Genetic prion disease: Experience of a rapidly progressive dementia center in the United States and a review of the literature

Abstract

Although prion diseases are generally thought to present as rapidly progressive dementias with survival of only a few months, the phenotypic spectrum for genetic prion diseases (gPrDs) is much broader. The majority have a rapid decline with short survival, but many patients with gPrDs present as slowly progressive ataxic or parkinsonian disorders with progression over a few to several years. A few very rare mutations even present as neuropsychiatric disorders, sometimes with systemic symptoms such as gastrointestinal disorders and neuropathy, progressing over years to decades. gPrDs are caused by mutations in the prion protein gene (PRNP), and have been historically classified based on their clinicopathological features as genetic Jakob-Creutzfeldt disease (gJCD), Gerstmann-Sträussler-Scheinker (GSS), or Fatal Familial Insomnia (FFI). Mutations in PRNP can be missense, nonsense, and octapeptide repeat insertions or a deletion, and present with diverse clinical features, sensitivities of ancillary testing, and neuropathological findings. We present the UCSF gPrD cohort, including 129 symptomatic patients referred to and/or seen at UCSF between 2001 and 2016, and compare the clinical features of the gPrDs from 22 mutations identified in our cohort with data from the literature, as well as perform a literature review on most other mutations not represented in our cohort. E200K is the most common mutation worldwide, is associated with gJCD, and was the most common in the UCSF cohort. Among the GSS-associated mutations, P102L is the most commonly reported and was also the most common at UCSF. We also had several octapeptide repeat insertions (OPRI), a rare nonsense mutation (Q160X), and three novel mutations (K194E, E200G, and A224V) in our UCSF cohort. © 2016 Wiley Periodicals, Inc.

Keywords: CJD; Creutzfeldt-Jakob disease; octapeptide repeat insertion; prion protein gene; rapidly progressive dementia.

Figure 1. Schematic of PRNP disease-associated variants

Mutations are color coded based on clinicopathological classifcation as gJCD, GSS, FFI or nonsense mutations. PRNP mutations present in the UCSF cohort are in bold. Most mutations are shown below the gene schematic; nonsense mutations and polymorphisms associated with prion disease risk are above the gene schematic. Low or intermediate penetrance variants are based on Minikel et al., 2016 (not all low/intermediate penetrance variants are shown)[Minikel et al., 2016]. For the F198V mutation, the clinical presentation was not classifiable as gCJD, GSS or FFI (see Table 3), and neuropathology was not reported [Zheng et al., 2008]. Variants that are probably benign (largely based on Minikel et al., 2016) are not included (e.g., G54S, P39L, E196A, R208C) [Beck et al., 2010; Minikel et al., 2016]. JCD= Jakob-Creutzfeldt disease; GSS= Gerstmann-Sträussler-Scheinker; FFI= Fatal Familial Insomnia. OPRI= Octapeptide repeat insertion; OPRD= Octapeptide repeat deletion.

Figure 2. Brain MRIs in Fast forms of gPrD

A. DWI MRI of a gJCD 47 year-old E200K patient 3 months after onset shows diffuse cortical hyperintensity (cortical ribboning; dashed arrows) of the bilateral frontal and insula (left > right) and temporo-parietal cortices. There was also DWI hyperintensity in the bilateral striata (left > right, solid arrows). B. The ADC map of the same gJCD E200K case showed hypointensity in most of the regions that were hyperintense on DWI, confirming reduced diffusion, consistent with prion disease. C. DWI MRI of an 85 year old V180I case 11 months after onset shows diffuse cortical atrophy and cortical hyperintensity (cortical ribboning; dashed arrows) of the bilateral frontal and cingulate (right > left) and the right temporal and parietal lobes. There was no clear abnormality in the deep nuclei. D. DWI in a 49 year old gJCD A224V case 11 months after the onset shows diffuse cortical ribboning (dashed arrows) greater on the right than the left and hyperinensity in the bilateral deep nuclei (solid arrows) also greater in the right. E. The ADC map of the same gJCD A224V case showed hypointensity in most of the regions that were bright on DWI, confirming restricted diffusion, consisent with JCD/prion disease. Orientation is radiological (left brain is right side of figure).

Figure 3. Brain MRIs in Slow forms of gPrD

A. FLAIR brain MRI in a 57 year old patient with P102L gPrD possibly 16.5 years after onset (precise age of onset unclear due to co-morbidities) shows mild cerebellar atrophy but no cortical atrophy or typical T2-weighted or DWI hyperintensites (cortical ribboning or deep nuclei hyperintensity), but only several punctate hyperintensities in the white matter consistent with small vessel ischemic vascular disease. The DWI and ADC map sequences showed no restricted diffusion (not shown). B. FLAIR brain MRI of with a 37 year old gPrD 6-OPRI patient showing diffuse cortical atrophy just 7 months after reported clinical onset; the amount of atrophy suggests the disease began years prior to obvious clinical onset. The DWI and ADC map sequences showed no restricted diffusion (not shown). C. Repeat brain MRI on same 6-OPRI patient 25 months later, 32 months after clinical onset, demonstrates progression of atrophy. The DWI and ADC map sequences still showed no restricted diffusion (not shown). Orientation is radiological.