Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Primer
  • Published:

Amyotrophic lateral sclerosis

A Correction to this article was published on 20 October 2017

Abstract

Amyotrophic lateral sclerosis (ALS), also known as motor neuron disease, is characterized by the degeneration of both upper and lower motor neurons, which leads to muscle weakness and eventual paralysis. Until recently, ALS was classified primarily within the neuromuscular domain, although new imaging and neuropathological data have indicated the involvement of the non-motor neuraxis in disease pathology. In most patients, the mechanisms underlying the development of ALS are poorly understood, although a subset of patients have familial disease and harbour mutations in genes that have various roles in neuronal function. Two possible disease-modifying therapies that can slow disease progression are available for ALS, but patient management is largely mediated by symptomatic therapies, such as the use of muscle relaxants for spasticity and speech therapy for dysarthria.

This is a preview of subscription content, access via your institution

Access options

Rent or buy this article

Prices vary by article type

from$1.95

to$39.95

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Clinical manifestations of ALS.
Figure 2: Histopathology of ALS.
Figure 3: Pathophysiology of ALS.
Figure 4: Staging systems for ALS.
Figure 5: Factors affecting QOL in patients with ALS.

Similar content being viewed by others

References

  1. Al-Chalabi, A., van den Berg, L. H. & Veldink, J. Gene discovery in amyotrophic lateral sclerosis: implications for clinical management. Nat. Rev. Neurol. 13, 96–104 (2017).

    Google Scholar 

  2. Phukan, J. et al. The syndrome of cognitive impairment in amyotrophic lateral sclerosis: a population-based study. J. Neurol. Neurosurg. Psychiatry 83, 102–108 (2012).

    Google Scholar 

  3. Elamin, M. et al. Cognitive changes predict functional decline in ALS: a population-based longitudinal study. Neurology 80, 1590–1597 (2013).

    Google Scholar 

  4. Neumann, M. et al. Ubiquitinated TDP-43 in frontotemporal lobar degeneration and amyotrophic lateral sclerosis. Science 314, 130–133 (2006). This seminal study provides evidence identifying TDP43 as a major constituent of the proteinaceous intraneuronal inclusions that are a hallmark of ALS pathology, which led the way to the identification of TARDBP mutations as rare causes of ALS.

    Google Scholar 

  5. DeJesus-Hernandez, M. et al. Expanded GGGGCC hexanucleotide repeat in noncoding region of C9ORF72 causes chromosome 9p-linked FTD and ALS. Neuron 72, 245–256 (2011).

    Google Scholar 

  6. Renton, A. E. et al. A hexanucleotide repeat expansion in C9ORF72 is the cause of chromosome 9p21-linked ALS-FTD. Neuron 72, 257–268 (2011). References 5 and 6 present evidence identifying a hexanucleotide repeat expansion in C9orf72 as the main genetic cause of both ALS and FTD.

    Google Scholar 

  7. Al-Chalabi, A. et al. Amyotrophic lateral sclerosis: moving towards a new classification system. Lancet Neurol. 15, 1182–1194 (2016). This review discusses the current classification systems for ALS and their limitations and highlights the need for different approaches, based on new research and findings, that could be used for both clinical and research purposes.

    Google Scholar 

  8. Rooney, J. P. K. et al. Benefits, pitfalls, and future design of population-based registers in neurodegenerative disease. Neurology 88, 2321–2329 (2017).

    Google Scholar 

  9. Logroscino, G. et al. Incidence of amyotrophic lateral sclerosis in Europe. J. Neurol. Neurosurg. Psychiatry 81, 385–390 (2010). This is one of the first studies to carry out a pooled analysis of six European population-based ALS registers and reports the incidence and clinical features of ALS in Europe. The design and the large number of patients with ALS involved in this study made it possible to compare the data collected in each country, unlike previous studies, and allowed the epidemiology of the disease to be accurately quantified.

    Google Scholar 

  10. Hardiman, O. et al. The changing picture of amyotrophic lateral sclerosis: lessons from European registers. J. Neurol. Neurosurg. Psychiatry 88, 557–563 (2017).

    Google Scholar 

  11. Chio, A. et al. Global epidemiology of amyotrophic lateral sclerosis: a systematic review of the published literature. Neuroepidemiology 41, 118–130 (2013).

    Google Scholar 

  12. Marin, B. et al. Population-based epidemiology of amyotrophic lateral sclerosis (ALS) in an ageing Europe — the French register of ALS in Limousin (FRALim register). Eur. J. Neurol. 21, 1292–1300, e78-9 (2014).

    Google Scholar 

  13. Gordon, P. H. et al. Incidence of amyotrophic lateral sclerosis among American Indians and Alaska natives. JAMA Neurol. 70, 476–480 (2013).

    Google Scholar 

  14. Joensen, P. Incidence of amyotrophic lateral sclerosis in the Faroe Islands. Acta Neurol. Scand. 126, 62–66 (2012).

    Google Scholar 

  15. Marin, B. et al. Clinical and demographic factors and outcome of amyotrophic lateral sclerosis in relation to population ancestral origin. Eur. J. Epidemiol. 31, 229–245 (2016).

    Google Scholar 

  16. Zaldivar, T. et al. Reduced frequency of ALS in an ethnically mixed population: a population-based mortality study. Neurology 72, 1640–1645 (2009). This is the first study that demonstrates how ancestral origin is a risk determinant in an admixed population; despite similar environmental exposures, individuals of mixed Spanish and African ancestral origin have lower rates of ALS than those of Spanish origin, in Cuba.

    Google Scholar 

  17. Heiman-Patterson, T. D. et al. Genetic background effects on disease onset and lifespan of the mutant dynactin p150Glued mouse model of motor neuron disease. PLoS ONE 10, e0117848 (2015).

    Google Scholar 

  18. Heiman-Patterson, T. D. et al. Effect of genetic background on phenotype variability in transgenic mouse models of amyotrophic lateral sclerosis: a window of opportunity in the search for genetic modifiers. Amyotroph. Lateral Scler. 12, 79–86 (2011).

    Google Scholar 

  19. van Rheenen, W. et al. Genome-wide association analyses identify new risk variants and the genetic architecture of amyotrophic lateral sclerosis. Nat. Genet. 48, 1043–1048 (2016).

    Google Scholar 

  20. Chio, A. et al. Genetic counselling in ALS: facts, uncertainties and clinical suggestions. J. Neurol. Neurosurg. Psychiatry 85, 478–485 (2014).

    Google Scholar 

  21. van Blitterswijk, M. et al. Evidence for an oligogenic basis of amyotrophic lateral sclerosis. Hum. Mol. Genet. 21, 3776–3784 (2012).

    Google Scholar 

  22. Renton, A. E., Chio, A. & Traynor, B. J. State of play in amyotrophic lateral sclerosis genetics. Nat. Neurosci. 17, 17–23 (2014).

    Google Scholar 

  23. Steele, J. C. & McGeer, P. L. The ALS/PDC syndrome of Guam and the cycad hypothesis. Neurology 70, 1984–1990 (2008).

    Google Scholar 

  24. Bradley, W. G. et al. Is exposure to cyanobacteria an environmental risk factor for amyotrophic lateral sclerosis and other neurodegenerative diseases? Amyotroph. Lateral Scler. Frontotemporal Degener. 14, 325–333 (2013).

    Google Scholar 

  25. Wang, M. D., Little, J., Gomes, J., Cashman, N. R. & Krewski, D. Identification of risk factors associated with onset and progression of amyotrophic lateral sclerosis using systematic review and meta-analysis. Neurotoxicology 61, 101–130 (2016).

    Google Scholar 

  26. Rooney, J. P. K. et al. A case–control study of hormonal exposures as etiologic factors for ALS in women: Euro-MOTOR. Neurologyhttp://dx.doi.org/10.1212/WNL.0000000000004390 (2017).

  27. Kabashi, E. et al. TARDBP mutations in individuals with sporadic and familial amyotrophic lateral sclerosis. Nat. Genet. 40, 572–574 (2008).

