<<

. 4
( 45 .)



>>

demonstration of a pathogemclty-associated point mutation at codon 102 of the
prion protein gene (PRNP) in patients with this phenotype (28), the Identical
mutation was identified m Gerstmann™s original family (29). DNA extracted from
archival material on the first described caseof familial CJD (“Paul Backer,” by
Klrschbaum rn 1924 [3U/) recently has revealed a point mutation at codon 178
of PRNP (32). To date, some 19 different point mutations and extra basepalr
msertlons of the PRNP open reading frame have been associated with cases of
familial CJD. Although specific clmlcal phenotypes are not consistently noted
with individual mutations, some general observations can be made.
3.1. Gerstmann-Strtiussler Syndrome
Although the clinical and pathological syndrome (described earlier) 1sclas-
sically associated with the codon 102 Pro-Leu change, mdlvlduals carrymg
this mutation even within the same pedigree will manifest highly variable phe-
notypes. For example, m the German “Sch”pedigree the clinical illness broadly
was that of GSS, but individual casesexhibited features as diverse as anxiety
and poor concentration, trtubation, and myoclonus (32). The evaluation of the
impact of other sites within the genome on this phenotyplc varlabllrty 1s m
progress, but m a recent attempt the common polymorphism at codon 129 was
not found to be mfluential(33).
Confusingly, point mutations at codons 117, 198, and 2 17 are also associ-
ated with the pathological features of GSS. In the case of the latter two, the
characteristic multicentric plaques are accompanied by neurofibrillary tangles
(“the Indiana variant”), but probably are indistinct from GSS clmlcally (34).
The codon 117 mutation has also been described m association with a so-called
“telencephallc” form of CJD, m which dementia 1saccompamed by pyramldal
and extrapyramidal features, and variable cerebellar signs (35).
3.2. Familial CJD Resembling Sporadic Disease
The point mutations at codons 200, 2 10, and 178 are associated with CJD
that resembles sporadic CJD clinically. The last, however, is not associated
22 de Silva

with characterrsttc EEG appearances. Even m the case of the first (the explana-
tion for the high inctdence of CJD among Libyan-born Jews) perusal of the
chmcal features of a large pedigree revealed considerable phenotypic hetero-
geneity, including rarmes (for CJD) such as demyelinating polyneuropathy (36)
3.3. Fatal Familial Insomnia
The Asp-Asn change at codon 178 of the PRNP open reading frame has also
been linked with an unusual neurodegenerattve process (3 7), first descrrbed m
1986 (38). A 53-yr-old man first presented with progressive msomma and
dysautonomia. A prevtously sound sleeper, he could sleep only for 2-3 h at
night He became Impotent and had loss of libido. There was eptsodtc sahva-
tron, lacrimatton, and rhinorrhoea, and he exhibited orthostatrc diaphoresrs,
pyrexla, dtfficultres with mlcturttion, and consttpatron Two months later, he
could only sleep for 1 h, and he was frequently dtsturbed by vivid dreams. He
developed progressrve dysarthrta, mtentron tremor of his limbs, and gait ataxla.
Examination at this stage revealed mtosts, cerebellar signs, and brisk tendon
reflexes He was noted to lapse mto a stuporose state tf left alone, m which he
performed complex and apparently purposeful gesturing and breathed notslly.
He could be awakened quickly by light strmuh. As his condmon progressed,
there were oculomotor disturbances (limitation of upward gaze and saccadtc
movements), myoclonus, and irregular breathing patterns Termmally he
became confused and disoriented, had episodes of motor agttatron, and exhibited
severe truncal dystomas. The total duration of his Illness was 9 mo. HIS EEG was
never characteristic of CJD, but revealed diffuse slow waves and later became
isoelectric. His dreamlike states comctded with EEG desynchronizatlon, but
phystological EEG patterns of sleep were absent. A pharmacologtcal response
to a short-acting benzodiazepine antagonist could be demonstrated both clini-
cally and electrophystologically There were at least four other affected mem-
bers in his pedigree, mcludmg two affected sisters. Study of the famtly m greater
detail revealed that insomnia, dysautonomza, dysarthria, ataxia, myoclonus,
andpyramidal szgns mvarlably werepresent m affected members. Memory and
attention deficits were mimmal m the early stages, but tended to progress with
time. During “sleep” there was loss of slow-wave and rapid-eye-movement
phases, The mean age of onset was 49 yr, and the mean duration was 13 mo.
3.4. CJD Associated with Extra Repeat Insertions
Extra mserttons of a variety of sizes have been described m the octapeptrde
repeat region of the PRNP open reading frame. The phenotyprc descrrptrons of
these cases resemble CJD, with two notable exceptions. First, m a large pedl-
gree reported from the South East of England with a 144-basepair msertion,
there was striking dtverslty m the clinical phenotypes of affected cases (39)
23
Human Spongiform Encephalopathy

