A case report of a patient with primary familial brain calcification with a PDGFRB genetic variant.

Fahr's disease, or primary familial brain calcification (PFBC), is a rare genetic neurologic disease characterized by abnormal calcification of the basal ganglia, subcortical white matter and cerebellum. Common clinical features include parkinsonism, neuropsychiatric symptoms, and cognitive decline. Genes implicated in Fahr's disease include PDGFB, PDGFRB, SLC20A2, XPR1, MYORG, and JAM2. We present the case of a 51-year-old woman who developed subacute cognitive and behavioral changes primarily affecting frontal-subcortical pathways and parkinsonism in association with extensive bilateral calcifications within the basal ganglia, subcortical white matter, and cerebellum on neuroimaging. Relevant family history included a paternal aunt with parkinsonism at age 50. Normal parathyroid hormone and calcium levels in the patient's serum ruled out hypoparathyroidism or pseudohypoparathyroidism as causes for the intracranial calcifications. Genetic panel sequencing revealed a variant of unknown significance in the PDGFRB gene resulting in a p.Arg919Gln substitution in the tyrosine kinase domain of PDGFRB protein. To our knowledge this is the first report of a p.Arg919Gln variant in the PDGFRB gene associated with PFBC. Although co-segregation studies were not possible in this family, the location of the variant is within the tyrosine kinase domain of PDGFRB and pathogenicity calculators predict it is likely to be pathogenic. This report adds to the list of genetic variants that warrant functional analysis and could underlie the development of PFBC, which may help to further our understanding of its pathogenesis and the development of targeted therapies for this disorder.

A Novel TBK1 Variant (Lys694del) Presenting With Corticobasal Syndrome in a Family With FTD-ALS Spectrum Diseases: Case Report.

Several variants of the TANK-Binding Kinase 1 (TBK1) gene have been associated with frontotemporal dementia - amyotrophic lateral sclerosis (FTD-ALS) spectrum diseases. Corticobasal syndrome (CBS) is characterized by asymmetric limb rigidity, dystonia or myoclonus, in association with speech or limb apraxia, cortical sensory deficit, and/or alien limb. It can result from a variety of underlying pathologies and although typically sporadic, it has been occasionally associated with MAPT and GRN variants. We describe here the proband of a family with multiple occurrences of FTD-ALS spectrum disease who developed an isolated right-sided primary asymmetric akinetic-rigid syndrome and subsequent speech and cognitive dysfunction associated with contralateral anterior temporal lobe atrophy on MRI and corresponding hypometabolism by FDG-PET. Genetic testing revealed a novel Lys694del variant of the TBK1 gene and Type A TDP-43 pathology in a predominantly frontotemporal distribution contralateral to the affected side. To our knowledge this is the first report of CBS as the initial expression of a TBK1 variant. This case emphasizes the importance of considering TBK1 genetic screening in patients with CBS, as this may be an underrepresented population on the spectrum of genetic FTD-ALS.

Challenging Cases of Neurocognitive Disorders.

Dementia is broadly defined by DSM-V as cognitive decline from a previous level that impacts the patient's functioning at work or play. This broad definition does not provide information about the underlying disease process, an aspect of clinical care that is of increasing importance, as therapeutic development inches closer to effective disease-modifying treatments. The most common neurodegenerative dementias include Alzheimer's disease, dementia with Lewy bodies, frontotemporal dementia, and Parkinson's disease dementia. Although rare, the prion diseases constitute an important group of dementias that should be routinely considered in the evaluation. Over the last two decades, advances in neuroimaging, biomarker development, and neurogenetics have not only led to a better understanding of the biology of these diseases, but they have improved our awareness of less common clinical subtypes of dementia. As such, to best define the disease process, the evaluation of a patient with cognitive decline requires attention to a myriad of disease aspects, such as the primary symptom at onset (memory, language, visual perception, praxis, etc.), the age at onset (younger or older than 65 years), the rate of disease progression (weeks to months or years), the cognitive and behavioral profile (neuropsychological assessment), and involvement of physical findings. We present here three cases that highlight the decision-making process in the evaluation of patients with atypical presentations of dementia.

Generation of human chronic wasting disease in transgenic mice.

