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DOI: 10.1177/0891988710383576

2010 23: 277 originally published online 11 October 2010J Geriatr Psychiatry NeurolKhalilah Brown and James A. Mastrianni

The Prion Diseases

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The Prion Diseases

Khalilah Brown, MD1 and James A. Mastrianni, MD, PhD1

Abstract

The prion diseases are a family of rare neurodegenerative disorders that result from the accumulation of a misfolded isoform ofthe prion protein (PrP), a normal constituent of the neuronal membrane. Five subtypes constitute the known human priondiseases; kuru, Creutzfeldt-Jakob disease (CJD), Gerstmann-Straussler-Scheinker syndrome (GSS), fatal insomnia (FI), and variant

CJD (vCJD). These subtypes are distinguished, in part, by their clinical phenotype, but primarily by their associated brain histo-pathology. Evidence suggests these phenotypes are defined by differences in the pathogenic conformation of misfolded PrP.Although the vast majority of cases are sporadic, 10% to15% result from an autosomal dominant mutation of the PrPgene (PRNP).General phenotype-genotype correlations can be made for the major subtypes of CJD, GSS, and FI. This paper will review some of

the general background related to prion biology and detail the clinical and pathologic features of the major prion diseases, with a

particular focus on the genetic aspects that result in prion disease or modification of its risk or phenotype.

Keywords

genetics, neurodegeneration, prion diseases, CJD, GSS, FI

Introduction

The human prion disorders include kuru, sporadic Creutzfeldt-

Jakob disease (sCJD), familial CJD (fCJD), iatrogenic CJD

(iCJD), Gerstmann-Straussler-Scheinker disease (GSS), fatal

insomnia (FI), and new variant CJD (vCJD). As a group, they

are unique among neurodegenerative diseases in that they not

only have a sporadic and genetic occurrence, but they are hor-

izontally transmissible. Additionally, prion diseases affect ani-

mals, some of which include scrapie of sheep, chronic wasting

disease of deer and elk (CWD), and bovine spongiform ence-

phalopathy (BSE). The transmissible nature of these diseases

was first demonstrated experimentally in 1936 by Cuille and

Chelle through intraocular administration of scrapie-infected

spinal cord to a goat.1 Thirty years later, kuru, a disease of the

Fore people of New Guinea related to the practice of cannibal-

ism, was transmitted to chimpanzees by Gajdusek,2 and 2 years

later, Gibbs followed suit with transmission of CJD.3 Initially

proposed to be a slow virus,4,5 the etiologic agent of these

diseases is now recognized as the prion, a misfolded isoform

of the prion protein (PrP).6-8 PrP exists in 2 major conforma-

tional isoforms: the nonpathogenic, predominantly a-helical,

protease-sensitive, cellular isoform (PrPC) and the pathogenic,

protease-resistant scrapie-inducing isoform (PrPSc) that is high

in b-pleated sheet structure9 (Figure 1). The initial conversion

of PrPC to PrPSc may be spontaneous or mutation-induced; how-

ever, once an infectious unit has been generated, propagation

of PrPSc occurs via protein-protein interaction, such that PrPSc

acts as a template to transfer its conformation onto PrPC, thereby

generating new PrPSc. Thus, PrP knockout mice (Prnp /) donot

develop prion disease when challenged with scrapie.10-12

In humans, a single exon on the short arm of chromosome

20 encodes the 253 amino acid PrP.13 Differential splicing does

not occur. A 22-amino acid signal peptide is cleaved from theamino terminus during synthesis in the endoplasmic reticulum

and a 23-residue signal sequence on the carboxy terminus is

cleaved upon addition of a glycoinositol phospholipid (GPI)

anchor,14 through which PrP attaches to the outer leaflet of the

plasma membrane. Two asparagine-linked glycosylation sites

lie within a loop region of the protein created by a disulfide

bond (Figure 2). PrP is regulated during development and con-

stitutively expressed in the adult. An increase in mRNA levels

has not been detected during disease development in ani-

mals.8,15 The highest levels of expression are within neurons,16

but lower levels are detected in other peripheral tissues includ-

ing lung, heart, kidney, pancreas, testis, white blood cells,17

and platelets.18 Peripheral and central anterograde neuronal

transport of PrPC has also been reported.15,19

1 Center for Comprehensive Care and Research on Memory Disorders,

Department of Neurology, University of Chicago, Chicago, IL, USA

Corresponding Author:

James A. Mastrianni, MD, Center for Comprehensive Care and Research on

Memory Disorders, Department of Neurology, University of Chicago,

Chicago IL, 60637, USA

Email: [email protected]

Journal of Geriatric Psychiatry

and Neurology

23(4) 277-298

The Author(s) 2010

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The normal function of PrPC is not known, although several

lines of evidence have led to a variety of proposed functions,

including the formation, function, and maintenance of

synapses20-23; signaling,24-26 neuritogenesis and neuroprotec-

tion27,28; copper binding and cellular delivery29-31; antioxidant

activity32; cellular adhesion33; and a possible role in immune

modulation (see ref34 for review). Interestingly, in PrP

knockout mice, no obvious developmental or behavioral

abnormalities were noted,10 suggesting redundancy of func-

tion, although an alteration in synaptic function within the hip-

pocampus of these animals has been reported by some20but not

others.35 Recent work also suggests that adult mice lacking PrP

display some hippocampal-dependent spatial memory defi-

cits36 and have impaired peripheral myelin maintenance.37

Some PrP knockout mouse lines also displayed disrupted circa-

dian rhythm,38 and ataxia, the latter found to be related to upre-

gulation ofPrnd, a downstream gene that encodes a truncated

homolog of PrP known as Doppel, as a result of gene

splicing that occurred during the deletion ofPrnp.39 An intri-

guing line of work has recently suggested a link between PrP

and Alzheimer disease, although the balance of its effect

has not been determined. For instance, 1 study suggests PrPC

normally inhibits b-secretase,40 a key enzyme involved in the

cleavage of amyloid precursor protein (APP) that generates

b-amyloid, thereby functioning in a protective role. In contrast,

other reports suggest PrPC might function as a receptor to

b-amyloid oligomers41 or to foster the generation of amyloid

plaques of Alzheimer disease,42 thereby functioning to promote

Alzheimer disease.

Molecular Genetics of Prion Disease

The worldwide incidence of prion disease is roughly 1 per 106

population per year for sporadic disease and 1 per 107 per year

Figure 1.Comparison of protease-sensitive, cellular isoform (PrPC) and protease-resistant scrapie-related isoform (PrPSc). Protease-resistantscrapie-related isoform carries greater b-sheet structure (flat ribbons), with loss of the a-helical structure (curly ribbons), and displays theproperties of infectivity, insolubility, and protease-resistance. The western blot demonstrates the protease-sensitive nature of PrPC and theprotease-resistant core of PrPSc that migrates faster in the gel because it is partially cleaved at the amino-terminal. The primary differencebetween PrPSc and PrPC is the proteinase-K resistance.

278 Journal of Geriatric Psychiatry and Neurology 23(4)

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for familial disease. There is no obvious gender bias.43 The

peak age for the sporadic form of disease is *67 years,

although patients aged 17 to 90 years have been reported.

Sporadic forms of the disease tend to occur in the seventh

decade and eighth and have a rapidly progressive course of

under a year (avg. 4 to 6 months), whereas inherited forms usu-

ally manifest at a younger age and have a more protracted

course (Table 1). True autosomal dominant forms of prion dis-

ease occur in about 10% to 15% of reported cases, although this

estimate may be spuriously low because of the variable and

often late age of disease onset in some forms of inherited prion

disease.44 No obvious environmental risk to disease has been

recognized, with the possible exception of vCJD that is linked

to BSE exposure and iCJD resulting from prion-contaiminated

biologicals or surgical instruments.

