Fatal familial insomnia is associated with mutation in the prion protein gene.
FFI, an autosomal dominant disorder, is characterized by neuronal degeneration limited to selected thalamic nuclei and progressive insomnia.
FFI is related to the asp178-to-asn mutation of the PRNP gene when the amino acid at position 129 is methionine; the same mutation results in Creutzfeldt-Jacob disease when the amino acid at position 129 is valine
Clinical Features
Dreamlike status, dysarthria, tremor, and myoclonus subsequently developed and led to coma and death after 9 months. Thus two sisters of the patient and many relatives over 3 generations had died of a similar disease.
Pathologic the brains’ studies of the patient and 1 of his sisters showed severe neuronal degeneration, with reactive astrocytosis limited to the anterior and dorsomedial thalamic nuclei and without spongiosis or vascular or inflammatory changes.
Though diffuse degenerative processes of the nervous system often affect the thalamus, this disorder appeared to be a genetically determined degenerative disease limited to selected thalamic nuclei.
In 1995 was found protease-resistant prion protein in gray matter but not white matter of peripheral organs from 9 autopsied subjects with fatal familial insomnia.
Generally, the degree of histopathologic change correlated with the amount of the abnormal protein.
Nevertheless, the mediodorsal thalamic nucleus showed severe neuronal loss and astrogliosis in association with relatively modest amounts of abnormal prion protein, suggesting to the authors a higher vulnerability of this region.
In 1990 was reported that despite a thorough search for similar cases in the literature and through neurologists and neuropathologists, the only additional cases they found were members of the same kindred: 4 in a branch of the family that emigrated from Italy to Belgium and France and 1 from the Italian branch of the family.
In 1999 was presented large German kindred with fatal familial insomnia. Molecular genetic study of the PRNP gene confirmed that the D178N mutation segregated with methionine at the polymorphic codon 129 in all 7 affected patients examined.
The researchers entered a wide spectrum of clinical presentations and emphasized the difficulty in establishing the diagnosis of fatal familial insomnia on clinical and pathologic grounds alone.
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