A prion disease with a novel 96-base pair insertional mutation in the prion protein gene

The transmissible spongiform encephalopathies (or prion diseases), a group of neurodegenerative conditions affecting both humans and other animals, are all associated with the accumulation in the brain of an abnormal, partially protease-resistant, isoform of a host-encoded glycoprotein, prion protein (PrP). ^[1] The human diseases are classically divided into Creutzfeldt-Jakob disease (CJD), Gerstmann-Straussler-Scheinker disease (GSS), and kuru. The animal diseases include scrapie and bovine spongiform encephalopathy. GSS is usually reported in a familial context and approximately 15% of CJD is familial. ^[2]

The first genetic mutation identified in the familial forms of the human transmissible spongiform encephalopathies (familial CJD and GSS) was an insertion consisting of six extra octapeptide repeat elements in a region of PrP that normally consists of four identical octarepeats immediately following a nonapeptide of related sequence. ^[3,4] Genetic linkage between GSS and a missense mutation at codon 102 of the PrP gene confirmed GSS to be an autosomal dominant Mendelian disorder in addition to being transmissible to experimental animals following inoculation with brain homogenates. ^[5] There is a family of prion protein gene mutations ^[6-9] consisting both of further missense mutations and further variants with respect to the number of octarepeat elements. The combined lod score from genetic linkage studies in these diseases exceeds 30 and these mutations are absent from the normal population. Together, this provides compelling statistical evidence that these mutations are causal for these diseases and therefore that their identification in an appropriate clinical setting is diagnostic of an inherited prion disease. The pathogenicity of one of the mutations was demonstrated in transgenic mice. ^[10] Such mice, overexpressing a murine prion protein encoding an analogous mutation to the codon 102 leucine substitution, develop spontaneous spongiform neurodegeneration. ^[10]

While some of these families display a phenotype that would fit the clinicopathologic, and in some cases …