Abstract
Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease of the corticomotorneuronal network responsible for voluntary movement. There are well-established clinical, genetic and pathological overlaps between ALS and frontotemporal dementia (FTD), which together constitute the ‘TDP-43 proteinopathies’. An ever-expanding list of genes in which mutation leads to typical ALS have implicated abnormalities in RNA processing, protein homoeostasis and axonal transport. How these apparently distinct pathways converge to cause the characteristic clinical syndrome of ALS remains unclear. Although there are major gaps in our understanding of the essential nature of ALS pathophysiology, the identification of genetic causes in up to 15% of ALS patients, coupled with advances in biotechnology and biomarker research provide a foundation for approaches to treatment based on ‘precision medicine’, and even prevention of the disease in pre-symptomatic mutation carriers in the future. Currently, multidisciplinary care remains the bedrock of management and this is increasingly being put onto an evidence-based footing.
Highlights
The clinical definition of amyotrophic lateral sclerosis (ALS) has not changed substantially since the first descriptions in the nineteenth century
It has been repeatedly noted that two areas which are relatively spared in ALS, the oculomotor nuclei and the motor neuron pools innervating sphincter function, only connect with higher cortical centres via interneurons
A further level of clinical, genetic and pathological heterogeneity is manifest in the overlap between ALS and frontotemporal dementia (FTD). 40–50% of patients presenting with isolated FTD have TDP-43 pathology at autopsy [6]
Summary
The majority of ALS patients do not have a family history of the condition and it is considered to be principally a ‘sporadic’ disease. Despite the lack of comprehensive pathophysiological explanations by which any of the ALS causing mutations cause motor system degeneration, a number of common themes are emerging (stress granule dynamics, protein quality control) which may serve as plausible therapeutic targets How mutations in these seemingly separate pathways all cause specific degeneration of the motor tract with or without frontotemporal dementia is unclear. Changes in cellular metabolism due to the cumulative effects of ageing undoubtedly contribute to pathology, as the majority of these mutations are tolerated for many decades without being detrimental to function, in contrast to the often severe and acute toxicity seen in model systems It remains unclear, if the onset of ALS is caused by a multifocal decompensation of the motor system or if a stochastic event in a single motor neuron pool acts as a ‘seed’ from which a pathological cascade propagates
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