Gerstmann–Sträussler–Scheinker syndrome, fatal familial ...

Journal of Clinical Neuroscience (2001) 8(5), 387–397
© 2001 Harcourt Publishers Ltd
doi: 10.1054/jocn.2001.0919, available online at http://www.idealibrary.com on

Review

Gerstmann–Sträussler–Scheinker syndrome,
fatal familial insomnia, and kuru: a review of
these less common human transmissible
spongiform encephalopathies

S. Collins1,2 MD FRACP, C. A. McLean2 MD FRCPA,1 C. L. Masters1,2 MD FRCPA

1Australian Creutzfeldt–Jakob Disease Registry; 2Department of Pathology, The University of Melbourne, Parkville, Victoria, Australia

Summary Creutzfeldt–Jakob disease (CJD), Gerstmann–Sträussler–Scheinker syndrome (GSS), fatal familial insomnia (FFI) and kuru con-
stitute major human prion disease phenotypes. Each has been successfully transmitted in animal models and all are invariably fatal neurode-
generative disorders, with the brains of affected individuals harbouring variable amounts of an abnormal, protease-resistant form of the prion
protein (PrPres), which is inextricably linked to pathogenesis and transmissibility. Classical sporadic CJD is the most common human trans-
missible spongiform encephalopathy (TSE), but recently the variant form (vCJD), first described in the UK in 1996, has drawn considerable
attention.

In contrast to sporadic CJD, FFI and GSS are almost invariably genetically determined TSEs, caused by a range of mutations within the
open reading frame of the prion protein gene (PRNP) on chromosome 20. By definition, the nosologic term FFI is reserved for patients mani-
festing prominent insomnia, generally in combination with dysautonomia, myoclonus, and eventual dementia, with the predominant patho-
logic changes lying within the thalami and a specific underlying mutation in PRNP. GSS, however, encompasses a more diverse clinical
spectrum ranging from progressive cerebellar ataxia or spastic paraparesis (both usually in combination with dementia), to isolated cognitive
impairment resembling Alzheimer’s disease. Additional extra-pyramidal features, which may respond to dopaminergic therapy can also be
seen. Neuropathological findings are also relatively diverse, partly overlapping with those found in Alzheimer’s disease, especially the pres-
ence of neurofibrillary tangles (NFTs). Although GSS and FFI in their classical forms are differentiable clinical profiles, such divisions may
have no intrinsic biological validity given the considerable intra-familial clinico-pathological diversity so commonly seen.

Kuru constitutes a horizontally transmitted prion disease, which after a lengthy incubation period, presents clinically as a progressive cere-
bellar ataxia associated with tremors. It has now almost disappeared since the cessation of ritualistic endocannibalism in the late 1950s but
was previously exclusively endemic amongst the Fore linguistic group and neighbouring tribes in the Eastern Highlands of New Guinea.
Uniform topographical central nervous system histopathology includes spongiform change and neuronal loss, with amyloid (kuru) plaques in
approximately 75% of cases. © 2001 Harcourt Publishers Ltd

Keywords: review, prion diseases, transmissible spongiform encephalopathies, kuru, fatal familial insomnia, Gerstmann–Sträussler–
Scheinker disease

INTRODUCTION whereas the other human TSE phenotypes (excluding kuru) are
increasingly recognised because of the greater accessibility, and
The human TSE phenotypic spectrum (also known as prion dis- recent availability, of specific confirmatory diagnostic capabilities,
eases) encompasses classical CJD and the variant form, GSS, FFI, including genotyping of PRNP. Currently, the Australian CJD
and kuru.1 Classical CJD may occur sporadically or on a genetic Registry is aware of more than 20 individuals from 10 different
or iatrogenic basis.1 In addition, less distinct or overlapping neu- kindreds manifesting familial forms of prion disease, with each of
rological and neuropsychiatric syndromes are seen in individual the three principal (CJD, GSS, FFI) heritable phenotypes repre-
families, often linked to specific mutations and polymorphisms sented. As is well described, considerable intra-familial clinico-
within PRNP, and these constitute the residual expanding, human pathological diversity is evident. Almost invariably, FFI and GSS
phenotypic TSE spectrum;2,3 they will not be considered further. represent genetically determined TSEs caused by a range of muta-
tions within the open reading frame (the specific nucleotide pro-
Sporadic CJD is arguably the best known and certainly the most tein encoding sequence) of PRNP on chromosome 20. Although
common of the human prion diseases, but it is the recent recogni- these are very rare disorders, their detailed study, especially at the
tion of vCJD that has heightened international awareness of this molecular level, has provided important insights into this group of
group of disorders. The high profile of vCJD arises for a number disorders. Analogously, it was the comprehensive investigations of
of reasons, including the likely zoonotic derivation of the disease kuru that lead to such profound progress in our understanding, and
from bovine spongiform encephalopathy (BSE) and the possibility delineated the archetypal human form of TSE. The detailed epi-
of greater potential for transmission from peripheral tissues.1 demiological data relating to kuru remain a very valuable and
Nevertheless, vCJD has not yet been seen within Australia, reassuring source of information concerning the lack of transmis-
sibility in routine domestic life and non-iatrogenic situations.
Received 22 November 2000
Accepted 2 February 2001 The Australian Creutzfeldt–Jakob Disease Registry is funded by the
Commonwealth Department of Health and Aged Care.
Correspondence to: S. Collins MD FRACP, Australian Creutzfeldt–Jakob
Disease Registry, University of Melbourne, Parkville, Victoria, Australia 3010.
Tel.:;613 8344 5867; Fax: ;613 8344 4004; E-mail: [email protected]

387

388 Collins et al.

There has also been a resurgence of interest in kuru because of beta-sheet form of the synthetic PrP peptide developed spongiform
parallels with vCJD, with horizontal transmission most likely degeneration and amyloid plaques at a mean of 360 days post-inoc-
occurring via the enteral route in both disorders. Hence, for these ulation, while those transgenic mice not inoculated or given the
various reasons, it was felt appropriate to review the clinicopatho- non-beta-sheet form of the synthetic peptide irregularly manifested
logical features, recent molecular biological data, and relevant disease after more than 550 days. Although clearly not the same as
epidemiological studies of these less common, but important, creating a spongiform encephalopathy de novo with synthetic PrP,
human prion diseases. Similar to CJD, each has been successfully the data is consistent with the hypothesis that exposure to the cor-
transmitted in animal models and all are invariably fatal neurode- rect protein template in a predisposed or vulnerable situation can
generative disorders, with the brains of affected individuals har- facilitate transcendence of kinetic and thermodynamic barriers
bouring variable amounts of an abnormal, protease-resistant, form inhibiting the transformation of wild type PrP to PrPres.
of the prion protein (PrPres), which is inextricably linked to
pathogenesis and transmissibility. Genetic basis of GSS

