In a French Alsatian patient with Gerstmann-Straussler disease (GSD; 137440), Doh-ura et al. (1989) identified an ala117-to-val (A117V) substitution in the PRNP gene. The patient's family had at least 8 affected individuals spanning 4 generations. Affected members presented with dementia characteristic of the so-called 'telencephalic Gerstmann-Straussler syndrome.'
Mastrianni et al. (1995) reported a family in which heterozygotes for the A117V mutation presented with ataxia rather than dementia. The proband was homozygous for val129 (176640.0005), and there was an additional silent GCA-to-GCG mutation at codon 117 on the normal allele (176640.0003).
Hegde et al. (1998) reported that the brain of a GSD patient with the A117V mutation had high levels of an ER transmembrane form of PrP (PrP-Ctm), but no PrP(Sc). The authors suggested that the A117V mutation resulted in increased generation of PrP-Ctm in vivo, indicating that PrP-Ctm accumulation is likely to be the cause of at least some of the neuropathologic changes seen in these cases of GSD.
Mallucci et al. (1999) described a large English family with the A117V mutation. The family showed autosomal dominant segregation of presenile dementia, ataxia, and other neuropsychiatric features. Diagnoses of demyelinating disease, Alzheimer disease (104300), Creutzfeldt-Jakob disease (123400), and Gerstmann-Straussler-Scheinker syndrome had been made in particular individuals at different times. Mallucci et al. (1999) also described an Irish family, likely to be part of the same kindred, in which diagnoses of multiple sclerosis (126200), dementia, corticobasal degeneration (600274), and 'new variant' CJD had been considered in affected individuals. The authors emphasized the diversity of phenotypic expression seen in these kindreds, and suggested that inherited prion disease should be excluded by PRNP analysis in any individual presenting with atypical presenile dementia or neuropsychiatric features and ataxia, including suspected cases of 'new variant' CJD.
