Genetics of Frontotemporal Dementia

Olszewska, Diana A.; Lonergan, Roisin; Fallon, Emer; Lynch, Tim

doi:10.1007/s11910-016-0707-9

Cited by 106 publications

(88 citation statements)

References 111 publications

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“…Three major genes contribute to the autosomal dominant cases: MAPT, GRN , and C9orf72 and mutations are listed in the AD and FTD mutation database (http://www.molgen.vib-ua.be/FTDMutations) [5, 26]. Pathogenic and risk variants have been reported at much lower frequencies in several additional genes including TARDBP [27], VCP [28], CHMP2B [29], ITM2B [30], TBP [30], DCTN1 ,[31] SQSTM1 [32], TREM2 [33], UBQLN 2[34], CHCHD10 [35], and TBK1 [36] [26]. The cumulative frequency of these genes accounts for less than 5% of all FTD [30].…”

Section: Frontotemporal Dementiamentioning

confidence: 99%

“…Pathogenic and risk variants have been reported at much lower frequencies in several additional genes including TARDBP [27], VCP [28], CHMP2B [29], ITM2B [30], TBP [30], DCTN1 ,[31] SQSTM1 [32], TREM2 [33], UBQLN 2[34], CHCHD10 [35], and TBK1 [36] [26]. The cumulative frequency of these genes accounts for less than 5% of all FTD [30]. However, founder effects may increase the prevalence of individual genes in certain populations (in Belgium TBK1 has been reported as third most common FTD risk gene) [36].…”

Section: Frontotemporal Dementiamentioning

confidence: 99%

“…Very few sporadic cases have been reported [40]. The average age of onset for MAPT mutation carriers is 45–65 years [30, 41]. Penetrance is age-dependent approaching 100% after age 65.…”

Section: Frontotemporal Dementiamentioning

confidence: 99%

“…Motor neuron disease (MND) is not a feature of MAPT -related FTD. Imaging usually reveals symmetrical frontotemporal atrophy and hypometobolism [30]. Tau pathology is found in all cases with a MAPT mutation.…”

Section: Frontotemporal Dementiamentioning

confidence: 99%

“…GRN appears to be nearly 100% penetrant by age 80. Age of onset is typically somewhat older than that of MAPT , ranging from 35–89 [30]. Clinical phenotypes show significant inter- and intra-familial variability.…”

Section: Frontotemporal Dementiamentioning

confidence: 99%

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Alzheimer’s Disease and Frontotemporal Dementia: The Current State of Genetics and Genetic Testing Since the Advent of Next-Generation Sequencing

Goldman

Deerlin

2018

Mol Diagn Ther

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The advent of next-generation sequencing has changed genetic diagnostics, allowing clinicians to test concurrently for phenotypically overlapping conditions such as Alzheimer's disease (AD) and frontotemporal dementia (FTD). However, to interpret genetic results, clinicians require an understanding of the benefits and limitations of different genetic technologies, such as the inability to detect large repeat expansions in such diseases as C9orf72-associated FTD and amyotrophic lateral sclerosis. Other types of mutations such as large deletions or duplications and triple repeat expansions may also go undetected. Additionally, the concurrent testing of multiple genes or the whole exome increases the likelihood of discovering variants of unknown significance. Our goal here is to review the current knowledge about the genetics of AD and FTD and suggest up-to-date guidelines for genetic testing for these dementias. Despite the improvements in diagnosis due to biomarkers testing, AD and FTD can have overlapping symptoms. When used appropriately, genetic testing can elucidate the diagnosis and specific etiology of the disease, as well as provide information for the family and determine eligibility for clinical trials. Prior to ordering genetic testing, clinicians must determine the appropriate genes to test, the types of mutations that occur in these genes, and the best type of genetic test to use. Without this analysis, interpretation of genetic results will be difficult. Patients should be counseled about the benefits and limitations of different types of genetic tests so they can make an informed decision about testing.