    Google Scholar 

  28. Van Deerlin, V. M. et al. TARDBP mutations in amyotrophic lateral sclerosis with TDP-43 neuropathology: a genetic and histopathological analysis. Lancet Neurol. 7, 409–416 (2008).

    Google Scholar 

  29. Ross, C. A. & Poirier, M. A. Opinion: what is the role of protein aggregation in neurodegeneration? Nat. Rev. Mol. Cell Biol. 6, 891–898 (2005).

    Google Scholar 

  30. Marino, M. et al. Differences in protein quality control correlate with phenotype variability in 2 mouse models of familial amyotrophic lateral sclerosis. Neurobiol. Aging 36, 492–504 (2015).

    Google Scholar 

  31. Aguzzi, A. & Rajendran, L. The transcellular spread of cytosolic amyloids, prions, and prionoids. Neuron 64, 783–790 (2009).

    Google Scholar 

  32. Polymenidou, M. & Cleveland, D. W. The seeds of neurodegeneration: prion-like spreading in ALS. Cell 147, 498–508 (2011).

    Google Scholar 

  33. Urushitani, M., Kurisu, J., Tsukita, K. & Takahashi, R. Proteasomal inhibition by misfolded mutant superoxide dismutase 1 induces selective motor neuron death in familial amyotrophic lateral sclerosis. J. Neurochem. 83, 1030–1042 (2002).

    Google Scholar 

  34. Deng, H. X. et al. Mutations in UBQLN2 cause dominant X-linked juvenile and adult-onset ALS and ALS/dementia. Nature 477, 211–215 (2011).

    Google Scholar 

  35. Chang, L. & Monteiro, M. J. Defective proteasome delivery of polyubiquitinated proteins by ubiquilin-2 proteins containing ALS mutations. PLoS ONE 10, e0130162 (2015).

    Google Scholar 

  36. Johnson, J. O. et al. Exome sequencing reveals VCP mutations as a cause of familial ALS. Neuron 68, 857–864 (2010).

    Google Scholar 

  37. Gaastra, B. et al. Rare genetic variation in UNC13A may modify survival in amyotrophic lateral sclerosis. Amyotroph. Lateral Scler. Frontotemporal Degener. 17, 593–599 (2016).

    Google Scholar 

  38. Basso, M. et al. Characterization of detergent-insoluble proteins in ALS indicates a causal link between nitrative stress and aggregation in pathogenesis. PLoS ONE 4, e8130 (2009).

    Google Scholar 

  39. Chang, H. Y., Hou, S. C., Way, T. D., Wong, C. H. & Wang, I. F. Heat-shock protein dysregulation is associated with functional and pathological TDP-43 aggregation. Nat. Commun. 4, 2757 (2013).

    Google Scholar 

  40. Bergemalm, D. et al. Superoxide dismutase-1 and other proteins in inclusions from transgenic amyotrophic lateral sclerosis model mice. J. Neurochem. 114, 408–418 (2010).

    Google Scholar 

  41. Chen, H. J. et al. Characterization of the properties of a novel mutation in VAPB in familial amyotrophic lateral sclerosis. J. Biol. Chem. 285, 40266–40281 (2010).

    Google Scholar 

  42. Nishimura, A. L. et al. A mutation in the vesicle-trafficking protein VAPB causes late-onset spinal muscular atrophy and amyotrophic lateral sclerosis. Am. J. Hum. Genet. 75, 822–831 (2004).

    Google Scholar 

  43. Webster, C. P., Smith, E. F., Bauer, C. S., Moller, A. & Hautbergue, G. M. The C9orf72 protein interacts with Rab1a and the ULK1 complex to regulate initiation of autophagy. EMBO J. 35, 1656–1676 (2016).

    Google Scholar 

  44. Katsuragi, Y. Ichimura, Y. & Komatsu, M. p62/SQSTM1 functions as a signaling hub and an autophagy adaptor. FEBS J. 282, 4672–4678 (2015).

    Google Scholar 

  45. Wong, Y. C. & Holzbaur, E. L. Optineurin is an autophagy receptor for damaged mitochondria in parkin-mediated mitophagy that is disrupted by an ALS-linked mutation. Proc. Natl Acad. Sci. USA 111, E4439–E4448 (2014).

    Google Scholar 

  46. Hjerpe, R. et al. UBQLN2 mediates autophagy-independent protein aggregate clearance by the proteasome. Cell 166, 935–949 (2016).

    Google Scholar 

  47. Ferguson, C. J., Lenk, G. M. & Meisler, M. H. Defective autophagy in neurons and astrocytes from mice deficient in PI(3,5)P2. Hum. Mol. Genet. 18, 4868–4878 (2009).

    Google Scholar 

  48. Hadano, S. et al. Functional links between SQSTM1 and ALS2 in the pathogenesis of ALS: cumulative impact on the protection against mutant SOD1-mediated motor dysfunction in mice. Hum. Mol. Genet. 25, 3321–3340 (2016).

    Google Scholar 

  49. Hadano, S. et al. Loss of ALS2/Alsin exacerbates motor dysfunction in a SOD1-expressing mouse ALS model by disturbing endolysosomal trafficking. PLoS ONE 5, e9805 (2010).

    Google Scholar 

  50. Otomo, A., Pan, L. & Hadano, S. Dysregulation of the autophagy-endolysosomal system in amyotrophic lateral sclerosis and related motor neuron diseases. Neurol. Res. Int. 2012, 498428 (2012).

    Google Scholar 

  51. Ju, J. S. et al. Valosin-containing protein (VCP) is required for autophagy and is disrupted in VCP disease. J. Cell Biol. 187, 875–888 (2009).

    Google Scholar 

  52. Goode, A. et al. Defective recognition of LC3B by mutant SQSTM1/p62 implicates impairment of autophagy as a pathogenic mechanism in ALS-FTLD. Autophagy 12, 1094–1104 (2016).

    Google Scholar 

  53. Weidberg, H. & Elazar, Z. TBK1 mediates crosstalk between the innate immune response and autophagy. Sci. Signal 4, e39 (2011).

    Google Scholar 

  54. Matsumoto, G., Shimogori, T., Hattori, N. & Nukina, N. TBK1 controls autophagosomal engulfment of polyubiquitinated mitochondria through p62/SQSTM1 phosphorylation. Hum. Mol. Genet. 24, 4429–4442 (2015).

    Google Scholar 

  55. Topp, J. D., Gray, N. W., Gerard, R. D. & Horazdovsky, B. F. Alsin is a Rab5 and Rac1 guanine nucleotide exchange factor. J. Biol. Chem. 279, 24612–24623 (2004).

    Google Scholar 

  56. Pasquali, L., Lenzi, P., Biagioni, F., Siciliano, G. & Fornai, F. Cell to cell spreading of misfolded proteins as a therapeutic target in motor neuron disease. Curr. Med. Chem. 21, 3508–3534 (2014).

    Google Scholar 

  57. Conicella, A. E., Zerze, G. H., Mittal, J. & Fawzi, N. L. ALS mutations disrupt phase separation mediated by alpha-helical structure in the TDP-43 low-complexity C-terminal domain. Structure 24, 1537–1549 (2016).

    Google Scholar 

  58. Zhou, Y., Liu, S., Ozturk, A. & Hicks, G. G. FUS-regulated RNA metabolism and DNA damage repair: implications for amyotrophic lateral sclerosis and frontotemporal dementia pathogenesis. Rare Dis. 2, e29515 (2014).

    Google Scholar 

  59. Amlie-Wolf, A. et al. Transcriptomic changes due to cytoplasmic TDP-43 expression reveal dysregulation of histone transcripts and nuclear chromatin. PLoS ONE 10, e0141836 (2015).

    Google Scholar 

  60. Arnold, E. S. et al. ALS-linked TDP-43 mutations produce aberrant RNA splicing and adult-onset motor neuron disease without aggregation or loss of nuclear TDP-43. Proc. Natl Acad. Sci. USA 110, E736–E745 (2013).

