Acta Neuropathologica

, Volume 124, Issue 3, pp 339–352 | Cite as

The genetics and neuropathology of amyotrophic lateral sclerosis

  • Ammar Al-ChalabiEmail author
  • Ashley Jones
  • Claire Troakes
  • Andrew King
  • Safa Al-Sarraj
  • Leonard H. van den Berg


Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease of motor neurons leading to death from respiratory failure within about 3 years of symptom onset. A family history of ALS is obtained in about 5 % but the distinction between familial and apparently sporadic ALS is artificial and genetic factors play a role in all types. For several years, only one gene was known to have a role in ALS pathogenesis, SOD1. In the last few years there has been a rapid advance in our genetic knowledge of the causes of ALS, and the relationship of the genetic subtypes with pathological subtypes and clinical phenotype. Mutations in the gene for TDP-43 protein, TARDBP, highlight this, with pathology mimicking closely that found in other types of ALS, and a phenotypic spectrum that includes frontotemporal dementia. Mutations in the FUS gene, closely related to TDP-43, lead to a similar clinical phenotype but distinct pathology, so that the three pathological groups represented by SOD1, TARDBP, and FUS are distinct. In this review, we explore the genetic architecture of ALS, highlight some of the genes implicated in pathogenesis, and describe their phenotypic range and overlap with other diseases.


Amyotrophic lateral sclerosis Frontotemporal dementia Gene Familial Sporadic c9orf72 sod1 tardbp tdp-43 fus ubqln2 optn ALS FTD FTLD Genetics Pathology 



We thank the Motor Neurone Disease Association of Great Britain and Northern Ireland, the ALS Association, the Angel Fund and the ALS Therapy Alliance for support. We thank the European Community’s Health Seventh Framework Programme (FP7/2007–2013) [259867 (to A.A.C. and L.vD.B.)]. A.A.C. receives salary support from the National Institute for Health Research (NIHR) Dementia Biomedical Research Unit at South London and Maudsley NHS Foundation Trust and King’s College London. The views expressed are those of the author and not necessarily those of the NHS, the NIHR or the Department of Health.


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Copyright information

© Springer-Verlag 2012

Authors and Affiliations

  • Ammar Al-Chalabi
    • 1
    Email author
  • Ashley Jones
    • 1
  • Claire Troakes
    • 1
    • 2
  • Andrew King
    • 1
    • 2
  • Safa Al-Sarraj
    • 1
    • 2
  • Leonard H. van den Berg
    • 3
  1. 1.Department of Clinical NeuroscienceKing’s College London, Institute of PsychiatryLondonUK
  2. 2.Department of Clinical NeuropathologyKing’s College HospitalLondonUK
  3. 3.Department of Neurology, Rudolf Magnus Institute of NeuroscienceUniversity Medical CentreUtrechtThe Netherlands

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