GERSTMANN–STRÄUSSLER–SCHEINKER Since the initial linkage of GSS to a P102L mutation in PRNP,8
SYNDROME a variety of mutations in this allele on chromosome 20 have been
described in association with this disorder (summarised in Table 1
The original description of this syndrome was in a large Austrian and Fig. 3). The most common is the P102L substitution,8,14,15
family with affected members manifesting slowly progressive although other mutations are sometimes relatively prevalent in
cerebellar ataxia admixed with cognitive decline at some time in particular ethnic groups.16 Only very uncommonly is GSS not
the course of their illness.4,5 Autosomal dominant inheritance best associated with a mutation in PRNP and occur sporadically.17
described the trans-generational pattern of afflicted family mem- This genetic diversity may partly explain the inter-familial pheno-
bers and continues to be the usual manner of vertical transmission typic variation reported.7,14,15,18–21 Nevertheless, considerable
seen in GSS kindreds. In subsequent years, a number of descrip- intra-pedigree phenotypic heterogeneity is also typical and recent
tive and eponymous titles were unwittingly applied to analogous reports continue to highlight how different members within one
disorders, and it was only relatively recently that this group of dis- family can vary from typical CJD to classic GSS21,22 or show sig-
eases was distilled as a cohesive clinicopathological entity with nificant divergence in age of onset or perhaps penetrance even in
nosological clarification as a TSE.6 Although the core clinical fea- monozygotic twins.23 Such variations point to likely additional
tures of dementia associated with progressive cerebellar ataxia genetic or environmental disease modifying factors. As described
and/or spastic paraparesis are somewhat non-specific, all GSS above, the likely causative role of PRNP mutations is strongly
patients share the distinctive underlying neuropathological feature supported by the spontaneous development of spongiform degen-
of widespread multicentric amyloid plaques which equally facili- eration in the brains of transgenic mice harbouring such
tated delineation of this group of disorders as a discrete entity. changes.12,13 In addition, regardless of pedigree, each of the mis-
Occasionally this pathological diagnostic requisite has subserved sense mutations is usually specifically associated with either
a broadening of the clinical phenotype.7 methionine or valine at codon 129, suggesting this normal poly-
morphic coding site may influence pathogenesis.24,25
Transmission studies
The P102L mutation has recently been confirmed in members
Although GSS is transmissible, studies on small numbers of from the original family described by Gerstmann.26 This mutation
patients, utilising both non-human primates and rodents as recipi- is usually associated with the more typical or classic ‘ataxic’ GSS
ents, have shown low overall success rates. Only patients harbour- clinicopathological profile but exceptions have been reported,
ing the most common causal GSS mutation (a codon 102 proline attributed to the modifying effects of non-pathogenic polymor-
to leucine change in PRNP; P102L)8 have been reproducibly phisms.25,27 Other mutations have been described often in associa-
transmissible, but even then in just 40% of such cases. Aside from tion with less typical phenotypes.7,18,20 The normal PRNP codes
a single patient with an insert mutation, the other less frequent for a nonapeptide sequence which with only very minor
mutations associated with GSS either have not transmitted or have nucleotide modification is repeated four times as an octapeptide
not been assessed.9–11 Transmissibility of GSS may be linked to between codons 51 to 91. Although insert mutations of varying
the presence of spongiform degeneration (most commonly seen in multiples of these octapeptide repeats are commonly found in
P102L patients), which in its turn may be related to the particular other familial prion diseases, especially CJD,28,29 to date GSS
type of PrPres isoforms present in the brain.11
Table 1 PRNP haplotypes associated with Gerstmann–Sträussler–
Transgenic murine models of GSS, utilising an overexpressed Scheinker syndrome
homologue of the P102L mutation, spontaneously reproduce many
of the features seen in human disease, although critical aspects such Missense mutations
as the presence of PrPres and multicentric amyloid plaques are only
inconsistently or incompletely recapitulated.12,13 Particularly intrigu- P102L*-129M***; P105L–129V***; A117V–129V; Y145STOP–129M;
ing was the finding of characteristic GSS neuropathology, including F198S–129V; D202N–129V; Q212P–129?; Q217R–129V
PrP-positive plaques, in some transgenic mice but the apparent total
absence of PrPres in their brains on Western blots.13 Also of poten- Inserts**
tial interest for providing fundamental insights into prion pathogen-
esis is the fact that it has been possible to prematurely and more 8 octapeptide repeat (192 bp) insert starting at codon 84–codon 129
consistently induce spongiform degeneration and amyloid plaque polymorphism not stated.
deposition in one of the transgenic mice lines when intracerebrally 8 octapeptide repeat (192 bp) insert starting at codon 76–cis 129 V.
inoculating a synthetic 55-mer peptide fragment of PrP chemically 8 octapeptide repeat (192 bp) insert–cis 129M; specific start site of
pre-treated to increase its beta-sheet content.13 The synthetic peptide octapeptide repeat not stated but located within codon 51 to 91 region.
spanned residues 89–143 of PrP and contained the murine equiva-
lent mutation of P102L. All mice inoculated with the heightened * This mutation has also been reported in cis with valine at codon 129.25
** The three octapeptide repeat insert mutations associated with GSS differ
from each other at the nucleotide level.
*** V denotes valine; M denotes methionine.

Journal of Clinical Neuroscience (2001) 8(5), 387–397 © 2001 Harcourt Publishers Ltd

