمرو :وعن

الحمر ) لحوم عن وسلم عليه الله صلى الله رسول نهىلحومها . : واكل ركوبها عن الجاللة وعن رواه ( االهلية

داوود وابو والنسائي احمدج: ( : السنة فقه سابق سيد )26ص 1المصدر

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.

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.

Prion Diseases: summary Creutzfeldt-Jakob Disease CJD humans

variant Creutzfeldt-Jakob Disease vCJD humans; acquired from cattle with BSE

Bovine Spongiform Encephalopathy BSE Infection with prion

contaminated MBM Kuru infectious; in humans who

practiced cannibalism in Papua New Guinea

Gerstmann-Sträussler-Scheinker disease GSS inherited disease of humans

Fatal Familial Insomnia FFI inherited disease of humans

Scrapie infectious disease of sheep and goats

other animal TSEs (cats, mink, elk, mule deer )

Infection with prion-contaminated MBM

THANK YOU

Could Prions Be In Milk And Dairy?

• Animal studies do suggest that meat (from animal muscle alone) can transmit prion-related diseases since muscle is interlaced with lymph and nervous tissue--known to be infected with BSE.

• Possibility that milk may also carry disease-inducing prions cannot be excluded.

• British BSE expert has pointed out that at least one human case suggests passage of prions in milk.

• Japanese woman dying of CJD was found to have the infectious agent in her colostrum.

• The risk from milk does appear to be much smaller than from eating beef or cattle organ tissues.

• Milk from BSE Infected Cattle is Banned by the British government as it is under suspesion.