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Fatal familial insomnia: Clinical features and

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J. Sleep Res. (1999) 8, Suppl. 1, 2329

Fatal familial insomnia: clinical features and molecular genetics

PIETRO CORTELLI, PIERLUIGI GAMBETTI 1 , PASQUALE MONTAGNA and
ELIO LUGARESI
Institute of Clinical Neurology, University of Bologna, Bologna, Italy and 1Division of Neuropathology, Institute of Pathology, Case Western
Reserve University, Cleveland, Ohio, USA

SUMMARY Fatal familial insomnia (FFI) is an autosomal dominant prion disease clinically
characterized by inattention, sleep loss, dysautonomia, and motor signs and
pathologically characterized by a preferential thalamic degeneration. FFI is linked to
a missense mutation at codon 178 of the prion protein gene, PRNP, coupled with the Ahed
Bhed
presence of the codon methionine at position 129, the locus of a methionine-valine
Ched
polymorphism. Homozygotes at codon 129, expressing methionine also in the
Dhed
nonmutated allele, have a shorter disease course (often less than 1 year), prominent
Ref mar-
sleep and autonomic disturbances at disease onset, and pathology restricted to the
ker
thalamus. Heterozygotes at codon 129, expressing valine in the nonmutated allele, have
Fig mar-
a longer disease course (often longer than 1 year), ataxia and dysarthria at disease ker
onset, and lesions widespread to cerebral cortex. Both in the thalamus and in the cortex, Table
the limbic structures are those most consistently and severely involved: the anterior marker
ventral and mediodorsal thalamic nuclei, the cingulate gyrus, and the orbitofrontal Ref end
cortex. FFI is thus a prion disease selectively damaging the thalamocortical limbic Ref start
structures. Loss of sleep, sympathetic hyperactivity, and flattening of vegetative and
hormonal circadian oscillations characterize FFI and result from a homeostatic
imbalance caused by the interruption of the thalamocortical limbic circuits, the
phylogenetically most advanced structures involved in the control of the sleepwake
cycle and the body's homeostasis. The selective atrophy of the limbic thalamus that
characterizes FFI might be due to the binding of FFI toxic PrP or PrPres to specific
receptors on thalamolimbic neurons.
KEYWORDS dysautonomia, heterozygotes, homozygotes, limbic thalamus, sleep loss,
thalamic degeneration

INTRODUCTION symptoms to the advanced stages of the disease. He turned to

us because in his opinion the array of specialists who had been
Fatal familial insomnia (FFI) is an autosomal dominant
consulted by his relatives had not grasped the fact that the
disease clinically characterized by a disordered sleepwake
basic disorder was a progressive loss of the ability to sleep. He
cycle, dysautonomia, and motor signs and pathologically
claimed that the patients would become ill and eventually die
characterized by predominant thalamic degeneration. Geneti-
because they had lost the ability to sleep. Attracted by his
cally the disease is associated with a missense mutation at
story, we decided to perform serial 24-h recordings in this
codon 178 coupled with methionine at the polymorphic codon
patient. We thereby confirmed what he had postulated at the
129 of the prion protein gene (PRNP) (Lugaresi et al. 1986;
outset: the sleep EEG pattern had already disappeared in the
Goldfarb et al. 1992; Medori et al. 1992).
very first recording. Alongside the loss of sleep, we found
persistent progressive sympathetic activation and alterations in
HISTORICAL NOTE circadian hormonal secretion. We termed the disease fatal
familial insomnia to stress that one of the cardinal symptoms
The first FFI case we examined was referred to us by a young
of the disease is a loss of sleep that inevitably proves fatal. The
physician, Dr Ignazio Roiter, who belonged to the affected
term `insomnia' subsequently created some misunderstanding
family. He was familiar with the clinical history of at least
in referring to these patients because neurologists and
three patients whom he had followed from the onset of the first
psychiatrists were used to considering insomnia as a subjective
complaint commonly affecting 1020% of the general popula-
Correspondence: Elio Lugaresi MD, Istituto di Clinica Neurologica,
Via Ugo Foscolo 7, 40123 Bologna, Italy. Tel.: +39 51 6442129; tion. They therefore had difficulties in classifying a different
fax: +39 51 6442165; e-mail: lugaresi@bo.nettuno.it form of insomnia that is not subjective, but presents as