Less common human transmissible spongiform encephalopathies 389

appears linked only to differing eight octapepetide repeat (192 paraparesis have been reported.37 Not surprisingly, post-mortem
base pair) expansions of this gene region (refer to Fig. 3).21,30,31 examination in the majority of P105L patients reveals the brunt of
the neuropathological changes to lie in the motor cortex and pyra-
Clinical Features midal tracts with relative preservation of the cerebellum. An
uncommon amber stop mutation, causing termination of PRNP
In families with typical GSS, symptoms usually begin in the fifth or translation at codon 145 (Y145stop), was found in a patient with
sixth decade, but the onset may be as young as 25 years, with illness isolated progressive dementia spanning 20 years, who at autopsy
durations ranging from three months to 13 years with the mean had the combination of Alzheimer changes and numerous neocorti-
around five to six years.6,20,21,32 Variation in age of onset appears cal and cerebellar PrP-positive amyloid plaques.7 Finally, the codon
most marked in association with the P102L mutation.33 However, as 117 alanine to valine (A117V) and 202 aspartic acid to asparagine
discussed below, exceptions are reported among kindreds with less (D202N) mutations are associated with what are sometimes referred
typical or variant forms of GSS. Although early complaints are to as ‘telencephalic’ variants of GSS wherein progressive dementia
often vague or non-specific, there is inexorable, usually slow pro- may be the predominant clinical feature. Nonetheless, even when
gression, so that eventually patients come to manifest differing cognitive impairment is dominant in A117V GSS, there is often
combinations of cerebellar and pyramidal dysfunction, behavioural coexisting lesser pyramidal, extra-pyramidal and cerebellar dys-
difficulties, and cognitive decline. function.14,33,35,38,39 Neuropathologically, the characteristic features
are largely confined to the telencephalon with occasional NFTs and
Features of pan-cerebellar dysfunction include: gait unsteadi- relative sparing of infra-tentorial structures.
ness; limb ataxia with dysmetria, dysdiadochokinesis and intention
tremor; titubation; nystagmus; and dysarthria. The latter is often Routine investigations
accompanied by dysphagia and both may also partly reflect corti- Most often, the EEG only shows a non-specific excess of slower
cobulbar pathway disturbances. Signs of corticospinal tract degen- frequencies, which may appear in bursts, but can be normal even
eration such as limb weakness, spasticity, hyperreflexia and in relatively advanced disease.23,32 However, the generalised, 1–2
positive Babinski’s responses are present in many patients, while Hertz triphasic or slow-wave complexes most often sought to aid
in some families (especially with the codon 105 proline to leucine the diagnosis of sporadic CJD can be seen, usually in patients with
mutation; P105L) spastic paraparesis may dominate the clinical the P102L mutation who exhibit more aggressive disease and
syndrome in the absence of cerebellar dysfunction.16,19,29,34 The shorter illness durations of less than 12 months.21,33
unusual combination of absent lower limb tendon reflexes with
extensor plantar responses is relatively frequent in the later stages Neuro-imaging (both CT and MRI scanning) may be normal32
of the illness.6 Extrapyramidal motor disturbances are common or show non-specific atrophy affecting the cerebral hemispheres
and take the form of adventitious movements (myoclonus and and/or cerebellum.
athetosis) and rigidity.21 Disturbances of the motor system are
usually symmetrical but exceptions have been reported.35 Neuropathology
The pathognomonic and syndromally delineating feature is the pres-
Memory impairment is usually the first indication of cognitive ence of widespread, large, multi-centric amyloid plaques (Fig. 1)
decline which can be evinced either early or later in the clinical which are selectively immunostained by antibodies to PrP.
course. With the passage of time more pervasive cognitive impair- Associated but less constant findings include white matter degenera-
ment usually manifests with learning difficulties, dysphasia, reduced tion, neuronal loss (which may occasionally show a striking
attention span and slowed information processing; however, patients regional, nuclear or lobar emphasis), spongiform change, gliosis,
with the Q212P mutation may not develop dementia.33 Intercurrent and NFTs.6,36 Hence, mirroring the clinical diversity, considerable
with the intellectual deterioration, changes in demeanour are com- variation in the location, extent, severity and type of neuropathologi-
mon and range through aggressivity, irritability, and emotional labil- cal changes are also widely recognised. At present, there is little
ity to apathy and withdrawal. Less common features are deafness,
cranial nerve palsies and seizures.21,32,35 Death in a bedridden, aki- Fig. 1 Multi-centric amyloid plaques (bracket) within the cerebral cortex of
netic-mute, totally dependent state is a frequent culmination.23 Gerstmann–Sträussler–Scheinker syndrome. Minor spongiform change is
also seen within the neuropil (arrow). Haemotoxylin and eosin stained section
Less typical forms of (scale bar:50 µm).
Gerstmann–Sträussler–Scheinker Syndrome

As already mentioned, the advent of PRNP genotyping has broad-
ened the spectrum of GSS to include less typical phenotypes,
although all have the common neuropathological denominator of
numerous and widespread amyloid plaques which are selectively
stained immunocytochemically by anti-PrP antibodies.

An American (Indiana) kindred, associated with a codon 198
phenylalanine to serine (F198S) change, was remarkable for both
the development of dopaminergic-responsive Parkinsonian features
(with minimal or absent tremor) and the presence of neocortical
NFTs.18 In the same report a Swedish family with late-onset cogni-
tive decline and cerebellar dysfunction (shown to have glutamine
replaced by arginine at coding position 217 (Q217R) also mani-
fested neocortical NFTs in addition to the widespread PrP-positive
plaques. Degenerative changes in the substantia nigra correlate with
Parkinsonian features.36 As already mentioned, the P105L mutation
usually causes a familial spastic paraparesis–dementia variant, with-
out clinical evidence of cerebellar dysfunction or myoclonus19,20
but patients with gait apraxia and Parkinsonism without spastic

© 2001 Harcourt Publishers Ltd Journal of Clinical Neuroscience (2001) 8(5), 387–397

