Do upper motor neurons cause spastic paralysis?

Pathogenesis

Motor neurons (motor nerve cells) normally transmit nerve stimuli 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 motor neuron (upper motor neuron) and the 2nd motor neuron (lower motor neuron). The 1st motor neuron arises from the cerebral cortex in the brain and triggers conscious movements. It has an axon (process) that leads to the 2nd motor neuron. This in turn is connected to the muscle by an axon. The lower motor neuron transmits the stimuli from the upper motor neuron to the muscle.

Both motor neurons are damaged as part of the ALS disease. The degeneration of the motor neurons of the spinal cord can be traced back to a degeneration of certain areas of the brain. A loss of ganglion cells in motor cranial nerve nuclei and the medullary anterior horn can also be detected. When the first motor neurons go under, there is initially no paralysis.

Manifest paresis (recognizable paralysis) only shows up when about 30-50% of the neurons have gone under. As a result, early treatment of the disease is rarely possible, as the disease only shows itself in an advanced stage. In competitive athletes, however, an early onset of the disease can be determined due to the early decline in statistically measurable performance. A prominent example is the American baseball star Lou Gehrig, who was diagnosed with the disease at the age of 36. Lou Gehrig died at the age of 37.

There is a growing body of evidence to support the hypothesis that ALS is caused by retroviruses. These have "sneaked" into the human genome in the course of evolution and may be reactivated by mutations in the course of life [1].

The protein TDP-43 may also be involved in the pathogenesis of ALS: a high concentration of pathogenic TDP-43 in the cytoplasm can impair the disposal of TDP-43 by autophagosomes. This leads to the fact that the "self-cleaning" of the nerve cells is weakened [7].

The degeneration of the 1st motor neuron (= upper motor neuron; located in the motor cortex (cerebral cortex)) leads to the following symptoms:

  • Adductor spasm (spasticity of the adductor muscles on the inside of the thigh)
  • Ataxia (gait disturbance)
  • dementia
  • epilepsy
  • Urinary incontinence
  • Paraspasticity of the legs (spastic paralysis of both legs)
  • Spasticity (increased muscle tone)
  • deafness

The degeneration of the 2nd motor neuron (lower motor neuron; anterior horn of the spinal cord / impulse generator for the muscles) leads to the following symptoms:

  • extinguished reflexes
  • facial twitches (muscle twitches)
  • Motor peripheral paralysis that progresses slowly
  • Muscular atrophies (Tissue atrophy of the muscles)

Etiology (causes)

The etiology of the disease is unclear. A genetic disposition is likely. Virus or autoimmune diseases are also discussed.

Biographical causes

  • Some of the cases (approx. 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 [2]; KIF5A (the single nucleotide polymorphism rs113247976 was found in six percent of ALS patients) [6]
    The following gene mutations are known:
    • Mutations of the superoxide dismutase 1 (SOD1) gene [12] (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 into liposarcoma) [14] (each approx. 5% of familial ALS cases)
    • GGGGCC hexanucleotide expansions in chromosome 9 open reading frame 72 (C9ORF72) gene (detect up to 50% of FALS and up to 20% of SALS cases)
  • jobs- Professional football player: wg. Head trauma [4]

Environmental pollution - intoxication (poisoning)

  • Diesel exhaust gases (contains hexane (chemical compound belonging to alkanes) and formaldehyde): 13% increased risk in men [8]
  • Extremely low-frequency electromagnetic fields (men) (observational study) [5]
  • Pesticides: pentachlorobenzene (OR 2.21; 1.06-4.60) and cis-chlorordane (OR 5.74; 1.80-18.20) [3]
  • Polybrominated diphenyl ethers 47 (OR 2.69; 1.49-4.85) [3]
  • Polychlorinated biphenyls (PCB): PCB 175 (OR 1.81; 1.20-2.72) and PCB 202 (OR 2.11; 1.36-3.27) [3]
    Note: Polychlorinated biphenyls belong to the group of endocrine disruptors (synonym: xenohormones), which can damage health even in the smallest amounts by changing the endocrine system.

literature

  1. Li W et al .: Human endogenous retrovirus-K contributes to motor neuron disease Science. Science Translational Medicine 30 Sep 2015: Vol. 7, Issue 307, pp. 307ra153 DOI: 10.1126 / scitranslmed.aac8201
  2. Freischmidt A et al .: Haploinsufficiency of TBK1 causes familial ALS and fronto-temporal dementia. Nat Neurosci 2015 18: 631-636
  3. Su FC et al .: Association of Environmental Toxins With Amyotrophic Lateral Sclerosis. JAMA Neurol. Published online May 09, 2016. doi: 10.1001 / jamaneurol.2016.0594
  4. Chio A et al .: Severely increased risk of amyotrophic lateral sclerosis among Italian professional foot-ball players. Brain 2005 Mar; 128 (Pt 3): 472-6
  5. Koeman T et al .: Occupational exposure and amyotrophic lateral sclerosis in a prospective cohort. Occup Environ Med Published Online First: 29 March 2017. doi: 10.1136 / oemed-2016-103780
  6. Brenner D et al .: Hot-spot KIF5A mutations cause familial ALS. Brain Published: 12 January 2018, awx370, https://doi.org/10.1093/brain/awx370
  7. Leibiger C et al .: TDP-43 controls lysosomal pathways thereby determining its own clearance and cytotoxicity, Human Molecular Genetics 2018 Feb 20. doi: 10.1093 / hmg / ddy066
  8. Dickerson AS et al .: Amyotrophic Lateral Sclerosis and Exposure to Diesel Exhaust in a Danish Cohort. Am J Epidemiol 2018; 187: 1613-1622 https://doi.org/10.1093/aje/kwy069
     
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