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From: TSS ()
Subject: SPORADIC FATAL INSOMNIA IN A FATAL FAMILIAL INSOMNIA PEDIGREE
Date: August 17, 2007 at 12:36 pm PST
GEN-07 SPORADIC FATAL INSOMNIA IN A FATAL FAMILIAL INSOMNIA PEDIGREE S. Capellari1a, P. Cortelli1, P. Avoni1, G.P. Casadei2, A. Baruzzi1, E.
Lugaresi1, M. Pocchiari3, P. Gambetti4, P.
Montagna1, P. Parchi1.
1Department of Neurological Sciences, University of Bologna, Bologna, Italy;
2Department of Cell Biology and
Neurosciences, ISS, Roma, Italy; 3Servizio di Anatomia Patologica, Ospedale
Maggiore, Bologna, Italy,
4Division of Neuropathology, CWRU, Cleveland, OH, USA. a
capellari@neuro.unibo.it
We describe a case of sporadic fatal insomnia (sFI) occurring in a family in
which several members
carried the D178N mutation in the PRNP gene and died of fatal familial
insomnia (FFI). A 43-year-old
woman presented with an 11-month history of diplopia, withdrawal, confusion,
memory loss, unsteady
gait and inability to sleep with episodes of agitation and dream enactment.
After a progressive course
characterized by cognitive impairment, marked gait ataxia, signs of
autonomic hyperactivity, and
myoclonus the patient died 24 months after the onset of symptoms. The
patient did not have any
personal contact with FFI affected relatives and her closest one was a
paternal uncle, the son of her
grand-grand mother. Analyses of DNA from various tissues of endo- ecto- and
meso-dermal origin,
including 5 different regions of the CNS revealed no pathogenic mutations
and methionine
homozygosity at codon 129 of PRNP. Brain histopathology and PrPSc typing
showed typical features
of FI such as thalamic and olivary atrophy, focal spongiform degeneration
limited to the cerebral
cortex, relative sparing of basal ganglia and cerebellum, and relatively low
amount of PrPSc type 2A
accumulation. sFI represents the rarest among the sporadic human TSE
subtypes described to
date with less than twenty cases described worldwide and only three cases
diagnosed in Italy
since the establishment of TSE surveillance. Similarly, only six unrelated
FFI families have been
observed in Italy to date, making the probability of a chance association
between sFI and FFI in the
same family extremely low. Thus, we believe that our observation emphasizes
the importance of
undiscovered factors modulating the susceptibility to human prion diseases.
Supported by the EU Network of Excellence “NeuroPrion”
(FOOD-CT-2004-506579).
http://www.neuroprion.com/pdf_docs/conferences/prion2006/abstract_book.pdf
Pre-symptomatic diagnosis in fatal familial insomnia: serial
neurophysiological and 18FDG-PET studies
Pietro Cortelli3, Daniela Perani1, Pasquale Montagna3, Roberto Gallassi3,
Paolo Tinuper3, Provini Federica3, Patrizia Avoni3, Franco Ferrillo4, Davide
Anchisi1, Rosa Maria Moresco2, Ferruccio Fazio2, Piero Parchi3, Agostino
Baruzzi3, Elio Lugaresi3 and Pierluigi Gambetti5
1 Department of Neuroscience, C.N.R.-I.B.F.M., Vita-Salute San Raffaele
University, 2 C.N.R.-I.B.F.M., University of Milan-Bicocca, Scientific
Institute H. S. Raffaele, Milan, 3 Department of Neurological Sciences,
University of Bologna, 4 DISMR, Department of Motor Sciences, Center for
Sleep Medicine, University of Genova, Italy and 5 Institute of Pathology,
Case Western Reserve University, Cleveland, OH, USA
Correspondence to: Pietro Cortelli MD, PhD, Alma Mater Studiorum-Universita'
di Bologna, Dipartimento di Scienze Neurologiche, Via Ugo Foscolo, 7, 40123
Bologna, Italy E-mail: pietro.cortelli@unibo.it
Summary
Knowing how and when the degenerative process starts is important in
neurodegenerative diseases. We have addressed this issue in fatal familial
insomnia (FFI) measuring the cerebral metabolic rate of glucose (CMRglc)
with 2-[18F]fluoro-2-deoxy-D-glucose PET in parallel with detailed clinical,
neuropsychological examinations and polysomnography with EEG spectral
analyses. Nine asymptomatic carriers of the D178N mutation, 10 non-carriers
belonging to the same family, and 19 age-matched controls were studied over
several years. The CMRglc as well as clinical and electrophysiological
examinations were normal in all cases at the beginning of the study. Four of
the mutation carriers developed typical FFI during the study but CMRglc and
the clinical and electrophysiological examinations remained normal 63, 56,
32 and 21 months, respectively before disease onset. The carrier whose tests
were normal 32 months before disease onset was re-examined 13 months before
the onset. At that time, selective hypometabolism was detected in the
thalamus while spectral-EEG analysis disclosed an impaired thalamic sleep
spindle formation. Following clinical disease onset, CRMglc was reduced in
the thalamus in all 3 patients examined. Our data indicate that the
neurodegenerative process associated with FFI begins in the thalamus between
13 and 21 months before the clinical presentation of the disease
snip...
