Epidemiology and pathogenesis of amyotrophic lateral sclerosis

INTRODUCTION — Amyotrophic lateral sclerosis (ALS), first described by Charcot in the 19^th century [1], is a relentlessly progressive, presently incurable neurodegenerative disorder that causes muscle weakness, disability, and eventually death. ALS is also known by the eponym "Lou Gehrig's disease," after the famous baseball player who was affected with the disorder. "Motor neuron disease" (MND) is the preferred term in the United Kingdom, but in the United States ALS and MND are sometimes used interchangeably.

The epidemiology and pathogenesis of ALS are discussed in this topic review. Other aspects of ALS are discussed separately.

●(See "Clinical features of amyotrophic lateral sclerosis and other forms of motor neuron disease".)

●(See "Diagnosis of amyotrophic lateral sclerosis and other forms of motor neuron disease".)

●(See "Disease-modifying treatment of amyotrophic lateral sclerosis".)

●(See "Symptom-based management of amyotrophic lateral sclerosis".)

EPIDEMIOLOGY — ALS is classified as either sporadic or familial:

●Sporadic forms account for 90 to 95 percent of ALS cases.

●Familial forms make up 5 to 10 percent of cases. (See "Familial amyotrophic lateral sclerosis".)

Incidence and prevalence — Incidence rates for ALS in Europe and North America range between 1.5 and 4.7 per 100,000 person-years, while prevalence rates range between 2.7 and 7.4 per 100,000 person-years [2-7]. In the United States, rates of ALS are higher among White individuals compared with those from other racial/ethnic groups [5,6,8]. Similarly, a systematic review of global epidemiologic data concluded that the incidence of ALS may be higher among White individuals than in other populations [9]. However, firm conclusions were precluded by the methodologic variation among studies.

The male-to-female ratio is approximately 1.3 to 1.5 for sporadic ALS, although the ratio becomes closer to unity in the age group over 70 years. The incidence of ALS increases with each decade, especially after age 40 years, and it peaks at age 74, decreasing thereafter [2,6]. In a systematic review, the peak incidence of ALS onset fell between 60 and 75 years in the majority of studies [10]. In the United States, approximately 7000 new cases of ALS are diagnosed each year.

The incidence and mortality rates of ALS have been slowly increasing over decades [11-13]. Part or all of this increase in ALS incidence may be due to longer life expectancy [14].

Risk factors — The only well-established risk factors for ALS are age and family history. Accumulating evidence suggests that cigarette smoking is also a risk factor for ALS [15-19]. The role of genetic variation in the pathogenesis of sporadic ALS is reviewed below. (See 'Genetic susceptibility in sporadic ALS' below.)

There are weaker or conflicting data for other putative risk factors, a list that includes military service, agricultural work, factory work, heavy manual labor, exposure to pesticides, exposure to welding or soldering, exposure to heavy metal, work in the plastics industry, repetitive muscle use, athleticism, playing professional football or soccer, trauma, electrical shock, low-frequency magnetic fields, early-onset alopecia, decreased premorbid body fat, and a diagnosis of polymyositis [20-42].

Paradoxically, other data suggest that mortality from ALS is increased among people with higher socioeconomic occupations (eg, education, computers and mathematics, law, and architecture and engineering) where exposure to toxins is unlikely, while ALS mortality is decreased among people with lower socioeconomic occupations (eg, mining and drilling, construction, farming, fishing, and forestry) where exposure to toxins is more likely [43].

Some studies suggest potential links between alterations of the gut microbiome and ALS that could provide opportunities for therapeutic intervention [44,45].

Despite reports of exposure to mercury, lead, and aluminum in ALS cases [21,26], the role of heavy metal exposure in the etiology of ALS remains controversial [27-29]. No convincing case of lead toxicity mimicking ALS has been reported in several decades [27].

The possible role of environmental exposure as an ALS trigger is supported by the finding that the incidence of ALS in young United States Gulf War veterans is approximately twofold higher than expected [31,32]. The risk ratio for developing ALS was statistically significant in Army and Air Force veterans, while a trend toward increased risk for veterans of the Reserves, National Guard, Marines, and Navy did not reach statistical significance, possibly because of the relatively small number of subjects in those branches. Despite the higher incidence among Gulf War veterans, no common link was identified among potential exposures or activities in veterans who developed ALS. Because ALS is a relatively rare disease, the strength of these findings is reduced by the small number of cases and potential methodologic flaws [46].

