D178N, 129Val and N171S, 129Val genotype in a family with Creutzfeldt-Jakob disease.

Abstract

Fatal familial insomnia (FFI) and genetic Creutzfeldt-Jakob disease (CJD(D178N,)(129V)) are two phenotypes that share a common point mutation at codon 178 of the prion protein gene (PRNP), but differ in their polymorphism at codon 129 of the mutant allele. A mutation at codon 171 of the PRNP gene has been described in a family with a strong psychiatric history without prion disease.
Clinical and genetic information of a family with CJD was obtained from medical records and family informants.
We identified an African-American family with molecular and genetically confirmed CJD(D178N,)(129V) that also carried the N171S, 129V polymorphism and had a strong psychiatric clinical presentation.
This is a complex family that carries the D178N, 129V and N171S, 129V genotype. This report is the first description of both genotypes occurring within a family with genetic human prion disease.

Full text

Page 1

Fax +41 61 306 12 34
E-Mail karger@karger.ch
www.karger.com
Original Research Article
Dement Geriatr Cogn Disord 2010;30:424–431
DOI: 10.1159/000321472
D178N, 129Val and N171S, 129Val
Genotype in a Family with
Creutzfeldt-Jakob Disease
Brian S. Appleby   a Kristin K. Appleby   b, c Ryan C.W. Hall   d Mitchell T. Wallin
  b, c
a   Division of Geriatric Psychiatry and Neuropsychiatry, Johns Hopkins University School of Medicine,
Baltimore, Md. , b   Department of Neurology, Georgetown University Hospital, and c   Department of Neurology,
Veterans Affairs Medical Center, Washington, D.C. , and d   Department of Medical Education for Psychiatry,
University of Southern Florida Medical School, Orlando, Fla. , USA
Introduction
Prion diseases, also known as transmissible spongi-
form encephalopathies, are caused by an abnormal iso-
form of the prion protein (PrP res ) [1] , which characteris-
tically causes rapid progressive neurodegeneration re-
sulting in death. Although 85% of prion diseases are
sporadic, 10–15% of cases are caused by pathological mu-
tations of the normal prion protein gene (PRNP) located
on chromosome 20, which commonly manifest them-
selves in genetic transmission of the disease. The genetic
forms of prion disease include fatal familial insomnia
(FFI), Gerstmann-Sträussler-Scheinker disease and ge-
netic Creutzfeldt-Jakob disease (gCJD) [2] . Over 30 path-
ological mutations of the PRNP gene have been identified
that include point, insertion, deletion and nonsense mu-
tations [3] .
The D178N mutation is caused by a GAC-to-AAC
point mutation at codon 178 of the PRNP gene resulting
in the substitution of asparagine for aspartic acid. This
point mutation is shared by FFI and CJD D178N,
the two phenotypes differ in their polymorphism at co-
don 129 of the mutant allele. FFI contains the amino acid
methionine (Met) at codon 129 of the mutant allele as op-
posed to gCJD, which contains valine (Val) at codon 129.
 129V [4] , but
Key Words
Prion disease ? Creutzfeldt-Jakob disease ? PRNP gene ?
D178N, 129V ? N171S, 129V ? Fatal familial insomnia ? Genetics
Abstract
Background: Fatal familial insomnia (FFI) and genetic
Creutzfeldt-Jakob disease (CJD D178N,
types that share a common point mutation at codon 178 of
the prion protein gene (PRNP) , but differ in their polymor-
phism at codon 129 of the mutant allele. A mutation at codon
171 of the PRNP gene has been described in a family with a
strong psychiatric history without prion disease. Methods:
Clinical and genetic information of a family with CJD was ob-
tained from medical records and family informants. Results:
We identified an African-American family with molecular
and genetically confirmed CJD D178N,
N171S, 129V polymorphism and had a strong psychiatric clin-
ical presentation. Conclusion: This is a complex family that
carries the D178N, 129V and N171S, 129V genotype. This re-
port is the first description of both genotypes occurring
within a family with genetic human prion disease.
 129V ) are two pheno-
 129V that also carried the
Copyright © 2010 S. Karger AG, Basel
Accepted: September 25, 2010
Published online: November 12, 2010
Brian S. Appleby, MD
Johns Hopkins Hospital, Meyer 279
600 North Wolfe Street
Baltimore, MD 21287 (USA)
Tel. +1 410 955 3902, Fax +1 410 614 1094, E-Mail bappleb1   @   jhmi.edu
© 2010 S. Karger AG, Basel
1420–8008/10/0305–0424$26.00/0
Accessible online at:
www.karger.com/dem