A single base pair (bp) change within codon 102 of the

PRNP gene, resulting in an amino acid change from proline

to leucine (P102L) was first linked to the typical clinical pre-

sentation of GSS in 1989.45 Since then, multiple-point muta-

tions, insertions, and deletions of the gene have been

identified (Figure 2, Tables 2 and 3). A handful of mutations

introduce an early stop signal at different positions within the

coding segment resulting in truncated forms of PrP, in 1 case

(Y145X) generating a protein roughly half the normal length.

Of the currently identified mutations, only 4 (P102L, D178N,

E200K, and a 144-bp insert) have been observed with high

enough frequency to generate significant logarithm of the odds

(LOD) scores for linkage. Several polymorphic sites of the

PRNP gene are known, the most common and best studied is

codon 129 that acts as a predisposing factor to sporadic,

Figure 2.General organization of human prion protein (PrP) and related mutations and polymorphisms. The 762 base pair (bp) open-readingframe ofPRNPencodes the 253 amino acid protease-sensitive, cellular isoform (PrPC). Nuclear magnetic resonance (NMR) studies predict3 a-helices (H1, H2, and H3), and 2 b strands (S1 and S2). Asn-linked glycosylation sites (CHO) occur at residues 181 and 197. The

octapeptide repeat segment extends between residues 51 and 91. Pathogenic mutations and polymorphisms of thePRNPgene are representedbelow and above the schematic, respectively. A single octapeptide repeat deletion and a small number of single bp changes are considerednonpathogenic polymorphisms, some of which act as phenotypic modifiers, most notably, residue 129. Octapeptide repeat insertions (OPRI)of 1 to 9, excluding 3, are pathogenic, as are *30 bp changes. Letters preceding the numbers indicate the normal amino acid residue forthe position and letters following the numbers designate the new residue due to the mutation. Bold mutations are associated with Gerstmann-Straussler-Scheinker syndrome (GSS), the remainder cause Creutzfeldt-Jakob disease (CJD). * D178N is associated with either CJD or familialfatal insomnia (FFI), depending on the allelic codon 129 sequence (Met FFI; Val CJD). H187R displays variable pathology in the limitedcases reported. Amino acid letter designations are as follows: A indicates alanine, D aspartate, E glutamate, F phenylalanine, H histidine, I isoleucine, K lysine, L leucine, P proline, Q glutamine, R arginine, S serine, T threonine, V valine, Y tyrosine,(-) stop signal.

Brown and Mastrianni 279

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iatrogenic, and vCJD, in addition to a phenotypic modifier of

sporadic and familial prion disease (discussed later).As mutations of PRNP have been discovered, genotype-

phenotype correlations have been made, many of which

generally hold true, especially with regard to the general

pathology associated with each mutation. However, as more

patients with similar mutations are described, it has become

increasingly evident that the clinical features associated with

specific mutations may vary, sometimes considerably and

even within the same pedigree. Whether this feature repre-

sents subtle alterations in the conformational subtype

of PrPSc (see below), or an influence of other modifying

genes, is not clear.

A general classification scheme for the major phenotypes ofprion disease is based primarily on the pathologic features of

disease, which appear to be more consistently linked to a spe-

cific set of mutations. Using this parameter, excluding kuru,

4 major prion disease subtypes in humans are known; CJD,

GSS, FI, and vCJD. The pathognomonic feature of diffuse

spongiosis with few or no PrP-amyloid plaques is characteristic

of CJD, while extensive PrP-amyloid deposits with minimal

spongiform change denotes GSS (Figure 3). Focal thalamic

gliosis with minimal or absent spongiosis is seen in FI, and the

presence of dense core PrP-amyloid plaques surrounded by a

halo of vacuolar change, designated florid plaques, are seen

in vCJD. In addition to PrP immunoreactive plaques in GSS,

neurofibrillary tangles have been detected with at least 4 muta-

tions (P105L, Y145Stop, F198S, and Q217R).102-105

Although it is not understood how PrPSc induces such a

broad range of pathological phenotypes, the distinct association

of the major subtypes with specific mutations and characteristic

pattern of protease-resistant PrPSc on Western blot (an indirect

measure of PrPSc conformation) argues that the conformational

subtype of PrPSc is ultimately responsible for the observed phe-

notypes (Figure 4). This was confirmed by the recognition that

sporadic FI is a phenocopy of familial FI that lacks the muta-

tion associated with the latter but displays a similar PrPSc by

Western blot and all other histopathologic and transmissible

characteristics of familial FI.106

These findings in human disease have their origin in the study

of animal strains of prion disease. The first evidence for thiscame from studies of hamsters infected with 2 phenotypically

different strains of transmissible mink encephalopathy (TME),

known as HYPER and DROWSY, which were found to be

linked to 2 distinct PrPSc conformations.107,108 Passage of these

2 PrPSc strains to new hamster hosts resulted in the stable trans-

mission of clinical and pathologic phenotypes. This property of

prions was instrumental in determining that vCJD resulted from

exposure to BSE, since passage of BSE to a variety of animal

hosts including mice, macaques, and hamsters resulted in a char-

acteristic migration pattern and glycosylation profile, by West-

ern blot, that was similar to that found in PrPSc isolated from

brains of participants with vCJD.

109-113

Evidence suggests thatboth host PrPC and prion strain (ie, conformation of PrPSc) are

important contributors to the observed phenotype,114 although

the mechanisms that underlie the targeting of PrPSc to specific

cell populations, which leads to the phenotype, is still obscure.

Major Subtypes of Prion Disease

Creutzfeldt-Jakob disease

The majority of patients with CJD present with confusion and

memory loss that progress to severe cortical dementia, generally

in combination with ataxia and myoclonus. The electroencepha-

logram (EEG) typically shows bilateral periodic discharges with

a frequency of 0.5 to 2 per second and, when seen in combina-

tion with the above presentation, predicts the diagnosis with

about 90% certainty.115-117 In addition to these defining features,

a host of neurologic signs and symptoms have been reported,

including weakness, rigidity, bradykinesia, tremor, chorea, alien

hand syndrome, and sensory disturbances, among others. Vague

complaints of fatigue, headache, sleep disturbance, vertigo, and

behavioral changes may precede the development of frank pro-

gressive dementia in many cases.116 As many as 25%begin with

ataxia118 while a smaller percentage begins with cortical blind-

ness, designated as the Heidenhain variant. Familial CJD has

been associated with point mutations at codons 178, 180, 183,

Table 1.Clinical Phenotypes of Prion Disease

Disease Primary features Age at Onset (Range) Duration Pathology

Kuru Ataxia, then dementia 40 years (29-60) 3 months1 year Kuru plaquessCJD Dementia, ataxia, myoclonus 61 years (17-83) rare


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196, 200, 203, 208, 210, 211, 232, and insertions of 1, 2, 4, 5, 6,

7, and 9 octarepeat segments.

