Phenotypic variability in familial prion diseases due to the D178N mutation

Abstract

patients with familial prion diseases due to the D178N mutation were referred to the regional epidemiological registry for spongiform encephalopathies in the Basque Country in Spain, a small community of some 2 100 000 inhabitants. Methods: Ten further patients belonging to the same pedigrees were retrospectively ascertained through neurological or neuropathological records. In four of the patients, the diagnosis was confirmed by analysing DNA obtained from paraffin blocks. In this article, we report on the clinical, genetic, and pathological features of the 23 patients carrying the D178N mutation confirmed by genetic molecular analysis. Haplotyping studies suggest a founder effect among Basque born families, explaining in part this unusually high incidence of the D178N mutation in a small community. Only two patients (8%) lack familial antecedents. Results: We have observed a phenotypic variability even among homozygous 129MM patients. Our findings challenge the currently accepted belief that MM homozygosity in codon 129 is always related to a fatal familial insomnia (FFI) phenotype. Indeed, seven out of 17 patients with a 129MM genotype in this series presented with a Creutzfeldt-Jakob disease (CJD) clinicopathological picture. Conclusions: The considerable clinical and pathological overlapping observed among homozygous 129MM patients favours the view that FFI and CJD178 are the extremes of a spectrum rather than two discrete and separate entities. Other genetic or environmental factors apart from the polymorphism in codon 129 may play a role in determining the phenotypic expression of the D178N mutation in the PRNP gene.

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.…”

“…The diagnostic importance of polysomnography in FFI noted in our study has been emphasized by other authors. 2,6,12,14 [ 18 F]FDG-PET studies were reported to support FFI diagnosis. 9 Selective thalamic changes were seen on PET in only two of our patients, whereas widespread cortical hypometabolism without clear preference for a particular cortical region was found in five patients.…”

“…However, only limited data on this subject have been reported. 2,6 Although diagnostic criteria for FFI have been proposed, 7 The aim of this study was to develop a detailed clinical description of FFI in a larger group of patients with respect to the M129V genotype to improve clinical diagnosis.…”

“…FFI cases with heterogeneous clinical phenotypes have been reported. [2][3][4] A methionine/valine (M129V) polymorphism located at codon 129 of PRNP significantly influences prion disease phenotype and duration, at least in sporadic Creutzfeldt-Jakob disease (sCJD). 5 The phenotype in FFI appears also to depend on the M129V polymorphism.…”

An in vivo 11C‐PK PET study of microglia activation in Fatal Familial Insomnia

“…The D178N mutation can trigger different clinico‐pathological syndromes, either thalamic‐dominant FFI or CJD, depending on a methionine‐valine polymorphism at PRNP codon‐129 8, 9, 10. FFI syndrome is almost exclusively associated with methionine in the mutated allele (D178N‐129M),9 but not all the carriers of the D178N‐129M mutation develop an FFI phenotype 11, 12. Additionally, methionine/valine polymorphism in the normal allele appears relevant for disease progression and severity, with FFI D178N‐129 M/M patients presenting with a more rapid decline compared to D178N‐129 M/V cases 9.…”