A subsequent, large cohort study of males (median age 57 years at cohort entry in 1982) found that United States military veterans had an increased death rate from ALS compared with non-veterans (adjusted relative risk 1.58, 95% CI 1.14-2.19) [33]. As with previous studies, this higher incidence seemed independent of the branch of the military in which subjects served, except for the Marines, a subgroup with a small number of subjects. The increased risk of death from ALS was similar in veterans who served in the military during World War II, Korea, or Vietnam. There was no association between risk for developing ALS and the number of years served in the military. This result argues against a specific environmental trigger related to the Gulf War being a cause of ALS, since the association with ALS in the larger cohort study was largely independent of the time period of military service.

The potential risk factors that military personnel would share over the many decades of military service studied are numerous and include inhalation of aerosolized lead used in vehicle finishing operations, exposure to the pesticide DEET, traumatic injuries, viral infections, and intense physical activity. However, none of these are established as risk factors, and confirmation of these factors awaits further study.

Genetic susceptibility in sporadic ALS — Variations in a number of genes and loci appear to be associated with ALS susceptibility [47]. The list includes known or suspected familial ALS genes, such as pathogenic variants in the SOD1, TARDBP, C9ORF72, FUS, ANG, OPTN, SETX, and SQSTM1 genes, and others not associated with familial ALS, such as variants in the TBK1 [48], ATXN2 [49], C21ORF2 [50], ITPR2 [51], NEK1 [52], and TP73 genes [53] and duplications in the SMN1 gene [54].

In a 2017 meta-analysis of 111 studies that evaluated the frequencies of genetic variants of the most common ALS-related genes (C9ORF72, SOD1, TARDBP, and FUS), there was a difference in the rates between European and Asian populations with sporadic ALS, as illustrated by the following observations [55]:

●In European populations, C9ORF72 repeat expansions were the most common (5.1 percent), followed by SOD1 variants (1.2 percent), TARDBP variants (0.8 percent), and FUS variants (0.3 percent).

●In Asian populations, SOD1 variants were the most common (1.5 percent), followed by FUS variants (0.9 percent), C9ORF72 repeat expansions (0.3 percent), and TARDBP variants (0.2 percent).

An earlier study found that rare or novel coding variants in known ALS genes, potentially pathogenic though not proven to be, were present in 28 percent of subjects with sporadic ALS, while variants in more than one ALS gene were found in 4 percent [56]. Thus, these genes may function as Mendelian genes in familial ALS or as low-penetrance susceptibility factors in sporadic ALS. (See "Familial amyotrophic lateral sclerosis".)

Some of the candidate genes for ALS are associated with other neurodegenerative disorders:

●Expanded polyglutamine repeats in ATXN2 are better known as the cause of spinocerebellar ataxia type 2 (SCA2). One issue is that occasional patients with SCA2 have a predominant phenotype of motor neuron disease (MND), and further study is needed to establish whether ATXN2 polyglutamine expansions are a risk factor for ALS [57]. (See "Autosomal dominant spinocerebellar ataxias", section on 'SCA2'.)

●The SMN gene is better known for its role in spinal muscular atrophy, a disease of neonatal or childhood onset characterized by degeneration of the anterior horn cells in the spinal cord and motor nuclei in the lower brainstem. (See "Spinal muscular atrophy".)

●The huntingtin (HTT) gene is known for its role in Huntington disease, a neurodegenerative disorder associated with dementia and choreiform movements. Pathogenic expansions in the HTT gene have been observed in a small number of patients with ALS with frontotemporal dementia (ALS-FTD) [58].

Familial ALS — Familial ALS accounts for 5 to 10 percent of all ALS cases [59], with the rest being sporadic (idiopathic) in origin. Familial ALS is phenotypically and genetically heterogeneous. This topic is discussed separately. (See "Familial amyotrophic lateral sclerosis".)

