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Year : 2016  |  Volume : 64  |  Issue : 3  |  Page : 382-386

Neither a virus nor a viriod: It is a prion

Department of Neurology, RG Kar Medical College and Hospital, Kolkata, West Bengal, India

Date of Web Publication3-May-2016

Correspondence Address:
Kalyan B Bhattacharyya
Department of Neurology, RG Kar Medical College and Hospital, Kolkata, West Bengal
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/0028-3886.181577

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How to cite this article:
Bhattacharyya KB, Dutta AK. Neither a virus nor a viriod: It is a prion. Neurol India 2016;64:382-6

How to cite this URL:
Bhattacharyya KB, Dutta AK. Neither a virus nor a viriod: It is a prion. Neurol India [serial online] 2016 [cited 2022 Aug 16];64:382-6. Available from: https://www.neurologyindia.com/text.asp?2016/64/3/382/181577

In 1920, Hans Gerhard Creutzfeldt (1885-1964), a pathologist, working in the laboratory of Walther Spielmeyer, famed for his works on neural histopathology and peripheral nerve injuries in Munich, described a 23-year old woman, named Berta E, having a 'peculiar nodule forming disease of the nervous system.' He distinguished it from multiple sclerosis, and called it 'pseudosclerosis.'[1],[2] In 1921, Alfons Maria Jakob (1884-1931), once again a pathologist from Germany, reported three such cases and called it 'spastic pseudosclerosis' and the eponym,  Creutzfeldt-Jakob disease More Details (CJD) was born which was assigned by Spielmeyer in 1922.[1],[2] Much later, scientists debated on the veracity of Creutzfeldt's case and concluded that his description did not conform to the present diagnostic criteria of Transmissible Spongiform Encephalopathy (TSE) and therefore, Jakob is now credited with the first description of the disease.[1],[2],[3]

The transmissible and infectious nature of CJD and the related conditions was discovered by Daniel Carleton Gajdusek and Joe Gibbs of the United States of America in their study on the South Fore tribes of New Guinea, who practiced endocannibalism as a ritual and devoured the brains of the those afflicted with the disease in their own community. The resulting disease, kuru, derived from the local word kuria, or guria, literally meaning 'trembling with fear,' presented with features like truncal ataxia, preceded by headaches, joint pains, and shaking of the limbs.[1],[2] Over 1000 persons belonging to that tribe died from this disease between 1957 and 1968. Gajdusek and his co-workers transmitted the disease to chimpanzees after a long incubation period of many years following intracerebral inoculation of the emulsified brain from the autopsied subjects and consequently, he was awarded the Nobel Prize in Medicine in 1976.[4] Stanley Prusiner, also from the United States of America, percipiently pursued this issue further for which he too, received the Nobel Prize in 1997.[5],[6] He presented evidence that the transmissible pathogen is a protinaceous infectious particle which is devoid of nucleic acid, resists the action of enzymes that destroy ribose nucleic acid and deoxyribose nucleic acid, fails to produce an immune response, and electron microscopy does not offer the structure of a virus. Thus, in order to distinguish it from viruses and viriods, the latter containing nucleic acid without a capsid structure, Prusiner introduced the term prion.[7] He stated persuasively that in mammals, prions reproduce by binding to the normal cellular isoform of the prion protein PrP c. PrP c thereafter replicates by an autocatalytic mechanism and produces PrP Sc, whereby the latter binds to endogenous PrP c and converts it to its own form.[7] PrP c is rich in α-helix with little β element, while PrP Sc has minimal α component and a high amount of the β material. This α to β transition in the prion protein is the fundamental event in the pathogenesis of prion diseases and it is unique that a normal constituent of the body turns into a virulent pathogen following conversion. The concept of prion disease explains the curious occurrence of an infectious disease turning into a heritable one and this is a rare example of an infectious disease encoded in a gene which is designated as PRioN Protein (PRNP) and is located in the short arm of chromosome 20, transmitted as an autosomal dominant trait.[6],[7]

