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Familial primary lateral sclerosis or dementia associated with Arg573Gly TBK1 mutation
  1. Estrella Gómez-Tortosa1⇑,
  2. Julie Van der Zee2,3,
  3. María Ruggiero1,
  4. Ilse Gijselinck2,3,
  5. Jesús Esteban-Pérez4,
  6. Alberto García-Redondo4,
  7. Daniel Borrego-Hernández4,
  8. Eloísa Navarro5,
  9. M. José Sainz1,
  10. Julián Pérez-Pérez6,
  11. Marc Cruts2,3,
  12. Christine Van Broeckhoven2,3,
  13. Rosa Guerrero-López1,7
  14. on behalf of the EU EOD Consortium
  1. 1 Department of Neurology, Fundación Jiménez Díaz, Madrid, Spain
  2. 2 Neurodegenerative Brain Diseases group, Center for Molecular Neurology, VIB, Antwerp, Belgium
  3. 3 Laboratory of Neurogenetics, Institute Born-Bunge, University of Antwerp, Antwerp, Belgium
  4. 4 ALS Unit, 12 de Octubre Hospital Health Research Institute 'imas12', and Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER U-723), Madrid, Spain
  5. 5 Department of Neurology, Hospital Infanta Leonor, Madrid, Spain
  6. 6 Department of Genetics, Secugen S.L., Madrid, Spain
  7. 7 Instituto de Investigaciones Sanitarias Fundación Jiménez Díaz (IIS-FJD) and Centro de Investigación Biomédica en Red de Enfermedades Raras, Madrid, Spain
  1. Correspondence to Dr Estrella Gómez-Tortosa, Department of Neurology, Fundación Jiménez Díaz, Avda. Reyes Catolicos 2, Madrid 28040, Spain; egomezt{at}fjd.es

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Primary lateral sclerosis (PLS) is a rare variant of motor neuron disease (MND) characterised by selective upper motor neuron features whose causes and pathogenic mechanisms remain largely unknown. While some familial cases of childhood to young–adult onset with recessive transmission have been reported in association with mutations in the Alsin, SPG11 and SPG7 genes,1 most adult cases occur sporadically. Recently, Tank-binding kinase 1 (TBK1) mutations have been identified in 1.9% of frontotemporal dementia(FTD) and/or Amyotrophic lateral sclerosis (ALS) cohorts.2 However, pathogenicity of many TBK1 missense mutations is difficult to establish in the absence of cosegregation data. A screening for TBK1 mutations carried out by the European Early-Onset Dementia (EU EOD) Consortium in a large series of FTD/ALS cases found one carrier of the Arg573Gly mutation.3 The index case belonged to a Spanish family with autosomal dominant disease manifesting in the sixth decade as either dementia or PLS, and in whom we were able to demonstrate cosegregation.

Methods

TBK1 screening included 2553 individuals with FTD and/or ALS and 2288 European controls, including 549 of Spanish origin, and was conducted by the EU EOD Consortium as previously described.3 The family with the Arg573Gly mutation comprises an affected father and nine offspring, of whom five have been affected by either dementia or PLS (figure 1). Four affected and one healthy sibling have been clinically and genetically examined. Retrospective information was obtained regarding the disease process in cases I.1 and II. 2.

Figure 1

Top: family tree. Bottom: sequence of recruitment of clinical features in the affected family members. Amnestic dementia refers to …

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