Infection without inflammation – Prion diseases
A. Pathogenesis
Human spongiform encephalopathies are a group of disorders that share certain clinical, pathological, and pathogenetic features. All cause a progressive, fatal, dementing illness; most are characterized by vacuoles within and among neurons (“spongiform change”); and all are believed due to abnormalities of prion protein (PrP). Other spongiform encephalopathies, which share these features, are recorded in animals (eg: sheep, cattle, cats, deer, elk). The most important of these is bovine spongiform encephalopathy (BSE), also known as “mad cow disease.” BSE was first described in Britain in 1986, and was formerly spread by use of nervous system tissue from slaughtered animals to make high-protein cattle feed.
B. Pathology
As prion diseases are caused by a conformational change in a normally expressed protein, the pathology of prion “infection” does not involve a classical immune/inflammatory response. Prion diseases are characterized by neuronal loss and reactive astrocytosis accompanied by spongiform degeneration of various regions of the central nervous system, and/or deposits of prion protein to form amyloid plaques. The distribution of these changes varies with the disease, which is in turn dependent on the mode of transmission (genetic, infectious, sporadic), the “strain” of the prion, and the genotype of the affected individual.
The prion protein gene (PRNP) is located on chromosome 20; more than 40 variations of this gene are known (insertions, deletions, mutations). Some variations are associated with familial forms of spongiform encephalopathy while others appear to affect susceptibility to developing sporadic or infectious forms of the disease.
The majority of human spongiform encephalopathy cases are idiopathic. About 15% occur as a result of hereditble mutations in PRNP, and rare cases have followed exposure to infectious CNS material. While transmissible, prion diseases are not “contagious.” In humans, infectivity is virtually confined to CNS tissue, with which one generally does not directly interact when dealing with patients. Hence, we should not let “prionophobia” interfere with our doctor-patient relationships.
C. Clinical Syndromes
Two of the human spongiform encephalopathies, Gerstmann-Straussler-Scheinker syndrome and fatal familial insomnia, are rare hereditary disorders. Kuru is an almost extinct disease affecting New Guinea’s Fore tribe, where it was spread by ritual cannibalism of dead family members. Sporadic Creutzfeld-Jakob disease (CJD) is, by far, the most common of the human prion diseases. Variant (intially called “new variant”) Creutzfeldt-Jakob disease (vCJD) is one of the world’s newest infectious diseases, and one which has important public health implications, due to proven transmission via blood transfusion.
1. Creutzfeldt-Jakob disease
While it is the most common form of human spongiform encephalopathy, CJD remains rare with an average frequency of approximately 1 case per million per year. The incidence doubles in the 60-75 year old age group. Onset is usually in the 50-75 age range, though it can occur at any time in adulthood. Approximately 85% of cases are sporadic, with most of the rest being familial (initial reports of case clustering felt to be due to casual transmission have ALL turned out to be familial). Familial cases are associated with mutations in the PRNP gene, and show autosomal dominant inheritance with incomplete penetrance. A small number of cases are iatrogenic, resulting from contamination of neurosurgical instruments, dural and corneal grafts from infected donors, and contaminated cadaveric pituitary hormones.
Clinical features of CJD are variable, making diagnosis difficult when the disease first presents. One fourth of patients report onset with vegetative symptoms, such as fatigue, insomnia, appetite change, and loss of libido. Patients usually first see a doctor for problems with concentration, memory, and cognition. Progressive dementia is the cardinal feature of the illness, but cerebellar signs are present in 60% of cases. Myoclonic jerking is a typical feature. Signs and symptoms referable to almost every site in the CNS have been reported. The disease is relentlessly progressive, with a mean survival time of 7 months in the most common form of the disease. Diagnosis is aided by EEG, which typically shows triphasic waves occurring at 1-2 second intervals. MRI often shows a distinctive pattern of homogenous signal increase in the basal ganglia and thalami. Routine CSF parameters are usually normal. The presence of 14-3-3 proteinase inhibitor protein in the CSF is released into the CSF from damaged neurons. While initially felt to be highly sensitive and specific for diagnosing CJD, subsequent studies have shown it to be an unreliable disease marker as levels are frequently normal in variant CJD, and may be increased in non-prion diseases.
