Novel optineurin frameshift insertion in a family with frontotemporal dementia and parkinsonism without amyotrophic lateral sclerosis

Frontotemporal Dementia (FTD) is a common cause of Young Onset Dementia and has diverse clinical manifestations involving behavior, executive function, language and motor function, including parkinsonism. Up to 50% of FTD patients report a positive family history, supporting a strong genetic basis,...

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Main Authors: Dominguez, Jacqueline, Yu, Jeryl Tan, Tan, Jayne Yi, Ng, Arlene, De Guzman, Ma Fe, Natividad, Boots, Daroy, Ma Luisa, Cano, Jemellee, Yu, Justine, Lian, Michelle Mulan, Zeng, Li, Lim, Weng Khong, Foo, Jia Nee, Ng, Adeline S. L.
Other Authors: Lee Kong Chian School of Medicine (LKCMedicine)
Format: Article
Language:English
Published: 2021
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Online Access:https://hdl.handle.net/10356/152052
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Institution: Nanyang Technological University
Language: English
id sg-ntu-dr.10356-152052
record_format dspace
institution Nanyang Technological University
building NTU Library
continent Asia
country Singapore
Singapore
content_provider NTU Library
collection DR-NTU
language English
topic Science::Medicine
Familial Frontotemporal Dementia
Novel Mutation
spellingShingle Science::Medicine
Familial Frontotemporal Dementia
Novel Mutation
Dominguez, Jacqueline
Yu, Jeryl Tan
Tan, Jayne Yi
Ng, Arlene
De Guzman, Ma Fe
Natividad, Boots
Daroy, Ma Luisa
Cano, Jemellee
Yu, Justine
Lian, Michelle Mulan
Zeng, Li
Lim, Weng Khong
Foo, Jia Nee
Ng, Adeline S. L.
Novel optineurin frameshift insertion in a family with frontotemporal dementia and parkinsonism without amyotrophic lateral sclerosis
description Frontotemporal Dementia (FTD) is a common cause of Young Onset Dementia and has diverse clinical manifestations involving behavior, executive function, language and motor function, including parkinsonism. Up to 50% of FTD patients report a positive family history, supporting a strong genetic basis, particularly in cases with both FTD and amyotrophic lateral sclerosis (FTD-ALS). Mutations in three genes are associated with the majority of familial FTD (fFTD) cases - microtubule associated protein tau gene (MAPT), granulin precursor (GRN), and hexanucleotide repeat expansions in chromosome 9 open reading frame 72- SMCR8complex subunit (C9orf72) while mutations in other genes such as optineurin (OPTN) have rarely been reported. Mutations in OPTN have been reported mostly in familial and sporadic cases of ALS, or in rare cases of FTD-ALS, but not in association with pure or predominant FTD and/or parkinsonian phenotype. Here, we report for the first time, a family from the Philippines with four members harboring a novel frameshift insertion at OPTN (Chr 10:13166090 G>GA) p.Lys328GluTer11, three of whom presented with FTD-related phenotypes. Additionally, one sibling heterozygous for the frameshift insertion had a predominantly parkinsonian phenotype resembling corticobasal syndrome, but it remains to be determined if this phenotype is related to the frameshift insertion. Notably, none of the affected members showed any evidence of motor neuron disease or ALS at the time of writing, both clinically and on electrophysiological testing, expanding the phenotypic spectrum of OPTN mutations. Close follow-up of mutation carriers for the development of new clinical features and wider investigation of additional family members with further genetic analyses will be conducted to investigate the possibility of other genetic modifiers in this family which could explain phenotypic heterogeneity.
author2 Lee Kong Chian School of Medicine (LKCMedicine)
author_facet Lee Kong Chian School of Medicine (LKCMedicine)
Dominguez, Jacqueline
Yu, Jeryl Tan
Tan, Jayne Yi
Ng, Arlene
De Guzman, Ma Fe
Natividad, Boots
Daroy, Ma Luisa
Cano, Jemellee
Yu, Justine
Lian, Michelle Mulan
Zeng, Li
Lim, Weng Khong
Foo, Jia Nee
Ng, Adeline S. L.
format Article
author Dominguez, Jacqueline
Yu, Jeryl Tan
Tan, Jayne Yi
Ng, Arlene
De Guzman, Ma Fe
Natividad, Boots
Daroy, Ma Luisa
Cano, Jemellee
Yu, Justine
Lian, Michelle Mulan
Zeng, Li
Lim, Weng Khong
Foo, Jia Nee
Ng, Adeline S. L.
