The Mystery of Prion Diseases
"Impossible!" critics screamed in reactionto Stanley B. Prusiner, MD's 1982announcement that "infectious proteins," lacking any nucleic acid material,caused several degenerative encephalopathies.Critics retreated, however,as mounting evidence supportedDr. Prusiner's theory, and in 1997 hereceived the Nobel Prize in medicine forhis research on prions.1
What Is a Prion?
Prusiner coined the term prion, meaningproteinaceous infectious particles.1Prions—animal tissue proteins—occur inhigher concentrations in the brain, spinalcord, and eyes. Their function is poorlyunderstood, but findings suggest thatthese proteins are vital to brain synapsefunctioning.1
By way of an unknown mechanism, anormal prion protein can become abnormallyshaped and pathologically variant.As it comes in contact with other prionproteins, it serves as a template, causingthem to mirror the abnormal shape.Unable to be metabolized by proteaseenzymes, protease-resistant infectiousprions replicate exponentially, accumulatein tissue cells, disrupt cellular function,and cause irreversible damage.2Prions have stealth characteristics andcan survive autoclaving and most chemicaltreatments.2,3
Prion diseases, labeled transmissiblespongiform encephalopathies (TSEs),exist in both humans and animals andpredominantly affect the central nervoussystem's gray matter, leading to neuralloss, gliosis, and accumulation of amyloidaggregates.4,5 Viewed microscopically,affected brain tissuecontains tiny sponge-likeholes, the remnants of cellulardeath.2,6 Animal prion diseasesinclude scrapie in sheep,bovine spongiform encephalopathy(BSE, or "mad cowdisease" ) in cows, felinespongiform encephalopathy incats, and chronic wasting diseasein mules, deer, and elk.1
Five human prion diseaseshave been identified. Creutzfeldt-Jakob disease (CJD) is characterizedby progressive deteriorating neurologicalfunctioning and myoclonic jerks. Patientsgenerally present with progressive cognitiveimpairment or cerebellar dysfunction.Disease progression includesbehavioral abnormalities, cortical visualabnormalities, higher cortical dysfunction,and pyramidal and extrapyramidalsymptoms. All patients eventually developmyoclonic jerks involving one limb orthe entire body. The mortality rate is 85%within 1 year, often from pneumonia. CJDaffects 1 in 1,000,000 adults, with anaverage onset age of 68 years.3,4,6
Variant Creutzfeldt-Jakob disease(vCJD) was first reported in 1995. Its etiologywas quickly traced to dietary consumptionof cow meat taken from BSEinfectedanimals. Transmission to humanswas previously thought impossiblebecause of species barriers betweenhumans and animals. It is a variant ofclassic CJD because of the following distinguishingcharacteristics:
- Younger onset age (median age is 26years)
- Psychiatric onset symptoms, notcognitive impairment
- Longer duration of disease pathology(2 years vs 6 months for CJD)
- An electroencephalogram patterndevoid of the sharp wave complexesobserved with CJD3,7,8
Initial psychiatric symptoms may alsoinclude peculiar sensory experiences,such as sticky skin. Cognitive decline andataxia accompany vCJD disease progression.Incubation time prior to symptomonset exceeds 4 years,3 with a medianage at death of 28 years.7
Gerstmann-Straussler-Scheinker diseasepresents with a slow, progressivelimb and truncal ataxia with dementia.Similar to Alzheimer's disease, affectedbrain tissue is replete with neurofibrillarytangles and amyloid plaque. Onset usuallybegins in people in their 40s with clumsinessand difficulty in walking. Deathoccurs within 3 to 8 years of symptomonset.4,6
Fatal familial insomnia affects the thalamus,resulting in intractable insomnia, acondition that always results from geneticmutations. Onset age is extremely variable,ranging from 18 to 60 years. Deathoccurs after 6 months to 3 years ofonset.4,6 Unlike other prion diseases,spongiform encephalopathies may beminor or even absent.4
Kuru, historically common in NewGuinea until the 1960s, presents with arapid mental functioning decline, loss ofmuscle coordination, limb stiffness, andmuscle twitching. Death generally occurswithin 3 months to 2 years. Prionswere acquired from cannibalistic ritualsof the dead that included eating braintissue, which was usually given towomen and children.6 New Guineabanned cannibalism in 1957, and incidencesof kuru decreased from 1% toonly 5 cases annually.3
CJD is the most common prion disease,accounting for ~85% of reportedcases, and appears in 3 forms: sporadic,familial, and iatrogenic. Approximately85% of CJD is sporadic, 15% is familial,and less than 1% is iatrogenic.9 Two populationsare disproportionately affected:Libyan-born Israelis and those living inSlovakia.4
Iatrogenic transmission has includedtransplantation of infected corneas,injection of growth hormone derivedfrom human pituitaries, contaminatedsurgical instruments or electroencephalogramdepth electrodes, humangonadotropin, and human dura matergrafts.3,10
Although vCJD averages 10 to 15 casesannually since its discovery in 1994, themagnitude and geographic distributionremains unknown.2 Whereas 159 caseshave been reported in Great Britain, only2 have been recorded in the UnitedStates.4 Previously assumed to be nontransmissiblevia blood transmission,several vCJD cases have been identifiedin patients who received transfusionsfrom donors with preclinical vCJD.7Epidemiologists fear that a large numberof people may be incubatingthe disease, increasing iatrogenictransmissions.