The prion diseases affect both animals and human beings. There are four varieties identified in man namely, CJD or its new variant (vCJD), Gerstmann-Sträussler-Scheinker syndrome (GSS), Kuru, and Fatal Familial Insomnia (FFI), of which the first one has been studied most extensively. Will et al., reported the first case of vCJD which occurred as an outbreak in the United Kingdom in 1996 and it took place in beef eaters, while the cattle suffered from Bovine Spongiform Encephalopathy (BSE), often known as the Mad Cow Disease.[8] A total of 229 patients afflicted with this disease from 12 countries have been identified as of June, 2014 and 177 cases have been reported from the United Kingdom alone, where 122 subjects died.[9] That apart, 27 cases have been identified in France, 5 in Spain, 4 in Ireland, 4 in the United States of America, 3 in the Netherlands, 2 each from Portugal, Italy and Canada and one each from Japan, Saudi Arabia, and Taiwan. Some of the cases from United States of America, Ireland, Canada and Japan were in all likelihood, exposed to the BSE agent, while residing in the United Kingdom and no country experienced the disease where the cattle did not suffer from it before.[9] The incidence of the disease has been on the decline since 2001 and no death has been reported since 2014.[7] Similar illness has been observed also in the animal world. In mule deer, elk, cat and in sheep, it is often known as the chronic wasting disease, and in the last mentioned species, it is given the name, scrapie. The transmission of this disease was demonstrated first in 1943 when a population of Scottish sheep was accidentally inoculated with a formalin extract of lymphoid tissue of an animal suffering from the disease. It is so named since the diseased animal has the curious habit of incessantly rubbing or scraping its body against the fence.[10]

All prion diseases are in general, rapidly fatal. Epidemiological studies have shown that they occur in three ways namely, sporadic, infectious or iatrogenic, and familial, where the sporadic variety constitutes about 85% of all cases and the other two varieties make up for the remaining 15%. That apart, a small number of conjugal cases have also been reported and at least one neurosurgeon turned into a victim of the disease.[11]

Canada and the United States of America prohibit blood transfusion from patients with vCJD but not with the classical form; and, it has also been observed that subjects who underwent more than two surgical operations were at a higher risk of contracting the disease.[12] The age of onset for sporadic cases is about 60 to 70 years and that for the familial cases is about 20 years less.[13] Zanusso et al., identified the infectious prion protein in the nasal mucosa of nine sporadic cases and this possibly suggests that the nose is its route of entry. Thus, nasal mucosal biopsy can serve as a diagnostic test material and interestingly, tonsillar biopsy and immunostaining are also found positive in vCJD.[14] The first case of iatrogenic infection was reported in 1974 by Duffy et al., following cadaveric corneal transplant derived from a patient with CJD.[15] Infectious or iatrogenic cases occur due to corneal or dural graft and the use of pooled growth hormone or human chorionic gonadotrophin (hCG) products, they have a shorter incubation period of about 2 years, and there is some evidence that genetic susceptibility has a role, albeit a small one, in its genesis.[10],[16],[17] If the inoculation is nearer to the brain, the incubation period is shorter and presents like classical CJD, whereas, with intravenous injection, as happens with the administration of pituitary hormone injections, it is longer and the clinical picture is of a progressive ataxic nature.[10] More than 120 cases of CJD have been recorded after dural graft surgery and all the grafts were presumably acquired from a single manufacturer, whose asceptic procedures were possibly inadequate to eradicate the prions. It is of some interest to note that one case of iatrogenic CJD has been recorded where a hiatus in the tympanic membrane was repaired with a pericardial graft.[10] Infected depth EEG electrodes can also transmit the disease, and in one case, the improperly disinfected electrodes which caused CJD in two young subjects with refractory epilepsy, also led to the development of the disease in a chimpanzee, 18 months after the experimental implantation of the same electrodes.[7] Injection of contaminated human growth hormone has led to the occurrence of CJD in more than 120 cases, and that with hCG in 4 cases, the incubation period ranging from 4 years to 30 years. Ingestion of sheep meat, infected with scrapie as a cause of CJD has not yet been reported though the speculation remains a serious contention.[7]

