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Large-scale SOD1 mutation screening provides evidence for genetic heterogeneity in amyotrophic lateral sclerosis
  1. Michael A van Es1,
  2. Caroline Dahlberg2,
  3. Anna Birve2,
  4. Jan Herman Veldink1,
  5. Leonard H van den Berg1,
  6. P M Andersen
  1. 1Department of Neurology, Rudolf Magnus Institute of Neuroscience, University Medical Center Utrecht, Utrecht, The Netherlands
  2. 2Institute of Clinical Neuroscience, Umeå University Hospital, Umeå, Sweden
  1. Correspondence to Dr Leonard H van den Berg, Department of Neurology, University Medical Center Utrecht, Utrecht, The Netherlands; l.h.vandenBerg{at}umcutrecht.nl

Abstract

Objective To estimate the frequency of SOD1 mutations in a large referral cohort of familial amyotrophic lateral sclerosis (FALS) and sporadic amyotrophic lateral sclerosis (SALS) patients from The Netherlands and to compare this frequency with that of other developed countries.

Methods A total of 451 sporadic and 55 FALS patients were screened for SOD1 mutations. The authors performed PCR amplification of all five coding exons of SOD1 followed by direct DNA sequencing using forward and reverse primers.

Results One novel mutation (p.I99V) and a homozygous p.D90A mutation were identified in SALS patients. In a pedigree with Mendelian dominant FALS, one patient was found to be heterozygous for the p.D90A mutation. SOD1 mutation frequency was found to be significantly lower in The Netherlands compared with other countries with p=0.0004 for FALS (21.9% vs 2.5%) and p=0.005 for SALS (2.5% vs 0.44%).

Conclusions The authors demonstrate that SOD1 mutations are rare in The Netherlands in familial and SALS. This observation suggests that the genetic background of amyotrophic lateral sclerosis differs between different populations, countries and regions. This may have consequences for the interpretation of association studies and explain why replication of association studies has proven difficult in amyotrophic lateral sclerosis.

  • ALS
  • genetics
  • SOD1
  • association study

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Footnotes

  • Leonard H van den Berg and Peter M Andersen contributed equally to this paper

  • Funding This work was supported by Netherlands Organization for Scientific Research (NWO) and the Prinses Beatrix Foundation (PBF). We would also like to thank H Kersten and M Kersten, for their generous support, as well as JR van Dijk and the Adessium foundation and the VSB fonds (LHvdB), The Brain Foundation of The Netherlands (JHV), the Kempe Foundation, the Swedish Brain Research Foundation and Bertil Hallsten, the Bjorklund Foundation for ALS Research, the Swedish Brain Power Foundation and the Swedish Association for the Neurologically Disabled (PMA).

  • Competing interests None.

  • Patient consent Obtained.

  • Ethics approval Ethics approval was provided by the regional medical school ethics committee.

  • Provenance and peer review Not commissioned; externally peer reviewed.

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