Prion diseases have longincubation periods, rangingfrom 1.5 to 40 years, and arealways fatal.5 The type of cellsinvolved in prion replicationremains unknown, althoughmost researchers believe immunocompetentcells areinvolved.7 vCJD occurs whenprions from contaminatedmeat crosses the gut's epithelium.Prions are known to first accumulatein the spleen and lymph nodesbefore affecting the brain. Interestingly,prions in nerve trunks appear to be intransit and not actively replicating.7
Diagnosis and Treatment
Probable diagnosis is based on clinicalmanifestations; definitive diagnosis isonly confirmed with postmortem tissueanalysis.5 Clinical manifestations resemblenumerous other conditions, includingAlzheimer's disease, Parkinson's disease,hydrocephalus, herpes simplex encephalitis,cortical basal ganglionic degeneration,chronic meningitis, diffuse Lewybody dementia, schizophrenia, multiplesclerosis, myoclonic epilepsy, multiinfarctdementia, and lithium poisoning.1,4It is not unusual for multiple clinicians tomisdiagnose patients before a prion diseaseis identified as the probable causefor the patient's symptoms. Given prion'schameleon-like symptoms, some believethe disease's reported prevalence iserroneously low.
Treatments directly targeting prions orslowing disease progression are nonexistent.6 Once clinical symptoms appear,considerable brain damage has alreadyoccurred; consequently, practitionersfocus on symptom management. Availableagents include psychoactive agentsfor hallucinations, antiepileptic drugs forseizures, and anti-Parkinson agents forextrapyramidal symptoms.4 Some antianxietyagents (eg, clonazepam) helpreduce muscle jerking.6
Ideally, treatment should inhibit theconformational change of prions. Researcherswould like to target those whoare asymptomatic, but the rarity of thedisease and its lack of diagnostic testsmake this impossible. Mouse modelsconfirm that prion accumulation firstoccurs in lymphoid tissue before migratingto the brain, and research is underwayto identify agents that blocklymphoid prion accumulation.5 Severalcompounds, such as the polyanions,polyene antibacterial agents, tetrapyrroles,and branched polyamines, interferewith prion propagation in animalmodels, but their toxicity and inability topass the blood-brain barrier (BBB) makethem unlikely candidates.7 Researchershave looked to agents known to becapable of crossing the BBB, and tricyclicderivatives of acridine and the phenothiazineshave been demonstrated toinhibit prion activity, but unfortunatelythey do not affect protease resistance inpreexisting prions.7
Tetracyclines have antiprion activityand are currently being tested with animalmodels.7 Copper is implicated inprion propagation, and chelation therapyis also being investigated. Preliminaryfindings suggest that the chelator D-penicillaminemay delay prion disease onset.4
Prion diseases' long incubation periods,along with their chameleon-likesymptoms, remain a major concern.vCJD is especially troubling, despiteincreased vigilance of the nation's foodsupply. Many experts believe that currentresearch efforts should emphasize prevention;the development of a vaccine isnot only desirable, but necessary.
Dr. Zanni is a psychologist andhealth-systems consultant based inAlexandria,Va.
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