The defining pathology for this prion disease is the presence of

spongiform degeneration, or vacuolation, of cortical grey mat-

ter (Figure 3). The vacuoles observed by light microscopy repre-

sent focal swellings of axonal and dendritic neuronal processes,

associated with the loss of synaptic organelles and accumulation

of abnormal membranes by electron microscopy.119-121 They

may be distributed throughout the gray and white matter but are

generally most prominent in the gray matter neuropil. They

typically range in size from 5 to 25 mm,122 but in advanced

cases, they may be as large as 100 mm. When large vacuoles

are seen in the presence of severe astrogliosis and neuronal

loss, the constellation is termed status spongiosis. The dis-

tribution of vacuolation is typically within the cerebral

neocortex, subiculum of the hippocampus, caudate, putamen,

thalamus, and the molecular layer of the cerebellar cortex.122

A reactive gliosis is also consistently present, while an inflam-

matory response is conspicuously absent. Protease-resistant

PrP is easily detected in brain tissue from the majority of

patients with CJD. Transmission of CJD to nonhuman pri-

mates is relatively efficient (85%)123 and highly efficient

(approaching 100%) to Tg mice that express human PrP.124,125

In recent years, the bank vole has also been shown to be an

efficient host for human prion transmission.126

Iatrogenic CJD

Prior to the introduction of recombinant human growth hor-

mone (hGH) in 1985, more than 80 individuals developed CJD

Table 2. Single Base Pair Changes ofPRNP

Codon Sequence Change Amino Acid Changea Codon 129 Pathologic Phenotype Reference

102 CCG ! CTG Pro (P) ! Leu (L) Met GSS 46102 CTG Leu (L) Val GSS 47105 CCA ! CTA Pro (P) ! Leu (L) Val GSS 48

105 ACA Thr (T) Val GSS 49105 TCA Ser (S) Val Atypical GSS 50114 GGT ! GTT Gly (G) ! Val (V) Met CJD 51117 GCA ! GTG Ala (A) ! Val (V) Val GSS 52-54129 ATG or GTG Met (M) or Val (V) b 45, 55131 GGA ! GTA Gly (G) ! Val (V) Met Atypical GSS 56133 GCA ! GTG Ala (A) ! Val (V) Met Atypical GSS 57145 TAT ! TAG Tyr (Y) ! Stop (-) Met GSS w/NFTs (PrP-CAA) 58148 CGT ! CAT Arg (R) ! His (H) Met CJD 59160 Gln (Q) ! Stop (-) Met GSS 60163 Tyr (Y) ! Stop (-) GSS 61171 AAC ! AGC Asn (N) ! Ser (S) Val b 62178 GAC ! AAC Asp (D) ! Asn (N) Val CJD 63178 AAC Asn (N) Met FFI 64

180 GTC ! ATC Val (V) ! Ile (I) Met CJD 65183 ACA ! ACG Thr (T) ! Ala (A) Met CJD 66187 CAC ! CGC His (H) ! Arg (R) Val Atypicalc 67, 68188 ACG ! AAG Thr (T) ! Lys (K) ? CJD 60196 GAG ! AAG Glu (E) ! Lys (K) Met CJD 69198 TTC ! TCC Phe (F) ! Ser (S) Val GSS w/NFTs 70200 GAG ! AAG Glu (E) ! Lys (K) Met/Val CJD 71, 72202 GAC ! AAC Asp (D) ! Asn (N) Val GSS 73203 GTT ! ATT Val (V) ! Ile (I) Met CJD 69208 CGC ! CAC Arg (R) ! His (H) Met CJD 74210 GTT ! ATT Val (V) ! Ile (I) Met CJD 75-77211 GAG ! CAG Glu (E) ! Gln (Q) Met CJD 69212 CAG ! CCG Gln (Q) ! Pro (P) Val GSS 73217 CAG ! CGG Gln (Q) ! Arg (R) Val GSS w/NFTs 78

219 GAG ! AAG Glu (E) ! Lys (K) Met b

79226 TAC ! TAA Tyr (Y) ! Stop (-) Val PrP-CAA 80227 CAG ! TAG Gln (Q) ! Stop (-) Val GSS 80232 ATG ! AGG Met (M) ! Arg (R) Met CJD 65, 81238 CCA ! TCA Pro (P) ! Ser (S) Met CJD 82

Abbreviations: CJD, Creutzfeldt-Jakob disease; CAA, cerebral amyloid angiopathy; GSS, Gerstmann-Stra ussler-Scheinker syndrome; NFTs, neurofibrillary tangles;PrP, prion protein.a Letters in parentheses indicate letter codes for amino acids.b Polymorphismsmay modify disease phenotype.c Either early psychiatric symptoms with or without dementia preceding ataxia with curly PrP deposits.


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through exposure to cadaver-derived human growth hormone

(hGH) from at least 3 separate sources in the United Kingdom,

France, and the United States.127-131 In contrast to sCJD,

patients with iCJD more often display cerebellar ataxia rather

than cognitive problems, and the EEG shows a diffusely slow

wave pattern instead of periodic sharp waves complexes.132,133

Table 3.Coding Alterations in Octarepeat Segmenta

Coding Change Extra inserts Sequence Codon 129 Pathologic Phenotype Reference

None R1,R2,R2,R3,R4 Met / Val24-bp deletion R3-R4 or R2 or R2-R3 Met 8324-bp insertion 1 R1,R2,R2,R2,R3,R4 Met N/A 84

48-bp insertion 2 R1,R2,R2, R3,R2a,R2a,R4 Met Spongiosis (CJD-like) 8596-bp insertion 4 R2,R3,R2,R3 Met 8696-bp insertion 4 R1,R2(6),R3,R4 Met CJD (spongiosis) 8796-bp insertion 4 R1,R2,R2,R3,R2,R2,R2,R3,R4 Val N/A 84120-bp insertion 5 R1,R2(2),R3,R2,R3g,R2(2),R3,R4 Met CJD (spongiosis) 86120-bp insertion 5 R1,R2(2),R3,R2,R2,R2,R2,R3,R4 Met CJD (spongiosis) 88144-bp insertion 6 R1,R2(3),R3,R2,R3g,R2(2),R3,R4 Met Variable, usu. spongiosis,

one pt. with PrP plaques89-91

144-bp insertion 6 R1,R2(2),R3g,R2(2),R3g,R2(2),R3,R4 Met CJD (spongiosis) 92144-bp insertion 6 R1,R2,R2,R3,R2,R3g,R2,R3g,R2,R3,R4 Met CJD (spongiosis-variable) 93144-bp insertion 6 R1,R2,R2,R2(6),R3,R4 Met CJD (spongiosis- variable) 94168-bp insertion 7 R1,R2,R2c,R3,R2,R3,R2,R3,R2,R3g,R3,R4 Met CJD (spongiosis) 95168-bp insertion 7 Met gliosis, no spongiosis

+PrP deposits96

192-bp insertion 8 R1,R2,R2,R3,R2(7),R2a,R4 Val GSS (PrP plaques) 86, 97192-bp insertion 8 R1,R2,R2,R3g,R3,R2(6),R3,R4 Val GSS (PrP plaques) 98216-bp insertion 9 R1,R2,R2,R3,R2,R3g,R2a,R2,R2,R2,R3g,R2,R3,R4 Met GSS (PrP plaques) 99, 100216-bp insertion 9 R1,R2,R2,R3,R2,R3,R3g,R2,R2a,R2,R3,R2,R3,R4 Met N/A 101

Abbreviations: R, an octarepeat unit (Pro-(His/Gln)-Gly-Gly-Gly-(-/Gly)-Trp-Gly-Gln); N/A, pathology not available.a Small case letters indicate repeat units which contain a single base pair alteration, although the amino acid coding is unchanged.

Figure 3.Pathologic features of prion disease. A, Hemotoxylin and Eosin staining demonstrates typical spongiform degeneration (vacuolation)of the grey matter neuropil characteristic of Creutzfeldt-Jakob disease (CJD). This feature is less obvious in fatal insomnia (FI) and Gerstmann-Straussler-Scheinker syndrome (GSS). B, PrP-positive multicentric plaques are pathognomonic for GSS. These are mostly present within themolecular layer of the cerebellum but may be diffusely present throughout the cerebrum. C, Glial fibrillary astrocytic protein (GFAP)antibodies demonstrate hypertrophy and proliferation of astrocytes. This feature is present in all prion subtypes. In FI, this is often found focallywithin the anterior nucleus and dorsomedial nucleus of the thalamus and brainstem, in combination with neuronal dropout. In GSS it mayparallel PrP plaque pathology. D, The florid plaques of variant CJD (vCJD) consist of dense core PrP amyloid deposits surrounded by vacuoles.


