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.

Transmissible spongiform encephalopathies with P102L mutation of PRNP manifesting different phenotypes: clinical, neuroimaging, and electrophysiological studies in Chinese kindred in Taiwan

“…Homozygosity at 129 was reported to increase disease susceptibility, and patients with heterozygosity at 129 had a later AO in sporadic CJD [1], GSS with F198S [10], and FFI [14,21]. Furthermore, the polymorphism in codon 129 was once found to affect the phenotypes of sporadic CJD [32].…”

Fatal familial insomnia: Clinical features and early identification

“…2,4 An influence of the M129V genotype on disease duration was seen in our FFI patients, a finding that corresponds to the longer survival associated with the MV genotype compared with the MM genotype in sCJD. 15 Whereas Montagna and colleagues 6 reported similar data, Harder and coauthors 3,16 did not ob- serve any significant association between disease duration and genotype at codon 129. However, data from different studies were analyzed; therefore, methodological aspects such as the definition of time of onset might have played a role.…”

Bovine spongiform encephalopathy (BSE): Its context in New Zealand and new tests

“…A review of familial haplotypes in 11 world populations concluded that independent mutations were the origins of specific familial CJD clusters (Lee et al 2001). Regardless of whether mutations were de novo or familial, many papers cited note the difficulty of correct diagnosis without genetic analysis as part of a complete TSE diagnosis (and see Harder et al 1999;Mallucci et al 1999;Goldman et al 2004).…”