Hereditary dysphasic dementia and the Pick‐Alzheimer spectrum

Morris, John C.; Cole, Monroe; Banker, Betty Q.; Wright, Brad

doi:10.1002/ana.410160407

Cited by 118 publications

(49 citation statements)

References 37 publications

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“…The most distinctive feature of FTD, on psychometric tests, was a signifi cant impairment of frontal lobe functioning, as reported earlier (25). The identifi cation of different mutations in the GRN gene in hereditary dysphasic disinhibition dementia families 1 and 2 (HDDD 1 and HDDD 2) (26,27) links these families to other FTLD-U families with GRN mutation (28,29). A complicating feature in both HDDD families is the presence of AD-type early memory loss which correlated with coexisting AD pathology in almost half of the cases, which distinguishes them from other families with no or little coexisting neurodegenerative disease (26,27).…”

Section: Clinical Phenotype Of Ftdsupporting

confidence: 54%

Frontotemporal Dementias: Update on Recent Developments in Molecular Genetics and Neuropathology

Liščić

2009

Archives of Industrial Hygiene and Toxicology

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Frontotemporal dementias (FTD) are the second most common type of presenile dementias, considered to be clinically and pathologically different from Alzheimer's dementia (AD). FTD differs clinically from AD because memory loss is rarely an early symptom. Instead, FTD is usually denoted by behavioural and language diffi culties, and may co-occur with motor neuron disease (MND). Frontotemporal lobar degeneration (FTLD) with ubiquitin-positive, tau-negative inclusions (FTLD-U) is the most common underlying pathology with and without MND. TAR DNA-binding protein 43 (TDP-43), encoded by the TARDBP gene, has been identifi ed as the major pathological protein of FTLD-U with or without MND, demonstrating that abnormal TDP-43 alone is suffi cient to cause neurodegeneration. FTLD is a genetically complex disorder. A proportion of cases of FTLD-U have various pathogenic mutations in the progranulin (GRN) gene. Other FTLD-U entities with TDP-43 proteinopathy include FTLD-U with valosin-containing protein (VCP) gene mutation and FTLD with MND linked to chromosome 9p. In contrast, chromosome 3-linked dementia, a FTLD-U with chromatic modifying protein 2B (CHMP2B) mutation, has TDP-43 negative inclusions. Thus, TDP-43 defi nes a novel class of neurodegenerative diseases called TDP-43 proteinopathies. These recent discoveries will contribute to an accurate diagnosis, and facilitate the development of diagnosis and therapy.

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Section: Clinical Phenotype Of Ftdsupporting

confidence: 54%

Frontotemporal Dementias: Update on Recent Developments in Molecular Genetics and Neuropathology

Liščić

2009

Archives of Industrial Hygiene and Toxicology

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“…Hereditary dysphasic dementia (HDDD), for example, appears to be related to the FTLD spectrum of disease 91,92 . More recently, HDDD-2 was associated with ubiquitinpositive, tau-negative pathology due to a PGRN mutation 93 .…”

Section: Genetic Associations Of Nonfluent/agrammatic Primary Progresmentioning

confidence: 99%

The non-fluent/agrammatic variant of primary progressive aphasia

Grossman¹

2016

The Behavioral Neurology of Dementia

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In an era of disease-modifying treatments, the non-fluent/agrammatic variant of primary progressive aphasia (naPPA) may help screen for a specific cause of neurodegenerative disease. However, there are controversies surrounding the identification of naPPA. This review describes the characteristic features associated with this discrete, young-onset neurodegenerative condition. Patients with naPPA have a distinct limitation in language emphasizingtheir poor grammatical comprehension and expression, as well as a disorder of speech sound production. Imaging studies associate an impairment of this uniquely human language capacity with disruption of a large-scale neural network centered in left inferior frontal and anterior-superior temporal regions. This corresponds to thepathologic burden of disease anatomically focused in left inferior frontal and anterior-superior temporal regions. A review of the histopathology underlying naPPA relates this condition to frontotemporal lobar degeneration spectrum pathology involving the microtubuleassociated protein tau in a majority of cases. While much work remains to be done, these observations point to unique clinical-pathological correlations that can advance care for an important class of diseases while supplementing our knowledge of human cognitive neuroscience.

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“…The mean AAO is 62 years (range 56-65 years) with a mean duration of 9.5 years. A detailed clinicopathological description of this kindred is available elsewhere [Morris et al, 1984;Behrens et al, 2007]. Briefly, disease in affected individuals is characterized by progressive language deterioration, mild memory problems, and disinhibition.…”

Section: Family Hddd1mentioning

confidence: 99%

Molecular characterization of novel progranulin (GRN) mutations in frontotemporal dementia

et al. 2008

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Frontotemporal dementia (FTD) is a clinical term encompassing dementia characterized by the presence of two major phenotypes: 1) behavioral and personality disorder, and 2) language disorder, which includes primary progressive aphasia and semantic dementia. Recently, the gene for familial frontotemporal lobar degeneration (FTLD) with ubiquitin-positive, tau-negative inclusions (FTLD-U) linked to chromosome 17 was cloned. In the present study, 62 unrelated patients from the Washington University Alzheimer's Disease Research Center and the Midwest Consortium for FTD with clinically diagnosed FTD and/or neuropathologically characterized cases of FTLD-U with or without motor neuron disease (MND) were screened for mutations in the progranulin gene (GRN; also PGRN). We discovered two pathogenic mutations in four families: 1) a single-base substitution within the 3′ splice acceptor site of intron 6/exon 7 (g.5913A>G [IVS6-2A>G]) causing skipping of exon 7 and premature termination of the coding sequence (PTC); and 2) a missense mutation in exon 1 (g.4068C>A) introducing a charged amino acid in the hydrophobic core of the signal peptide at residue 9 (p.A9D). Functional analysis in mutation carriers for the splice acceptor site mutation revealed a 50% decrease in GRN mRNA and protein levels, supporting haploinsufficiency. In contrast, there was no significant difference in the total GRN mRNA between cases and controls NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author Manuscript carrying the p.A9D mutation. Further, subcellular fractionation and confocal microscopy indicate that although the mutant protein is expressed, it is not secreted, and appears to be trapped within an intracellular compartment, possibly resulting in a functional haploinsufficiency.

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Hereditary dysphasic dementia and the Pick‐Alzheimer spectrum

Cited by 118 publications

References 37 publications

Frontotemporal Dementias: Update on Recent Developments in Molecular Genetics and Neuropathology

Frontotemporal Dementias: Update on Recent Developments in Molecular Genetics and Neuropathology

The non-fluent/agrammatic variant of primary progressive aphasia

Molecular characterization of novel progranulin (GRN) mutations in frontotemporal dementia

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