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Page 305 Guerra et al. J Transl Genet Genom 2022;6:304-21 https://dx.doi.org/10.20517/jtgg.2022.08

INTRODUCTION
Neurogenic dysphagia (ND) refers to any swallowing disorder associated with central and peripheral
nervous system conditions, as well as muscle and neuromuscular diseases. ND is linked to multiple
degenerative and nondegenerative congenital, traumatic, vascular, neoplastic, and iatrogenic disorders as
diverse as cerebral palsy, traumatic brain injury (TBI), amyotrophic lateral sclerosis (ALS), multiple sclerosis
[1]
(MS), Parkinson’s syndromes, myasthenia gravis (MG), and myositis . Based on clinical observations, ND
can be classified into the following seven distinct phenotypes, which are particularly useful when etiological
diagnosis is in doubt: (i) premature bolus spillage; (ii) delayed swallowing reflex, both characteristic of
stroke; (iii) predominance of residue valleculae, common in patients with Parkinson’s disease; (iv)
predominance of residue in the piriform sinus, characteristic of myositis, motor neuron disease, or
brainstem stroke; (v) pharyngolaryngeal movement disorder, observed in patients with parkinsonism and
stroke; (vi) fatigable swallowing weakness in individuals with myasthenia gravis; and (vii) complex disorder,
as occurs in ALS .
[2]
The importance of dysphagia stems mostly from the increased risk of death caused by aspiration
[3,4]
pneumonia, and conditions related to dehydration or malnutrition . In addition to these factors, aging
reduces the frequency of spontaneous swallowing . To ensure proper diagnosis and management of ND, it
[5]
is mandatory to: (i) obtain a complete medical history; (ii) perform screenings that assess the risk of
aspiration (e.g., a swallowing test with water and other consistencies); (iii) conduct counseling tests and
clinically evaluate dysphagia by videofluoroscopy (VFSS), swallowing endoscopy (FEES), or manometry,
and other additional tests such as ultrasonography or electromyography); (iv) perform treatments based on
dietary therapeutic interventions, behavioral interventions, oral hygiene measures, neurostimulation,
pharmacotherapy, and surgical treatments . In this third step, the management of special groups such as
[6]
[6]
tracheostomized patients and patients with nasogastric tubes is of particular interest .

The treatment of ND is mainly based on rehabilitation therapies performed by speech therapists and other
non-pharmacological approaches. However, some medications may be effective in improving impairment
[6,7]
during the different phases of swallowing . The majority of medications used to treat oropharyngeal
dysphagia have a general effect on swallowing function that is independent of the underlying neurological
[8]
disease; this allows for standardized use . Pharmacotherapy, however, produces limited results and should
therefore not be used as a stand-alone treatment, but rather as an adjunct to other therapies . Furthermore,
[8]
medications such as antidopaminergic agents, anticholinergic drugs, or benzodiazepines induce or
exacerbate dysphagia [9-12] .

In view of these considerations, research into specific ND-related genes may be useful in the prognosis of
this condition. Because pharmacogenetics also plays a key role in both the diagnosis and the correct
pharmacological management of patients with dysphagia, to increase the benefit of compounds that can
improve swallowing difficulty and minimize the risk with the use of dysphagia-inducing drugs, in this
review, we highlight these ND mechanisms from a pharmacogenomic perspective.

DOPAMINE AS A NEUROTRANSMITTER
Dopamine is a neurotransmitter of high relevance in the swallowing process. Its precursor, L-DOPA, is
synthesized from the essential amino acid tyrosine or indirectly through phenylalanine, a non-essential
amino acid. Dopamine β-hydroxylase (DBH) catalyzes the conversion of dopamine to norepinephrine (NE),
and NE is then converted into epinephrine by phenylethanolamine N-methyltransferase with
S-adenosyl-L-methionine as the cofactor. Dopamine is degraded by monoamine oxidase (MAO-A and
MAO-B), catechol-O-methyl transferase (COMT), and aldehyde dehydrogenase (ALDH), which act