Arya reported that the injection of sheep-brain derived anti-rabies vaccine could theoretically lead to the development of iatrogenic CJD, though no case has been reported so far, and three cases of CJD mediated by blood transfusion have been reported in the literature.[18],[19] In sporadic cases, somatic mutation may occur or alternatively, PrP Sc which is present in a very low and undetectable quantity, as estimated by the conventional bioassay, may actually rise following altered cellular mechanisms and clearance of the elevated level may be compromised. The other hypothesis is that PrP Sc is not simply a misfolded protein; on the contrary, it is an alternatively folded molecule with a definite function.[7]

In the inherited forms, missense mutations and expansions in the octapeptide repeat region of the gene is the culprit and five different forms of PRNP gene mutation have been linked to CJD.[7]

Certain phenotypes have been linked to specific mutations and a clinical phenotype, indistinguishable from that of the typical sCJD is seen with substitutions at codons 180,183,200,208, and 210; and, the typical CJD is seen if the amino acid valine is encoded in the 129th position of the same allele, while methionine-to-valine polymorphism at the same position determines the age of onset and clinical phenotype of sCJD.[7]

The incidence of CJD is 1 to 2 cases per million population per year without any specific sex predilection in the western world.[20]

People of two countries, the Libya-born Israelis and some people in a restricted area of Slovakia are disproportionately afflicted with the disease and the incidence is 60 to 100 times greater than expected. This has been attributed to a higher prevalence of codon 200 mutation in the PRNP gene.[21]

The disease is rare in India and this is possibly due to the lack of clinical awareness and facilities for investigations. Therefore, it is grossly underreported in our country. The first case was reported from the National Institute of Mental Health and Neurosciences (NIMHANS), Bengaluru in 1965 and a CJD registry was established there in 1988-89 by utilising the Master's Clinical Criteria.[20],[21] Till 2014, the CJD registry contained 138 cases, of which 46 cases belonged to the definite category and clinically, they were identical with what has been described elsewhere in the world.[20],[22],[23] Importantly, there were two clusters of patients in Mumbai and Bengaluru, while sporadic cases have been reported from Kolkata, Hyderabad and the state of Kerala. Four cases are considered familial in the registry, since the index case was a patient of definite CJD, while three other members of the family suffered from dementing illnesses.[10] The cardinal observations which emerged from the study are that the majority of the patients were aged between 45 and 65 years of age, males outnumbered females, the duration of the disease was longer, and thus the Indian patients were one to two decades younger than that seen in the western world. Most of the patients were businessmen, agriculturists and housewives. Till 2000, it was observed that 11 of the 70 cases in the registry had undergone surgery or some invasive procedure like a lumbar puncture or electroconvulsive therapy in the past. One interesting observation was that none underwent corneal or dural grafting, nor did they receive growth hormone or hCG injection.[10] Among 39 cases where dietary history was available, only 6 subjects were non-vegetarians, which indicates the sporadic nature of the disease and therefore, conversion of the normal cellular PrP c protein to infective PrP Sc protein.[10] Twenty two cases have been reported by Katrak, Puranik and Collinge from Mumbai over four generations, where the clinical and neuroimaging features were highly suggestive of CJD. Bubelis et al., reported a single case of infantile CJD in 1966, but it is more likely that it was a case of status spongiosis secondary to some metabolic disease.[24],[25] Mehndiratta et al., from New Delhi reported 10 cases in 2001, where the age of the patients conformed to those reported earlier, startle myoclonus was a consistent feature, and abnormal behaviour was present in 7 subjects. The Heidenheim variety, where agnosia and cortical blindness predominated; and, the Brownell-Oppenheimer variety, represented fundamentally by cerebellar ataxia,[8] were found in one case each, and 7 subjects presented with extrapyramidal features. All the patients had classical features in the EEG. Three patients underwent brain biopsy where features suggestive of subacute spongiform encephalopathy were noted in 2 subjects.[26] Furthermore, Biswas et al., studied 10 cases of sCJD from Kolkata, Eastern India, where facilities for brain biopsy are limited. The clinical features were again consistent with the reported cases. 60% of the patients showed classical EEG changes and all had typical MRI features like the cortical ribbon sign, the hockey stick sign or the pulvinar sign. Eight of the 10 patients died within a mean period of 4.56 months from the onset of the disease, thus attesting once again, the rapid fatality from the condition.[27]