Discussion
Two major unanswered questions concerning familial neurodegenerative
diseases are when and where the degenerative process starts. This issue is
raised by the common observation that familial neurodegenerative diseases
usually become symptomatic at mature or advanced age although the mutated
protein thought to trigger the disease is present from the early stages of
brain development. However, prion diseases may differ from other
neurodegenerative diseases in that the mutated protein probably maintains a
normal conformation until some time in adulthood, when it changes
conformation converting adjacent PrPs and ultimately leading to neuronal
injury and loss.
Knowing the time and anatomical location of the initial degenerative and
dysfunctional process is important not only for understanding the pathogenic
mechanisms, but also for timing the therapeutical interventions that might
prevent the disease, if and when these interventions become available. The
present study addresses these issues in FFI using longitudinal 18FDG-PET and
electrophysiological recordings to assess metabolism and function of
neuronal populations during the pre-symptomatic and symptomatic stages of
thedisease in subjects carrying the FFI genetic mutation. FFI is particularly suitable for this kind of study for several reasons. FFI
has a rapid course and high penetrance, therefore, it is easier to follow
the disease progression, and virtually all mutation carriers become
symptomatic. The disease presents with impairment of sleep and autonomic
functions that can be tested fairly accurately. The pathology is relatively
simple, at least in cases with short duration, because it is mostly limited
to the thalamus and essentially consists of neuronal loss and gliosis.
Furthermore, the central event that triggers the pathogenesis of FFI and
other familial prion diseases is believed to be the conversion of the
mutated PrP into an abnormal isoform through a conformational change that
renders the PrP unfit to perform its normal function and makes it
pathogenic. Both these PrP changes may result in the impairment of rCMRglc
in FFI patients that can be assessed by 18FDG-PET (Perani et al., 1993;
Cortelli et al., 1997). Tests of autonomic system function,
neuropsychological assessments and analysis of the macro-structure of sleep
in a 24 h polysomnogram revealed no difference between the members of the
FFI affected family with and without the mutation and between these two
populations and a control group until the disease became symptomatic in the
mutation carriers. This indicates that, at least in this FFI pedigree, the
presence of the D178N-129M haplotype has no effect that can be detected even
with extensive clinical examination before the disease becomes clearly
symptomatic. Assessment of the baseline regional glucose metabolism in the
brain (rCMRglc) with 18FDG-PET also failed to disclose any difference among
pre-symptomatic carriers, non-carriers and the control group. PET studies
and the EEG spectral analyses also were normal 63, 56, 32 and 21 months
before clinical disease onset in four carriers, respectively. One of these
four, subject 6, who had been assessed and found normal at 32 months, was
tested again 13 months before the disease onset. At 13 months both 18FDG-PET
and spectral analysis of sleep recording were significantly different from
those of the controls. Even if spectral EEG analysis is a less consistent
method than PET, it is noteworthy that the 18FDG-PET revealed a metabolic
reduction confined to the thalamus while the spectral EEG analysis
demonstrated a reduction of the sigma band EEG power which is related to the
mechanisms of cortical thalamic synchronization and involved in sleep
spindles formation (Nunez et al., 1992; Steriade et al., 1993). The
concomitant occurrence of these two changes suggests a relationship between
the thalamic dysfunction demonstrated with PET and the reduction of spindle
frequency activity, a typical polysomnographic presenting sign of FFI
(Sforza et al., 1995). Furthermore, it indicates that thalamic dysfunction
resulting in the lack of efficiency of the mechanisms involved in cortical
thalamic synchronization is the first detectable change in FFI, before the