Geographic clusters — High prevalence clusters of ALS are found in three regions of the western Pacific including Guam, West New Guinea, and the Kii Peninsula in Japan. The first cluster described was found in the indigenous people of Guam [60,61]. The frequent association of ALS with parkinsonism and Alzheimer disease in this population has led to the designation of this entity as the amyotrophic lateral sclerosis-parkinsonism dementia complex (ALS-PDC).

Although intensively studied since World War II, the cause of Guamanian ALS-PDC is unknown. One hypothesis proposed that the neurotoxicity was mediated by the local dietary consumption of cycad (Cycas circinalis) [62]. Cycad is rich in beta-N-methylamino-L-alanine (BMAA), an excitatory amino acid that has been shown to induce neuronal cell death in the rhesus monkey [62]. Another hypothesis proposed that human consumption of the local flying fox, an animal that forages on the cycad, may have generated sufficiently high and cumulative levels of the neurotoxin to cause ALS-PDC. This hypothesis was supported by data demonstrating that the incidence of ALS-PDC on Guam fell significantly and in parallel with the loss of population of the flying fox [63]. However, many remain unconvinced that cycad ingestion is the cause of Guamanian ALS [64]. No single genetic defect, environmental toxin, or virus has been convincingly linked to these cases.

PATHOLOGY

Motor neuron degeneration — ALS is characterized by motor neuron degeneration and death with gliosis replacing lost neurons. Cortical motor cells (pyramidal and Betz cells) disappear, leading to retrograde axonal loss and gliosis in the corticospinal tract. This gliosis results in the bilateral white matter changes sometimes seen in the brain magnetic resonance imaging (MRI) of patients with ALS. The spinal cord becomes atrophic. The ventral roots become thin, and there is a loss of large myelinated fibers in motor nerves. The affected muscles show denervation atrophy with evidence of reinnervation such as fiber type grouping.

Cerebral and other pathologic findings — Additional pathologic findings may include a loss of frontal or temporal cortical neurons, particularly in ALS with frontotemporal dementia (ALS-FTD). Mounting evidence from pathologic and genetic studies has led to the hypothesis that similar molecular pathways are involved in both disorders. (See "Familial amyotrophic lateral sclerosis", section on 'C9ORF72 gene' and "Frontotemporal dementia: Epidemiology, pathology, and pathogenesis", section on 'Genetic factors'.)

Loss of nonmotor neurons whose axons contribute to the descending fronto-ponto-cerebellar tract has been reported [65]. Pathology in nonmotor systems such as the posterior columns may be seen in familial forms of ALS. (See "Familial amyotrophic lateral sclerosis".)

While sensory involvement is not obvious clinically, the density of myelinated sensory fibers is reduced by approximately 30 percent in peripheral nerves [66].

Intracellular inclusions — Intracellular inclusions in degenerating neurons and glia are frequent neuropathological findings of ALS.

●Phosphorylated and nonphosphorylated neurofilament inclusions are prominent in spinal motor neurons; these may be associated with immunoreactive SOD1, even in sporadic ALS, or with nitric oxide.

●Bunina bodies are unique to ALS and consist of eosinophilic aggregates that are positive for cystatin C, a cysteine protease inhibitor.

●Ubiquitinated inclusions are seen in ALS and several other neurodegenerative disorders, including FTD with ubiquitin positive/tau negative inclusions, but the ALS variety is unique in that it does not react with antibodies against neurofilament or tau. In both the familial or sporadic types of ALS-FTD, frontal and temporal lobe ubiquitinated inclusions are found in cortical neurons. Inclusions may be absent in some genetic forms of familial ALS [67].

●TDP-43 accumulation and inclusion formation (ie, TDP-proteinopathy) is observed in most sporadic cases of ALS, FTD with ubiquitin-positive but tau-negative inclusions (see "Frontotemporal dementia: Epidemiology, pathology, and pathogenesis", section on 'FTLD-TDP'), and overlapping ALS with FTD [68,69]. In addition, TDP-43 neuronal cytoplasmic inclusions are found in familial ALS (see "Familial amyotrophic lateral sclerosis") related to pathologic variants in a number of genes, which include the TARDBP gene that encodes for TDP-43, the VAPB gene, the CHMP2B gene, and to a lesser extent the C9ORF72 gene; in postmortem tissue from patients with C9ORF72 gene variants, TDP-43-positive inclusions appear to be less common than TDP-43-negative inclusions containing ubiquitin [70]. However, TDP-43 inclusions are not found in SOD1-related familial ALS, with a few exceptions [71,72]. These findings suggest a potentially important role for TDP-43 in the pathogenesis of ALS, non-SOD1 ALS, ALS-FTD, and non-tau FTD. (See 'Altered RNA processing' below.)