    Google Scholar 

  61. Walsh, M. J. et al. Invited review: decoding the pathophysiological mechanisms that underlie RNA dysregulation in neurodegenerative disorders: a review of the current state of the art. Neuropathol. Appl. Neurobiol. 41, 109–134 (2015).

    Google Scholar 

  62. Chen-Plotkin, A. S., Lee, V. M. & Trojanowski, J. Q. TAR DNA-binding protein 43 in neurodegenerative disease. Nat. Rev. Neurol. 6, 211–220 (2010).

    Google Scholar 

  63. Ratti, A. & Buratti, E. Physiological functions and pathobiology of TDP-43 and FUS/TLS proteins. J. Neurochem. 138 (Suppl. 1), 95–111 (2016).

    Google Scholar 

  64. Haeusler, A. R. et al. C9orf72 nucleotide repeat structures initiate molecular cascades of disease. Nature 507, 195–200 (2014).

    Google Scholar 

  65. Reddy, K., Zamiri, B., Stanley, S. Y., Macgregor, R. B. Jr & Pearson, C. E. The disease-associated r(GGGGCC)n repeat from the C9orf72 gene forms tract length-dependent uni- and multimolecular RNA G-quadruplex structures. J. Biol. Chem. 288, 9860–9866 (2013).

    Google Scholar 

  66. Lee, Y. B. et al. Hexanucleotide repeats in ALS/FTD form length-dependent RNA foci, sequester RNA binding proteins, and are neurotoxic. Cell Rep. 5, 1178–1186 (2013).

    Google Scholar 

  67. Donnelly, C. J. et al. RNA toxicity from the ALS/FTD C9ORF72 expansion is mitigated by antisense intervention. Neuron 80, 415–428 (2013).

    Google Scholar 

  68. Cooper-Knock, J. et al. Sequestration of multiple RNA recognition motif-containing proteins by C9orf72 repeat expansions. Brain 137, 2040–2051 (2014).

    Google Scholar 

  69. Cooper-Knock, J. et al. C9ORF72 GGGGCC expanded repeats produce splicing dysregulation which correlates with disease severity in amyotrophic lateral sclerosis. PLoS ONE 10, e0127376 (2015).

    Google Scholar 

  70. Haeusler, A. R., Donnelly, C. J. & Rothstein, J. D. The expanding biology of the C9orf72 nucleotide repeat expansion in neurodegenerative disease. Nat. Rev. Neurosci. 17, 383–395 (2016).

    Google Scholar 

  71. Santos-Pereira, J. M. & Aguilera, A. R loops: new modulators of genome dynamics and function. Nat. Rev. Genet. 16, 583–597 (2015).

    Google Scholar 

  72. Walker, C. et al. C9orf72 expansion disrupts ATM-mediated chromosomal break repair. Nat. Neurosci. 20, 1225–1235 (2017).

    Google Scholar 

  73. Chan, Y. A., Hieter, P. & Stirling, P. C. Mechanisms of genome instability induced by RNA-processing defects. Trends Genet. 30, 245–253 (2014).

    Google Scholar 

  74. Skourti-Stathaki, K., Proudfoot, N. J. & Gromak, N. Human senataxin resolves RNA/DNA hybrids formed at transcriptional pause sites to promote Xrn2-dependent termination. Mol. Cell 42, 794–805 (2011).

    Google Scholar 

  75. Pizzo, E. et al. Ribonuclease/angiogenin inhibitor 1 regulates stress-induced subcellular localization of angiogenin to control growth and survival. J. Cell Sci. 126, 4308–4319 (2013).

    Google Scholar 

  76. Saxena, S. K., Rybak, S. M., Davey, R. T., Youle, R. J. & Ackerman, E. J. Angiogenin Is a cytotoxic, tRNA-specific ribonuclease in the RNase-A superfamily. J. Biol. Chem. 267, 21982–21986 (1992).

    Google Scholar 

  77. Simpson, C. L. et al. Variants of the elongator protein 3 (ELP3) gene are associated with motor neuron degeneration. Hum. Mol. Genet. 18, 472–481 (2009).

    Google Scholar 

  78. Kapeli, K. et al. Distinct and shared functions of ALS-associated proteins TDP-43, FUS and TAF15 revealed by multisystem analyses. Nat. Commun. 7, 12143 (2016).

    Google Scholar 

  79. Couthouis, J. et al. Evaluating the role of the FUS/TLS-related gene EWSR1 in amyotrophic lateral sclerosis. Hum. Mol. Genet. 21, 2899–2911 (2012).

    Google Scholar 

  80. Han, Q. J. et al. Gcn5- and Elp3-induced histone H3 acetylation regulates hsp70 gene transcription in yeast. Biochem. J. 409, 779–788 (2008).

    Google Scholar 

  81. Huang, B., Johansson, M. J. O. & Bystrom, A. S. An early step in wobble uridine tRNA modification requires the Elongator complex. RNA 11, 424–436 (2005).

    Google Scholar 

  82. Kim, H. J. et al. Mutations in prion-like domains in hnRNPA2B1 and hnRNPA1 cause multisystem proteinopathy and ALS. Nature 495, 467–473 (2013).

    Google Scholar 

  83. Johnson, J. O. et al. Mutations in the Matrin 3 gene cause familial amyotrophic lateral sclerosis. Nat. Neurosci. 17, 664–666 (2014).

    Google Scholar 

  84. Vanderweyde, T., Youmans, K., Liu-Yesucevitz, L. & Wolozin, B. Role of stress granules and RNA-binding proteins in neurodegeneration: a mini-review. Gerontology 59, 524–533 (2013).

    Google Scholar 

  85. Winton, M. J. et al. Disturbance of nuclear and cytoplasmic TAR DNA-binding protein (TDP-43) induces disease-like redistribution, sequestration, and aggregate formation. J. Biol. Chem. 283, 13302–13309 (2008).

    Google Scholar 

  86. Parker, S. J. et al. Endogenous TDP-43 localized to stress granules can subsequently form protein aggregates. Neurochem. Int. 60, 415–424 (2012).

    Google Scholar 

  87. Walsh, M. J., Hautbergue, G. M. & Wilson, S. A. Structure and function of mRNA export adaptors. Biochem. Soc. Trans. 38, 232–236 (2010).

    Google Scholar 

  88. Hautbergue, G. M., Castelli, L. M., Ferraiuolo, L. & Sanchez-Martinez, A. SRSF1-dependent nuclear export inhibition of C9ORF72 repeat transcripts prevents neurodegeneration and associated motor deficits. Nat. Commun. 8, 16063 (2017).

    Google Scholar 

  89. Zhang, K. et al. The C9orf72 repeat expansion disrupts nucleocytoplasmic transport. Nature 525, 56–61 (2015).

    Google Scholar 

  90. Freibaum, B. D. et al. GGGGCC repeat expansion in C9orf72 compromises nucleocytoplasmic transport. Nature 525, 129–133 (2015).

    Google Scholar 

  91. Boeynaems, S. et al. Phase separation of C9orf72 dipeptide repeats perturbs stress granule dynamics. Mol. Cell 65, 1044–1055.e5 (2017).

    Google Scholar 

  92. Schwenk, B. M. et al. TDP-43 loss of function inhibits endosomal trafficking and alters trophic signaling in neurons. EMBO J. 35, 2350–2370 (2016).

    Google Scholar 

  93. Devon, R. S. et al. Als2-deficient mice exhibit disturbances in endosome trafficking associated with motor behavioral abnormalities. Proc. Natl Acad. Sci. USA 103, 9595–9600 (2006).

    Google Scholar 

  94. Bohme, M. A. et al. Active zone scaffolds differentially accumulate Unc13 isoforms to tune Ca2 + channel-vesicle coupling. Nat. Neurosci. 19, 1311–1320 (2016).

    Google Scholar 

  95. Smith, B. N. et al. Exome-wide rare variant analysis identifies TUBA4A mutations associated with familial ALS. Neuron 84, 324–331 (2014).

