Amyotrophic lateral sclerosis (abbreviation: ALS) is one of the so-called motor neuron diseases and is a degenerative disease of the motor nervous system, i.e. the nervous system that is responsible for all voluntary movements. It is also called amyotrophic lateral sclerosis or myatrophic lateral sclerosis. It is often referred to in English as Lou Gehrig's syndrome, after a 20th-century baseball player, or Charcot's disease after its first describer, Jean-Martin Charcot.

Epidemiology

ALS has an incidence of 1.5-2.6/100,000 and a prevalence of 6-8/100,000 population. Males are more commonly affected than females, with a ratio of 1.5-2:1. Most cases occur between the ages of 40 and 70 (mean age 58 years), with the earliest cases observed at the age of 20. The incidence increases with age. The course is rapidly progressive. Approximately 10-15% of patients survive 10 years, isolated cases of patients surviving >40 years have been described. The bulbar form usually has a worse prognosis (mean survival 2-2.5 years). However, there are large inter-individual fluctuations that do NOT allow a reliable prognosis for the respective patient.

Physiology

In ALS there is a combined degeneration of the 1st and 2nd motor neurons. The muscles that are responsible for voluntary movement (so-called striated muscles) are innervated by so-called motor neurons. Each muscle is supplied by its own second motor neuron (α-motor neuron), the cell body of which is located in the spinal cord and only the extension of it extends to the periphery. The longest extensions are those that extend from the spinal cord of the lumbar spine to the muscles of the foot, which are >1 m in length. The cell bodies of the second motoneurons are distributed over the entire length of the spinal cord, depending on which muscles are innervated by them. For example, the motoneurons for the arm muscles are in the area of the lower cervical cord, those for the torso muscles in the area of the upper thoracic spine and those for the leg muscles in the area of the lumbar cord. Every 2nd motor neuron is innervated by a 1st motor neuron (so-called Betz pyramidal cells), which is located in the motor cortex in the cerebrum. From these, in turn, they only send out their extensions in the direction of the spinal cord. Each 1st motor neuron is connected to a special, separate 2nd motor neuron. Smooth functioning of the respective 1st and 2nd motor neurons is essential for every movement.

Pathology

If the second motor neuron degenerates, the patient notices a flaccid paralysis of the corresponding muscle. In addition, so-called fasciculations, muscle twitching, can occur. In the course of this, there is a significant decrease in muscle mass (atrophy). A degeneration of the 1st motor neuron alone often does not result in paralysis in the actual sense, but in increasing stiffness of the muscles (so-called spasticity). Patients often first notice this when climbing stairs or when walking unsteadily, up to severe limitations and pain with every movement. In addition, the muscle reflexes become very lively. ALS is a combined degeneration in which there are large interindividual differences in the involvement of the 1st and 2nd motor neurons.

Disease/course

Clinically, a distal, unilateral extremity atrophy is the most common initially. It is only later that other muscles are affected and the picture is paralyzed on both sides, later affecting all extremities. About 1/3 of the patients have a so-called bulbar form. This involves paralysis of the swallowing and speech muscles, sometimes also associated with a weakness in holding the head. Only as the disease progresses does increasing paralysis of the arms, legs and, above all, the respiratory muscles occur. In both forms of the disease, the eye muscles and the muscles of the anus are usually spared. It is still not known why these are not affected. The final stage of the disease is characterized by the attack on the respiratory muscles. Patients usually die from respiratory failure. Often there is also pneumonia caused by swallowed saliva or food (aspiration pneumonia). The bulbar form is therefore the one with the poorer prognosis because the respiratory muscles are often affected early on without paralysis of the extremities necessarily occurring. As the disease progresses, sooner or later all voluntary muscles are affected, i.e. not only paralysis of all extremities but also speech and swallowing disorders up to the inability to communicate and eat. What all forms have in common is that patients are usually fully conscious to the end. About 20% form a dementia syndrome of varying degrees.

Special forms

If only or primarily the 1st motor neuron is affected, this is referred to as primary lateral sclerosis. The prognosis for this is significantly better. In some cases, both arms become paralyzed with no signs of further paralysis. This is known as the so-called "flail arm syndrome". Both forms described have in common the transition to ALS in full development over the course of the disease. If only the 2nd motor neuron is affected, this is referred to as spinal muscular atrophy. These are usually hereditary and in most cases occur in childhood.

Reasons

The cause of the selective degeneration of only the motoneurons is not known to this day. There are numerous theories (not detailed here) that involve mitochondrial, cytoskeletal, oxidative stress, inflammatory responses, or neurotransmitter imbalances. What they all have in common is that no clear causal connection between all ALS diseases has been established for any theory to date. The main problem in research to date is that it is so difficult to examine the diseased cells because they cannot be taken from the human without causing serious damage. New techniques, such as the so-called induced pluripotent stem cells, could possibly make this possible in the future.

ALS is a sporadic disease. Only about 5-10% of cases are hereditary. One also speaks of familial ALS syndromes. Of these 5-10%, around 20% have mutations in the SOD1 gene (copper-zinc-superoxide-dismutase). For a long time, this was the only known gene that causes ALS. Therefore, until recently, the animal models on which most drugs were tested were based on mutations in the SOD1 gene. A lot has happened in the last five years. Three other genes were discovered, angiogenin (ANG), TDP-43 (synonym TARDP) and FUS. ANG is responsible for about 2%, TDP-43 for 1-4%, FUS about 5% of familial ALS diseases. Interestingly, 1-5% of patients without a familial cluster also show mutations in the TDP-43 or FUS gene. In summary, the genes responsible for >50% of familial ALS diseases remain unknown.

Data from pathological examinations recently revealed an interesting piece of news. The spinal cords of patients with sporadic ALS were compared with those of patients with gene defects in SOD1, FUS and TDP-43. It turned out that the pathological changes of all forms were similar except for those suffering from SOD1 mutations. This could mean that until recently the only available animal models of the disease (those with SOD1 mutations) may not reflect the disease process/etiology of most ALS diseases. It will be interesting to see whether newer animal models will be better for testing new drugs.