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Novel Variants in the CLCN1, RYR2, and DCTN1 Found in Elderly Japanese Dementia Patients: A Case Series

Dementia has an enormous impact on medical and financial resources in aging societies like Japan. Diagnosis of dementia can be made by physical and mental examinations, imaging tests, and findings of high abnormal proteins in cerebrospinal fluids. In addition, genetic tests can be performed in neuro...

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Autores principales: Hori, Atsushi, Ai, Tomohiko, Isshiki, Miwa, Motoi, Yumiko, Yano, Kouji, Tabe, Yoko, Hattori, Nobutaka, Miida, Takashi
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7931039/
https://www.ncbi.nlm.nih.gov/pubmed/33562224
http://dx.doi.org/10.3390/geriatrics6010014
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author Hori, Atsushi
Ai, Tomohiko
Isshiki, Miwa
Motoi, Yumiko
Yano, Kouji
Tabe, Yoko
Hattori, Nobutaka
Miida, Takashi
author_facet Hori, Atsushi
Ai, Tomohiko
Isshiki, Miwa
Motoi, Yumiko
Yano, Kouji
Tabe, Yoko
Hattori, Nobutaka
Miida, Takashi
author_sort Hori, Atsushi
collection PubMed
description Dementia has an enormous impact on medical and financial resources in aging societies like Japan. Diagnosis of dementia can be made by physical and mental examinations, imaging tests, and findings of high abnormal proteins in cerebrospinal fluids. In addition, genetic tests can be performed in neurodegenerative diseases such as Alzheimer’s disease (AD), frontotemporal dementia (FTD), and Parkinson’s disease (PD). In this case series, we presented three cases of dementia with unknown causes who carry novel variants in the genes associated with neurodegenerative diseases. Three patients (Patients 1, 2, and 6) were found by screening 18 dementia patients using a gene panel including 63 genes. The age of onset for Patient 1 was 74 years old, and his father had PD and mother had AD. The age of onset for Patient 2 was 75 years old, and her mother had AD. The age of onset for Patient 6 was 83 years old, and her father, two sisters, and daughter had dementia. The Mini-Mental State Examination produced results of 20, 15, and 22, respectively. The suspected diagnosis by neurological examinations and imaging studies for Patients 1 and 2 was AD, and for Patient 6 was FTD. Patient 1 was treated with donepezil; Patient 2 was treated with donepezil and memantine; and Patient 6 was treated with donepezil, galantamine, and rivastigmine. The three rare variants identified were: CLCN1, encoding a chloride channel, c.2848G>A:p.Glu950Lys (Patient 1); RYR2, encoding a calcium releasing ryanodine receptor, c.13175A>G:p.Lys4392Arg (Patient 2); and DCTN1, encoding a subunit of dynactin, c. 3209G>A:p.Arg1070Gln (Patient 6). The detected variants were interpreted according to the American College of Medical Genetics (ACMG) guidelines. The minor allele frequency for each variant was 0.025%, 0.023%, and 0.0004% in East Asians, respectively. The DCTN1 variant found in Patient 6 might be associated with FTD. Although none of them were previously reported in dementia patients, all variants were classified as variants of unknown significance (VUS). Our report suggests that results of genetic tests in elderly patients with dementia need to be carefully interpreted. Further data accumulation of genotype–phenotype relationships and development of appropriate functional models are warranted.
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spelling pubmed-79310392021-03-05 Novel Variants in the CLCN1, RYR2, and DCTN1 Found in Elderly Japanese Dementia Patients: A Case Series Hori, Atsushi Ai, Tomohiko Isshiki, Miwa Motoi, Yumiko Yano, Kouji Tabe, Yoko Hattori, Nobutaka Miida, Takashi Geriatrics (Basel) Article Dementia has an enormous impact on medical and financial resources in aging societies like Japan. Diagnosis of dementia can be made by physical and mental examinations, imaging tests, and findings of high abnormal proteins in cerebrospinal fluids. In addition, genetic tests can be performed in neurodegenerative diseases such as Alzheimer’s disease (AD), frontotemporal dementia (FTD), and Parkinson’s disease (PD). In this case series, we presented three cases of dementia with unknown causes who carry novel variants in the genes associated with neurodegenerative diseases. Three patients (Patients 1, 2, and 6) were found by screening 18 dementia patients using a gene panel including 63 genes. The age of onset for Patient 1 was 74 years old, and his father had PD and mother had AD. The age of onset for Patient 2 was 75 years old, and her mother had AD. The age of onset for Patient 6 was 83 years old, and her father, two sisters, and daughter had dementia. The Mini-Mental State Examination produced results of 20, 15, and 22, respectively. The suspected diagnosis by neurological examinations and imaging studies for Patients 1 and 2 was AD, and for Patient 6 was FTD. Patient 1 was treated with donepezil; Patient 2 was treated with donepezil and memantine; and Patient 6 was treated with donepezil, galantamine, and rivastigmine. The three rare variants identified were: CLCN1, encoding a chloride channel, c.2848G>A:p.Glu950Lys (Patient 1); RYR2, encoding a calcium releasing ryanodine receptor, c.13175A>G:p.Lys4392Arg (Patient 2); and DCTN1, encoding a subunit of dynactin, c. 3209G>A:p.Arg1070Gln (Patient 6). The detected variants were interpreted according to the American College of Medical Genetics (ACMG) guidelines. The minor allele frequency for each variant was 0.025%, 0.023%, and 0.0004% in East Asians, respectively. The DCTN1 variant found in Patient 6 might be associated with FTD. Although none of them were previously reported in dementia patients, all variants were classified as variants of unknown significance (VUS). Our report suggests that results of genetic tests in elderly patients with dementia need to be carefully interpreted. Further data accumulation of genotype–phenotype relationships and development of appropriate functional models are warranted. MDPI 2021-02-07 /pmc/articles/PMC7931039/ /pubmed/33562224 http://dx.doi.org/10.3390/geriatrics6010014 Text en © 2021 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Hori, Atsushi
Ai, Tomohiko
Isshiki, Miwa
Motoi, Yumiko
Yano, Kouji
Tabe, Yoko
Hattori, Nobutaka
Miida, Takashi
Novel Variants in the CLCN1, RYR2, and DCTN1 Found in Elderly Japanese Dementia Patients: A Case Series
title Novel Variants in the CLCN1, RYR2, and DCTN1 Found in Elderly Japanese Dementia Patients: A Case Series
title_full Novel Variants in the CLCN1, RYR2, and DCTN1 Found in Elderly Japanese Dementia Patients: A Case Series
title_fullStr Novel Variants in the CLCN1, RYR2, and DCTN1 Found in Elderly Japanese Dementia Patients: A Case Series
title_full_unstemmed Novel Variants in the CLCN1, RYR2, and DCTN1 Found in Elderly Japanese Dementia Patients: A Case Series
title_short Novel Variants in the CLCN1, RYR2, and DCTN1 Found in Elderly Japanese Dementia Patients: A Case Series
title_sort novel variants in the clcn1, ryr2, and dctn1 found in elderly japanese dementia patients: a case series
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7931039/
https://www.ncbi.nlm.nih.gov/pubmed/33562224
http://dx.doi.org/10.3390/geriatrics6010014
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