Human prion diseases: An overview | Medicina Clínica (English Edition)

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          "en" => "<p id="spar0005" class="elsevierStyleSimplePara elsevierViewall">Schematic representation of exon 2 of the <span class="elsevierStyleItalic">PRNP</span> gene&#46; The schematic shows the point mutations <span class="elsevierStyleItalic">&#40;missense&#41;</span> with more than 100 cases published in the medical literature and the polymorphic codon 129&#46; These 5 mutations are responsible for approximately 85&#37; of genetic prion diseases&#46; D&#58; aspartic acid&#59; E&#58; glutamate&#59; I&#58; isoleucine&#59; K&#58; lysine&#59; L&#58; leucine&#59; M&#58; methionine&#59; N&#58; asparagine&#59; P&#58; proline&#46;</p>"
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    "textoCompleto" => "<span class="elsevierStyleSections"><span id="sec0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0025">Introduction</span><p id="par0005" class="elsevierStylePara elsevierViewall">Prion diseases are a group of closely related and rapidly progressive neurodegenerative diseases affecting mammals&#44; including humans&#46;<a class="elsevierStyleCrossRefs" href="#bib0005"><span class="elsevierStyleSup">1&#8211;3</span></a> In these diseases&#44; a normal brain protein known as <span class="elsevierStyleItalic">prion</span> protein &#40;PrP&#41; aggregates into an abnormal conformation&#46;<a class="elsevierStyleCrossRefs" href="#bib0005"><span class="elsevierStyleSup">1&#8211;3</span></a> This abnormal form of the protein&#44; known as <span class="elsevierStyleItalic">&#34;prion&#34;</span>&#44; acts as an infectious agent and can transmit the disease to other hosts&#46; The <span class="elsevierStyleItalic">&#34;prion&#34;</span> is therefore an &#34;infectious&#34; protein conformation containing no nucleic acids&#46;<a class="elsevierStyleCrossRef" href="#bib0010"><span class="elsevierStyleSup">2</span></a> The majority of prion diseases in humans correspond to the entity known as Creutzfeldt&#8211;Jakob disease &#40;CJD&#41;&#44; although other clinical forms can also occur&#46;</p><p id="par0010" class="elsevierStylePara elsevierViewall">Their diagnosis is always a challenge for clinicians&#46; However&#44; early detection and monitoring is crucial for care planning and public health implications&#46; The recent introduction of techniques allowing the detection of prions in biological samples has been a remarkable achievement for the understanding of these entities&#46; In the light of these developments&#44; it seems appropriate to briefly review the pathogenesis&#44; clinical and diagnostic features of these diseases&#44; as well as their public health implications and possible therapeutics&#46;</p></span><span id="sec0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0030">Epidemiology</span><p id="par0015" class="elsevierStylePara elsevierViewall">Prion diseases have a worldwide distribution&#44; with an annual incidence of 1&#8211;2 cases per million population&#46;<a class="elsevierStyleCrossRefs" href="#bib0005"><span class="elsevierStyleSup">1&#44;2&#44;4</span></a> They can occur sporadically &#40;85&#8211;90&#37; of cases&#41; or by genetic transmission &#40;10&#8211;15&#37;&#41;&#46;<a class="elsevierStyleCrossRefs" href="#bib0005"><span class="elsevierStyleSup">1&#44;2</span></a> In addition&#44; there is a third form of presentation&#44; the acquired or &#34;infectious&#34; form &#40;&#60;1&#37;&#41;&#44; either by dietary consumption of prion contaminated meat or by iatrogenic transmission&#46;<a class="elsevierStyleCrossRefs" href="#bib0005"><span class="elsevierStyleSup">1&#8211;3</span></a></p><p id="par0020" class="elsevierStylePara elsevierViewall">Sporadic cases affect subjects in a highly variable age range&#44; from 16 to 98 years old&#46;<a class="elsevierStyleCrossRef" href="#bib0010"><span class="elsevierStyleSup">2</span></a> However&#44; they typically occur later in life&#44; with a peak in the 8th decade of life&#46; The highest incidence of genetic forms is in the 6th decade of life&#46;<a class="elsevierStyleCrossRefs" href="#bib0005"><span class="elsevierStyleSup">1&#8211;3</span></a></p><p id="par0025" class="elsevierStylePara elsevierViewall">There have been 2 outbreaks transmitted through ingestion&#58; kuru and variant CJD&#46; The first was an epidemic disease among the Fore-speaking Aborigines in Papua New Guinea&#46; The disease probably appeared sporadically and spread due to ritual practices of cannibalism&#46; This custom was banned in the 1950s&#44; so the last observed cases of kuru occurred in 2009 &#40;incubation period of at least 50 years&#41;&#46;<a class="elsevierStyleCrossRefs" href="#bib0005"><span class="elsevierStyleSup">1&#44;2&#44;5</span></a></p><p id="par0030" class="elsevierStylePara elsevierViewall">The CJD variant&#44; known in the media as &#34;mad cow disease&#34; at the time&#44; appeared in the UK in 1994&#44; due to the consumption of beef contaminated with Bovine Spongiform Encephalopathy prions&#44;<a class="elsevierStyleCrossRef" href="#bib0015"><span class="elsevierStyleSup">3</span></a> a neurological disease of cattle that can be transmitted to cattle or humans by consumption of prion-infected parts of the animal&#46; This outbreak occurred 10 years after a massive epidemic of the disease in cattle&#46;<a class="elsevierStyleCrossRefs" href="#bib0010"><span class="elsevierStyleSup">2&#44;3</span></a> Despite millions of people consuming this meat&#44; only 228 patients had the disease by 2016&#46;<a class="elsevierStyleCrossRefs" href="#bib0005"><span class="elsevierStyleSup">1&#8211;3</span></a> Currently&#44; the incidence of variant CJD has decreased significantly due to the control of spongiform encephalopathy in cattle and vigilance to prevent contaminated meat from entering the human food chain&#46;<a class="elsevierStyleCrossRefs" href="#bib0005"><span class="elsevierStyleSup">1&#8211;3</span></a> In addition&#44; one case has been reported in 2020 possibly related to occupational exposure&#46;<a class="elsevierStyleCrossRef" href="#bib0030"><span class="elsevierStyleSup">6</span></a></p><p id="par0035" class="elsevierStylePara elsevierViewall">Finally&#44; iatrogenic cases of CJD have occurred from dura mater grafts &#40;228 cases&#41; and growth hormone injections &#40;226 cases&#41; prior to the use of recombinant growth hormone&#44; introduced around 1980&#46;<a class="elsevierStyleCrossRef" href="#bib0010"><span class="elsevierStyleSup">2</span></a> There are 3 documented cases of variant CJD transmission to blood transfusion recipients&#46;<a class="elsevierStyleCrossRefs" href="#bib0005"><span class="elsevierStyleSup">1&#8211;3</span></a> These are the only proven cases of transmission by this mechanism&#59; interestingly&#44; transfusion of blood products from patients with sporadic CJD or genetic prion diseases has not transmitted the disease&#46;<a class="elsevierStyleCrossRefs" href="#bib0005"><span class="elsevierStyleSup">1&#8211;3&#44;5</span></a> Other iatrogenic forms of transmission are exceptional&#46; For example&#44; 6 cases of CJD transmitted via surgical and medical instruments&#59; and 2 cases via corneal transplantation&#46;<a class="elsevierStyleCrossRefs" href="#bib0010"><span class="elsevierStyleSup">2&#44;5</span></a></p></span><span id="sec0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0035">Pathogenesis</span><p id="par0040" class="elsevierStylePara elsevierViewall">PrP