author_sort Dominguez, Jacqueline
title Novel optineurin frameshift insertion in a family with frontotemporal dementia and parkinsonism without amyotrophic lateral sclerosis
title_short Novel optineurin frameshift insertion in a family with frontotemporal dementia and parkinsonism without amyotrophic lateral sclerosis
title_full Novel optineurin frameshift insertion in a family with frontotemporal dementia and parkinsonism without amyotrophic lateral sclerosis
title_fullStr Novel optineurin frameshift insertion in a family with frontotemporal dementia and parkinsonism without amyotrophic lateral sclerosis
title_full_unstemmed Novel optineurin frameshift insertion in a family with frontotemporal dementia and parkinsonism without amyotrophic lateral sclerosis
title_sort novel optineurin frameshift insertion in a family with frontotemporal dementia and parkinsonism without amyotrophic lateral sclerosis
publishDate 2021
url https://hdl.handle.net/10356/152052
_version_ 1759856366882652160
spelling sg-ntu-dr.10356-1520522023-03-05T16:44:09Z Novel optineurin frameshift insertion in a family with frontotemporal dementia and parkinsonism without amyotrophic lateral sclerosis Dominguez, Jacqueline Yu, Jeryl Tan Tan, Jayne Yi Ng, Arlene De Guzman, Ma Fe Natividad, Boots Daroy, Ma Luisa Cano, Jemellee Yu, Justine Lian, Michelle Mulan Zeng, Li Lim, Weng Khong Foo, Jia Nee Ng, Adeline S. L. Lee Kong Chian School of Medicine (LKCMedicine) Genome Institute of Singapore, A*STAR Science::Medicine Familial Frontotemporal Dementia Novel Mutation Frontotemporal Dementia (FTD) is a common cause of Young Onset Dementia and has diverse clinical manifestations involving behavior, executive function, language and motor function, including parkinsonism. Up to 50% of FTD patients report a positive family history, supporting a strong genetic basis, particularly in cases with both FTD and amyotrophic lateral sclerosis (FTD-ALS). Mutations in three genes are associated with the majority of familial FTD (fFTD) cases - microtubule associated protein tau gene (MAPT), granulin precursor (GRN), and hexanucleotide repeat expansions in chromosome 9 open reading frame 72- SMCR8complex subunit (C9orf72) while mutations in other genes such as optineurin (OPTN) have rarely been reported. Mutations in OPTN have been reported mostly in familial and sporadic cases of ALS, or in rare cases of FTD-ALS, but not in association with pure or predominant FTD and/or parkinsonian phenotype. Here, we report for the first time, a family from the Philippines with four members harboring a novel frameshift insertion at OPTN (Chr 10:13166090 G>GA) p.Lys328GluTer11, three of whom presented with FTD-related phenotypes. Additionally, one sibling heterozygous for the frameshift insertion had a predominantly parkinsonian phenotype resembling corticobasal syndrome, but it remains to be determined if this phenotype is related to the frameshift insertion. Notably, none of the affected members showed any evidence of motor neuron disease or ALS at the time of writing, both clinically and on electrophysiological testing, expanding the phenotypic spectrum of OPTN mutations. Close follow-up of mutation carriers for the development of new clinical features and wider investigation of additional family members with further genetic analyses will be conducted to investigate the possibility of other genetic modifiers in this family which could explain phenotypic heterogeneity. Ministry of Health (MOH) National Medical Research Council (NMRC) National Research Foundation (NRF) Published version This study was funded by Philippine Council for Health Research and Development of the Philippine Department of Science and Technology [FP 15026], the St. Luke's Medical Center (No. 15-020), Singapore's Ministry of Health National Medical Research Council [ASLN under the NMRC Transition Award (MOH-TA18may-0003)], and National Research Foundation Singapore Fellowship (JF under NRF-NRFF2016-03). 2021-11-18T02:14:07Z 2021-11-18T02:14:07Z 2021 Journal Article Dominguez, J., Yu, J. T., Tan, J. Y., Ng, A., De Guzman, M. F., Natividad, B., Daroy, M. L., Cano, J., Yu, J., Lian, M. M., Zeng, L., Lim, W. K., Foo, J. N. & Ng, A. S. L. (2021). Novel optineurin frameshift insertion in a family with frontotemporal dementia and parkinsonism without amyotrophic lateral sclerosis. Frontiers in Neurology, 12, 645913-. https://dx.doi.org/10.3389/fneur.2021.645913 1664-2295 https://hdl.handle.net/10356/152052 10.3389/fneur.2021.645913 34093394 2-s2.0-85107227128 12 645913 en NRF-NRFF2016-03 MOHTA18may- 0003 Frontiers in Neurology © 2021 Dominguez, Yu, Tan, Ng, De Guzman, Natividad, Daroy, Cano, Yu, Lian, Zeng, Lim, Foo and Ng. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms. application/pdf