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Fatal Familial Insomnia H_Fatal.qxd 27/04/2004 10:06 Page 2 (Black plate) CURRENT MEDICINE FATAL FAMILIAL INSOMNIA N Gordon, Retired Neurologist, Wilmlslow, Cheshire INTRODUCTION symptom, and four of the patients developed insomnia Fatal familial insomnia (FFI) is a rapidly progressive and autonomic dysfunction Analysis of the prion autosomal dominant disease, and may be the third most protein gene revealed the codon 178 point mutation and common inherited prion disease1, 2 Its duration is from methionine homozygosity at position 129 Autopsies in about 736 months, with an onset of between ages 35 four of the patients confirmed thalamic and olivary and 61 years There are two groups, one with a short degeneration, as well as cortical and brain stem lesions duration (9·1+1·1 months) and one with a prolonged In another report, in a 12-generation kindred from duration (30·8+21·3 months)3 Apart from the Germany, the difficulties of diagnosis are stressed due to examples of inherited disease a number of sporadic the variability of the clinical and pathological findings14 cases have been reported,4 and animal experiments have shown that it shares transmissibility with other prion THE PATHOLOGY OF FFI diseases5 Typical findings include marked atrophy of the anteroventral and mediodorsal thalamic nuclei, and SYMPTOMS AND SIGNS varying degrees of cerebral and cerebellar cortical The condition presents with a progressive loss of the gliosis, as well as olivary atrophy15 Spongiosis of the ability to sleep, associated with dysautonomia and cortex can also be present7 In contrast to other prion endocrine and motor disturbances6 The autonomic diseases pavalbumin-positive neurons, which are a subset ones include hyperhidrosis, hyperthermia, tachycardia of GABAergic interneurons, are well preserved or only and hypertension; respiratory problems have also been moderately reduced, especially in the temporal cortex 7 reported that may be related to brainstem lesions and adjacent hippocampus16 The differences from other Overall motor activity is markedly increased, and this prion diseases on light microscopy are not found on energy expenditure can contribute to progressive electron microscopy, the ultrastructural picture being 8 exhaustion and death Neurological abnormalities much the same, including the presence of comprise diplopia, ataxia, dysarthria, pyramidal tract tubulovesicular structures17 signs, abnormalities of muscle tone and myoclonus Complex hallucinations and dreams are common9 Cortisol levels may be high with normal The lesions in the thalamus may well be related to the adrenocorticotrophic hormone (ACTH) levels disturbances of sleep and endocrine functions in this suggesting hypercortisolism, while melatonin and condition, as the role of the thalamus in controlling sleep somatotropin levels gradually decline3 Poly- and sleep-related behavioural and metabolic changes, somnographic recordings can confirm a markedly and of growth hormone, prolactin, and melatonin reduced total sleep time, and gross regulation, has been reported18, 19 The role of thalamic electroencephalographic disorganisation of sleep lesions in causing insomnia is supported by the finding of patterns including a virtual absence of typical rapid-eye- a variety of Creutzfeldt-Jakob disease (CJD) in which the movement (REM) periods and deeper non-REM phases thalamus is particularly affected and in whom intractable characterised by K-complexes, spindles and slow insomnia is a prominent feature20 The lesions in the waves10 thalamus consist of selective atrophy of the anteroventral and mediodorsal nuclei that constitute the Fatal familial insomnia has been reported in many limbic part of the thalamus, interconnecting limbic and countries in Europe and around the world11 For paralimbic regions of the cortex and other subcortical example, Padovani et al12 have reported a family in Italy structures in the limbic system, including the The propositus showed disorders of behaviour, sleep, hypothalamus The connections of the mediodorsal cognition and motor function, associated with thalamic nuclei are of particular importance The hypothalamus and olivary atrophy, and with spongiosis confined to the released from cortico-limbic control is shifted to a parahippocampal gyrus However,the protease-resistant prevalence of activating, as opposed to deactivating, prion protein was widely distributed in the brain It was functions such as loss of sleep, sympathetic hyperactivity considered that the duration of the disease determined and the attendant attenuation of autonomic circadian the histopathology and the distribution of this protein, and endocrine oscillations This confirms that the limbic rather than codon 129 polymorphism Almer et al13 thalamus has an important role, through