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Section: Frontotemporal Dementiamentioning

confidence: 99%

Section: Frontotemporal Dementiamentioning

confidence: 99%

“…Very few sporadic cases have been reported [40]. The average age of onset for MAPT mutation carriers is 45–65 years [30, 41]. Penetrance is age-dependent approaching 100% after age 65.…”

Section: Frontotemporal Dementiamentioning

confidence: 99%

Section: Frontotemporal Dementiamentioning

confidence: 99%

Section: Frontotemporal Dementiamentioning

confidence: 99%

See 3 more Smart Citations

Alzheimer’s Disease and Frontotemporal Dementia: The Current State of Genetics and Genetic Testing Since the Advent of Next-Generation Sequencing

Goldman

Deerlin

2018

Mol Diagn Ther

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Nuclear pore complex and nucleocytoplasmic transport disruption in neurodegeneration

Cristi,

Rapuri,

Coyne

2023

FEBS Letters

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Nuclear pore complexes (NPCs) play a critical role in maintaining the equilibrium between the nucleus and cytoplasm, enabling bidirectional transport across the nuclear envelope, and are essential for proper nuclear organization and gene regulation. Perturbations in the regulatory mechanisms governing NPCs and nuclear envelope homeostasis have been implicated in the pathogenesis of several neurodegenerative diseases. The ESCRT‐III pathway emerges as a critical player in the surveillance and preservation of well‐assembled, functional NPCs, as well as nuclear envelope sealing. Recent studies have provided insights into the involvement of nuclear ESCRT‐III in the selective reduction of specific nucleoporins associated with neurodegenerative pathologies. Thus, maintaining quality control of the nuclear envelope and NPCs represents a pivotal element in the pathological cascade leading to neurodegenerative diseases. This review describes the constituents of the nuclear‐cytoplasmic transport machinery, encompassing the nuclear envelope, NPC, and ESCRT proteins, and how their structural and functional alterations contribute to the development of neurodegenerative diseases.

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

Tan

Yong

Foo

et al. 2023

Ann Clin Transl Neurol

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Objective Frontotemporal dementia (FTD) encompasses a spectrum of neurodegenerative disorders, including behavioural variant FTD (bvFTD), semantic variant primary progressive aphasia (svPPA) and non‐fluent variant PPA (nfvPPA). While a strong genetic component is implicated in FTD, genetic FTD in Asia is less frequently reported. We aimed to investigate the frequency of Southeast Asian FTD patients harbouring known genetic FTD variants. Methods A total of 60 FTD‐spectrum patients (25 familial and 35 sporadic) from Singapore and the Philippines were included. All underwent next‐generation sequencing and repeat‐primed PCR for C9orf72 expansion testing. Neurofilament light chain (NfL) levels were measured in a subset of patients. Results Overall, 26.6% (16/60 cases) carried pathogenic or likely pathogenic variants in a FTD‐related gene, including: MAPT Gln351Arg (n = 1); GRN Cys92Ter (n = 1), Ser301Ter (n = 2), c.462 + 1G > C (n = 1); C9orf72 expansion (35–70 repeats; n = 8); TREM2 Arg47Cys (n = 1); and OPTN frameshift insertion (n = 2). Genetic mutations accounted for 48% (12/25) of patients with familial FTD, and 11.4% (4/35) of patients with sporadic FTD. C9orf72 repeat expansions were the most common genetic mutation (13.3%, 8/60), followed by GRN (6.7%, 4/60) variants. Within mutation carriers, plasma NfL was highest in a C9orf72 expansion carrier, and CSF NfL was highest in a GRN splice variant carrier. Interpretation In our cohort, genetic mutations are present in one‐quarter of FTD‐spectrum cases, and up to half of those with family history. Our findings highlight the importance of wider implementation of genetic testing in FTD patients from Southeast Asia.

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Genetics of Frontotemporal Dementia

Cited by 106 publications

References 111 publications

Alzheimer’s Disease and Frontotemporal Dementia: The Current State of Genetics and Genetic Testing Since the Advent of Next-Generation Sequencing

Alzheimer’s Disease and Frontotemporal Dementia: The Current State of Genetics and Genetic Testing Since the Advent of Next-Generation Sequencing

Nuclear pore complex and nucleocytoplasmic transport disruption in neurodegeneration

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

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