is a cell surface protein found in the brain and some other tissues whose function is unknown&#46;<a class="elsevierStyleCrossRef" href="#bib0035"><span class="elsevierStyleSup">7</span></a> The primary structure of PrP consists of 253 amino acid residues&#44; and contains an unstable region in the N-terminal domain&#44; termed octapeptide repeat region &#40;OPR&#41;&#44; consisting of a non-peptide &#40;R1&#41; followed by 4 octapeptide repeats &#40;R2&#44; R2&#44; R3&#44; R4&#41;&#46;<a class="elsevierStyleCrossRefs" href="#bib0040"><span class="elsevierStyleSup">8&#44;9</span></a> After translation&#44; 22 amino acid residues are removed from the N-terminal region and 23 from the C-terminal domain of the protein&#44; and a glycosylphosphatidylinositol anchor is attached to the C-terminal domain &#40;residue 230&#41; for binding to the plasma membrane of the cell&#46;<a class="elsevierStyleCrossRefs" href="#bib0040"><span class="elsevierStyleSup">8&#8211;10</span></a> PrP can also be internalised and recycled between the cell membrane and the endosome&#46;<a class="elsevierStyleCrossRef" href="#bib0040"><span class="elsevierStyleSup">8</span></a> The globular domain of the protein extends from amino acid residues 125&#8211;228&#44; and contains 3 &#9001; helices &#40;amino acids 144&#8211;154&#44; 173&#8211;194&#44; and 200&#8211;228&#41; and 2 &#174; antiparallel folds &#40;residues 128&#8211;131 and 161&#8211;164&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0040"><span class="elsevierStyleSup">8</span></a> PrP can be glycosylated at asparagine residues 181 and 197&#59; resulting in non-&#44; mono- or di-glycosylated&#46;<a class="elsevierStyleCrossRefs" href="#bib0040"><span class="elsevierStyleSup">8&#44;9</span></a></p><p id="par0045" class="elsevierStylePara elsevierViewall">In prion diseases&#44; aggregates of an abnormal form of PrP&#44; known as PrP<span class="elsevierStyleSup">Sc</span>&#44; accumulate in the brain <span class="elsevierStyleItalic">&#40;scrapie prion protein&#41;</span>&#46; PrP consists mainly of &#9001;&#8239;helices&#44; while PrP<span class="elsevierStyleSup">Sc</span> has a high proportion of &#174;folds&#46; This conformational change affects the biochemical properties of PrP&#59; thus&#44; PrP<span class="elsevierStyleSup">Sc</span> is relatively resistant to degradation by proteases&#46;<a class="elsevierStyleCrossRefs" href="#bib0040"><span class="elsevierStyleSup">8&#8211;10</span></a> PrP<span class="elsevierStyleSup">Sc</span> has the property of &#39;recruiting&#39; the normal protein &#40;PrP&#41; to join the abnormal protein aggregate&#46; Neither the structure of PrP<span class="elsevierStyleSup">Sc</span>&#44; nor the mechanisms for prion propagation are known exactly&#46; A basic conceptual model proposes that the normal helical structure of the &#9001; helical regions of PrP interacts directly with the regions of PrP<span class="elsevierStyleSup">Sc</span> in &#223;-fold&#44; losing its normal helical structure &#9001; and then binds to the aggregate&#46;<a class="elsevierStyleCrossRef" href="#bib0010"><span class="elsevierStyleSup">2</span></a> The protein aggregate&#44; during its growth&#44; may fracture at some point&#44; thus creating additional particles for aggregation&#46; In this way&#44; the PrP<span class="elsevierStyleSup">Sc</span> aggregate can spread as an infectious agent&#46; Aggregates of PrP<span class="elsevierStyleSup">Sc</span> constitute a proteinaceous fibrillar material&#44; rich in folded proteins &#174;&#44; known as &#39;amyloid&#39;&#44; which cause central nervous system &#40;CNS&#41; toxicity&#46;<a class="elsevierStyleCrossRefs" href="#bib0005"><span class="elsevierStyleSup">1&#44;2&#44;9&#44;10</span></a></p><p id="par0050" class="elsevierStylePara elsevierViewall">In prion diseases&#44; the appearance of the abnormally conformed protein can occur by spontaneous conversion due to a modification after synthesis &#40;translation&#41; of the normal protein &#40;PrP&#41;&#59; by mutation in the gene encoding the protein&#59; or by exogenous acquisition of the protein&#46; In infectious or acquired food-borne forms&#44; prions first replicate in the enteric lymphatic system and Peyer&#39;s patches&#46;<a class="elsevierStyleCrossRefs" href="#bib0010"><span class="elsevierStyleSup">2&#44;3</span></a> Subsequently&#44; they reach the CNS via the sympathetic nerves of the lymphoid tissue&#46; In the CNS&#44; prions spread synaptically&#46;<a class="elsevierStyleCrossRef" href="#bib0010"><span class="elsevierStyleSup">2</span></a></p></span><span id="sec0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0040">Pathological anatomy</span><p id="par0055" class="elsevierStylePara elsevierViewall">No macroscopic CNS changes are usually observed in these patients&#44; except for variable degrees of atrophy if the process has had a long course&#46; The characteristic histopathological picture of prion diseases consists of a combination of vacuolisation <span class="elsevierStyleItalic">&#40;status spongiosus&#41;</span> of the grey matter&#44; astrocytic gliosis and loss of neurons&#44; without inflammation&#46;<a class="elsevierStyleCrossRefs" href="#bib0010"><span class="elsevierStyleSup">2&#44;11</span></a> Spongiform changes consist of the appearance of small round or oval vacuolated voids in the neuropil surrounding the neurons&#46;<a class="elsevierStyleCrossRef" href="#bib0055"><span class="elsevierStyleSup">11</span></a> Some forms of prion diseases have their own anatomopathological features&#44; such as the &#34;florid plaque&#34; found in variant CJD&#44; which consists of an eosinophilic amyloid plaque surrounded by a halo of vacuolisation &#40;spongiosis&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0015"><span class="elsevierStyleSup">3</span></a> Aggregates of PrP<span class="elsevierStyleSup">Sc</span> &#40;amyloid&#41; in the CNS can form plaques or deposits at neuronal synapses&#46;<a class="elsevierStyleCrossRef" href="#bib0050"><span class="elsevierStyleSup">10</span></a> Prion detection is based on the resistance of PrP<span class="elsevierStyleSup">Sc</span> aggregates to enzymatic proteolysis&#46; Nerve tissue is treated with proteinase K and then <span class="elsevierStyleItalic">Western blotting</span> for the detection of PrP<span class="elsevierStyleSup">Sc</span>&#44; which&#44; if present&#44; has not been broken down by the enzyme&#46; There are 2 main types of PrP<span class="elsevierStyleSup">Sc</span> in the nerve tissue of patients with prion diseases and they are observed in the <span class="elsevierStyleItalic">Western blot</span> as non-glycosylated bands of 21&#8239;KDa &#40;type 1&#41; or 19&#8239;KDa &#40;type 2&#41;&#46;<a class="elsevierStyleCrossRefs" href="#bib0045"><span class="elsevierStyleSup">9&#44;12</span></a> Most patients with CJD have only one type of PrP<span class="elsevierStyleSup">Sc</span>&#44; although both may coexist in one third of cases&#46;<a class="elsevierStyleCrossRefs" href="#bib0040"><span class="elsevierStyleSup">8&#44;9</span></a> These PrP<span class="elsevierStyleSup">Sc</span> types combined with the codon 129 polymorphism form the basis for the molecular classification of sporadic CJD &#40;see below&#41;&#46;<a class="elsevierStyleCrossRefs" href="#bib0005"><span class="elsevierStyleSup">1&#44;4&#44;8&#44;12&#8211;14</span></a></p></span><span id="sec0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0045">Genetics</span><p id="par0060" class="elsevierStylePara