Early-onset, conjugal, twin-discordant, and clusters of sporadic ALS: Pathway to discovery of etiology via lifetime exposome research

Abstract

The identity and role of environmental factors in the etiology of sporadic amyotrophic lateral sclerosis (sALS) is poorly understood outside of three former high-incidence foci of Western Pacific ALS and a hotspot of sALS in the French Alps. In both instances, there is a strong association with exposure to DNA-damaging (genotoxic) chemicals years or decades prior to clinical onset of motor neuron disease. In light of this recent understanding, we discuss published geographic clusters of ALS, conjugal cases, single-affected twins, and young-onset cases in relation to their demographic, geographic and environmental associations but also whether, in theory, there was the possibility of exposure to genotoxic chemicals of natural or synthetic origin. Special opportunities to test for such exposures in sALS exist in southeast France, northwest Italy, Finland, the U.S. East North Central States, and in the U.S. Air Force and Space Force. Given the degree and timing of exposure to an environmental trigger of ALS may be related to the age at which the disease is expressed, research should focus on the lifetime exposome (from conception to clinical onset) of young sALS cases. Multidisciplinary research of this type may lead to the identification of ALS causation, mechanism, and primary prevention, as well as to early detection of impending ALS and pre-clinical treatment to slow development of this fatal neurological disease.

Diffusion magnetic resonance imaging-based surrogate marker in amyotrophic lateral sclerosis

“…Amyotrophic lateral sclerosis (ALS) is the most prevalent type of motor neuron disease (MND), a neurodegenerative illness that causes muscle weakness [1]. The incidence of sporadic ALS shows little variation in Western countries, ranging from 1 to 2 per 100,000 person-years [2][3][4][5][6], with an estimated lifetime risk of 1 in 400 [7]. MND is caused by upper motor neuron (UMN) or lower motor neuron (LMN) lesion weakness as shown in Table 1 [8][9][10].…”

“…Thus, ALS has a wide range of survival duration. Most ALS is a sporadic disorder (around 70-80%) and hardly distinguished from a family history case (around 10-20%) [2,[11][12][13][14][15]. The most common familial ALS cases include mutation of the chromosome 9 open reading frame 72 (C9orf72, present in 7.7% of ALS cases), followed by Cu/Zn-superoxide dismutase 1 (SOD1, 2.0%), never in mitosis A (NIMA)related kinase 1 (NEK1, 1.8%), TAR DNA binding protein (TARDBP) (1.4%), and kinesin family member 5A ( KIF5A, 0.8%) [11].…”

Corrected speciation and gyromitrin content of false morels linked to ALS patients with mostly slow-acetylator phenotypes

“…The present finding that gyromitrin-rich false morels were eaten by subjects who subsequently developed ALS raises public health concerns and, in regard to the etiology of sporadic neurodegenerative disease, important questions on the molecular mechanisms that might underpin long-latency, tardive neurotoxicity. While properly focused on environmental exposure to hydrazinic substances—whether in nature or synthetic [ 25 ]—it is also important to understand the role of any genetic susceptibilities, notably acetylation status [ 28 ], which employs the enzyme arylamine N -acetyltransferase 2 (NAT2) to regulate the duration of endogenous exposure to xenobiotics. NAT2 genetic variability determines whether subjects are slow, intermediate or fast acetylators [ 4 , 15 ].…”

Presymptomatic geographical distribution of ALS patients suggests the involvement of environmental factors in the disease pathogenesis

“…Some anecdotal reports have also described unexpected geographic occurrences of ALS [ 37 ]. For instance, conjugal cases have been repeatedly described [ 37 – 39 ], despite spouses are likely to share many exposures beyond their residency.…”

“…Some anecdotal reports have also described unexpected geographic occurrences of ALS [ 37 ]. For instance, conjugal cases have been repeatedly described [ 37 – 39 ], despite spouses are likely to share many exposures beyond their residency. In 1974, it was reported that three unrelated patients living within one block developed the disease within a short time from each other [ 40 ].…”