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- TBK1 gene
- frontotemporal lobar degeneration
- amyotrophic lateral sclerosis
- primary lateral sclerosis
- genotype-phenotype correlations
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.
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.
Contributors Study concept and design: EG-T, JVDZ, CVB. Gathering of data: EG-T, JVDZ, MR, JE-P, AG-R, EN, MJS, JP-P, RG-L, IG, MC, CVB, DB-H. Analysis and interpretation of data: EG-T, JVDZ, MR, MJS, JP-P, IG, MC, CVB. Drafting of the manuscript: EG-T. Critical revision of the manuscript for important intellectual content: JVDZ, MR, CVB, AG-R, EN, RG-L. Obtained funding: EG-T, JP-P, CVB. Administrative, technical and material support: MR, RG-L, JP-P, MJS. Study supervision: EG-T, CVB, RG-L.
Funding Supported by grants from the Ministry of Science and Technology (SAF2010-18277), Instituto de Investigación Sanitaria Carlos III (PI14-00088 and PI14-00099), FUNDELA (Spanish Foundation to the development of ALS research), ADELA (ALS Spanish Association) and funds from FEDER (Spain). Genetic studies of TBK1 in the EU EOD Consortium were funded in part by the Belgian Science Policy Office Interuniversity Attraction Poles program, the Flemish Government initiated Flanders Impulse Program on Networks for Dementia Research (VIND), the Flemish Government initiated Methusalem Excellence Program, the Research Foundation Flanders (FWO), the University of Antwerp Research Fund (Belgium).
Competing interests None declared.
Ethics approval Research Ethics Committee at Fundacin Jimnez Daz (Madrid, Spain).
Provenance and peer review Not commissioned; externally peer reviewed.