elsevierViewall">All genetic forms of prion disease are caused by mutations in the sequence of the <span class="elsevierStyleItalic">PRNP</span> gene encoding the PrP<span class="elsevierStyleSup">2</span> protein&#46; This gene is located on human chromosome 20p13&#59; and consists of 2 exons&#44; although the complete open reading frame of the gene is in exon 2 &#40;<a class="elsevierStyleCrossRef" href="#fig0005">Fig&#46; 1</a>&#41;&#46;<a class="elsevierStyleCrossRefs" href="#bib0040"><span class="elsevierStyleSup">8&#44;9</span></a> Codons 51&#8211;91 normally contain the sequences encoding a nonapeptide and 4 octapeptide repeats &#40;OPR region&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0075"><span class="elsevierStyleSup">15</span></a> Among the polymorphic codons of the <span class="elsevierStyleItalic">PRNP</span> gene&#44; codon 129&#44; with 2 alleles coding for methionine or valine&#44; is the most relevant for its clinical implications&#46;<a class="elsevierStyleCrossRefs" href="#bib0010"><span class="elsevierStyleSup">2&#44;8&#44;15</span></a> Codon 129 is a factor that modifies the clinical characteristics of prion diseases&#46; For this reason&#44; genetic prion diseases have been classified into haplotypes based on the mutation of the <span class="elsevierStyleItalic">PRNP</span> gene and the polymorphic codon 129 of the mutated allele&#46;<a class="elsevierStyleCrossRef" href="#bib0075"><span class="elsevierStyleSup">15</span></a></p><elsevierMultimedia ident="fig0005"></elsevierMultimedia><p id="par0065" class="elsevierStylePara elsevierViewall">About 50 mutations associated with prion genetic diseases have been identified&#46;<a class="elsevierStyleCrossRefs" href="#bib0040"><span class="elsevierStyleSup">8&#44;9</span></a> It is generally considered that mutation of the <span class="elsevierStyleItalic">PRNP</span> gene confers on the protein an increased susceptibility to its abnormal conformation&#46;<a class="elsevierStyleCrossRefs" href="#bib0040"><span class="elsevierStyleSup">8&#44;10</span></a> Known mutations associated with prion diseases include more than 35 point mutations <span class="elsevierStyleItalic">&#40;missense&#41;</span> leading to amino acid substitutions&#59; 5 mutations leading to the appearance of a premature stop codon <span class="elsevierStyleItalic">&#40;nonsense&#41;</span> in protein synthesis&#59; and 24 base pair insertions in the OPR region that will encode between 2 and 12 octapeptides&#46;<a class="elsevierStyleCrossRefs" href="#bib0010"><span class="elsevierStyleSup">2&#44;8&#44;9&#44;11</span></a><span class="elsevierStyleSup">&#44;</span><a class="elsevierStyleCrossRef" href="#bib0075"><span class="elsevierStyleSup">15</span></a> In addition&#44; deletions of 2 octapeptides in the OPR<a class="elsevierStyleCrossRefs" href="#bib0070"><span class="elsevierStyleSup">14&#8211;16</span></a> region have been described in 3 patients&#46; The insertion or deletion of a single octapeptide is not considered pathogenic&#46;<a class="elsevierStyleCrossRefs" href="#bib0040"><span class="elsevierStyleSup">8&#44;9&#44;15</span></a> Among all these mutations&#44; 5 point mutations are considered to be responsible for 85&#37; of genetic prion diseases&#58; E200&#8239;K&#44; V210I&#44; V180I&#44; D178&#8239;N and P102L&#46;<a class="elsevierStyleCrossRef" href="#bib0045"><span class="elsevierStyleSup">9</span></a> The genetic forms of prion diseases are transmitted in an autosomal dominant pattern&#44; generally with high&#44; but usually incomplete&#44; penetrance&#46;<a class="elsevierStyleCrossRefs" href="#bib0010"><span class="elsevierStyleSup">2&#44;8&#8211;10&#44;15&#8211;17</span></a></p><p id="par0070" class="elsevierStylePara elsevierViewall">Historically&#44; genetic prion diseases have been classified into 3 clinicopathological phenotypes&#58; &#40;a&#41; genetic CJD&#44; &#40;b&#41; Gerstmann&#8211;Str&#228;ussler&#8211;Scheinker syndrome and &#40;c&#41; fatal familial insomnia&#46;<a class="elsevierStyleCrossRefs" href="#bib0005"><span class="elsevierStyleSup">1&#44;2&#44;8</span></a> Base pair insertions may be associated with atypical clinical phenotypes that are difficult to classify between CJD or Gerstmann&#8211;Str&#228;ussler&#8211;Scheinker syndrome&#59; like stop codon mutations&#44; they may present as a dementia syndrome with variable progression&#46;<a class="elsevierStyleCrossRefs" href="#bib0040"><span class="elsevierStyleSup">8&#44;15</span></a></p><p id="par0075" class="elsevierStylePara elsevierViewall">There are 23 known point mutations associated with genetic CJD&#46;<a class="elsevierStyleCrossRefs" href="#bib0040"><span class="elsevierStyleSup">8&#44;9</span></a> The most common mutation worldwide in genetic prion diseases is the substitution of glutamic acid &#40;E&#41; for lysine &#40;K&#41; at codon 200 &#40;E200&#8239;K&#41;&#44; which is clinically and histologically indistinguishable from sporadic CJD&#46;<a class="elsevierStyleCrossRefs" href="#bib0005"><span class="elsevierStyleSup">1&#44;8&#44;9&#44;11</span></a><span class="elsevierStyleSup">&#44;</span><a class="elsevierStyleCrossRefs" href="#bib0075"><span class="elsevierStyleSup">15&#44;17</span></a> Transmission is autosomal dominant&#44; with an estimated penetrance between 54&#37; and 100&#37;&#46;<a class="elsevierStyleCrossRefs" href="#bib0025"><span class="elsevierStyleSup">5&#44;8&#44;9&#44;15</span></a></p><p id="par0080" class="elsevierStylePara elsevierViewall">Familial Gerstmann&#8211;Str&#228;ussler&#8211;Scheinker syndrome is due to more than 20 described point mutations and <span class="elsevierStyleItalic">PRNP</span> gene insertions&#46; The most common of these is the substitution for leucine coding instead of proline at codon 102 &#40;P102&#8239;L&#41;&#46;<a class="elsevierStyleCrossRefs" href="#bib0010"><span class="elsevierStyleSup">2&#44;8&#44;9&#44;16</span></a> The incidence of this disease is difficult to determine but has been estimated at 1&#8211;10 cases per 100&#44;000&#44;000 population&#46;<a class="elsevierStyleCrossRef" href="#bib0040"><span class="elsevierStyleSup">8</span></a> From a histopathological point of view&#44; this mutation leads to the appearance of multifocal PrP<span class="elsevierStyleSup">Sc</span> amyloid plaques in the brain&#44; especially in the cerebellum&#46;<a class="elsevierStyleCrossRefs" href="#bib0010"><span class="elsevierStyleSup">2&#44;8&#44;16</span></a></p><p id="par0085" class="elsevierStylePara elsevierViewall">Fatal familial insomnia is caused by the D178&#8239;N &#40;aspartic acid substituted for asparagine&#41; mutation associated with the allele encoding methionine at codon 129 of the mutated allele &#40;i&#46;e&#46;&#44; in <span class="elsevierStyleItalic">cis</span>&#41;&#46;<a class="elsevierStyleCrossRefs" href="#bib0010"><span class="elsevierStyleSup">2&#44;8&#8211;10&#44;15</span></a> Histopathologically&#44; these patients show neuronal loss&#44; gliosis and accumulation of PrP<span class="elsevierStyleSup">Sc</span> in the thalamus and inferior olivary nucleus&#46; Isolated gliosis may be present in the midbrain and hypothalamus&#46;<a class="elsevierStyleCrossRefs" href="#bib0040"><span class="elsevierStyleSup">8&#44;9</span></a> In contrast&#44; the spongiform changes characteristic of prion diseases are usually absent&#46; However&#44; the D178&#8239;N mutation associated with the allele coding for valine at codon 129 results in a disease that is clinically and histologically indistinguishable