Abstract
Prion diseases are neurodegenerative disorders which are caused by an accumulation of the abnormal, misfolded prion protein known as scrapie prion protein (PrPSc). These disorders are unique as they occur as sporadic, genetic and acquired forms. Sporadic Creutzfeldt-Jakob Disease (CJD) is the most common human prion disease, accounting for approximately 85-90% of cases, whereas autosomal dominant genetic forms, due to mutations in the prion protein gene (PRNP), account for 10-15% of cases. Genetic forms show a striking variability in their clinical and neuropathological picture and can sometimes mimic other neurodegenerative diseases. We report a novel PRNP mutation (V189I) in four CJD patients from three unrelated pedigrees. In three patients, the clinical features were typical for CJD and the diagnosis was pathologically confirmed, while the fourth patient presented with a complex phenotype including rapidly progressive dementia, behavioral abnormalities, ataxia and extrapyramidal features, and the diagnosis was probable CJD by current criteria, on the basis of PrPSc detection in CSF by Real Time Quaking-Induced Conversion assay. In all the three patients with autopsy findings, the neuropathological analysis revealed diffuse synaptic type deposition of proteinase K-resistant prion protein (PrPres), and type 1 PrPres was identified in the brain by western blot analysis. So, the histopathological and biochemical profile associated with the V189I mutation was indistinguishable from the MM1/MV1 subtype of sporadic CJD. Our findings support a pathogenic role for the V189I PRNP variant, confirm the heterogeneity of the clinical phenotypes associated to PRNP mutations and highlight the importance of PrPSc detection assays as diagnostic tools to unveil prion diseases presenting with atypical phenotypes.
| Original language | English |
|---|---|
| Article number | 1 |
| Journal | Acta neuropathologica communications |
| Volume | 7 |
| Issue number | 1 |
| DOIs | |
| Publication status | Published - Jan 3 2019 |
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Keywords
- CJD
- Creutzfeldt-Jakob disease
- Dementia
- Mutation
- Prion
- PRNP
- PrP
- V189I
ASJC Scopus subject areas
- Pathology and Forensic Medicine
- Clinical Neurology
- Cellular and Molecular Neuroscience
Cite this
Clinical and neuropathological phenotype associated with the novel V189I mutation in the prion protein gene. / Di Fede, Giuseppe; Catania, Marcella; Atzori, Cristiana; Moda, Fabio; Pasquali, Claudio; Indaco, Antonio; Grisoli, Marina; Zuffi, Marta; Guaita, Maria Cristina; Testi, Roberto; Taraglio, Stefano; Sessa, Maria; Gusmaroli, Graziano; Spinelli, Mariacarmela; Salzano, Giulia; Legname, Giuseppe; Tarletti, Roberto; Godi, Laura; Pocchiari, Maurizio; Tagliavini, Fabrizio; Imperiale, Daniele; Giaccone, Giorgio.
