JNNP: A unique pattern of temporal lobe atrophy in patients with frontal temporal lobe dementia and I383V variation in TARDBP

Frontal temporal lobe dementia (FTD) and amyotrophy lateral sclerosis (ALS) are closely related diseases that are pathologically and genetically linked through TAR-DNA binding protein-43 (TDP-43).
pathogenic variants in TARDBP coded TDP-43 appear less frequently in FTD than ALS, and clinical pathology studies are rare.
high rate of I383V variants in TARDBP was previously observed in the Dutch FTD patient queue.
this paper provides further evidence for the pathogenicity of this variant and puts forward its clinical pathological characteristics.
all FTD (n-13) and ALS patients with I383V variants (NM_.3:c.1147A-gt; G, p.Ile383Val) in TARDBP (NM_.3:c.1147A-gt; G, p.Ile383Val) were identified in clinical or research settings by whole exosomes or genome-wide sequencing.
20 other genetically pathogenic variants associated with ALS, FTD, or other forms of dementia were excluded from all patients.
brain imaging (CT or MRI) is available to all FTD patients.
quantitative assessment of translenguous brain region volume loss was performed on patients with T1-weighted MRI images with sufficient mass (n-5) and compared with reference populations with gender/age matching.
, extensive genealogy studies have been conducted to investigate possible correlations between exponential patients.
2 FTD patients were brain dissected and routine immunoglostification tested in the Dutch brain bank.
clinical esolysation and exodes of variants of the I383V variant were reduced.
FTD patients with I383V variants in 13 TARDBP cases showed behavioral changes and semantic defects.
svPPA semantic variation of primary adaffesy (svPPA) is an interesting problem because it is often considered an exudable disease.
patient (4M) showed additional motor symptoms, but did not meet the ALS standard.
in 4 ALS patients with I383V variants, 3 were relatively slow and had a course of up to 9 years.
alS patients did not show cognitive or behavioral symptoms.
6 FTD patients and 1 ALS patient were related.
, two FTD patients and two ALS patients may be connected to Family 1 through a distant common ancestor.
the variable estype of the I383V variant takes family 1 as an example, in which different family members are affected by svPPA, FTD behavioral variant, unknown dementia, ALS or aggressive spinal myotrophy, with a wide range of age (44-69 years) and course of illness (7-23 years).
to estimate age-related exoded rates requires larger-scale prospective studies.
family history study found that three families share a common ancestor.
these families included 8 FTD patients and 3 ALS patients, confirming the presence of I383V variants (number a-K; full color) in TARDBP.
semi-colored symbols represent clinically diagnosed patients who have not been genetically tested.
red: clinically diagnosed as FTD or PPA.
black: clinical diagnosis of ALS or PSMA.
gray: relatives of index patients affected by other forms of dementia or mental illness.
numbers within the symbol represent additional family members and do not require further clinical information.
number below the symbol indicates the age of death or the current age.
Clinical diagnosis: bvFTD, behavioral variation of frontal lobe dementia; svPPA, semantic variation of primary aphdropia; ALS, amyotrophic lateral sclerosis; PSMA, traumatic spinal myotrophy; UD, unspecified dementia; mental illness, mental disorders.
noteworthy observation is that despite the presence of potential pathogenic TARDBP variants, the cortical regions of two FTD patients (patient 1F and previously reported patient 4M1) lacked TDP-43 responsiveness.
only a few different forms of TDP-43 cytokine inclusions were found in the prey cortical, toothy back and tail nuclei.
possible explanation for the rare temporal lobe pathology may be severe neurodegenerative changes, especially given the patient's longer course of 1F (23 years).
interestingly, we also detected tau-positive inclusions in the sea mass and clusters of star-shaped glial cells in the shell and tail cores.
a single other neuropathological study of I383V carriers showed similar small amounts of TDP-43 enumeration, as well as the presence of α-synhaptic nucleoprotein deposition and τ protein disease, including clustered astrological glial cells in the amygdala.
, neuropathological changes in FTD caused by TARDBP mutations are not easily classified.
detected co-diseases occur by accident, it needs to be determined in other cases with TDP-43 mutations.
results show the pathogenic effects of the I383V variant, which has previously been debated due to SIFT and PolyPhen's more conservative amino acid substitution and benign electronic predictions.
current family lineage, especially family lineage 1, clearly shows the separation of variation from disease, although the exoded rate appears to be incomplete.
In addition to the patients described here, the I383V variant was also reported in 16 FTD and 8 ALS patients, with frequencies of 0% to 0.9% in alS queues and 0% to 2.5% in clinical FTD queues, which were not present in health control groups in different populations.
data also support its pathogenicity.
study provides sufficient evidence for the pathogenicity of I383V variants and helps to describe the characteristics of TARDBP-related FTD.
the large esolysic variability and incomplete exonymism of the I383V variant.
significant reduction in the volume of the biceps in all FTD patients should prompt clinicians to conduct genetic testing of TARDBP.
Mo MO, Nijmeijer SW, van Rooij JGJ, et al Noton pattern of temporal atrophy in patients with frontotemporal dementia and the I383V variant in TARDBP Journal of Neurology, Neurosurgery Psython Published Online First: 15 January 2021. doi:10.1136/jnnp-2020-325150MedSci Original Source: MedSci Original Copyright Notice: All notes on this website "Source: Met Medical" or "Source: MedSci Original" text, images and audio and video materials, copyrighted by Met Medical, not authorized No media, website or individual may be reproduced, and authorization must be made with the "Source: Metz Medicine" in the authorizing the reprint.
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