Dataset Information

ANXA11 mutations are associated with amyotrophic lateral sclerosis-frontotemporal dementia.

ABSTRACT:

Background

The Annexin A11 (ANXA11) gene has been newly identified as a causative gene of amyotrophic lateral sclerosis (ALS) with or without frontotemporal dementia (FTD). The current study aimed to investigate the ANXA11 mutations in a Chinese ALS-FTD or FTD cohort.

Methods

We included ten probands/patients with suspected ALS-FTD or FTD. Mutational analysis of ANXA11 was performed through Next Generation Sequencing (NGS) and Sanger sequencing. We collected and reviewed clinical presentation, neuropsychology test results, brain-imaging findings, and electrophysiological examination findings.

Results

In total, six probands presented with ALS-FTD, and four with behavior variant FTD (bv-FTD). We identified a non-synonymous heterozygous mutation (c.119A>G, p.D40G) of ANXA11 in proband 1, which is associated with ALS. However, this is the first report of the mutation causing ALS-FTD. Proband 1 started with abnormal behavior and progressed to classic upper motor nervous disease. Magnetic resonance imaging (MRI) showed significant bilateral temporal lobe atrophy and bilateral hyperintensities along the corticospinal tracts.18F-AV45-PET imaging showed negative amyloid deposits.

Conclusion

ANXA11-related diseases have high clinical and genetic heterogeneity. Our study confirmed the contribution of ANXA11 mutations to ALS-FTD. The ANXA11 mutations established a complex genotype-phenotype correlation in ALS-FTD. Our research further elucidated the genetic mechanism of ALS-FTD and contributed to setting the foundation of future targeted therapy.

SUBMITTER: Wang Y

PROVIDER: S-EPMC9549789 | biostudies-literature | 2022

REPOSITORIES: biostudies-literature

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Publications

<i>ANXA11</i> mutations are associated with amyotrophic lateral sclerosis-frontotemporal dementia.

Wang Yu Y Duan Xiaohui X Zhou Xiao X Wang Renbin R Zhang Xiangfei X Cao Zhenhua Z Wang Xiaoxia X Zhou Zhi Z Sun Yu Y Peng Dantao D

Frontiers in neurology 20220926

<h4>Background</h4>The Annexin A11 (<i>ANXA11</i>) gene has been newly identified as a causative gene of amyotrophic lateral sclerosis (ALS) with or without frontotemporal dementia (FTD). The current study aimed to investigate the <i>ANXA11</i> mutations in a Chinese ALS-FTD or FTD cohort.<h4>Methods</h4>We included ten probands/patients with suspected ALS-FTD or FTD. Mutational analysis of <i>ANXA11</i> was performed through Next Generation Sequencing (NGS) and Sanger sequencing. We collected a ...[more]

PMID: 36226077

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Project description:Amyotrophic lateral sclerosis and frontotemporal dementia are two progressive, adult onset neurodegenerative diseases, caused by the cell death of motor neurons in the motor cortex and spinal cord and cortical neurons in the frontal and temporal lobes, respectively. Whilst these have previously appeared to be quite distinct disorders, in terms of areas affected and clinical symptoms, identification of cognitive dysfunction as a component of amyotrophic lateral sclerosis (ALS), with some patients presenting with both ALS and FTD, overlapping features of neuropathology and the ongoing discoveries that a significant proportion of the genes underlying the familial forms of the disease are the same, has led to ALS and FTD being described as a disease spectrum. Many of these genes encode proteins in common biological pathways including RNA processing, autophagy, ubiquitin proteasome system, unfolded protein response and intracellular trafficking. This article provides an overview of the ALS-FTD genes before summarizing other known ALS and FTD causing genes where mutations have been found primarily in patients of one disease and rarely in the other. In discussing these genes, the review highlights the similarity of biological pathways in which the encoded proteins function and the interactions that occur between these proteins, whilst recognizing the distinctions of MAPT-related FTD and SOD1-related ALS. However, mutations in all of these genes result in similar pathology including protein aggregation and neuroinflammation, highlighting that multiple different mechanisms lead to common downstream effects and neuronal loss. Next generation sequencing has had a significant impact on the identification of genes associated with both diseases, and has also highlighted the widening clinical phenotypes associated with variants in these ALS and FTD genes. It is hoped that the large sequencing initiatives currently underway in ALS and FTD will begin to uncover why different diseases are associated with mutations within a single gene, especially as a personalized medicine approach to therapy, based on a patient's genetics, approaches the clinic.