390 Collins et al.

insight into the precise sequence of occurrence and mechanisms forms of amyloid plaque may be seen including the unicentric form
subserving the pathological changes which are seen. usually observed in kuru (with which it is ultrastructurally identical;
refer to Fig. 1b) and occasionally the senile or neuritic form found in
Spongiform change was a prominent feature in the original kin- Alzheimer’s disease.6,35,36,43 Further, detailed immunohistochemistry
dred reported by Gerstmann and colleagues6 but its presence varies in some P105L and Q217R patients has revealed greater overlap,
considerably both within and between GSS pedigrees and is not with hybrid amyloid plaques showing central staining with anti-PrP
clearly linked to duration of illness. For example, microvacuolation ligands while the periphery was reactive with antibodies to the A␤
is relatively common in kindreds with the P102L mutation (but can domain of the amyloid precursor protein (APP) of Alzheimer’s dis-
still range from absent to severe in affected members of the same ease.37,40 Also, these plaques were frequently associated with abnor-
family), although it can also be seen in association with the A117V mal neurites harbouring tau-immunoreactive NFTs.
and octapeptide repeat insert mutations.21,28,32,36 However, in
contra-distinction, it is rarely or never seen in the P105L, Confirming some degree of neuropathological overlap with
Y145STOP, F198S, D202N or Q217R mutations.7,20,33,36,40 Such Alzheimer’s disease, NFTs and neuropil threads are commonly seen
variations in neuropathologic changes may relate to the specific in the cerebral cortex of patients carrying the P105L, A117V,
PrPres isoforms which arise in association with a given mutation. Y145STOP, F198S, D202N, and Q217R mutations.7,24,33,36,43
Although biochemical studies confirm the presence of protease- However, their topography can be even more widespread and include
resistant PrP in the brains of all GSS patients, the absolute amounts, subcortical nuclei and the brain stem in P105L, F198S and Q217R
topographical distribution and specific isoforms as revealed by pedigrees.36,37 As described in Alzheimer’s disease, they are immuno-
immuno-electrophoresis vary considerably, but show some correla- reactive with antibodies raised against the tau protein, and ultrastruc-
tion with the underlying mutation. A range of PrPres fragment sizes turally are composed of paired helical filaments each around 10 nm
is usually seen in GSS patients, varying from 7 to 30 kDa. in diameter with a periodicity of approximately 80 nm.
However, the likely proteolytic 7 or 8 kDa ‘core’ PrPres fragments
are not seen in CJD or FFI, and in GSS are derived from the mutant FATAL FAMILIAL INSOMNIA
allele.11 Predominance of the higher molecular weight (21–30 kDa)
PrPres fragments, similar to those found in sporadic CJD, have been The descriptive diagnosis FFI was first used in 1986 to depict an ill-
shown to correlate with the presence of spongiform degeneration ness afflicting five members of a large Italian family44 but it was not
and are almost exclusively seen in P102L patients.11,33 However, until 1992 that the disorder was proposed as a novel, genetically
while the isoform pattern can vary considerably between indivi- determined prion disease.45 Sequencing of PRNP in three sympto-
duals with the same mutation, and even between different brain matic members of the family confirmed a GAC-to-AAC mutation at
regions of the same patient (especially in P102L GSS), some muta- codon 178 of the gene, causing substitution of asparagine for aspar-
tions such as F198S appear to manifest a more uniform pattern of tic acid (D178N) (refer to Fig. 3). Correlating immunopathological
PrPres isoforms both between patients and amongst various brain confirmation was achieved by demonstrating the presence of PrPres
locations.33 Hence, it is possible that some mutations permit a range in both cortical and sub-cortical locations in the two family mem-
of catabolic or processing cleavage reactions, while others are more bers studied.45 Final nosologic verification as a TSE was achieved
restricting, with the consequent PrPres fragment profile imparting with its eventual successful transmission to laboratory animals.9,46
its influence on the neuropathological changes which develop, Since its clarification as a TSE, a number of additional FFI pedi-
regardless of the precise PRNP haplotype.11 grees have been described.47–52

White matter degeneration most commonly affects the cerebral The brains of typical D178N FFI patients show a characteristic
hemispheres, cerebellum, and spinal cord, especially the posterior restricted degeneration, largely confined to the thalami, especially
columns and spinocerebellar and corticospinal tracts. Additional the mediodorsal and anteroventral nuclei, as well as the inferior
infra-tentorial structures often involved include the superior cerebel- olivary nuclei.44,45 A family history of similar disorder may be
lar peduncles and basis pontis while occasionally the basal ganglia absent in FFI patients carrying the D178N mutation,53 and rarely,
may be affected.6 The extent of white matter loss often appears close clinicopathological phenocopies are encountered in indivi-
more marked than can be explained solely on the basis of wallerian duals without a PRNP mutation (referred to as sporadic fatal insom-
degeneration. nia),54,55 and also in patients with other PRNP mutations, such as
E200K usually found in association with familial CJD.56 Of impor-
Neuronal depletion shows a predilection for the cerebral cortex tance, retrospective genetico-pathological analysis of families clas-
(sometimes with marked lobar emphasis) and the cerebellum, sified generically as ‘selective thalamic degeneration’ showed the
including Purkinje cells, dentate nuclei, and granular layer, but majority of pedigrees examined to harbour the same D178N PRNP
occasionally also the subcortical telencephalic nuclei, thalami and mutation, prompting their more correct classification as FFI.57
anterior horn cells.6 Parkinsonian features generally correlate with
neuronal loss and gliosis in the substantia nigra.36,37 Of interest, the same (D178N) mutation had previously been
described as the cause of familial CJD in a number of unrelated kin-
The defining multi-centric amyloid plaques consist of a central dreds, stimulating discussion as to explanations for this apparent
dense core, irregularly encircled by smaller satellite globules which clinico-genetic disparity.58,59 The answer was postulated to reside in
immunocytochemically are bound by antibodies to PrP.41 Extraction the modifying influence of a normal polymorphism at codon 129 of
and chemical analysis of the amyloid plaques has confirmed them to PRNP: FFI was found to segregate with the D178N mutation when
be constituted by PrP peptide fragments derived from the mutant combined in cis with methionine at codon 129 (D178N–129M),
allele.42 The plaques are usually widely distributed, being most com- whereas CJD was linked to valine at the latter coding position
mon in the cerebral cortex and cerebellum but may also be seen in (D178N–129V).60 Subsequent investigations revealed subtle differ-
the basal ganglia, brain stem and sub-cortical white matter.6 ences in the cellular metabolism of D178N–129M and D178N–
Ultrastructurally, electron microscopy shows the amyloid plaques to 129V gene products after transfection into human neuroblastoma
consist of masses of radiating bundles of curvilinear filaments 8–10 nm cells61 as well as more clear-cut differences in the glycoform
in diameter without definite periodicity,35 often with enlarged inter- ratios and electrophoretic mobilities of their protease-resistant
digitating astrocytic processes encircling the rim of the core.39 derivatives.62 In association with the CJD phenotype coupled to the
Routine application of anti-PrP immuno-reactive ligands usually D178N–129V genotype, the relative mobility of deglycosylated
reveals a plaque burden far greater than the number manifesting the PrPres is approximately 21 kDa (designated type 1), whereas in FFI
tinctorial properties of amyloid. In addition, other morphological

Journal of Clinical Neuroscience (2001) 8(5), 387–397 © 2001 Harcourt Publishers Ltd