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This disease has also been linked to dura mater obtained

primarily from a single manufacturer in Germany whose

preparative procedures were inadequate to decontaminate

prions.132,134-139 Throughout the world, more than 100 cases

of iCJD related to contaminated dura exposure between 1979

and 1996 have been reported.138,140 Other iatrogenic forms of

prion disease include a single corneal transplant,141 2 patients

exposed to improperly decontaminated depth electrodes used

for seizure focus localization,142 and at least 5 cases of CJD

in women after receiving human pituitary gonadotropin.143-145

Variant CJD

To date, since 1995, vCJD has been reported in more than 200

patients throughout the world, with the greatest number of

cases in the United Kingdom (170) and France (25), but

also reported in the Republic of Ireland, Italy, the United States

(3 emigrants from the United Kingdom and Saudi Arabia),

Canada, Japan, The Netherlands, Portugal, and Spain.146-151

Compared with sCJD, vCJD more often presents with psy-

chiatric features, particularly apathy and depression, in addi-

tion to painful distal sensations, it occurs in younger

individuals (ages 17 to 42 years), and has a slightly protracted

course of greater than 1 year. The pathognomonic feature in

the brain is the presence of dense core PrP plaques surrounded

by a halo of spongiform change, also known as florid pla-

ques (Figure 3). The protease-resistant fraction of PrPSc in

the brain of these patients has a faster migration rate on West-

ern blot than typical sCJD, and the diglycosylated PrP (the

highest of the 3 bands of PrP) is more prominent, in contrast

to sCJD, in which PrPSc is predominantly monoglycosylated.152

As mentioned above, this predominance of the diglycosylated

form was a key feature used in transmission studies to support

the hypothesis that vCJD resulted from exposure to BSE-

tainted beef. All but 1 case of vCJD resulting from primary

infection with BSE have been homozygous for Met at codon

129 (see below), further supporting this as a risk factor to prion

disease. Secondary infection was first reported in an asympto-

matic codon 129 heterozygote (129MV) who died of unrelated

causes 5 years after receiving a transfusion of blood derived

from a patient who developed signs of vCJD 18 months follow-

ing blood donation.153 Since then, 4 additional cases of potential

transfusion-related vCJD have been reported, one of which was a

hemophiliac who received blood products rather than whole

Figure 4.Western blot comparing the major isoforms observed in the 4 principal subtypes of prion disease. To the left of the blot displays theprion protein (PrP) segment that is represented in the adjacent blot. The highest molecular weight of PrP is the diglycosylated fraction of PrP,whereas the monoglycosylated and unglycosylated fractions run faster in the gel, because of their lower molecular weight. In CJD, FI, and vCJD,

proteinase-K cleaves the first *67 amino acids of protease-resistant scrapie-related isoform (PrPSc

), leaving the PK-resistant core, PrP90-231.In most cases of Gerstmann-Straussler-Scheinker syndrome (GSS), a second C-terminal cleavage that removes the glycosylated segmentoccurs endogenously, leaving a nonglycosylated central segment.


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blood.154-156 These findings have raised concerns about the

prevalence of asymptomatic carriers of vCJD in the United

Kingdom and the safety of the blood supply and has led to

major changes in the handling of blood products in the United

Kingdom and the United States.

Gerstmann-Straussler-Scheinker Syndrome

This subtype of prion disease is always familial and has been

found associated with point mutations at codons 102, 105,

117, 131, 145, 160, 198, 202, 212, 217, and in some cases of

octapeptide repeat insertions (OPRI), especially those with a

higher number of inserts. In its classic form, as originally

described by Gerstmann,157,158 ataxia of gait and/or dysarthria

are presenting features followed by variable degrees of pyrami-

dal and extrapyramidal symptoms and often late development

of dementia. There are, however, several variants of this dis-

ease in which ataxia is not a prominent feature. Reports of

impaired memory, spastic paraparesis, movement disorder, orbehavioral features, with a presentation suggestive of fronto-

temporal dementia or Alzheimer disease have been reported.

The EEG commonly lacks periodic discharges but may show

slow waves. Duration of disease typically ranges from 2 to 7,

but up to 10 or more years. Aspiration pneumonia is a signifi-

cant risk because of impaired coordination of swallowing.

The presence of plaque deposits immunoreactive to anti-PrP

antibodies is the defining hallmark of GSS. Vacuolation may

be minimal. PrP amyloid is PAS positive and shows birefrin-

gence under polarized light after Congo Red staining in most

cases. The most characteristic is the multicentric plaque,

defined as a dense central core surrounded by smaller satel-lites122 (Figure 3), although other morphologies, from punctate

to diffuse, have been recognized. Various-sized plaques, often

termed primitive because they lack the characteristic green

birefringence with Congo red staining, are seen in many of the

GSS cases, suggesting there are variations in the maturity of

amyloid formed among the different mutations. Plaque depos-

its isolated from at least 4 of the GSS-associated mutations

(P102L, A117V, F198S, Q217R) appear to be composed of

peptide fragments of 7 and/or 11-14 kDa, which have been

amino- and carboxy-terminally clipped and span residues of

58-150 and 81-150 of the mutant alleles.159

Fatal insomnia

Originally reported and defined as a familial form of prion dis-

ease, this is now known to occur on a familial (FFI) and spora-

dic (sFI) basis.64,160-162 The characteristic clinical profile

includes intractable insomnia, which may be observed for sev-

eral months prior to the obvious onset of disease that may

include dysautonomia, ataxia, variable pyramidal and extrapyr-

amidal signs and symptoms, and relatively spared cognitive

function until late in the course. Diffuse slowing rather than

periodic discharges is observed on the EEG.161 Magnetic reso-

nance imaging (MRI) is unhelpful, but functional imaging

(PET or SPECT) shows a reduction in metabolic activity or

blood flow to the thalamus early in the disease.163 Age at

disease onset ranges from 25 to 61 years (avg. 48 years), and

time to death is generally 1 to 2 years (range of 7 to 33

months).161 Not all cases are clear-cut. A sleep study may be

required in less clinically obvious cases to recognize a shorten-

ing of total sleep time. A family with phenotypic heterogeneity

from Australia was reported with the FFI haplotype(D178N,129M),164 and while some members were found to have

clinically apparent insomnia early or late in the presentation, oth-

ers did not exhibit it, suggesting even this disease may have a

variable presentation.164

The neuropathologic features of FI include neuronal loss

and astrogliosis within the thalamus and inferior olives, and

to a lesser degree, the cerebellum. Vacuolation is minimal to

absent in typical cases. Protease-resistant PrP is detectable in

the brains of affected patients but is usually present only in

small amounts and is often restricted to specific regions such

as the thalamus and temporal lobe.165

Polymorphisms and Mutations ofPRNP

Several polymorphisms have been identified in thePRNPgene.

The most common and important ones are highlighted.