symptomatic onset of the disease. Although our data have been obtained from
a limited number cases due to the complexity and time requirements of the
tests, when combined they argue that the D178N-129M haplotype might trigger
the disease process associated with FFI as little as 13 months before the
appearance of the clinical signs. These findings together with our previous
data also are consistent with the notion that FFI arises in the thalamus and
subsequently spreads to other areas of the brain by an as yet unknown
mechanism (Perani et al., 1993; Cortelli et al., 1997). In the context of the commonly accepted pathogenesis of familial prion
diseases, the present findings of decreased metabolism of the neuronal cells
of the thalamus 13 months before clinical onset in case 6 might be explained
by postulating that at that time the mutated PrP begins to convert into or
to accumulate in sufficient amount as a pathogenic isoform impairing
neuronal metabolism and subsequently leading to the neuronal loss found at
post-mortem examination. The 18FDG-PET findings in the follow-up study of
this patient showed a further metabolic reduction from 16% (when the patient
was asymptomatic) to 40% seven months after clinical disease onset. Hence,
an impairment or loss of about twice as many neurons is likely to be needed
for the disease to become symptomatic, although these findings await
confirmation in additional FFI patients also from other pedigrees. The scenario of initial impairment of neuronal metabolism followed by
neuronal death is supported by the PET data from other neurodegenerative
diseases showing that glucose utilization may be significantly reduced with
no significant neuronal loss (Meltzer et al., 1996; Ibanez et al., 1998).
Few serial 18FDG-PET studies carried out through the pre-symptomatic and
symptomatic disease stages have been performed in other neurodegenerative
diseases. In Alzheimer's disease, 18FDG-PET studies or MRI scans (to
determine the volume of the hippocampal formation) have been performed in
individuals at risk for Alzheimer's disease because they were carriers of
either an Alzheimer's disease pathogenic mutation or of the Alzheimer's
disease risk factor APO 4 (Kennedy et al., 1995; Small et al., 1995; Fox et
al., 1996; Reiman et al., 1996; Perani et al., 1997; Small et al., 2000).
Significant changes in glucose metabolism or hippocampal volume were
observed when the carriers were still asymptomatic. In one study, subjects
at risk for Alzheimer's disease had an abnormal 18FDG-PET 12 years before
the age at which they were expected to become symptomatic according to the
mean historical age at disease onset of affected members in their families
(Small et al., 1995). Another 2 year follow-up of ten at risk, asymptomatic
subjects with an already abnormal baseline 18FDG-PET showed a significant
decline of the glucose metabolism without any of the subjects becoming
symptomatic (Small et al., 2000). Similar observations have been made in
Huntington's disease and frontotemporal dementia (Janssen et al., 2005;
Kipps and Hodges, 2005). Combined these findings indicate that tissue impairment, as revealed by
impaired metabolism or atrophy, occurs longer before the symptomatic onset
in these neurodegenerative diseases than in FFI. This discrepancy probably
reflects the rapid course of FFI and other familial prion diseases (Kong et
al., 2004) or the normal functioning of the mutated prion until it changes
conformation to become PrPSc. Nonetheless, the findings in our FFI pedigree suggest that there may be a
time interval of between 13 and 21 months before clinical disease onset
which may allow preventive treatment. Studies that can detect the initial
damage to the nervous system before the disease impairs patient performance
will be essential for accurate timing of preventive treatment in familial
prion diseases. http://brain.oxfordjournals.org/cgi/reprint/129/3/668 © 2006 American Academy of Neurology Sleep-wake disturbances in sporadic Creutzfeldt-Jakob disease
H. -P. Landolt, PhD, M. Glatzel, MD, T. Blättler, MD, P. Achermann, PhD, C.
Roth, PhD, J. Mathis, MD, J. Weis, MD, I. Tobler, PhD, A. Aguzzi, MD and C.
