Fatal Familial Insomnia: Clinical Aspects and Molecular Alterations.
Fatal familiar insomnia (FFI) is an autosomal dominant inherited prion disease caused by D178N mutation in the prion protein gene (PRNP D178N) accompanied by the presence of a methionine at the codon 129 polymorphic site on the mutated allele. FFI is characterized by severe sleep disorder, dysautonomia, motor signs and abnormal behaviour together with primary atrophy of selected thalamic nuclei and inferior olives, and expansion to other brain regions with disease progression. This article reviews recent research on the clinical and molecular aspects of the disease.



New clinical and biomarker tools have been implemented in order to assist in the diagnosis of the disease. In addition, the generation of mouse models, the availability of 'omics' data in brain tissue and the use of new seeding techniques shed light on the molecular events in FFI pathogenesis. Biochemical studies in human samples also reveal that neuropathological alterations in vulnerable brain regions underlie severe impairment in key cellular processes such as mitochondrial and protein synthesis machinery. Although the development of a therapy is still a major challenge, recent findings represent a step toward understanding of the clinical and molecular aspects of FFI.
Department of Neurology, Clinical Dementia Center, University Medical Center, Georg-August University, Robert Koch Strasse 40, Göttingen, Germany. Franc.llorens@gmail.com.|German Center for Neurodegenerative Diseases (DZNE)-site Göttingen, Göttingen, Germany. Franc.llorens@gmail.com.
Franc
F
Llorens
Neurology Department, University Hospital Cruces, University of the Basque Country, Bilbao, Bizkaia, Spain.
Juan-José
JJ
Zarranz
German Center for Neurodegenerative Diseases (DZNE)-site Göttingen, Göttingen, Germany.
Andre
A
Fischer
Department of Neurology, Clinical Dementia Center, University Medical Center, Georg-August University, Robert Koch Strasse 40, Göttingen, Germany.|German Center for Neurodegenerative Diseases (DZNE)-site Göttingen, Göttingen, Germany.
Inga
I
Zerr
Institute of Neuropathology, Bellvitge University Hospital-IDIBELL, L'Hospitalet de Llobregat, c/Feixa Llarga sn, 08907, Barcelona, Spain. 8082ifa@gmail.com.|University of Barcelona, L'Hospitalet de Llobregat, Barcelona, Spain. 8082ifa@gmail.com.|CIBERNED (Network Centre for Biomedical Research of Neurodegenerative Diseases), Institute Carlos III, Ministry of Health, Madrid, Spain. 8082ifa@gmail.com.
Isidro
I
Ferrer
D000818:Animals; D015415:Biomarkers / Q000032:analysis; D001921:Brain; D006801:Humans; D034062:Insomnia, Fatal Familial / Q000175:diagnosis / Q000235:genetics*; D009154:Mutation; D000072002:Prion Proteins / Q000235:genetics
D015415:Biomarkers; D000072002:Prion Proteins
Fatal familial insomnia; Hereditary prion disease; Neurodegenerative diseases; Prion protein; Thalamus