from sporadic CJD&#46;<a class="elsevierStyleCrossRefs" href="#bib0040"><span class="elsevierStyleSup">8&#8211;10&#44;15</span></a> It is now thought that the haplotype effect is not so absolute&#44; and that the D178&#8239;N mutation may present as a clinical spectrum ranging from CJD to fatal familial insomnia&#46;<a class="elsevierStyleCrossRefs" href="#bib0040"><span class="elsevierStyleSup">8&#44;9&#44;18&#44;19</span></a></p><p id="par0090" class="elsevierStylePara elsevierViewall">Finally&#44; there is a relationship between codon 129 genotype and susceptibility to prion diseases&#46; Thus&#44; persons homozygous &#40;129&#8239;MM or 129&#8239;V&#8239;V&#41; for this allele are over-represented among sporadic CJD patients&#44;<a class="elsevierStyleCrossRefs" href="#bib0010"><span class="elsevierStyleSup">2&#44;8&#8211;10</span></a> and all variant CJD victims &#40;but 1&#41; have 129&#8239;M on both alleles of the <span class="elsevierStyleItalic">PRNP</span> gene&#46;<a class="elsevierStyleCrossRefs" href="#bib0005"><span class="elsevierStyleSup">1&#44;3&#44;8&#44;10</span></a><span class="elsevierStyleSup">&#44;</span><a class="elsevierStyleCrossRef" href="#bib0100"><span class="elsevierStyleSup">20</span></a></p></span><span id="sec0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0050">Signs and symptoms</span><p id="par0095" class="elsevierStylePara elsevierViewall">In human prion diseases&#44; 4 entities and some clinical variants are distinguished&#46; These are&#58; kuru&#44; CJD&#44; Gerstmann&#8211;Stra&#252;ssler&#8211;Scheinker syndrome&#44; and fatal familial insomnia&#46;</p><p id="par0100" class="elsevierStylePara elsevierViewall">Sporadic CJD is the most common form of prion disease in humans&#46;<a class="elsevierStyleCrossRefs" href="#bib0005"><span class="elsevierStyleSup">1&#8211;3</span></a> Clinically&#44; it is characterised by rapidly progressive dementia&#44; ataxia and myoclonias&#46;<a class="elsevierStyleCrossRef" href="#bib0005"><span class="elsevierStyleSup">1</span></a> In general&#44; a rapidly progressive dementia syndrome can be considered as a dementia syndrome with onset within 1&#8211;2 years from the onset of symptoms or a dementia syndrome with a total disease course &#8804;2 years&#46;<a class="elsevierStyleCrossRef" href="#bib0020"><span class="elsevierStyleSup">4</span></a> In approximately 25&#37; of cases&#44; patients or their relatives report a prodromal phase with psychiatric symptoms&#44; such as anxiety&#44; depression or sleep disturbances&#46;<a class="elsevierStyleCrossRef" href="#bib0010"><span class="elsevierStyleSup">2</span></a> Cognitive impairment is the most clinically expressive neurological sign&#44; with clear neurological function losses over a period of weeks&#46;<a class="elsevierStyleCrossRef" href="#bib0010"><span class="elsevierStyleSup">2</span></a> Neurological motor disturbances are prominent in the form of ataxia&#44; bradykinesia or spasticity&#46;<a class="elsevierStyleCrossRef" href="#bib0010"><span class="elsevierStyleSup">2</span></a> A characteristic but not pathognomonic sign of CJD is the presence of myoclonus&#46;<a class="elsevierStyleCrossRef" href="#bib0010"><span class="elsevierStyleSup">2</span></a> Visual disturbances are common&#44; in the form of visual deficits&#44; distortion of visual perception or hallucinations due to involvement of the occipital cortex&#46;<a class="elsevierStyleCrossRefs" href="#bib0005"><span class="elsevierStyleSup">1&#44;13</span></a> In Heidenhain&#39;s variant&#44; isolated visual symptoms&#44; without ocular disease&#44; precede the rest of the neurological symptomatology&#46;<a class="elsevierStyleCrossRef" href="#bib0065"><span class="elsevierStyleSup">13</span></a> The death of the patient occurs after a phase of akinetic mutism within 4&#8211;6 months from the onset of symptoms&#46;<a class="elsevierStyleCrossRefs" href="#bib0005"><span class="elsevierStyleSup">1&#44;4</span></a></p><p id="par0105" class="elsevierStylePara elsevierViewall">There are sporadic cases of CJD showing atypical clinical manifestations&#46;<a class="elsevierStyleCrossRef" href="#bib0010"><span class="elsevierStyleSup">2</span></a> In some patients&#44; without mutations in the <span class="elsevierStyleItalic">PRNP</span> gene&#44; they are clinically indistinguishable from fatal familial insomnia&#46;<a class="elsevierStyleCrossRef" href="#bib0010"><span class="elsevierStyleSup">2</span></a> Another example of clinical atypicality is variably protease-sensitive prionopathy&#44; which presents with frontal lobe dementia&#46;<a class="elsevierStyleCrossRefs" href="#bib0010"><span class="elsevierStyleSup">2&#44;8</span></a> These variants may be caused by different prion &#34;strains&#34;&#44; in analogy to infectious diseases&#46; Prion &#34;strains&#34; refer to aggregates of PrP<span class="elsevierStyleSup">Sc</span> with a different biochemical and neuropathological profile&#44; and which would produce differential neurotoxicity&#44; presumably through interaction with other factors&#46;<a class="elsevierStyleCrossRefs" href="#bib0010"><span class="elsevierStyleSup">2&#44;10&#44;13&#44;21</span></a> The result would be the presentation of different clinical phenotypes&#46;<a class="elsevierStyleCrossRefs" href="#bib0010"><span class="elsevierStyleSup">2&#44;10&#44;13&#44;21</span></a> Some researchers have pointed out that the type of PrP<span class="elsevierStyleSup">Sc</span> together with the genotype at codon 129 of the <span class="elsevierStyleItalic">PRNP</span> gene determines 6 clinicopathological subtypes of sporadic CJD&#44;<a class="elsevierStyleCrossRefs" href="#bib0005"><span class="elsevierStyleSup">1&#44;4&#44;8&#44;12&#8211;14</span></a> which are summarised in <a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>&#46; As indicated in this table&#44; the thalamic and cortical MM2 subtypes do not differ molecularly &#40;in both the PrP<span class="elsevierStyleSup">Sc</span> deposition is type 2&#41;&#44; but they do differ in terms of neuropathology and clinical phenotype&#46;<a class="elsevierStyleCrossRefs" href="#bib0005"><span class="elsevierStyleSup">1&#44;4&#44;8&#44;12&#8211;14</span></a> The MM2-thalamic subtype is also called fatal sporadic insomnia&#44; and is clinically characterised by insomnia&#44; psychomotor agitation&#44; ataxia and progressive dementia&#46; Histopathologically&#44; thalamic and inferior olivary atrophy &#40;similar to fatal familial insomnia&#41; and spongiform changes may be absent&#46; The MM2-cortical subtype presents clinically with progressive dementia&#44; whereas spongiform degeneration can be observed in the cerebral cortex and striatum&#44; but not in the cerebellum&#46;</p><elsevierMultimedia ident="tbl0005"></elsevierMultimedia><p id="par0110" class="elsevierStylePara elsevierViewall">Variant CJD&#44; acquired by consumption of meat from bovine spongiform encephalopathy-positive cattle&#44; is clinically distinguished from sporadic CJD by the age of presentation in much younger patients &#40;mean&#44; 26 yrs&#59; range&#44; 11&#8211;74 years&#41;&#44;<a class="elsevierStyleCrossRefs" href="#bib0010"><span class="elsevierStyleSup">2&#44;3</span></a> psychiatric disturbances are more prominent and sensory disturbances are of early onset in the form of limb pain or paraesthesias&#46;<a class="elsevierStyleCrossRefs" href="#bib0010"><span class="elsevierStyleSup">2&#44;3</span></a> Motor disturbances&#44; visual disturbances and dementia develop