Novel Optineurin Frameshift Insertion in a Family With Frontotemporal Dementia and Parkinsonism Without Amyotrophic Lateral Sclerosis

Abstract

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.

Semantic and right temporal variant of FTD: Next generation sequencing genetic analysis on a single-center cohort

“…Patient P06 had Q314L OPTN and R795H DCTN1 variants. OPTN , earlier reported as causative of primary open-angle glaucoma, was afterwards linked to ALS ( Maruyama et al, 2010 ), or to FTD ( Dominguez et al, 2021 ), with dominant or recessive transmission. Heterozygous Q314L in OPTN was described in some sporadic ALS cases ( Del Bo et al, 2011 ; Pensato et al, 2020 ).…”

C9orf72 expansions are the most common cause of genetic frontotemporal dementia in a Southeast Asian cohort

“…Ethics approval was obtained from Singapore Health Services Centralised Institutional Review Board and St. Luke's Medical Centre Institutional Ethics Review Committee. A subset of patients included in the current updated cohort were previously published 18,21 …”

“…Shortlisted candidate variants were further confirmed by Sanger sequencing. Methods on Sanger sequencing, C9orf72 expansion testing with repeat‐primed polymerase chain reaction (rp‐PCR) have been described previously 21 . Primer sequences are available upon request.…”

“…Methods on Sanger sequencing, C9orf72 expansion testing with repeat‐primed polymerase chain reaction (rp‐PCR) have been described previously. 21 Primer sequences are available upon request. A genetic diagnosis was conferred if a variant classified as pathogenic or likely pathogenic was identified and had appropriate clinical correlation.…”

Regulating Phase Transition in Neurodegenerative Diseases by Nuclear Import Receptors

“…Further, the accumulation of the microtubule-associated protein tau is observed in FTLD patients [ 177 ]. A number of mutant genes have been recently identified as causing ALS and FTLD [ 154 , 168 , 180 , 181 , 182 , 183 , 184 , 185 , 186 , 187 , 188 , 189 , 190 , 191 , 192 , 193 , 194 ]. Various pathophysiological mechanisms, such as dysregulation in protein homeostasis due to compromised protein degradation pathways (e.g., perturbed ubiquitin-proteasome system pathway, disturbed autophagy, and inhibition of endocytosis), abnormal stress granule assembly, glutamate excitotoxicity, dysregulation in metal ion homeostasis, and defects in nucleocytoplasmic transport, are involved in ALS and FTLD [ 195 , 196 , 197 , 198 ].…”