Less common human transmissible spongiform encephalopathies 391

linked to D178N–129M, the anaolgous fragment runs at around Dysautonomia is the other major distinguishing clinical feature
19 kDa (referred to as type 2).63 It is hypothesised that some of of FFI, and may be noticeably episodic. Often reflecting sym-
these differences are an inherent physical consequence of variations pathetic overactivity, its broader manifestations include: impo-
in the mutant PrP structural conformation, postulated to reflect dif- tence; sphincteric dysfunction; excessive salivation; rhinorrhea;
fering protease cleavage sites. Additionally, it was argued that these lacrimation; hyperthermia; hyperhidrosis; tachycardia; and hyper-
distinguishing mutant PrPres molecular properties culminate in the tension.44,67 Autonomic dysfunction tends to occur relatively early
distinct clinicopathological phenotypes recognised as CJD and FFI, in the clinical course and may be the presenting symptom. As
and may represent the phenomenon of prion ‘strains’.64 However, already mentioned, the disrupted sleep–wake cycle and autonomic
detailed studies of kindreds containing the D178N mutation have irregularities are believed to predominantly reflect damage to the
shown sufficient clinicopathological diversity and overlap to sug- mediodorsal thalamic nuclear group and its connections to the
gest that FFI and CJD most likely represent somewhat artificial but hypothalamus and other central (cortical and subcortical) auto-
frequently identifiable clinical patterns, and cast doubt on the claim nomic control areas, because of the intactness of these other sites
that ultimate phenotype is governed entirely by associated codon at neuropathological examination.67,71
129 allelic polymorphisms.47,49,50,56,65–67 When diversity is seen in
D178N–129M patients, more often there is relatively greater clini- As the illness evolves, a range of motor abnormalities usually
cal than pathological heterogeneity, with predominant thalamic evolve in variable combinations. Cerebellar and pyramidal dys-
involvement often a salient finding despite less typical symptom function culminate in prominent limb, gait, and bulbar difficulties,
profiles which include cerebellar ataxia and dementia. Certainly, accompanied by hyperreflexia, upgoing plantar responses, inten-
very modest or absent insomnia and essentially normal sleep elec- tion tremor and dysmetria. Spontaneous and reflex myoclonus are
troencephalographic studies are well described throughout the ill- commonly present. Disorders of ocular movement and generalised
nesses of symptomatic D178N–129M patients.53,68 hypertonia may also be seen. Respiration is frequently altered and
may display tachypnea, or an irregular noisy pattern with intermit-
Clinical Features tent apnea and hypoventilation.44,52

FFI kindreds show inheritance patterns consistent with autosomal Cognitive impairment usually develops later in the evolution of
dominance.45,47 Incomplete penetrance is possibly quite common the illness, but may remain relatively mild and restricted to amnesive
as 11 members of the original, large Italian FFI kindred were difficulties on formal neuropsychological testing.44,67 Difficulties
found to harbour the mutation (three older than 60 years) and yet with attention and concentration are often evident early in the
were asymptomatic at the time of the report. Within FFI pedi- patient’s illness and may be the dominant cognitive impairment
grees, onset is usually in the fifth decade, but ranges from 20 to 63 for quite a period of time. Invariably, patients eventually become
years, with illness durations averaging around 13–15 months confused and disoriented, usually accompanied by more wide-
(range 6–42 months).45,47–50,63 Non-specific symptoms such as spread intellectual decline, culminating in stupor and coma with
marked weight loss can be an early feature as well as lethargy and death from intercurrent pneumonia a common outcome. Seizures
tiredness.51,69 are not commonly seen during the course of typical FFI.

The core clinical features of FFI consist of profound disruption Clinical investigations
of the normal sleep–wake cycle (with complete disorganisation of
the electroencephalographic patterns of sleep), sympathetic overac- Systematic neuroendocrine monitoring typically discloses a range of
tivity, diverse endocrine abnormalities (particularly attenuation of hormonal irregularities in patients with FFI, comprising alterations
the normal circadian oscillations) and markedly impaired attention. in basal blood levels, changes in the circadian pattern of secretion,
The manifestations of defective homeostasis are subserved by the or both.44,49 Serum cortisol is continuously increased, with or with-
severe, selective loss of the thalamic mediodorsal and anteroventral out preservation of circadian fluctuations. Circulating levels of both
nuclei which have prominent integrative and relay functions melatonin and thyrotropin (TSH) are reduced, with greatly attenu-
between the cerebral cortex and brain stem within the limbic sytem ated or absent variations over a 24-hour period. Despite this, thyroid
and central autonomic network.70 Dysfunction of the mediodorsal hormone levels are reported as normal and TSH levels increase in
nucleus is believed to be most closely linked to the disordered response to challenges with thyrotropin-releasing hormone. In addi-
sleep, with failure of transmission of spindling activity from the tion, normal circadian oscillations are lost for growth hormone, pro-
reticular nucleus of the thalamus thought to explain its absence at lactin, and follicle stimulating hormone (FSH), with impaired
the cerebral cortex. Analogously, this functional disconnection responses of FSH and luteinising hormone (LH) to LH-releasing
between the limbic cortex and the hypothalamus is postulated to hormone. Basal gonadal hormones may be increased (progesterone)
explain the autonomic dysregulation and endocrine disturbances. or decreased (testosterone and estradiol) but can be partly stimulated
Degeneration of the thalamic anteroventral nucleus is proposed to artificially with human chorionic gonadotropin.
underlie the behavioural changes and attention deficits.70
Polysomnographic recordings confirm markedly reduced total
Sleep disruption, characterised by prominent nocturnal insom- sleep time and gross electroencephalographic disorganisation of
nia, constitutes the salient clinical hallmark of this disorder. The sleep including virtual absence of typical rapid-eye-movement
disturbance may initially be relatively minor but usually pro- (REM) periods and deeper non-REM phases characterised by
gresses over weeks to months until in its fully developed form K-complexes, spindles and slow waves.44,49,69 Instead, non-
normal sleep may not be possible, supplanted by stupor usually wakefulness may be replaced by something approximating poorly
accompanied by frequent, vivid dreams which may be acted upon developed REM phases which coincide with periods of dreaming.
while still somnolent.44 Prompt arousal with light stimuli remains Even pharmacologic agents such as benzodiazepines and barbitu-
characteristic but not invariable,50 and as cognition fails patients rates may be unable to induce sleep-like EEG activity44 but
may not be able to recall their intrusive dreams. A variety of prob- promising results were reported in a single patient given gamma-
able (auditory, visual and tactile) hallucinations may occur in hydroxybutyrate.49
addition to the parasomnias, and further contribute to the bizarre
nocturnal behaviours and oneiric automatisms which can be Routine biochemical and hematological parameters are typically
observed.47,49 normal as are CSF findings, although modest nonspecific eleva-
tions of liver enzymes and spinal fluid protein are reported,53 and
also oligoclonal banding of uncertain significance and relevance

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392 Collins et al.

