Abstract
Fatal Familial Insomnia is a hereditary prion disease characterized by a mutation at codon 178 of the prion protein gene cosegregating with the methionine polymorphism at codon 129 of the mutated allele. It is characterized by disturbances of the wake‐sleep cycle, dysautonomia and somatomotor manifestations (myoclonus, ataxia, dysarthria, spasticity). PET studies disclose severe thalamic and additionally cortical hypometabolism. Neuropathology shows marked neuronal loss and gliosis in the thalamus, especially the medio‐dorsal and anterior‐ventral nuclei, olivary hypertrophy and some spongiosis of the cerebral cortex. Detailed analysis of 14 cases from 5 unrelated families showed that patients ran either a short (9.1+ 1.1 months) or a prolonged (30.8 + 21.3 months) clinical course according to whether they were homozygote met/met or heterozygote met/val at codon 129. Moreover, homozygotes had more prominent oneiric episodes, insomnia and dysautonomia at onset, whereas heterozygotes showed ataxia and dysarthria at onset, earlier sphincter loss and epileptic Grand Mai seizures; they also displayed more extensive cortical involvement on PET and at postmortem examination. Our data suggest that the phenotype expression of Fatal Familial Insomnia is related, at least partly, to the polymorphism at codon 129 of the prion protein‐gene.
Full Text
The Full Text of this article is available as a PDF (89.4 KB).
References
- 1. Baker HF, Poulter M, Crow TJ, Frith CD, Lofthouse R, Ridley RM and Collinge J (1991) Amino acid polymorphism in human prion protein and age at death in inherited prion disease. Lancet 337: 1286. [DOI] [PubMed] [Google Scholar]
- 2. Chen SG, Parchi P, Brown P, Capellari S, Zou W, Cochran EJ, Vnencak‐Jones CL, Julien J, Vital C, Mikol J, Lugaresi E, Autilio‐Gambetti L and Gambetti P (1997) Allelic origin of the abnormal prion protein isoform in familial prion diseases. Nature Med 3: 1009–1015. [DOI] [PubMed] [Google Scholar]
- 3. Collinge J, Palmer MS, Dryden AJ (1991) Genetic predisposition to iatrogenic Creutzfeldt‐Jakob disease. Lancet 337:1441–1442. [DOI] [PubMed] [Google Scholar]
- 4. Cortelli P, Parchi P, Contin M, Pierangeli G, Avoni P, Tinuper P, Montagna P, Baruzzi A, Gambetti P, Lugaresi E (1991) Cardiovascular dysautonomia in fatal familial insomnia. Clin Autonom Res 1: 15–21. [DOI] [PubMed] [Google Scholar]
- 5. Cortelli P, Perani D, Parchi P, Grassi F, Montagna P, De Martin M, Castellani R, Tinuper P, Gambetti P, Lugaresi E, and Fazio F (1997) Cerebral metabolism in fatal familial insomnia: Relation to duration, neuropathology, and distribution of protease‐resistent prion protein. Neurology 49: 126–133. [DOI] [PubMed] [Google Scholar]
- 6. Gallassi R, Morreale A, Montagna P, Gambetti P, Lugaresi E (1992) “Fatal Familial Insomnia”: neuropsychological study of a disease with thalamic degeneration. Cortex 28: 175–187. [DOI] [PubMed] [Google Scholar]
- 7. Gallassi R, Morreale A, Montagna P, Cortelli P, Avoni P, Castellani R, Gambetti P, and Lugaresi E (1996) Fatal Familial Insomnia: behavioral and cognitive features. Neurology 46: 935–939. [DOI] [PubMed] [Google Scholar]
- 8. Gambetti P, Medori R, Manetto V, Petersen R, LeBlanc A, Tritschler HJ, Monari L, Tabaton M, and Autilio‐Gambetti L (1994) Fatal Familial Insomnia. A Prion Disease with Distinctive Histopathological and Genotypic Features. In: Guilleminault C, Lugaresi E, Montagna P, Gambetti P, (Eds.), Fatal Familial Insomnia: Inherited Prion Diseases, Sleep, and the Thalamus, Chapter 3, pp. 27–31, Raven Press, New York . [Google Scholar]
- 9. Julien J, Vital C, Deleplanque B, Lagueny A, Ferrer X (1990) Atrophie thalamique subaiguë familiale. Troubles mnésiques et insomnie totale. Rev Neurol (Paris) 146: 173–178. [PubMed] [Google Scholar]
- 10. Lugaresi A, Baruzzi A, Cacciari E, Cortelli P, Medori R, Montagna P, Tinuper P, Zucconi M, Roiter I, Lugaresi E (1987) Lack of vegetative and endocrine circadian rhythms in fatal familial thalamic degeneration. Clin Endocrinol 26: 573–580. [DOI] [PubMed] [Google Scholar]
- 11. Montagna P, Cortelli P, Tinuper P, Sforza E, Avoni P, Gallassi R, Morreale A, Roiter I, Perani D, Lucignani G, Fazio F, and Lugaresi E (1994) Fatal Familial Insomnia. A Disease That Emphasizes the Role of the Thalamus in the Regulation of Sleep and Vegetative Functions. In: Guilleminault C, Lugaresi E, Montagna P, Gambetti P, (Eds.), Fatal Familial Insomnia: Inherited Prion Diseases, Sleep, and the Thalamus, Chapter 1, pp. 1–14, Raven Press, New York . [Google Scholar]
- 12. Medori R, Tritschler HJ, LeBlanc A, Villare F, Manetto V, Chen HY, Xue R, Leal S, Montagna P, Cortelli P, Tinuper P, Avoni P, Mochi M, Baruzzi A, Hauw JJ, Ott J, Lugaresi E, Autilio‐Gambetti L, and Gambetti P (1992) Fatal Familial Insomnia, a prion disease with a mutation at codon 178 of the prion protein gene. N Engl J Med 326: 444–449. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 13. Owen F, Poulter M, Collinge J, Leach M, Shah T, Lofthouse R, Chen Y, Crow TJ, Harding AE, Hardy J and Rossor MN (1991) Insertions in the prion protein gene in atypical dementias. Exp Neurol 112: 240–242. [DOI] [PubMed] [Google Scholar]
- 14. Palmer MS, Dryden AJ, Hughes JT, Collinge J (1991) Homozygous prion protein genotype predisposes to sporadic Creutzfeldt‐Jakob disease. Nature 352:340–342. [DOI] [PubMed] [Google Scholar]
- 15. Parchi P, Castellani R, Cortelli P, Montagna P, Chen SG, Petersen RB, Manetto V, Vnencak‐Jones CL, McLean MJ, Sheller JR, Lugaresi E, Autilio‐Gambetti L, and Gambetti P (1995) Regional Distribution of Protease‐resistant Prion Protein in Fatal Familial Insomnia. Ann Neurol 38: 21–29. [DOI] [PubMed] [Google Scholar]