●Immunoreactive inclusions to FUS in spinal motor neurons have been detected in both sporadic and familial ALS, with the exception of those associated with SOD1 variants [73,74]. Earlier studies had not detected FUS-positive immunoreactive inclusions in patients with ALS except for those who had FUS variants.

ETIOLOGY — The etiology of ALS is unknown. A number of potential mechanisms have been proposed including abnormal RNA processing, disorders of protein quality control, excitotoxicity, cytoskeletal derangements, mitochondrial dysfunction, viral infections, apoptosis, growth factor abnormalities, inflammatory responses, and others [75].

Altered RNA processing — Mounting evidence supports the hypothesis that altered RNA processing and aggregation of abnormal proteins plays a major role in the pathogenesis of ALS [76-79]. Variants in a number of genes that encode for RNA binding proteins, including TDP-43 and FUS, are known to cause ALS (see "Familial amyotrophic lateral sclerosis") and related neurodegenerative disorders. These proteins contain prion-like domains that have an intrinsic propensity to self-aggregation [80]. They may normally function by assembling RNA into stress granules, which are temporary structures that help to regulate protein synthesis as part of the stress response [81]. Variants in the prion-like domains of these proteins may promote excess incorporation of the proteins into stress granules that are resistant to degradation, and/or promote self-aggregation of abnormal RNA binding proteins (such as TDP-43), thereby leading to the formation of cytoplasmic inclusions (see 'Intracellular inclusions' above) and neurodegenerative disease. TDP-43 also normally functions by repressing the splicing of nonconserved regions of the genome known as cryptic exons [82]. Depletion or aggregation of TDP-43 permits the splicing of cryptic exons into messenger RNA, which disrupts translation and leads to cell death [83,84].

The co-localization of TDP-43 and FUS in non-SOD1 ALS inclusions also supports the hypothesis that these DNA/RNA binding proteins are involved in the pathogenesis of non-SOD1 forms of ALS. In vitro studies indicate that abnormal TDP-43 polypeptides have greater stability than those of the wildtype TDP-43 [85], rather than lesser stability as occurs with abnormal SOD1 protein. In addition, abnormal TDP-43 shows enhanced binding to normal FUS/TLS. These findings imply that abnormal TDP-43 may disrupt normal FUS/TLS function and suggest a convergence of their pathogenic mechanisms in ALS [85]. The TDP-43 and FUS proteins are normally found predominantly in the nucleus, where they are involved in RNA processing [76,77]. Wildtype TDP-43 and FUS are transported to the nucleus by nuclear import receptors. However, variant forms of TDP-43 with C-terminal truncations lack the nuclear transport signal, causing mislocalization of the protein to the cytoplasm. Similarly, ALS-associated FUS variants impair nuclear transport and result in mislocalization to the cytoplasm. In sporadic ALS, aging may cause an accelerated increase in nuclear permeability and leakiness, with wildtype TDP-43 and FUS accumulating in the cytoplasm. The accumulation of TDP-43 and FUS in the cytoplasm may lead to neurodegeneration by disturbing the RNA quality control regulation or by the formation of stress granules (figure 1).

The ALS susceptibility factor ataxin 2 (see 'Genetic susceptibility in sporadic ALS' above), a constituent of stress granules and a putative RNA binding protein, may interact in the common pathologic pathway formed by TDP-43 and FUS (figure 2) [76]. By contrast, the pathologic process related to SOD1 variants (see 'SOD1-mediated toxicity' below) may be independent of the TDP-43 and FUS pathologic cascade.