Chronic wasting disease (CWD) is a cervid prion disease caused by the accumulation of an infectious misfolded conformer (PrPSc) of cellular prion protein (PrPC). It has been spreading rapidly in North America and also found in Asia and Europe. Although bovine spongiform encephalopathy (i.e. mad cow disease) is the only animal prion disease known to be zoonotic, the transmissibility of CWD to humans remains uncertain. Here we report the generation of the first CWD-derived infectious human PrPSc by elk CWD PrPSc-seeded conversion of PrPC in normal human brain homogenates using in vitro protein misfolding cyclic amplification (PMCA). Western blotting with human PrP selective antibody confirmed that the PMCA-generated protease-resistant PrPSc was derived from the human PrPC substrate. Two lines of humanized transgenic mice expressing human PrP with either Val or Met at the polymorphic codon 129 developed clinical prion disease following intracerebral inoculation with the PMCA-generated CWD-derived human PrPSc. Diseased mice exhibited distinct PrPSc patterns and neuropathological changes in the brain. Our study, using PMCA and animal bioassays, provides the first evidence that CWD PrPSc can cross the species barrier to convert human PrPC into infectious PrPSc that can produce bona fide prion disease when inoculated into humanized transgenic mice.

An atypical presentation of primary central nervous system lymphoma: A case report.

RATIONALE: Primary central nervous system lymphoma (PCNSL) involving the choroid plexus is exceedingly rare. The differential diagnosis for choroid plexus enhancing lesions in addition to lymphoma includes infections, sarcoidosis, tuberculosis, papilloma, meningioma, subependymoma, and metastatic lesions. PATIENT CONCERNS: A 71-year-old man presented with 3 days of episodic memory loss and gait disturbance. Brain magnetic resonance imaging showed homogenously enhancing lesions with mildly restricted diffusion and T2 hypointensity in the lateral ventricles, as well as T2 hyperintensity and enhancement in the right hippocampus. His episodic memory loss was thought to be secondary to subclinical focal seizures, supported by EEG revealing right temporal lobe epileptiform discharges. DIAGNOSES: Large B-cell lymphoma, nongerminal center type was revealed on pathological examination. INTERVENTIONS: Stereotactic biopsy of his right thalamic lesion was performed. OUTCOMES: The patient underwent induction therapy with high-dose methotrexate, temozolomide, and rituximab, which resulted in complete resolution of the enhancing lesions. He then underwent conditioning chemotherapy with carmustine and thiotepa, followed by autologous stem cell transplantation. His PCNSL remains in remission 42 weeks after the onset of symptoms. LESSONS: We report a patient with multifocal PCNSL involving the choroid plexus, who presented with abnormal gait and episodic confusion and memory loss. PCNSL should be considered in the differential diagnosis of acute encephalopathy among immunocompetent older individuals who have choroid plexus enhancing lesions.

"Dual Disease" TgAD/GSS mice exhibit enhanced Alzheimer's disease pathology and reveal PrPC-dependent secretion of Aß.

To address the question of cross-talk between prion protein (PrP) and Alzheimer's disease (AD), we generated TgAD/GSS mice that develop amyloid-ß (Aß) plaques of AD and PrP (specifically mutated PrPA116V) plaques of Gerstmann-Sträussler-Scheinker disease (GSS) and compared plaque-related features in these mice to AD mice that express normal (TgAD), high (TgAD/HuPrP), or no (TgAD/PrP-/-) PrPC. In contrast to PrPC, PrPA116V weakly co-localized to Aß plaques, did not co-immunoprecipitate with Aß, and poorly bound to Aß in an ELISA-based binding assay. Despite the reduced association of PrPA116V with Aß, TgAD/GSS and TgAD/HuPrP mice that express comparable levels of PrPA116V and PrPC respectively, displayed similar increases in Aß plaque burden and steady state levels of Aß and its precursor APP compared with TgAD mice. Our Tg mouse lines also revealed a predominance of intracellular Aß plaques in mice lacking PrPC (TgAD/PrP-/-, TgAD/GSS) compared with an extracellular predominance in PrPC-expressing mice (TgAD, TgAD/HuPrP). Parallel studies in N2aAPPswe cells revealed a direct dependence on PrPC but not PrPA116V for exosome-related secretion of Aß. Overall, our findings are two-fold; they suggest that PrP expression augments Aß plaque production, at least in part by an indirect mechanism, perhaps by increasing steady state levels of APP, while they also provide support for a fundamental role of PrPC to bind to and deliver intraneuronal Aß to exosomes for secretion.

Anle138b prevents PrP plaque accumulation in Tg(PrP-A116V) mice but does not mitigate clinical disease.

