“Frontotemporoparietal” dementia

Moreno, Fermín; Indakoetxea, Begoña; Barandiarán, Miriam; Alzualde, Ainhoa; Gabilondo, Alazne; Estanga, Ainara; Ruiz, Julio; Ruibal, M.; Bergareche, Alberto; Martí-Massó, J F; Munáin, Adolfo López de

doi:10.1212/wnl.0b013e3181bd82a7

Cited by 33 publications

(21 citation statements)

References 36 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…However, as is the case with his brother, clinical presentations of PNFA due to PGRN mutation are also frequent [22]. Several studies have confirmed this strong association between PNFA and PGRN mutations with the typical FTLD-U/TDP-43 pathology [21,23–25]. In particular, similar to the brother’s pathological findings, FTLD-U, type 3 pathology, was found to be most commonly associated with the clinical phenotype of PNFA [26].…”

Section: Discussionmentioning

confidence: 92%

Intra-Familial Clinical Heterogeneity due to FTLD-U with TDP-43 Proteinopathy Caused by a Novel Deletion in Progranulin Gene (PGRN)

Gabryelewicz

Masellis

Berdyński

et al. 2011

JAD

View full text Add to dashboard Cite

Frontotemporal dementia (FTD) is one of the commonest forms of early-onset dementia, accounting for up to 20% of all dementia patients. Recently, it has been shown that mutations in progranulin gene (PGRN) cause many familial cases of FTD. Members of a family affected by FTD spectrum disorders were ascertained in Poland and Canada. Clinical, radiological, molecular, genetic, and pathological studies were performed. A sequencing analysis of PGRN exons 1-13 was performed in the proband. Genotyping of the identified PGRN mutation and pathological analysis was carried out in the proband's brother. The onset of symptoms of FTD in the proband included bradykinesia, apathy, and somnolence followed by changes in personality, cognitive deficits, and psychotic features. The proband's clinical diagnosis was FTD and parkinsonism (FTDP). DNA sequence analysis of PGRN revealed a novel, heterozygous mutation in exon 11 (g. 2988_2989delCA, P439_R440fsX6). The mutation introduced a premature stop codon at position 444. The proband's brother with the same mutation had a different course first presenting as progressive non-fluent aphasia, and later evolving symptoms of behavioral variant of FTD. He also developed parkinsonism late in the disease course evolving into corticobasal syndrome. Pathological analysis in the brother revealed Frontotemporal Lobar Degeneration-Ubiquitin (FTLD-U)/TDP-43 positive pathology. The novel PGRN mutation is a disease-causing mutation

show abstract

Section: Discussionmentioning

confidence: 92%

Intra-Familial Clinical Heterogeneity due to FTLD-U with TDP-43 Proteinopathy Caused by a Novel Deletion in Progranulin Gene (PGRN)

Gabryelewicz

Masellis

Berdyński

et al. 2011

JAD

View full text Add to dashboard Cite

show abstract

“…We previously described a prevalent ancestral c.709-1G>A mutation related to Basque population [17], [18]. The c.709-1G>A mutation results in null allele, as most of the pathogenic mutations described up to now, suggesting that FTLD in these families results from PGRN haploinsufficiency [5].…”

Section: Introductionmentioning

confidence: 89%

Inactivation of CDK/pRb Pathway Normalizes Survival Pattern of Lymphoblasts Expressing the FTLD-Progranulin Mutation c.709-1G>A