C9ORF72 expansions — Expansion of a hexanucleotide repeat sequence in a noncoding region of the C9ORF72 gene is the most common genetic cause of familial ALS and is also detected in occasional patients with sporadic ALS. Several mechanisms may account for the disease-causing effect of the genetic variant [86]:

●The hexanucleotide repeat is made up of guanine-rich sequences, (GGGGCC)n, which can fold to form a secondary structure called a G-quadruplex [87]. One hypothesis is that expansion of the hexanucleotide repeat sequence and G-quadruplex formation initiates a cascade of pathologic molecular alterations. These include formation of RNA/DNA hybrids called R-loops; production of abortive, defective RNA transcripts; and decreased production of full-length RNA transcripts. The defective RNA transcripts bind to a number of ribonucleoproteins including nucleolin, causing mislocalization of this essential protein within the nucleolus and leading to decreased cell viability. The C9ORF72 hexanucleotide repeat expansion also interacts with Ran GTPase activating protein 1, which is an important regulator of nucleocytoplasmic transport, and may disrupt nucleocytoplasmic transport by clogging the nuclear membrane pores [88,89].

●Another hypothesis is that repeat-associated non-ATG translation (RAN translation) occurs within the expanded repeat sequence, leading to the production of toxic dipeptide repeat proteins that are aggregation prone and can interfere with multiple steps of RNA processing [90-92].

●The expansion may lead to reduced expression of C9ORF72 protein levels, causing disease by a loss-of-function mechanism [93-95].

While not mutually exclusive, the contribution of each of these proposed mechanisms remains to be determined [86,96].

SOD1-mediated toxicity — Superoxide dismutase type 1 (SOD1) is a metalloenzyme that catalyzes the conversion of toxic superoxide radicals to oxygen (O₂) and hydrogen peroxide (H₂O₂). The discovery that variants in the SOD1 gene are associated with some cases of familial ALS suggested that free radical toxicity may play a role in the process of neuronal cell death or apoptosis [97]. In addition, SOD1 variants have been found in 0.7 to 4 percent of patients with "sporadic" ALS [98,99]. (See 'Familial ALS' above.)

Gain-of-function — Damaging accumulation of superoxide could result if SOD1 variants impaired its antioxidant function. However, several lines of evidence from cell culture and transgenic SOD1 mouse models of ALS have disproved the loss-of-function hypothesis [100,101]. As an example, SOD1-knockout mice do not develop motor neuron disease (MND) [101].

It is more likely that SOD1 pathogenic variants cause disease by a toxic gain-of-function [102]. SOD1 has pro-oxidant as well as antioxidant activity, and the variant SOD1 protein could lead to oxidative injury by an increase in pro-oxidant pathways, including generation of hydroxyl radicals and nitration of tyrosine. In support of the toxic gain-of-function hypothesis, there is evidence that abnormal SOD1 directly stimulates NADPH oxidase (Nox) in transgenic mice and in human cell lines, and thereby causes overproduction of reactive oxygen species [103,104].

It has also been hypothesized that oxidation leads to post-translational modifications of wildtype SOD1 protein, causing it to misfold and thereby gain toxic properties similar to abnormal SOD1 [105]. This mechanism could then be the cause of the majority of cases of classic ALS, which lack SOD1 pathogenic variants.

Protein misfolding — Another hypothesis is that abnormal SOD1 induces protein aggregates that are potentially toxic to motor neurons [106,107].

However, accumulation of disulfide cross-linked aggregates of abnormal SOD1 protein may be a secondary manifestation of end-stage disease rather than a primary event in the pathogenesis of ALS [108]. This hypothesis is supported by a study in transgenic mice, which found that a number of pathologic abnormalities (eg, Golgi apparatus degradation, endplate denervation, reactive astrogliosis) occurred before the levels of aggregated forms of abnormal SOD1 increased [108]. Elevated levels of abnormal SOD1 protein were observed only in the final stages of the disease.

Nevertheless, very low levels of SOD1 aggregates may be sufficient to mediate toxicity [108]. Another possibility is that other forms of SOD1 may be pathologic at early stages of disease. The initial step in the SOD protein assembly pathway is folding of the protein into a homodimeric apo state, and this apo-SOD1 protein is typically associated with severe instability in abnormal SOD1 proteins [109].