Anle138b is an anti-aggregating compound previously shown to delay the onset of scrapie, a transmissible prion disease, although its in vivo efficacy against other prion disease subtypes has not been fully assessed. TgGSS mice that model Gerstmann-Sträussler-Scheinker disease (GSS) via expression of mouse PrPA116V accumulate PrP amyloid plaques in their brains and develop progressive ataxia leading to death in ~160 days. When allowed to feed on food pellets containing anle138b from weaning until death, the brains of TgGSS mice displayed significant reductions in PrP plaque burden, insoluble PrP, and proteinase K-resistant PrPSc at end stage, compared with TgGSS mice allowed to feed on placebo food pellets. Despite these effects on biological markers of disease, there was no difference in the onset of symptoms or the age at death between the two treatment groups. In contrast, scrapie-inoculated wild-type mice treated with anle138b survived nearly twice as long (254 days) as scrapie-inoculated mice fed placebo (~136 days). They also displayed greater reductions in insoluble and PK-resistant PrPSc than TgGSS mice. Although these results support an anti-aggregating effect of anle138b, the discordance in clinical efficacy noted between the two prion disease models tested underscores the pathophysiological differences between them and highlights the need to consider differences in susceptibilities among prion subtypes when assessing potential therapies for prion diseases.

IVIG Delays Onset in a Mouse Model of Gerstmann-Sträussler-Scheinker Disease.

Our previous studies showed that intravenous immunoglobulin (IVIG) contained anti-Aß autoantibodies that might be able to treat Alzheimer's disease (AD). Recently, we identified and characterized naturally occurring autoantibodies against PrP from IVIG. Although autoantibodies in IVIG blocked PrP fibril formation and PrP neurotoxicity in vitro, it remained unknown whether IVIG could reduce amyloid plaque pathology in vivo and be used to effectively treat animals with prion diseases. In this study, we used Gerstmann-Sträussler-Scheinker (GSS)-Tg (PrP-A116V) transgenic mice to test IVIG efficacy since amyloid plaque formation played an important role in GSS pathogenesis. Here, we provided strong evidence that demonstrates how IVIG could significantly delay disease onset, elongate survival, and improve clinical phenotype in Tg (PrP-A116V) mice. Additionally, in treated animals, IVIG could markedly inhibit PrP amyloid plaque formation and attenuate neuronal apoptosis at the age of 120 days in mice. Our results indicate that IVIG may be a potential, effective therapeutic treatment for GSS and other prion diseases.

Impaired transmissibility of atypical prions from genetic CJDG114V.

OBJECTIVE: To describe the clinicopathologic, molecular, and transmissible characteristics of genetic prion disease in a young man carrying the PRNP-G114V variant. METHODS: We performed genetic, histologic, and molecular studies, combined with in vivo transmission studies and in vitro replication studies, to characterize this genetic prion disease. RESULTS: A 24-year-old American man of Polish descent developed progressive dementia, aphasia, and ataxia, leading to his death 5 years later. Histologic features included widespread spongiform degeneration, gliosis, and infrequent PrP plaque-like deposits within the cerebellum and putamen, best classifying this as a Creutzfeldt-Jakob disease (CJD) subtype. Molecular typing of proteinase K-resistant PrP (resPrPSc) revealed a mixture of type 1 (∼21 kDa) and type 2 (∼19 kDa) conformations with only 2, rather than the usual 3, PrPSc glycoforms. Brain homogenates from the proband failed to transmit prion disease to transgenic Tg(HuPrP) mice that overexpress human PrP and are typically susceptible to sporadic and genetic forms of CJD. When subjected to protein misfolding cyclic amplification, the PrPSc type 2 (∼19 kDa) was selectively amplified. CONCLUSIONS: The features of genetic CJDG114V suggest that residue 114 within the highly conserved palindromic region (113-AGAAAAGA-120) plays an important role in prion conformation and propagation.

In vivo parahippocampal white matter pathology as a biomarker of disease progression to Alzheimer's disease.

