Novel genes associated with amyotrophic lateral sclerosis: diagnostic and clinical implications

Abstract

Since 2014, seven additional genes have been associated with ALS (MATR3, CHCHD10, TBK1, TUBA4A, NEK1, C21orf2, and CCNF), all of which were identified by genome-wide association studies, whole genome studies, or exome sequencing technologies. Each of the seven novel genes code for proteins associated with one or more molecular pathways known to be involved in ALS. These pathways include dysfunction in global protein homoeostasis resulting from abnormal protein aggregation or a defect in the protein clearance pathway, mitochondrial dysfunction, altered RNA metabolism, impaired cytoskeletal integrity, altered axonal transport dynamics, and DNA damage accumulation due to defective DNA repair. Because these novel genes share common disease pathways with other genes implicated in ALS, therapeutics targeting these pathways could be useful for a broad group of patients stratified by genotype. However, the effects of these novel genes have not yet been investigated in animal models, which will be a key step to translating these findings into clinical practice. WHERE NEXT?: The identification of these seven novel genes has been important in unravelling the molecular mechanisms underlying ALS. However, our understanding of what causes ALS is not complete, and further genetic research will provide additional detail about its causes. Increased genetic knowledge will also identify potential therapeutic targets and could lead to the development of individualised medicine for patients with ALS. These developments will have a direct effect on clinical practice when genome sequencing becomes a routine and integral part of disease diagnosis and management.

Dysregulation of MicroRNAs and Target Genes Networks in Peripheral Blood of Patients With Sporadic Amyotrophic Lateral Sclerosis

“…Indeed, the family history ascertained in a limited percentage of ALS patients (fALS) contributed to the identification of inherited mutations in more than 30 genes (Renton et al, 2014; Zou et al, 2017; Chia et al, 2018). However, in the (apparently) sporadic occurrence of the disease only few of these genes (i.e., SOD1, TARDBP, FUS) were found to be implicated.…”

Early weight loss in amyotrophic lateral sclerosis: outcome relevance and clinical correlates in a population-based cohort

“…Its cause is still unknown, with the exception of genetically determined cases which account for about 10% of published series 1. One recent observation is the phenotypic heterogeneity of the disease, encompassing cases with a predominance of either upper motor or lower motor neuron degeneration, different degrees of bulbar function involvement and levels of cognitive impairment, ranging from normal cognition to frontotemporal dementia 2.…”

Role of <b><i>MAPT</i></b> in Pure Motor Neuron Disease: Report of a Recurrent Mutation in Italian Patients

“…Since the discovery of SOD1 (superoxide dismutase 1) mutations [2], owing to the progress made in molecular genetics, many further ALS genes have been published [1]. Recent reviews [3, 4] confirm the continuous progress in the identification of the genetic causes of ALS and their contribution to understanding the disease pathogene sis. However, a few major genes (e.g., SOD1 , C9orf72 , TARDBP , FUS , and OPTN ) together account for about 60% of the familial ALS and 10–13% of the sALS cases, while mutations in other genes are found in ≤1% of the patients [5].…”