The conformational instability of ALS-linked SOD1 variants may be related to reductional cleavage of the disulfide bond that normally links two cysteine subunits (C57-C146), resulting in an increased propensity of the protein to unfold or misfold and aggregate [110]. More unstable and therefore short-lived variants unfold and become prone to aggregation. In mice, unfolded or misfolded disulfide-reduced SOD1 variants showed higher steady-state levels in the spinal cord and brain than in peripheral organs, suggesting inefficient recognition and degradation in the central nervous system (CNS) [110].

In a study that analyzed SOD1 from 29 patients with 22 different variants, lower levels (ie, greater instability) of abnormal SOD1 were associated with shorter disease survival time [111]. Thus, patients with less stable SOD1 who accumulate less abnormal protein have a more rapid disease course. However, levels of abnormal SOD1 were not associated with age at disease onset.

These results suggest that the misfolded unstable forms of SOD1 contribute to toxicity and disease progression but not directly to onset, implying different mechanisms of disease onset and progression [112]. Supporting this viewpoint is experimental evidence that suppressing abnormal SOD1 synthesis selectively in motor neurons delays onset of disease in mice expressing abnormal SOD1 [113].

Non-neuronal cell types influence disease — Data from ALS murine models and human ALS-induced pluripotent stem cells (iPSC) suggest that non-neuronal cells may also be involved in the pathogenesis of ALS [114-119]. Supporting evidence comes from studies in mice with abnormal SOD1 show that cell types besides motor neurons play a role in disease onset and progression [120-123]. In chimeric ALS mice, simple expression of the pathologic variant SOD1 in neurons/motor neurons was insufficient to lead to neuronal death without concomitant expression in glial cells. Wildtype motor neurons appeared to undergo degeneration when surrounded by abnormal SOD1 astroglia. Conversely, wildtype non-neuronal cells surrounding motor neurons expressing abnormal SOD1 extended the survival of such motor neurons [120] and increased disease-free life [124]. Likewise, the deletion of abnormal SOD1 from oligodendrocytes showed a protective effect on motor neurons and improved survival in animal models [123]. Other reports demonstrated that the reduction of abnormal SOD1 selectively from astrocytes in mice [122] or in microglia [125] resulted in a slowing of disease progression but had no effects on disease onset.

Inflammatory responses — A number of studies have shown that inflammatory processes are involved in ALS disease progression and neuronal death [125-132]. These inflammatory responses include activation of microglia and astrocytes as well as infiltration of natural killer cells, peripheral T cells, and monocytes into the CNS. Many of these reports have focused on microglia, which are immune-modulating cells of the CNS. Once activated, microglia elaborate a host of factors, including nitric oxide, oxygen radicals, cytokines, glutamate, and others that may play roles in part of the cascade leading to motor neuron cell death [125,133]. Several lines of evidence suggest that microglia are relevant to disease progression in ALS models [104,134,135].

Excitotoxicity — The excitotoxicity hypothesis postulates that excessive levels of the excitatory neurotransmitter glutamate may initiate a cascade resulting in cellular death of motor neurons in ALS. Excessive activation of glutamate receptors may lead to increased entry of calcium into cells. In turn, intracellular calcium may trigger a cascade of events that causes neuronal cell death via lipid peroxidation, nucleic acid damage, and mitochondrial disruption.

The role of excitotoxicity in ALS remains unsettled. In support of the excitotoxicity hypothesis is the finding of elevated glutamate levels in the cerebrospinal fluid of patients with sporadic ALS [136,137]. In addition, defects in glutamate transport that may contribute to excessive extracellular glutamate have been noted in 80 percent of patients with sporadic ALS and in the transgenic SOD1 mouse model of ALS [138-140]. These defects involve transmembrane glutamate transporters located on neurons and particularly on glial cells that are normally responsible for rapid inactivation of glutamate after its release.

One longstanding hypothesis suggests that nonfunctional, truncated forms of one glutamate transporter subtype (EAAT2), the primary glutamate transporter on astrocytes, may be particularly prominent in ALS tissues [138]. However, some of these truncated forms have also been found in normal tissue. Additionally, it appears that a splice-variant of this protein (EAAT2b) may actually be upregulated in ALS, particularly in neurons. These findings suggest that there may be a potential compensatory effect to increase other glutamate transporters in the presence of elevated extracellular glutamate [141].