Clinical variability of sporadic CJD results partly from polymorphism at codon 129 of the PrP gene and partly from different higher order structures (“strains”) of PrP. Polymorphism between methionine and valine creates three different genotypes (129MM, 129MV, 129VV). Independent of genotype, PrP generally yields either a 19kd or 21 kd product when treated with proteinase K depending on the protein conformation. Three genotypes and two protein conformations allows for 6 total different gene/structural combinations with some distinctive clinical and histological features. Established clinical variants include Heidenhain and Oppenheimer-Brownell. The Heidenhain variant is most common (70% of CJD) and is associated with 129MM-1 and 129MV-1 genotypes; initial presentation includes cognitive decline, ataxia and visual disturbances (eg: hallucinations, cortical blindness). The Oppenheimer-Brownell variant initially presents as ataxia without cognitive decline, and is associated with the type 2 prion protein (digesting to 19kd).
There is no specific treatment for CJD. Universal precautions are maintained for hospitalized patients. In sporadic CJD, PrP is present in the CSF, but not in blood, tears, saliva, perspiration, urine or stool. Transmission of sporadic CJD to close contacts has not been reported.
2. (New) variant Creutzfeldt-Jakob disease.
This disorder was first described in the United Kingdom in 1995. In contrast to typical CJD patients, those with vCJD were (much) younger (mean age 27years at onset), had a longer clinical course (average 14 months), and showed different clinical signs. Early features include sensory symptoms such as painful dysesthesias (infrequent in CJD), and affective and behavioral changes (depression and anxiety). Eventually, all patients develop ataxia. Patients do not have the EEG abnormalities seen with CJD.
Several lines of evidence combined to prove that vCJD represents transmission of BSE to humans who consumed beef from infected cattle. vCJD was identified nine years after the beginning of an epidemic of BSE in Britain. Transmission of BSE to nonhuman primates produces neuropathologic findings very similar to those seen in vCJD patients. Finally, both BSE and vCJD demonstrate identical immunoblot patterns distict from those seen in sporadic CJD. As of December 2003, approximately 140 cases of definite or probable variant CJD had been confirmed in England, with six cases in France and one each in Italy, Canada, Ireland, and the USA. Presently, the risk of contracting vCJD from beef is considered very low, due to a ban on using brain tissue in animal feed, and culling of infected cattle. Still under investigation is the possible risk of a second wave of vCJD as a result of human to human hematologenous transmission.
All cases of vCJD have been associated with methionine homozygosity at codon 129 of the PrP gene. The 129MM genotype frequency is less than 50% of the general population which demonstrates a genetic susceptibility to developing disease upon exposure to BSE prion.
3. Gerstmann-Straussler-Scheinker (GSS)
GSS is an extremely rare hereditary spongiform encephalopathy associated with mutations in the PrP gene. Approximately 60 families have been documented to have GSS. It is inherited in an autosomal dominant fashion with nearly 100% penetrance. Symptoms at onset are variable but the most common presentations include cerebellar ataxia, parkinsonism, pyramidal signs and cognitive dysfunction. Duration of disease varies from a months to years (depending on the MV polymorphism at codon 129 of PRNP).
4. Familial Fatal Insomnia (FFI)
FFI is even rarer than GSS. It is associated with replacement of aspartic acid with asparagine at codon 178 with concurrent methionine at codon 129; FFI is inherited in an autosomal dominant fashion. Onset age ranges from the third to sixth decade of life. Symptoms most commonly include REM sleep disturbances, mild autonomic dysfunction and various motor dysfunctions (eg: dysphagia, abnormal gait, diplopia).
----
References used:
Dickson, Dennis, ed. Neurodegeneration: The Molecular Pathology of Dementia and Movement Disorders. International Society of Neuropathology, 2003. Chapter 6 (Prion Disorders), p 282-335. ISBN 3952231212.
Parchi P, Giese A, Capellari S et al. Classification of sporadic Creutzfeldt-Jakob disease based on molecular and phenotypic analysis of 300 subjects. Ann Neurol. 1999 Aug;46(2):224-33. PMID: 10443888
Mead, Simon. Prion disease genetics. European Journal of Human Genetics (2006) 14, 273–281. PMID: 16391566
Appleby BS, Appleby KK, Crain BJ, Onyike CU, Wallin MT, Rabins PV. Characteristics of established and proposed sporadic Creutzfeldt-Jakob disease variants. Arch Neurol. 2009 Feb;66(2):208-15. PMID: 19204157
Kovács GG, Trabattoni G, Hainfellner JA, Ironside JW, Knight RS, Budka H. Mutations of the Prion Protein Gene. J Neurol. 2002 Nov;249(11):1567-82. PMID: 12420099.
Aguzzi A. Staining, straining and restraining prions. Nat Neurosci. 2008 Nov;11(11):1239-40. PMID: 18956007.
