Elsevier

Neurologic Clinics

Volume 29, Issue 3, August 2011, Pages 689-711
Neurologic Clinics

Amyotrophic Lateral Sclerosis: What Role Does Environment Play?

https://doi.org/10.1016/j.ncl.2011.06.001Get rights and content

Section snippets

Disease overview

Amyotrophic lateral sclerosis (ALS) is a disorder of progressive upper and lower motor neuron degeneration and was initially described by Charcot in 1874.1 Lower motor neuron loss manifests as weakness, muscular atrophy, and fasciculations, whereas brisk muscle stretch reflexes, clonus, motor dyscontrol, and Babinski signs reflect upper motor neuron disease. Sensory and autonomic systems are spared. Now the evidence also suggests frontal executive deficits in half of patients with ALS and frank

Heavy metals and trace elements

Because of clinical similarities between some heavy metal poisoning cases and ALS, and also because of the correlation of certain trace elements with clusters of motor neuron disease, early importance was placed on investigation of these factors. Callaghan and colleagues26 reviewed the relevant literature regarding metal exposures and the risk of developing ALS and found that many different metals have been implicated in ALS. However, metals either have inconclusive, conflicting, or

Toxins/chemicals/solvents

The incidence of ALS in the western Pacific region was far higher than elsewhere worldwide and remains increased today. Therefore, reports of clusters of ALS cases in a particular household, geographic location, workplace, or occupation promote speculation concerning common environmental factors afflicting particular populations or geographic locales. Both a husband and wife may develop ALS. Because reports of conjugal ALS remain rare, this occurrence probably reflects the combined odds of both

Gulf War service

A decade after the end of the 1990 to 1991 Persian Gulf War, 2 studies observed an increased incidence of ALS in military personnel with deployment to the Persian Gulf region. Horner and colleagues95 derived an increased relative risk (RR) for all deployed personnel (RR, 1.92; 95% CI, 1.29, 2.84), deployed active duty military (RR, 2.15; 95% CI, 1.38, 3.36), deployed Air Force members (RR, 2.68; 95% CI, 1.24, 5.78), and deployed Army troops (RR, 2.04; 95% CI, 1.10, 3.77). Subgroup analyses

Infections

One prominent early theory concerning the cause of ALS was that of an underlying viral agent causing the disease directly, indirectly, or in a latent state. An early case-control study found a history of polio in 5 of 80 patients with ALS, and none of 78 controls.32 However, large case-control studies failed to find any association between previous polio infection and ALS risk,110 and a review of the epidemiologic literature came to the same determination. Detection of enterovirus nucleic acid

Neoplasms

Patients with ALS may also develop cancer. An association between lymphoma and a lower motor neuron disorder has been reported. Some cases present signs of classic ALS with evidence of upper and lower motor neuron disease.130 Patients with other cancers also manifest ALS-like symptoms.131 Infrequently, patients who initially present with PLS and breast cancer eventually develop both upper and lower motor neuron dysfunction.132 Motor neuron disease may also be a manifestation of a paraneoplastic

Electrical shock and electromagnetic fields

Instances of myeloradiculopathy as a delayed neurologic consequence of electrical injuries spurred conjecture as to the association of electrical trauma and ALS.136 Two case-control studies from the 1980s described a greater association of electrical injury in patients with ALS compared with controls.37, 137 A nationwide Danish mortality study conducted a comparison of all men employed in utility companies from 1900 to 1993 and compared them with national death rates for different causes. This

Physical factors

Physical exertion, participation in athletics, bodily trauma, bone fractures, and surgeries have all been posited to be antecedent events more common in patients with ALS than in controls. Famous athletes have developed ALS, and their popularity may highlight this association in peoples’ minds despite no true association or causation. However, this prominence of athletes in a culture’s collective mind has led to use of the term Lou Gehrig's disease for ALS in the United States. Possible

Diet

Ingestion of certain foods, toxins associated with foods, or toxins within foods might predispose to development of ALS. In Texas, Felmus and colleagues31 found that consumption of large quantities of milk was associated with patients with ALS.32 As a prominent source of calcium, milk might affect absorption or body stores of heavy metals and could alter parathyroid function. Parathyroid disease causes weakness, exercise intolerance, and muscle atrophy, but is now known not to be associated

Western Pacific ALS

Three foci in the western Pacific, Guam, the Kii Peninsula of Japan, and western New Guinea, were determined to have markedly increased rates of ALS in the middle of the last century.157 In the 1940s and 1950s, the annual incidence rates for the Chamorro natives on the island of Guam were 50 per 100,000, with incidence rates in certain municipalities or districts as high as 250 per 100,000.158 These Guamanian ALS incidence rates were as much as 100-fold increased compared with age-adjusted

Education/socioeconomic status

Levels of education or socioeconomic status have only infrequently been studied as risk factors for ALS. Two case-control studies showed inconsistent findings.35, 38 A large population-based study showed a lack of association between social class of patients with ALS and controls.35 An older case-control study performed between 1964 and 1982 showed a low level of education to be associated with an increased risk of ALS.38 Other epidemiologic studies have suggested both an increased risk of ALS

Summary

Environmental exposures in sporadic ALS remain mostly associations without causation. More than 20 genetic loci are known to be responsible for cases of familial motor neuron disease. Research into sporadic ALS suggests that numerous factors may be contributory in the disease process, but a singular cause and unifying pathogenesis remain elusive. A multitude of genetic, toxic, autoimmune, infectious, and systemic processes may be at play in ALS, similar to muscle diseases, neuromuscular

First page preview

First page preview
Click to open first page preview

References (176)

  • T. Tanridag et al.