Glutamate receptor dysfunction is another potential mechanism for excitotoxicity. A number of postsynaptic glutamate receptors may be involved in this process, including the N-methyl-D-aspartic acid (NMDA) receptor, the alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) receptor, the kainate receptor, and the G-protein-coupled receptor. As an example, defective editing of messenger RNA that encodes for a subunit of glutamate AMPA receptors has been found in spinal motor neurons of patients with ALS [142]. This glutamate editing defect has been linked to increased permeability to calcium ions through this AMPA receptor subtype and may result in downstream effects leading to neuronal death.

Perhaps some of the best evidence suggesting that glutamate excitotoxicity may have a role in ALS disease progression is the demonstration that the antiglutaminergic drug riluzole improves survival in patients with the disease. (See "Disease-modifying treatment of amyotrophic lateral sclerosis", section on 'Riluzole'.)

However, other drugs affecting glutamate neurotransmission have not been successful in clinical trials [143].

Cytoskeletal derangements — The intracellular neurofilament inclusions found within degenerating motor neurons may be involved in the pathogenesis of ALS [144,145]. Neurofilaments are a type of intermediate filament expressed at high levels by motor neurons, and they are formed by the assembly of light, medium, and heavy subunits. They normally function as structural elements that perform vital roles in maintaining cell shape, axonal caliber, and axonal transport.

Deranged neurofilaments could disrupt axonal transport and cause axonal strangulation [146]. Variants in the neurofilament heavy subunit gene have been found in sporadic and familial forms of ALS [147,148]. Reduction in the light subunit mRNA levels was detected in spinal motor neurons of ALS patients [149]. Overexpression or deletion of neurofilament subunits in transgenic mice resulted in motor neuron degeneration and axonal swellings with neurofilaments similar to those seen in ALS patients [146,150]. Intracellular neurofilament inclusions may be a potential biomarker in ALS, but whether they represent a cause or effect of neuronal degeneration remains uncertain [151,152].

Inhibition of axonal transport may be a cause of motor neuron degeneration. Defects in the dynein-dynactin complex, a molecular motor responsible for axonal transport along microtubules, have been linked with motor degeneration in the mouse [153], and a variant form of dynactin has been linked with a progressive lower motor neuron disorder in a human family [154,155].

Impaired microtubule dynamics have been widely implicated in neurodegeneration. While disruption of TDP-43 nuclear function affects the processing of numerous RNA targets, a link between increased motor neuron vulnerability in ALS and suppression of stathmin-2, a tubulin-binding protein previously established to affect microtubule dynamics, has been suggested as a possible common role for mechanisms of axon dysfunction in sporadic ALS [156,157].

Mitochondrial dysfunction — Mitochondrial dysfunction occurs early in the transgenic SOD1 mouse model, preceding other evidence of motor neuron damage [158]. Data suggest that a selective recruitment of abnormal SOD1 to spinal cord mitochondria, when compared with less affected tissues, may explain the abundant pathology in the spinal cord of the transgenic SOD1 mouse [159]. Human biochemical and morphologic studies demonstrate consistent mitochondrial abnormalities [160,161]. These abnormalities may be the result of oxidative stress and, in turn, may potentiate it.

Viral infections — Poliovirus, enteroviruses, and exogenous or inherited endogenous retroviruses have been proposed to be causative agents of ALS [162-166]. However, exhaustive studies have never confirmed a clear etiologic relationship. Human immunodeficiency virus (HIV) infection and Lyme disease rarely cause an ALS-like syndrome [167,168]. (See "Acute and early HIV infection: Clinical manifestations and diagnosis", section on 'Neurologic findings'.)

Apoptosis — Apoptosis or programmed cell death cascades have been implicated in several studies of the variant SOD1 mouse model of ALS. These reports have shown a number of the hallmarks of apoptosis including DNA fragmentation, caspase activation, and altered expression of the antiapoptotic protein Bcl-2 [106,169]. One report of 87 patients with sporadic ALS identified multiple variants in the TP73 gene [53]. These variants were associated with impaired normal cellular differentiation, increased apoptosis, and reduced motor neuron survival.