The World Health Organization has recommended guidelines for the control of spread of CJD.[28]

  • No tissue that is likely to contain the BSE agent, nor part or product of any animal which has shown signs of a TSE should enter the human or animal food chain. All countries should ban the use of ruminant tissues in ruminant feed
  • The pharmaceutical industry should avoid the use of bovine materials and materials from other animal species in which TSEs naturally occur. If their use is absolutely necessary, these materials should be obtained from countries which have a surveillance system for BSE in place and which report zero cases of BSE
  • The guidelines on tissue infectivity distribution in transmissible spongiform encephalopathies in 2006 provide information and assist national regulatory authorities in conducting risk assessments of vCJD transmission.

There is no significant difference in the pathological changes, electrocephalographic and magnetic resonance imaging findings, cerebrospinal fluid biomarkers and treatment options between what is seen in India and the western world. However, electroencephalography usually does not reveal the classical triphasic waves or short-duration burst suppression pattern in vCJD, the typical findings seen in classical CJD or its familial variant.

A startling report, carrying with it substantial political, diplomatic and religious overtone, was mooted and brought to the fore by Alan Colchester of Kent University, England, and his daughter Nancy of Edinburgh University, in the celebrated journal Lancet on September 3rd, 2005.[29] They contended that BSE had its origin in the rituals of the funeral process practised in the Indian subcontinent.[29],[30] Colchester, a consummate academician of repute, claimed that in the 1960s and '70s, India exported cattle feed which contained pulverized remains of human and bovine skeleton, and the human component was the principal perpetrator for the outbreak of BSE in the United Kingdom in the 1990s. He argued pertinaciously, if not obdurately, that incompletely incinerated corpses condemned to the river Ganges, reached far away and the peasants collected the remains, sold to the animal recycling plants, and the stuff was exported as fertiliser and food for the cattle in the United Kingdom. As a result, a number of people in East Kent, the so called 'Kent Cluster', contracted the disease. However, some researchers in Edinburgh dismissed the idea as puerile and the United Government Environment Agency was equally not disposed favourably towards Colchester.[30],[31],[32] Though attractive and worth pursuing at the first sight it might have seemed to many investigators, the hypothesis met nonetheless, with scathing criticisms and scornful repercussions, and Shankar, the noted neuropathologist from NIMHANS, Bengaluru, was not ready to buy it; he said that even if the hypothesis was novel, the amount of human remains in the bovine feed would be scanty and therefore, inconsequential as a causative agent. Furthermore, no case of BSE was observed in the cattle in India. David Brown, an expert on prion diseases at the University of Bath, endorsed the view of Shankar.[30] The fundamental charge labelled against this hypothesis was that majority of the population in the Indian subcontinent in general, treat cows with utmost reverence and scrupulously avoid their meat and many of them are conscientious and avowed vegetarians. Additionally, never in the recorded history of India was cannibalism practised. The Department of Environment, Food and Rural Affairs said that it was entirely 'speculative', and Bandopadhyay, the Commissioner for Husbandry for the Government of India, retorted, 'I have not seen the publication but I think the hypothesis appears highly preposterous. I would like to see what evidence there is to support it. I know that some websites have put forward a theory about half-burnt human remains in Benares. But I would not expect this to appear in the Lancet. If it is true. then we should have had an epidemic in India. But there have been no cases of variant CJD. It defies logic, really.'[32] Shankar and Satishchandra, the latter a noted clinical neurologist, from NIMHANS, Bengaluru, retorted, 'Scientists must proceed cautiously when hypothesising about a disease that has such wide geographic, cultural and global implications.'[33]

Thus, CJD is a rare and fatal disease. It calls for keen and acute clinical acumen on the part of the neurologists and once suspected, the diagnosis is fairly simple with the conventional electroencephalographic, imaging and cerebrospinal fluid examinations, no matter whether or not brain biopsy can be carried out. The treatment is hopelessly frustrating and therefore, prevention is of paramount importance. Strict surveillance over cattle products, limiting pharmaceutical companies from manufacturing drugs from putatively diseased animals, and prompt and careful disposal of the carcasses shall go a long way to prevent this deadly and presently, incurable malady.

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