L. Bassetti, MD
From the Institute of Pharmacology & Toxicology (H.-P.L., P.A., I.T.),
University of Zürich; Departments of Neuropathology (M.G., A.A.) and
Neurology (T.B., C.L.B.), University Hospital, Zürich, Switzerland; Sleep
Center and Department of Neurology (C.R., J.M.) and Institute of
Neuropathology (J.W.), University Hospital, Bern, Switzerland; Institute of
Neuropathology (J.W.); RWTH University, Aachen, Germany; and Institute of
Neuropathology (M.G.), University Clinic, Hamburg-Eppendorf, Hamburg,
Germany. Address correspondence and reprint requests to Prof. Claudio L. Bassetti,
Neurologische Universitätsklinik, Universitätsspital Zürich,
Frauenklinikstrasse 26, 8091 Zürich, Switzerland; e-mail:
claudio.bassetti@usz.ch Background: The prevalence and characteristics of sleep-wake disturbances in
sporadic Creutzfeldt-Jakob disease (sCJD) are poorly understood. Methods: Seven consecutive patients with definite sCJD underwent a
systematic assessment of sleep-wake disturbances, including clinical
history, video-polysomnography, and actigraphy. Extent and distribution of
neurodegeneration was estimated by brain autopsy in six patients. Western
blot analyses enabling classification and quantification of the
protease-resistant isoform of the prion protein, PrPSc, in thalamus and
occipital cortex was available in four patients. Results: Sleep-wake symptoms were observed in all patients, and were
prominent in four of them. All patients had severe sleep EEG abnormalities
with loss of sleep spindles, very low sleep efficiency, and virtual absence
of REM sleep. The correlation between different methods to assess sleep-wake
functions (history, polysomnography, actigraphy, videography) was generally
poor. Brain autopsy revealed prominent changes in cortical areas, but only
mild changes in the thalamus. No mutation of the PRNP gene was found. Conclusions: This study demonstrates in sporadic Creutzfeldt-Jakob disease,
first, the existence of sleep-wake disturbances similar to those reported in
fatal familial insomnia in the absence of prominent and isolated thalamic
neuronal loss, and second, the need of a multimodal approach for the
unambiguous assessment of sleep-wake functions in these patients.
snip...
A recent study of 153 patients with sCJD reported
that sleep disturbances are present in up to 45% of
patients.19 Moreover, prominent sleep EEG changes
were reported at an early stage of the disease24,25 and
in single-case studies.26-28 Based also on our own observations,
29 we investigated the hypothesis that patients
with sCJD may present with clinical and sleep
EEG changes similar to those described in FFI.
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Supported by the Swiss National Science Foundation and the Human Frontiers
Science Program.
Disclosure: The authors report no conflicts of interest. Received June 7, 2005. Accepted in final form January 19, 2006. http://www.neurology.org/cgi/content/abstract/66/9/1418
Articles
Science, Vol 258, Issue 5083, 806-808
Copyright © 1992 by American Association for the Advancement of Science
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articles Fatal familial insomnia and familial Creutzfeldt-Jakob disease: disease
phenotype determined by a DNA polymorphism
LG Goldfarb, RB Petersen, M Tabaton, P Brown, AC LeBlanc, P Montagna, P
Cortelli, J Julien, C Vital, WW Pendelbury, and al. et
Laboratory of Central Nervous System Studies, National Institute of
Neurological Diseases and Stroke, National Institutes of Health, Bethesda,
Maryland 20892. Fatal familial insomnia (FFI) and a subtype of familial Creutzfeldt-Jakob
disease (CJD), two clinically and pathologically distinct diseases, are
linked to the same mutation at codon 178 (Asn178) of the prion protein gene.
The possibility that a second genetic component modified the phenotypic
expression of the Asn178 mutation was investigated. FFI and the familial CJD
subtype segregated with different genotypes determined by the Asn178
mutation and the methionine-valine polymorphism at codon 129. The Met129,
Asn178 allele segregated with FFI in all 15 affected members of five
kindreds whereas the Val129, Asn178 allele segregated with the familial CJD
subtype in all 15 affected members of six kindreds. Thus, two distinct
disease phenotypes linked to a single pathogenic mutation can be determined
by a common polymorphism.
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Cellular Biology of Prion Diseases.
D. A. Harris (1999)
Clin. Microbiol. Rev. 12, 429-444
| Abstract » | Full Text » | PDF »
Prion Protein Conformation in a Patient with Sporadic Fatal Insomnia.
