
This article contains a summary of causal research conducted by Dr Anton V Mathey (MBChB, MBL) on primary and secondary responders and other factors that may affect the onset, efficacy and duration of Botulism neurotoxin (BoNTA1) when injected to treat facial wrinkles.
Clostridium Botulism is a group of gram-positive bacteria that produce a toxic and potential lethal toxin that causes flaccid paralysis at the neuro muscular junction lasting from days to months. Botulism neurotoxin (BoNT) produced by the organism is a protein organised into a heavy chain (HC) and light chain (LC) bound by a double sulphite bond. The heavy chain binds with receptors on the neuronal plasma membrane and facilitates the entry of the zinc dependent, enzymatic active, light chain into the neuronal cell.
There are seven serotypes of botulism neurotoxin BoNT (A-G) and every serotype has an array of subtypes with its own activity and duration of effect. Currently Botulism neurotoxin serotype A subtype 1 (BontA1) is used for the treatment of facial wrinkles. BoNTA1 causes flaccid paralysis at the neuro muscular junction for three to six months.
The activity and toxicity of the neurotoxin is due to both the heavy and light chain of the neurotoxin. The length of duration of the neurotoxin effect is a function of the light chain. It is thought that the localisation of the light chain in the neuronal cell is an indication of the period that flaccid paralysis will occur and is different for the different serotypes. The light chain of BoNTA1 is localised at the plasma membrane of the neuronal cell and compared to the localization of the light chain for short acting BoNTA3 that is at the nucleus of the neuronal cell.

NAP 25 is a membrane protein that facilitates the binding of synaptic vesicles in the neuronal cell that is filled with acetylcholine to the plasma membrane. Acetylcholine is an exitory neurotransmitter that causes the nerve to move impulses or messages from one neuron to the next. BoNTA1 cleaves the SNAP25 protein and therefore blocks nerve transmission and then inhibits muscle movement.
All eucaryotic cells have a protein that deactivates or remove foreign proteins from cells. One such a protein, ubiquitin binds to the foreign protein, BoNTA through a complex enzymatic process called ubiquination. The ubiquinated protein is then degraded by a protease enzyme.
Proteins can also be protected by a deubiquination process, and this is important during the immune response to protect the immune system. BoNTA light chain is protected from degradation by the deubiquination process and therefore lengthens its duration to between three and six months.
It is postulated that the light chain of BoNTA1 is protected from degradation by tyrosine phosphorylation and that increases the duration of action of BoNTA1. Phosphorylation is a process where a phosphate group is added to the tyrosine amino acid in the light chain.
Neurite sprouting also influences the duration of action of BoNT. Sprouting takes place when the neuro muscular junction (NMJ) is blocked by BoNT. The neuronal sprouts dissipate as soon as the function of the NMJ returns. The speed at which sprouting takes place is a function of the BONT used. BoNTA3 has a quick onset due to the speed at which sprouting takes place.
Ubiquination, deubiquination, tyrosine phosphorylation and sprouting all influence the onset and duration of effect of BONT. There may be a genetic difference between patients or there may be epigenetic factors affecting these processes such as stress or sleep deprivation (the author’s own hypothesis).
In practice, some patients report that the neurotoxin did not work at all or that it did not last as long as they expected.
Based on my experience, apart from the primary and secondary non responders discussed above, the following factors may influence the onset, efficacy and duration of BoNTA1:Cold chain interruption
- Constitution of product
- Injection technique
- Lack of anatomy knowledge
- Patient aftercare
- Ubiquination
- Deubiquination
- Tyrosine phosphorylation
- Neurite sprouting
Whilst physicians have no influence on the genetics of a patient that may affect the onset, efficacy and duration of BoNTA1, but the factors that are within the physician’s control must be managed diligently to enhance results and ensure patient satisfaction.