Some evidence suggests that apoptosis may be a late pathway for motor neuron degeneration in ALS, but its importance in ALS has been controversial [170,171]. However, one study found that genetic deletion of the mitochondrial apoptotic pathway in a mouse model of ALS halted neuronal loss and prevented axonal degeneration, symptom onset, and paralysis [172]. In addition, survival was extended. These findings suggest that inhibition of apoptosis is a possible therapeutic strategy for ALS.

Growth factors — Growth factors such as brain-derived neurotrophic factor (BDNF), ciliary neurotrophic factor (CNTF), insulin-like growth factor (IGF-1), and vascular endothelial growth factor (VEGF) have been studied previously both for their possible role in the etiology of ALS and for their therapeutic potential [173-180].

CLINICAL SPECTRUM OF DISEASE — Historically, ALS was identified as a clinical syndrome distinguishable from other motor neuron diseases (MNDs) such as primary lateral sclerosis, progressive muscular atrophy, and progressive bulbar palsy, based upon the location of first symptom and the extent to which anterior horn cells or corticomotor neurons are initially involved. However, it is increasingly evident that ALS is clinically and pathophysiologically diverse [181], with clear overlap with frontotemporal dementia (FTD) [182,183]. Multiple genetic variants may lead to a similar clinical phenotype, while a single variant may be associated with pure ALS, ALS with FTD (ALS-FTD), or pure FTD. These conditions exist on a clinicopathologic spectrum, with potentially different etiologies that share a final common pathway leading to upper and lower motor neuron degeneration. It is therefore appropriate to place ALS among other neurodegenerative diseases, such as Alzheimer disease, Parkinson disease, and Huntington disease. (See "Clinical features of amyotrophic lateral sclerosis and other forms of motor neuron disease", section on 'Spectrum of motor neuron disease'.)

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Motor neuron disease".)

SUMMARY

●Epidemiology – Amyotrophic lateral sclerosis (ALS) is classified as either sporadic or familial. Sporadic forms account for approximately 90 percent of ALS cases, while familial forms make up the remaining 10 percent. (See 'Epidemiology' above and "Familial amyotrophic lateral sclerosis".)

•Incidence rates for ALS in Europe and North America range between 1.5 and 2.7 per 100,000 person-years, while prevalence rates range between 2.7 and 7.4 per 100,000 person-years. The incidence of ALS increases with each decade, especially after age 40 years.

•The male-to-female ratio is approximately 1.3 to 1.5 for sporadic ALS, although the ratio becomes closer to unity in the age group over 70 years. (See 'Incidence and prevalence' above.)

●Risk factors – Established risk factors for ALS are age and family history. Cigarette smoking also appears to be a risk factor for ALS. There are weak or conflicting data for other nongenetic risk factors, a list that includes military service, agricultural work, factory work, heavy manual labor, exposure to welding or soldering, exposure to heavy metal, work in the plastics industry, repetitive muscle use, athleticism, playing professional soccer, trauma, and electrical shock. (See 'Risk factors' above.)

●Genetic susceptibilities – Several genes that act as Mendelian genes in familial ALS (SOD1, C9ORF72, FUS, TARDBP, ANG, OPTN, and SETX) may also be low-penetrance susceptibility factors in sporadic ALS. Expansions in the ATXN2 gene and duplications of the SMN1 gene are also associated with an increased risk of ALS. (See 'Genetic susceptibility in sporadic ALS' above.)

●Pathologic findings – ALS is characterized by motor neuron degeneration and death with gliosis replacing lost neurons. Degenerating neurons and glia show intracellular inclusions. (See 'Pathology' above.)

•Cortical motor cells (pyramidal and Betz cells) degenerate, leading to retrograde axonal loss and gliosis in the corticospinal tract.

•The spinal cord becomes atrophic. The ventral roots become thin, and there is a loss of large, myelinated fibers in motor nerves.

•The affected muscles show denervation atrophy with evidence of reinnervation such as fiber type grouping.

●Etiologies – The development of ALS appears to result from a complex interplay between genes and environmental factors that trigger several downstream biochemical cascades. Proposed mechanisms include abnormalities in RNA metabolism, SOD1-mediated toxicity, excitotoxicity, cytoskeletal derangements, mitochondrial dysfunction, viral infections, apoptosis, growth factor abnormalities, and inflammatory responses. (See 'Etiology' above.)