Page 2

D178N, 129Val and N171S, 129Val in
Creutzfeldt-Jakob Disease
Dement Geriatr Cogn Disord 2010;30:424–431
425
Distinct phenotypes have been described for each haplo-
type, which are differentiated by variations in clinical
symptoms, age at onset of illness, survival time, electro-
encephalogram (EEG) findings, neuropathological fea-
tures and PrP res type [5] .
In 1997, Samaia et al. [6] reported a family with a
strong psychiatric history and a genetic variant at codon
171 of the PRNP gene that was associated with Val at co-
don 129 (N171S, 129V). The affected pedigree demon-
strated incomplete penetrance with varied expressions of
the illness, including depression, suicidality and psycho-
sis. In this report, we present a family affected by genetic
prion disease that carried the D178N, 129V and N171S,
129V genotype that had a strong psychiatric clinical pre-
sentation.
Methods
The patient’s clinical information was obtained from the
Washington, D.C., Veterans Administration Medical Center fol-
lowing institutional review board approval and receiving permis-
sion from the family. All medical records, EEG tracings and neu-
roimaging results were obtained for the clinical evaluation and
were available for our review. Further family history, spanning 3
generations, was obtained from several family members. Geno-
typing was performed at the Center for Human Genetics of the
University Hospitals of Cleveland, and analyses of pathological
specimens were performed at the National Prion Disease Pathol-
ogy Surveillance Center after obtaining informed consent and us-
ing a standardized protocol. PRNP genotyping was done using
polymerase chain reaction amplification followed by sequence
analysis of a DNA sample from the individuals as per protocol of
the Center for Human Genetics of the University Hospitals of
Cleveland. Western blots were performed by the National Prion
Disease Pathology Surveillance Center in the following fashion.
Frozen tissue was taken from the frontal and occipital cortices,
hippocampus and cerebellum when available. The tissue was ho-
mogenized in a lysis buffer, and 2 aliquots were taken. One aliquot
was digested with proteinase K at 37   °   C for 1 h and the other did
not undergo proteinase K digestion. Both samples were boiled for
10 min after the addition of equal amounts of Laemmli sample
buffer with mercaptoethanol. The samples were run on a 15%
Tris-HCl gel and transferred to a polyvinylidene fluoride mem-
brane that was probed with the primary antibody 3F4, then the
secondary antibody sheep versus mouse IgG, and developed with
an ECL Plus detection system.
Results
The proband was a 52-year-old African-American
Vietnam War veteran who initially presented to a local
Veterans Administration Medical Center with symptoms
of depression and anxiety that were similar to his initial
symptoms of posttraumatic stress disorder (PTSD) 20
years ago. This constellation of symptoms prompted him
to file a PTSD military service connection claim. After
his initial diagnosis of PTSD, he attended group therapy
sessions for 18 months and had not required subsequent
treatment. At the time he filed his PTSD disability claim,
he was suffering from depression, frequent nightmares
and daily intrusive thoughts pertaining to his combat ex-
periences. These symptoms caused repeated awakenings
throughout the night and were associated with symptoms
of hyperarousal, hypervigilance, poor concentration, dis-
tractibility, irritability and profuse sweating that required
him to change his clothes and bedding several times per
night. In the subsequent 18 months, he developed com-
pulsions that manifested in frequent checking of the
doors and windows, suspiciousness, a propensity towards
anger, aloofness and frequent crying spells. He attended
group therapy during this period, but he was not pre-
scribed any medications. Within 2 years, he retired from
his job because of considerable emotional and psycho-
logical distress brought about by the illness, but would
later take a part-time job in the hope that it would provide
some distraction from these symptoms.
In the 36th month of his illness, sertraline and psycho-
therapy were prescribed for the treatment of PTSD and
depression because of the persistent worsening of his ill-
ness that now included anhedonia, argumentativeness,
an episode of belligerence that involved threats of vio-
lence and intermittent contemplation of suicide. By the
40th month of his illness, he had resigned from his part-
time job, was smoking and drinking excessively, and was
prescribed bupropion for depression and nicotine depen-
dence in addition to risperidone for worsening insomnia.
In the 40th month of illness, he was noted to have a
new mild intention tremor of his right hand and impaired
proprioception of his lower extremities. His insomnia
had progressed to an average of 4 h of sleep a night with
daily nightmares, anxiety with new-onset panic attacks
and tremors, all of which were resistant to treatment with
clonazepam. He was diagnosed with REM sleep behavior
disorder when he was noted to have repeated episodes of
arm flailing and punching. During this time, a computed
tomography scan of the brain was reported as normal.
During the 40th–42nd months of illness, he developed
agraphia, anomia and dysmetria of his upper and lower
extremities. These symptoms were followed by a 2-week
period of rapid neuropsychiatric decline that culminated
in mutism, impairment of smooth eye pursuits, spastic
paralysis, asymmetric choreiform movements, myoclo-
nus, frequent falls and urinary incontinence. Over this