#1999 European Sleep Research Society 23

 Paper 05 Disc

24 P. Cortelli et al.

Figure 1. Pedigree of the first FFI patient (completed by Dr I. Roiter). The young doctor who sent us the first patient had patiently reconstructed
the family tree consulting parish archives in his region, the Veneto. The family is traced back to the 19th century, but it was impossible to go back
further because the archives had been destroyed during the Napoleonic wars.

hypersomnolence. This is why the physicians who had
examined other patients with FFI referred to subacute familial
encephalopathy with hypersomnia. We may have avoided
confusion had we adopted the term agrypnia, but the term is
virtually obsolete and was thus deemed inappropriate.
EPIDEMIOLOGY (PREVALENCE DATA)
Currently, 25 apparently unrelated FFI families have been
described: five Italian, two French, four American, one
Japanese, two Australian, eight German, one Austrian, and
two British (Gambetti and Lugaresi 1998).
Recently Parchi et al. (unpublished data) observed some
patients with a prion disease in which the clinical and
pathological features were indistinguishable from those of
FFI but lacked the D178N mutation in the prion protein gene.
These subjects were homozygous for methionine at codon 129
and the prion protein resistant fragments had the same size
and shape observed in FFI. These data seem to confirm the
existence of sporadic cases of FFI. In all we have studied three

#1999 European Sleep Research Society, J. Sleep Res., 8 (Suppl. 1), 2329.

Figure 2. Twenty-four hour records of blood pressure (A) and heart rate (B). Circadian oscillations of blood pressure and heart rate in controls (1),
short-evolution cases (2), and long-evolution (3) cases.
families: 17 family members were examined directly, 13
belonged to FFI kindred I (Fig. 1), three belonged to FFI
kindred II, and one belonged to FFI kindred III.
CLINICAL FEATURES
Onset and duration
The disease presents at 51 + 8 years. In homozygotes at codon
129 (coding methionine also in the nonmutated allele) the clinical
course is relatively short (12 + 4 months). In heterozygotes
(expressing valine in the nonmutated allele) the clinical course is
longer (21 + 15 months) (Gambetti and Lugaresi 1998).
Neuropsychology
Patients appear apathetic and unable to pay sustained atten-
tion to their surroundings. When not stimulated, they tend to
become sleepy and manifest recurrent behavioural episodes
mimicking a dream (oneiric stupor). In more advanced stages,
the vigilance level declines leading to a persistent stupor; a
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Paper 05 Disc
Fatal familial insomnia 25
vegetative state may precede death by days or months (Gallassi
et al. 1996; Montagna et al. 1998).
Motor signs
Ataxia and dysarthria appear weeks or months after the sleep
wake behavioural disturbances in homozygotes, or at disease
onset in heterozygotes. In addition, in short evolution cases
(homozygotes) ataxia and dysarthria may be milder until death,
whereas long evolution cases (heterozygotes) worsen displaying
astasia-abasia and incomprehensible speech; evoked and
spontaneous myoclonic jerks are seen in the middle and the
advanced stages of the disease. In some cases transient dyplopia
and sporadic GM seizures are reported (Montagna et al. 1998).
Autonomic and hormonal findings
Increased perspiration and salivation, impotence and con-
stipation, tachycardia, systemic hypertension, and mild fever
appear early and progressively worsen. Cardiovascular func-
tion tests disclose elevated background and stimulated

