{
  "abstract": "Objectives The identification of bi-allelic intermediate ATXN2 repeat expansions in a pedigree with amyotrophic lateral sclerosis (ALS) through clinical testing prompted us to investigate its relevance in the wider ALS population.Methods ATXN2 repeat size was assessed in a large international cohort of ALS patients (n=6653 from Project MinE) and in neurologically intact control populations (n=13 515 controls from Project MinE and gnomad). For bi-allelic cases, we retrieved medical records, family history and MRI imaging. For familial cases, we obtained DNA samples from relatives for segregation analyses.Results In total, we identified bi-allelic intermediate ATXN2 repeat expansions in five familial cases from three different pedigrees and five apparently sporadic cases. There is a relatively homogeneous phenotype characterised by lower limb onset and long survival (median 6 years) without significant cerebellar atrophy. Bi-allelic expansions were absent in controls (0 out of 13 515).Discussion Here we report an apparently novel autosomal recessive form of familial ALS caused by bi-allelic intermediate ATXN2 repeat expansions, which is characterised by high penetrance, lower limb onset and slow progression. Although rare, testing for ATXN2 expansions should be performed in the clinical setting given its relevance to prognosis and genetic counselling.",
  "authors": [
    {
      "affiliations": [
        "Department of Neurology, UMC Utrecht, Utrecht, the Netherlands",
        "Laboratory of Neurobiology, Department of Neuroscience, KU Leuven, Leuven, Belgium"
      ],
      "name": "Koen Cedric Demaegd"
    },
    {
      "affiliations": [
        "Department of Genetics, UMC Utrecht, Utrecht, Utrecht, the Netherlands"
      ],
      "name": "Wouter Koole"
    },
    {
      "affiliations": [
        "Department of Neurology, UMC Utrecht, Utrecht, the Netherlands"
      ],
      "name": "Joke JFA van Vugt"
    },
    {
      "affiliations": [
        "Department of Radiology, UMC Utrecht, Utrecht, the Netherlands"
      ],
      "name": "Jan Willem Dankbaar"
    },
    {
      "affiliations": [
        "Department of Radiology, UMC Utrecht, Utrecht, the Netherlands"
      ],
      "name": "Jeroen Hendrikse"
    },
    {
      "affiliations": [
        "Suna and İnan Kıraç Foundation, Neurodegeneration Research Laboratory (NDAL), KUTTAM, Koç University School of Medicine, Istanbul, Turkey"
      ],
      "name": "A Nazlı Başak"
    },
    {
      "affiliations": [
        "University of Lisbon, Lisbon, Lisbon, Portugal"
      ],
      "name": "Mamede de Carvalho"
    },
    {
      "affiliations": [
        "Universite de Tours Faculte de Medecine, Tours, Centre-Val de Loire, France"
      ],
      "name": "Philippe Corcia"
    },
    {
      "affiliations": [
        "Angers University Hospital, Angers, Pays de la Loire, France"
      ],
      "name": "Philippe Codron"
    },
    {
      "affiliations": [
        "Rare Disease Reference Center for ALS (CRMR SLA), Pierre Wertheimer Hospital, Hospices Civils de Lyon, Institut NeuroMyoGène-PGNM, Claude Bernard University, Lyon, France"
      ],
      "name": "Emilien Bernard"
    },
    {
      "affiliations": [
        "Montpellier University, Montpellier, Occitanie, France"
      ],
      "name": "Claire Guissart"
    },
    {
      "affiliations": [
        "ALS Centre, Departement of Neurology, CHU Limoges, Limoges, Aquitaine-Limousin-Poitou-Charentes, France"
      ],
      "name": "Philippe Couratier"
    },
    {
      "affiliations": [
