Amyotrophic lateral sclerosis: a clinical review

Abstract

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder affecting primarily the motor system, but in which extra-motor manifestations are increasingly recognized. The loss of upper and lower motor neurons in the motor cortex, the brain stem nuclei and the anterior horn of the spinal cord gives rise to progressive muscle weakness and wasting. ALS often has a focal onset but subsequently spreads to different body regions, where failure of respiratory muscles typically limits survival to 2-5 years after disease onset. In up to 50% of cases, there are extra-motor manifestations such as changes in behaviour, executive dysfunction and language problems. In 10%-15% of patients, these problems are severe enough to meet the clinical criteria of frontotemporal dementia (FTD). In 10% of ALS patients, the family history suggests an autosomal dominant inheritance pattern. The remaining 90% have no affected family members and are classified as sporadic ALS. The causes of ALS appear to be heterogeneous and are only partially understood. To date, more than 20 genes have been associated with ALS. The most common genetic cause is a hexanucleotide repeat expansion in the C9orf72 gene, responsible for 30%-50% of familial ALS and 7% of sporadic ALS. These expansions are also a frequent cause of frontotemporal dementia, emphasizing the molecular overlap between ALS and FTD. To this day there is no cure or effective treatment for ALS and the cornerstone of treatment remains multidisciplinary care, including nutritional and respiratory support and symptom management. In this review, different aspects of ALS are discussed, including epidemiology, aetiology, pathogenesis, clinical features, differential diagnosis, investigations, treatment and future prospects.

Keywords: TDP-43 pathology; amyotrophic lateral sclerosis; sporadic and familial ALS.

Figure 1

Clustering of ALS genes in pathogenic pathways. (1) Mutations in TBK‐1, OPTN, SQSTM1 (= p62), UBQLN2, C9orf72 and VCP affect the protein degradation pathways and may contribute to TDP‐43 accumulation. (2) Mutations in TARDBP, FUS, MATR3, TIA1, hnRNPA1, hnRNA2B1 and ATXN2 may all affect RNA metabolism. (3) Mutations in TUBA4A, PFN1, KIF5A and DCTN1 alter cytoskeletal dynamics and axonal transport.

Figure 2

Phenotypic presentations of ALS. Motor features of ALS vary in regional distribution and relative UMN versus LMN involvement. Cognitive and behavioural features are detectable in up to 50% of patients.