Page 3

Appleby   /Appleby   /Hall   /Wallin  

Dement Geriatr Cogn Disord 2010;30:424–431
426
2-week period, his Mini Mental State Examination score
declined from 27/30 to 1/30, the scoring of which was
complicated by his ability to only speak 1-word answers.
Additionally, he had lost approximately 30 lb (13.6 kg)
over the previous 2 months. An EEG performed during
the 44th month of illness displayed diffuse symmetrical
slowing of the background rhythm ( fig. 1 ). Magnetic res-
onance imaging (MRI) of his brain using a General Elec-
tric 1.5-tesla MRI at this time showed hyperintensity of
the left superior frontal cortex, initially interpreted as a
stroke until the following study that included diffusion-
weighted imaging sequences showed hyperintensity in
the basal ganglia and a gyriform pattern in the axial plane
as shown in figure 2 . A lumbar puncture was declined by
the family. The combination of his clinical symptoms
(dementia, cerebellar, visual and pyramidal symptoms)
and brain MRI findings (high signal abnormalities in the
caudate, putamen and more than 2 cortical regions on
diffusion-weighted imaging) were consistent with the
updated criteria for probable sporadic CJD [7] . Although
no diagnostic criteria for the use of brain MRI in gCJD
has been established, MRI findings similar to those ob-
served in sporadic CJD cases occur in approximately 1/3
of all genetic prion diseases [8] . Unfortunately, a lumbar
puncture and polysomnography were not performed.
Following discharge from the hospital, he developed
new-onset tachycardia and hypertension (blood pressure
151/101), and died 8 months later, thus ending a 52-month-
Fig. 1. EEG tracings of the proband at 40 months of illness duration. Generalized slowing of the background
rhythm is observed without evidence of periodic sharp wave complexes.
Color version available online

Page 4

D178N, 129Val and N171S, 129Val in
Creutzfeldt-Jakob Disease
Dement Geriatr Cogn Disord 2010;30:424–431
427
long illness. The patient and his family declined a post-
mortem examination.
Discussions with the proband’s sister revealed a strong
family history of gCJD, which is depicted in the pedigree
in figure 3 . Affected family members displayed similar
symptoms at disease onset ( table 1 ). Neuropathological
and molecular data had been obtained from 2 family
members (cases No. 3 and 4). Case 3 had Met at codon 129
of the nonmutant allele and displayed global underrepre-
sentation of the unglycosylated form of the type 1 prion
protein on immunohistochemistry ( fig. 4 ) and a different
pattern of spongiform changes ( fig. 5 ) compared to case
No. 4, which contained Val at codon 129 of the normal
allele. The proband consented to PRNP genotyping,
which confirmed the presence of the D178N, 129V and
N171S, 129V genotype with Met at codon 129 of the non-
mutant allele.
Discussion
Twelve separate families with CJD D178N,
previously identified [3] . Despite the ethnic heterogeneity
described in genetic prion diseases, this is the first re-
ported African-American family with CJD D178N, 129V . The
first-generation female of this family identified in fig-
ure 3 is thought to have been of mixed black and white
ancestry, raising the possibility that this family may be
related to one of the previously described families. Al-
though the family history is incomplete, it is possible that
the phenomenon of genetic anticipation, determined by
the mean age at disease onset, is observed through sub-
sequent generations (3rd generation – 60 years old, 4th
generation – 58 years old, 5th generation – 49 years old),
which has been observed in several other families with
genetically transmitted prion diseases [4, 9, 10] . A higher
proportion of males are affected in this family (n = 6, ra-
tio 2.0), which is similar to other reports [11] .
The constellation of symptoms experienced by the
proband somewhat overlaps with symptoms commonly
seen in patients with FFI as first described by Lugaresi et
al. [12] . The proband’s initial symptoms of progressive
and persistent insomnia, parasomnia as evidenced by
nightmares and nocturnal agitation, dysautonomia in the
form of hypervigilance, diaphoresis and paranoia that
progressed to hypertension and tachycardia in later stag-
es are symptoms that are frequently seen in FFI [13, 14] .
The strong predominance and progression of insomnia
for an extended duration, which preceded the onset of
neurological symptoms by over 3 years, have not previ-
ously been reported in CJD D178N,
proband displayed symptoms more consistent with the
FFI phenotype, a disease that may be mimicked by symp-
toms of PTSD [3] . The late appearance of cognitive im-
pairment in the proband is consistent with the FFI phe-
notype, in which dementia is uncommon, in contrast to
its occurrence as a principal component of gCJD [13] . The
proband also manifested limb and gait ataxia which are
 129V have been
 129V , and suggest that the
Fig. 2. MRI of the brain of the proband at 40 months of illness
duration. Diffusion-weighted imaging sequences demonstrate
hyperintensity in the basal ganglia and in a gyriform pattern of
bilateral frontal and temporal lobes and left parietal and occipital
lobes.
Table 1. Presenting symptoms and genotype of several affected family members
Case GenotypeNonmutant allele Presenting symptoms
1
2
3
4
D178N, 129Val + N171S, 129Val
D178N, 129Val + N171S, 129Val
D178N, 129Val + N171S, 129Val
D178N, 129Val + N171S, 129Val
codon 129Met
codon 129Met
codon 129Met
codon 129Val
depression and anxiety
depression and anxiety
depression
depression and visuospatial disorientation