26 P. Cortelli et al.
Figure 3. Norepinephrine (NE), cortisol, and melatonin plasma
concentrations in blood samples taken from a representative FFI
patient every 30 min for 24 h (^) compared with a normal sex-and
age-matched control (.). Black bar indicates lights-out time.
sympathetic activity, progressively worsening throughout the
clinical course (Cortelli et al. 1991). Twenty-four hour
recordings show body temperature, heart and breathing rates,
and systemic arterial pressure higher than normal. As the
disease develops these values progressively rise, whereas the
amplitude of circadian fluctuations diminishes (Fig. 2).
Twenty-four hour hormonal secretion studies disclose persis-
tently elevated catecholamines (adrenalin and noradrenalin)
and cortisol plasma concentration, whereas ACTH remains at
normal levels and lacks physiological peaks. The nocturnal
increase in melatonin secretion progressively subsides. The
amplitude of the circadian oscillations of all hormones tested
flattens with disease progression (Fig. 3) (Lugaresi et al. 1986,
1987; Portaluppi et al. 1994a, b).
EEG and polysomnography
In FFI short evolution cases 34 months after disease onset all
patients we observed presented an EEG pattern characterized
by continuous oscillations between a diffuse alpha activity
typical of relaxed wakefulness and a widespread low amplitude
theta activity associated with a condition of drowsiness or
subwakefulness (SubW, Fig. 4). At that time the hallmarks of
stage 2 non-rapid-eye-movement (NREM) sleep, spindles and
K complexes were completely absent. Brief recurrent episodes
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Paper 05 Disc
of rapid-eye-movement (REM) sleep or, more seldom, delta
sleep (SWS) would abnormally emerge directly from wakeful-
ness. Any cyclic organization was lacking. In long evolution
cases sleep spindles persisted a year or even longer after disease
onset. In more advanced stages (1 or 2 years after onset),
polygraphic recordings showed the same pattern as short
evolution cases, i.e. a persistent state of wakefulness or
drowsiness interrupted by very brief REM or delta sleep
episodes. By this time, spindling and K complexes were absent
and any cyclic organization was lost.
From the very first observations (after a few months of
disease in homozygotes or a year in heterozygotes), this
condition of persistent subwakefulness or drowsiness was
interspersed with episodes of unresponsiveness during which
the patient would be animated by massive twitches and
perform complex purposeful gestures that they subsequently
referred to dreams. These episodes, which we termed oneiric
stupor or enacted dreams, are one of the most characteristic
features of FFI and usually correspond to brief recurring
episodes of sleep without atonia.
EEG background activity progressively slows down, flatten-
ing in the terminal stages of the disease. Periodic sharp waves at
0.51 Hz may appear transiently in advanced stages of the long-
evolution cases (Tinuper et al. 1989). Twenty-four hour
polygraphic recordings display an EEG pattern oscillating
between diffuse alpha activity and low amplitude theta activity
(vigilance level oscillating between relaxed wakefulness and
drowsiness). The most prominent EEG sign is the disappear-
ance of sleep spindles and K complexes, which occurs after a
few months (34) in short-evolution cases and after a year or
even more in long-evolution cases. After disappearance of
spindling, EEG characteristic of wake or subwake persists
throughout the 24 h, being interrupted only by brief recurrent
episodes of REM sleep or, more seldom, delta sleep abnormally
emerging from wakefulness. Total sleep time is progressively
shortened (Sforza et al. 1995; Montagna et al. 1998).
Neuroradiological investigation and positron emission
tomography (PET) scans
In short evolution cases brain magnetic resonance imaging and
computed tomography are normal, whereas [18F] FDG PET
scans document a marked hypometabolism in the thalamus
with milder and inconsistent involvement of the cingulate
gyrus. In long-evolution cases computed tomography and
magnetic resonance imaging show mild to severe cortical and
cerebellar atrophy, whereas [18F] FDG PET discloses a
marked hypometabolism involving the frontotemporal cortex
and basal ganglia as well as the thalamus (Cortelli et al. 1997;
Montagna et al. 1998).
HISTOPATHOLOGY
The hallmarks of the disease are a loss of neurons and
astrogliosis in the thalamus. The anterior ventral (AV) and
mediodorsal (MD) thalamic nuclei are those most severely and

