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    Tools & Reference>Neurology

    Amyotrophic Lateral Sclerosis (ALS)

    Updated: Sep 15, 2026
    • Author: Carmel Armon, MD, MSc, MHS; Chief Editor: Nicholas Lorenzo, MD, CPE, MHCM, FAAPL  more...
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    Overview

    Background

    Amyotrophic lateral sclerosis (ALS) is a progressive, fatal neurodegenerative disorder characterized by upper and lower motor neuron degeneration within the cortex, brainstem, and ventral spinal cord. [1, 2]  ALS is the most common degenerative disease of the motor neuron system. [3, 4] The disease is named for its underlying amyotrophy of muscle fibers and the sclerosis that it causes in the lateral columns of the spinal cord. [5, 6]  

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    Epidemiology

    Prevalence

    The annual incidence of ALS in the US is approximately 5.2-7.9 per 100,000 people. [2]  The worldwide annual incidence of ALS is estimated at 4.42 per 1,000,000 people. [2]  Approximately 5,600 people in the US are diagnosed with ALS each year. [2] 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. [7]

    Age-adjusted European incidence data are similar to those for members of the US population who are of European descent. [8, 9] Most variability between countries has been attributed to different age composition or differences in case findings. [10, 11, 12]

    Demographics

    In the US, the ALS White-to-non-White case ratio is approximately 1.6:1. [10]  Incidence of ALS is higher in men than in women, with an estimated male-to-female ratio of 1.5:1 to 2:1. [13] Later in life, the incidence tends to equalize; this occurs at age 40-50 years in some populations and after the age of 65-70 years in others. [7]

    The onset of ALS may occur from teenage years to the late 80s. [8, 14]  Incidence of ALS rises with increasing age until approximately age 75-80 years. [15] The mean age of onset of sporadic ALS is 65 years. [14] The mean age of onset of familial ALS ranges from 46-55 years. [14]

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    Etiology

    The etiology of amyotrophic lateral sclerosis (ALS) is defined as being either sporadic or familial in nature. Approximately 95% of ALS cases are classified as sporadic. [1, 2] An estimated 5% of ALS cases are classified as familial based on an autosomal dominant pattern of inheritance. [1, 2]

    The cause of sporadic ALS is thought to be driven by a complex convergence of genetic susceptibility, environmental exposures, and age-dependent pathways. Genetic risk factors may influence disease initiation in apparently sporadic ALS. [16]

    Increased risk for ALS, and clustering of non-ALS neurodegenerative disease, has been documented in relatives of patients with apparently sporadic ALS. [17, 18, 19, 20]  First-degree relatives of patients with apparently sporadic disease have an increased risk of ALS. The overall lifetime risk ratio of ALS in first-degree relatives is approximately 1 in 50. [17]

    The distinction between familial and sporadic disease is based on obtaining patient family history, which in turn depends on gene penetrance, family size, age of family members, and the level of knowledge of the person being interviewed. [21]

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    Pathophysiology

    The pathophysiology of amyotrophic lateral sclerosis (ALS) is a complex, multistep process characterized by the systematic breakdown of the motor neuron system. [1, 2] This course of the disease is driven by heterogeneous genetic, cellular, and molecular mechanisms. [1, 2]  ALS typically progresses within the area first affected and then to adjacent, contiguous regions. [1, 2] The pace of disease progression varies from patient to patient, and the symptoms depend on the muscles affected. [1, 2]

    Disease initiation and pathogenesis

    • Multistep initiation: the onset of amyotrophic lateral sclerosis (ALS) onset is a cumulative process (typically requiring 6 steps in sporadic forms, and fewer in genetic carriers with incomplete penetrance) likely originating within a cortical motor neuron. [22, 23, 24]
    • Triggering factors:  acquired somatic mutations (genetic mosaicism) or environmental exposures trigger onset. Cigarette smoking remains the only firmly established environmental risk factor, operating upstream via nucleic acid modifications. [25, 26, 27]