    Google Scholar 

  96. Puls, I. et al. Mutant dynactin in motor neuron disease. Nat. Genet. 33, 455–456 (2003).

    Google Scholar 

  97. Wu, C. H. et al. Mutations in the profilin 1 gene cause familial amyotrophic lateral sclerosis. Nature 488, 499–503 (2012).

    Google Scholar 

  98. Garcia, M. L. et al. Mutations in neurofilament genes are not a significant primary cause of non-SOD1-mediated amyotrophic lateral sclerosis. Neurobiol. Dis. 21, 102–109 (2006).

    Google Scholar 

  99. Gros-Louis, F. et al. A frameshift deletion in peripherin gene associated with amyotrophic lateral sclerosis. J. Biol. Chem. 279, 45951–45956 (2004).

    Google Scholar 

  100. Corrado, L. et al. A novel peripherin gene (PRPH) mutation identified in one sporadic amyotrophic lateral sclerosis patient. Neurobiol. Aging 32, 552.e1–552.e6 (2011).

    Google Scholar 

  101. Wang, W. Y. et al. Interaction of FUS and HDAC1 regulates DNA damage response and repair in neurons. Nat. Neurosci. 16, 1383–1391 (2013).

    Google Scholar 

  102. Sama, R. R., Ward, C. L. & Bosco, D. A. Functions of FUS/TLS from DNA repair to stress response: implications for ALS. ASN Neuro.http://dx.doi.org/10.1177/1759091414544472 (2014).

  103. Kenna, K. P. et al. NEK1 variants confer susceptibility to amyotrophic lateral sclerosis. Nat. Genet. 48, 1037–1042 (2016).

    Google Scholar 

  104. Fang, X. et al. The NEK1 interactor, C21ORF2, is required for efficient DNA damage repair. Acta Biochim. Biophys. Sin. (Shanghai) 47, 834–841 (2015).

    Google Scholar 

  105. Laslo, P., Lipski, J., Nicholson, L. F., Miles, G. B. & Funk, G. D. GluR2 AMPA receptor subunit expression in motoneurons at low and high risk for degeneration in amyotrophic lateral sclerosis. Exp. Neurol. 169, 461–471 (2001).

    Google Scholar 

  106. Wang, S. J., Wang, K. Y. & Wang, W. C. Mechanisms underlying the riluzole inhibition of glutamate release from rat cerebral cortex nerve terminals (synaptosomes). Neuroscience 125, 191–201 (2004).

    Google Scholar 

  107. Kretschmer, B. D., Kratzer, U. & Schmidt, W. J. Riluzole, a glutamate release inhibitor, and motor behavior. Naunyn Schmiedebergs Arch. Pharmacol. 358, 181–190 (1998).

    Google Scholar 

  108. Kang, S. H. et al. Degeneration and impaired regeneration of gray matter oligodendrocytes in amyotrophic lateral sclerosis. Nat. Neurosci. 16, 571–579 (2013).

    Google Scholar 

  109. Philips, T. et al. Oligodendrocyte dysfunction in the pathogenesis of amyotrophic lateral sclerosis. Brain 136, 471–482 (2013).

    Google Scholar 

  110. Rinholm, J. E. et al. Regulation of oligodendrocyte development and myelination by glucose and lactate. J. Neurosci. 31, 538–548 (2011).

    Google Scholar 

  111. Lee, Y. et al. Oligodendroglia metabolically support axons and contribute to neurodegeneration. Nature 487, 443–448 (2012).

    Google Scholar 

  112. Ferraiuolo, L. et al. Oligodendrocytes contribute to motor neuron death in ALS via SOD1-dependent mechanism. Proc. Natl Acad. Sci. USA 113, E6496–E6505 (2016).

    Google Scholar 

  113. Corcia, P. et al. Molecular imaging of microglial activation in amyotrophic lateral sclerosis. PLoS ONE 7, e52941 (2012).

    Google Scholar 

  114. Brites, D. & Vaz, A. R. Microglia centered pathogenesis in ALS: insights in cell interconnectivity. Front. Cell Neurosci. 8, 117 (2014).

    Google Scholar 

  115. Wang, L., Gutmann, D. H. & Roos, R. P. Astrocyte loss of mutant SOD1 delays ALS disease onset and progression in G85R transgenic mice. Hum. Mol. Genet. 20, 286–293 (2011).

    Google Scholar 

  116. Liao, B., Zhao, W., Beers, D. R., Henkel, J. S. & Appel, S. H. Transformation from a neuroprotective to a neurotoxic microglial phenotype in a mouse model of ALS. Exp. Neurol. 237, 147–152 (2012).

    Google Scholar 

  117. Vande Velde, C. et al. Misfolded SOD1 associated with motor neuron mitochondria alters mitochondrial shape and distribution prior to clinical onset. PLoS ONE 6, e22031 (2011).

    Google Scholar 

  118. Magrane, J., Cortez, C., Gan, W. B. & Manfredi, G. Abnormal mitochondrial transport and morphology are common pathological denominators in SOD1 and TDP43 ALS mouse models. Hum. Mol. Genet. 23, 1413–1424 (2014).

    Google Scholar 

  119. Higgins, C. M., Jung, C. & Xu, Z. ALS-associated mutant SOD1G93A causes mitochondrial vacuolation by expansion of the intermembrane space and by involvement of SOD1 aggregation and peroxisomes. BMC Neurosci. 4, 16 (2003).

    Google Scholar 

  120. Parone, P. A. et al. Enhancing mitochondrial calcium buffering capacity reduces aggregation of misfolded SOD1 and motor neuron cell death without extending survival in mouse models of inherited amyotrophic lateral sclerosis. J. Neurosci. 33, 4657–4671 (2013).

    Google Scholar 

  121. Laird, F. M. et al. Motor neuron disease occurring in a mutant dynactin mouse model is characterized by defects in vesicular trafficking. J. Neurosci. 28, 1997–2005 (2008).

    Google Scholar 

  122. Bilsland, L. G. et al. Deficits in axonal transport precede ALS symptoms in vivo. Proc. Natl Acad. Sci. USA 107, 20523–20528 (2010).

    Google Scholar 

  123. De Vos, K. J. et al. VAPB interacts with the mitochondrial protein PTPIP51 to regulate calcium homeostasis. Hum. Mol. Genet. 21, 1299–1311 (2012).

    Google Scholar 

  124. Stoica, R. et al. ALS/FTD-associated FUS activates GSK-3β to disrupt the VAPB-PTPIP51 interaction and ER-mitochondria associations. EMBO Rep. 17, 1326–1342 (2016).

    Google Scholar 

  125. Stoica, R. et al. ER-mitochondria associations are regulated by the VAPB-PTPIP51 interaction and are disrupted by ALS/FTD-associated TDP-43. Nat. Commun. 5, 3996 (2014).

    Google Scholar 

  126. Wang, W. et al. The inhibition of TDP-43 mitochondrial localization blocks its neuronal toxicity. Nat. Med. 22, 869–878 (2016).

    Google Scholar 

  127. Lopez-Gonzalez, R. et al. Poly(GR) in C9ORF72-related ALS/FTD compromises mitochondrial function and increases oxidative stress and DNA damage in iPSC-derived motor neurons. Neuron 92, 383–391 (2016).

    Google Scholar 

  128. Genin, E. C. et al. CHCHD10 mutations promote loss of mitochondrial cristae junctions with impaired mitochondrial genome maintenance and inhibition of apoptosis. EMBO Mol. Med. 8, 58–72 (2016).

    Google Scholar 

  129. Iyer, P. M. et al. Functional connectivity changes in resting-state EEG as potential biomarker for amyotrophic lateral sclerosis. PLoS ONE 10, e0128682 (2015).

    Google Scholar 

  130. Hegedus, J., Putman, C. T., Tyreman, N. & Gordon, T. Preferential motor unit loss in the SOD1 G93A transgenic mouse model of amyotrophic lateral sclerosis. J. Physiol. 586, 3337–3351 (2008).