Codon 129

This codon may be either ATG, which codes for Met, or GTG,

which codes for Val. The allelic frequency of Val in the general

Caucasian population is 0.34 while that of Met is 0.66.55 The

genotype distribution in this population is 37% Met/Met,

51%

Met/Val, and 12%

Val/Val. Homozygosity at this positionpredominates in sCJD. In 1 series of 45 patients with sCJD

from the United Kingdom, 89% were homozygous (Met/Met

or Val/Val) at codon 129,166 compared with only 49% of 106

normal participants.55 Similar findings were reported in France

and Italy. The frequency of Met homozygosity was found to be

between 41% and 45% in unaffected control participants and

between 71% and 81% in 41 definite and/or probable sCJD

patients.167,168 Homozygosity at codon 129 is also overrepre-

sented in iCJD, but most dramatically in vCJD, where all but

1 patient with confirmed vCJD, resulting from primary expo-

sure to BSE, carried the 129MM genotype.169 The importance

of homozygosity in prion susceptibility is further supported by

studies in transgenic (Tg) mice that demonstrate more efficient

transmission of prions when the recipient Tg mouse expresses

human PrPC carrying the same amino acid at position 129 of

the human PrPSc inoculum.170-172 These epidemiologic and

Tg animal studies support the concept that sequence homology

between PrPSc and PrPC facilitates their interaction and subse-

quent generation of more PrPSc, which have also recently been

demonstrated using FRET to assess the specific interaction of

homologous and heterologous PrP molecules.171 It should be

noted that the allelic frequencies in Japan are 0.96 for Met and

0.04 for Val, masking a relative risk of homozygosity.173

The codon 129 genotype also modifies the phenotype of

sCJD. A cognitive onset with rapid progression is associated


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with the 129MM genotype, while slower progression and an

ataxic onset is more common with the 129MV or 129VV gen-

otype.174 The conformation of PrPSc, which is approximated by

limited protease digestion and gel electrophoresis, differs

between 129MM patients (Type 1 PrPSc migrates *21 kDa)

and 129VV (Type 2 PrPSc migrates *19kDa).174,175 These

findings imply an important function of the amino acid residueat position 129 in protein-protein interaction and PrPSc confor-

mation determination.171

In familial prion disease, the polymorphic codon 129 also

plays a modifying role. This is most striking with the D178N

mutation; when D178N is coupled to 129M, the clinicopatho-

logic phenotype of FFI results in a protease-resistant PrPSc

fragment of *19 kDa, whereas coupling of D178N with

129V results in the fCJD phenotype and a PrPSc fragment of

*21 kDa.176 Coupling of the F198S and 144-bp insert muta-

tions with homozygosity at 129 also appears to lower the age

at onset and decrease the duration of disease.

Other Polymorphisms:

a. 24-base pair (bp) deletion:This results in the loss of a

stretch of 8 amino acids within the octapeptide repeat

segment of PrP. Codons 51 through 91 encode a series of

5 repeating elements of Pro-(His/Gln)-Gly-Gly-Gly-

(-/Gly)-Trp-Gly-Gln, the first of which includes 27

nucleotides encoding 9 amino acid residues, while the

4 subsequent ones are 24 bp in length encoding 8 residues

each. A deletion of 1 of the repeat elements was initially

detected in 3 healthy members of a Moroccan family177

and then incidentally in a cosmid library construct derivedfrom the HeLa human cell line.178 It is generally consid-

ered to be a nonpathogenic polymorphism occurring in

about 3% of the normal population.83,177,179

b. N171S: This rare polymorphism was incidentally noted in

a 69-year-old healthy control participant.62 A family with

psychiatric disease was reported with this polymorphism,

and although it was suggested that it may be linked to schi-

zophrenia, 1 healthy member carried the polymorphism180

and another study found no evidence for the N171S poly-

morphism in a schizophrenia population.181

c. E219K polymorphism: Codon 219 normally encodes glu-

tamate (E) in the Caucasian population, although lysine

(K) coding is found in about 6% of the Japanese popula-

tion.79 This polymorphism was also reported on the same

allele as the P102L mutation in a Japanese family in which

dementia rather than ataxia was prominent and cerebellar

plaque pathology was less prominent compared with

cases of the P102L mutation alone.182 However, variabil-

ity in presentation of GSS was also observed in an Italian

family in the absence of the E219K polymorphism.

Recent transmission studies in transgenic knock-in mice

suggest a heterozygous state at codon 219 confers

reduced susceptibility to prion transmission.183

d. G127V polymorphism: This rare polymorphism was

recently reported in the population within New Guinea, in

the area where kuru was endemic. Sampling the population

suggests that this polymorphism is protective against

prion infection.184 Studies are in progress to determine this

experimentally.

SelectedPRNP

Mutations That Cause CJDD178N, 129V

A transition of G to A at the first nucleotide of codon 178 of the

PRNP gene was initially reported in a Finnish family63 and

then shortly thereafter in 2 American families, one of Dutch

and the other of Hungarian origin,185 and in a French family

from Brittany 186. The clinical phenotype displays a younger

mean age at onset (46 vs 62 years), a more prolonged disease

duration (avg 2 years, range 9 to 51 months), and slowing of the

EEG rather than periodic triphasic waves, compared with

typical sCJD.185,187,188 Memory disturbance is the presenting

feature in the vast majority of carriers, followed typically by

cerebellar ataxia and myoclonus, in addition to varying degreesof visual disturbance, reduced speech output, extrapyramidal,

and pyramidal tract features. Less than 10% develop seizures.

Brain pathology shows diffuse spongiform degeneration, glio-

sis, and neuronal loss within the frontotemporal cerebral cor-

tex, caudate, and basal ganglia, with relative sparing of deep

thalamic nuclei and the cerebellum.161,185,189

V180I

This point mutation (GTC to ATC) was initially reported in

2 unrelated individuals with no obvious family history and a

presentation similar to fCJD associated with the D178N muta-tion.65 Since then, only a handful of cases have been detailed,

although a recent genetic survey in Japan identified the muta-

tion in 84 cases of prion disease over the past 10 years.190 Most

reported cases appear to lack a clear family history. The muta-

tion has been consistently found allelic with 129M. A presenta-

tion of subacute dementia, often with aphasia, and subsequent

myoclonus, but no periodic discharges on EEG, is most com-

mon. Neuropathological findings include typical CJD changes

of diffuse vacuolation, neuronal loss, and gliosis of the cortex.

Western analysis shows protease-resistant PrP that lacks the

higher molecular weight diglycosylated fraction of PrPSc,

although expression of PrP

V180I

in cell culture appears nor-mally glycosylated, suggesting selective conversion of mono-

and unglycosylated PrPV180I.50,191

T183A

This was first described in a Brazilian family with 9 affected

members who developed a progressive dementia with clinical

features suggesting a frontotemporal neurodegenerative pro-

cess.66 Behavioral features, including aggressiveness, hyperoral-

ity, and verbal stereotypes, were prominent early in the disease

course with all patients. Disease begins in the fourth or fifth

decade (average 45 years, range 37 to 49 years) and has a some-

what protracted course of 2 to 9 years (average 4.2 years).


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Spongiform change was prominent in frontotemporal regions.

Another report in a 40-year-old with more typical CJD and rel-

atively prolonged course of 4 years, with similar pathology, was

also reported.192 This mutation was allelic with 129M.

E200KThis is the most common mutation of PRNP worldwide. A

change in coding from GAG to AAG at codon 200 of the gene

was first detected in an unusual cluster of CJD cases in rural

Slovakia72 where the annual mortality rate was about 100 per

million population and almost simultaneously in a Libyan Jew-

ish family.193 It is linked to CJD with a LOD score of 4.85.194

Carriers of this mutation have been identified from more than

10 different countries71,195-197 and were initially thought to

have a common ancestral origin of a Sephardic Jew whose des-

cendents emigrated from Spain and Portugal during the Inqui-

sition. This was further supported by the consistent association

of the E200K mutation with the 129M. A report of this muta-tion in a Japanese family with no evidence of racial intermix-

ing198 and the detection of the mutation in association with

Val coding at codon 12972 indicates at least 2 additional foun-

ders and supports the more likely possibility that the mutation

arose spontaneously in several populations from the deamination

of a methylated CpG in a germline PRNPgene. Clusters of this

mutation are seen in populations from Israel, Chile, and Eastern

Europe. Surveillance studies from France and England have

detected the E200K mutation in patients without a clear family

history, supporting the variable onset of CJD(E200K).167,199

The phenotype associated with this mutation is quite vari-

able but is generally comparable to sCJD.