Diagnoses, such as General Paralysis of the Insane, “spinal sclerosis,” “cere-
bral softening,” cerebral thrombosis, dementia praecox, Parkmsonrsm,
Huntington disease, Pick disease, and Alzhelmer disease, had been attached to
affected members of the pedigree through the ages. This was accompanied by
considerable variation m the neuropathologlcal features of cases With respect
to the molecular biology, an important pomt of note was the stablhty of the
expanded sequence over five successive generations. This contrasts with
expansions of trinucleotlde repeat sequences m successive generatlons, which
are associated with the phenomenon of antlclpatlon m associated neuro-
degenerative disorders, such as Huntington disease (40). Antlcipatlon 1snot a
feature of inherited CJD. The age at death in this pedigree was affected by the
common polymorphism at codon 129. The mutation was always carried on an
allele encoding methlonine at this site; caseshomozygous for methlonme had a
significantly younger age at death than heterozygous cases (42).
Second, in then- report on a case of dementia associated with a 2 16-basepatr
insertion, Duchen et al. argued that the presence of neurltlc plaques staining
positively for P-amylold protein and ˜c protein indicated that this case repre-
sented a transition (neuropathologlcally, at least) between CJD and Alzhelmer
disease (42). From the clmical perspective, however, this patient™s illness was
entirely compatible with familial CJD.
3.5. Some Unusual Mutations, and Conclusions on Familial CJD
Two recent mutations described m cases of famlhal CJD from Japan are
associatedwith a Pro-Leu change at codon 105, and an amber mutation at codon
145 Almost uniquely for casesof CJD (sporadic or famlhal), patients carrying
the former mutation presented with spastic paraparesis (43). Dementia eventu-
ally supervened, but there were no cerebellar features or myoclonic Jerks The
latter mutation was associated (in a single patient) with a slowly progressive
dementia of >lO yr duration (44)
Familial CJD encompasses a wide variety of clmlcal syndromes, some of
which have highly unusual features, such as dysautonomia and spastic
paraparesis. There is considerable overlap of clinical features associated with
individual PRNP mutations, and the variability of clinical features wdhin pedi-
grees cannot be accounted for consistently by the common polymorphism at
codon 129. Famlhal CJD may be associated with longer disease durations than
sporadic cases.This would account for the higher prevalence of famlhal cases
among series of CJD patients with long disease durations.
4. latrogenic CJD
Although rare, forms of iatrogenic CJD are of considerable clinical and pub-
lic health importance. In particular, the disease phenotype appears to be mflu-
de Silva
24

