Amyotrophic lateral sclerosis (ALS) is a rare progressive, paralytic disorder characterized by degeneration of upper and lower motor neurons in the motor cortex, brainstem, and spinal cord.

It represents the most common form of degenerative motor neuron disease [1-4]. Involvement of the upper motor neurons causes weakness, spasticity, hyperreflexia, and Babinski signs, whereas degeneration of the lower motor neurons results in weakness, muscular atrophy, fasciculations, and cramps [4]. Brainstem involvement may lead to bulbar symptoms.

The clinical course varies depending on the initially affected region and presenting symptoms, but respiratory failure is typically the final cause of death [5]. The worldwide incidence is approximately 1/50,000 per year, and the prevalence around 1/20,000. These rates are relatively uniform across Western countries, although higher frequency has been observed in the Western Pacific [6]. Both incidence and prevalence increase with age [1].

The mean age of onset for sporadic ALS is late 50s, while familial cases may present earlier. There is a slight male preponderance in sporadic cases (male to female ratio ∼ 1.5-2:1), whereas familial cases show an equal distribution [1, 6]. Approximately 5-10 % of ALS cases are familial (typically autosomal-dominant inheritance), while 90-95 % occur sporadically. However, both forms are clinically indistinguishable [1,3].

More than 40 genes have been associated with ALS, although the pathogenetic mechanism(s) remain unknown [7]. Interestingly, different mutations can result in distinct phenotypes (e.g., similar age of onset, site of onset, and disease duration), whereas identical gene mutations may lead to multiple phenotypic presentations [3]. Current research focuses on genes involved in cytoskeletal dynamics, protein and RNA homeostasis, and trafficking processes [1].

Environmental factors are believed to influence disease pathogenesis, though their precise roles are not yet clear. Reported risk factors include military service, different kinds of (head) trauma, smoking and exposure to heavy metals and pesticides [1].

ALS displays marked phenotypic heterogeneity with respect to onset, distribution, and neuronal populations affected, resulting in diverse clinical manifestations [1, 3, 8]. “Classical” ALS typically begins with focal limb weakness, progressing within weeks to months to involve most skeletal muscles. Notably, ocular and bladder muscles usually remain spared until late in the disease course [1, 3]. In addition to weakness, muscle atrophy, fasciculations, spasticity and hyperreflexia are common [8].

About one-third of patients initially present with bulbar symptoms such as dysphagia, dysarthria, drooling and slurred speech [1, 9]. Dysphagia may eventually lead to aspiration of liquids and solids [10]. Emotional lability caused by involvement of frontopontine motor neurons can manifest as pseudobulbar palsy, characterized by facial spasticity and inappropriate laughter or crying in response to minor emotional stimuli [1]. Up to 50 % of patients develop behavioral or cognitive changes, 5-15 % meeting the criteria for (frontotemporal) dementia [11].

Beyond “classical” ALS, several related motor neuron disorders within the ALS spectrum (“non-classical” or “atypical forms”) exist, including those with predominant upper or lower motor neuron involvement and slower progression, such as Primary Lateral Sclerosis (PLS) and Progressive Muscular Atrophy (PMA) [7]. ALS shows marked heterogeneity in the degree of upper and lower motor neuron involvement, affected regions, cognitive or behavioral changes, and rate of progression [3,7].

The average time from symptom onset to diagnosis is approximately 12 months. Diagnosis is primarily clinical, supported by the Gold coast criteria (or the revised El Escorial and Awaji criteria), imaging (head, spine), electromyography, and laboratory testing to exclude alternative causes of paralysis [1, 7]. Disease progression and functional impairment can be monitored using the ALS Functional Rating Scale-Revised (ALSFRS-R) [4].

Currently, no curative therapy exists for ALS. Treatment options are usually palliative and focus on symptom control through interventions such as nasogastric feeding, speechassistive surgery, cough-assist devices, diaphragmatic pacing, ventilatory support or tracheostomy. Botulinum toxin B, as a supportive symptomatic therapy, can reduce sialorrhea in ALS patients [12]. The survival benefit of gastrostomy remains controversial [13-15]. Discussions about tracheostomy and long-term ventilation are integral to ethical considerations in advanced care planning, as these interventions may prolong life but can lead to a locked-in state with complete paralysis and loss of communication.

Pharmacologic options such as riluzole offer only modest benefit [1]. Edaravone has been approved for ALS in numerous countries, its clinical benefit remains debated, and it has not achieved approval in all regions worldwide [16]. In addition, several new and experimental disease-modifying therapies are currently under development [11].

Given the lack of effective disease-modifying treatments, the overall prognosis is poor [1, 17]. Progressive weakness of the diaphragm and respiratory muscles leads to dyspnea, orthopnea, hypoventilation, pneumonia and finally death from respiratory failure or complications such as dysphagia or immobility within 3-5 years [1, 4, 8]. The mean life expectancy after symptom onset is approximately three years [4]; however, about 20% of patients survive for five to ten years, and around 10% live longer than ten years with a slower disease progression [18].