200

Forgetfulness andconfusion are typically early manifestations, followed by ataxia

and myoclonus and the appearance of periodic discharges on

EEG.201 The average age at disease onset is *61 and time to

death is typically under 1 year (*4.5 months), similar charac-

teristics to that of sCJD. Pathology is also similar to sCJD, with

widespread spongiform degeneration and no PrP plaque pathol-

ogy. However, the fCJD(E200k,129V) case included PrP pla-

que deposits within the cerebellum.72 Chapman et al,202

compared clinical data from 14 patients with fCJD(E200K) and

noted a wide variability in age at onset (34 to 65 years) and in

disease duration (2 to 66 months), along with a host of varied

clinical features that included cerebral, basal ganglia, brain-

stem, cerebellar, and spinal cord dysfunction. A large kindred

of German ancestry was reported in which 5 of 9 members with

CJD, for whom neuro-ophthalmologic data were available, had

supranuclear palsy as an early feature, while myoclonus and

periodic EEG were uncommon.196 Demyelinating peripheral

neuropathy, which could not be attributed to a coexisting dis-

ease process, was reported in 2 patients who developed CJD

related to the E200K mutation,203 while three others have been

described with motor axonal neuropathy.202 Severe insomnia

was prominent, but not the presenting feature of disease in a

single E200K carrier.204

The variable age at onset with this disease suggests reduced

penetrance; however, using life-table analyses, the risk to

disease development for fCJD(E200K) is age-dependent and

penetrance is nearly complete by the ninth decade of life.44,205

The situation in which a child develops the disease yet one of

the parents either is a healthy carrier or died from other causes

prior to developing disease is therefore a potential feature to

consider when ruling out familial disease by history alone.

Transmission of this familial form of prion disease to experi-mental animals was initially demonstrated in nonhuman pri-

mates,206 and later in Tg transgenic mice.125

R208H

A transition at the second nucleotide of codon 208 from G to A

resulting in a missense coding for histidine rather than arginine

was reported in a 60-year-old who presented with confusion

and memory problems and later developed paranoia, ataxia,

myoclonus, and a positive EEG, over a 7-month course.74

Neuropathology was typical of CJD (diffuse spongiosis, neu-

ronal loss, and gliosis) and protease-resistant PrP was presentthroughout the brain. A family history was not evident, possi-

bly related to the premature deaths of the patients father,

from an unrelated condition. Additional reports of R208H

linked to 129M, include a clinicopathologic phenotype char-

acteristic of sCJD,207 another with tau pathology in the

entorhinal cortex, ballooned neurons, and an extra 17 kDa

PK-resistant PrPSc fragment,208 and a unique case, allelic with

129V, was reported with a rapidly progressive syndrome of

behavioral changes, cerebellar ataxia, and kuru type cerebel-

lar plaques.209

V210I

This was initially reported in Italy75 and France76,77 without

evidence of a family history but has now been reported in sev-

eral countries, including the United States.77,210,211 As with the

E200K mutation, the presentation is somewhat variable and

includes a cerebellar syndrome, bilateral myoclonic jerks,

dysarthria, stroke-like features such as hemisensory loss and

hemiparesis, sudden onset of visual disturbances, or the onset

of behavioral changes, all beginning between 50 and 70 years

of age. The EEG displays periodic discharges. Disease dura-

tion is typically less than 6 months. Protease-resistant PrP is

similar to that of typical sCJD. Spongiform degeneration isdiffusely present in the brain. Because healthy carriers of the

V210I mutation aged 67 to 82 years76 have been detected and

some patients lack a clear family history, this mutation also

appears to display variable penetrance compared with other

PRNP mutations.

M232R

Clear evidence for an autosomal dominant effect of this

mutation is lacking, but it has been reported in several cases,

primarily in the Japanese population. It too presents as sCJD,

with a typically rapid disease course and an absent family


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history.65,82,212,213 In addition, this sequence alteration was

reported in a V180I carrier on the normal allele.

144-bp insertion

This 6 octapeptide repeat insertion (OPRI) was described in a

large kindred in the United Kingdom. It is linked to an interest-ing disease phenotype in which behavioral symptoms and per-

sonality disorders of long-standing duration are observed prior

to the onset of a slowly progressive dementia.89,90,91,214-216 A

variation in the degree of cerebellar ataxia, dysarthria, and pyr-

amidal and extrapyramidal signs are observed among affected

individuals, as is myoclonus. The pathology is also quite vari-

able, ranging from severe spongiosis to no obvious signs of

pathology, generally without plaques, although in 1 patient,

cerebellar plaques were observed.90,216 Since the initial report

of a family with this insertion, additional families from the

United Kingdom,93 Japan,92 the United States,88 and Basque94

have been described. All have similar variations in disease phe-notype and all have the mutation on the Met 129 allele. Cur-

iously, there are slight variations in the sequence of the insert

(Table 3), although their role in phenotype modification is not

apparent.

Additional OPRI Mutations

Although there is significant variability in the presentation

and pathologic features of prion disease related to the repeat

expansions, they are discussed here as a group for ease of pre-

sentation. Between codons 51 and 91 of PRNP, 9 different

insertions of the gene have been described, none of which dis-rupt the overall sequence of the remainder of the protein

beyond residue 91. Most are coupled to Met coding at codon

129. The largest family reported is the British family with

6-OPRI described above (144-bp insert). Octapeptide repeat

insertions of 1 to 9 additional repeats have been described

(Table 3). Genotype-phenotype correlations have been difficult

to make, based on the small number of affected patients within

most families and because variability of presentation is com-

mon with these mutations. There is no obvious anticipation and

the length of the insert appears stable during meiosis.217 In gen-

eral, the length of the insert correlates inversely with the age at

onset of disease. In patients with 7 to 9 extra repeats, disease

presents in the 30s, while in those with 1 to 4 extra repeats, dis-

ease may be delayed until the sixth to seventh decade.94,218 The

duration of illness, however, appears to be proportional to the

length of insert, ranging from 5 to 120 months, with an increase

in insert number from 1 to 7.218 A Huntington disease-like phe-

notype (HDL-1) was reported in a family with an 8-OPRI.219

Interestingly, another individual was reported with the HDL-

1 phenotype but later found to be a member of the 6-OPRI

kindred described above, further supporting the variable phe-

notype observed with OPRI mutations, in addition to the

importance of genetic testing in neurodegenerative disease.220

A minority of patients has the typical clinicopathologic fea-

tures of sCJD; rather, the majority has a more chronic course

often including atypical features such as aphasia, apraxia, and

a personality disorder associated with memory loss. The per-

sonality disorder may appear as a primary or early feature in

as many as half of the carriers of these mutations. Dementia

eventually occurs in all and may be precipitous after a long

prodrome of mild cognitive problems or behavioral features.

Cerebellar ataxia and extrapyramidal features are also some-what common in their course. Myoclonus may occur in less

than one half of carriers, while periodic discharges on EEG are

even less frequent (


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the P102L mutation in a Japanese family that showed variabil-

ity in presentation and weak Congo Red staining of plaques

compared with typical GSS plaques associated with the

P102L mutation alone,182 suggesting that polymorphisms other

than codon 129 (ie, codon 219) might influence the phenotype

of dominant mutations.

The clinical and pathologic features of GSS, including obvi-ous ataxia and PrP plaque deposits, were duplicated in a mouse

constructed with a transgene harboring the equivalent P102L

human mutation.230 These mice, which overexpress the mouse

equivalent (PrP-P101L) of human PrP-P102L, develop sponta-

neous ataxia at about 150 days. Transmission of GSS(P102L)

has been reported in nonhuman primates and mice, although

the rates of transmission (*40%) is much less than sporadic

and familial CJD (*85%).231

P105L

A cytosine (C) to thymine (T) transition at the second nucleo-

tide of codon 105 (CCA to CTA) results in the substitution of

leucine for proline in the protein, and in all cases, is coupled

to 129V. This mutation, recognized primarily in Japan, is

classically associated with the development of spastic para-

paresis, manifest as weakness with hyperreflexia and extensor

plantar responses, prior to, or along with, the development of

dementia, progressing eventually to tetraparesis with a pseu-

dobulbar affect over a 7- to 12-year course.48,232,233 Although

cerebellar symptoms were uncommon and neither periodic dis-

charges on the EEG nor myoclonus were present in most

patients reported with this mutation, subsequent reports sug-

gested some members of this pedigree did develop more typ-

ical signs of GSS. Age at onset ranged from 38 to 48 years.