Figure 4. Sleep architecture in 24 h in a short-evolution (A) and long-evolution (B) case of FFI. In the short-evolution case (homozygote at codon
129) sleep is completely lost 3 months after disease onset. In the long-evolution case (heterozygote at codon 129) SWS and REM sleep are still
present 13 months after disease onset. W, wakefulness; SubW, subwakefulness; SWS, slow wave sleep; REM, rapid-eye-movement sleep.
consistently affected. The involvement of other thalamic nuclei
is milder and less consistent. In short duration cases
pathological changes of the cerebral cortex are absent or
confined to mild spongiosis and gliosis in the orbitofrontal
region. In long duration cases, spongiosis and gliosis diffusely
involve the limbic cortical regions (orbitofrontal cortex and
cingulate gyrus) and less severely the neocortical regions
(frontotemporal and parietal lobes are more affected than the
occipital lobes). The inferior olives are often and severely
affected (Parchi et al. 1998).
MOLECULAR PATHOLOGY
FFI cosegregates with a point mutation of the PRNP gene at
codon 178 resulting in the substitution of aspartic acid with
asparagine in the prion protein and with methionine at the
methionine/valine polymorphic codon 129 of the mutated
allele (Medori et al. 1992; Goldfarb et al. 1992). The same
point mutation at codon 178 coupled with valine at codon 129
in the mutated allele leads to a disease clinically and
pathologically different from FFI and characterized by ataxia
and dementia and by diffuse cortical spongiosis, while the
thalamus is relatively spared. This disease is known as CJD
178, a familial variant of Creutzfeldt-Jakob disease. As
mentioned above, homozygotes at codon 129 have a shorter
clinical course, a sleepwake disorder and dysautonomia more
prominent at onset, hypometabolism as evidenced by PET
studies, and pathology restricted to the thalamus.
PrP R E S AND APOPTOSIS
In FFI, PrPres has two characteristic features. First, the size of
the fragment generated by treatment with proteases is about 19
#1999 European Sleep Research Society, J. Sleep Res., 8 (Suppl. 1), 2329.
Paper 05 Disc
Fatal familial insomnia 27
kDa. Second, the glycoform ratio (i.e. the ratio among the
PrPres forms that contain two, one, and no sugars, respectively)
is characterized by a marked under-representation of the
unglycosylated form. In contrast, CJD178 is characterized by a
protease-resistant PrPres fragment of & 21 kDa (Monari et al.
1994; Parchi et al. 1995). The finding that protease treatment
generates PrPres of a different size is an indication that the two
types of PrPres have a different conformation. Moreover, in
FFI, the PrPres is distributed more widely than the histo-
pathological lesions. In the short-evolution cases PrPres was
detected in significant amounts in cortical limbic regions
(orbitofrontal cortex and cingulate gyrus) in the hypothalamus
and mid-brain (periaqueductal gray matter) as well as in the
thalamus. In the long-evolution cases, PrPres fragments
become detectable in significant amounts also in the neocortex
and basal ganglia. The average amount of PrPres in FFI,
however, is 510-fold less than that detected in the most
common variants of sporadic and familial CJD (Parchi et al.
1995, 1998).
Apoptotic neurons were identified only in the cerebral
lesions presenting histopathological injury (thalamus, bulbar
olives in homozygotes, and additionally the neocortex in
heterozygotes (Dorandeu et al. 1998). They were accompanied
by major microglial proliferation, but were not specifically
related to the location of PrPres fragments. Thus, neuronal
apoptosis originates from biopathological processes not linked
to PrPres deposits.
TRANSMISSIBILITY OF FFI
Intracerebral inoculation of transgenic mice (Tg) expressing a
chimeric human mouse PrPc, with a homogenate from FFI
brains gives rise to a prion disease 200 days after inoculation