et al. 2012

View full text Add to dashboard Cite

BackgroundMutations in the progranulin (PGRN) gene, leading to haploinsufficiency, cause familial frontotemporal lobar degeneration (FTLD-TDP), although the pathogenic mechanism of PGRN deficit is largely unknown. Allelic loss of PGRN was previously shown to increase the activity of cyclin-dependent kinase (CDK) CDK6/pRb pathway in lymphoblasts expressing the c.709-1G>A PGRN mutation. Since members of the CDK family appear to play a role in neurodegenerative disorders and in apoptotic death of neurons subjected to various insults, we investigated the role of CDK6/pRb in cell survival/death mechanisms following serum deprivation.Methodology/Principal FindingsWe performed a comparative study of cell viability after serum withdrawal of established lymphoblastoid cell lines from control and carriers of c.709-1G>A PGRN mutation, asymptomatic and FTLD-TDP diagnosed individuals. Our results suggest that the CDK6/pRb pathway is enhanced in the c.709-1G>A bearing lymphoblasts. Apparently, this feature allows PGRN-deficient cells to escape from serum withdrawal-induced apoptosis by decreasing the activity of executive caspases and lowering the dissipation of mitochondrial membrane potential and the release of cytochrome c from the mitochondria. Inhibitors of CDK6 expression levels like sodium butyrate or the CDK6 activity such as PD332991 were able to restore the vulnerability of lymphoblasts from FTLD-TDP patients to trophic factor withdrawal.Conclusion/SignificanceThe use of PGRN-deficient lymphoblasts from FTLD-TDP patients may be a useful model to investigate cell biochemical aspects of this disease. It is suggested that CDK6 could be potentially a therapeutic target for the treatment of the FTLD-TDP.

show abstract

“…The penetrance reaches 90% at age 70 years [27, 28, 29, 30]. A wide spectrum of cognitive, behavioral, and motor features in FTDP-17 is associated with PGRN mutations, but the particular type of mutation does not predict the clinical syndrome [27, 28, 29, 31, 32]. PGRN mutations are usually associated with bvFTD, but unlike MAPT mutation carriers, an isolated language dysfunction and primary progressive aphasia syndrome (PPA) can be also observed [3].…”

Section: Clinical Genetics General Characteristic and Parkinsonimentioning

confidence: 99%

Parkinsonian syndrome in familial frontotemporal dementia

Siuda¹,

Fujioka²,

Wszołek³

2014

Parkinsonism & Related Disorders

View full text Add to dashboard Cite

Parkinsonism in frontotemporal dementia (FTD) was first described in families with mutations in the microtubule-associated protein tau (MAPT) and progranulin (PRGN) genes. Since then, mutations in several other genes have been identified for FTD with Parkinsonism, including chromosome 9 open reading frame 72 (C9ORF72), chromatin modifying protein 2B (CHMP2B), valosin-containing protein (VCP), fused in sarcoma (FUS) and transactive DNA-binding protein (TARDBP). The clinical presentation of patients with familial forms of FTD with Parkinsonism is highly variable. The Parkinsonism seen in FTD patients is usually characterized by akinetic-rigid syndrome and is mostly associated with the behavioral variant of FTD (bvFTD); however, some cases may present with classical Parkinson’s disease. In other cases, atypical Parkinsonism resembling progressive supranuclear palsy (PSP) or corticobasal syndrome (CBS) has also been described. Although rare, Parkinsonism in FTD may coexist with motor neuron disease. Structural neuroimaging, which is crucial for the diagnosis of FTD, shows characteristic patterns of brain atrophy associated with specific mutations. Structural neuroimaging is not helpful in distinguishing among patients with parkinsonian features. Furthermore, dopaminergic imaging that shows nigrostriatal neurodegeneration in FTD with Parkinsonism cannot discriminate parkinsonian syndromes that arise from different mutations. Generally, Parkinsonism in FTD is levodopa unresponsive, but there have been cases where a temporary benefit has been reported, so dopaminergic treatment is worth trying, especially, when motor and non-motor manifestations can cause significant problems with daily functioning. In this review, we present an update on the clinical and genetic correlations of FTD with Parkinsonism.

show abstract

“Frontotemporoparietal” dementia

Abstract: Patients carrying the c.709-1G>A mutation in the PGRN gene showed heterogeneous clinical and neuropsychological features and commonly developed corticobasal syndrome as the disease progressed.

Cited by 33 publications

References 36 publications

Intra-Familial Clinical Heterogeneity due to FTLD-U with TDP-43 Proteinopathy Caused by a Novel Deletion in Progranulin Gene (PGRN)

Intra-Familial Clinical Heterogeneity due to FTLD-U with TDP-43 Proteinopathy Caused by a Novel Deletion in Progranulin Gene (PGRN)

Inactivation of CDK/pRb Pathway Normalizes Survival Pattern of Lymphoblasts Expressing the FTLD-Progranulin Mutation c.709-1G>A

Parkinsonian syndrome in familial frontotemporal dementia

Contact Info

Product

Resources

About