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Paper 05 Disc
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
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 Japanese, two Australian, eight German, one Austrian, and
examined other patients with FFI referred to subacute familial two British (Gambetti and Lugaresi 1998).
encephalopathy with hypersomnia. We may have avoided Recently Parchi et al. (unpublished data) observed some
confusion had we adopted the term agrypnia, but the term is patients with a prion disease in which the clinical and
virtually obsolete and was thus deemed inappropriate. 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
EPIDEMIOLOGY (PREVALENCE DATA)
and the prion protein resistant fragments had the same size
Currently, 25 apparently unrelated FFI families have been and shape observed in FFI. These data seem to confirm the
described: five Italian, two French, four American, one existence of sporadic cases of FFI. In all we have studied three
#1999 European Sleep Research Society, J. Sleep Res., 8 (Suppl. 1), 2329.
Paper 05 Disc
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 vegetative state may precede death by days or months (Gallassi
belonged to FFI kindred I (Fig. 1), three belonged to FFI et al. 1996; Montagna et al. 1998).
kindred II, and one belonged to FFI kindred III.
Motor signs
CLINICAL FEATURES
Ataxia and dysarthria appear weeks or months after the sleep
wake behavioural disturbances in homozygotes, or at disease
Onset and duration
onset in heterozygotes. In addition, in short evolution cases
The disease presents at 51 + 8 years. In homozygotes at codon (homozygotes) ataxia and dysarthria may be milder until death,
129 (coding methionine also in the nonmutated allele) the clinical whereas long evolution cases (heterozygotes) worsen displaying
course is relatively short (12 + 4 months). In heterozygotes astasia-abasia and incomprehensible speech; evoked and
(expressing valine in the nonmutated allele) the clinical course is spontaneous myoclonic jerks are seen in the middle and the
longer (21 + 15 months) (Gambetti and Lugaresi 1998). advanced stages of the disease. In some cases transient dyplopia
and sporadic GM seizures are reported (Montagna et al. 1998).
Neuropsychology
Autonomic and hormonal findings
Patients appear apathetic and unable to pay sustained atten-
tion to their surroundings. When not stimulated, they tend to Increased perspiration and salivation, impotence and con-
become sleepy and manifest recurrent behavioural episodes stipation, tachycardia, systemic hypertension, and mild fever
mimicking a dream (oneiric stupor). In more advanced stages, appear early and progressively worsen. Cardiovascular func-
the vigilance level declines leading to a persistent stupor; a tion tests disclose elevated background and stimulated
#1999 European Sleep Research Society, J. Sleep Res., 8 (Suppl. 1), 2329.
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26 P. Cortelli et al.
#1999 European Sleep Research Society, J. Sleep Res., 8 (Suppl. 1), 2329.
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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 kDa. Second, the glycoform ratio (i.e. the ratio among the
is milder and less consistent. In short duration cases PrPres forms that contain two, one, and no sugars, respectively)
pathological changes of the cerebral cortex are absent or is characterized by a marked under-representation of the
confined to mild spongiosis and gliosis in the orbitofrontal unglycosylated form. In contrast, CJD178 is characterized by a
region. In long duration cases, spongiosis and gliosis diffusely protease-resistant PrPres fragment of & 21 kDa (Monari et al.
involve the limbic cortical regions (orbitofrontal cortex and 1994; Parchi et al. 1995). The finding that protease treatment
cingulate gyrus) and less severely the neocortical regions generates PrPres of a different size is an indication that the two
(frontotemporal and parietal lobes are more affected than the types of PrPres have a different conformation. Moreover, in
occipital lobes). The inferior olives are often and severely FFI, the PrPres is distributed more widely than the histo-
affected (Parchi et al. 1998). 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
MOLECULAR PATHOLOGY
and mid-brain (periaqueductal gray matter) as well as in the
FFI cosegregates with a point mutation of the PRNP gene at thalamus. In the long-evolution cases, PrPres fragments
codon 178 resulting in the substitution of aspartic acid with become detectable in significant amounts also in the neocortex
asparagine in the prion protein and with methionine at the and basal ganglia. The average amount of PrPres in FFI,
methionine/valine polymorphic codon 129 of the mutated however, is 510-fold less than that detected in the most
allele (Medori et al. 1992; Goldfarb et al. 1992). The same common variants of sporadic and familial CJD (Parchi et al.
point mutation at codon 178 coupled with valine at codon 129 1995, 1998).
in the mutated allele leads to a disease clinically and Apoptotic neurons were identified only in the cerebral
pathologically different from FFI and characterized by ataxia lesions presenting histopathological injury (thalamus, bulbar
and dementia and by diffuse cortical spongiosis, while the olives in homozygotes, and additionally the neocortex in
thalamus is relatively spared. This disease is known as CJD heterozygotes (Dorandeu et al. 1998). They were accompanied
178, a familial variant of Creutzfeldt-Jakob disease. As by major microglial proliferation, but were not specifically
mentioned above, homozygotes at codon 129 have a shorter related to the location of PrPres fragments. Thus, neuronal
clinical course, a sleepwake disorder and dysautonomia more apoptosis originates from biopathological processes not linked
prominent at onset, hypometabolism as evidenced by PET to PrPres deposits.
studies, and pathology restricted to the thalamus.
TRANSMISSIBILITY OF FFI
PrP R E S AND APOPTOSIS
Intracerebral inoculation of transgenic mice (Tg) expressing a
In FFI, PrPres has two characteristic features. First, the size of chimeric human mouse PrPc, with a homogenate from FFI
the fragment generated by treatment with proteases is about 19 brains gives rise to a prion disease 200 days after inoculation
#1999 European Sleep Research Society, J. Sleep Res., 8 (Suppl. 1), 2329.
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28 P. Cortelli et al.
