Objective: Fatal familial insomnia (FFI) and Creutzfeldt-Jakob disease (CJD) are two phenotypes that share a common point mutation at codon 178 of the prion protein gene (PRNP), with the substitution of aspartic acid to asparagine (D178N). The phenotype depends on the polymorphism at codon 129, when methionine (129M) is associated with FFI, and Valine (129V) with CJD.

Background: We here report on a Jewish family from Iraqi origin with D178N-129V genotype presenting with overt insomnia, cerebellar ataxia, and an atypical duration of disease.

Method: Patient 1, a 56 year old woman with no relevant family history, presented in 1996 with rapidly progressive dementia and gait ataxia. MRI showed frontal cortical but not basal ganglia or thalamic involvement. CSF was positive for protein 14-3-3, and genetic testing for E200K mutation in the PRNP gene was negative. Brain biopsy showed typical spongiform changes, and she was diagnosed with sporadic CJD. She passed away 7 years after symptoms onset. Her son (patient 2) presented in 2012 with rapidly progressive dementia at the age of 41 and was diagnosed with CJD. He died a few months later. Patient 3, her daughter, presented in 2018 at the age of 50 with cerebellar ataxia and mild cognitive impairment. She described severe insomnia for more than a year before arrival. Brain MRI showed overt restriction in diffusion across the frontal, parietal and temporal cortices, with marked involvement of basal ganglia and thalami. Genetic analysis of the PRNP gene revealed a heterozygous D178N mutation in combination with the polymorphism Met129Val on both alleles (homozygous). Patient 4, her daughter, 45 years old, presented in 2018 suffering from severe aphasia, gait disturbances, and cognitive decline. Her symptoms started 8 months prior to her admission. Brain MRI was almost identical to that of patient 3.

Results: The phenotype of patient 1 was clearly different from that of FFI and more suggestive of CJD, although the long duration of the disease is highly unusual for CJD. Severe insomnia was reported in the “prodromal” phase in patient 3, however the genetic signature that is consistent with CJD. Patients 2 and 3 both have a relatively slow rate of progression.

Conclusion: Our findings support the notion that there is a phenotypic variability in the D178N genotype within the same family and emphasize the heterogeneity of inherited prion disease and the possibility that genetic and other modifiers exist.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/familial-creutzfeldt-jakob-disease-with-d178n-and-met129val/