Noninvasive diagnostic tests for Alzheimer's disease (AD) are limited. Postmortem diagnosis is based on density and distribution of neurofibrillary tangles (NFTs) and amyloid-rich neuritic plaques. In preclinical stages of AD, the cells of origin for the perforant pathway within the entorhinal cortex are among the first to display NFTs, indicating its compromise in early stages of AD. We used diffusion tensor imaging (DTI) to assess the integrity of the parahippocampal white matter in mild cognitive impairment (MCI) and AD, as a first step in developing a noninvasive tool for early diagnosis. Subjects with AD (N = 9), MCI (N = 8), or no cognitive impairment (NCI; N = 20) underwent DTI-MRI. Fractional anisotropy (FA) and mean (MD) and radial (RD) diffusivity measured from the parahippocampal white matter in AD and NCI subjects differed greatly. Discriminant analysis in the MCI cases assigned statistical membership of 38% of MCI subjects to the AD group. Preliminary data 1 year later showed that all MCI cases assigned to the AD group either met the diagnostic criteria for probable AD or showed significant cognitive decline. Voxelwise analysis in the parahippocampal white matter revealed a progressive change in the DTI patterns in MCI and AD subjects: whereas converted MCI cases showed structural changes restricted to the anterior portions of this region, in AD the pathology was generalized along the entire anterior-posterior axis. The use of DTI for in vivo assessment of the parahippocampal white matter may be useful for identifying individuals with MCI at highest risk for conversion to AD and for assessing disease progression.

Systemic transthyretin amyloidosis in a patient with bent spine syndrome.

Wild-type and mutant transthyretin (TTR) are implicated in systemic amyloidosis (ATTR). Myopathy is a rare complication of ATTR amyloidosis, however no patient with bent spine syndrome secondary to ATTR amyloidosis has been reported so far. We present the first case of bent spine syndrome in a patient with wild-type ATTR amyloidosis who also had concomitant Alzheimer's disease.

Early Delivery of Misfolded PrP from ER to Lysosomes by Autophagy.

Prion diseases are linked to the accumulation of a misfolded isoform (PrP(Sc)) of prion protein (PrP). Evidence suggests that lysosomes are degradation endpoints and sites of the accumulation of PrP(Sc). We questioned whether lysosomes participate in the early quality control of newly generated misfolded PrP. We found PrP carrying the disease-associated T182A mutation (Mut-PrP) was delivered to lysosomes in a Golgi-independent manner. Time-lapse live cell imaging revealed early formation and uptake of GFP-tagged Mut-PrP aggregates into LysoTracker labeled vesicles. Compared with Wt-PrP, Mut-PrP expression was associated with an elevation in several markers of the autophagy-lysosomal pathway, and it extensively colocalized with the autophagosome-specific marker, LC3B. In autophagy deficient (ATG5(-/-)) mouse embryonic fibroblasts, or in normal cells treated with the autophagy-inhibitor 3-MA, Mut-PrP colocalization with lysosomes was reduced to a similar extent. Additionally, 3-MA selectively impaired the degradation of insoluble Mut-PrP, resulting in an increase in protease-resistant PrP, whereas the induction of autophagy by rapamycin reduced it. These findings suggest that autophagy might function as a quality control mechanism to limit the accumulation of misfolded PrP that normally leads to the generation of PrP(Sc).

Rapamycin delays disease onset and prevents PrP plaque deposition in a mouse model of Gerstmann-Sträussler-Scheinker disease.

Autophagy is a cell survival response to nutrient deprivation that delivers cellular components to lysosomes for digestion. In recent years, autophagy has also been shown to assist in the degradation of misfolded proteins linked to neurodegenerative disease (Ross and Poirier, 2004). In support of this, rapamycin, an autophagy inducer, improves the phenotype of several animal models of neurodegenerative disease. Our Tg(PrP-A116V) mice model Gerstmann-Sträussler-Scheinker disease (GSS), a genetic prion disease characterized by prominent ataxia and extracellular PrP amyloid plaque deposits in brain (Yang et al., 2009). To determine whether autophagy induction can mitigate the development of GSS, Tg(PrP-A116V) mice were chronically treated with 10 or 20 mg/kg rapamycin intraperitoneally thrice weekly, beginning at 6 weeks of age. We observed a dose-related delay in disease onset, a reduction in symptom severity, and an extension of survival in rapamycin-treated Tg(PrP-A116V) mice. Coincident with this response was an increase in the autophagy-specific marker LC3II, a reduction in insoluble PrP-A116V, and a near-complete absence of PrP amyloid plaques in the brain. An increase in glial cell apoptosis of unclear significance was also detected. These findings suggest autophagy induction enhances elimination of misfolded PrP before its accumulation in plaques. Because ataxia persisted in these mice despite the absence of plaque deposits, our findings also suggest that PrP plaque pathology, a histopathological marker for the diagnosis of GSS, is not essential for the GSS phenotype.