    Google Scholar 

  131. Saxena, S. & Caroni, P. Selective neuronal vulnerability in neurodegenerative diseases: from stressor thresholds to degeneration. Neuron 71, 35–48 (2011).

    Google Scholar 

  132. Tartaglia, M. C. et al. Differentiation between primary lateral sclerosis and amyotrophic lateral sclerosis: examination of symptoms and signs at disease onset and during follow-up. Arch. Neurol. 64, 232–236 (2007).

    Google Scholar 

  133. Van den Berg-Vos, R. M. et al. A long-term prospective study of the natural course of sporadic adult-onset lower motor neuron syndromes. Arch. Neurol. 66, 751–757 (2009).

    Google Scholar 

  134. Visser, J. et al. Disease course and prognostic factors of progressive muscular atrophy. Arch. Neurol. 64, 522–528 (2007).

    Google Scholar 

  135. van den Berg-Vos, R. M. et al. Sporadic lower motor neuron disease with adult onset: classification of subtypes. Brain 126, 1036–1047 (2003).

    Google Scholar 

  136. Kiernan, M. C. et al. Amyotrophic lateral sclerosis. Lancet 377, 942–955 (2011).

    Google Scholar 

  137. Dupuis, L., Pradat, P. F., Ludolph, A. C. & Loeffler, J. P. Energy metabolism in amyotrophic lateral sclerosis. Lancet Neurol. 10, 75–82 (2011).

    Google Scholar 

  138. Moglia, C. et al. Influence of arterial hypertension, type 2 diabetes and cardiovascular risk factors on ALS outcome: a population-based study. Amyotroph. Lateral Scler. Frontotemporal Degener. http://dx.doi.org/10.1080/21678421.2017.1336560 (2017).

  139. Strong, M. J. et al. Amyotrophic lateral sclerosis — frontotemporal spectrum disorder (ALS-FTSD): revised diagnostic criteria. Amyotroph. Lateral Scler. Frontotemporal Degener. 18, 153–174 (2017).

    Google Scholar 

  140. Burke, T. et al. A cross-sectional population-based investigation into behavioral change in amyotrophic lateral sclerosis: subphenotypes, staging, cognitive predictors, and survival. Ann. Clin. Transl Neurol. 4, 305–317 (2017).

    Google Scholar 

  141. Brooks, B. R., Miller, R. G., Swash, M. & Munsat, T. L. El Escorial revisited: revised criteria for the diagnosis of amyotrophic lateral sclerosis. Amyotroph. Lateral Scler. Other Motor Neuron Disord. 1, 293–299 (2000). El Escorial diagnostic criteria were developed by the World Federation of Neurology Research Group on motor neuron diseases to define research-based consensus diagnostic criteria. This was initially published in 1994 but subsequently underwent revisions, which are outlined in this review, and it is currently used in clinical settings.

  142. Reniers, W. et al. Prognostic value of clinical and electrodiagnostic parameters at time of diagnosis in patients with amyotrophic lateral sclerosis. Amyotroph. Lateral Scler. Frontotemporal Degener. 18, 341–350 (2017).

    Google Scholar 

  143. Agosta, F. et al. The El Escorial criteria: strengths and weaknesses. Amyotroph. Lateral Scler. Frontotemporal Degener. 16, 1–7 (2015).

    Google Scholar 

  144. Ludolph, A. et al. A revision of the El Escorial criteria — 2015. Amyotroph. Lateral Scler. Frontotemporal Degener. 16, 291–292 (2015). This paper presents the first definitive evidence that ALS and schizophrenia are biologically linked, and was later validated shown using a combined GWAS of 13,000 ALS and 30,000 schizophrenia samples.

    Google Scholar 

  145. Byrne, S. et al. Proposed criteria for familial amyotrophic lateral sclerosis. Amyotroph. Lateral Scler. 12, 157–159 (2011).

    Google Scholar 

  146. Vajda, A. et al. Genetic testing in ALS: a survey of current practices. Neurology 88, 991–999 (2017).

    Google Scholar 

  147. Abrahams, S., Newton, J., Niven, E., Foley, J. & Bak, T. H. Screening for cognition and behaviour changes in ALS. Amyotroph. Lateral Scler. Frontotemporal Degener. 15, 9–14 (2014). This is one of the first studies to validate and support the use of the Edinburgh Cognitive and Behavioural ALS Screen to determine the cognitive status of patients with ALS. This measure is used as a standard test during clinical examinations in multiple countries.

    Google Scholar 

  148. Pinto-Grau, M. et al. Screening for cognitive dysfunction in ALS: validation of the Edinburgh Cognitive and Behavioural ALS Screen (ECAS) using age and education adjusted normative data. Amyotroph. Lateral Scler. Frontotemporal Degener. 18, 99–106 (2017).

    Google Scholar 

  149. Burke, T., Elamin, M., Galvin, M., Hardiman, O. & Pender, N. Caregiver burden in amyotrophic lateral sclerosis: a cross-sectional investigation of predictors. J. Neurol. 262, 1526–1532 (2015).

    Google Scholar 

  150. Steinacker, P. et al. Neurofilaments in the diagnosis of motoneuron diseases: a prospective study on 455 patients. J. Neurol. Neurosurg. Psychiatry 87, 12–20 (2016).

    Google Scholar 

  151. Gaiottino, J. et al. Increased neurofilament light chain blood levels in neurodegenerative neurological diseases. PLoS ONE 8, e75091 (2013).

    Google Scholar 

  152. Gaiani, A. et al. Diagnostic and prognostic biomarkers in amyotrophic lateral sclerosis: neurofilament light chain levels in definite subtypes of disease. JAMA Neurol. 74, 525–532 (2017).

    Google Scholar 

  153. Schuster, C., Elamin, M., Hardiman, O. & Bede, P. Presymptomatic and longitudinal neuroimaging in neurodegeneration — from snapshots to motion picture: a systematic review. J. Neurol. Neurosurg. Psychiatry 86, 1089–1096 (2015).

    Google Scholar 

  154. Bede, P. et al. The selective anatomical vulnerability of ALS: ‘disease-defining’ and ‘disease-defying’ brain regions. Amyotroph. Lateral Scler. Frontotemporal Degener. 17, 561–570 (2016).

    Google Scholar 

  155. Bede, P. & Hardiman, O. Lessons of ALS imaging: pitfalls and future directions — a critical review. Neuroimage Clin. 4, 436–443 (2014).

    Google Scholar 

  156. Canosa, A. et al. 18F-FDG-PET correlates of cognitive impairment in ALS. Neurology 86, 44–49 (2016).

    Google Scholar 

  157. Turner, M. R. et al. The diagnostic pathway and prognosis in bulbar-onset amyotrophic lateral sclerosis. J. Neurol. Sci. 294, 81–85 (2010).

    Google Scholar 

  158. Hanemann, C. O. & Ludolph, A. C. Hereditary motor neuropathies and motor neuron diseases: which is which. Amyotroph. Lateral Scler. Other Motor Neuron Disord. 3, 186–189 (2002).

    Google Scholar 

  159. Mastaglia, F. L. & Needham, M. Inclusion body myositis: a review of clinical and genetic aspects, diagnostic criteria and therapeutic approaches. J. Clin. Neurosci. 22, 6–13 (2015).

    Google Scholar 

  160. Traynor, B. J. et al. Amyotrophic lateral sclerosis mimic syndromes: a population-based study. Arch. Neurol. 57, 109–113 (2000).

    Google Scholar 

  161. Balendra, R. et al. Estimating clinical stage of amyotrophic lateral sclerosis from the ALS Functional Rating Scale. Amyotroph. Lateral Scler. Frontotemporal Degener. 15, 279–284 (2014).

    Google Scholar 

  162. Chio, A., Hammond, E. R., Mora, G., Bonito, V. & Filippini, G. Development and evaluation of a clinical staging system for amyotrophic lateral sclerosis. J. Neurol. Neurosurg. Psychiatry 86, 38–44 (2015).

