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UNC13A polymorphism contributes to frontotemporal disease in sporadic amyotrophic lateral sclerosis.

ABSTRACT: The majority (90%-95%) of amyotrophic lateral sclerosis (ALS) is sporadic, and ?50% of patients develop symptoms of frontotemporal degeneration (FTD) associated with shorter survival. The genetic polymorphism rs12608932 in UNC13A confers increased risk of sporadic ALS and sporadic FTD and modifies survival in ALS. Here, we evaluate whether rs12608932 is also associated with frontotemporal disease in sporadic ALS. We identified reduced cortical thickness in sporadic ALS with T1-weighted magnetic resonance imaging (N = 109) relative to controls (N = 113), and observed that minor allele (C) carriers exhibited greater reduction of cortical thickness in the dorsal prefrontal, ventromedial prefrontal, anterior temporal, and middle temporal cortices and worse performance on a frontal lobe-mediated cognitive test (reverse digit span). In sporadic ALS with autopsy data (N = 102), minor allele homozygotes exhibited greater burden of phosphorylated tar DNA-binding protein-43 kda (TDP-43) pathology in the middle frontal, middle temporal, and motor cortices. Our findings demonstrate converging evidence that rs12608932 may modify frontotemporal disease in sporadic ALS and suggest that rs12608932 may function as a prognostic indicator and could be used to define patient endophenotypes in clinical trials.

SUBMITTER: Placek K

PROVIDER: S-EPMC6251755 | biostudies-literature | 2019 Jan

REPOSITORIES: biostudies-literature

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UNC13A polymorphism contributes to frontotemporal disease in sporadic amyotrophic lateral sclerosis.

Placek Katerina K Baer G Michael GM Elman Lauren L McCluskey Leo L Hennessy Laura L Ferraro Pilar M PM Lee Edward B EB Lee Virginia M Y VMY Trojanowski John Q JQ Van Deerlin Vivianna M VM Grossman Murray M Irwin David J DJ McMillan Corey T CT

Neurobiology of aging 20180927

The majority (90%-95%) of amyotrophic lateral sclerosis (ALS) is sporadic, and ∼50% of patients develop symptoms of frontotemporal degeneration (FTD) associated with shorter survival. The genetic polymorphism rs12608932 in UNC13A confers increased risk of sporadic ALS and sporadic FTD and modifies survival in ALS. Here, we evaluate whether rs12608932 is also associated with frontotemporal disease in sporadic ALS. We identified reduced cortical thickness in sporadic ALS with T1-weighted magnetic ...[more]

PMID: 30368160

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Project description:Background and Objectives To characterize the clinical and cognitive behavioral phenotype and brain 18F-2-fluoro-2-deoxy-d-glucose-PET (18F-FDG-PET) metabolism of patients with amyotrophic lateral sclerosis (ALS) carrying the rs12608932 variant of the UNC13A gene. Methods The study population included 1,409 patients with ALS without C9orf72, SOD1, TARDBP, and FUS mutations identified through a prospective epidemiologic ALS register. Control participants included 1,012 geographically matched, age-matched, and sex-matched participants. Clinical and cognitive differences between patients carrying the C/C rs12608932 genotype and those carrying the A/A + A/C genotype were assessed. A subset of patients underwent 18F-FDG-PET. Results The C/C genotype was associated with an increased risk of ALS (odds ratio: 1.54, 95% confidence interval 1.18–2.01, p = 0.001). Patients with the C/C genotype were older, had more frequent bulbar onset, and manifested a higher rate of weight loss. In addition, they showed significantly reduced performance in the letter fluency test, fluency domain of Edinburgh Cognitive and Behavioural ALS Screen (ECAS) and story-based empathy task (reflecting social cognition). Patients with the C/C genotype had a shorter survival (median survival time, C/C 2.25 years, interquartile range [IQR] 1.33–3.92; A/A + C/C: 2.90 years, IQR 1.74–5.41; p = 0.0001). In Cox multivariable analysis, C/C genotype resulted to be an independent prognostic factor. Finally, patients with a C/C genotype had a specific pattern of hypometabolism on brain 18F-FDG-PET extending to frontal and precentral areas of the right hemisphere. Discussion C/C rs12608932 genotype of UNC13A is associated with a specific motor and cognitive/behavioral phenotype, which reflects on 18F-FDG-PET findings. Our observations highlight the importance of adding the rs12608932 variant in UNC13A to the ALS genetic panel to refine the individual prognostic prediction and reduce heterogeneity in clinical trials.

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.

Dataset Information

UNC13A polymorphism contributes to frontotemporal disease in sporadic amyotrophic lateral sclerosis.

Publications

UNC13A polymorphism contributes to frontotemporal disease in sporadic amyotrophic lateral sclerosis.

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