de novo MAPT mutation G335A causes severe brain atrophy, 3R and 4R PHF-tau pathology and early onset frontotemporal dementia

Ando, Kunie; Ferlini, Lorenzo; Suain, Valérie; Yilmaz, Zehra; Mansour, Salwa; Ber, Isabelle Le; Bouchard, Cécile; Leroy, Karelle; Dürr, Alexandra; Clot, Fabienne; Sarazin, Marie; Brion, Jean Pierre

doi:10.1186/s40478-020-00977-8

Cited by 8 publications

(9 citation statements)

References 10 publications

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“…AD-like presentation and slow progression have already been associated with other MAPT mutations [13,14] and in some cases, a mixed 3R and 4R tau pathology with neurofibrillary tangles similar to AD was found. This is also demonstrated for the G335A MAPT mutation, contiguous to the codon 336 mutation of our patients, characterized by a very early onset and mixed 3R and 4R tau, without Pick bodies [15]. However, the neuropathology of the first MAPT carrier Q336H was analogous to sporadic Pick disease, with a predominance of 3R tau Pick bodies, and minor amount of 3R+4R tau neurofibrillary tangles [3].…”

Section: Discussionsupporting

confidence: 80%

MAPT Q336H mutation: Intrafamilial phenotypic heterogeneity in a new Italian family

Villa

Rossi

Bizzozero

et al. 2022

Euro J of Neurology

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Background and purpose: Q336H is a rare MAPT mutation, previously found in a single patient with behavioral variant frontotemporal dementia and tau pathology (Pick bodies).Here, we describe the clinical characteristics of two members of a new family carrying the Q336H MAPT mutation.Methods: Clinical, genetic, and neuroradiological assessment and follow-up of the proband were made.Results: At age 37 years, the proband developed naming and object recognition impairment, due to a lack of knowledge. After 3 years, he developed behavioral disorders.Magnetic resonance imaging (MRI) and fluorodeoxyglucose positron emission tomography showed the involvement of the left temporal pole. A diagnosis of semantic variant primary progressive aphasia (svPPA) was made. At follow-up after 6 and 12 months, a rapid worsening of cognitive deficits occurred. His parent presented, at age 65 years, slowly progressive memory deficits without behavioral impairment, and, on MRI, evidence of mesial temporal atrophy, consistent with a clinical diagnosis of Alzheimer disease (AD).Conclusions: This is the second family carrying the MAPT Q336H mutation reported so far. We showed that svPPA and AD-like phenotype can be associated with this mutation. A wide clinical variability exists at the intrafamilial level for Q336H MAPT mutation, pointing to genetic and/or environmental influencing factors on disease expression. We also confirmed that svPPA can be associated with MAPT mutations, suggesting that this gene should be analyzed also in patients with svPPA, especially with early onset. In addition, an AD-like phenotype may be associated with this mutation, suggesting its different effects on protein misfolding and aggregation.

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Section: Discussionsupporting

confidence: 80%

MAPT Q336H mutation: Intrafamilial phenotypic heterogeneity in a new Italian family

Villa

Rossi

Bizzozero

et al. 2022

Euro J of Neurology

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“…All the reported pathogenic mutations were located on the MAPT gene [4,19,20,23,[26][27][28][30][31][32]; this differs from the genetic distribution of typical FTD in that C9 has been reported as the most common type in Western countries [38]; MAPT abnormalities are more common in China [39]. In addition, we also found some specific mutation sites that might…”

Section: Neuropathological Analysismentioning

confidence: 69%

“…One clinical feature of FTD is an early onset; most patients experience disease onset between the ages of 45 and 65 years [ 2, 3 ]. However, some cases of extremely early onset have been reported in which the initiation of neurodegeneration occurred in patients in their 20 s to 30 s. The youngest onset age reported thus far is 14 years [ 4 ], although this is relatively rare in clinical practice.…”

Section: Introductionmentioning

confidence: 99%

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Extremely Early-Onset Frontotemporal Dementia: A Case Report and Literature Review

Chu

Liu

Nan

et al. 2022

JAD

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Background: In most cases, the onset of frontotemporal dementia (FTD) occurs between the ages of 45 and 65 years. However, some patients experience an extremely early disease onset. Objective: To investigate the clinical, genetic, and pathological features of extremely early-onset FTD. Methods: We conducted a comprehensive clinical, genetic, and neuropathological analysis of a 25-year-old patient experiencing the onset of behavioral variant frontotemporal dementia (bvFTD). In addition, we conducted a literature review and summarized the clinical, genetic, and pathological features of patients with FTD with onset age≤25 years. Results: The patient was diagnosed with bvFTD; however, there was no family history of FTD, no positive genetic test results and no deposition of TDP43, tau, ubiquitin, and synuclein in the brain. Literature screening identified 18 patients with onset age≤25 years with FTD. The youngest patient was 14-years-of-age. Most patients (8/14) had a positive family history. The most common clinical phenotype was the behavioral variant (12/14). Genetic results were reported for 11 patients; the most common pathogenic gene was MAPT (10/12), with four cases of G389 R, two cases of P301 S, one case of G335 S, one case of G335A, one case of G335 V, and one case of L315 R. Pathological results were reported for 13 patients; the most common pathological subtype was tau (8/13). Conclusion: FTD can start at an extremely early age. The most common phenotype of extremely early onset FTD was the behavioral variant, the most common pathogenic gene was MAPT, and the most common neuropathological type was tau.

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“…Instead, they reduce the ability of tau to promote microtubule assembly [ 17 , 117 ]. Conversely, Q336H and Q336R mutations increased tau-mediated microtubule assembly [ 17 , 118 ]. Despite not altering the 3R/4R ratio or having the ability to bind MTs, the D348G tau mutation was associated with early amyotrophic lateral sclerosis (ALS) onset.…”

Section: Tau Protein Metabolismmentioning

confidence: 99%

Tau mRNA Metabolism in Neurodegenerative Diseases: A Tangle Journey

et al. 2022

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Tau proteins are known to be mainly involved in regulation of microtubule dynamics. Besides this function, which is critical for axonal transport and signal transduction, tau proteins also have other roles in neurons. Moreover, tau proteins are turned into aggregates and consequently trigger many neurodegenerative diseases termed tauopathies, of which Alzheimer’s disease (AD) is the figurehead. Such pathological aggregation processes are critical for the onset of these diseases. Among the various causes of tau protein pathogenicity, abnormal tau mRNA metabolism, expression and dysregulation of tau post-translational modifications are critical steps. Moreover, the relevance of tau function to general mRNA metabolism has been highlighted recently in tauopathies. In this review, we mainly focus on how mRNA metabolism impacts the onset and development of tauopathies. Thus, we intend to portray how mRNA metabolism of, or mediated by, tau is associated with neurodegenerative diseases.

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de novo MAPT mutation G335A causes severe brain atrophy, 3R and 4R PHF-tau pathology and early onset frontotemporal dementia

Cited by 8 publications

References 10 publications

MAPT Q336H mutation: Intrafamilial phenotypic heterogeneity in a new Italian family

MAPT Q336H mutation: Intrafamilial phenotypic heterogeneity in a new Italian family

Extremely Early-Onset Frontotemporal Dementia: A Case Report and Literature Review

Tau mRNA Metabolism in Neurodegenerative Diseases: A Tangle Journey

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