        "Department of Neurology, Hospital Universitari de Bellvitge, L’Hospitalet de Llobregat, Catalunya, Spain"
      ],
      "name": "Mónica Povedano Panades"
    },
    {
      "affiliations": [
        "Department of Neurology, Erasmus MC, Rotterdam, the Netherlands"
      ],
      "name": "Pieter A van Doorn"
    },
    {
      "affiliations": [
        "Department of Neurology, Radboudumc, Nijmegen, the Netherlands"
      ],
      "name": "Bart P Warrenburg"
    },
    {
      "affiliations": [
        "Department of Neurology, Sheffield Institute for Translational Neuroscience (SITraN), Sheffield, South Yorkshire, UK"
      ],
      "name": "Johnathan Cooper-Knock"
    },
    {
      "affiliations": [
        "Department of Neurology, UMC Utrecht, Utrecht, the Netherlands",
        "Laboratory of Neurobiology, Department of Neuroscience, KU Leuven, Leuven, Belgium",
        "Department of Genetics, UMC Utrecht, Utrecht, Utrecht, the Netherlands",
        "Department of Radiology, UMC Utrecht, Utrecht, the Netherlands",
        "Suna and İnan Kıraç Foundation, Neurodegeneration Research Laboratory (NDAL), KUTTAM, Koç University School of Medicine, Istanbul, Turkey",
        "University of Lisbon, Lisbon, Lisbon, Portugal",
        "Universite de Tours Faculte de Medecine, Tours, Centre-Val de Loire, France",
        "Angers University Hospital, Angers, Pays de la Loire, France",
        "Rare Disease Reference Center for ALS (CRMR SLA), Pierre Wertheimer Hospital, Hospices Civils de Lyon, Institut NeuroMyoGène-PGNM, Claude Bernard University, Lyon, France",
        "Montpellier University, Montpellier, Occitanie, France",
        "ALS Centre, Departement of Neurology, CHU Limoges, Limoges, Aquitaine-Limousin-Poitou-Charentes, France",
        "Department of Neurology, Hospital Universitari de Bellvitge, L’Hospitalet de Llobregat, Catalunya, Spain",
        "Department of Neurology, Erasmus MC, Rotterdam, the Netherlands",
        "Department of Neurology, Radboudumc, Nijmegen, the Netherlands",
        "Department of Neurology, Sheffield Institute for Translational Neuroscience (SITraN), Sheffield, South Yorkshire, UK",
        "Department of Translational Neuroscience, UMC Utrecht, Utrecht, Utrecht, the Netherlands",
        "Department of Neurology, University Hospitals Leuven, Leuven, Belgium"
      ],
      "name": "ALS Sequencing Consortium, Project MinE PI’s"
    },
    {
      "affiliations": [
        "Department of Translational Neuroscience, UMC Utrecht, Utrecht, Utrecht, the Netherlands"
      ],
      "name": "R Jeroen Pasterkamp"
    },
    {
      "affiliations": [
        "Department of Neurology, UMC Utrecht, Utrecht, the Netherlands"
      ],
      "name": "Wouter van Rheenen"
    },
    {
      "affiliations": [
        "Laboratory of Neurobiology, Department of Neuroscience, KU Leuven, Leuven, Belgium",
        "Department of Neurology, University Hospitals Leuven, Leuven, Belgium"
      ],
      "name": "Philip van Damme"
    },
    {
      "affiliations": [
        "Department of Neurology, UMC Utrecht, Utrecht, the Netherlands"
      ],
      "name": "Leonard H van den Berg"
    },
    {
      "affiliations": [
        "Department of Neurology, UMC Utrecht, Utrecht, the Netherlands"
      ],
      "name": "Jan Herman Veldink"
    },
    {
      "affiliations": [
        "Department of Neurology, UMC Utrecht, Utrecht, the Netherlands"
      ],
      "name": "Michael A van Es"
    }
  ],
  "title": "Bi-allelic intermediate ATXN2 repeat expansions are associated with slow progressing, leg-onset familial ALS",
  "uid": "27601fd9-a50d-5501-8ba9-a2bf8000651e"
}