A novel homozygous mutation in TBK1 gene causing ALS-FTD

Excerpt

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease characterized by the progressive loss of both upper and lower motor neurons that leads to a fatal paralysis and death, mainly due to respiratory failure [1] typically after 3–5 years post onset [2]. The average age of onset is between 50 and 65 years[3]. It is a multifactorial disorder with environmental and genetic components [4]. In up to 10% [5] of cases, there is a family history positive for ALS. Mutations in several genes have been linked to the pathogenesis of ALS, such as SOD1, C9orf72, TARDPB, FUS, and NEK1 [5], and many of them are also associated with frontotemporal dementia (FTD) [6], a heterogeneous neurocognitive syndrome characterized by the progressive impairment of language, executive functions, and change in behavior. Two main FTD clinical variants are to date recognized: behavioral (bv-FTD) and primary progressive aphasia (PPA) [7]. The brain usually shows marked atrophy of frontal and temporal lobes [8]. ALS and FTD often overlap in their clinical presentation, genetic mutations, and physiopathology. For many researchers, they represent a spectrum of disease continuum [1, 9]. Recently, thanks to exome sequencing techniques, mutations in the TANK binding kinase 1 (TBK1) have been identified as a cause of ALS [10, 11] and FTD [12]. TBK1 is a multifunctional protein, member of the IKK kinase family, involved in the regulation of multiple processes as innate immunity, inflammation, autophagy, and cell proliferation [13]. Here we present a case of ALS associated with bv-FTD of an Italian woman with a novel homozygous mutation in TBK1 gene. …