    Neuro-anatomical targets and manifestations

    ALS involves system-wide dismantling of the motor network across the following hierarchical levels:

    • Lower motor neuron (LMN) loss  (anterior horn/brainstem) causes progressive weakness, muscle wasting (atrophy), fasciculations, and loss of reflexes/muscle tone. [28, 13, 29, 30, 31]
    • Upper motor neuron (UMN) loss  (corticospinal/precentral gyrus) induces stiffness, severe spasticity, hyperreflexia, and milder weakness. [28, 13, 29, 30, 31]
    • Prefrontal loss  drives executive dysfunction, cognitive impairment, maladaptive social behaviors, and frontotemporal dementia (FTD). Premotor cell loss can also cause apraxia. [28, 13, 29, 30, 31]
    • Spared patterns  involve extraocular motor nerves (CN III, IV, VI), posterior columns, spinocerebellar tracts, and Onuf's nucleus (controlling bowel/bladder sphincters) are characteristically spared until late disease. Clarke's column is typically preserved, except in some familial forms. [28, 13, 29, 30, 31]

    Cellular pathways and axonal degeneration

    • Pathways to cell death  are mediated by glutamate excitotoxicity, oxidative stress, mitochondrial dysfunction, caspase-driven apoptosis, axonal transport defects, proteasome failure, and glial pathology. [32]  
    • Axonal pathology  involves large motor axons that undergo Wallerian degeneration secondary to anterior horn cell body death. [32] Schwann cells break down the myelin sheath into myelin ovoids, which are subsequently cleared by macrophages. [32]
    • Compensatory dynamics  are characterized by early denervation that triggers collateral sprouting and reinnervation, presenting histologically as fiber-type grouping and clinically as regional weakness. [32] Once reinnervation can no longer compensate, permanent muscle weakness and group atrophy ensue. [32]

    Molecular genetics and RNA metabolism

    • Protein propagation:  Regional symptoms spread via a focal, prion-like cell-to-cell transmission of misfolded proteins within the functional motor network. [33]
    • TDP-43 proteinopathy: TDP-43 is a nuclear-to-cytoplasmic mRNA transporter protein that misfolds and forms ubiquitinated cytoplasmic inclusions in ≥90% of sporadic and most non-SOD1 familial cases. [34, 35, 36, 37, 38, 39]  Depletion of nuclear TDP-43 downregulates stathmin-2 (STMN2) expression by uncovering a cryptic polyadenylation site that generates truncated, non-functional mRNA, disabling axonal regeneration. [34, 35, 36, 37, 38, 39]
    • C9orf72 gene expansion:  A mutation of the C9orf72 gene is the most common genetic variant across sporadic and familial cases, featuring a noncoding hexanucleotide repeat expansion that forms toxic nuclear RNA foci and repeat-associated non-ATG (RAN) translated poly-dipeptide deposits. [40, 41]
    • Other genes:  FUS/TLS gene mutations induce FUS-positive, TDP-43-negative cytoplasmic deposits. SOD1 gene mutations cause gain-of-function misfolding and aggregation. The ELP3 and ANG genes are also implicated in pathogenic RNA metabolic pathways. [42, 43]
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    Prognosis

    Amyotrophic lateral sclerosis (ALS) is a fatal disease. The majority of ALS patients eventually succumb to ventilatory failure. [44, 45, 46] Less than 5% of patients die of other causes, such as a heart attack, a serious infection, or blood clots that migrate to the lungs. [1, 2, 44]

    The estimated median survival rate for ALS is 3 years from clinical onset of weakness. Approximately 15% of patients with ALS live 5 years after diagnosis. [1, 2, 44] An estimated 5% of ALS patients survive for more than 10 years. Long-term survival with ALS is associated with male patients, young age at the time onset, and the onset of limb symptoms, rather than the onset of bulbar symptoms. [1, 2] Rare cases of spontaneous remission from ALS have been reported. [47]

    A clinically recognized predictor of ALS survival is the rate of observed disease progression. [47, 48]  This prognostic estimate may be ascertained in the following ways:

