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The phenotypic variability of amyotrophic lateral sclerosis

Key Points

  • Amyotrophic lateral sclerosis (ALS) is a highly heterogeneous entity

  • Cognitive impairment is a common feature of ALS: frontotemporal dementia and ALS constitute the ends of a spectrum reflecting different manifestations of the same pathogenic mechanism

  • Upper and lower motor neuron involvement is variable in ALS, and yields a spectrum with primary lateral sclerosis and progressive muscular atrophy at the two ends

  • In rare cases, extrapyramidal, cerebellar, sensory and autonomic systems can be affected in ALS, indicating that ALS should be seen as a multisystem neurodegenerative disease

  • The method and timing of assessment of a patient account for a considerable proportion of the clinical variability

  • The biology underlying the ALS phenome needs to be elucidated, as the pathophysiological mechanisms of the disease could be targets for therapeutic interventions

Abstract

Classic textbook neurology teaches that amyotrophic lateral sclerosis (ALS) is a degenerative disease that selectively affects upper and lower motor neurons and is fatal 3–5 years after onset—a description which suggests that the clinical presentation of ALS is very homogenous. However, clinical and postmortem observations, as well as genetic studies, demonstrate that there is considerable variability in the phenotypic expression of ALS. Here, we review the phenotypic variability of ALS and how it is reflected in familial and sporadic ALS, in the degree of upper and lower motor neuron involvement, in motor and extramotor involvement, and in the spectrum of ALS and frontotemporal dementia. Furthermore, we discuss some unusual clinical characteristics regarding presentation, age at onset and disease progression. Finally, we address the importance of this variability for understanding the pathogenesis of ALS and for the development of therapeutic strategies.

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Figure 1: Pattern of motor involvement in different ALS phenotypes.
Figure 2: Preferential sites of neuronal involvement in ALS.
Figure 3: Variability of disease progression in ALS.
Figure 4: ALS, a spectrum disorder.
Figure 5: Disease severity correlates with extent of neuronal involvement.

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Acknowledgements

B.S. is funded by the Fund for Scientific Research Flanders FWO (11Y9515N). W.R. is funded by the European Research Council (under the European Commission Seventh Framework Programme [FP7/2007-2013 under grant agreements #340429 and #259867), the Fund for Scientific Research Flanders (FWO; G.0983.14N and G.0996.14N), the University of Leuven (GOA/11/014 and Fund Hart voor ALS), the Interuniversity Attraction Poles Programme (P7/16), the ALS association (039CYK), the Packard Center for ALS research, the Thierry Latran Foundation and the ALS Therapy Alliance. The authors are grateful to P. N. Leigh for reading and commenting on the manuscript.

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B.S. and W.R. researched data for the article. Both authors made substantial contributions to discussions of the content, writing the article, and reviewing and/or editing of the manuscript before submission.

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Correspondence to Wim Robberecht.

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Swinnen, B., Robberecht, W. The phenotypic variability of amyotrophic lateral sclerosis. Nat Rev Neurol 10, 661–670 (2014). https://doi.org/10.1038/nrneurol.2014.184

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