enced by the route by which the agent of mfecttvity gains entry mto the host.
Cases where “peripheral” (outside the CNS) moculatton has taken place
(recipients of contaminated human pmutary-derived hormones) are character-
ized by a progressive cerebellar ataxia, wtth little or no cogmttve impairment
and the absence of charactertsttc EEG findings (4.5). The disease phenotype m
these mdividuals IS remarkably homogeneous, and mevttable compartsons with
the clmical course of kuru have been made. In addition to exhibiting relent-
lessly progressive truncal and limb ataxia, patients demonstrate a characteris-
tic change m then personalmes, appearing apathetic and unconcerned about
then predtcament. As then disease progresses, more CJD-like features emerge.
hmb rigtdity, myoclonus, startle responses, and akmetic mutism are all apparent
The clinical course of patients who have had the CJD agent inoculated cen-
trally have had disease phenotypes consistent with sporadic CJD However, rn a
recent report, four “Lyodura” recipients who had grafts placed in their posterior
fossae were descrtbed (46). They had presented with cerebellar syndromes (all
four were ataxic at presentation, and three were dysarthnc), possibly owing to
the proximity of the cerebellum to the site of graft placement, but m our opinion the
disease phenotypes were distinct from those with peripherally inoculated iatrogemc
CJD. One patient had characteristic periodic sharp wave complexes on the EEG

5. Diagnostic Tests
5. I. Electroencephalography
In the large epidemiological studies referred to prevtously, the EEG was found
to be the most useful dtagnosttc test for CJD. However, because the inclusion
crtterta for these studies included characteristic EEG appearances, there has been
a tendency for over-ascertainment of this feature. Also, gtven the subJective
nature of EEG interpretation, there may have been some variatton m the types of
abnormalities included in the drfferent series. Will and Matthews found character-
istic EEG abnormahttes m 84% of “subacute” cases (I 7). In their “mtermedtate”
group (with a longer disease duration) the EEG was typical in only two out of nine
cases Brown et al report “pertodic” EEG appearances m 60-80% and “triphasic
I cycle/second” m 48-56% (I 3,14). In our experience, an EEG showing periodic
sharp wave complexes m the approprtate clinical setting is vzrtually diugnostlc of
CJD. Anecdotal reports of false positive diagnoses have usually arisen from the
mcorrect assessment of EEGs, and the maccurate descrtption of nonspecific EEG
findmgs as “characteristic” of CJD. However, a proportion of CJD patients
never mamfest typical EEG appearances, reducing the sensitivity of this test.
5.2. Liver “Function” Tests
In the large eptdemtological series, routme biochemistry and hematology
usually were normal, with the exceptton of liver functton tests (32 out of 80 cases
25
Human Spongiform Encephalopathy
in Will and Matthews™ study). These amounted to mild elevations of hepatlc
enzymes, and overt liver failure was not observed. Although serial measure-
ments rarely have been reported, the lmpresslon gained IS that the elevations
are transient (4 7,48).
5.3. Neuroimaging
Computerized tomography m CJD 1susually normal but sometimes atrophy
is found, especially m caseswith protracted Illnesses Radiology reports may
overemphasize any degree of cortical atrophy in view of the clinical history of
dementia. MRI abnormalltles have been reported m CJD. The extensive white
matter degeneration reported by Uchmo et al may be specific for the Japanese
panencephalopathic variant of CJD (49). In reports from Western countries,
high T2-signal lesions m the basal ganglia have been described (50,5 I) In our
experience these abnormalities are not universal; nor are they necessarily asso-
ciated with basal ganglia dysfunction. Magnetic resonance spectroscopy (for
N-acetylaspartate) has been disappointing as an early diagnostic tool (52).
5.4. Cerebrospinal Fluid
Exammatlon of the cerebrospmal fluid (CSF) m patients with CJD IS some-
times abnormal. Extrapolatmg from Will and Matthews™ data, the CSF protein
was >0.4 g/L m 45% of cases where it was examined. The protein content
rarely exceeds 1.0 g/L, and a leukocyte response is absent. A pair of novel
proteins m the CSF, Identified by two-dlmenslonal electrophoresls, has been
described m CJD (53,54), but may not be specific for this condition (see note
added m proof)
6. Data from the UK National Surveillance Unit
Surveillance of CJD has been ongoing in the UK since 1990, and affords an
opportunity for the systematic collection of clmrcal data on patients with this
disorder. Cases designated “defimte” and “probable” using criteria modified
from Masters et al. are Included m the survey (55). During the first 4 yr of the
study, 144 sporadic and 14 famlhal cases of CJD were Identified. The ages of
onset and disease durations of these patients are tabulated m Table 2. As can be
seen, patients with familial disease tend to present approx 10 yr earlier than
sporadic cases,and have a disease duration approximately twice as long.
The frequency of chmcal features during the course of illness m sporadic cases
was entirely consistent with the previous surveys. The detailed chmcal questlon-
naire, however, enabled a closer scrutiny of patients™ presenting features. It
emerges that at presentation, approx 40% of patients with CJD have some aspect
of cognitive dysfunction m isolation, 30% present with cerebellar ataxla alone,
10% have a combmatlon of cognitive and cerebellar dysfunction, and IO%
26 de Silva
Table 2
Ages at Onset and Disease Durations of Sporadic and Familial CJD Cases
Age at onset, yr Disease duration, mo
Mean Mmlmum Maximum Median Mean Mmlmum Maxlmum Median
Sporadic 65a 86 65 7b 62 4
(n = 143114443) (n = 139114:)
Famliral 52a 67 55 196 112 8
(n = 14,14:5 (n = 1244) *
“z-4 1270, p < 0 000 1, corrected for ties
˜z-2 2424, p < 0 0249, corrected for ties