Page 5

Appleby   /Appleby   /Hall   /Wallin  

Dement Geriatr Cogn Disord 2010;30:424–431
428
Possibly mixed race
Breast
cancer
CAD Ages
65–80
years
3
days
old
Female
Deceased
* = positive brain biopsy
# = positive serum genotyping for D178N, 129Val and N171S, 129Val of the PRNP gene
Information regarding the first and second generations is incomplete and has therefore been left blank.
Male
Proband
Unknown gender
Black shading = definite/probable CJD
Gray shading = death from other cause
White = death from unknown cause
18
months
old
43
stroke
52#
321
4
×6
×6
×5
*
×9
58#57#
45#
65
60
Fig. 3. Genealogy of an African-American
family with D178N, 129Val and N171S,
129Val genotype. CAD = Coronary artery
disease.
Case 3 Case 4
PK
Gel loading
+
C-T1
+
C-T2
+
F
+
O
+
C
+
C-T1
+
C-T2
+
F
6.518 6.51888
Fig. 4. Western blots of cases 3 and 4 show-
ing PrP res type 1 with relative underpre-
sentation of the unglycosylated form (ar-
row). These findings are typical of the
D178N, 129V haplotype carried by these
cases. PK = Proteinase K; C-T1 and C-T2 =
PrP res types 1 and 2 control samples; F =
frontal cortex; O = occipital cortex; C =
cerebellum.