J. A. Mastrianni, R. Nixon, R. Layzer, G. C. Telling, D. Han, S. J.
DeArmond, and S. B. Prusiner (1999)
N. Engl. J. Med. 340, 1630-1638
| Full Text » | PDF »
Basis of phenotypic variability in sporadic Creutzfeldt-Jakob disease.
C. Tranchant, L. Geranton, C. Guiraud-Chaumeil, M. Mohr, and J. M. Warter
(1999)
Neurology 52, 1244
| Abstract » | Full Text » | PDF »
Fatal familial insomnia: a new Austrian family.
G. Almer, J. A. Hainfellner, T. Brucke, K. Jellinger, R. Kleinert, G. Bayer,
O. Windl, H. A. Kretzschmar, A. Hill, K. Sidle, J. Collinge, and H. Budka
(1999)
Brain 122, 5-16
| Abstract » | Full Text » | PDF »
Genetic Classification of Primary Neurodegenerative Disease.
J. Hardy and K. Gwinn-Hardy (1998)
Science 282, 1075-1079
| Abstract » | Full Text »
Endogenous Proteolytic Cleavage of Normal and Disease-Associated Isoforms of
the Human Prion Protein in Neural and Non-Neural Tissues.
A. Jimenez-Huete, P. M. J. Lievens, R. Vidal, P. Piccardo, B. Ghetti, F.
Tagliavini, B. Frangione, and F. Prelli (1998)
Am. J. Pathol. 153, 1561-1572
| Abstract » | Full Text » | PDF »
Phenotype-genotype studies in kuru: Implications for new variant
Creutzfeldt-Jakob disease.
L. Cervenakova, L. G. Goldfarb, R. Garruto, H.-S. Lee, D. C. Gajdusek, and
P. Brown (1998)
PNAS 95, 13239-13241
| Abstract » | Full Text » | PDF »
Prion protein NMR structure and familial human spongiform encephalopathies.
R. Riek, G. Wider, M. Billeter, S. Hornemann, R. Glockshuber, and K.
Wuthrich (1998)
PNAS 95, 11667-11672
| Abstract » | Full Text » | PDF »
A Recurrent Missense Mutation in the KAL Gene in Patients with X-Linked
Kallmann's Syndrome.
G. Maya-Nuñez, J. C. Zenteno, A. Ulloa-Aguirre, S. Kofman-Alfaro, and J. P.
Mendez (1998)
J. Clin. Endocrinol. Metab. 83, 1650-1653
| Abstract » | Full Text »
Polyvariant Mutant Cystic Fibrosis Transmembrane Conductance Regulator Genes
. The Polymorphic (TG)m Locus Explains the Partial Penetrance of the T5
Polymorphism as a Disease Mutation.
H. Cuppens, W. Lin, M. Jaspers, B. Costes, H. Teng, A. Vankeerberghen, M.
Jorissen, G. Droogmans, I. Reynaert, M. Goossens, B. Nilius, and J.-J.
Cassiman (1998)
J. Clin. Invest. 101, 487-496
| Abstract » | Full Text »
Solution structure of a 142-residue recombinant prion protein corresponding
to the infectious fragment of the scrapie isoform.
T. L. James, H. Liu, N. B. Ulyanov, S. Farr-Jones, H. Zhang, D. G. Donne, K.
Kaneko, D. Groth, I. Mehlhorn, S. B. Prusiner, and F. E. Cohen (1997)
PNAS 94, 10086-10091
| Abstract » | Full Text » | PDF »
Neurofibrillary tangles in Gerstmann-Straussler-Scheinker syndrome with the
A117V prion gene mutation.
C Tranchant, N Sergeant, A Wattez, M Mohr, J M Warter, and A Delacourte
(1997)
J. Neurol. Neurosurg. Psychiatry 63, 240-246
| Abstract » | Full Text » | PDF »
In Situ Formation of Protease-resistant Prion Protein in Transmissible
Spongiform Encephalopathy-infected Brain Slices.
R. A. Bessen, G. J. Raymond, and B. Caughey (1997)
J. Biol. Chem. 272, 15227-15231
| Abstract » | Full Text » | PDF »
Interactions between wild-type and mutant prion proteins modulate
neurodegeneration in transgenic mice..
