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Amyotrophic lateral sclerosis is not linked to multiple sclerosis in a population based study
  1. Perry T C van Doormaal,
  2. Alessandro Gallo,
  3. Wouter van Rheenen,
  4. Jan H Veldink,
  5. Michael A van Es,
  6. Leonard H van den Berg
  1. Department of Neurology, Rudolf Magnus Institute of Neuroscience, University Medical Centre Utrecht, Utrecht, The Netherlands
  1. Correspondence to Professor Leonard H van den Berg, Department of Neurology, G03.228, Rudolf Magnus Institute of Neuroscience, University Medical Center Utrecht, PO Box 85500, Utrecht 3508 GA, The Netherlands; l.h.vandenberg{at} PTCvD and AG contributed equally

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Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease characterised by progressive paralysis, leading to death from respiratory failure within 3–7 years. Approximately 5% of the cases are familial in nature, mostly inherited in an autosomal dominant mode. A relatively high rate of concurrence of ALS and multiple sclerosis (MS), a progressive inflammatory disorder of the central nervous system, has recently been reported.1 Interestingly, 80% of these ALS–MS cases were found to carry hexanucleotide repeat expansions in C9ORF72, which is a major ALS gene (found in 37% of familial ALS patients and 6.1% of sporadic ALS patients in the Netherlands2). Repeat expansions in C9ORF72 are also a major cause of frontotemporal dementia and have also been implicated in Alzheimer's disease, Parkinsonism, ataxia and psychosis. It is therefore considered to be a pleiotropic gene and could perhaps also play a role in MS pathogenesis.

The coincidence of ALS and MS is not undisputed. The available studies are mostly case reports or case series and are subject to referral and publication bias. A population based study approach is better to avoid this bias and to determine the relationship between ALS and MS. In a large prospective, population based ALS study in the Netherlands we identified all patients with ALS and MS and subsequently screened them for repeat expansions in the C9ORF72 gene.


Patients were identified from 1 January 2006 to 1 September 2011 in a large, prospective population based case control study on ALS in the Netherlands3 (mean population 16 469 029). Complete case ascertainment was pursued by the inclusion of patients by neurologists and consultants in rehabilitation medicine throughout the country via the Dutch Neuromuscular Patient Association and by our ALS website. It was expected to have 2132 new motor neuron disease (MND) patients during this study period. After excluding patients with progressive muscular atrophy, primary lateral sclerosis, progressive bulbar palsy and familial ALS patients, 1439 incident sporadic ALS patients remain in the Netherlands. Our database has 1241 patients who fulfilled these inclusion criteria. Due to several reasons (inclusion after death, awaiting recruitment, not willing to take part in the study or no available contact information), 1006 of them were contacted and gave written informed consent. All the patients who were included in this study fulfilled the revised El Escorial Criteria for possible, probable laboratory-supported, probable or definite ALS. The study was approved by the Medical Research Ethics Committee of the University Medical Center Utrecht.

Patients filled in questionnaires and blood samples were collected. The questionnaires contain a detailed segment on previous medical history. We obtained the medical records for those patients who reported to have also been diagnosed with MS and subsequently verified this diagnosis (according to the 2010 revised McDonald criteria).

Genomic DNA was extracted from whole blood using standard procedures. The C9ORF72 GGGGCC repeat analysis was performed using the methods described earlier.2 All samples were genotyped twice to avoid false-negative calls.

Power calculations were performed using G*Power (V.3.1 Heinrich Heine Universität Düsseldorf, Germany). Binomial probability distributions were analysed using R V.2.14.1 (


From 1006 eligible ALS patients who gave informed consent, a total of 810 patients (81%) returned the questionnaire. With this sample size, the power to detect an MS proportion of 0.011 (as found in the previous article1) is 0.99. Three of these patients reported to also have been diagnosed with MS. After re-examining the medical records for these patients, we could confirm the diagnosis of MS in two patients (0.25%). Patient characteristics are summarised in table 1.

Table 1

Clinical characteristics of two patients

The prevalence of MS in the Dutch population is 88 per 100 000 inhabitants in 2007.4 Binomial distribution analysis shows the probability that, in a group of 810 persons and a prevalence of 0.00088, two persons have MS is 0.16. Since ALS has its main occurrence between 45 and 75 years,3 it is more accurate to use the prevalence of MS for this age group. This prevalence is even higher, 161 per 100 000 inhabitants per year, and the probability to have two MS patients in a cohort as ours rises further to 0.37.

The repeat primed PCR revealed that both patients have hexanucleotide repeat numbers below 30 and therefore have no expansion of the repeat in C9ORF72.


In our population based cohort two out of 810 ALS patients were diagnosed with MS before the first symptoms of ALS started. The rate of this MS–ALS concurrence is lower than in the previous study (0.25% in this study vs 1.1% in the previous study) and, based on the incidence of MS, is not higher than expected. Therefore our data do not support the previous findings1 of an MS–ALS concurrence.

The two patients described in this article have no repeat expansion in the C9ORF72 gene. In the previous article, four of the five MS–ALS patients had this repeat expansion. Combining these two studies results in a repeat expansion in 57% of these patients. This is still a relatively high proportion compared with the general ALS population although our findings did not add to the finding.

The possible relation of ALS and MS was reported previously in other populations, including a higher occurrence of MS among relatives of ALS patients in Iran.5 It is possible that the MS–ALS concurrence related to C9ORF72 repeat expansions is population specific and, like UBQLN2 and SOD1 mutations, does not occur in the Netherlands. It is also possible that the high concurrence of ALS and MS is due to biased numbers in other studies. The advantage of this study compared with the previous studies is the prospective population based ascertainment of patients. This prevents a referral bias that can occur when patients are recruited from a tertiary referral centre, as in previous studies. This referral bias could be the reason that the previous study reports a higher concurrence of ALS and MS. Therefore, with this prospective population based case ascertainment we can conclude that MS is not more common in ALS patients in the Netherlands.



  • Funding This work was supported by the Prinses Beatrix Fonds (PB 0703) (Prinses Beatrix Fonds and Kersten Foundation, Postbus 85810, 2508 CM Den Haag, The Netherlands) and The Netherlands ALS Foundation (The Netherlands ALS Foundation, Zekeringstraat 42, 1014 BT Amsterdam, The Netherlands). The research leading to these results has received funding from the European Community's Health Seventh Framework Programme (FP7/2007–2013) (259867) (European Commission, DG Research—Unit F06, CDMA 02/069, B-1049 Brussels, Belgium).

  • Contributors PTCvD, AG, WvR, JHV, MAvE and LHvdB were all involved in the conception, design and acquisition of data. Analysis was performed by PTCvD, AG and WvR. PTCvD and AG wrote the first draft that was revised and approved by JHV, MAvE and LHvdB.

  • Competing interests LHvdB received travel grants and consultancy fees from Baxter, and serves on the advisory board for Biogen, Cytokinetics. JHV received travel grants from Baxter. The other authors report no competing financial interests.

  • Patient consent Obtained.

  • Ethics approval Medical Research Ethics Committee University Medical Center Utrecht.

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