Page 6

D178N, 129Val and N171S, 129Val in
Creutzfeldt-Jakob Disease
Dement Geriatr Cogn Disord 2010;30:424–431
429
signs often seen in the later stages of FFI [15] . Neverthe-
less, the proband’s prolonged illness duration over 4 years
and D178N, 129V PRNP mutation are characteristic of
gCJD. Despite progressive and persistent insomnia, the
proband did not display fatigue or drowsiness that is
characteristic of the inability to achieve slow-wave sleep
that is typically seen in FFI [16] . With respect to the pro-
band’s relatives, a considerable amount of PrP res was not-
ed in the cerebral cortex of cases 3 and 4, an atypical find-
ing in FFI, which usually displays less PrP res that can be
particularly difficult to detect in the cerebral cortex [17] .
However, the codon 129 genotype of the normal allele can
affect phenotype severity amongst family members with
the same mutation [17] . In this family, case No. 3 con-
tained Met at codon 129 of the normal allele as opposed
to case No. 4, which contained Val at codon 129 of the
normal allele. As demonstrated elsewhere, clinical phe-
notype does not always directly correlate with genotype
as demonstrated by gCJD cases caused by several muta-
tions presenting with insomnia [18, 19] and the lack of
insomnia in neuropathologically confirmed cases of FFI
[20–22] .
The question arises whether this case represents an
atypical phenotype of CJD D178N,
gence of PTSD that was complicated by genetic prion dis-
ease and/or the concomitant N171S, 129V polymorphism
that is associated with neuropsychiatric illness. We favor
the view that either mutation could have been the cause
or precipitant of his psychiatric symptoms for a variety of
reasons, particularly because his symptoms were atypical
of PTSD. Additionally, the proband developed symptoms
of PTSD that had remained quiescent for two decades
without the need for treatment.
Although psychiatric symptoms are commonly ob-
served in the early stages of sporadic and variant CJD,
they are less common in gCJD [23] . In a study of genetic
prion diseases by Kovács et al. [11] , 30% of all cases dis-
played psychiatric symptoms during the course of the
disease, including 51% of FFI and 26% of gCJD cases, but
only 3% of all cases with genetic prion disease presented
 129V or a late-life re-emer-
50 μm
100 μm
100 μm
100 μm
a
b
c
d
Fig. 5. Immunohistochemistry (3F4 antibodies) of cases 3 and 4. Case 3: codon 129Met, nonmutant allele; case
4: codon 129Val, nonmutant allele. ! 40. a Case 3, frontal cortex. b Case 3, hippocampus. c Case 4, frontal cor-
tex. d Case 4, hippocampus.
Color version available online

Page 7

Appleby   /Appleby   /Hall   /Wallin  

Dement Geriatr Cogn Disord 2010;30:424–431
430
with psychiatric symptoms. Psychiatric presentations of
CJD D178N,
involve behavioral and/or cognitive symptoms as op-
posed to mood disturbances that are described in this
report [3, 24] .
The limitations of this study include an incomplete
history of symptoms, lack of polysomnography and CSF
analyses in the proband and neuropathological diagnoses
in all family members. We acknowledge that it is possible
that his initial assessment by a psychiatrist ensured a lev-
el of detail in the description of neuropsychiatric symp-
toms that may not have been matched in other published
cases of CJD D178N,
scribed by neurologists and neuropathologists. Addition-
ally, PTSD is a common diagnosis made in the Veterans
Administration Medical Center, making ascertainment
of such symptoms more likely in this setting. Finally, we
concede that while the D178N, 129V haplotype was iden-
tified in the proband and the prion protein type remains
unknown, two family members demonstrated the type 1
prion protein that is characteristic of gCJD as opposed to
type 2 PrP res that is seen in FFI [25] . Further research
should also examine differences between gCJD patients
with the N171S versus N171N genotype.
In summary, we have provided a report of the follow-
ing: (1) a family with a D178N, 129V and N171S, 129V
genotype, (2) an African-American family with the
D178N, 129V mutation, (3) a case of CJD D178N,
 129V have been reported though they typically
 129V , which have typically been de-
 129V that
overlaps with the FFI phenotype, and (4) prion disease
mimicking the late-life recurrence of combat-related
PTSD. Atypical presentations of genetic forms of prion
diseases are important in that they can signal the possi-
bility that other phenotype-modifying factors exist. This
could include prion protein types, PRNP polymorphisms,
other PRNP mutations, non- PRNP mutations, environ-
mental factors, and coexisting medical and/or neuropsy-
chiatric conditions. Atypical cases such as the one that we
report can facilitate the investigation of factors that influ-
ence clinical phenotypes of prion diseases, thereby pro-
viding opportunities to develop methods for earlier and
more accurate diagnoses and understanding of the natu-
ral history of these diseases. Furthermore, this report
adds to the evidence that prion diseases may display an
identifiable prodrome that can be clinically detected [26,
27] . This may present opportunities for prophylactic
therapies for individuals at risk for developing genetic
prion disease [28, 29] .
Acknowledgements
The authors would like to thank the National Prion Disease
Pathology Surveillance Center and Dr. Pierluigi Gambetti for
providing us with the neuropathological and genetic data. This
work was supported in part by the Stempler Fund for Dementia
Research and the Richmond Family Fund for Alzheimer’s and
Related Diseases.

