title: Novel twelve-generation kindred of fatal familial insomnia from germany representing the entire spectrum of disease expression.
abstract: We present a novel large German kindred of fatal familial insomnia (FFI) consisting of three branches and comprising more than 800 individuals of 12 generations, the largest pedigree of any familial prion disease known today. There is a wide spectrum of clinical presentations leading to misdiagnoses of Olivo-Ponto-Cerebellar Atrophy (OPCA), Parkinson's or Alzheimer's disease in addition to Creutzfeldt-Jakob disease (CJD) and Gerstmann-Sträussler-Scheinker (GSS) syndrome. Molecular genetic analysis of the prion protein gene (PRNP) confirmed the mutation D178N segregating with methionine at the polymorphic codon 129 of PRNP in all 7 patients examined. This polymorphism at codon 129 is supposed to discriminate between familial CJD (fCJD) and FFI; the 129M allele determines FFI and 129V fCJD. Furthermore, heterozygosity at this site appears to induce prolonged disease duration as compared to the homozygous condition. The variability of the clinical and pathological findings documented for our patients indicates the difficulty in establishing the diagnosis of FFI on clinical and on pathological grounds alone. In three cases (IX-97, XI-21, V-2) followed up by us prospectively insomnia was an early and severe symptom; however, in case notes analyzed retrospectively this symptom was frequently missed. In contrast to previous reports and in agreement with recent studies we cannot confirm a clear relationship between the status of the M/V polymorphism at codon 129 and the age-of-onset of this disease.
authors.affiliation: Institut für Medizinische Genetik, Universitätsklinikum Charité, Humboldt-Universität zu Berlin, Berlin, Germany.
authors.forename: A
authors.initials: A
authors.lastname: Harder
authors.forename: K
authors.initials: K
authors.lastname: Jendroska
authors.forename: F
authors.initials: F
authors.lastname: Kreuz
authors.forename: T
authors.initials: T
authors.lastname: Wirth
authors.forename: C
authors.initials: C
authors.lastname: Schafranka
authors.forename: N
authors.initials: N
authors.lastname: Karnatz
authors.forename: A
authors.initials: A
authors.lastname: Théallier-Janko
authors.forename: J
authors.initials: J
authors.lastname: Dreier
authors.forename: K
authors.initials: K
authors.lastname: Lohan
authors.forename: D
authors.initials: D
authors.lastname: Emmerich
authors.forename: J
authors.initials: J
authors.lastname: Cervós-Navarro
authors.forename: O
authors.initials: O
authors.lastname: Windl
authors.forename: H A
authors.initials: HA
authors.lastname: Kretzschmar
authors.forename: P
authors.initials: P
authors.lastname: Nürnberg
authors.forename: R
authors.initials: R
authors.lastname: Witkowski
mesh_terms: D017668:Age of Onset; D000682:Amyloid / Q000235:genetics; D004247:DNA / Q000737:chemistry / Q000235:genetics; D004252:DNA Mutational Analysis; D005192:Family Health; D017809:Fatal Outcome; D005260:Female; D015870:Gene Expression; D005858:Germany; D006801:Humans; D008297:Male; D010375:Pedigree; D017354:Point Mutation; D011110:Polymorphism, Genetic; D017096:Prion Diseases / Q000235:genetics* / Q000473:pathology; D000072002:Prion Proteins; D011328:Prions; D011498:Protein Precursors / Q000235:genetics
chemical_list: D000682:Amyloid; C512656:PRNP protein, human; D000072002:Prion Proteins; D011328:Prions; D011498:Protein Precursors; D004247:DNA