Amyotrophic Lateral Sclerosis: Causes

Pathogenesis (disease development)

Motoneurons (motor nerve cells) normally transmit nerve impulses from the brain and spinal cord (= CNS, central nervous system) to the muscles of the body. Each skeletal muscle receives its nerve stimuli from two nerve cells, the 1st motoneuron (upper motoneuron) and the 2nd motoneuron (lower motoneuron). The 1st motoneuron originates in the cerebral cortex in the brain and triggers conscious movements. It has an axon (process) that leads to the 2nd motoneuron. This in turn is connected to the muscle by an axon. The lower motoneuron transmits the stimuli from the upper motoneuron to the muscle. In ALS disease, both motoneurons are damaged. The loss of the spinal cord motoneurons can be attributed to a degeneration of certain brain areas. Atrophy of ganglion cells in motor nerve nuclei and the medullary anterior horn can also be demonstrated. When the first motor neurons perish, paralysis does not initially occur. Manifest paresis (recognizable paralysis) does not become apparent until about 30-50% of the neurons have perished. Consequently, early treatment of the disease is rarely possible, as the disease only becomes apparent at an advanced stage. In competitive athletes, on the other hand, an early onset of the disease can be determined by the early decline in statistically detectable performance. A prominent example is the American baseball star Lou Gehrig, who was diagnosed with the disease at the age of 36. At the age of 37, Lou Gehrig passed away. There is increasing evidence to support the hypothesis that ALS is caused by retroviruses. These have “snuck” into the human genome in the course of evolution and may be reactivated by mutations during life. It is also possible that the protein TDP-43 is involved in the pathogenesis of ALS: a high concentration of pathogenic TDP-43 in the cell plasma may lead to impaired disposal of TDP-43 by autophagosomes. This leads to a weakening of the “self-cleaning” of the neurons. Degeneration of the 1st motoneuron (= upper motoneuron; located in the motor cortex (cerebral cortex)) leads to the following symptoms:

  • Adductor spasm (spasticity of the adductor muscles on the inner side of the thigh).
  • Ataxia (gait disorders)
  • Dementia
  • Epilepsy
  • Urinary bladder incontinence
  • Paraspasticity of the legs (spastic paralysis of both legs).
  • Spasticity (increased muscle tone)
  • Numbness

Degeneration of the 2nd motoneuron (lower motoneuron; anterior horn of the spinal cord/impulse generator for muscles) results in the following symptoms:

  • Extinguished intrinsic reflexes
  • Fascial twitching (muscle twitching).
  • Motor peripheral paralysis that progresses slowly.
  • Muscular atrophies (tissue atrophy of the muscles).

Etiology (causes)

The etiology of the disease is unclear. A genetic predisposition is likely. Viral or autoimmune diseases are also discussed. Biographic causes

  • A proportion of cases (approximately 10%) are irregularly hereditary (familial ALS; FALS), mostly autosomal dominant but also recessive; 90% of ALS cases are sporadic (SALS). FALS: most commonly affected genes are C9ORF72, SOD1, TDP-43, FUS, and TBK1; KIF5A (single nucleotide polymorphism rs113247976 was found in six percent of ALS patients)The following gene mutations are known:
    • Mutations of the superoxide dismutase 1 (SOD1) gene (15-20% of FALS cases).
    • Mutations in the DNA-/RNA-binding proteins TDP-43 (TAR DNA-binding protein 43) and FUS/TLS (fused in sarcoma/translated in liposarcoma) (approximately 5% of familial ALS cases each).
    • GGGCC hexanucleotide expansions in the chromosome 9 open-reading frame 72(C9ORF72) gene (detect up to 50% of FALS and up to 20% of SALS cases).
  • Occupations – professional football players: due tohead trauma.

Environmental pollution – intoxications (poisonings).

  • Diesel exhaust (contain hexane (chemical compound belonging to the alkanes) and formaldehyde): 13% increased risk in men.
  • Extremely low frequency electromagnetic fields (men) (observational study).
  • Pesticides: pentachlorobenzene (OR 2.21; 1.06-4.60) and cis-chlordane (OR 5.74; 1.80-18.20).
  • Polybrominated diphenyl ether 47 (OR 2.69; 1.49-4.85).
  • Polychlorinated biphenyls (PCBs): PCB 175 (OR 1.81; 1.20-2.72) and PCB 202 (OR 2.11; 1.36-3.27)Note: Polychlorinated biphenyls belong to the endocrine disruptors (synonym: xenohormones), which even in the smallest amounts can damage health by altering the hormonal system.