Pathologic findings were confined to the telencephalon where

diffuse-type PrP immunoreactive plaques were present

throughout the gray matter of the cortex, particularly within

frontal motor cortex and temporal lobes and deep gray nuclei

of the basal ganglia and thalamus. Severe neuronal loss and

gliosis were also present within those same areas, although

spongiform change was absent.

In addition to the leucine mutation at codon 105, a threo-

nine substitution (ie, P105T) was identified in a Canadian

family49 and a serine substitution (P105S) in an American

family.50 P105T appears to have a generally typical GSSclinical phenotype, with the exception of an unusual onset

of psychiatric symptoms found in a 13-year-old family

member, whereas the P105S mutation was detected in a

31-year-old woman who developed a clinical presentation

characteristic of frontotemporal lobar dementia without

ataxia or spastic paraplegia, and a combination of intense

focal vacuolation of the basal ganglia and dramatic plaque

pathology in the cerebellum and hippocampus. These find-

ings provide support to the concept that the substitution

itself, rather than the loss of the normal amino acid, is the

determinant of phenotype, presumably by inducing different

PrPSc conformations.

A117V

This mutation was initially identified in a French family with

8 affected members spanning 4 generations52 and later in 2

American families of German descent.53,54 In all cases, the

dominant mutation is carried on the 129V allele. In the

French family, the presentation was consistent with a primary

dementing syndrome with variable degrees of pyramidal,

extrapyramidal, and cerebellar features. The affected mem-

bers of one American family (designated GCSA) presented

with presenile dementia followed by pyramidal and extrapyr-

amidal features without obvious cerebellar involvement.53,234

The disease was originally considered to be familial Alzhei-

mer disease, based on this clinical presentation and the neu-

ropathologic finding of multiple amyloid plaques scattered

throughout the cerebral but not the cerebellar cortex.234 The

plaques, however, did not immunoreact with anti-Ab anti-

body but did with anti-PrP antibody,235 confirming it to be

a prion disease. In contrast to this telencephalic presenta-

tion, the second US family with the A117V mutation dis-

played the classic GSS phenotype of ataxia with pyramidal

and extrapyramidal features and late-developing dementia.54

The proband of that family had widespread deposition of

PrP-plaques throughout both the cerebral and cerebellar cor-

tex. Follow-up reports of some members from subsequent

generations of the French family also suggested a cerebellar

onset with progressive gait difficulties, dysarthria, and dys-

phagia, leading eventually to mental deterioration and

dementia,236 and plaque deposition in some was wide-

spread.237 These findings suggest a clear correlation of pla-

que pathology with clinical phenotype and variability of

clinical phenotype due to the same point mutation. Commonfeatures include the absence of periodic discharges on EEG,

an early onset (third to fifth decade), moderately prolonged

duration (average 3 years), and the presence of GSS plaque

pathology. In some cases, protease-resistant PrP is difficult

to detect, whereas in most, a low level of a 14 kDa fragment

is observed. Several attempts to transmit this disease to

rodents have been unsuccessful.236 A Tg mouse that

expresses the mouse-equivalent PrP-A116V mutation allelic

with 129V and develops severe progressive ataxia beginning

at *120 days until their death *30 days later, has been gen-

erated.238 The brains demonstrate PrP amyloid deposits in the

cerebellum and hippocampus and a *13 to 14 kDa protease-resistant PrP fragment. In humans with GSS(A117V), PrP

displayed a significantly higher level of a transmembrane

form of PrP, suggesting that this mutation affects the translo-

cation of PrP.239 Whether this can fully explain the patho-

genic properties of the molecule and the reduced

transmissibility seen with this particular prion disease variant

remains to be determined.

F198S

This mutation, which is coupled to Val at codon 129, was

identified in a very large kindred in Indiana.240 Of the


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1200-member family spanning 6 generations, 67 individuals

were affected at the time of the report in 1989. Linkage of the

mutation was demonstrated with a LOD score of 6.37.240 The

presentation is generally one of progressive gait ataxia, dysar-

thria, and impaired short-term memory, often associated with

extrapyramidal symptoms of bradykinesia and rigidity, and less

often with pyramidal tract signs. The dementia is slowlyprogressive, occurring at a mean age of 52 (range 30s to 60s)

and lasting on average 6 years (range 2 to 12).241 Disease may

present 10 years earlier in patients homozygous for Val at codon

129.240 Ocular signs, including supranuclear gaze palsy, jerky

pursuits, and gaze-evoked nystagmus in all directions, were

noted in the early phase of the disease. Myoclonus is present

in some but not all patients. The EEG may show slowing, but

it does not exhibit periodic discharges, consistent with other GSS

diseases. Histopathology includes diffusely distributed PrP pla-

ques throughout the cerebrum and cerebellum with minimal

spongiform change.242 In addition, tau-positive neurofibrillary

tangles are found primarily in frontal, parahippocampal cortex,cingulate gyrus, and insular cortex.243,244

Q217R

An A to G transition at the second nucleotide of codon 217

(CAG to CGG) results in the missense coding of arginine

instead of glutamine. A small number of individuals in a single

American family of Swedish origin have been described, each

of whom developed a progressive dementia at least 4 years

before they developed progressive gait ataxia, dysphagia, and

parkinsonism several months prior to their deaths at the ages

of 67 and 71 years.78 Disease duration was 5 and 6 years. EEG

results were not reported. The primary neuropathologic feature

was diffusely deposited PrP plaques throughout the neocortex.

The plaques were shown to be derived from the mutant PrP and

composed of amino and carboxy-terminal clipped fragments

extending from residues 81 or 82 to 145 or 146.245 In addition,

neurofibrillary tangles were diffusely present throughout the

neocortex and several subcortical grey structures that denote

the similarity of pathologic phenotype with that of GSS(F198S)

and GSS(Y145Stop). Experimental transmission of this prion

disease has not been demonstrated.

Truncation Mutations of GSSA stop sequence (TAG) at codon 145 was initially described on

the 129M allele in a Japanese patient with a clinical diagnosis

of Alzheimer disease, with plaque deposits of truncated

PrP.58,104 The patient developed a 20-year course of distur-

bance in memory, eventually progressing to severe dementia

and death at 59 years of age. Periodic discharges were not evi-

dent on EEG. Neuronal loss and gliosis was severe, but spongi-

form change was absent. PrP deposits were found in and around

small- and medium-sized blood vessels and neurofibrillary tan-

gles (NFTs) were evident throughout the cerebral cortex,104

labeling this as a vascular variant of GSS and a cerebral

amyloid angiopathy (PrP-CAA) 159.

Since that case, 4 additional truncation mutations have been

described; Q160X,60 Y163X,61 Y226X, and Q227X.80 The

Q160X case does show GSS type pathology, but it has not yet

been fully described (personal communication). The Y163X

case also displayed PrP-CAA, whereas the Y226X and

Q227X mutations, although differing by only 1 residue, were

found in 2 Dutch patients with 2 distinct disease subtypes. TheY226X mutation was found in a 55-year-old woman who

developed cognitive problems, aphasia, and hallucinations. In

contrast to typical GSS, the CSF 14-3-3 was positive and the

EEG displayed PSWCs. The disease ran a course of 27 months

and the histopathology revealed PrP-CAA in the absence of

neurofibrillary tangles. The Western blot was not described.