    Google Scholar 

  163. Fang, T. et al. Comparison of the King's and MiToS staging systems for ALS. Amyotroph. Lateral Scler. Frontotemporal Degener. 18, 227–232 (2017).

    Google Scholar 

  164. Ferraro, D. et al. Amyotrophic lateral sclerosis: a comparison of two staging systems in a population-based study. Eur. J. Neurol. 23, 1426–1432 (2016).

    Google Scholar 

  165. Elamin, M. et al. Predicting prognosis in amyotrophic lateral sclerosis: a simple algorithm. J. Neurol. 262, 1447–1454 (2015).

    Google Scholar 

  166. Hothorn, T. & Jung, H. H. RandomForest4Life: a Random Forest for predicting ALS disease progression. Amyotroph. Lateral Scler. Frontotemporal Degener. 15, 444–452 (2014).

    Google Scholar 

  167. Oh, S. I. et al. Prognostic role of serum levels of uric acid in amyotrophic lateral sclerosis. J. Clin. Neurol. 11, 376–382 (2015).

    Google Scholar 

  168. Chio, A. et al. Amyotrophic lateral sclerosis outcome measures and the role of albumin and creatinine: a population-based study. JAMA Neurol. 71, 1134–1142 (2014).

    Google Scholar 

  169. Kori, M., Aydin, B., Unal, S., Arga, K. Y. & Kazan, D. Metabolic biomarkers and neurodegeneration: a pathway enrichment analysis of Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis. Omics 20, 645–661 (2016).

    Google Scholar 

  170. Pinto, S. & de Carvalho, M. Correlation between Forced Vital Capacity and Slow Vital Capacity for the assessment of respiratory involvement in amyotrophic lateral sclerosis: a prospective study. Amyotroph. Lateral Scler. Frontotemporal Degener. 18, 86–91 (2017).

    Google Scholar 

  171. Morgan, R. K. et al. Use of Sniff nasal-inspiratory force to predict survival in amyotrophic lateral sclerosis. Am. J. Respir. Crit. Care Med. 171, 269–274 (2005).

    Google Scholar 

  172. Roggenbuck, J. & Quick, A. Genetic testing and genetic counseling for amyotrophic lateral sclerosis: an update for clinicians. Genet. Med. 19, 267–274 (2017).

    Google Scholar 

  173. Benatar, M. et al. Presymptomatic ALS genetic counseling and testing: experience and recommendations. Neurology 86, 2295–2302 (2016).

    Google Scholar 

  174. Miller, R. G. et al. Practice parameter update: the care of the patient with amyotrophic lateral sclerosis: drug, nutritional, and respiratory therapies (an evidence-based review): report of the Quality Standards Subcommittee of the American Academy of Neurology. Neurology 73, 1218–1226 (2009).

    Google Scholar 

  175. Andersen, P. M. et al. EFNS guidelines on the clinical management of amyotrophic lateral sclerosis (MALS) — revised report of an EFNS task force. Eur. J. Neurol. 19, 360–375 (2012).

    Google Scholar 

  176. Traynor, B. J., Alexander, M., Corr, B., Frost, E. & Hardiman, O. Effect of a multidisciplinary amyotrophic lateral sclerosis (ALS) clinic on ALS survival: a population based study, 1996–2000. J. Neurol. Neurosurg. Psychiatry 74, 1258–1261 (2003).

    Google Scholar 

  177. Chio, A., Bottacchi, E., Buffa, C., Mutani, R. & Mora, G. Positive effects of tertiary centres for amyotrophic lateral sclerosis on outcome and use of hospital facilities. J. Neurol. Neurosurg. Psychiatry 77, 948–950 (2006).

    Google Scholar 

  178. Rooney, J. et al. A multidisciplinary clinic approach improves survival in ALS: a comparative study of ALS in Ireland and Northern Ireland. J. Neurol. Neurosurg. Psychiatry 86, 496–501 (2015).

    Google Scholar 

  179. Van den Berg, J. P. et al. Multidisciplinary ALS care improves quality of life in patients with ALS. Neurology 65, 1264–1267 (2005).

    Google Scholar 

  180. Beghi, E. et al. The epidemiology and treatment of ALS: focus on the heterogeneity of the disease and critical appraisal of therapeutic trials. Amyotroph. Lateral Scler. 12, 1–10 (2011).

    Google Scholar 

  181. Lacomblez, L., Bensimon, G., Leigh, P. N., Guillet, P. & Meininger, V. Dose-ranging study of riluzole in amyotrophic lateral sclerosis. Amyotrophic Lateral Sclerosis/Riluzole Study Group II. Lancet 347, 1425–1431 (1996). Based on the landmark trial of riluzole in patients with ALS in 1994, this study presents an assessment of the efficacy of the drug at different doses in a double-blind, placebo-controlled, multicentre trial, identifying that the 100 mg dose of riluzole had the best benefit-to-risk ratio; this is the recommended dose used to treat the symptoms of ALS today.

    Google Scholar 

  182. Dyer, A. M. & Smith, A. Riluzole 5 mg / mL oral suspension: for optimized drug delivery in amyotrophic lateral sclerosis. Drug Des. Devel Ther. 11, 59–64 (2017).

    Google Scholar 

  183. Writing Group, Edaravone (MCl-186) ALS 19 Study Group. Safety and efficacy of edaravone in well defined patients with amyotrophic lateral sclerosis: a randomised, double-blind, placebo-controlled trial. Lancet Neurol. 16, 505–512 (2017).

    Google Scholar 

  184. Hardiman, O. & van den Berg, L. H. Edaravone: a new treatment for ALS on the horizon? Lancet Neurol. 16, 490–491 (2017).

    Google Scholar 

  185. Smith, R. et al. Enhanced bulbar function in amyotrophic lateral sclerosis: the Nuedexta Treatment Trial. Neurotherapeutics 14, 762–772 (2017).

    Google Scholar 

  186. Amtmann, D., Weydt, P., Johnson, K. L., Jensen, M. P. & Carter, G. T. Survey of cannabis use in patients with amyotrophic lateral sclerosis. Am. J. Hosp. Palliat. Care 21, 95–104 (2004).

    Google Scholar 

  187. Jackson, C. E. et al. Randomized double-blind study of botulinum toxin type B for sialorrhea in ALS patients. Muscle Nerve 39, 137–143 (2009).

    Google Scholar 

  188. Guidubaldi, A. et al. Botulinum toxin A versus B in sialorrhea: a prospective, randomized, double-blind, crossover pilot study in patients with amyotrophic lateral sclerosis or Parkinson's disease. Mov. Disord. 26, 313–319 (2011).

    Google Scholar 

  189. Weikamp, J. G. et al. Botulinum toxin-A injections versus radiotherapy for drooling in ALS. Acta Neurol. Scand. 134, 224–231 (2016).

    Google Scholar 

  190. Chio, A., Mora, G. & Lauria, G. Pain in amyotrophic lateral sclerosis. Lancet Neurol. 16, 144–157 (2017).

    Google Scholar 

  191. Stephens, H. E., Joyce, N. C. & Oskarsson, B. National study of muscle cramps in ALS in the USA. Amyotroph. Lateral Scler. Frontotemporal Degener. 18, 32–36 (2017).

    Google Scholar 

  192. Weiss, M. D. et al. A randomized trial of mexiletine in ALS: safety and effects on muscle cramps and progression. Neurology 86, 1474–1481 (2016).

    Google Scholar 

  193. Fujimura-Kiyono, C. et al. Onset and spreading patterns of lower motor neuron involvements predict survival in sporadic amyotrophic lateral sclerosis. J. Neurol. Neurosurg. Psychiatry 82, 1244–1249 (2011).

    Google Scholar 

  194. ProGas Study Group. Gastrostomy in patients with amyotrophic lateral sclerosis (ProGas): a prospective cohort study. Lancet Neurol. 14, 702–709 (2015).