Tunicamycin produces TDP-43 cytoplasmic inclusions in cultured brain organotypic slices.

The cellular distribution of TAR DNA binding protein (TDP-43) is disrupted in several neurodegenerative disorders, including frontotemporal lobar degeneration with ubiquitin-positive inclusions (FTLD-U subtype) and amyotrophic lateral sclerosis (ALS). In these conditions, TDP-43 is found in neuronal cytoplasmic inclusions, with loss of the normal nuclear expression. The mechanisms leading to TDP-43 redistribution and its role in disease pathophysiology remain unknown. We describe an in vitro neural tissue model that reproduces TDP-43 relocalization and inclusion formation. Two week-old coronal organotypic mouse brain slice cultures were treated with tunicamycin for 7 days. In cortical regions of treated slice cultures, cytoplasmic inclusions of TDP-43 immunoreactivity were observed, with loss of nuclear TDP-43 immunoreactivity. These inclusions were found in both astrocytes and neurons, and were of both skein-like and round morphologies. In contrast, TDP-43 cytoplasmic inclusions were not found in slices treated with staurosporine to induce apoptosis, or with trans-4-carboxy-l-proline (PDC) to induce chronic glutamate excitotoxicity. Furthermore, TDP-43 cytoplasmic inclusions did not co-localize with cleaved caspase-3, suggesting that TDP-43 mislocalization does not generally accompany caspase activation or apoptosis. The induction of TDP-43 cytoplasmic translocation in cerebrocortical slice cultures by tunicamycin provides a platform for further mechanistic investigations of pathological processing of TDP-43.

Acute encephalopathy as the initial manifestation of CADASIL.

A 29-year-old right-handed G1P1 Caucasian woman presented with acute bifrontal headache (which resolved within 1 day), confusion, and difficulty using her right hand on postpartum day 10. She did not report nausea, vomiting, or visual complaints. The patient was previously healthy except for her recent preeclampsia, which required emergent cesarean section. On examination, the patient was afebrile, awake, alert, and apathetic. She was able to follow few one-step midline commands (e.g., eye opening and closing) inconsistently but not appendicular commands. Her neurologic deficits were remarkable for expressive aphasia, intermittent receptive aphasia, and hyperreflexia with bilateral extensor plantar responses. No meningismus or other focal neurologic deficits were present. Routine laboratory testing including urine toxicology screen was normal. C-reactive protein was 23 mg/L (reference range: <5 mg/L), and erythrocyte sedimentation rate (ESR) was 38 mm/h (reference range: 0-20 mm/h). Rheumatologic panel was negative. Brain MRI showed extensive non-contrast-enhancing T2/fluid-attenuated inversion recovery hyperintensities involving periventricular and deep white matter, especially the centrum semiovale, corpus callosum, bilateral anterior temporal lobes, bilateral caudate nucleus, and globus pallidus (figure, A-C). No evidence of acute or previous stroke was found. CT angiogram and venogram revealed no cerebral sinus thrombosis or large vessel vasculitis. Lumbar puncture opening pressure was 18.5 cm H2O. CSF showed normal cell counts, protein, and glucose levels without oligoclonal bands. EEG recorded in awake, drowsy, and sleep state was normal. Dilated ophthalmic examination showed no microangiopathy or retinal branch arterial occlusion. Audiologic examination was normal.

Familial prion disease with Alzheimer disease-like tau pathology and clinical phenotype.

OBJECTIVE: To describe the Alzheimer disease (AD)-like clinical and pathological features, including marked neurofibrillary tangle (NFT) pathology, of a familial prion disease due to a rare nonsense mutation of the prion gene (PRNP). METHODS: Longitudinal clinical assessments were available for the proband and her mother. After death, both underwent neuropathological evaluation. PRNP was sequenced after failure to find immunopositive Aß deposits in the proband and the documentation of prion protein (PrP) immunopositive pathology. RESULTS: The proband presented at age 42 years with a 3-year history of progressive short-term memory impairment and depression. Neuropsychological testing found impaired memory performance, with relatively preserved attention and construction. She was diagnosed with AD and died at age 47 years. Neuropathologic evaluation revealed extensive limbic and neocortical NFT formation and neuritic plaques consistent with a Braak stage of VI. The NFTs were immunopositive, with multiple tau antibodies, and electron microscopy revealed paired helical filaments. However, the neuritic plaques were immunonegative for Aß, whereas immunostaining for PrP was positive. The mother of the proband had a similar presentation, including depression, and had been diagnosed clinically and pathologically as AD. Reevaluation of her brain tissue confirmed similar tau and PrP immunostaining findings. Genetic analysis revealed that both the proband and her mother had a rare PRNP mutation (Q160X) that resulted in the production of truncated PrP. INTERPRETATION: We suggest that PRNP mutations that result in a truncation of PrP lead to a prolonged clinical course consistent with a clinical diagnosis of AD and severe AD-like NFTs.