controlling studied five patients in an Austrian family, suffering from autonomic responses, in regulating the bodys this condition Severe loss of weight was an early homeostasis19, 21 106 J R Coll Physicians Edinb 2004; 34:106108 H_Fatal.qxd 27/04/2004 10:06 Page 3 (Black plate) CURRENT MEDICINE Neuronal loss is certainly a predominant feature in FFI, magnetic resonance imaging are non-specific, although and Dorandeu et al22 have shown that this loss may positron emission tomography may be helpful32 Bär et occur through an apoptotic process al33 and Cortelli et al34 have confirmed that the results of the latter were compatible with progressive thalamic Wanschitz et al23 studied the serotonergic system in hypometabolism, and that this was a stable finding, eight patients with FFI, and found no total neuronal loss present in the early stages of the disease; while cortical in median raphe nuclei but a substantial increase of hypometabolism varied with the clinical presentation tyrosine hydroxylase positive (TH+) neurons compared and the stage of the disease with controls This may result in an enhanced role for serotonin and explain some of the symptoms of the However, there seems to be no doubt that the prion condition For example, the disturbance of the protein gene plays a part in regulating sleep in both sleepwake cycle and some of the exaggerated normal subjects and in those with this disease In FFI cardiovascular responses However, Correlli et al24 there is a progressive reduction in total sleep time, early advised against contributing too many of the symptoms disappearance of sleep spindles, loss of slow wave sleep to this finding as there may be a number of other and disintegration of sleep cycle organisation35 It has reasons Klöppel et al25 have also demonstrated a also been found that the relevant mutation at codon 178 significantly reduced availability of serotonin in FFI does not induce any sleep spindling or slow wave transporters in the thalamus-hypothalamus region in activity alteration before the clinical onset, or differences affected patients in the sleep EEG composition between carriers and non- carriers of the codon 178 FFI mutation36 THE GENETICS OF FFI This condition is a transmissible spongiform Apart from differentiating FFI from other prion diseases, encephalopathy linked to a point mutation at codon 178 especially Gerstmann-Sträussler-Scheinker disease,37 it of the prion protein gene located on the short arm of may be necessary to exclude other degenerative chromosome 20,26 which results in an aspartic acid to disorders by appropriate investigations For example, asparigine substitution In FFI the mutation is coupled Morvans syndrome of myokymia, muscle pain, excessive with the methionine codon at position 129 of the sweating, and disordered sleep, which can show almost mutant allele in a cis relation (on the same chromosome identical biochemical findings but not antibodies to pair),27 to the 178 codon mutation, whereas in CJD the voltage-gated K+ channels38 coupling is with the valine codon at position 1298, 12 Some studies have shown that the genotype-phenotype THE TREATMENT OF FFI correlation is not as tight for the aspartic acid to The giving of sedatives and hypnotics such as asparigine mutation at codon 178 as had been benzodiazepines and barbiturates may well be of limited supposed,27 and that the phenotypic expression may be value, but treatment with gammahydroxybutyrate may influenced by multiple factors28 For example, a subtype be of some help11 If a significant disturbance of of sporadic prion disease has been described which serotonin function is confirmed there may be a role for mimics closely the characteristics of FFI but lacks the treatment with serotonin antagonists in the treatment mutation at codon 178 of the prion protein gene29 of FFI24 Patients with short duration of the disease have been found to be homozygous (methionine/methionine) at CONCLUSIONS codon 129, whereas those with a long duration were Fatal familial insomnia is certainly an unusual and heterozygous (methionine/valine) at this codon30 It has uncommon disease, but it does help to shed new light on also been shown that the homozygotes had more prion diseases in general and on sleep disorders in prominent dreams, insomnia and dysautonomia at the particular Its study emphasises the role of the thalamus onset, and histopathological changes are more restricted in controlling sleep and in causing dreams The hope for to the thalamus, whereas the heterozygotes showed an the future is that the ongoing research into prion onset with ataxia, dysarthria, earlier sphincter loss and diseases will result in more effective prevention and grand mal seizures, and more extensive cortical treatment involvement9, 31 REFERENCES THE DIAGNOSIS
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