    Google Scholar 

  195. Dorst, J. et al. Percutaneous endoscopic gastrostomy in amyotrophic lateral sclerosis: a prospective observational study. J. Neurol. 262, 849–858 (2015).

    Google Scholar 

  196. Abdelnour-Mallet, M. et al. Safety of home parenteral nutrition in patients with amyotrophic lateral sclerosis: a French national survey. Amyotroph. Lateral Scler. 12, 178–184 (2011).

    Google Scholar 

  197. Juntas-Morales, R., Pageot, N., Alphandery, S. & Camu, W. The use of peripherally inserted central catheter in amyotrophic lateral sclerosis patients at a later stage. Eur. Neurol. 77, 87–90 (2017).

    Google Scholar 

  198. Londral, A., Pinto, A., Pinto, S., Azevedo, L. & De Carvalho, M. Quality of life in amyotrophic lateral sclerosis patients and caregivers: impact of assistive communication from early stages. Muscle Nerve 52, 933–941 (2015).

    Google Scholar 

  199. Marchetti, M. & Priftis, K. Brain-computer interfaces in amyotrophic lateral sclerosis: a metanalysis. Clin. Neurophysiol. 126, 1255–1263 (2015).

    Google Scholar 

  200. Geronimo, A., Simmons, Z. & Schiff, S. J. Performance predictors of brain-computer interfaces in patients with amyotrophic lateral sclerosis. J. Neural Eng. 13, 026002 (2016).

    Google Scholar 

  201. Qureshi, M. M., Cudkowicz, M. E., Zhang, H. & Raynor, E. Increased incidence of deep venous thrombosis in ALS. Neurology 68, 76–77 (2007).

    Google Scholar 

  202. Gladman, M., Dehaan, M., Pinto, H., Geerts, W. & Zinman, L. Venous thromboembolism in amyotrophic lateral sclerosis: a prospective study. Neurology 82, 1674–1677 (2014).

    Google Scholar 

  203. Gallagher, J. P. Pathologic laughter and crying in ALS: a search for their origin. Acta Neurol. Scand. 80, 114–117 (1989).

    Google Scholar 

  204. Pioro, E. P. et al. Dextromethorphan plus ultra low-dose quinidine reduces pseudobulbar affect. Ann. Neurol. 68, 693–702 (2010).

    Google Scholar 

  205. Merrilees, J., Klapper, J., Murphy, J., Lomen-Hoerth, C. & Miller, B. L. Cognitive and behavioral challenges in caring for patients with frontotemporal dementia and amyotrophic lateral sclerosis. Amyotroph. Lateral Scler. 11, 298–302 (2010).

    Google Scholar 

  206. Bourke, S. C. et al. Effects of non-invasive ventilation on survival and quality of life in patients with amyotrophic lateral sclerosis: a randomised controlled trial. Lancet Neurol. 5, 140–147 (2006).

    Google Scholar 

  207. Chio, A. et al. Non-invasive ventilation in amyotrophic lateral sclerosis: a 10 year population based study. J. Neurol. Neurosurg. Psychiatry 83, 377–381 (2012).

    Google Scholar 

  208. Rafiq, M. K. et al. A preliminary randomized trial of the mechanical insufflator-exsufflator versus breath-stacking technique in patients with amyotrophic lateral sclerosis. Amyotroph. Lateral Scler. Frontotemporal Degener. 16, 448–455 (2015).

    Google Scholar 

  209. Simmons, Z. Patient-perceived outcomes and quality of life in ALS. Neurotherapeutics 12, 394–402 (2015).

    Google Scholar 

  210. Baile, W. F. et al. SPIKES-A six-step protocol for delivering bad news: application to the patient with cancer. Oncologist 5, 302–311 (2000).

    Google Scholar 

  211. McCluskey, L., Casarett, D. & Siderowf, A. Breaking the news: a survey of ALS patients and their caregivers. Amyotroph. Lateral Scler. Other Motor Neuron Disord. 5, 131–135 (2004).

    Google Scholar 

  212. Aoun, S. M. et al. Receiving the news of a diagnosis of motor neuron disease: what does it take to make it better? Amyotroph. Lateral Scler. Frontotemporal Degener. 17, 168–178 (2016).

    Google Scholar 

  213. Green, C. et al. Patients’ health-related quality-of-life and health state values for motor neurone disease/amyotrophic lateral sclerosis. Qual. Life Res. 12, 565–574 (2003).

    Google Scholar 

  214. Maessen, M. et al. Trends and determinants of end-of-life practices in ALS in the Netherlands. Neurology 73, 954–961 (2009).

    Google Scholar 

  215. Wang, L. H. et al. Death with dignity in Washington patients with amyotrophic lateral sclerosis. Neurology 87, 2117–2122 (2016).

    Google Scholar 

  216. Felgoise, S. H. et al. Psychological morbidity in ALS: the importance of psychological assessment beyond depression alone. Amyotroph. Lateral Scler. 11, 351–358 (2010).

    Google Scholar 

  217. Pagnini, F., Simmons, Z., Corbo, M. & Molinari, E. Amyotrophic lateral sclerosis: time for research on psychological intervention? Amyotroph. Lateral Scler. 13, 416–417 (2012).

    Google Scholar 

  218. Neudert, C., Oliver, D., Wasner, M. & Borasio, G. D. The course of the terminal phase in patients with amyotrophic lateral sclerosis. J. Neurol. 248, 612–616 (2001).

    Google Scholar 

  219. Arthur, K. C. et al. Projected increase in amyotrophic lateral sclerosis from 2015 to 2040. Nat. Commun. 7, 12408 (2016).

    Google Scholar 

  220. Schwartz, C. E. & Sprangers, M. A. Methodological approaches for assessing response shift in longitudinal health-related quality-of-life research. Soc. Sci. Med. 48, 1531–1548 (1999).

    Google Scholar 

  221. Carr, A. J., Gibson, B. & Robinson, P. G. Measuring quality of life: is quality of life determined by expectations or experience? BMJ 322, 1240–1243 (2001).

    Google Scholar 

  222. Barclay, R. & Tate, R. B. Response shift recalibration and reprioritization in health-related quality of life was identified prospectively in older men with and without stroke. J. Clin. Epidemiol. 67, 500–507 (2014).

    Google Scholar 

  223. Simmons, Z., Bremer, B. A., Robbins, R. A., Walsh, S. M. & Fischer, S. Quality of life in ALS depends on factors other than strength and physical function. Neurology 55, 388–392 (2000).

    Google Scholar 

  224. Korner, S. et al. Speech therapy and communication device: impact on quality of life and mood in patients with amyotrophic lateral sclerosis. Amyotroph. Lateral Scler. Frontotemporal Degener. 14, 20–25 (2013).

    Google Scholar 

  225. Korner, S. et al. Weight loss, dysphagia and supplement intake in patients with amyotrophic lateral sclerosis (ALS): impact on quality of life and therapeutic options. BMC Neurol. 13, 84 (2013).

    Google Scholar 

  226. Lyall, R. A. et al. A prospective study of quality of life in ALS patients treated with noninvasive ventilation. Neurology 57, 153–156 (2001).

    Google Scholar 

  227. Bourke, S. C., Bullock, R. E., Williams, T. L., Shaw, P. J. & Gibson, G. J. Noninvasive ventilation in ALS: indications and effect on quality of life. Neurology 61, 171–177 (2003).

    Google Scholar 

  228. Walsh, S. M., Bremer, B. A., Felgoise, S. H. & Simmons, Z. Religiousness is related to quality of life in patients with ALS. Neurology 60, 1527–1529 (2003).

    Google Scholar 

  229. Montel, S., Albertini, L. & Spitz, E. Coping strategies in relation to quality of life in amyotrophic lateral sclerosis. Muscle Nerve 45, 131–134 (2012).

    Google Scholar 

  230. Mandler, R. N. et al. The ALS Patient Care Database: insights into end-of-life care in ALS. Amyotroph. Lateral Scler. Other Motor Neuron Disord. 2, 203–208 (2001).

