# Personalized Prevention in Mercury-Induced Amyotrophic Lateral Sclerosis: A Case Report
## 3 Discussion
Exposure to toxic metals (Hg included) can induce a series of cellular metabolic and energetic alterations, including faulty autophagy [62; 63]. Moreover, up-to-date evidence highlights the existence of mitoautophagy, a self-destructive mitochondrial dysfunction which occurs at early stages of ALS [64]. Mitochondrial autophagy can be hypothesized as a common link for both ALS and Hg intoxication. In fact, Hg ions have been implicated in faulty mitochondrial autophagy even with continuous low-dose exposures [63]. Studies associating mercury and ALS have been conducted mainly with methylmercury, which is the most toxic form of the metal. In experimental conditions, methylmercury (MeHg) caused LDH release, caspase activation, cell-cycle alteration, and ROS generation, in accordance with a decrease in cell viability [65]. The neurotoxicity of Hg (particularly MeHg) is associated with three main mechanisms: (1) increase of intracellular Ca\({}^{2+}\) levels; (2) induction of oxidative stress by overproduction of ROS or by reduced oxidative defense capacity; (3) interactions with sulfhydryl groups with the formation of a thiol-containing complex [66]. Intracellular calcium levels also appear to be linked to autophagic processes within cells [67]. Autophagic processes and the formation of autophagosomes increase in cells exposed to Cys-S-Hg-S-Cys [68]. HgCl\({}_{2}\) treatments decreased mitochondrial functionality, suggesting that nonessential metals compromise mitochondrial homeostasis and activity [69]. Moreover, the binding of MeHg to GSH is known to decrease the availability of this antioxidant, exposing cells to free-radical-mediated damage [70]. Since ALS has a multifactorial genesis, in the reported case, both genetic predisposition (pathogenic TBK1 variant) and occupational Hg exposure concurred in the development of the disease. A conceivable hypothesis suggests that acute/subacute subclinical reduction in the motor neuron pool may occur with the initial phases of occupational exposure to Hg, but the defect remains unrecognized until that pool becomes further depleted through the normal aging process [71] or the additive effect of several successive occupational exposures. This case proved the key role of health surveillance in the workplace. The great variability in the individual responses of workers requires strong attention by the occupational physician, who must promptly identify the first symptoms of an excessive response. In the reported case, the observation of intermittent subacute flares of Hg intoxication, firmly assessed through high Hg levels in urine, should have been considered a red flag that must induce deeper analysis of the worker's genetic pattern long before the onset of the neurological disorder. The intervention of the occupational physician to prevent occupational mercury intoxication should be directed primarily at modifying the environment, rather than assessing the worker's adaptation to the job. However, a small maintenance contractor has little chance of influencing the chlor-alkali plant safety strategy. In these cases, the decision to allow exposure to risk, declaring the worker \"fit for the job\", or to declare him unfit, exposing him to dismissal, is very difficult. Even if the causes of ALS are multifactorial and a single gene mutation might not be sufficient to cause ALS, personalized occupational health practices and searching for genetic biomarkers of susceptibility in selected cases with documented frequent episodes of mercury intoxication recorded during health surveillance programs could be an aid in the doctor's decision, allowing to customize prevention measures in the workplace and act before serious and irreversible consequences of occupational exposure appear. The use of genetic tests must be reserved for specifically motivated cases and should not be considered a universal screening measure. Ethical considerations [72] and the Italian Constitution [73] do not allow occupational physicians to perform genetic screening tests in the pre-assumptive phase.