    Motor neuron degeneration due to aluminum deposition in the spinal cord: a light microscopical study

    Acta Histochem

    (1999)
  • T. Kihira et al.

    ALS-like skin changes in mice on a chronic low-Ca/Mg high-Al diet

    J Neurol Sci

    (2004)
  • H. Nagata et al.

    Heavy metal concentrations in blood cells in patients with amyotrophic lateral sclerosis

    J Neurol Sci

    (1985)
  • J.S. Parboosingh et al.

    Absence of mutations in the Mn superoxide dismutase or catalase genes in familial amyotrophic lateral sclerosis

    Neuromuscul Disord

    (1995)
  • L.P. Rowland et al.

    Amyotrophic lateral sclerosis

    N Engl J Med

    (2001)
  • C. Lomen-Hoerth et al.

    Are amyotrophic lateral sclerosis patients cognitively normal?

    Neurology

    (2003)
  • P.N. Leigh et al.

    Motor neuron disease

    J Neurol Neurosurg Psychiatry

    (1994)
  • V. Govoni et al.

    Incidence of amyotrophic lateral sclerosis in the local health district of Ferrara, Italy, 1964-1998

    Neuroepidemiology

    (2003)
  • A.M. Chancellor et al.

    Adult onset motor neuron disease: worldwide mortality, incidence and distribution since 1950

    J Neurol Neurosurg Psychiatry

    (1992)
  • B.R. Brooks et al.

    World Federation of Neurology Research Group on Motor Neuron Diseases. El Escorial revisited: revised criteria for the diagnosis of amyotrophic lateral sclerosis

    Amyotroph Lateral Scler Other Motor Neuron Disord

    (2000)
  • W.J. Triggs et al.

    Transcranial magnetic stimulation identifies upper motor neuron involvement in motor neuron disease

    Neurology

    (1999)
  • M. Sach et al.

    Diffusion tensor MRI of early upper motor neuron involvement in amyotrophic lateral sclerosis

    Brain

    (2004)
  • R.K. Olney et al.

    Statistical motor unit number estimation: reproducibility and sources of error in patients with amyotrophic lateral sclerosis

    Muscle Nerve

    (2000)
  • G. Bensimon et al.

    A controlled trial of riluzole in amyotrophic lateral sclerosis

    N Engl J Med

    (1994)
  • T. Siddique et al.

    Linkage analysis in familial amyotrophic lateral sclerosis

    Neurology

    (1989)
  • D.R. Rosen et al.

    Mutations in copper/zinc superoxide dismutase gene are associated with familial amyotrophic lateral sclerosis

    Nature

    (1993)
  • T. Siddique et al.

    Genetic aspects of amyotrophic lateral sclerosis

  • D. Majoor-Krakauer et al.

    Genetic epidemiology of amyotrophic lateral sclerosis

    Clin Genet

    (2003)
  • Neuromuscular Disease Center Website. Hereditary Motor Syndromes Page. St Louis (MO): Washington University. Available...
  • A. Al-Chalabi et al.

    Recessive amyotrophic lateral sclerosis families with the D90A SOD1 mutation share a common founder: evidence for a linked protective factor

    Hum Mol Genet

    (1998)
  • T. Ratovitski et al.

    Variation in the biochemical/biophysical properties of mutant superoxide dismutase 1 enzymes and the rate of disease progression in familial amyotrophic lateral sclerosis kindreds

    Hum Mol Genet

    (1999)
  • A.G. Reaume et al.

    Motor neurons in Cu/Zn superoxide dismutase-deficient mice develop normally but exhibit enhanced cell death after axonal injury

    Nat Genet

    (1996)
  • C.T. Jones et al.

    Superoxide dismutase mutations in an unselected cohort of Scottish amyotrophic lateral sclerosis patients

    J Med Genet

    (1995)
  • M. Jackson et al.

    Copper/zinc superoxide dismutase 1 and sporadic amyotrophic lateral sclerosis: analysis of 155 cases and identification of a novel insertion mutation

    Ann Neurol

    (1997)
  • I. Puls et al.

    Mutant dynactin in motor neuron disease

    Nat Genet

    (2003)
  • B. Callaghan et al.

    The association of exposure to lead, mercury, and selenium and the development of amyotrophic lateral sclerosis and the epigenetic implications

    Neurodegener Dis

    (2011)
  • S.A. Wilson

    The amyotrophy of chronic lead poisoning – amyotrophic lateral sclerosis of toxic origin

    Rev Neurol Psychiatry

    (1907)
  • D. Mishra et al.

    Distal spinal muscular atrophy of upper limb (Hirayama disease) associated with high serum lead levels

    Indian Pediatr

    (2003)
  • B. Livesley et al.

    Chronic lead intoxication mimicking motor neurone disease

    BMJ

    (1968)
  • J.A. Boothby et al.

    Reversible forms of motor neuron disease: lead “neuritis”

    Arch Neurol

    (1974)
  • M.T. Felmus et al.

    Antecedent events in amyotrophic lateral sclerosis

    Neurology

    (1976)
  • R. Pierce-Ruhland et al.

    Repeat study of antecedent events in motor neuron disease

    Ann Clin Res

    (1981)
  • R.A. Roelofs-Iverson et al.

    ALS and heavy metals: a pilot case-control study

    Neurology

    (1984)
  • C. Armon et al.

    Epidemiologic correlates of sporadic amyotrophic lateral sclerosis

    Neurology

    (1991)
  • A.M. Chancellor et al.

    Risk factors for motor neuron disease: a case-control study based on patients from the Scottish Motor Neuron Disease Register

    J Neurol Neurosurg Psychiatry

    (1993)
  • F. Fang et al.

    Association between blood lead and the risk of amyotrophic lateral sclerosis

    Am J Epidemiol

    (2010)
  • D.M. Deapen et al.

    A case-control study of amyotrophic lateral sclerosis

    Am J Epidemiol

    (1986)
  • E. Granieri et al.

    Motor neuron disease in the province of Ferrara, Italy, in 1964-1982

    Neurology

    (1988)
  • V. McGuire et al.

    Occupational exposures and amyotrophic lateral sclerosis: a population-based case-control study

    Am J Epidemiol

    (1997)
  • S. Conradi et al.

    Increased plasma levels of lead in patients with amyotrophic lateral sclerosis compared with control subjects as determined by flameless atomic absorption spectrophotometry

    J Neurol Neurosurg Psychiatry

    (1978)
  • Cited by (39)

    • Alcohol consumption and the risk of amyotrophic lateral sclerosis

      2019, Neuroscience of Alcohol: Mechanisms and Treatment
    • Identification of risk factors associated with onset and progression of amyotrophic lateral sclerosis using systematic review and meta-analysis

      2017, NeuroToxicology
      Citation Excerpt :

      Therefore, the discussion below seeks primary to establish how likely it is for the risk factors for ALS onset identified in our analyses to be causal, as systematic review per se cannot be used to determine causality between risk factors and ALS. Exposure to heavy metals has been shown to increase the risk of ALS (Sutedja et al., 2009a,b; Johnson and Atchison, 2009; Ahmed and Wicklund, 2011; Vinceti et al., 2012; Iwami et al., 1994; Mitchell, 1987; Mitchell et al., 1991; Valentine et al., 2005; Trumbull and Beckman, 2009; Bowman et al., 2011; Caban-Holt et al., 2005). The most widely studied heavy metals in ALS patients are lead and mercury, both of which have been shown to be neuron toxicants in in vitro or in vivo studies, and to have accumulated in neural tissues (Kurlander and Patten, 1979).

    • Stem cells for ALS: An overview of possible therapeutic approaches

      2017, International Journal of Developmental Neuroscience
      Citation Excerpt :

      It was also shown that work and home exposure to some chemicals, such as pesticides and fertilizers, appears to be greater in ALS cases as compared to control groups matched for age and gender (Yu et al., 2014). In addition, the increased risk of ALS is associated with lifestyle factors, such as smoking, diet, history of trauma and intense physical activity (Ahmed and Wicklund, 2011). The relationship between the genetic predisposition and environmental influence indicates the involvement of epigenetic factors in the pathogenesis of ALS.

    • Expression of microRNAs in human post-mortem amyotrophic lateral sclerosis spinal cords provides insight into disease mechanisms

      2016, Molecular and Cellular Neuroscience
      Citation Excerpt :

      Thus, identification of the molecular mechanisms underlying ALS is critical to support effective therapy development. Evidence suggests that environmental exposures, physical stress, and altered immunity may promote epigenetic changes and contribute to ALS (Ahmed and Wicklund, 2011; Callaghan et al., 2011; Qureshi and Mehler, 2013). Epigenetic mechanisms, including DNA methylation, histone remodeling, and microRNAs (miRNAs), reversibly regulate gene expression without altering the basic genetic code (Qureshi and Mehler, 2011).

    • DNA Methylation in Neurodegenerative Diseases

      2016, Epigenetic Biomarkers and Diagnostics
    • Endocannabinoids and amyotrophic lateral sclerosis

      2015, Cannabinoids in Neurologic and Mental Disease
    View all citing articles on Scopus

    The views expressed herein are those of the authors. The authors have no external sources of funding to report.

    View full text