has been described in a single patient.49 The presence of 14-3-3 emphasised in a few thalamic nuclei. Nonetheless, in longer surviv-
proteins in the CSF, diagnostically useful in sporadic CJD,72,73 are ing patients (usually heterozygous at codon 129) relatively greater
typically absent in FFI.52,53 Conventional neuroimaging with MRI amounts of PrPres are found ubiquitously in the neocortex in asso-
or CT scanning is often normal53 or shows nonspecific cerebral ciation with more obvious and widespread spongiform change. It
and/or cerebellar atrophy, whereas positron emission tomography appears that longer survival allows a different topographical evolu-
using radiolabeled flourodeoxyglucose typically shows characteris- tion of the disease, with perhaps regional variation in the type of
tic diminished metabolic activity in the thalami.69,74 PrPres isoform (i.e. PrPFFI in D178N–129M compared to PrPCJD in
D178N–129V) possibly subserving the different neuropathological
The EEG is often normal in the early stages, but usually shows responses observed. This mechanistic postulate also draws some
the progressive development of widespread, non-specific slower support from the similarities in the PrPres glycoforms (both are type
(theta and delta) frequencies as the disorder advances.44,47,49,50,67 2) found in sporadic fatal insomnia and FFI.54
However, generalised less responsive alpha activity has been
reported during the course of a patient’s illness.44 Periodic com- Although many issues remain unresolved in FFI, the findings,
plexes or triphasic waves are usually not seen in typical FFI asso- including dissociation between PrPres burden and the severity of
ciated with the D178N-129M haplotype44,47,49,50,67 but may be neuropathological changes, suggest a selective vulnerability of cer-
seen in affected family members exhibiting clinical features more tain brain regions, especially the thalamus and medullary olives. It
in keeping with CJD67 or in patients manifesting prominent is unclear whether the enhanced susceptibility of the most affected
insomnia associated with other PRNP mutations.56 regions pertains to PrPres toxicity or to possibly unrelated mecha-
nisms, such as loss of normal PrP function.76 However, the latter is
Neuropathology generally considered less likely in prion diseases77 and in contrast
to other TSEs, in FFI any selective neuronal vulnerability appears
In typical FFI, macroscopic examination of the brain generally unlikely to be directly related to the presence of calcium binding
shows no gross abnormalities44,49,67 but diffuse cerebral atrophy proteins such as parvalbumin in GABAergic neurons.78
may be seen.50 In the seminal report of Lugaresi et al.,44 the only Nevertheless, it remains plausible that other hitherto unrecognised
significant histopathological abnormalities were restricted to the factors may cause a significant functional disturbance which can
anterior ventral and dorsomedial nuclear groups of the two thalami, precede the histopathological abnormalities in those areas that are
where greater than 95% of the neurons had been lost from both less damaged. Irrespective of the precise mechanistic pathway,
the magnocellular and parvicellular populations, and prominent neuronal loss is most likely ultimately achieved through
astrocytosis was also present; spongiosus was not seen. All other apoptosis.76 Utilising an in situ end labelling technique to study
thalamic nuclei, the neocortex, cerebral white matter, brain stem various brain locations in 10 FFI cases, prominent apoptosis corre-
and spinal cord were normal, even after detailed regional morpho- lated with those sites revealing the most severe neuropathological
metric comparisons with three age-matched controls. However, changes, including microglial activation as reflected by immunocy-
when further symptomatic members of the original family were tochemical markers of class II major histocompatibility antigen
eventually examined neuropathologically, a varying number of expression.76 Whether microglia constitute primary, or secondary,
additional thalamic nuclei were found to show similar abnormali- non-specific participants in the entire process remains moot.
ties but usually to a less severe extent.67 Those affected included
the ventral mediodorsal, centromedian, reticular, and ventral lateral KURU
posterior nuclear groups but the geniculate bodies were spared.
Further, outside the thalami, mild patchy gliosis was observed in This neurological disorder first came to the attention of Western
the deep cerebral cortical grey matter and subjacent white matter of medicine in the mid-1950s, as the more remote parts of New
most family members with one even showing widespread spongi- Guinea came under external influence through the provision of
form change. Also, the cerebellum invariably revealed mild medical and other services.79 Within a short period of time, a
Purkinje cell loss and gliosis, while the inferior olivary nucleus number of reports confirmed and clarified the clinical features of
manifested severe neuronal depletion and reactive astrogliosis. this illness.80–83 Kuru was recognised to be endemic amongst the
Fore linguistic and cultural group resident in the Eastern
Subsequent reports have generally detailed similar neuropatho- Highlands of New Guinea since at least 1941,81 but was also seen
logical findings45,47,49,69 but tended to elaborate a broader spec- (20% of all cases) in the neighbouring Keiagana, Kanite, Kimi,
trum of abnormalities that can be seen in affected members of an Usurufa and Auiyana with whom the Fore often inter-married.79,84
FFI pedigree, partly correlating with duration of survival. The Hence, kuru occurred in a circumscribed, remote, mountainous
entorhinal cortex usually reveals some spongiform change and region populated by approximately 17 000 people dispersed over
gliosis in most patients, but these changes are either absent or more than 160 villages.79,84 ‘Kuru’ in the Fore language means ‘to
quite modest and patchy in the remainder of the cerebral cortex, shiver’ (or ‘to be afraid’), and, along with cerebellar ataxia,
especially in patients who manifest a shorter illness.63 Although constitutes the salient clinical hallmarks of the disorder.
the basal ganglia, midbrain, pons, spinal cord and hypothalamus
have generally been considered to be relatively unaffected, more The clarification of kuru as a TSE commenced with the perspica-
detailed recent accounts have described diffuse astrocytic gliosis cious observations of a veterinary pathologist who noted a number
in the neocortex, basal ganglia, cerebellum and brain stem, with of epidemiological, clinical and neuropathological similarities
considerable neuronal loss in the latter two regions.51 between kuru and scrapie, the ovine spongiform encephalopathy.85
Most striking in their shared neuropathology were widespread neu-
Careful correlative immunopathological studies of FFI have ronal degeneration (often manifesting large single or multilocular
given important insights into human TSE.63,75 Regardless of illness vacuoles), intense gliosis and absence of inflammation: it is of inter-
duration in FFI, low-levels of PrPres are found diffusely in the est that the currently appreciated diagnostic pathologic features of
sub-cortical gray matter and the brain stem using immunoblot spongiform change in the neuropil and amyloid plaques did not
techniques, whereas it is only uncommonly detectable using constitute the overlap upon which the tentative nosologic connec-
immunohistochemistry (most often in a synaptic pattern or as small tion was based.86 Nevertheless, awareness of this association con-
discrete patches) in the cerebellum and inferior olivary nuclei.51,52,76 tributed to the performance of experiments analogous to those that
However, as outlined above, the histopathological abnormalities (in had already proven scrapie to be transmissible, with successful
the form of severe neuronal loss and gliosis) are stereotypically

Journal of Clinical Neuroscience (2001) 8(5), 387–397 © 2001 Harcourt Publishers Ltd

