What Is Fatal Familial Insomnia?
Fatal familial insomnia (FFI) is an inherited (autosomal dominant) prion disease in which asparagine is substituted for aspartic acid at the 178 codon of the PrNP gene. Additionally, methionine (Met) occurs at codon 129 of the same mutated gene.[1,2] When methionine is also found at codon 129 of the nonmutated allele (Met-Met), the disease tends to run a shorter course than when the position is occupied by valine (Met-Val).
The chief clinical features of FFI include a progressive and ferocious insomnia, waking "sleep," hallucinations, autonomic disturbances suggestive of sympathetic overdrive (tachycardia, hypertension, hyperhidrosis, hyperthermia), a rise in circulating catecholamine levels, cognitive changes (such as attentional disturbance and short-term memory deficits without a loss in general intelligence), motor system deficits (ataxia), and endocrine manifestations. Later cognitive changes involve a confusional state resembling dementia and, ultimately, death.
Mean age at onset is approximately 50 years, with most cases occurring between age20 and 61 years of age.[3,4,5] Age of onset cannot be predicted from polymorphism at the 129 codon. Before clinical onset, the presence of FFI PrP mutant does not seem to affect function. Sensitive tests such as the PET scan and the premorbid EEG are normal. Onset occurs when a critical amount of PrP is converted to PrPres (prion) protein. The trigger for this protein conversion is unknown.
The typical duration of FFI is between 7 and 36 months, with a mean duration of 18 months. Population studies show shorter mean survival time for Met-Met patients (12 ± 4 months) than for Met-Val patients, (21 ± 15 months).[3,9] These values are of particular relevance, because our case involves a Met-Met patient who surpassed 26 months of illness.
Clinically, 4 stages of FFI have been delineated, progressing from moderately disturbing to totally disabling. Although clinical symptomatology is related to polymorphism at codon 129, most end-stage patients are noninteractive and unable to care for themselves.
The neuropathologic manifestations of FFI include thalamic degeneration, with selective involvement of the anterior ventral and mediodorsal thalamic nuclei, inferior olivary and cerebellar changes, and some spongiform change of the cerebral cortex. Pathology of the neocortex varies with the disease duration and appears essentially spared of spongiosis in cases lasting less than 1 year (eg, Met-Met patients). The occipital lobe is relatively unaffected compared with the frontal, parietal, and temporal lobes. By contrast, the entorhinal cortex shows spongiosis and astrogliosis in virtually all patients. Insofar as the magnitude of degeneration increases with the disease duration, those who die early show far less neurologic involvement than those who live longer.
The relationship between the topography of PrPres (prion protein) and neural dysfunction is unclear. In FFI, PrPres appears to be more widespread than suggested by lesions or areas of hypometabolic function. Furthermore, the magnitude of PrPres is not correlated with clinical severity, nor does its distribution parallel that of cellular apoptosis. Finally, structures that contain equal amounts of PrPres (such as the thalamus and brainstem) are differentially vulnerable, the thalamus being much more so. All FFI patients show similar amounts of PrPres in the thalamus and brainstem. However, those whose disease runs a short duration show the least amount and most focal distribution of PrPres, with the main accumulation being primarily in limbic areas (eg, entorhinal cortex or the cingulate gyrus) and in subcortical structures (including the thalamus, hypothalamus, and brainstem). With disease of longer duration, the abnormal protein becomes detectable in the cerebral cortex and eventually exceeds the amount observed in subcortical areas.
Thus, 2 interpretations regarding the role of PrPres are possible. Either PrPres is not toxic and programmed cell death results from the loss of important signals from the normally protective PrNP, or PrPres is toxic but different types of neural tissue are differentially vulnerable to it, in ways related to both tissue type and polymorphic status of C 129. Tobler and colleagues studied PrP knockout mice and suggested that normal PrP is necessary for sleep. Compared with the sleep of wild-type mice, sleep of knockout mice was more fragmented, showed smaller amplitude, slow waves of non-REM, and a stronger response to sleep deprivation.
Apoptosis or programmed cell death is a dynamic process, the consequence of activating signals and specific protein synthesis in the dying cell. It differs from necrosis in that it is not accompanied by local inflammation. In FFI patients (but not controls), apoptotic tissue was observed in a distribution and abundance that closely correlated with neuronal loss. The mechanism of apoptosis in FFI is unknown, although a possible cause is the differentiation of microglia into macrophages, which is known to occur following neural damage. This transformation is accompanied by the release of cytotoxins including free oxygen radicals, cytokines, or nitric oxide (NO), which may contribute to both cell death and the gliosis observed in FFI. In Dorandeu's study, immunologic evidence for the presence of NO was supportive but relatively weak. To the extent that free oxygen radicals underlie cellular apoptosis, antioxidant therapy may possibly offer some protection against these ravages.
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Cite this: Self Management of Fatal Familial Insomnia. Part 1: What Is FFI? - Medscape - Sep 12, 2006.