De novo seven extra repeat expanded mutation in the PRNP gene in an Italian patient with early onset dementia.

Point and octapeptide repeat (24 bp) insertional mutations in the prion protein gene (PRNP) cause a dominantly transmitted dementia, associated with spongiform degeneration of the brain, astrocytic gliosis and neuronal loss due to cell accumulation of mutated protease resistant prion protein. Theoctapeptide repeat region lies between codon 51 and 91, and comprises a nonapeptide followed by a tandem repeat containing four copies of an octapeptide. The normal tandemlength in healthy individuals is five repeats R1- R2-R2-R3-R4, but mutations can contain up to nine additional extra repeats. An extra repeat number has been related to anticipated age at onset in affected subjects. When genetic testing fails to disclose evidence of parental transmission in a dominant disease, a negative family history in patients carrying extra repeats in PRNP could be related either to non-paternity, to variability in mutation penetrance or to de novo mutations. Even in the absence of positive genetic tests in mutation carrier parents, Goldfarb et al hypothesised that genetic mechanism generating extra repeats might be unequal crossover.2 Some insight into this genetic mechanism comes from the de novo meiotic insertional extra repeat mutation in PRNP we detected in a patient whose parents had a normal phenotype and a wild-type sequence in the same gene. To our knowledge, this is the first time this condition has been described.