Less common human transmissible spongiform encephalopathies 393

transmission of kuru to three chimpanzees eventually reported in Cognition tends to be relatively spared, at least until late in the
1966.87 Confirmatory serial passage was soon demonstrated in course of the illness when its accurate assessment is very difficult
chimpanzees and other primates.88,89 due to the incapacitating impairments of motor function, including
speech. Emotional lability and a pseudo-bulbar affect with inap-
Clinical features propriate excesses of laughter or crying may be seen, but the pre-
vailing mood tends to be one of euphoria through the early phases
The onset is typically insidious without any antecedent acute of the illness.80 Ultimately, the patient’s demeanour becomes one
febrile or infectious illness, and among those afflicted the overall of apathetic withdrawal.
clinical picture is extremely uniform, predominantly manifesting
as inexorably progressive pan-cerebellar dysfunction. Therapeutic Once the patient cannot ambulate unassisted because of pro-
trials with a range of antibiotics, vitamins, corticosteroids and gressive cerebellar dysfunction, they are considered to have
chelation agents uniformly failed.90 There are no definite reports entered the second or sedentary phase of the illness. However,
of clinical recovery but occasionally patients were encountered within a matter of weeks or a few months, all voluntary motor
who displayed features suggestive of kuru whose subsequent activity is so impaired that the patient cannot even sit unsupported
improvement within the overall context of their presentation sug- and is then described as having entered the third or terminal phase
gested an hysterical basis;80 however, rarely the illness may during which they are bedridden, totally dependent for feeding
appear to fluctuate during its course.80,83 Fever and seizures are and all personal care, and typically incontinent of urine and feces.
not features and the general physical examination is normal until Decubitus ulcers are a common complication, and by this stage
late in the disease when effects of under-nutrition may become the patient’s bulbar functions have usually deteriorated to the
evident. Routine biochemical and hematological investigations are point where they are anarthric and aglutic, with inanition an
normal, as is the cerebrospinal fluid. Total illness duration is usu- invariable feature. Death quickly ensues as a consequence of static
ally six to nine months, but ranges from four to 24 months, with bronchopneumonia, infected pressure sores or starvation.
homozygosity (particularly for methionine) at the polymorphic
codon 129 of PRNP apparently linked to younger age at onset and Epidemiology
shorter duration of illness.91 There are conflicting reports as to
whether polymorphism at this codon influences the presence of At the time of its original description, kuru was estimated to have a
kuru plaques neuropathologically, but other clinical and pathologi- prevalence of approximately 1% within a geographically circum-
cal features appear unrelated to coding variations at this locus.91–93 scribed area of the Eastern Highlands of New Guinea, situated just
east of Mt Michael, and centred around the Okapa Patrol Post.
Three broad, somewhat overlapping, phases of the illness are Within this region, a population of approximately 17 000 were
recognised but approximately 30% of patients may report non- spread among 11 different cultural and linguistic groups, but the
specific prodromal symptoms in the form of lower limb arthralgias, predominant ethnic identity was the Fore.84 An annual incidence of
headache, malaise or cough.80,94 Subtle ataxia affecting gait and dis- kuru up to 10% was seen in some Fore tribes and accounted for
equilibrium usually herald the first or ambulant phase and may be over 50% of all deaths in certain communities, and 5% of all deaths
initially appreciated by family or friends rather than by the patient. in the total population per year at the peak of the epidemic.79,80
Within a few weeks the patient is noticeably unsteady walking, with Seasonal variation in the occurrence of kuru was not seen.
the gait characterised by a broadened base and lurching appearance, Consequently, kuru was often seen in multiple members of the one
with a heightened propensity to falls. Eventually, resort to a walking family and never in the non-indigenous. Coupled with thorough
stick or aid is required to maintain independent ambulation. negative toxicological investigations, this led to the early a priori
Incoordination of the upper limbs, eye movements and articulation belief that kuru represented a genetically determined disorder.82,90
also appear at this stage, with dysarthria gradually vitiating intelligi-
ble speech. Nystagmus is rarely evident but a convergent strabismus Over three-quarters of the originally described kuru victims were
frequently occurs, usually late in the clinical course. adult women with the initial adult male-to-female ratio around
1 : 25.79,80 Children of either sex constituted the next major sub-
Irregular and coarse ‘tremors’ soon accompany the limb and group but symptoms never commenced prior to 4 years of age; adult
gait ataxia and may give rise to body actions resembling shivering. males only rarely developed kuru. When kuru occurred in commu-
The tremors are usually only observed during voluntary motor nities neighbouring the Fore region, it was usually observed in a
activity and also often take the form of an intention tremor affect- woman who had moved to marry a non-Fore from a community
ing purposeful appendicular movements and/or titubation of the where kuru was endemic. Her illness typically presented many
head and trunk. With the passage of time, such tremulousness may years after marriage and appeared sporadic, developing in an ethnic
become very large in amplitude and appear dramatic and some- group where kuru was uncommon or rare. Although less frequent,
what threatening to those nearby. Uncommonly, clonus secondary the converse was also recognised, with women from low-prevalence
to underlying pyramidal dysfunction may develop95 and may be kuru regions manifesting the malady years after marrying into a
accompanied by hyper-reflexia in some patients; however, plantar Fore tribe with a high incidence of the disorder.80
responses are typically flexor throughout the illness.83,95 Over a
period of one to two months, the tremors also gradually worsen Despite its experimental transmissibility, there is no epidemio-
and contribute to the patient’s loss of fine motor skills for various logical evidence to suggest vertical transmission, with pregnant
daily tasks such as eating. symptomatic women (at various stages of kuru) typically deliver-
ing healthy infants who, to this date, have not gone on to manifest
Additional involuntary movements having the appearance of the illness. Although kuru appears to have no effect on the preg-
chorea or athetosis may be seen,80 although there is not universal nancy, the gravid state may temporarily slow the rate of progres-
agreement on this issue, with some authors ascribing adventitious sion, with a subsequent possible acceleration post-partum.94
motor activity of this type to represent misunderstood features of
cerebellar ataxia.83 Extra-pyramidal features in the form of akine- Around the time transmissibility of kuru was demonstrated,
sia and rigidity are not usually observed. Muscle weakness and additional atypical epidemiological features for a genetically deter-
wasting are not seen until the secondary effects of malnutrition mined disease were apparent. Over the first decade of detailed
supervene, and somatic sensory functions appear maintained investigation, the prevalence of kuru declined significantly, with a
throughout the course of the illness. progressive increase in the youngest age of onset in children, such
that whereas the illness was initially observed in children as young

© 2001 Harcourt Publishers Ltd Journal of Clinical Neuroscience (2001) 8(5), 387–397

