Etiology

ALS is mostly a sporadic disease without a clear cause. However, there is an autosomal dominant genetic cause in 10% of people with ALS. In the 90% of patients without a monogenic cause, a single factor cannot be identified. A gene-time-environment hypothesis has been put forward, suggesting that genetic susceptibility, age-related cellular damage, and a burden of environmental exposures may combine to trigger ALS.[1]

Pathophysiology

ALS is a neurodegenerative disorder characterized by progressive loss of cortical (frontotemporal), bulbar (pons, medulla), and ventral cord motor neurons. After motor cell death, retrograde axonal degeneration follows, with subsequent denervation and reinnervation in corresponding muscles.

Although the mechanism of disease is unknown, several theories regarding pathophysiology have been proposed.

  • Glutamate toxicity. Excessive extracellular levels of glutamate (excitatory neurotransmitter) result in increased calcium entry in neuronal cells, causing cell dysfunction - mitochondrial dysfunction and oxidative stress, and ultimately cell death. This may occur due to defective activity of glial glutamate transport proteins, with posttranslational defects in mRNA for these proteins being reported. The antiglutaminergic drug riluzole improves survival in patients with ALS, thus supporting a role for glutamate neurotoxicity.[15][16]

  • Protein misfolding. Aggregation of both wild-type and mutant proteins is a universal pathologic feature in sporadic and familial ALS.[17] Aggregated proteins can result in either gain-of-function pathology due to direct toxicity, or loss-of-function pathology via aggregates sequestering normal proteins and preventing normal function. For example, aggregation of the DNA- and RNA-binding proteins TDP-43 and FUS into inclusions impairs their normal function, causing changes to transcription and processing of RNA.[17]

  • Oxidative stress. Superoxide radicals, oxygen, and hydrogen peroxide might induce neuronal damage and ultimately death through activation of the apoptotic pathway or by damaging neuronal mitochondria. Damaged mitochondria will also worsen oxidative stress.[18]

  • Inflammation. There are inflammatory components to the pathophysiologic mechanism of ALS. However, the story around inflammation is complicated, as some components of inflammation are toxic in ALS and other components are protective.​[17]

  • Mitochondrial dysfunction. Mitochondrial impairment might cause neuronal degeneration and ultimately death through various mechanisms, including oxidative stress, calcium-mediated excitotoxicity, and activation of programmed cell death/apoptosis. Mitochondrial abnormalities are well documented in patients with sporadic as well as familial ALS.[19]

  • Disrupted axonal transport. This might result from accumulation of neurofilament inclusions with subsequent slowing of the neurofilament transport and deficient dynein-dynactin complex, with dysfunction of retrograde axonal transport. Deficient axonal transport appears to relate to initiation and progression of the disease.[20]

  • DNA and RNA metabolism. One of the core pathologic features of the majority of ALS cases is the presence of TDP-43 (TAR-DNA binding protein 43) aggregates. TDP-43 is known to have various functions in transcription, pre-mRNA splicing, and translation control. The finding that other ALS genes are also involved in RNA regulation (e.g., C9orf72 and FUS) emphasizes the importance of RNA biology to understanding ALS pathophysiology.[21]​ In normal cells, TDP-43 shuttles back and forth between the nucleus and the cytoplasm. The loss of nuclear TDP-43 induces accumulation of double-stranded DNA breaks, which could impair genome stability. In addition, aggregates of TDP-43, mutant FUS, and C9orf72 repeat expansions impair shuttling of cargo between the nucleus and the cytoplasm, which can negatively affect cell function.[17]

Classification

Motor neuron disease (MND) may be primary (neurodegenerative) or secondary (related to a non-neurodegenerative cause). Primary motor neuron diseases can be classified by phenotype, site of onset, and genetics. Patients should be assessed to determine if they have:

  • Only upper motor neuron (UMN) signs, only lower motor neuron (LMN) signs, or both

  • Only motor signs, or also nonmotor signs such as behavioral or cognitive changes

  • Bulbar onset, limb onset, or respiratory onset (defined by the location of the first symptom)

  • Hereditary MND or sporadic MND.

Primary motor neuron diseases

Amyotrophic lateral sclerosis (ALS)[1]

  • The most common form of motor neuron disease (MND); the name is often used synonymously with the term MND.

  • Represents a combination of UMN and LMN findings. Typical UMN findings include loss of coordinated movement, spasticity, muscle spasms, and hyperreflexia. LMN symptoms and signs are weakness with atrophy and fasciculations.

  • ALS has a progressive, unrelenting course with median survival of 3-5 years.

Primary lateral sclerosis (PLS)[1][2][3]​​

  • An isolated UMN disorder characterized by progressive weakness with generalized spasticity affecting speech, upper extremities, and lower extremities.

  • Patients may go on to develop LMN features assessed either clinically or neurophysiologically, so that the disease evolves to "UMN-dominant ALS," but this is rare after 4 years from diagnosis.

  • Survival is usually often greater than 10 years if there is no conversion to ALS.

Progressive muscular atrophy[2]

  • An isolated LMN disorder characterized by progressive weakness, atrophy, and fasciculations.

  • Some patients develop UMN symptoms and signs later during the disease course, converting into "LMN-dominant ALS."

Progressive bulbar palsy

  • MND that remains isolated to the bulbar segment.

  • Most patients with just bulbar involvement initially will progress to have limb involvement, converting to "bulbar-onset ALS."

  • A minority of patients will remain as having progressive bulbar palsy.

Amyotrophic lateral sclerosis with frontotemporal dementia

  • Presents as a combination of symptoms and signs suggestive of ALS and frontotemporal dementia.

  • Cognitive deficits might include language, executive function, personality, and behavior. These features can precede or follow ALS symptoms.

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