G C Telling, T Haga, M Torchia, P Tremblay, S J DeArmond, and S B Prusiner
(1996)
Genes & Dev. 10, 1736-1750
| Abstract » | PDF »
Effect of the D178N Mutation and the Codon 129 Polymorphism on the
Metabolism of the Prion Protein.
R. B. Petersen, P. Parchi, S. L. Richardson, C. B. Urig, and P. Gambetti
(1996)
J. Biol. Chem. 271, 12661-12668
| Abstract » | Full Text » | PDF »
Mutant and Infectious Prion Proteins Display Common Biochemical Properties
in Cultured Cells.
S. Lehmann and D. A. Harris (1996)
J. Biol. Chem. 271, 1633-1637
| Abstract » | Full Text » | PDF »
Risk of human exposure to bovine spongiform encephalopathy.
K. L Tyler (1995)
BMJ 311, 1420-1421
| Full Text »
Prion Protein Isoforms, a Convergence of Biological and Structural
Investigations.
M. A. Baldwin, F. E. Cohen, and S. B. Prusiner (1995)
J. Biol. Chem. 270, 19197-19200
| Full Text » | PDF »
Structural clues to prion replication.
F. Cohen, K. Pan, Z Huang, M Baldwin, R. Fletterick, and S. Prusiner (1994)
Science 264, 530-531
| PDF »
Molecular genetics of neurological diseases.
J. Martin (1993)
Science 262, 674-676
| PDF »
Functional Synergism between the Most Common Polymorphism in Human
Alanine:Glyoxylate Aminotransferase and Four of the Most Common
Disease-causing Mutations.
M. J. Lumb and C. J. Danpure (2000)
J. Biol. Chem. 275, 36415-36422
| Abstract » | Full Text » | PDF »
Novel Differences between Two Human Prion Strains Revealed by
Two-dimensional Gel Electrophoresis.
T. Pan, M. Colucci, B.-S. Wong, R. Li, T. Liu, R. B. Petersen, S. Chen, P.
Gambetti, and M.-S. Sy (2001)
J. Biol. Chem. 276, 37284-37288
| Abstract » | Full Text » | PDF »
Genetic and environmental factors modify bovine spongiform encephalopathy
incubation period in mice.
K. Manolakou, J. Beaton, I. McConnell, C. Farquar, J. Manson, N. D. Hastie,
M. Bruce, and I. J. Jackson (2001)
PNAS 98, 7402-7407
| Abstract » | Full Text » | PDF »
http://www.sciencemag.org/cgi/content/abstract/258/5083/806
Science 29 June 2007:
Vol. 316. no. 5833, pp. 1845 - 1848
DOI: 10.1126/science.1146320
Prev | Table of Contents | Next
Books
SUMMER READING:
To While Away Some Time …
Barbara Jasny and Sherman Suter
We asked a number of our advisers, reviewers, and colleagues what
thought-provoking and enjoyable books they would recommend for summer
reading. We suggested that the books have some link (however tenuous) to
science, but that they could be factual or fiction. And while admitting a
bias toward titles from recent years, we agreed not to ignore older
classics. Here is a selection from the results of our queries, along with
brief explanations for each recommendation. We hope that you will find
something on the list to reward you for a few hours of reading while
reclining on a beach, settled in for a long flight, or lazing in a hammock.
If you wish to rest your eyes as well, several of the titles on the list are
available as audiobooks. And if you find yourself reading some other book
this summer that you can't put down, we would like to hear from you.
snip...
D. T. Max, The Family That Couldn't Sleep: A Medical Mystery. Max
interweaves histories of the desperate struggles of an Italian family with
fatal familial insomnia and the rise of prion diseases--scrapie in English
sheep and kuru in the Fore of Papua New Guinea. He presents a Nobelist as a
self-confessed "pedagogic pedophiliac pediatrician," the bitter jealousies
and pettiness of cutting-edge research, and the tearing up of biological
dogma. Max's detective story gradually reveals that, against all
expectations, each disease is caused by a nonliving infectious
agent--protein.
-GUY RIDDIHOUGH
snip...
10.1126/science.1146320
http://www.sciencemag.org/cgi/content/full/316/5833/1845
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