References
1 Prusiner SB: Novel proteinaceous infectious
particles cause scrapie. Science 1982;
136–144.
2 Brown P: The phenotypic expression of dif-
ferent mutations in transmissible human
spongiform encephalopathy. Rev Neurol
(Paris) 1992;
3 Kong Q: Inherited prion diseases; in Prusin-
er S (ed): Prion Biology and Disease. Cold
Spring Harbor, Cold Spring Harbor Labora-
tory Press, 2004, pp 673–775.
4 Goldfarb LG, Brown P, Haltia M, Cathala F,
McCombie WR, Kovanen J, Cervenáková L,
Goldin L, Nieto A, Godec MS: Creutzfeldt-
Jakob disease cosegregates with the codon
178Asn PRNP mutation in families of Euro-
pean origin. Ann Neurol 1992;
5 Gambetti P, Parchi P, Petersen RB, Chen SG,
Lugaresi E: Fatal familial insomnia and fa-
milial Creutzfeldt-Jakob disease: clinical,
pathological and molecular features. Brain
Pathol 1995;
216:

148:
317–327.
31:
274–281.
5:
43–51.
6 Samaia HB, de Jesus Mari J, Vallada HP,
Moura RP, Simpson AJG, Brentania RR: A
prion-linked psychiatric disorder. Nature
1997;
7 Zerr I, Kallenberg K, Summers DM, Romero
C, Taratuto A, Heinemann U, Breithaupt M,
Varges D, Meissner B, Ladogana A, Schuur
M, Haik S, Collins SJ, Jansen GH, Stokin GB,
Pimentel J, Hewer E, Collie D, Smith P, Rob-
erts H, Brandel JP, van Duijn C, Pocchiari M,
Begue C, Cras P, Will RG, Sanchez-Juan P:
Updated clinical diagnostic criteria for spo-
radic Creutzfeldt-Jakob disease. Brain 2009;
132:
8 Kovács GG, Puopolo M, Ladogana A, Poc-
chiari M, Budka H, van Duijn C, Collins SJ,
Boyd A, Giulivi A, Coulthart M, Delasnerie-
Laupretre N, Brandel JP, Zerr I, Kretzschmar
HA, de Pedro-Cuesta J, Calero-Lara M, Glat-
zel M, Aguzzi A, Bishop M, Knight R, Belay
G, Will R, Mitrova E: Genetic prion disease:
the EUROCJD experience. Hum Genet 2005;
118:
390:
241.

2659–2668.

166–174.
9 Haltia M, Kovanen J, Goldfarb LG, Brown P,
Gajdusek DC: Familial Creutzfeldt-Jakob
disease in Finland: epidemiological, clinical,
pathological and molecular genetic studies.
Eur J Epidemiol 1991;
10 Goldfarb LG, Petersen RB, Tabaton M,
Brown P, LeBlanc AC, Montagna P, Cortelli
P, Julien J, Vital C, Pendelbury WW: Fatal
familial insomnia and familial Creutzfeldt-
Jakob disease: disease phenotype deter-
mined by a DNA polymorphism. Science
1992;
11 Kovács GG, Trabattoni G, Hainfellner JA,
Ironside JW, Knight RSG, Budka H: Muta-
tions of the prion protein gene phenotypic
spectrum. J Neurol 2002;
12 Lugaresi E, Medori R, Montagna P, Baruzzi
A, Cortelli P, Lugaresi A, Tinuper P, Zucconi
M, Gambetti P: Fatal familial insomnia and
dysautonomia with selective degeneration of
thalamic nuclei. N Engl J Med 1986;
1003.
7:
494–500.
258:
806–808.
249:
1567–1582.
315:
997–

