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A case report of genetic prion disease with two different PRNP variants

BACKGROUND: Prion diseases are a group of lethal neurodegenerative conditions that occur when the normal, cellular form of the prion protein (PrP(C)) is converted into an abnormal, scrapie, form of the protein (PrP(Sc)). Disease may be caused by genetic, infectious, or sporadic etiologies. The genet...

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Autores principales: Piazza, Megan, Prior, Thomas W., Khalsa, Prabhjot S., Appleby, Brian
Formato: Online Artículo Texto
Lenguaje:English
Publicado: John Wiley and Sons Inc. 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7057106/
https://www.ncbi.nlm.nih.gov/pubmed/31953922
http://dx.doi.org/10.1002/mgg3.1134
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author Piazza, Megan
Prior, Thomas W.
Khalsa, Prabhjot S.
Appleby, Brian
author_facet Piazza, Megan
Prior, Thomas W.
Khalsa, Prabhjot S.
Appleby, Brian
author_sort Piazza, Megan
collection PubMed
description BACKGROUND: Prion diseases are a group of lethal neurodegenerative conditions that occur when the normal, cellular form of the prion protein (PrP(C)) is converted into an abnormal, scrapie, form of the protein (PrP(Sc)). Disease may be caused by genetic, infectious, or sporadic etiologies. The genetic form of prion disease comprises~10%–15% of all cases. Prion disease is typically inherited in an autosomal dominant manner. The low incidence of disease makes it highly unlikely that a patient would have two different pathogenic variants. However, we recently identified a case in which the patient did have two pathogenic PRNP variants and presented with an atypical phenotype. METHODS: The patient was evaluated at the Washington Hospital Healthcare System in Fremont, CA. The clinical information for this case report was obtained retrospectively. Variants in the PRNP were identified by polymerase chain reaction (PCR) amplification of exon two of the gene followed by bi‐directional sequence analysis. To determine the phase of the identified variants, a restriction enzyme digestion was utilized, followed by sequence analysis of the products. Cerebral spinal fluid (CSF) was analyzed for surrogate markers of prion disease, 14–3–3 and Tau proteins. CSF real‐time quaking‐induced conversion (RT‐QuIC) assays were also performed. RESULTS: The patient was a compound heterozygote for the well‐characterized c.628G>A (p.Val210Ile) variant and the rare octapeptide deletion of two repeats [c.202_249del48 (p.P68_Q83del)]. Clinically, the patient presented with an early onset demyelinating peripheral neuropathy, followed by later onset cognitive symptoms. CONCLUSION: This presentation is reminiscent of prion protein knockout mice whose predominate symptom, due to complete loss of PrP, was late‐onset peripheral neuropathy. To our knowledge this is the first case reported of a patient with prion disease who had two different pathogenic variants in PRNP.
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spelling pubmed-70571062020-03-12 A case report of genetic prion disease with two different PRNP variants Piazza, Megan Prior, Thomas W. Khalsa, Prabhjot S. Appleby, Brian Mol Genet Genomic Med Original Articles BACKGROUND: Prion diseases are a group of lethal neurodegenerative conditions that occur when the normal, cellular form of the prion protein (PrP(C)) is converted into an abnormal, scrapie, form of the protein (PrP(Sc)). Disease may be caused by genetic, infectious, or sporadic etiologies. The genetic form of prion disease comprises~10%–15% of all cases. Prion disease is typically inherited in an autosomal dominant manner. The low incidence of disease makes it highly unlikely that a patient would have two different pathogenic variants. However, we recently identified a case in which the patient did have two pathogenic PRNP variants and presented with an atypical phenotype. METHODS: The patient was evaluated at the Washington Hospital Healthcare System in Fremont, CA. The clinical information for this case report was obtained retrospectively. Variants in the PRNP were identified by polymerase chain reaction (PCR) amplification of exon two of the gene followed by bi‐directional sequence analysis. To determine the phase of the identified variants, a restriction enzyme digestion was utilized, followed by sequence analysis of the products. Cerebral spinal fluid (CSF) was analyzed for surrogate markers of prion disease, 14–3–3 and Tau proteins. CSF real‐time quaking‐induced conversion (RT‐QuIC) assays were also performed. RESULTS: The patient was a compound heterozygote for the well‐characterized c.628G>A (p.Val210Ile) variant and the rare octapeptide deletion of two repeats [c.202_249del48 (p.P68_Q83del)]. Clinically, the patient presented with an early onset demyelinating peripheral neuropathy, followed by later onset cognitive symptoms. CONCLUSION: This presentation is reminiscent of prion protein knockout mice whose predominate symptom, due to complete loss of PrP, was late‐onset peripheral neuropathy. To our knowledge this is the first case reported of a patient with prion disease who had two different pathogenic variants in PRNP. John Wiley and Sons Inc. 2020-01-17 /pmc/articles/PMC7057106/ /pubmed/31953922 http://dx.doi.org/10.1002/mgg3.1134 Text en © 2020 The Authors. Molecular Genetics & Genomic Medicine published by Wiley Periodicals, Inc. This is an open access article under the terms of the http://creativecommons.org/licenses/by/4.0/ License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.
spellingShingle Original Articles
Piazza, Megan
Prior, Thomas W.
Khalsa, Prabhjot S.
Appleby, Brian
A case report of genetic prion disease with two different PRNP variants
title A case report of genetic prion disease with two different PRNP variants
title_full A case report of genetic prion disease with two different PRNP variants
title_fullStr A case report of genetic prion disease with two different PRNP variants
title_full_unstemmed A case report of genetic prion disease with two different PRNP variants
title_short A case report of genetic prion disease with two different PRNP variants
title_sort case report of genetic prion disease with two different prnp variants
topic Original Articles
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7057106/
https://www.ncbi.nlm.nih.gov/pubmed/31953922
http://dx.doi.org/10.1002/mgg3.1134
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