later&#46;<a class="elsevierStyleCrossRef" href="#bib0015"><span class="elsevierStyleSup">3</span></a> The average duration of the disease is approximately 14 months&#46;<a class="elsevierStyleCrossRef" href="#bib0015"><span class="elsevierStyleSup">3</span></a> Iatrogenic CJD is similar to the sporadic form&#44; but there is an ataxic form that clinically and histopathologically resembles Gerstmann&#8211;Stra&#252;ssler&#8211;Scheinker syndrome&#46;<a class="elsevierStyleCrossRef" href="#bib0010"><span class="elsevierStyleSup">2</span></a> Kuru starts with pain in the limbs&#44; followed by cerebellar ataxia and tremor &#40;&#34;kuru&#34; means tremor in the Fore language&#41;&#46; The onset of frank dementia occurred later in the course of the disease&#46;<a class="elsevierStyleCrossRef" href="#bib0010"><span class="elsevierStyleSup">2</span></a></p><p id="par0115" class="elsevierStylePara elsevierViewall">The most common form of presentation in Gerstmann&#8211;Str&#228;ussler&#8211;Scheinker syndrome is a slowly progressive cerebellar syndrome and cerebellar signs are almost universal with disease progression&#46;<a class="elsevierStyleCrossRef" href="#bib0040"><span class="elsevierStyleSup">8</span></a> One group of patients may develop prominent psychiatric symptoms at onset&#46;<a class="elsevierStyleCrossRef" href="#bib0040"><span class="elsevierStyleSup">8</span></a> Cognitive impairment is common with disease progression&#44; but rare as presenting symptoms&#46;<a class="elsevierStyleCrossRefs" href="#bib0040"><span class="elsevierStyleSup">8&#44;16</span></a> The progression is usually slower than in sporadic CJD&#44; and the time lag between the onset of symptoms and death is usually 5&#8211;6 years&#46;<a class="elsevierStyleCrossRef" href="#bib0010"><span class="elsevierStyleSup">2</span></a> The fourth prion disease entity is fatal familial insomnia&#46; In Spain&#44; 35 cases had been diagnosed up to 2008&#44; of which 16 were from the Basque Autonomous Community&#46;<a class="elsevierStyleCrossRef" href="#bib0090"><span class="elsevierStyleSup">18</span></a> Clinically&#44; the disease is characterised by severe insomnia&#44; dysautonomia and hallucinations in the early stages&#44; followed by ataxia&#44; myoclonia and signs of pyramidal involvement&#44; such as hyperreflexia&#46;<a class="elsevierStyleCrossRefs" href="#bib0010"><span class="elsevierStyleSup">2&#44;8</span></a> This symptomatology may be preceded by anxiety and depression&#46; Dementia is relatively late onset&#46;<a class="elsevierStyleCrossRef" href="#bib0010"><span class="elsevierStyleSup">2</span></a> Some familial forms of prion diseases have a very slow course that resembles familial Alzheimer&#39;s disease or Huntington&#39;s disease&#46;<a class="elsevierStyleCrossRefs" href="#bib0010"><span class="elsevierStyleSup">2&#44;9&#44;15</span></a></p></span><span id="sec0035" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0055">Diagnosis</span><p id="par0120" class="elsevierStylePara elsevierViewall">From a clinical point of view&#44; prion disease should be suspected in any patient with rapidly &#180;progressing cognitive impairment&#46; However&#44; its diagnosis is difficult&#44; as many clinically overlapping and often treatable neurological processes are considered in its differential diagnosis &#40;<a class="elsevierStyleCrossRef" href="#tbl0010">Table 2</a>&#41;&#46; As a general rule&#44; it should be noted that any evidence of inflammation in the cerebrospinal fluid &#40;CSF&#41; is contrary to a diagnosis of prion disease and an alternative diagnosis should be investigated&#46;<a class="elsevierStyleCrossRefs" href="#bib0010"><span class="elsevierStyleSup">2&#44;4</span></a> However&#44; one third of patients with CJD may show a slight increase in CSF proteins and&#44; occasionally&#44; in oligoclonal bands&#46;<a class="elsevierStyleCrossRef" href="#bib0020"><span class="elsevierStyleSup">4</span></a></p><elsevierMultimedia ident="tbl0010"></elsevierMultimedia><p id="par0125" class="elsevierStylePara elsevierViewall">Certain findings on complementary examinations indicate prion disease&#46; Magnetic resonance imaging &#40;MRI&#41; is an essential test for suspected prion disease&#46; The MRI study should include contrast-enhanced T1-weighted sequences &#40;to rule out alternative neurological diseases&#41;&#44; as well as FLAIR and diffusion sequence with the apparent diffusion coefficient map&#46;<a class="elsevierStyleCrossRefs" href="#bib0020"><span class="elsevierStyleSup">4&#44;22</span></a> In two thirds of patients with CJD&#44; MRI shows signal enhancement in the basal ganglia&#44; thalamus&#44; and sometimes in the cortical grey matter on T2&#44; FLAIR or diffusion sequences<a class="elsevierStyleCrossRefs" href="#bib0005"><span class="elsevierStyleSup">1&#44;2&#44;13&#44;22</span></a> &#40;<a class="elsevierStyleCrossRef" href="#fig0010">Fig&#46; 2</a>&#41;&#46; On the other hand&#44; it has been reported that a typical CJD MRI will show diffusion restriction in at least 2 cortical areas &#40;temporal-parietal-occipital&#41;&#59; and&#47;or in the caudate region&#44; caudate-putamen&#44; or caudate-putamen-thalamus&#44;<a class="elsevierStyleCrossRef" href="#bib0110"><span class="elsevierStyleSup">22</span></a> without white matter involvement&#46;</p><elsevierMultimedia ident="fig0010"></elsevierMultimedia><p id="par0130" class="elsevierStylePara elsevierViewall">The electroencephalogram &#40;EEG&#41; may show large amplitude periodic three-phase complexes with a frequency of approximately 1 per second <span class="elsevierStyleItalic">&#40;periodic sharp wave complexes&#41;&#46;</span><a class="elsevierStyleCrossRefs" href="#bib0010"><span class="elsevierStyleSup">2&#8211;4&#44;11&#44;22</span></a> These typical EEG findings are seen in late stages of the disease and may occur in other forms of dementia&#46; Overall&#44; EEG alterations have a sensitivity of 64&#37; and a specificity of 80&#8211;91&#37;&#46;<a class="elsevierStyleCrossRefs" href="#bib0010"><span class="elsevierStyleSup">2&#44;22</span></a> Elevated levels of neuronal proteins 14&#8722;3-3 &#40;sensitivity&#58; 61&#8211;95&#37;&#59; specificity&#58; 40&#8211;92&#37;&#41;<a class="elsevierStyleCrossRef" href="#bib0025"><span class="elsevierStyleSup">5</span></a> and tau can be found in CSF&#44; which also occurs in other neurological processes with neuronal injury&#46;<a class="elsevierStyleCrossRefs" href="#bib0010"><span class="elsevierStyleSup">2&#44;4&#44;5&#44;22</span></a> On the other hand&#44; the sensitivity of these biomarkers decreases in the early stages of the disease and with the different molecular subtypes of CJD&#44; with lower sensitivity in the MV2 and MM2 subtypes&#46;<a class="elsevierStyleCrossRef" href="#bib0110"><span class="elsevierStyleSup">22</span></a></p><p id="par0135" class="elsevierStylePara elsevierViewall">Procedures for the detection of prions in vitro in clinical samples&#44; such as <span class="elsevierStyleItalic">real-time quaking-induced conversion</span> &#40;RT-QuIC&#41; or <span class="elsevierStyleItalic">protein-misfolding cyclic amplification</span> &#40;PMCA&#41;&#44; are now available and have led to significant advances in the ante-mortem diagnosis of prion diseases&#46;<a class="elsevierStyleCrossRefs" href="#bib0025"><span class="elsevierStyleSup">5&#44;11&#44;22&#44;23</span></a> The rationale for RT-QuIC is that if CSF contains prions&#44; incubation with recombinant PrP &#40;with thioflavin T&#41; will