    1. Rate of progression:  a short time span between symptom onset and diagnosis generally translates to a worse prognosis. [44, 46, 49]
    2. Level of loss:  the degree of loss of function at the time the patient is first seen using quantitative measures such as the ALS Functional Rating Scale Revised (ALSFRS-R). [44]  Bulbar functional losses tend to result in a worse prognosis than spinal functional losses of equal numerical value using the ALSFRS-R. [44, 46, 49]
    3. Loss-onset ratio:  estimates of rates of progression may be derived as a ratio between loss and time since symptom onset. The measurement of functional loss may be obtained using the ALSFRS-R, the forced vital capacity (FVC) as percent of predicted, strength, or motor unit number estimates (MUNEs). [45, 48, 46, 50, 49]  In each case, the current number is subtracted from a presumptive baseline to give the magnitude of the loss.

    Multifactorial algorithms have been developed to predict survival and loss of critical functions associated with ALS. [51, 52, 53, 54] Clinicians of ALS patients should consider whether or not these complex algorithms confer meaningful prognostic precision beyond what may be inferred by ascertaining patient age, rate of progression and degrees of bulbar, respiratory and cognitive involvement at presentation.

      Clinical predictors

      • Rate of progression:  a shorter interval between symptom onset and diagnosis predicts a worse prognosis. [1, 2, 55]
      • Functional scores:  baseline evaluation using the ALS Functional Rating Scale (ALSFRS) acts as a readily available survival predictor. Functional losses are not structurally identical. Bulbar losses portend a worse prognosis than spinal losses of equal numerical value. [55, 53] True progression rates are derived as a ratio between functional loss, quantified by the ALSFRS-Revised (ALSFRS-R), forced vital capacity (FVC) percent predicted, strength, or motor unit number estimates (MUNEs), and time since symptom onset.
      • Prognostic predictors:  high-reliability poor prognostic indicators include elevated neurofilament light chain (NfL) in serum and cerebrospinal fluid (CSF), comorbid frontotemporal dementia (FTD), rapid ALSFRS-R functional change, respiratory subtype, executive dysfunction, and advanced age of onset. [56] Pure LMN or UMN phenotypes, higher baseline ALSFRS-R scores, and longer diagnostic delays correlate with positive survival outcomes. [49, 54]
      • Biomarkers:  plasma and CSF NfL serve as the most reliable biological markers of progression velocity in research settings, though they are not yet routine in clinical practice. [56, 33, 57] Intuitive assessment of presenting age, trajectory rate, and bulbar/respiratory/cognitive status can provide high baseline predictive precision at the point of care. [1, 2, 33, 57]

      Phenotypic trajectories

      • Baseline survival:  ALS is a fatal disease with a median survival of 3 years from clinical onset of weakness. [1, 2] Approximately 15% of patients survive 5 years post-diagnosis, and 5% survive more than 10 years. [49, 53, 54] Long-term survival favors patients with a younger age at onset, male sex, and limb rather than bulbar symptom onset. [46, 53] Spontaneous remission is rare. [49]
      • Genetic variants:  the SOD1 A4V gene mutation causes rapidly progressive disease with an average survival of 12 months from onset, whereas survival with other SOD1 gene mutations typically exceeds that of sporadic ALS. [58]
      • Phenotypic variances:  regionally limited forms (e.g., brachial diplegia, lumbosacral diplegia, and restricted progressive bulbar palsy) progress slower than classic ALS. [44] Progressive muscular atrophy (PMA) progresses at the same rate as classic ALS, while UMN-predominant ALS follows a slower course, indicating that lower motor neuron loss determines overall prognosis. Primary lateral sclerosis (PLS) survival is measured in decades. [59, 55, 51, 53]
      • Cognitive impact:  while cognitive impairment is usually subtle, approximately 15% of patients develop frontotemporal dementia (FTD), which significantly shortens survival compared to patients with ALS alone. [60, 61, 62, 63]
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