Mercury and motor neuron disease: Hooked on a hypothesis

In 1830, Charles Bell described a middle-aged woman with progressive paralysis of the limbs and tongue associated with degenerative changes of the anterior spinal cord. Since that time, identifying the cause(s) of this syndrome that we refer to as amyotrophic lateral sclerosis (ALS) or motor neuron disease has remained elusive. Pathology has provided limited insight. Genetics, to date, has generated more questions than answers. Epidemiology has suggested many potential environmental risk factors but never with sufficient reproducibility, frequency, or defined pathophysiology to result in acceptance of these as unequivocal causative agents by ALS physicians and scientists. The quest to identify a biomarker(s) with sufficient specificity and sensitivity to provide pathogenic insight has also remained unsuccessful to date. Compounding our difficulty in understanding ALS pathogenesis, a requisite for prevention and/or meaningful treatment, is the realization that ALS is a syndrome, disguised as a similar phenotype in affected individuals, but resulting from multiple causes and characterized by loss of motor neurons. It has been proposed that sporadic ALS (sALS) represents a confluence of genetic susceptibility and environmental influence. The discordant ALS prevalence in twin studies supports this hypothesis. Thus, a patient who harbors 1 or more mutations may develop an ALS phenotype later in life as a consequence of a complementary, injurious environmental exposure(s). This hypothesis of a low-level environmental exposure rendered toxic by a defect in a patient’s genome, provides an attractive and rational explanation for the delayed development of accelerated motor neuron demise, superimposed on normal agerelated loss of motor neurons. In this model, the environmental influence (exposome) does not cause the mutation(s) nor is it, or the concurrent genomic alteration, sufficient to by itself to cause the phenotype. What is the responsible environmental culprit(s) if any? This is of considerable public health concern. Suggested exposomal risks are numerous. Proving causation is thwarted by a seemingly unlimited number of confounding variables that exist in vivo. An additional impediment is the inherent inaccuracy of retrospective estimation of the magnitude of any environmental exposure. Studies have suggested an association of ALS or an ALS-like illness, with specific geographic locations (Guam and the Kii Peninsula of Honshu Island, Japan), a direct or indirect (trauma) response to physical activity (military service, Italian soccer, or American football), electromagnetic fields, toxic exposure (tobacco, excitatory amino acids from cyanobacteria, organochlorine pesticides, polychlorinated biphenyls, fertilizers, bromated flame retardants, heavy metals), or infectious agents (retroviruses). To date, none of these appears sufficient to be the sole cause of ALS. In the case of Guam, a genetic risk is considered insufficient to explain the magnitude of the historical prevalence of the disease, implicating an environmental influence. In contrast, in the Kii Peninsula, it would appear that the increased prevalence of ALS may not be exposomal as originally considered but may represent a geographic clustering of the C9orf72 mutation in that region. What seems certain is that, if genomic risk and exposomal influence are pathogenetically complementary, identification of one would greatly facilitate the identification of the other(s). In this issue, Andrew and colleagues attempt to do so by suggesting a relationship between elevated tissue methylmercury levels, ALS, and fish consumption. They found increased levels of methylmercury in the toenails of 46 ALS patients compared with 66 nondegenerative neurological controls. Furthermore, they demonstrated a relationship between the amount and type of lifetime fish consumption and tissue mercury levels in both ALS patients and controls. To do so, they used a self-reported questionnaire that attempted to See editorial on pages 36–41, this issue.