Page 8

D178N, 129Val and N171S, 129Val in
Creutzfeldt-Jakob Disease
Dement Geriatr Cogn Disord 2010;30:424–431
431
13 Gambetti P, Parchi P, Petersen RB, Chen SG,
Lugaresi E: Fatal familial insomnia and fa-
milial Creutzfeldt-Jakob disease: clinical,
pathological and molecular features. Brain
Pathol 1995;
14 Gistau VS, Pintor L, Matrai S, Saiz A: Fatal
familial insomnia. Psychosomatics 2006;
527–528.
15 Collins S, McLean CA, Masters CL: Gerst-
mann-Sträussler-Scheinker syndrome, fatal
familial insomnia, and kuru: a review of
these less common human transmissible
spongiform encephalopathies. J Clin Neuro-
sci 2001;
16 Montagna P: Fatal familial insomnia: a mod-
el disease in sleep physiopathology. Sleep
Med Rev 2005;
17 Gambetti P, Parchi P, Chen SG: Hereditary
Creutzfeldt-Jakob disease and fatal familial
insomnia. Clin Lab Med 2003;
18 Chapman J, Arlazoroff A, Goldfarb LG, Cer-
venakova L, Neufeld MY, Werber E, Herbert
M, Brown P, Gajdusek DC, Korczyn AD: Fa-
tal insomnia in a case of familial Creutzfeldt-
Jakob disease with the codon 200(Lys) muta-
tion. Neurology 1996;
19 Taratuto AL, Piccardo P, Reich EG, Chen SG,
Sevlever G, Schultz M, Luzzi AA, Rugiero M,
Abecasis G, Endelman M, Garcia AM, Capel-
lari S, Xie Z, Lugaresi E, Gambetti P, Dlouhy
SR, Ghetti B: Insomnia associated with tha-
lamic involvement in E200K Creutzfeldt-Ja-
kob disease. Neurology 2002;
5:
43–51.
47:

8:
387–397.
9:
339–353.
23:
43–64.
46:
758–761.
58:
362–367.
20 Guerreiro RJM, Vaskov TM, Crews C, Sin-
gleton A, Hardy J: A case of dementia with
PRNP D178Ncis-129M and no insomnia.
Alzheimer Dis Assoc Disord 2009;
417.
21 Zarranz JJ, Digon A, Atarés B, Rodríguez-
Martínez AB, Arce A, Carrera N, Fernán-
dez-Manchola I, Fernández-Martínez M,
Fernández-Maiztegui C, Forcadas I, Galdos
L, Gómez-Esteban JC, Ibáñez A, Lezcano E,
López de Munain A, Martí-Massó JF,
Mendibe MM, Urtasun M, Uterga JM, Sara-
cibar N, Velasco F, de Pancorbo MM: Pheno-
typic variability in familial prion diseases
due to the D178N mutation. J Neurol Neuro-
surg Psychiatry 2005;
22 Zerr I, Giese A, Windl O, Kropp S, Schulz-
Schaeffer W, Riedemann C, Skworc K, Bode-
mer M, Kretzschmar HA, Poser S: Phenotyp-
ic variability in fatal familial insomnia
(D178N-129M) genotype. Neurology 1998;
51:
23 Appleby B, Appleby K, Rabins P: Does the
presentation of Creutzfeldt-Jakob disease
vary by age or presumed etiology? A meta-
analysis of the past 10 years. J Neuropsychia-
try Clin Neurosci 2007;
23:
415–
76:
1491–1496.

1398–4105.
19:
428–435.
24 Holm IE, Abelskov K, Bojsen-Moller M,
Nielsen AL, Jorgensen AL: Creutzfeldt-Jakob
disease segregating in a three generation
Danish family. Acta Neurol Scand 2001;
139–147.
25 Monari L, Chen SG, Brown P, Parchi P, Pe-
tersen RB, Mikol J, Gray F, Cortelli P, Mon-
tagna P, Ghetti B: Fatal familial insomnia
and familial Creutzfeldt-Jakob disease: dif-
ferent prion proteins determined by a DNA
polymorphism. Proc Natl Acad Sci 1994;
2839–2842.
26 Gigi A, Vakil E, Kahana E, Hadar U: Pres-
ymptomatic signs in healthy CJD mutation
carriers. Dement Geriatr Cogn Disord 2005;
19:
27 Cortelli P, Perani D, Montagna P, Gallassi R,
Tinuper P, Federica P, Avoni P, Ferrillo F,
Anchisi D, Moresco RM, Fazio F, Parchi P,
Baruzzi A, Lugaresi E, Gambetti P: Pre-
symptomatic diagnosis in fatal familial in-
somnia: serial neurophysiological and
18 FDG-PET studies. Brain 2006;
675.
28 Pilon J, Loiacono C, Okeson D, Lund S, Ver-
cauteren K, Rhyan J, Miller L: Anti-prion ac-
tivity generated by a novel vaccine formula-
tion. Neurosci Lett 2007;
29 Wisniewski T, Chabalgoity JA, Goni F: Is
vaccination against transmissible spongi-
form encephalopathy feasible? Rev Sci Tech
2007;

103:

91:


246–255.
129:
668–
429:
161–164.
26:
243–251.

Page 9

Reproducedwithpermissionofthecopyrightowner.Furtherreproductionprohibitedwithoutpermission.