Neuromuscular junction in amyotrophic lateral sclerosis. Is there more to follow?

. Background. Amyotrophic lateral sclerosis (ALS) causes progressive degeneration of upper motor neurons in the cortex, and lower motor neurons in the spine. In addition, it is unclear where motor neuron dysfunction begins and what causes motor neuron degeneration: whether it is the dying forward process or the dying back phenomenon where motor neuron degeneration begins distally at the nerve terminal or at the neuromuscular junction and progresses toward the cell body, is still a matter of debate. Materials and methods. Are there neuromuscular junction disorders in the early stages of ALS? To answer this, we described 5 patients with ALS presented at Petre Sarajishvili Institute of Neurology in 2018–2022, 3 males and 2 females aged 50–61 years. ALS diagnosis was based on clinical signs, the Gold Coast criteria, electromyography (Awaji), neuroimaging, blood and urine tests. At the early stage of the disease, only asymmetric ptosis and diplopia were noted, which did not improve on pyridostigmine or steroids. Results. We studied patients’ anamnesis, physical data, evaluated their mental, cognitive functions and neurological status. We have also interviewed family members, as it was often difficult for the patient to accurately describe the symptoms. Acetylcholine receptor antibodies were mildly positive only in one patient. Thymoma was excluded. The neurophysiological study showed only marked neuromuscular transmission failure in orbicularis oculi, there were no clinical and electromyographic signs of motor neuron damage. Conclusions. Approximately 2 years later, all five patients developed clinical and electromyographic signs of ALS. In the present study, neuromuscular junction disorders are found to play an important role in the pathogenesis of ALS and may serve as a useful early diagnostic marker


Introduction
As of 2017, the Amyotrophic Lateral Sclerosis (ALS) Registry has found up to 31,843 cases of ALS in the United States with a mean of 24,821 and a lower estimate of 17,800.ALS is not a reportable disease in most states and CDC/ ATSDR is not notified of these cases at this time.ALS is slightly more common in men than in women.ALS is age related; most people find out they have it when they are between 55 and 75 years of age and live from 2 to 5 years after symptoms develop.How long a person lives with ALS seems to be related to age; people who are younger when the illness starts live slightly longer [3][4][5].
The topic of the present paper is pressing as there are no data available regarding the spread of ALS in Georgia [1,2].
ALS causes progressive degeneration of upper motor neurons in the cortex, and lower motor neurons in the spine.In addition, it is unclear where motor neuron dysfunction begins and what causes motor neuron degeneration: whether it is the dying forward process or the dying back phenomenon when motor neuron degeneration begins distally at the nerve terminal or at the neuromuscular junction and progresses toward the cell body, is still a matter of debate.

Material and methods
Are there neuromuscular junction disorders in the early stages of ALS?To answer this, we described 5 patients with ALS presented at Petre Sarajishvili Institute of Neurology in 2018-2022, 3 males and 2 females aged 50-61 years.
ALS diagnosis was based on clinical signs, the Gold Coast criteria, electromyography (Awaji), neuroimaging, blood and urine tests.

Results
We studied patients' anamnesis, physical data, evaluated their mental, cognitive functions and neurological status.We have also interviewed family members, as it was often difficult for the patient to accurately describe the symptoms.
At the early stage of the disease, only asymmetric ptosis and diplopia were noted, which did not improve on pyridostigmine or steroids.Acetylcholine receptor antibodies were mildly positive only in one patient.Thymoma was excluded.
The neurophysiological study showed only marked neuromuscular transmission failure in orbicularis oculi, there were no clinical and electromyographic signs of motor neuron damage.
Approximately 2 years later, all five patients developed clinical and electromyographic signs of ALS.According to our research, the diagnosis of ALS is difficult until muscle atrophy and tremors are detected.
There are relatively less cases of ALS (2 patients) with symptoms on one or both legs.At this time, the patients felt uncomfortable while walking, the ankle lost its flexibility, its range of motion was limited.Muscle weakness is expressed; there were muscle spasms, increase of deep reflexes or expansion of the reflexogenic zone, pathological reflexes, pronounced muscle atrophy, increased spasticity.The upper limbs were less damaged, although the flexibility of the fingers is limited.

Discussion
Bulbar-onset ALS was detected in one patient with difficulty speaking, the patient spoke "through the nose", later had difficulty swallowing.Speech disturbances (dysarthria, anarthria), voice production disorders (dysphonia, aphonia) were noted.Disappearance of gag reflex, salivation, breathing disorders were soon added to the symptoms.At the same time, in two patients with ALS confirmed by us, the symptoms included signs of both lower and upper motor neuron lesion.Damage to the upper motor neuron manifested itself in muscle hypertonia, hyperreflexia, pathological Babinski sign, and in case of the lower motor neuron lesion, muscle weakness, atrophy, involuntary fasciculations were present.

Conclusions
In the present study, neuromuscular junction disorders are found to play an important role in the pathogenesis of ALS and may serve as a useful early diagnostic marker.Ключові слова: бічний аміотрофічний склероз; розлади нервово-м'язового з'єднання; Грузія Conflicts of interests.Authors declare the absence of any conflicts of interests and own financial interest that might be construed to influence the results or interpretation of the manuscript.Authors' contribution.Shorena Vashadze, Mariam Kekenadze, Kvirkvelia Nana -study design and gathering, writing and submitting manuscript; Beridze Maia -study design and gathering, editing and approval of final draft.