The Q227X mutation was found in a 44-year-old woman with

a 72-month slowly progressive course of hypokinetic rigid gait

with cognitive and behavioral changes, and parkinsonian fea-

tures, suggesting frontotemporal dementia (FTD). The histo-

pathology displayed multicentric amyloid plaques throughout

the cerebrum and severe neurofibrillary lesions without PrP-CAA, and Western blot revealed a 7 kDa unglycosylated PrPSc

fragment truncated at both the N- and C-terminal ends.

The consistent demonstration that PrP amyloid deposits are

linked to truncation mutations validates the finding in Tg

mice that express PrP lacking the GPI anchor, and develop

extensive PrP amyloid plaque deposits.246 Thus, the absence

of the GPI anchor results in PrP secretion to the extracellular

space, leading to amyloid formation. Why specific point

mutations result in this presumed secretion of PrP is currently

undetermined.

Diagnostic ConsiderationsA rapidly progressive dementia associated with ataxia, myoclo-

nus, and periodic discharges on the EEG, in an afebrile 65-

year-old individual provides a straightforward diagnosis of

CJD. However, this constellation of features may be observed

in less than 60% of cases. It should be clear from the above

descriptions of the presentations of prion disease that the range

of clinical phenotypes now is quite broad. As such, the diagno-

sis of prion disease should be considered as part of the differ-

ential in all cases presenting with dementia, an atypical

movement disorder, or late onset psychiatric disease, especially

if the rate of disease progression is rapid or if it is accompanied

or preceded by other neurological signs or symptoms and/or a

family history of a similar disease. Other diseases with overlap-

ping symptoms include Alzheimer disease, cortical basal

degeneration (CBD), dementia with Lewy bodies (DLB), Hun-

tington disease (HD), Spinocerebellar ataxias (SCAs), and the

frontotemporal lobar dementias (FTLD), including the beha-

vioral variant of FTD, semantic dementia, and progressive non-

fluent aphasia, among other conditions. Central nervous system

(CNS) vasculitis may be entertained in some rapidly progres-

sive forms of prion disease, although a normal MRI usually

argues against it. Angiogram may be considered in some cases.

The inherited metabolic disorder of ceroid lipofuscinosis (Kufs

disease in the adult) can also present with dementia and


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myoclonus. Metabolic causes of a prion-like presentation

include bismuth or lithium toxicity. Hashimotos encephalopa-

thy is an important treatable condition to rule out. It can pro-

duce intermittent episodes of confusion, cerebellar ataxia,

and may even demonstrate periodic discharges. Antithyroper-

oxidase antibody (anti-TPO) and antithyroglobulin will be con-

siderably elevated. Corticosteroid therapy may completelyreverse the symptoms.

Key diagnostic studies include MRI, EEG, cerebrospinal

fluid (CSF) analysis, and sometimes PET scan. EEG findings

of periodic sharp wave complexes (PSWCs) consisting of

triphasic or sharp wave bursts every 0.5 to 2.0 seconds support

the diagnosis of prion disease. Although PSWCs are observed

in a small percentage of individuals with genetic prion

disease, their presence seems to be highly dependent on the

associated causal mutation and resultant clinical phenotype;

those mutations that produce a CJD-like clinical phenotype

and spongiform degeneration pathology seem more likely to

have a positive EEG.Hyperintensity on diffusion weighted magnetic resonance

imaging (DWI), especially within the basal ganglia or involv-

ing the cortical ribbon, appears to be highly predictive of CJD,

although the studies with familial CJD are limited, as are those

with GSS. A PET scan is typically uninformative for CJD or

GSS, but it may show focal hypometabolism of the thalamus

in sporadic and familial forms of FI. In addition, a clear pattern

of Alzheimer disease (hypometabolism of temporoparietal

lobes) or frontal lobar dementia (focal frontal and temporal

lobe hypometabolism) may be useful to rule out prion disease,

but this may not be 100% certain.

Cerebrospinal fluid often shows a mild,*10%

, elevation oftotal protein without a cytological response. Significant eleva-

tions in 14-3-3, total tau, or neuron-specific enolase have been

shown to be highly predictive of prion disease, more specifi-

cally sCJD.247-250 An elevation in the level of these proteins

represents rapid neuronal death with leakage of the cell con-

tents into the spinal fluid. Thus, these appear to be more predic-

tive of faster-progressing, nonfamilial forms of prion disease.

False negatives are known in some reports over 40% of the

time.250 False positives have been reported with herpes ence-

phalitis, hypoxic brain damage, acute stroke, and other condi-

tions that induce neuronal damage. Genetic analysis of the

PRNPgene may be helpful whether a family history of disease

is present, as the late and often variable age at onset of the prion

diseases may obscure a positive family history.

A definitive diagnosis of prion disease can only be made by

pathologic confirmation following biopsy (no longer a com-

mon practice because of the preparation and cleanup required

for the operating room) or autopsy. Transmission of disease

to a proper host animal is considered the ultimate diagnostic

test for the presence of prions; however, these studies are

expensive and time consuming, in some cases requiring more

than 2 years to complete. Newer technologies, using in vitro

methods such as the protein misfolding cyclic amplification

(PMCA) process may prove more useful. In this process, a

small amount of prion-affected sample is mixed with a large

excess of normal brain homogenate and subjected to a series

of incubations and sonications to break up PrP fibrils and cre-

ate new PrPSc seeds resulting in the amplification of PrPSc

several fold.251 This technique has been shown to detect

prions in blood and, as such, might eventually be used in diag-

nostic testing of peripherally infected individuals, such as in

vCJD.252

Therapy

There are currently no therapeutic agents designed to slow the

progression or reverse the effects of prion disease. Thus, therapy

is aimed at controlling symptoms. If present, seizures may be

treated with general antiepileptic agents such as phenytoin or car-

bamazepine. Myoclonus often responds to low doses of clonaze-

pam. Issues related to dysphagia are often difficult to resolve and

the decision to place a feeding tube should be weighed against the

confidence of the diagnosis of these terminal diseases. Severe

psychiatric symptoms that may include hallucinations and/ordelusionsare best managed by small doses of atypicalantipsycho-

tics, such as quetiapine. Evaluation by a social worker is manda-

tory to assist the family in management planning.

The most extensive clinical trials for prion therapy focused

on quinacrine, an antimalarial that showed promise in curing

infectious PrPSc from cultured neuroblastoma cells chronically

infected with scrapie.253 The results of studies from the United

States and the United Kingdom did not support a clinical ben-

efit of quinacrine for CJD. Other agents, particularly polysul-

fated compounds such as pentosan polysulfate, suramin, and

heparan sulfate,254,255 prolong the incubation period of experi-

mental scrapie in animals, although they must be administeredprior to, or simultaneous with, the inoculation of the animal

with prions, making these impractical for the symptomatic

patient who presented for medical attention.256 Pentosan poly-

sulfate was administered intracerebrally to a single patient with

vCJD, with unclear clinical benefit although his course

appeared to be prolonged.257 The mechanism by which these

drugs exert their effects is unclear, but some consider that the

highly charged molecules sequester prions away from other

interacting proteins. In addition to these agents, anti-PrP anti-

body therapy, designed to block the interaction of PrPSc with

PrPC,258-260 is under investigation, as is the attractive approach

of siRNA therapy, which will act to knock down PrPC expres-

sion, leading to less substrate for conversion to PrPSc.261

Although such treatments are in dire need, better methods of

detection and early diagnosis will need to be developed, to

afford the best chance for successfully inhibiting disease pro-

gression. Genetic detection of familial forms paired with devel-

oping strategies of brain imaging and PMCA of body fluids

may assist in that goal.

Declaration of Conflicting Interests

The author(s) declared a potential conflict of interest (e.g. a financial

relationship with the commercial organizations or products discussed

in this article) as follows: Dr. Mastrianni is a consultant to the FDA

TSE Advisory Committee.


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Funding

The author(s) disclosed receipt of the following financial support for

the research and/or authorship of this article: Dr. Mastrianni receives

funding from the NIH for prion disease research.

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