394 Collins et al.

as 4 years in 1957, by 1967, symptom onset was never seen under the gray matter.90 It may exceed the prominence of the accompany-
14 years of age.96 Eventually, the confluence of scientific and epi- ing neuronal abnormalities. The gliosis approximates the topo-
demiological data culminated in the theory that kuru had been graphical distribution of the neuronal abnormalities, but can extend
transmitted, and sustained at endemic proportions, by cannibalistic into subcortical white matter, and subpial and periventricular
rituals observed as part of the funeral rites mourning deceased rela- regions. Microglial proliferation is another frequent finding, and
tives.84 Detailed field studies confirmed deaths from kuru over a similar to the astrocytic changes tends to mirror the anatomical
period of a few months, in two or more family members, who had pattern of neuronal degeneration, with a predilection for the cere-
actively participated in the same cannibalistic feast of a kuru rela- bellum and basal ganglia. Perivascular mononuclear cell infiltrates
tive 25–30 years previously.97 Women and children at these cere- are also commonly observed, especially in the brain stem, but vary
monies ate the less desirable (including the highly infectious considerably in both prominence and location within the affected
central nervous system) tissues while adult males partook of the regions of the central nervous system.
(relatively non-infectious) organs, such as skeletal muscle. In addi-
tion to ingestion of infectious tisues, conjunctival, nasal and skin Myelin degeneration and loss is usually conspicuous in the
contamination were other likely modes of transmission.97 Since the anterior and lateral columns of the spinal cord, particularly the
outlawing of cannibalism in the mid-to-late 1950s, there has been spinocerebellar and corticospinal tracts, with the changes in the lat-
a gradual and steady decline in the occurrence of kuru so that only ter usually traceable through the brain stem, cerebral peduncle
two or three cases are now diagnosed annually, accompanied by and internal capsule. In addition, myelin pallor may be evident in
a progressive increase in age at onset, with the youngest in recent the brachium pontis and brachium conjunctivum, as well as the
times being older than 40 years.95 Many observations purport incu- cerebellar white matter and corpus callosum.90,99
bation periods of greater than two, and up to four decades.95,97,98
Although the ultimate cause of kuru remains uncertain, a cannibal- Kuru plaques, 20–60 microns in diameter, staining with periodic
istic serial passage of a sporadic case of indigenous CJD remains acid schiff and having the tinctorial properties of amyloid, are a
the most plausible hypothesis.84 common finding, seen in approximately 50–75% of cases6,90,100.
Their likelihood increases with the duration of clinical illness,6,90
Neuropathology and can be evident in large numbers. Morphologically, the plaques
have a delicate fibrillary radiating halo surrounding a dense core,
Typically, the macroscopic appearance of the brain is normal, while and a neighbouring astroglial and microglial reaction is common.
histopathologically, a characteristic constellation of abnormalities Ultrastructurally, kuru plaques are composed of filaments 7–10 nm
showing relatively uniform topographical emphasis is dispersed in diameter. When present, they are most often seen in the granu-
throughout the central nervous system. The pons, thalamus, cere- lar layer of the cerebellum, but can also be found in other
bellum, cerebral cortex and basal ganglia are the most commonly locations, especially the thalamus, cerebral cortex and basal gan-
affected regions, but considerable inter-case variation in neu- glia. Although typical kuru plaques generally show the dual char-
ropathological emphasis is usual.90 In the earliest accounts, the acteristics of amyloid with routine histological stains such as
salient light microscopic changes were described as: neuronal loss congo red, and strong binding with anti-PrP immuno-ligands,
and degeneration; myelin degeneration; astrocytic gliosis; (Fig. 2) recent reports (incorporating monoclonal antibodies to
microglial proliferation; and perivascular accumulations of PrP in modified immunohistochemical protocols) invariably reveal
mononuclear cells.90 Amyloid (kuru) plaques were an inconstant a far greater burden of positive plaques and deposits.92,93 Hence,
feature. However, subsequent reports have also recognised and as in other human spongiform encephalopathies, there is a far
reported the presence of the nosologically distinctive spongiform greater abundance of immuno-detectable PrP deposits which do
degeneration characteristic of this group of disorders.92,93,99 not show the tinctorial properties of amyloid.

Microvacuolation appears to be an almost invariable and wide- PrP deposition, as revealed by specific antibodies, is most pro-
spread finding in the cerebral cortex.92,93,99,100 Its prominence nounced in regions showing the greatest spongiform and gliotic
varies regionally, tending to parallel the severity of coexistent glio- changes. There are three main morphological patterns of immunore-
sis, and is usually most marked in the deeper layers (3–5) of the activity: synaptic or diffuse fine granular; plaque-like; and perineu-
cortex. Restricted to gray matter, additional common sites of ronal.93 Immuno-detectable plaques vary in size up to 30 or 40
prominent spongiform change in the neuropil include: the striatum; microns and often appear as unicentric, dense compact spherical
mesencephalon; and cerebellum. Less severe spongiform change is forms (corresponding to typical kuru plaques), or as small
often present in the thalamus, pons, medulla, and spinal cord.93 clumps.92,93 However, larger plaques may assume more irregular

Common distinctive cytoarchitectural features of neuronal Fig. 2 Several unicentric plaques immunoreactive with PrP in the cortex of
degeneration in kuru include loss of Nissl substance, and single or Kuru (arrow). 3F4 immunoreaction. (Scale bar:50 µm).
multiple cytoplasmic vacuoles of various sizes.90,101 Neuronal loss
often accompanies these morphological findings (with consider-
able regional variation in severity) although degenerative changes
in the remaining cells usually constitute the predominant neu-
ropathological finding. Within the cerebellum, there is often a ver-
mal predilection to the neuronal degeneration. Despite the late and
often apparently minor extent of cognitive difficulties at a cursory
clinical level, the cerebral cortex frequently reveals widespread
neuronal abnormalities, often accentuated in the deeper layers
and accompanied by distortion of the laminar organisation.
Involvement of the spinal cord is more variable, but neuronal
degeneration can be seen in the anterior, and less commonly, lat-
eral and posterior horns, as well as Clarke’s column.

Astrocytic proliferation is another salient neuropathological fea-
ture of kuru, and is typically intense and widespread, especially in

Journal of Clinical Neuroscience (2001) 8(5), 387–397 © 2001 Harcourt Publishers Ltd

Less common human transmissible spongiform encephalopathies 395

Fig. 3 Schematic illustration of the mature human prion protein with the 8. Hsiao K, Baker H, Crow TJ et al. Linkage of a prion protein missence variant to
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1–22) and the glycosylphosphatidylinositol (GPI) anchor coding region
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