result in a conformational change of PrP in vitro leading to amyloid formation&#46;<a class="elsevierStyleCrossRefs" href="#bib0025"><span class="elsevierStyleSup">5&#44;22&#44;23</span></a> Amyloid formation is detected by the emission of fluorescence by thioflavin T&#46; In this technique&#44; repeated cycles of substrate incubation and agitation are used to fragment the protein cluster formed&#59; so that it can act as a template &#40;&#39;seed&#39;&#41; for further abnormal folding of recombinant PrP&#46;<a class="elsevierStyleCrossRefs" href="#bib0025"><span class="elsevierStyleSup">5&#44;22&#44;23</span></a> In this way&#44; prions are continuously amplified&#46; RT-QuIC applied to CSF samples has a sensitivity of between 92&#8211;97&#37;<a class="elsevierStyleCrossRefs" href="#bib0025"><span class="elsevierStyleSup">5&#44;10&#44;22</span></a> and a specificity close to 100&#37; in symptomatic patients&#59; thus its positive results leave little room for a false positive diagnosis&#46;<a class="elsevierStyleCrossRefs" href="#bib0010"><span class="elsevierStyleSup">2&#44;5&#44;10&#44;22</span></a><span class="elsevierStyleSup">&#44;</span><a class="elsevierStyleCrossRef" href="#bib0115"><span class="elsevierStyleSup">23</span></a> The sensitivity of the test is higher in MM1&#47;MV1 and VV2 molecular subtypes than in other sporadic CJD subtypes&#46;<a class="elsevierStyleCrossRefs" href="#bib0110"><span class="elsevierStyleSup">22&#44;23</span></a> Similarly&#44; sensitivity is higher in genetic CJD associated with E200&#8239;K and V210I mutations than in other mutations&#46;<a class="elsevierStyleCrossRefs" href="#bib0110"><span class="elsevierStyleSup">22&#44;23</span></a> RT-QuIC has also been applied to skin and olfactory mucosa samples with high sensitivity&#46;<a class="elsevierStyleCrossRefs" href="#bib0110"><span class="elsevierStyleSup">22&#44;23</span></a> Given the performance of RT-QuICR&#44; an international expert committee has recommended this test on CSF or other clinical samples as an essential diagnostic procedure in suspected CJD&#46;<a class="elsevierStyleCrossRefs" href="#bib0020"><span class="elsevierStyleSup">4&#44;11&#44;22&#44;23</span></a></p><p id="par0140" class="elsevierStylePara elsevierViewall">Variant CJD can be difficult to diagnose&#44; because previously noted markers&#44; such as 14-3-3 protein or CSF prion amplification with RT-QuIC&#44; as well as EEG alterations may be absent&#46; A characteristic finding in patients with variant CJD is signal enhancement on MRI in the posterior nucleus of the thalamus&#44; which will be brighter than the anterior putamen &#40;pulvinar sign&#41;&#44; and which is seen in more than 90&#37; of cases&#46;<a class="elsevierStyleCrossRefs" href="#bib0005"><span class="elsevierStyleSup">1&#44;3&#44;22</span></a> A very useful diagnostic test for diagnosis of variant CJD is PMCA&#44; which shows excellent sensitivity in CSF &#40;100&#37;&#41;&#44; plasma &#40;100&#37;&#41; and urine &#40;93&#37;&#41; in these patients&#44; while its yield in other prion diseases is low&#46;<a class="elsevierStyleCrossRefs" href="#bib0015"><span class="elsevierStyleSup">3&#44;22&#44;23</span></a> In PMCA&#44; the fragmentation of the protein cluster to act as the &#39;seed&#39; of the abnormal folding in the test cycles is sonication&#46;<a class="elsevierStyleCrossRefs" href="#bib0055"><span class="elsevierStyleSup">11&#44;22&#44;23</span></a></p><p id="par0145" class="elsevierStylePara elsevierViewall">The definitive diagnosis of prion disease is established by histopathological study and immunohistochemical staining that reveals the presence of PrP<span class="elsevierStyleSup">Sc</span> in brain tissue samples obtained at necropsy or through biopsy&#46;<a class="elsevierStyleCrossRefs" href="#bib0010"><span class="elsevierStyleSup">2&#44;5&#44;22</span></a> Biopsy has a low sensitivity &#40;20&#8211;60 &#37;&#41; and&#44; moreover&#44; ante-mortem diagnosis does not change the treatment&#46; For these reasons&#44; specialists only recommend brain biopsy for the diagnosis of alternative neurological diseases&#46;<a class="elsevierStyleCrossRefs" href="#bib0005"><span class="elsevierStyleSup">1&#44;2&#44;5&#44;22</span></a> Apart from the definitive diagnosis&#44; there are 2 other diagnostic categories for sporadic CJD&#44; the most common form of prion disease&#46;<a class="elsevierStyleCrossRefs" href="#bib0025"><span class="elsevierStyleSup">5&#44;22</span></a> According to an International Expert Committee<a class="elsevierStyleCrossRef" href="#bib0110"><span class="elsevierStyleSup">22</span></a> any progressive neuropsychiatric syndrome&#44; in the absence of other alternative diagnoses after a thorough clinical assessment&#44; with a positive RT-QuICR test&#59; or a rapidly progressive cognitive disorder with 2 of the following 4 criteria&#44; is considered probable sporadic CJD&#58; &#40;a&#41; myoclonia&#44; &#40;b&#41; visual or cerebellar disturbances&#44; &#40;c&#41; pyramidal&#47;extrapyramidal signs&#44; and &#40;d&#41; akinetic mutism&#59; provided he&#47;she has a typical EEG &#40;periodic sharp wave complexes&#41;&#44; or a characteristic MRI&#44; or a positive CSF 14-3-3 protein test&#46; Characteristic MRI is considered when there is diffusion restriction in the caudate nucleus or caudate-putamen or caudate-putamen-thalamus&#44; or in at least 2 cortical regions &#40;temporal&#44; occipital parietal&#41;&#44; without white matter involvement or diffusion restriction limited to the thalamus&#46; Finally&#44; patients analogous to the above&#44; with a disease duration of less than 2 years&#44; but without EEG&#44; MRI or 14-3-3 protein in CSF are included in the category of possible sporadic CJD&#46;<a class="elsevierStyleCrossRef" href="#bib0110"><span class="elsevierStyleSup">22</span></a></p><p id="par0150" class="elsevierStylePara elsevierViewall">Given the complexity of diagnosing prion disease and the scarcity of patients&#44; a national centre &#40;National Prion Disorders Pathology Service Center&#41; has been established in the USA to advise on histopathology and to facilitate prion amplification and determination of neuronal proteins in CSF&#46;</p></span><span id="sec0040" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0060">Treatment</span><p id="par0155" class="elsevierStylePara elsevierViewall">Prion diseases are currently incurable and there is no treatment that will ameliorate the course of the disease&#46;<a class="elsevierStyleCrossRefs" href="#bib0005"><span class="elsevierStyleSup">1&#44;2</span></a> Most patients with sporadic CJD die within a year of symptom onset&#46; Patients with other variants of prion disease may have a more protracted course&#46; Therapeutic measures should be oriented towards the early establishment of palliative care&#46; Authorisation for clinical autopsy should be sought from patients or relatives&#46; Obviously&#44; post-mortem examination&#44; even restricted to the brain&#44; is a risky operation and WHO recommendations should be followed to the utmost&#46;<a class="elsevierStyleCrossRef" href="#bib0120"><span class="elsevierStyleSup">24</span></a> Similarly&#44; biosafety level 3 facilities are advisable for the processing of histological specimens&#46;<a class="elsevierStyleCrossRef" href="#bib0120"><span class="elsevierStyleSup">24</span></a></p></span><span id="sec0045" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0065">Prevention</span><p id="par0160" class="elsevierStylePara