(Telling et al. 1996). In the recipient animals, the pathology is could also account for the autonomic and hormonal dysregu-
prominent in the thalamus and the PrPres belongs to the PrPres lation associated with the sleepwake disorder characterizing
of about 19 kDa, identical to that of the FFI PrPres despite the FFI (Benarroch and Stotz-Potter 1998).
absence of the FFI mutation in the recipient animal. In Starting from von Economo's pioneer findings, clinical and
contrast, Tg mice infected with sporadic or familial CJD experimental studies have demonstrated the existence of
develop a prion disease that preferentially involves the cerebral activating and deactivating structures, favouring wakefulness
cortex and form PrPres of about 21 kDa, identical to that of the and sleep, running from the lower brain stem to the limbic
donor. These experiments demonstrate that FFI shares cortex (von Economo 1926; Nauta 1946; Sterman and
transmissibility with other prion diseases and provide evidence Clemente 1962; Moruzzi 1972). The most archaic level of this
that prion strain diversity is encrypted in the conformation of complex neuronal network is probably represented by the
the prion and does not require nucleic acid coded information. 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
FINAL COMMENTS
hypothalamus and subsequently in the limbic part of the
thalamus and cortex. From this standpoint, the thalamocor-
Pathophysiology of FFI
tical limbic circuitry therefore represents the highest level of a
The cardinal symptoms of FFI, i.e. apathetic behaviour, neuronal network controlling the complex psychological
attention deficit, hypovigilance and loss of sleep, sympathetic somatomotor and viscero-endocrine behaviour, which char-
hyperactivity, and progressive attenuation of autonomic and acterizes sleep and wakefulness in mammals and humans
hormonal circadian oscillations, may be related to selective (Lugaresi 1992). The cardinal symptoms that distinguish FFI
involvement of the AV and MD thalamic nuclei. In fact, the from other prion diseases, i.e. loss of sleep, sympathetic
severe and consistent atrophy of these nuclei is the only hyperactivity, and flattening of vegetative and endocrine
common finding shared by all FFI cases. The importance of circadian oscillations, are due to the disconnection between
the thalamus in sleep physiology was first reported by Hess thalamolimbic and more caudal structures in the central
(1954). Hess' experimental data were criticized and dismissed, network that regulates the sleepwake cycle and body home-
but Villablanca and coworkers later documented that cats in ostasis in general (Lugaresi et al. 1998).
which the cerebral cortex or thalamus had been ablated
became persistently insomniac (Villablanca and Marcus 1972;
Molecular pathogenesis of FFI
Villablanca and Salinas-Zeballos 1972). These experimental
findings confirmed the importance of the corticothalamic It is not yet known whether the symptoms of FFI are due to a
circuits in sleepwake regulation. Even more recently, Marini loss or a gain of function by cellular PrP, the latter resulting
et al. showed that bilateral lesions to the mediodorsal, but not in synaptic damage provoked by the mutated but protease
to the anterior ventral thalamic nuclei impair sleep (Marini et sensitive PrP (PrPM) or by PrPres. PrP knockout animals
al. 1988). Clinical evidence confirms these findings: haemor- (PrP8/8 or null mice) do not present evident pathological
rhage in the anterior poles of the thalamus affecting the changes, but compared with controls they have longer
anterior ventral and not the mediodorsal thalamic nuclei circadian periods and a stronger reaction to sleep deprivation
provokes apathetic behaviour, but does not impair sleep (Tobler et al. 1996). Thus, it cannot be ruled out that the
(Chung et al. 1996), whereas bilateral paramedian thalamic impairment of the sleepwake rhythm and other circadian
strokes affecting the mediodorsal thalamic nuclei result in functions is, at least in part, due to a loss of the natural
hypersomnolent insomnia mimicking in some ways the function of PrPc. On the other hand, the close topographic
disturbed sleepwake cycle characterizing FFI (Guilleminault link between apoptotic neurons and neuronal loss in FFI
et al. 1993). The inability to generate physiological sleep suggests that PrPM or PrPres trigger a selective loss of neurons
typical of FFI could be correlated to sleep spindling. Spindling in the limbic thalamus and corticolimbic regions. This
activities originate in the reticular nucleus, but as this nucleus hypothesis is supported by the finding that disease trans-
is devoid of extrathalamic efferents they must be transmitted mitted to experimental animals selectively affects the thala-
to the cerebral cortex through other thalamic nuclei (Steriade mus, sparing cortical regions. The selective localization of the
et al. 1985). The AV thalamic nuclei, however, do not have lesions to the limbic thalamus might be due to the binding of
reciprocal links with the reticular nucleus, whereas strong the FFI PrPres to specific receptors of thalamo-limbic
reciprocal bonds link the reticular nucleus to the MD thalamic neurons. A recently identified protein on the surface of
nuclei. It is therefore likely that the disappearance of sleep cortical and subcortical limbic neurons is not detected in
spindles in the prefrontal cortex is due to atrophy of the MD nonlimbic cortical and subcortical regions and was therefore
nuclei. As the anterior ventral and mediodorsal nuclei connect named `limbic associated membrane protein' (LAMP) (Zacco
the cortical limbic regions (cingulate gyrus and orbitofrontal et al. 1990). Proteins such as LAMP could therefore act as
cortex) to the hypothalamus, they are considered the visceral specific receptors for PrPM or PrPres associated with FFI, and
or limbic part of the thalamus. Degeneration of the limbic thus explain, at least in part, the selectivity of neuronal
thalamus, releasing the hypothalamus from cortical control, changes in FFI.
#1999 European Sleep Research Society, J. Sleep Res., 8 (Suppl. 1), 2329.
Paper 05 Disc
#1999 European Sleep Research Society, J. Sleep Res., 8 (Suppl. 1), 2329.