# Personalized Prevention in Mercury-Induced Amyotrophic Lateral Sclerosis: A Case Report
## 3 Discussion  
In this case report, we showed a worker who was chronically exposed to Hg in a chlor-alkali plant and developed ALS after recurrent episodes of neurotoxicity. Interestingly, genetic testing carried out in this worker showed a TBK1 mutation (deletion in c.1852_1854 delGAA: p.E618 del). ALS is the most common neurodegenerative disease affecting motor neurons. The diagnosis of ALS is based on two different criteria: the revised El Escorial criteria (rEEC) [40] and the Awaji criteria [41], that may have overall superiority [42], though they are not always more sensitive than rEEC [43]. The criteria have high inter-rater variation [44]. Although up to 10% of ALS is heritable (familial ALS) and, in most cases, caused by genetic mutations, the majority of the cases of this fatal neurodegenerative disease occurs in individuals with no prior family history (sporadic ALS), and is of unknown etiology. As it is a complex and heterogeneous disease, polyfactorial interaction between genetic characteristics, metabolic, and environmental factors might be at the basis of sporadic ALS cases [45]. Regarding the genetic factors, through the years, several genetic mutations which interfere with the onset and progression of the disease, have been associated with ALS, being either causative or disease-modifying. Mutations can have different cellular sites of attack: coding of proteins implicated in the antioxidative response system (e.g., SOD1), RNA stability, function and metabolism, nucleocytoplasmic trafficking (e.g., ANG, TARDBP, FUS, HNRNPA1, MATR3), cytoskeletal dynamics (e.g., DCTN1, PFN1, TUBA4A), the ubiquitin-proteasome system (e.g., VCP), mitochondrial functions (e.g., CHCHDI0), and autophagic pathways (e.g., C9 ORF72, OPTTN, UBQLN2, SQSTM1, VCP, CCNF, TBK1) [46]. In particular, mutations in TANK-binding kinase 1 (TBK1) have been associated with the sporadic form of ALS and other neurological diseases such as frontotemporal dementia [47]. The frequency of TBK1 variants is 0.5-1.6% in pure ALS patients [48], and 3.5-4.5% in ALS cases with frontotemporal dementia [49]. The protein encoded by TBK1 is a serine/threonine protein kinase, which has an important role in the induction of autophagy and innate immune response pathways [50]. Moreover, TBK1 variants are associated with reduction of the corresponding protein level [51], leading to accumulation of protein aggregates and defective mitochondria in motor neurons, which may contribute to ALS pathology by disrupting axonal transport [50]. In addition to and, most probably, in association with the genetic background, a proportion of ALS cases are likely to be attributable to occupational exposure. High-dose occupational exposure of workers in the 1950s and 1980s induced several cases of neurological impairment similar to ALS, which regressed after cessation of exposure [52; 53; 54; 55]. Nowadays, low-dose occupational exposure of sensitive individuals remains an occupational health concern worldwide. Genetic polymorphisms and epigenetic changes have been correlated to different health effects of Hg in exposed workers [56]. For example, it is known that Hg can induce direct and indirect DNA post-translational modifications (PTMs) such as phosphorylation, ubiquitination, acetylation, nitrosylation, and S-mercuration on targeted proteins implicated in many cellular pathways [57; 58]. Specific polymorphisms of glutathione-related genes (e.g., glutamate-cysteine ligase regulatory subunit, glutamate-cysteine ligase), Hg transporter proteins (e.g., MTs, ABCs), cytochrome p450 3A, \(\epsilon\)4 APOE, and Brain Derived Neurotrophic Factor (BDNF) have been associated with the magnitude of toxic Hg effects in biological tissues [39; 58; 59; 60; 61]. The induction of oxidative stress, which can activate the process of mitochondrial autophagy, is the initial step of Hg neurotoxicity [62]. Autophagy represents an important defense mechanism in cells that allows to selectively eliminate organelles and/or dysfunctional proteins, subsequently reusing their molecular components.