elsevierViewall">Prion diseases are potentially transmissible&#46; The risk of contracting the disease depends on 3 factors&#58; the likelihood of the patient suffering from prion disease&#44; the infectivity of the fluid&#47;tissue and the route of exposure&#46;<a class="elsevierStyleCrossRef" href="#bib0005"><span class="elsevierStyleSup">1</span></a> Recently&#44; the detection of prions in a cadaver donated for anatomical practice<a class="elsevierStyleCrossRef" href="#bib0125"><span class="elsevierStyleSup">25</span></a> was reported&#44; raising concerns about accidental exposure to prions through contact with infected tissues&#46; In general&#44; the material with the highest prion load and the highest infectivity is nervous tissue &#40;brain&#44; spinal cord&#44; eye&#41;&#46; CSF&#44; blood and other tissues have low infectivity&#46; The risk of contracting the disease through dermal exposure is negligible&#46;<a class="elsevierStyleCrossRef" href="#bib0005"><span class="elsevierStyleSup">1</span></a> Normal social contact or clinical practice &#40;including non-invasive procedures&#41; presents no risk&#46;<a class="elsevierStyleCrossRef" href="#bib0005"><span class="elsevierStyleSup">1</span></a> Nor are isolation measures or contact precautions required for routine medical practice&#46; Neurosurgical or reusable material should be destroyed or decontaminated according to WHO recommendations&#46;<a class="elsevierStyleCrossRef" href="#bib0120"><span class="elsevierStyleSup">24</span></a></p></span><span id="sec0050" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0070">Conclusions</span><p id="par0165" class="elsevierStylePara elsevierViewall">Prion diseases are a group of diseases with a unique pathogenesis&#46; The disease occurs sporadically or through genetic transmission&#46; There is a third form of onset&#44; acquired or infectious&#44; through dietary consumption or contact with prion-contaminated tissues&#46; The causative agent of the disease is an abnormally folded protein&#44; which induces the normal protein&#44; PrP&#44; to transform into the disease-associated protein PrP<span class="elsevierStyleSup">Sc</span>&#46; PrP<span class="elsevierStyleSup">Sc</span> is resistant to degradation by proteases and to physical or chemical decontamination&#46; For this reason&#44; special protocols are required for the complete disinfection of PrP<span class="elsevierStyleSup">Sc</span> from highly infective tissues&#46; From a clinical point of view&#44; diagnosis is difficult&#46; Familiarity with the clinical presentation of the different phenotypes together with the appropriate use of diagnostic procedures with high sensitivity and specificity&#44; such as MRI and RT-QuIC&#44; allow for a confident ante-mortem diagnosis&#46; However&#44; definitive diagnosis requires histopathological examination of the patient&#39;s brain tissue&#46; Standard clinical practice requires only standard preventive measures&#44; but special protocols are needed when handling nerve tissue&#46; There is currently no treatment available to modify the course of the disease&#46; However&#44; there is active research into the development of effective therapeutic strategies for prion diseases&#46; For example&#44; the use of antisense oligonucleotides could prevent or avoid the accumulation of prions&#46;<a class="elsevierStyleCrossRef" href="#bib0085"><span class="elsevierStyleSup">17</span></a> On the other hand&#44; a fundamental pathogenic role is now attributed to neuroinflammatory mechanisms mediated by microglial activation and astrogliosis in all neurodegenerative diseases&#44; including prion diseases&#46;<a class="elsevierStyleCrossRef" href="#bib0130"><span class="elsevierStyleSup">26</span></a> The study of neuroinflammation opens up the possibility of modulating glial cell activation in prion diseases&#44; and also in other more common neurodegenerative diseases such as Alzheimer&#39;s disease or Parkinson&#39;s disease&#46;</p></span><span id="sec0055" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0075">Conflict of interest</span><p id="par0170" class="elsevierStylePara elsevierViewall">None&#46;</p></span></span>"
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        "resumen" => "<span id="abst0005" class="elsevierStyleSection elsevierViewall"><p id="spar0030" class="elsevierStyleSimplePara elsevierViewall">Prion diseases are a group of neurodegenerative diseases&#46; The disease-causing agent is a protein &#40;PrP&#41;&#44; that is normally produced in the nervous system&#44; aggregated in an abnormal form&#46; The abnormal protein&#44; known as prion &#40;PrP<span class="elsevierStyleSup">Sc</span>&#41;&#44; is capable of self-propagation promoting the misfolding of the normal protein &#40;PrP&#41;&#46; These conditions can be acquired sporadically&#44; genetically&#44; or infectiously either by eating meat contaminated with prions or from iatrogenic exposure&#46; The diagnosis of these diseases is often challenging&#46; The use of highly sensitive and specific diagnostic tools&#44; such as MRI and RT-QuIC&#44; may aid in the diagnosis&#46; Neuropathological examination of brain tissue ensures a definite diagnosis&#46; At present&#44; no treatment significantly improves the course of prion diseases&#59; however&#44; an early diagnosis is of paramount importance for patient care decision planning&#44; infection control purposes and genetic counseling&#46;</p></span>"
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        "resumen" => "<span id="abst0010" class="elsevierStyleSection elsevierViewall"><p id="spar0035" class="elsevierStyleSimplePara elsevierViewall">Las enfermedades por priones constituyen un grupo de enfermedades neurodegenerativas&#44; cuyo agente causal es una prote&#237;na normal del cerebro &#40;PrP&#41; que se agrega en una conformaci&#243;n an&#243;mala&#46; La prote&#237;na anormal&#44; conocida como prion &#40;PrP<span class="elsevierStyleSup">Sc</span>&#41;&#44; tiene la propiedad de auto-propagarse induciendo la plegadura an&#243;mala de la prote&#237;na normal PrP&#46; Estas enfermedades se presentan de manera espor&#225;dica&#44; por transmisi&#243;n gen&#233;tica&#44; o de forma adquirida por ingesta de carne contaminada con priones o por exposici&#243;n iatr&#243;gena&#46; Su diagn&#243;stico resulta dif&#237;cil&#46; La utilizaci&#243;n de exploraciones complementarias de alta sensibilidad y especificidad&#44; como la resonancia magn&#233;tica o la RT-QuIC&#44; facilitan su diagn&#243;stico&#46; El diagn&#243;stico definitivo se establece por el estudio histopatol&#243;gico de muestras de tejidos&#46; Actualmente&#44; no se dispone de ning&#250;n tratamiento que modifique el curso de la enfermedad&#44; pero su diagn&#243;stico precoz es fundamental para planificar los cuidados del enfermo&#44; adoptar las medidas de prevenci&#243;n necesarias y el consejo gen&#233;tico&#46;</p></span>"