In: Acta neuropathologica communications, Vol. 7, No. 1, 1, 03.01.2019.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Clinical and neuropathological phenotype associated with the novel V189I mutation in the prion protein gene
AU - Di Fede, Giuseppe
AU - Catania, Marcella
AU - Atzori, Cristiana
AU - Moda, Fabio
AU - Pasquali, Claudio
AU - Indaco, Antonio
AU - Grisoli, Marina
AU - Zuffi, Marta
AU - Guaita, Maria Cristina
AU - Testi, Roberto
AU - Taraglio, Stefano
AU - Sessa, Maria
AU - Gusmaroli, Graziano
AU - Spinelli, Mariacarmela
AU - Salzano, Giulia
AU - Legname, Giuseppe
AU - Tarletti, Roberto
AU - Godi, Laura
AU - Pocchiari, Maurizio
AU - Tagliavini, Fabrizio
AU - Imperiale, Daniele
AU - Giaccone, Giorgio
PY - 2019/1/3
Y1 - 2019/1/3
N2 - Prion diseases are neurodegenerative disorders which are caused by an accumulation of the abnormal, misfolded prion protein known as scrapie prion protein (PrPSc). These disorders are unique as they occur as sporadic, genetic and acquired forms. Sporadic Creutzfeldt-Jakob Disease (CJD) is the most common human prion disease, accounting for approximately 85-90% of cases, whereas autosomal dominant genetic forms, due to mutations in the prion protein gene (PRNP), account for 10-15% of cases. Genetic forms show a striking variability in their clinical and neuropathological picture and can sometimes mimic other neurodegenerative diseases. We report a novel PRNP mutation (V189I) in four CJD patients from three unrelated pedigrees. In three patients, the clinical features were typical for CJD and the diagnosis was pathologically confirmed, while the fourth patient presented with a complex phenotype including rapidly progressive dementia, behavioral abnormalities, ataxia and extrapyramidal features, and the diagnosis was probable CJD by current criteria, on the basis of PrPSc detection in CSF by Real Time Quaking-Induced Conversion assay. In all the three patients with autopsy findings, the neuropathological analysis revealed diffuse synaptic type deposition of proteinase K-resistant prion protein (PrPres), and type 1 PrPres was identified in the brain by western blot analysis. So, the histopathological and biochemical profile associated with the V189I mutation was indistinguishable from the MM1/MV1 subtype of sporadic CJD. Our findings support a pathogenic role for the V189I PRNP variant, confirm the heterogeneity of the clinical phenotypes associated to PRNP mutations and highlight the importance of PrPSc detection assays as diagnostic tools to unveil prion diseases presenting with atypical phenotypes.
AB - Prion diseases are neurodegenerative disorders which are caused by an accumulation of the abnormal, misfolded prion protein known as scrapie prion protein (PrPSc). These disorders are unique as they occur as sporadic, genetic and acquired forms. Sporadic Creutzfeldt-Jakob Disease (CJD) is the most common human prion disease, accounting for approximately 85-90% of cases, whereas autosomal dominant genetic forms, due to mutations in the prion protein gene (PRNP), account for 10-15% of cases. Genetic forms show a striking variability in their clinical and neuropathological picture and can sometimes mimic other neurodegenerative diseases. We report a novel PRNP mutation (V189I) in four CJD patients from three unrelated pedigrees. In three patients, the clinical features were typical for CJD and the diagnosis was pathologically confirmed, while the fourth patient presented with a complex phenotype including rapidly progressive dementia, behavioral abnormalities, ataxia and extrapyramidal features, and the diagnosis was probable CJD by current criteria, on the basis of PrPSc detection in CSF by Real Time Quaking-Induced Conversion assay. In all the three patients with autopsy findings, the neuropathological analysis revealed diffuse synaptic type deposition of proteinase K-resistant prion protein (PrPres), and type 1 PrPres was identified in the brain by western blot analysis. So, the histopathological and biochemical profile associated with the V189I mutation was indistinguishable from the MM1/MV1 subtype of sporadic CJD. Our findings support a pathogenic role for the V189I PRNP variant, confirm the heterogeneity of the clinical phenotypes associated to PRNP mutations and highlight the importance of PrPSc detection assays as diagnostic tools to unveil prion diseases presenting with atypical phenotypes.
KW - CJD
KW - Creutzfeldt-Jakob disease
KW - Dementia
KW - Mutation
KW - Prion
KW - PRNP
KW - PrP
KW - V189I
UR - http://www.scopus.com/inward/record.url?scp=85059493925&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85059493925&partnerID=8YFLogxK
U2 - 10.1186/s40478-018-0656-4
DO - 10.1186/s40478-018-0656-4
M3 - Article
C2 - 30606247
AN - SCOPUS:85059493925
VL - 7
JO - Acta neuropathologica communications
JF - Acta neuropathologica communications
SN - 2051-5960
IS - 1
M1 - 1
ER -