    Google Scholar 

  231. Ferraiuolo, L., Kirby, J., Grierson, A. J., Sendtner, M. & Shaw, P. J. Molecular pathways of motor neuron injury in amyotrophic lateral sclerosis. Nat. Rev. Neurol. 7, 616–630 (2011).

    Google Scholar 

  232. Tsang, C. K., Liu, Y., Thomas, J., Zhang, Y. & Zheng, X. F. Superoxide dismutase 1 acts as a nuclear transcription factor to regulate oxidative stress resistance. Nat. Commun. 5, 3446 (2014).

    Google Scholar 

  233. Lee, S. & Kim, H. J. Prion-like Mechanism in amyotrophic lateral sclerosis: are protein aggregates the key? Exp. Neurobiol. 24, 1–7 (2015).

    Google Scholar 

  234. Rosen, D. R. Mutations in Cu/Zn superoxide dismutase gene are associated with familial amyotrophic lateral sclerosis. Nature 364, 362 (1993).

    Google Scholar 

  235. Siddique, T. et al. Linkage of a gene causing familial amyotrophic lateral sclerosis to chromosome 21 and evidence of genetic-locus heterogeneity. N. Engl. J. Med. 324, 1381–1384 (1991).

    Google Scholar 

  236. Hadano, S. et al. A gene encoding a putative GTPase regulator is mutated in familial amyotrophic lateral sclerosis 2. Nat. Genet. 29, 166–173 (2001).

    Google Scholar 

  237. Yang, Y. et al. The gene encoding alsin, a protein with three guanine-nucleotide exchange factor domains, is mutated in a form of recessive amyotrophic lateral sclerosis. Nat. Genet. 29, 160–165 (2001).

    Google Scholar 

  238. Hand, C. K. et al. A novel locus for familial amyotrophic lateral sclerosis, on chromosome 18q. Am. J. Hum. Genet. 70, 251–256 (2002).

    Google Scholar 

  239. Chen, Y. Z. et al. DNA/RNA helicase gene mutations in a form of juvenile amyotrophic lateral sclerosis (ALS4). Am. J. Hum. Genet. 74, 1128–1135 (2004).

    Google Scholar 

  240. Hentati, A. et al. Linkage of recessive familial amyotrophic lateral sclerosis to chromosome 2q33-q35. Nat. Genet. 7, 425–428 (1994).

    Google Scholar 

  241. Kwiatkowski, T. J. Jr et al. Mutations in the FUS/TLS gene on chromosome 16 cause familial amyotrophic lateral sclerosis. Science 323, 1205–1208 (2009).

    Google Scholar 

  242. Vance, C. et al. Mutations in FUS, an RNA processing protein, cause familial amyotrophic lateral sclerosis type 6. Science 323, 1208–1211 (2009).

    Google Scholar 

  243. Sapp, P. C. et al. Identification of two novel loci for dominantly inherited familial amyotrophic lateral sclerosis. Am. J. Hum. Genet. 73, 397–403 (2003).

    Google Scholar 

  244. Greenway, M. J. et al. ANG mutations segregate with familial and ‘sporadic’ amyotrophic lateral sclerosis. Nat. Genet. 38, 411–413 (2006).

    Google Scholar 

  245. Sreedharan, J. et al. TDP-43 mutations in familial and sporadic amyotrophic lateral sclerosis. Science 319, 1668–1672 (2008).

    Google Scholar 

  246. Chow, C. Y. et al. Deleterious variants of FIG4, a phosphoinositide phosphatase, in patients with ALS. Am. J. Hum. Genet. 84, 85–88 (2009).

    Google Scholar 

  247. Maruyama, H. et al. Mutations of optineurin in amyotrophic lateral sclerosis. Nature 465, 223–226 (2010).

    Google Scholar 

  248. Elden, A. C. et al. Ataxin-2 intermediate-length polyglutamine expansions are associated with increased risk for ALS. Nature 466, 1069–1075 (2010).

    Google Scholar 

  249. Luty, A. A. et al. Sigma nonopioid intracellular receptor 1 mutations cause frontotemporal lobar degeneration-motor neuron disease. Ann. Neurol. 68, 639–649 (2010).

    Google Scholar 

  250. Al-Saif, A., Al-Mohanna, F. & Bohlega, S. A mutation in sigma-1 receptor causes juvenile amyotrophic lateral sclerosis. Ann. Neurol. 70, 913–919 (2011).

    Google Scholar 

  251. Parkinson, N. et al. ALS phenotypes with mutations in CHMP2B (charged multivesicular body protein 2B). Neurology 67, 1074–1077 (2006).

    Google Scholar 

  252. Takahashi, Y. et al. ERBB4 mutations that disrupt the neuregulin-ErbB4 pathway cause amyotrophic lateral sclerosis type 19. Am. J. Hum. Genet. 93, 900–905 (2013).

    Google Scholar 

  253. Bannwarth, S. et al. A mitochondrial origin for frontotemporal dementia and amyotrophic lateral sclerosis through CHCHD10 involvement. Brain 137, 2329–2345 (2014).

    Google Scholar 

  254. Fecto, F. et al. SQSTM1 mutations in familial and sporadic amyotrophic lateral sclerosis. Arch. Neurol. 68, 1440–1446 (2011).

    Google Scholar 

Download references

Acknowledgements

The images in Figure 2 were prepared with the help of R. Highley (University of Sheffield).

Author information

Authors and Affiliations

Authors

Contributions

Introduction (O.H.); Epidemiology (G.L.); Mechanisms/pathophysiology (W.R. and P.J.S.); Diagnosis, screening and prevention (O.H. and L.H.v.d.B.); Management (A.C.); Quality of life (Z.S.); Outlook (A.A.-C.); Overview of Primer (E.M.C. and O.H.).

Corresponding author

Correspondence to Orla Hardiman.

Ethics declarations

Competing interests

O.H. declares grants from the Health Research Board and Science Foundation Ireland and receives funding through the EU Joint Programme in Neurodegenerative Disease Research (JPND), has served on advisory boards for Biogen Idec, Cytokinetics, Orion, Merck and Roche and has consulted for Mitsubishi. She is Editor-in-Chief of the journal ALS and Frontotemporal Degeneration. A.A.-C. has consulted for Biogen Idec, Chronos Therapeutics, Cytokinetics, GlaxoSmithKline, Mitsubishi Tanabe Pharma and Orion Pharma, has received speaking honoraria from Cytokinetics and Lilly, has been the chief or principal investigator of clinical trials for Biogen Idec, Cytokinetics, GlaxoSmithKline and Orion Pharma and receives royalties for the books The Brain (OneWorld Publications) and Genetics of Complex Human Diseases (Cold Spring Harbor Laboratory Press). A.C. has served on scientific advisory boards for Biogen Idec, Cytokinetics, Italfarmaco, Neuraltus and Mitsubishi. G.L. is an Associate Editor of Neuroepidemiology (Karger Publishers). P.J.S. has served on scientific advisory boards for Biogen, Orion Pharma, Sanofi and Treeway and has received research grants from AstraZeneca, Heptares and Reneuron. Z.S. has received consultation fees from Cytokinetics and Neuralstem and research funding from Biogen, Cytokinetics and GlaxoSmithKline. L.H.v.d.B. declares grants from the ALS Foundation Netherlands, grants from The Netherlands Organization for Health Research and Development (Vici scheme), grants from The Netherlands Organization for Health Research and Development (SOPHIA, STRENGTH, ALS-CarE project), funded through the EU JPND, has served on the Scientific Advisory Boards of Biogen, Cytokinetics and Orion and has received honoraria for presentations from Baxalta. E.M.C. and W.R. declare no competing interests.

PowerPoint slides

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Hardiman, O., Al-Chalabi, A., Chio, A. et al. Amyotrophic lateral sclerosis. Nat Rev Dis Primers 3, 17071 (2017). https://doi.org/10.1038/nrdp.2017.71

Download citation

  • Published:

  • DOI: https://doi.org/10.1038/nrdp.2017.71

This article is cited by

Search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing