eMedicine Specialties > Neurology > Neuromuscular Diseases

Amyotrophic Lateral Sclerosis

Author: Carmel Armon, MD, MSc, MHS, Professor of Neurology, Tufts University School of Medicine; Chief, Division of Neurology, Baystate Medical Center
Contributor Information and Disclosures

Updated: Jun 29, 2009

Introduction

Background

Amyotrophic lateral sclerosis (ALS) is the most common neurodegenerative disease of the motor neuron system. In its classic form, it affects motor neurons at 2 or more levels supplying multiple regions of the body. It affects lower motor neurons that reside in the anterior horn of the spinal cord and in the brain stem; corticospinal upper motor neurons that reside in the precentral gyrus; and, frequently, prefrontal motor neurons that are involved in planning or orchestrating the work of the upper and lower motor neurons.1

Loss of lower motor neurons leads to progressive muscle weakness and wasting (atrophy). Loss of corticospinal upper motor neurons may produce stiffness (spasticity), abnormally active reflexes, and pathological reflexes. Loss of prefrontal neurons may result in special forms of cognitive impairment that include, most commonly, executive dysfunction, but may also include an altered awareness of social implications of an individual’s circumstances and, consequently, maladaptive social behaviors.2 In its fully expressed forms, the prefrontal dysfunction meets established criteria for frontotemporal dementia.3,4 See eMedicine article Frontotemporal Dementia.

The classic form of sporadic ALS usually starts as dysfunction or weakness in one part of the body and spreads gradually within that part and then to the rest of the body. Ventilatory failure results in death, on average, 3 years after the onset of focal weakness. ALS is also known as motor neurone disease (MND), Charcot’s disease, and Lou Gehrig disease.

The term classic amyotrophic lateral sclerosis is reserved for the form of disease that involves upper and lower motor neurons. If only lower motor neurons are involved, the disease is called progressive muscular atrophy (PMA). Although many patients with PMA have a course indistinguishable from that of classic ALS, others have a course that may be longer. When only upper motor neurons are involved, the disease is called primary lateral sclerosis (PLS). (See eMedicine article Primary Lateral Sclerosis.) The course of PLS is different from that of ALS, and is usually measured in decades. Rarely, the disease is restricted to bulbar muscles, and called progressive bulbar palsy (PBP). Most patients who present with initial involvement of bulbar muscles evolve to classic ALS.

Worldwide, ALS occurs sporadically in 90-95% of cases and with Mendelian patterns of heredity (familial ALS [FALS]) in 5-10% of cases. Most familial ALS is inherited in an autosomal dominant pattern.1 Approximately 20% of cases with familial ALS are due to a mutation in the Cu, Zn superoxide dusmutase 1 (SOD1) gene; however, its phenotype is of lower motor neuron disease.5 More than 100 mutations in the SOD1 gene have been reported. In the United States, 50% of mutant SOD1 ALS patients have an alanine-to-valine mutation in codon 4 of the gene (A4V mutation); their survival is on average 12 months from disease onset.6

Three Western Pacific foci of increased incidence have been found in Guam, in western New Guinea, and in the Kii peninsula in Japan.1

Pathophysiology

In 2006, ubiquinated inclusions containing pathologic forms of TAR DNA-binding protein-43 (TDP-43) were identified in the cytoplasm of motor neurons of patients with sporadic ALS and in a subset of patients with frontotemporal dementia.7,8 TDP-43 is an RNA processing protein. It is normally found mainly in the nucleus. Shortly after their identification, TDP-43 positive inclusions were identified in patients with non-SOD1 FALS9,10 , and mutations in the gene on chromosome 1 coding for TDP-43 were identified in patients with sporadic and familial ALS11,12,13,14,15,16 .

Mutations in the TDP-43 gene account for 5% of patients with FALS. TDP-43 inclusions have been found in more than 90% of patients with sporadic ALS, in patients with Guamanian parkinsonism-dementia complex17 and in patients with familial British dementia.18 A review of the continuum of multisystem TDP-43 proteinopathies concluded that the phenotypic expression is linked to the specific cells that are affected by the proteinopathy.19

In February of 2009, 2 groups20,21 reported that mutations in the gene for another RNA processing protein, fused in sarcoma/translated in liposarcoma (FUS/TLS) (located on chromosome 16), cause ALS-6, an autosomal dominant form of FALS. Patients with the FUS/TLS mutations have cytoplasmic inclusions containing FUS/TLS but not TDP-43. Usually, FUS/TLS is concentrated in the nucleus. Mutations in FUS/TLS account for 4% of patients with FALS. These observations have placed derangements of RNA metabolism at the core of current thinking with regard to the pathophysiology of most types of ALS.

Prior to the recent observations implicating TDP-43 and FUS/TLS pathology in ALS, much of the information had been derived from studies in transgenic mice carrying the human SOD1 mutation.22 Mutant SOD1 exerts its effect through “gain of function” (ie, toxicity that is not related to loss of its natural activity). Oxidative damage, mitochondrial dysfunction, caspase-mediated cell death (apoptosis), defects in axonal transport, growth factor expression, glial cell pathology, and glutamate excitotoxicity may all mediate the pathways, causing cell death in ALS.22

Inferences from animal models, including transgenic models of familial disease, to sporadic human disease are tenuous, at best. However, recognition of the role of glutamate excitotoxicity in sporadic disease and in animal models paved the way to the testing and approval of riluzole, the only treatment that has been shown to ameliorate the course of sporadic ALS, extending life by 2-3 months.23,24

In contrast to these advances in understanding the pathophysiology of ALS, the mechanisms that lead to disease onset, which may be distinguished by use of term pathogenesis, remain unknown.

Assuming that the abnormal gene or gene product plays a role in triggering disease onset in FALS and may have a role in disease propagation is reasonable. However, having an abnormal gene is neither a necessary nor a sufficient condition for developing ALS since not all familial gene carriers develop the disease and the normalcy of these genes does not prevent development of sporadic ALS. Additional factors must be postulated to intervene between birth and disease onset even in patients with FALS who develop the disease, because the disease does not appear to start at birth. ALS should not be considered a single disease entity, but rather a clinical diagnosis for different pathophysiological cascades that share the common consequence that they cause preferential progressive loss of motor neurons.

Making the distinction between pathogenesis and pathophysiology matters because the mechanisms underlying each of these stages are probably different, and, therefore, interfering with those mechanisms likely requires different approaches. Prevention of ALS requires modifying or removing factors that are part of disease pathogenesis. A precondition is identifying probable risk factors for ALS.25  Mechanism-specific treatments directed at the processes that cause the disease to evolve after it has expressed itself sufficiently to be diagnosed may, at best, have an ameliorative effect. Treatments that halt the spread of the disease may be more effective than those that try to salvage affected motor neurons. Adaptive treatments directed at the clinical manifestations of the disease are the mainstay of contemporary treatment of ALS. The author has hypothesized that acquired nucleic acid changes trigger disease onset in sporadic ALS.26

Loss of motor neurons bridges disease pathophysiology and its clinical expression. When advanced, this results in the characteristic picture seen in a cross section of the spinal cord. At the level of the muscle, loss of discrete lower motor neurons results in loss of innervation of individual motor units. Early in the disease, surviving nerve fibers establish connections and reinnervate motor units that have lost their connection to axons that have died; as a result, larger motor units are formed. These large motor units manifest in histological stains as type grouping (see Media file 3). They also have special characteristics on electromyographic testing. Later in the disease, when the motor neurons that supply the large motor units die, group atrophy ensues.


Muscle in nerve disease. Image courtesy of Dr. Fr...

Muscle in nerve disease. Image courtesy of Dr. Friedlander, Associate Professor and Chair of Pathology at Kansas City University of Medicine and Biosciences.

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Muscle in nerve disease. Image courtesy of Dr. Fr...

Muscle in nerve disease. Image courtesy of Dr. Friedlander, Associate Professor and Chair of Pathology at Kansas City University of Medicine and Biosciences.


As long as reinnervation can keep up with denervation, clinical weakness may not be detectable. However, as the motor units grow larger and as their number starts to decrease, the earliest consequence is that affected muscle may fatigue faster than muscle with normal motor units; consequently, one of the first symptoms of ALS may be fatigability of function in the region of onset (for example, “his speech got muffled toward the end of his sermons”). As the number of motor units innervating a muscle decreases further, reinnervation is not able to keep up with denervation, permanent weakness develops and progresses, and the affected muscles gradually shrivel (atrophy). In general, loss of cortical neurons may result also in weakness, but more commonly in ALS it results in other upper motor neuron signs. One of the most subtle signs may be mild loss of dexterity. See Clinical for further discussion of the clinical features of ALS.

Frequency

United States

The incidence of ALS in populations of European descent is approximately 2 per 100,000 population per year. The lifetime risk for developing ALS for individuals aged 18 years has been estimated to be 1 in 350 for men and 1 in 420 for women.27 These estimates are close to those reported from 2 European databases, using different methods.28,29

Average disease duration from clinical onset is 3 years. Therefore, disease prevalence is estimated at 6 per 100,000 population.

International

European, age-adjusted incidence data are similar to those in the US population of European descent.28 Most variability between countries has been attributed to different age composition or differences in case finding. However, recent data suggest that there may be ethnic variability in disease incidence30,31 that may not be explained entirely by differences in case finding, with lower incidence in nonwhites or individuals of mixed ethnicity. This area merits further study.

Mortality/Morbidity

  • Average disease duration from clinical onset to death is 3 years.
  • Younger onset age and limb onset are favorable prognostic factors.
  • Some ALS variants have a more extended course.
  • Some forms of familial ALS have a course that is faster than average, and some have a course slower than average.

Race

In the United States, ALS affects whites more often than nonwhites; the white-to-nonwhite ratio is 1.6:1.30 Uncertainty surrounds this finding; is it true or due to reduced case-finding in non-whites. See also International.

Sex

Men are affected more frequently than women. The male-to-female ratio is approximately 1.5:1.0.1

Age

The incidence of ALS increases with age. Average age of onset is 65 years. Different series report peak incidence in those aged 75-85 years, but whether the peak is a true peak or due to less complete case findings in older patients is uncertain.

Clinical

History

ALS may be suspected whenever an individual develops loss of function or gradual, slowly progressive, painless weakness in 1 or more regions in the body, without changes in the ability to feel, and no other cause immediately evident. ALS is more likely to be suspected based on clinical presentation alone when the disease is more widespread, (ie, when more parts of the body are involved, and when upper and lower motor neuron signs are present together in more regions of the body). When the disease has progressed far in its course and involves many parts of the body, it may be possible to make the diagnosis based on the way the patient looks and on the findings on the neurologic examination. However, when a patient presents with the first symptoms, making the diagnosis is not straightforward.2

Physical

The symptoms that some patients with ALS may experience and the signs that are found on their neurologic examination are summarized below. Not all patients experience all symptoms or have all signs. While the symptoms of motor dysfunction are best recognized, affecting all patients with ALS, a fair proportion of patients also experience emotional and special cognitive difficulties that are part of the disease. These difficulties may adversely affect the patients’ ability to plan and relate appropriately to others. Their interactions with caregivers and their willingness to accept treatment recommendations are impaired, and their prognosis is worse than of unaffected patients.2

  • Upper or lower motor neuron dysfunction
    • Weakness (However, classic ALS weakness is usually due to lower motor neuron dysfunction or loss)
    • Muscle cramps
    • Difficulties with speech and swallowing
    • Unsteadiness
  • Upper motor neuron dysfunction
    • Stiffness (spasticity)
    • Tendon reflexes which are brisk or spread abnormally
    • Presence of abnormal reflexes
    • Loss of dexterity in the presence of normal strength
  • Lower motor neuron dysfunction
    • Twitching muscles (fasciculations)
    • Reduction of muscle bulk (atrophy)
    • Foot drop
    • Breathing difficulties
  • Emotional symptoms
    • Involuntary laughing or crying
    • Depression
  • Special cognitive changes

Diagnosis of ALS

The World Federation of Neurology (WFN) has developed an algorithm that combines the clinical findings and, in some cases, electrophysiologic findings, to express in each patient the degree of involvement by ALS at the time of the examination (the El Escorial criteria).32 The WFN uses adjectives that in usual speech imply a degree of certainty. However, when these criteria are applied to patients with ALS, the adjectives need to be understood as reflective of the degree of clinical involvement, particularly if no alternative diagnosis has been found and the disease has progressed out of a single limb.
 
For the diagnosis of ALS, the WFN criteria require all of the following:

  • Evidence of upper motor neuron findings 
  • Evidence of lower motor neuron findings
  • Evidence of progression (within the site of onset and beyond the site of onset)

Alternative causes for this presentation and findings need to be excluded.
 
For the purpose of applying the WFN criteria, 4 regions or levels of the body are recognized (see Media file 1):2

  • Bulbar - Muscles of the face, mouth, and throat
  • Cervical - Muscles of the back of the head and the neck, shoulders, and upper back, and the upper extremities
  • Thoracic - Muscles of the chest and abdomen and the middle portion of the spinal muscles
  • Lumbosacral - Muscles of the lower back, groin, and lower extremities


The 4 regions or levels of the body. Bulbar (musc...

The 4 regions or levels of the body. Bulbar (muscles of the face, mouth, and throat); cervical (muscles of the back of the head and the neck, the shoulders and upper back, and the upper extremities); thoracic (muscles of the chest and abdomen and the middle portion of the spinal muscles); lumbosacral (muscles of the lower back, groin, and lower extremities)

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The 4 regions or levels of the body. Bulbar (musc...

The 4 regions or levels of the body. Bulbar (muscles of the face, mouth, and throat); cervical (muscles of the back of the head and the neck, the shoulders and upper back, and the upper extremities); thoracic (muscles of the chest and abdomen and the middle portion of the spinal muscles); lumbosacral (muscles of the lower back, groin, and lower extremities)

The qualifying term possible is applied to the diagnosis of ALS when both upper and lower neuron involvement at one level is seen. The term laboratory-supported probable ALS is used when upper motor neurons are involved at one level and electrophysiologic evidence of lower motor neurons are involved in more than 1 limb. The qualifying term probable is applied when upper and lower motor neuron involvement is seen at 2 levels, and the term definite ALS is used when the involvement is at 3 or more levels of the body. If something other than ALS can be explained for the patient’s symptoms and findings, then these terms do not apply.

Recently, a group of experts proposed to revise the WFN criteria further, primarily by giving equal weight to clinical and electrophysiologic evidence of denervation.33 However, even when there is no uncertainty, this system still retains use of the term probable ALS, which denotes uncertainty. There are other differences between this system and the previous one, and for now the author believes forgoing the use of the revised WFN criteria is premature.32  

Patients with a family history of Mendelian ALS are considered to have definite ALS as soon as any evidence of motor neuron disease arises that cannot be accounted for by an alternative explanation, regardless of the extent of involvement.
 
Patients with definite, probable, and laboratory-supported probable ALS are considered eligible for inclusion in clinical trials of disease-modifying treatments. Most patients with possible ALS progress to more extensive disease, but because it is not possible to predict who will not progress, they have not been included in clinical trials.
 
The term suspected ALS is given special meaning in the WFN classification system. The term is applied to patients with a pure upper motor neuron presentation, particularly if it is too early to diagnose them with primary lateral sclerosis, and to patients with a pure lower motor neuron presentation (particularly early in their presentation) if there is uncertainty if they will remain pure lower motor neuron and thus might be diagnosed more precisely as having progressive muscular atrophy.
 
From a practical standpoint, patients with primary lateral sclerosis have a course that is measured in decades (approximately 20 y). See eMedicine article Primary Lateral Sclerosis. Some patients with a predominantly upper motor neuron form of ALS may have a longer course than those with classical ALS.34
 
Most patients with progressive muscular atrophy have a course indistinguishable from that of patients with classical ALS (except for the absence of upper motor neuron findings). Some patients may have a longer course, particularly those with "flail arm" or "flail leg" syndromes.35 Since the distinction between a diagnosis of PMA and laboratory-supported possible ALS hinges on the identification of 1 upper motor neuron sign, at some point in the patient’s disease, this distinction may prove to be of greater significance to researchers than to clinicians and patients, for whom rate of progression is the factor that determines the patients’ course and outcome.
 
Patients with progressive bulbar palsy (PBP) may be classified while the disease is restricted to the bulbar region as suspected ALS if only upper or lower motor abnormalities are evident, and as possible ALS if there is upper and lower involvement. When neurophysiologic or clinical spread beyond the bulbar level is evident, the condition would be reclassified as probable, laboratory-supported probable, or definite ALS.

In day-to-day practice, clinicians will inevitably use the term suspected ALS whenever they suspect ALS, regardless of the extent of clinical involvement at the time, and may or may not use the WFN qualifiers when they conclude that the patient has the disease.

Causes

Sporadic amyotrophic lateral sclerosis

The causes of sporadic ALS are considered to be unknown, but we are getting closer to understanding them. Interactions between genetic, environmental, and age-dependent risk factors have been hypothesized to trigger disease onset.

Malignant biochemical transformation hypothesis. ...

Malignant biochemical transformation hypothesis. Risk factors operate up-stream to a putative malignant biochemical transformation, which causes the appearance of endogenous ALS-specific toxins. These putative toxins spread, behaving like a metastasizing biochemical malignancy, and cause the downstream biochemical, histologic and clinical consequences of ALS. (Adapted from Armon C. ALS: Clinical and Epidemiologic Clues to Pathogenesis. In: Neurobiology of ALS. Course Syllabus, 51st Annual Meeting. American Academy of Neurology, 1999.)

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Malignant biochemical transformation hypothesis. ...

Malignant biochemical transformation hypothesis. Risk factors operate up-stream to a putative malignant biochemical transformation, which causes the appearance of endogenous ALS-specific toxins. These putative toxins spread, behaving like a metastasizing biochemical malignancy, and cause the downstream biochemical, histologic and clinical consequences of ALS. (Adapted from Armon C. ALS: Clinical and Epidemiologic Clues to Pathogenesis. In: Neurobiology of ALS. Course Syllabus, 51st Annual Meeting. American Academy of Neurology, 1999.)


There are theoretical reasons to hypothesize that genetic risk factors may influence disease initiation in sporadic ALS with a non-Mendelian pattern of inheritance. Supporting this hypothesis is the observation of increased frequency of non-ALS neurodegenerative diseases in relatives of patients with ALS, suggesting a shared genetic predisposition.36,37 However, a methodologically superior population-based study in incident cases38 did not confirm excess non-ALS neurodegenerative disease in relatives of patients with ALS. Genome wide analyses looking for allelic variations have produced some loci of interest, but different series have tended to identify different loci.39,40 The lack of reproducibility suggests that non-Mendelian patterns of inheritance may have a more limited role than had been expected in triggering sporadic ALS, possibly increasing the lifetime risk by no more than 50%.

Several possible ways exist to try to make sense of the epidemiological data with regard to exogenous risk factors for ALS. Of them, application of an evidence-based approach is most likely to lead to reliable conclusions25 because it considers the evidence-worthiness of each information source, acts as a sieve separating the wheat from the chaff, and allows only information generated using the most rigorous methods available to influence conclusions. The level of certainty in the conclusions is made explicit and is linked in a transparent manner to the quality of the evidence supporting it.

The American Academy of Neurology recently developed evidence-based criteria that infers causation from epidemiologic data. Its first report using these criteria was published in April 2009.41 A more conservative approach separates the process of evaluating the relation of epidemiologic data to occurrence of disease into 3 steps: (1) to seek credible associations; (2) to determine if an association is identifying a risk factor (rather than a confounder, a surrogate, or a consequence of a joint risk factor); and (3) to determine if the risk factor is causal. The reason for this approach is that "association is not causation"42 but rather the first step in identifying a possible risk factor. Furthermore, even an established risk factor is not automatically a cause. 

The approach advocated by Hill43 exemplifies this type of caution, even as he himself indicated that absolute criteria for inferring causality are difficult to establish. Exceptions can be found to most of the criteria he proposed44 , except for the requirement that cause needs to precede effect (temporality). In the case of ALS, putative causes need to precede not only clinical onset, but also biologic onset that may occur several years before the first clinical symptoms emerge. The author’s preference25 was to focus the analysis of epidemiologic data first on identifying credible risk factors and deal with issues of causation separately. 

Applying this evidence-based approach to the analysis of the epidemiological data25,45 , smoking is the only exogenous risk factor that is probably (more likely than not) associated with ALS (Level of Evidence B, 2 Class II studies46,47 and 2 Class III studies48,49 ). Other lower class studies (Class IV, V) show divergent results, reflecting their methodologic limitations, and do not detract from this conclusion. No other risk factor has attained this level of certainty regarding its association with ALS. Trauma, physical activity, residence in rural areas and alcohol consumption are probably not risk factors for ALS (Level B conclusion25 ).

Three putative risk factors that have gained recent attention include service in the US military, deployment to the Persian Gulf in the First Persian Gulf War, and being an Italian soccer player. However, close scrutiny generates doubts about the quality of the evidence supporting their role in triggering ALS.

ALS was established as a presumptive compensable illness by the Secretary of the US Department of Veterans’ Affairs on September 23, 2008.50 This decision was based on a 2006 Institute of Medicine (IOM) committee report that concluded that "limited and suggestive" evidence showed association between military service and later development of ALS.51 In the IOM system of classifying possible associations between risk factors and disease, use of the term limited and suggestive evidence for an association reflects a stronger endorsement of the possibility of association than the terms inadequate or insufficient evidence to determine whether an association exists or limited and suggestive evidence of no association, but a weaker endorsement than would be reflected by use of the terms sufficient evidence for an association or sufficient evidence for a causal association. 

The IOM system of evaluating data appears to be less rigorous than the author’s evidence-based system.25 Using an evidence-based approach to analyze the same data, the author concluded that the data are insufficient to infer even a possible association, due to the methodological limitations of the studies and the conflicting information they provide. For example, one study suggested an increased risk of ALS associated with military service during World War II, the Korean War, and Vietnam.52 It was an exploratory study in an existing database that was likely not representative of the general population; overall mortality from ALS was not excessive in this database; military service was one of many risk factors evaluated; the numbers were small; and there was no adjustment for the increased possibility that chance alone may result in an apparent statistically significant finding when many comparisons are conducted simultaneously (Class IV Evidence).

In contrast, a prospective study in a contemporary cohort of veterans53  that alleged an increased risk of ALS associated with deployment to the Persian Gulf in the first Gulf War (see discussion below) showed no overall increased incidence of ALS associated with contemporary military service (Class I Evidence).54 In an evidence-based framework, higher quality evidence (Class I Evidence) would trump lower quality evidence (Class IV Evidence). Thus, while the author is pleased that US veterans will be supported by the Department of Veterans’ Affairs if they are diagnosed with ALS, the determination of eligibility does not establish the state of the science.

Two reports of increased risk of ALS due to deployment to the Persian Gulf in the first Gulf War were published simultaneously.53,55 The soundness of the methods used in each study individually was questioned, based on the published reports, suggesting that their conclusions should not be accepted at face value.56,57 The chief critique was that underestimation of the cases expected (or counted) in nondeployed personnel resulted in the observed numbers appearing excessive.

The estimates of ALS cases expected in nondeployed veterans varied between the 2 reports, further suggesting that they could not both be correct. Furthermore, the initial public concern was for excess occurrence of ALS in individuals younger than 45 years, but the greatest excess of cases of ALS in deployed individuals seemed to have occurred in individuals aged 45-54 years, of whom 6 developed ALS. The reason for the qualified tone is that the numerators and denominators were not presented up front. These small numbers seemed to drive the entire appearance of excess in deployed individuals. Selective under-ascertainment in the nondeployed group was confirmed in part by the original authors53 when they analyzed their data further58 .

An article published independently by authors affiliated with the United States Department of Veterans' Affairs and the United Kingdom Ministry of Defense59 appears to validate this critique.56 . The privileged position of its authors, which seems to have given them full access to relevant data beyond what was published,53 lends additional weight to their comments. The article states, "…the findings of the ALS study53 have had to be qualified by 2 considerations:

(i) the results could have been influenced by ascertainment bias because they were based on just seven additional cases of ALS among Gulf War veterans in a study of 2.5 million participants; and
(ii) the mortality rate of Gulf War veterans due to ALS has not yet been found to be elevated."

Not only was this information not circulated widely at the time of the original report53 , but it appeared in a publication that is not read by most neurologists, and awareness of it is not reflected in the IOM report.51

Moreover, the increase has not persisted over time60 leading the authors to conclude that this was a point epidemic. Whether this is a plausible explanation is unclear, because an exogenous biologic factor causing relatively early excess clinical occurrence of ALS (which ordinarily has a long preclinical period of biologic activity) without a delayed latency effect is without precedent. The sobering aspect of the story lies in the gap between the reverberations generated by the original reports and the silence engulfing the information, which suggests a more conservative interpretation of the findings. The most encouraging aspect is that there no longer appears to be any reason for veterans deployed to the Persian Gulf in the First Gulf War to fear that they are at increased risk of developing ALS.

Reports of an increased risk of ALS in Italian soccer players61,62 also may have been due to underestimation of the expected number of cases of ALS, which led to the appearance that the observed number of cases was excessive.27 The subsequent discussion63,64 provided an opportunity to affirm the validity of the critique65,66 . However, the appearance of preferential presentation of cases with bulbar onset in this population61,62,67 merits attention, even if no increased incidence is shown overall. In that regard, a recent report of an upper motor neuron phenotype in young Italian male patients68 is of great interest.

Other putative exogenous risk factors25,69 , also have not risen to the level of probable.

Familial ALS

Of ALS cases, 5-10% are familial with a Mendelian pattern of inheritance.70 The disease is transmitted in an autosomal dominant fashion in most cases and is rarely autosomal recessive. Mean age at onset is 10-20 years younger in patients with FALS than in patients with sporadic disease, and variability between families is greater than variability within families.1 While some cases of FALS are indistinguishable from sporadic disease, others have unique phenotypes.70

The copper/zinc SOD1 gene is mutated in 10-20% of familial cases. SOD1-ALS is a lower motor neuron form of the disease. More than 140 allelic variations have been seen in the SOD1 mutants, and they determine the mean age of onset and rate of disease progression. The most common SOD1 mutation in the US is the A4V mutation, accounting for 50% of SOD1 patients. It causes rapidly progressive lower motor disease with mean survival of 1 year. The North American SOD1 A4V mutation descended from 2 founders (Amerindian and European) 400-500 years ago.6

Not all patients with an SOD1 mutation develop ALS. SOD1 ALS has been shown to be a gain-of-function disease; knockout mice who are depleted of SOD1 do not develop ALS, and transgenic mice with 1 mutated gene and 2 normal genes have worse disease than those with 1 normal and 1 mutated gene. Misfolding and precipitation of the abnormal (and normal) SOD1 proteins are thought to be part of the pathophysiology of SOD1 ALS, but why the disease begins when it does, and how it causes the lower motor neuron ALS phenotype is not clear.

Recent work in animal models suggests that silencing from birth the expression of mutant SOD1 using silencing RNA molecules (siRNA) may prevent disease onset in transgenic mouse models.71 This is an exciting direction for research in humans with the SOD1 mutations, but major barriers need to be overcome first, including demonstrating that this approach is effective in halting the disease after its clinical onset. Additional forms of familial ALS are summarized elsewhere.70

Abnormal genes resulting in abnormalities in proteins that regulate RNA metabolism have been discovered in patients with autosomal dominant familial ALS. Mutations in TDP-43 have been found in 5% of patients with FALS.9,10,11,12,13,14,15,16 Mutations in the FUS/TLS gene have been found in 3-4% of patients with FALS.20,21

The mechanism by which these mutations cause ALS is distinct from that which takes place in the SOD1 mutants. Although ubiquinated pathological TDP-43 aggregates have been found in motor neuron cytoplasm of sporadic ALS, they are not specific for this disease and have been found in affected nonmotor cells in patients with Guamanian parkinsonism-dementia complex17 , British familial dementia18 , and Alzheimer disease.72 Thus, formation of pathological TDP-43 and its ubiquination may prove to be a mechanism of cell death that is not specific to ALS and is triggered by upstream processes, causing clinical pathology that depends on the cells affected.

Western Pacific amyotrophic lateral sclerosis

Most of the research on Western Pacific ALS has focused on Guam. Ingestion of food products derived from the false sago palm Cycas micronesica (recently separated from Cycas Circinalis) was proposed by Marjorie Whiting as the process implicated in predisposing to the development of this form of ALS.73 A recent epidemiologic study in Guam appears to have confirmed that hypothesis74 ; its conclusions have been challenged,75 but the challenges themselves have been questioned.76

The nature of the precise toxic component of cycad responsible for delayed-onset neurodegenerative disease has also been a matter of intense debate. One hypothesis is that excitotoxic components of cycad exert a delayed effect many years after they have been ingested, but not at the time of ingestion.77,78 An alternative hypothesis is that alkylating components induce changes in nucleic acids79,80 that increase the likelihood that subsequent, additional, age-dependent nucleic acid changes trigger disease onset in Guamanian ALS/PDC.

Linking risk factors to triggering of amyotrophic lateral sclerosis onset

The author has hypothesized that acquired nucleic acid changes may trigger disease onset in sporadic ALS.26 This hypothesis relies on the observation that smoking is the only probable risk factor for sporadic ALS and provides a mechanism by which smoking might cause the disease, namely, by induction of changes in nucleic acids. It follows a similar logic that suggests that the alkylating components in the cycad are responsible for delayed onset of Western pacific ALS/PDC.79,80

In support of this hypothesis, recent work by Ravits et al has shown the simultaneous initial involvement of cortical and spinal motor neurons responsible for the same body part in ALS and the independent spread of disease at spinal and cortical levels.81 These observations establish the existence of one or more "agents of spread" and the irrefutable role of corticospinal neurons in the early spread of the disease.82 The affirmation of spread substantiates the concept of a biological focal onset to ALS. This in turn lends credibility to the concept of a focal trigger to ALS onset that generates the production of one or more agents of spread.26

Under his hypothesis, disease phenotype in each patient depends on the site of onset and the relative affinity of the specific agent of spread in that patient to motor neurons at the different hierarchical levels of the motor system (prefrontal, corticospinal, spinal/bulbar).82 The concept of preferential affinity of the agent of spread may apply even to specific motor neurons within a given hierarchy, resulting, for example, in the special predominantly lower motor neuron phenotypes (flail arm syndrome, flail leg syndrome).35

Most of the biochemical changes found in lower and upper motor neurons of diseased patients are probably downstream from those that initiate the disease and cause its spread. Some of these changes may represent the processes by which the motor neurons die, but others may reflect the efforts of the motor neurons to survive, by compensating for the primary pathological processes driving progression of ALS.