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                  \t\t\t\t">65&#8722;70&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Rapidly progressive dementia&#44; early and prominent myoclonus&#44; typical EEG&#44; visual impairment common&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Classical distribution of spongiosis &#40;cerebral cortex&#44; striatum&#44; thalamus and cerebellum&#41;&#44; prominent occipital cortex involvement&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">VV2&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">15&#8722;20&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Ataxia onset&#44; late onset dementia&#44; atypical EEG&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Cortical and subcortical spongiform involvement&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">MV2&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">10&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Ataxia&#44; progressive dementia&#44; atypical EEG&#44; long disease duration&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Similar to VV2&#44; but with amyloid plaques in the cerebellum&#46;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">MM2-T&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">2&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Insomnia&#44; psychomotor agitation&#44; ataxia&#44; progressive dementia&#44; atypical EEG&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Thalamic and inferior olivary atrophy&#44; spongiosis may be absent&#46;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">MM2-C&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">2&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Progressive dementia&#44; atypical EEG&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Large confluent vacuoles and perivascular PrP<span class="elsevierStyleSup">Sc</span> staining&#46; Cerebral cortex and striatum affected&#44; but not cerebellum&#46;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">VV1&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">1&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Frequent onset with psychiatric symptoms&#44; progressive dementia&#44; atypical EEG&#44; long course &#40;often &#62;2 years&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Cerebral cortex and striatum affected&#44; with preserved cerebellum&#46; No confluent vacuoles&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></tbody></table>
                  """
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          "en" => "<p id="spar0015" class="elsevierStyleSimplePara elsevierViewall">Clinicopathological features of molecular variants of sporadic Creutzfeldt&#8211;Jakob disease&#46;</p>"
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                  \t\t\t\t\ttable-entry\n
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                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>Progressive supranuclear palsy&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-entry\n
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                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>Septic encephalopathy&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-entry\n
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                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
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                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>Stroke&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-entry\n
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                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>Cerebral Vasculitis&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>Cerebral amyloid angiopathy&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
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                  \t\t\t\t"><span class="elsevierStyleItalic">Toxic-metabolic encephalopathies</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
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                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>Korsakoff&#8211;Wernicke syndrome&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>Hepatic encephalopathy&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>Uraemic encephalopathy&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>Poisoning &#40;lithium&#44; bismuth&#44; methotrexate&#41;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-entry\n
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                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleItalic">Brain neoplasms</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>Primary cerebral lymphoma&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleHsp" style=""></span>Intravascular lymphoma&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></tbody></table>
                  """
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          "en" => "<p id="spar0025" class="elsevierStyleSimplePara elsevierViewall">Differential diagnosis of rapidly progressive dementia&#46;</p>"
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      "titulo" => "References"
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        0 => array:2 [
          "identificador" => "bibs0005"
          "bibliografiaReferencia" => array:26 [
            0 => array:3 [
              "identificador" => "bib0005"
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              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Human prion diseases"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:3 [
                            0 => "H&#46; Wang"
                            1 => "D&#46;D&#46; Rhoads"
                            2 => "B&#46;S&#46; Appleby"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1097/QCO.0000000000000552"
                      "Revista" => array:6 [
                        "tituloSerie" => "Curr Opin Infect Dis"
                        "fecha" => "2019"
                        "volumen" => "32"
                        "paginaInicial" => "272"
                        "paginaFinal" => "276"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/31008724"
                            "web" => "Medline"
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                      "titulo" => "Prion diseases"
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                          "etal" => false
                          "autores" => array:1 [
                            0 => "P&#46;J&#46; Bosque"
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                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "LibroEditado" => array:6 [
                        "editores" => "L&#46;Goldmann, A&#46;I&#46;Schafer"
                        "titulo" => "Goldman-Cecil Medicine"
                        "paginaInicial" => "2467"
                        "paginaFinal" => "2469"
                        "edicion" => "26&#170; ed"
                        "serieFecha" => "2020"
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              "identificador" => "bib0015"
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                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Variant CJD&#58; reflections a quarter of a century on"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
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                            0 => "D&#46;L&#46; Ritchie"
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                            2 => "M&#46;A&#46; Barria"
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                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.3390/pathogens10111413"
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                        "tituloSerie" => "Pathogens"
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                            0 => "P&#46; Hermann"
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                    0 => array:2 [
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