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Case Report/Case Series |

Unusual Clinical and Molecular-Pathological Profile of Gerstmann-Sträussler-Scheinker Disease Associated With a Novel PRNP Mutation (V176G)

Marion Simpson, MBChB1,2; Vanessa Johanssen, PhD1; Alison Boyd, DipGenCouns1,2; Genevieve Klug, BSc1,2; Colin L. Masters, MD2,3; Qiao-Xin Li, PhD3; Roger Pamphlett, MBChB, MD, FRCPath, FRACP4; Catriona McLean, MD5; Victoria Lewis, PhD1,3; Steven J. Collins, MD1,2,3
[+] Author Affiliations
1Department of Pathology, University of Melbourne, Victoria, Australia
2Australian National Creutzfeldt-Jakob Disease Registry, University of Melbourne, Victoria, Australia
3Mental Health Research Institute of Victoria, University of Melbourne, Victoria, Australia
4The Stacey MND Laboratory, Sydney Medical School, University of Sydney, Camperdown, Australia
5Department of Anatomical Pathology, Alfred Health, Commercial Road, Prahran, Australia
JAMA Neurol. 2013;70(9):1180-1185. doi:10.1001/jamaneurol.2013.165.
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Importance  Here we describe the unusual clinical and molecular-neuropathological profile of a case of Gerstmann-Sträussler-Scheinker disease associated with a novel prion protein (PRNP) gene mutation.

Observations  This case report from the Australian National Creutzfeldt-Jakob Disease Registry concerns a 61-year-old British-born woman with no history of neurodegenerative disorder in first-degree relatives. Rapidly progressive dementia, altered behavior, and cerebellar ataxia dominated the clinical picture in the period immediately following minor elective surgery, with death 1 month later in an akinetic-mute state. Brain histopathological examination revealed neuronal loss, scant foci of spongiform change, and diffuse multicentric amyloid plaques, selectively immunoreactive for prion protein, within the cerebral and cerebellar cortices and deep gray matter. Tau immune-reactive neurofibrillary tangles and neuritic threads were present in the cerebral cortex. PRNP sequencing demonstrated a valine to glycine mutation at codon 176, with valine homozygosity at polymorphic codon 129. Western-blot analysis of frozen brain tissue displayed a nonclassic protease-resistant prion protein banding pattern, with a prominent approximately 8-kDa protease-resistant fragment.

Conclusions and Relevance  Reported is a proband with a novel PRNP mutation associated with neuropathologically confirmed Gerstmann-Sträussler-Scheinker disease displaying a somewhat unusual constellation of clinicopathological features, which overall subserve to further broaden an already diverse phenotypic spectrum.

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Figure 1.
Family Tree

Family tree depicting the proband (solid fill) and first-degree relatives with current ages or ages at death (in years). No first-degree relative was reported to have had any neurological disease with the exception of 1 son (line fill) with schizophrenia. Circles indicate females; squares, males; strikethrough, deceased.

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Figure 2.
Representative Proband Brain Magnetic Resonance Images

Fluid-attenuated inversion recovery (A), diffusion-weighted (B), and apparent diffusion coefficient map (C) images demonstrate mild age-appropriate cerebral atrophy, associated with some nonspecific T2 hyperintensities, but absence of changes typically found in human prion disease, especially sporadic Creutzfeldt-Jakob disease.

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Figure 3.
Neuropathological Findings

Temporal cortex showing numerous plaques (A, encircled) in combination with neuronal loss and astrocytic gliosis (A, arrowheads) (hematoxylin and eosin, original magnification x 200). The plaques are immunoreactive with the anti-PrP monoclonal antibody 12F10 (B, original magnification x 100) and associated with tau-immunoreactive neurofibrillary tangles and prominent neuropil threads (C, original magnification x 200).

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Figure 4.
Molecular-Genetic Characterization

A, Schematic representation of the prion protein open reading frame and protein, with the nucleotide changes, codon positions, and resulting amino acid changes detected in the proband as indicated. B, Proteinase K (PK) digest and polyacrylamide gel electrophoresis/Western blot analysis (using 3F4 antibody) of frozen brain tissue from 2 brain regions of the proband (cerebellum [Ce] and occipital pole [OP]) compared with glycotype controls (T1, T2, T3, and T4: protease-resistant prion protein [PrPres] glycotypes 1, 2, 3, and 4).14 C, Characterization of the small amyloidogenic PrPres fragment by polyacrylamide gel electrophoresis/Western blot epitope mapping, using anti-prion protein antibodies spanning the length of the protein as specified. Schematic representations of the small fragment and oligomeric species and of the potential N- and C-terminal truncation sites based on antibody epitopes are highlighted on the right and below, respectively. WT indicates wild type.

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