More on Amyotrophic Lateral Sclerosis

Overview: Amyotrophic Lateral Sclerosis
Differential Diagnoses & Workup: Amyotrophic Lateral Sclerosis
Treatment & Medication: Amyotrophic Lateral Sclerosis
Follow-up: Amyotrophic Lateral Sclerosis
Multimedia: Amyotrophic Lateral Sclerosis
References
Further Reading
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References

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  2. Armon C. ALS 1996 and Beyond: New Hopes and Challenges. A manual for patients, families and friends. Fourth Edition. California: Published by the LLU Department of Neurology, Loma Linda; 2007:[Full Text].

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Further Reading

  • ALS Association, Living With ALS Manuals
  • Muscular Dystrophy Association: MDA ALS Caregiver’s Guide  
  • Brown Jr, RH, Swash M, Pasinelli P, eds. Amyotrophic Lateral Sclerosis. 2nd Edition. Informa Healthcare,
2006.
  • Mitsumoto H, Przedborski S, Gordon PH, eds. Amyotrophic Lateral Sclerosis. Taylor and Francis. 2006.
  • Miller RG, Gelinas D, O'Connor P. Amyotrophic Lateral Sclerosis. AAN Press. Demos 2004.

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Keywords

amyotrophic lateral sclerosis, ALS, Lou Gehrig disease, Lou Gehrig's disease, Charcot disease, Charcot's disease, motor neuron disease

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Contributor Information and Disclosures

Author

Carmel Armon, MD, MSc, MHS, Professor of Neurology, Tufts University School of Medicine; Chief, Division of Neurology, Baystate Medical Center
Carmel Armon, MD, MSc, MHS is a member of the following medical societies: American Academy of Neurology, American Academy of Sleep Medicine, American Association of Neuromuscular and Electrodiagnostic Medicine, American Clinical Neurophysiology Society, American College of Physicians, American Epilepsy Society, American Medical Association, American Neurological Association, American Stroke Association, Massachusetts Medical Society, Movement Disorders Society, and Sigma Xi
Disclosure: Nothing to disclose.

Medical Editor

Donald B Sanders, MD, EMG Laboratory Director, Professor of Medicine (Neurology), Division of Neurology, Duke University Medical Center
Donald B Sanders, MD is a member of the following medical societies: American Academy of Neurology, American Association of Neuromuscular and Electrodiagnostic Medicine, American Neurological Association, and New York Academy of Sciences
Disclosure: Nothing to disclose.

Pharmacy Editor

Francisco Talavera, PharmD, PhD, Senior Pharmacy Editor, eMedicine
Disclosure: eMedicine Salary Employment

Managing Editor

Neil A Busis, MD, Chief, Division of Neurology, Department of Medicine, Head, Clinical Neurophysiology Laboratory, University of Pittsburgh Medical Center-Shadyside
Neil A Busis, MD is a member of the following medical societies: American Academy of Neurology and American Association of Neuromuscular and Electrodiagnostic Medicine
Disclosure: Nothing to disclose.

CME Editor

Selim R Benbadis, MD, Professor, Director of Comprehensive Epilepsy Program, Departments of Neurology and Neurosurgery, University of South Florida School of Medicine, Tampa General Hospital
Selim R Benbadis, MD is a member of the following medical societies: American Academy of Neurology, American Academy of Sleep Medicine, American Clinical Neurophysiology Society, American Epilepsy Society, and American Medical Association
Disclosure: Nothing to disclose.

Chief Editor

Nicholas Y Lorenzo, MD, Chief Editor, eMedicine Neurology; Consulting Staff, Neurology Specialists and Consultants
Nicholas Y Lorenzo, MD is a member of the following medical societies: Alpha Omega Alpha and American Academy of Neurology
Disclosure: Nothing to disclose.

 
 
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