Clinical and genetic characteristics of amyotrophic lateral sclerosis-frontotemporal dementia continuum

Abstract

Clinical and genetic characteristics of amyotrophic lateral sclerosis-frontotemporal dementia continuum

Wonjae Sung Department of Medical Science The graduate School of Hanyang University

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder characterized by progressive motor deficit resulting from destruction of motor neurons in the brain and spinal cord. However, a broader extent of central nervous system involvement is currently accepted in ALS since various clinical, pathological, and genetic evidence has emerged. Cognitive impairment is accompanied in about 50% of patients with ALS. Specifically, 15% of patients diagnosed with ALS meet the diagnostic criteria of frontotemporal dementia (FTD). ALS and FTD share the common pathophysiological characteristics known as the accumulation of protein aggregates consisting of TAR DNA-binding protein 43 or Fused in Sarcoma. ALS and FTD are recognized as a disease spectrum, and the diagnostic criteria for these conditions are continually being revised. Recent advances in genetics, such as next-generation sequencing, have enabled the identification of distinct genetic variants responsible for the ALS- FTD spectrum. The clinical manifestations of the ALS-FTD spectrum vary based on the type of genetic variants and specific variant locations within the genes. However, given the diverse array of genetic variants wherein their clinical manifestations are not yet clearly reported, studies determining the relationship between genetic variants and phenotype are necessary to understand the diversity of the ALS-FTD continuum. In this study, we aimed to analyze the clinical and genetic characteristics of patients with ALS-FTD. Additionally, comprehensive analysis of the identified genes and clinical characteristics will be discussed. Participants’ data were collected from the database of ALS referral cohort center from November 2014 to August 2022. From the 1281 individuals’ ALS/MND database, patients having genetic data and diagnosed with FTD compatible with Neary criteria were registered. Overall, 89 patients diagnosed with the ALS-FTD continuum were enrolled, and their clinical and genetic features were analyzed. The mean age of onset was 60.2 years, and the average duration from symptom onset to assessment was 17.7 months. Bulbar-onset ALS was observed in 50.6% of individuals. Among 89 patients, behavioral or language dysfunctions preceded voluntary motor weakness in 21 participants. The predominant FTD subtypes were behavioral variant FTD (bvFTD) (n=41, 46.1%), semantic dementia (SD) (n=33, 37.1%), and progressive nonfluent aphasia (PNFA) (n=15, 16.9%). Genetic variants associated with ALS-FTD were identified in 22% (20/89) of cases, with ANXA11 gene being the most prevalent gene (n=7, 35%) harboring pathogenic or likely pathogenic variants. Notably, the ANXA11 variants were localized within the low-complexity domain (LCD), suggesting a potential hotspot for pathogenicity. Pathogenic variants of TBK1 and VCP genes were also identified. The study highlights distinctive clinical characteristics associated with ANXA11 variants, particularly in the LCD, indicating differences in onset age, disease progression rate, and ALS-FTD prevalence. The data of genotypic-phenotypic analysis on the Korean ALS-FTD continuum would be useful information not only for differentiating the Western data but also for developing personalized future therapeutic strategies for ALS-FTD.