have corttcal blindness (Herdenham syndrome). These presentations account
for 90% of cases, and alternative presenting features, such as expresstve
dysphasra, motor dyspraxia, and pyramidal signs, are all much less common
Patients with the Brownell-Oppenheimer vartant of CJD (with progressive cer-
ebellar ataxia and no cognitive impairment until late m the illness) were
unusual, accountmg for no more than 4% of sporadic cases.
6.1. Differential Diagnosis
Cases of suspect CJD referred to the survetllance unit but whose neuro-
pathological exammatton revealed an alternative neurodegenerative process
are listed m Table 3. It can be seen that the maJority of these (58%) had
Alzhetmer disease. These patients had a mean disease duration of 31 mo
(median 16; range l-l 5 1), which was significantly longer than that m sporadic
cases(Mann-Whitney U-test, z [corrected for ties] -4.8675, p < 0 0001).
Comparison of clinical features during the course of illness between CJD
and non-CJD cases enabled the estimation of then relative sensitivities and
specrficities. These are tabulated in Table 4. Most of the clinical criterta on
which the diagnosis of CJD 1straditionally based emerge with high sensittvt-
ties, with the exceptions of Parkinsomsm and (parttcularly) neurogemc muscle
wasting. Disortentation is found by this analysis to have a poor specrfictty, but
this IS owmg to the inclusion of a large number of patients with dementia In the
non-CJD group
7. Conclusions
In this chapter, the clmtcal characteristics of the human transmissible
spongrform encephalopathtes have been revtewed. These disorders are sum-
marized in Table 5. The dragnosts essentially 1sbased on a high index of clim-
cal susptcion backed up by neuropathological confirmation, usually at
postmortem. Brown™s NIH study gives systematic data on brain biopsy: The
Human Spongiform Encephalopathy 27

Table 3
Cases with (Pathologically Confirmed) Non-CJD
Dtagnosis Frequency
Alzheimer-type dementia (ATD) 17
ATD + multt-infarct dtsease (MID) 5
MID 3
Diffuse Lewy body disease (DLBD) 1
ATD + DLBD 1
Motor neuron disease 2
Cerebrovascular disease 1
Cerebellar degeneration 1
Pick drsease 1
Progressive supranuclear palsy 1
Multiple system atrophy 1
Corttcobasal degeneration 1
Viral encephalomyelitts 1
Metastattc carcinoma 1
Hypoxia 1
Epilepsy 1
No abnormality found 1

Table 4
Sensitivities and Specificities of Clinical Features in CJD
Sign Sensitivity Specificrty
Cognitive impairment
Personality change 0.5223 0.6389
Behavtor change 0.6242 0 5000
Memory loss 0 6369 0.4117
Disorientation 0.7898 0 2500
Myoclonus 0.8535 0.4444
Cortical blindness 0.5096 0 8333
Pyramidal signs 0.5924 0.4444
Parkmsomsm 0.3312 0.6944

<<

. 4
( 45 .)



>>