Generation of a new form of human PrP(Sc) in vitro by interspecies transmission from cervid prions.

Prion diseases are infectious neurodegenerative disorders that affect humans and animals and that result from the conversion of normal prion protein (PrP(C)) into the misfolded prion protein (PrP(Sc)). Chronic wasting disease (CWD) is a prion disorder of increasing prevalence within the United States that affects a large population of wild and captive deer and elk. Determining the risk of transmission of CWD to humans is of utmost importance, considering that people can be infected by animal prions, resulting in new fatal diseases. To study the possibility that human PrP(C) can be converted into the misfolded form by CWD PrP(Sc), we performed experiments using the protein misfolding cyclic amplification technique, which mimics in vitro the process of prion replication. Our results show that cervid PrP(Sc) can induce the conversion of human PrP(C) but only after the CWD prion strain has been stabilized by successive passages in vitro or in vivo. Interestingly, the newly generated human PrP(Sc) exhibits a distinct biochemical pattern that differs from that of any of the currently known forms of human PrP(Sc). Our results also have profound implications for understanding the mechanisms of the prion species barrier and indicate that the transmission barrier is a dynamic process that depends on the strain and moreover the degree of adaptation of the strain. If our findings are corroborated by infectivity assays, they will imply that CWD prions have the potential to infect humans and that this ability progressively increases with CWD spreading.

The prion diseases.

The prion diseases are a family of rare neurodegenerative disorders that result from the accumulation of a misfolded isoform of the prion protein (PrP), a normal constituent of the neuronal membrane. Five subtypes constitute the known human prion diseases; kuru, Creutzfeldt-Jakob disease (CJD), Gerstmann-Sträussler-Scheinker syndrome (GSS), fatal insomnia (FI), and variant CJD (vCJD). These subtypes are distinguished, in part, by their clinical phenotype, but primarily by their associated brain histopathology. Evidence suggests these phenotypes are defined by differences in the pathogenic conformation of misfolded PrP. Although the vast majority of cases are sporadic, 10% to 15% result from an autosomal dominant mutation of the PrP gene (PRNP). General phenotype-genotype correlations can be made for the major subtypes of CJD, GSS, and FI. This paper will review some of the general background related to prion biology and detail the clinical and pathologic features of the major prion diseases, with a particular focus on the genetic aspects that result in prion disease or modification of its risk or phenotype.

Variably protease-sensitive prionopathy: a new sporadic disease of the prion protein.

OBJECTIVE: The objective of the study is to report 2 new genotypic forms of protease-sensitive prionopathy (PSPr), a novel prion disease described in 2008, in 11 subjects all homozygous for valine at codon 129 of the prion protein (PrP) gene (129VV). The 2 new PSPr forms affect individuals who are either homozygous for methionine (129MM) or heterozygous for methionine/valine (129MV). METHODS: Fifteen affected subjects with 129MM, 129MV, and 129VV underwent comparative evaluation at the National Prion Disease Pathology Surveillance Center for clinical, histopathologic, immunohistochemical, genotypical, and PrP characteristics. RESULTS: Disease duration (between 22 and 45 months) was significantly different in the 129VV and 129MV subjects. Most other phenotypic features along with the PrP electrophoretic profile were similar but distinguishable in the 3 129 genotypes. A major difference laid in the sensitivity to protease digestion of the disease-associated PrP, which was high in 129VV but much lower, or altogether lacking, in 129MV and 129MM. This difference prompted the substitution of the original designation with "variably protease-sensitive prionopathy" (VPSPr). None of the subjects had mutations in the PrP gene coding region. INTERPRETATION: Because all 3 129 genotypes are involved, and are associated with distinguishable phenotypes, VPSPr becomes the second sporadic prion protein disease with this feature after Creutzfeldt-Jakob disease, originally reported in 1920. However, the characteristics of the abnormal prion protein suggest that VPSPr is different from typical prion diseases, and perhaps more akin to subtypes of Gerstmann-Sträussler-Scheinker disease.