Fatal Familial Insomnia (FFI)

What is Fatal Familial Insomnia (FFI)?
Fatal Familial Insomnia (FFI) is an inherited disease that affects a brain region called the thalamus, which is partially responsible for controlling sleep. The disease causes dementia and a progressive insomnia that eventually leads to a complete lack of sleep.

Fatal Familial Insomnia (FFI) and its sporadic form (sFI) are two phenotypically similar prion diseases characterized by the loss of the ability to sleep (especially nonREM sleep) and other related circadian rhythms, dysautonomia and motor signs associated with early and severe neuronal loss in thalamic nuclei, especially of the medial dorsal and anterior ventral nuclei.

Although the pathogenic mechanism remains to be identified, evidence suggests that the D178N- 129M mutated PrP likely plays a central role in the sleep impairment of FFI and sFI, pointing to normal PrP as having a role in sleep regulation. It has been proposed that the severe neuronal loss in medial dorsal and anterior ventral thalamic nuclei disconnects the limbic cortex from the brain stem, leading to a generalized activation syndrome (GAS) with inability to sleep, autonomic and motor activation.

This hypothesis is supported by the observation that Morvan's chorea, a rare autoimmune disorder, and delirium tremens are also characterized by the inability of generate slow wave sleep, and by autonomic and motor over activation, and both are related to thalamic dysfunction. However, in FFI and sFI the presence of the mutated PrP and PrPSc in the brain of FFI and sFI patients is widespread and goes far beyond the thalamus. Therefore, other mechanism and brain locales cannot be excluded. Animal models may serve to clarify the mechanisms of sleep impairment in FFI and sFI.

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