28 P. Cortelli et al.
(Telling et al. 1996). In the recipient animals, the pathology is
prominent in the thalamus and the PrPres belongs to the PrPres
of about 19 kDa, identical to that of the FFI PrPres despite the
absence of the FFI mutation in the recipient animal. In
contrast, Tg mice infected with sporadic or familial CJD
develop a prion disease that preferentially involves the cerebral
cortex and form PrPres of about 21 kDa, identical to that of the
donor. These experiments demonstrate that FFI shares
transmissibility with other prion diseases and provide evidence
that prion strain diversity is encrypted in the conformation of
the prion and does not require nucleic acid coded information.
FINAL COMMENTS
Pathophysiology of FFI
The cardinal symptoms of FFI, i.e. apathetic behaviour,
attention deficit, hypovigilance and loss of sleep, sympathetic
hyperactivity, and progressive attenuation of autonomic and
hormonal circadian oscillations, may be related to selective
involvement of the AV and MD thalamic nuclei. In fact, the
severe and consistent atrophy of these nuclei is the only
common finding shared by all FFI cases. The importance of
the thalamus in sleep physiology was first reported by Hess
(1954). Hess' experimental data were criticized and dismissed,
but Villablanca and coworkers later documented that cats in
which the cerebral cortex or thalamus had been ablated
became persistently insomniac (Villablanca and Marcus 1972;
Villablanca and Salinas-Zeballos 1972). These experimental
findings confirmed the importance of the corticothalamic
circuits in sleepwake regulation. Even more recently, Marini
et al. showed that bilateral lesions to the mediodorsal, but not
to the anterior ventral thalamic nuclei impair sleep (Marini et
al. 1988). Clinical evidence confirms these findings: haemor-
rhage in the anterior poles of the thalamus affecting the
anterior ventral and not the mediodorsal thalamic nuclei
provokes apathetic behaviour, but does not impair sleep
(Chung et al. 1996), whereas bilateral paramedian thalamic
strokes affecting the mediodorsal thalamic nuclei result in
hypersomnolent insomnia mimicking in some ways the
disturbed sleepwake cycle characterizing FFI (Guilleminault
et al. 1993). The inability to generate physiological sleep
typical of FFI could be correlated to sleep spindling. Spindling
activities originate in the reticular nucleus, but as this nucleus
is devoid of extrathalamic efferents they must be transmitted
to the cerebral cortex through other thalamic nuclei (Steriade
et al. 1985). The AV thalamic nuclei, however, do not have
reciprocal links with the reticular nucleus, whereas strong
reciprocal bonds link the reticular nucleus to the MD thalamic
nuclei. It is therefore likely that the disappearance of sleep
spindles in the prefrontal cortex is due to atrophy of the MD
nuclei. As the anterior ventral and mediodorsal nuclei connect
the cortical limbic regions (cingulate gyrus and orbitofrontal
cortex) to the hypothalamus, they are considered the visceral
or limbic part of the thalamus. Degeneration of the limbic
thalamus, releasing the hypothalamus from cortical control,
#1999 European Sleep Research Society, J. Sleep Res., 8 (Suppl. 1), 2329.
Paper 05 Disc
could also account for the autonomic and hormonal dysregu-
lation associated with the sleepwake disorder characterizing
FFI (Benarroch and Stotz-Potter 1998).
Starting from von Economo's pioneer findings, clinical and
experimental studies have demonstrated the existence of
activating and deactivating structures, favouring wakefulness
and sleep, running from the lower brain stem to the limbic
cortex (von Economo 1926; Nauta 1946; Sterman and
Clemente 1962; Moruzzi 1972). The most archaic level of this
complex neuronal network is probably represented by the
activating and deactivating neuronal structures of the rhom-
bencephalon. With phylogenetic evolution a second and third
operative level may have formed in the mesencephalon and
hypothalamus and subsequently in the limbic part of the
thalamus and cortex. From this standpoint, the thalamocor-
tical limbic circuitry therefore represents the highest level of a
neuronal network controlling the complex psychological
somatomotor and viscero-endocrine behaviour, which char-
acterizes sleep and wakefulness in mammals and humans
(Lugaresi 1992). The cardinal symptoms that distinguish FFI
from other prion diseases, i.e. loss of sleep, sympathetic
hyperactivity, and flattening of vegetative and endocrine
circadian oscillations, are due to the disconnection between
thalamolimbic and more caudal structures in the central
network that regulates the sleepwake cycle and body home-
ostasis in general (Lugaresi et al. 1998).
Molecular pathogenesis of FFI
It is not yet known whether the symptoms of FFI are due to a
loss or a gain of function by cellular PrP, the latter resulting
in synaptic damage provoked by the mutated but protease
sensitive PrP (PrPM) or by PrPres. PrP knockout animals
(PrP8/8 or null mice) do not present evident pathological
changes, but compared with controls they have longer
circadian periods and a stronger reaction to sleep deprivation
(Tobler et al. 1996). Thus, it cannot be ruled out that the
impairment of the sleepwake rhythm and other circadian
functions is, at least in part, due to a loss of the natural
function of PrPc. On the other hand, the close topographic
link between apoptotic neurons and neuronal loss in FFI
suggests that PrPM or PrPres trigger a selective loss of neurons
in the limbic thalamus and corticolimbic regions. This
hypothesis is supported by the finding that disease trans-
mitted to experimental animals selectively affects the thala-
mus, sparing cortical regions. The selective localization of the
lesions to the limbic thalamus might be due to the binding of
the FFI PrPres to specific receptors of thalamo-limbic
neurons. A recently identified protein on the surface of
cortical and subcortical limbic neurons is not detected in
nonlimbic cortical and subcortical regions and was therefore
named `limbic associated membrane protein' (LAMP) (Zacco
et al. 1990). Proteins such as LAMP could therefore act as
specific receptors for PrPM or PrPres associated with FFI, and
thus explain, at least in part, the selectivity of neuronal
changes in FFI.

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