Introductory Chapter: Motor Neurons – New Insights

1. Introduction

Motor neuron diseases (MNDs) are a group of progressive neurodegenerative disorders associated with the degradation of the upper (UMN) and lower motor neurons (LMN), without affecting sensory and autonomic systems [1]. MNDs can be classified based on the pattern of motor neuron involvement; they encompass pure LMN syndromes, mixed upper and lower motor neuron diseases, and pure UMN syndromes [2]. MNDs patients display a large heterogeneity of clinical symptoms, including muscular weakness, atrophy, and corticospinal tract signs in varying combinations and severities, presenting a unique diagnostic challenge to clinicians [3]. In this chapter, we provide an overview of MNDs, in particular amyotrophic lateral sclerosis (ALS), spinal muscular atrophy (SMA), spinobulbar muscular atrophy (SBMA), and hereditary spastic paraparesis (HSP) [2].

2. Lower motor neuron (LMN) syndromes

The pure LMN syndromes are characterized by a selective degeneration of the anterior horn cells in the spinal cord and the motor nuclei in the brain stem, which inevitably leads to muscle weakness, atrophy, and fasciculations. They encompass spinal muscular atrophy (SMA) and spinobulbar muscular atrophy (SBMA), which is also known as Kennedy’s disease [4]. Progressive muscular atrophy (PMA) will be described together with ALS [5].

2.1 Spinal muscular atrophy (SMA)

SMA is an autosomal recessive disease with a prevalence of 1 per 10,000 live born infants. It is most often related to mutations in the Survival Motor Neuron 1 (SMN1) gene, which encodes SMN, a protein essential for the development and survival of motor neurons. A paralogous gene, SMN2, also encodes the SMN protein but produces considerably less of it. SMA is associated with the degradation of anterior horn cells in the spinal cord and motor nuclei in the brain stem, producing weakness of limb, trunk, bulbar, and respiratory muscles [6]. SMA can be classified into five types (SMA 0–IV) according to age of onset and its clinical course. The beginning of symptoms varies from before birth (type 0) to adulthood (type IV) [7]. SMA type 0 is the rarest and the most severe form of SMA, usually resulting in death due to respiratory failure and bulbar deterioration within the first month of life. SMA type I is the most common form, accounting for approximately 60% of SMA cases, and, if not treated, leads to death by 2 years of age. The other SMA variants (II, III, and IV) are usually less debilitating [6].

The three relatively new therapies (nusinersen, onasemnogene abeparvovec, and risdiplam) have proven to be effective in slowing the progression of SMA. The first milestone has been reached with the discovery of nusinersen (marketed as Spinraza®), a modified antisense oligonucleotide drug that influences the splicing of the SMN2 pre-messenger RNA and thus enhances the expression of the full-length SMN protein. The intrathecal administration of nusinersen prolongs survival and significantly enhances the motor function both in pediatric and adult SMA patients [8, 9]. Onasemnogene abeparvovec (Zolgensma®) was the first single-dose gene-replacement SMA therapy approved in the USA and Europe [10]. The third drug, risdiplam (Evrysdi®), is a molecule that binds the SMN2 pre-mRNA in two locations, consequently increasing levels of the functional SMN protein. Risdiplam administered orally significantly increases survival and leads to motor improvement of patients with SMA compared with a natural history cohort [11, 12]. Numerous clinical trials and real-world data support the efficacy and safety profiles of the available drugs, which are meanwhile becoming new standards of therapy and may redefine the natural course of the disease. Nevertheless, there is still a number of important issues that need to be addressed, such as lack of evidence regarding superiority of one product compared to the others and combined therapies [13, 14].

In addition, stem cell-based treatments have shown the potential to repair the injured tissue and differentiate into neurons in animal models of SMA. Its therapeutic clinical translation, however, remains a challenge and requires further investigations [15, 16].

2.2 Spinobulbar muscular atrophy (SBMA)

SBMA is characterized by progressive weakness and atrophy of the proximal limb and bulbar muscles. The disease has its onset in adulthood, progresses much slower than other MNDs, and is X-linked. It is caused by a CAG repeat expansion in the androgen receptor gene and therefore affects exclusively males [17]. The life span of individuals with SBMA is typically normal; some patients, nonetheless, may be constrained to wheelchairs 15–20 years after symptom onset. Moreover, SMBA patients often show hormonal disturbances like gynecomastia, testicular atrophy, and reduced fertility [18]. Despite collaborative effort in developing therapeutic strategies, no curative treatment has been found up to this date. The latest preclinical studies focus on modifying the activity of androgen receptor (AR) in a selective manner [19].

3. Mixed upper and lower motor neuron diseases

3.1 Amyotrophic lateral sclerosis (ALS)

The term “motor neuron disease” encompasses, among others, amyotrophic lateral sclerosis (ALS), which with its prevalence of about 5.5–9.9 per 100,000 persons is the most frequent form of MND [20, 21]. ALS, also known as Lou Gehrig’s disease, is believed to have a large genetic component; hence, its prevalence depends strongly on the study population, being higher in Australia, Europe, and North America, than in Asia [22]. The disease is more common in men than in women, especially in the younger groups of patients with ALS [23]. In most individuals with ALS, symptoms first appear in the sixth decade of life [24]. There are, however, other rare presentations of the disease. “Juvenile ALS,” which is typically associated with a positive family history and slow progression, starts before 25 years of age, whereas the patients with sporadic “young-onset ALS” develop symptoms before reaching 45 years of age [25, 26].

In ALS, neuronal degeneration typically occurs in the cortex (UMN), as well as in the brain stem and the spinal cord (LMN) [27]. The majority of ALS patients present with limb onset of the disease, whereas bulbar onset of ALS occurs in up to 30% of the patients [28]. The disease progresses rapidly, spreading to various body regions, including respiratory muscles, causing death within 2–3 years for the bulbar onset cases and 3–5 years for the limb onset cases [27]. Recent studies regarding disease progression have led to a development of the model to predict survival without tracheostomy and noninvasive ventilation depending on a number of individual factors [29]. An overview of clinical spectrum of the most important ALS phenotypes is shown in Table 1.

Phenotype	Affected motor neurons	Important features
Classical spinal onset (Charcot’s type)	UMN + LMN	asymmetric weakness in a limb, which progresses to a contralateral limb or to other spinal and/or bulbar areas
Flail arm (Vulpian-Bernhardt’s type)	LMN in UEs, UMN in LEs	predominantly proximal, progressive and symmetric wasting, and paresis of the upper limb muscles, while lower limbs and bulbar muscles are spared; occasionally present UMN signs in the legs
Flail leg (Marie-Patrikios’ type, or a peroneal form of ALS)	LMN in LEs	asymmetric weakness confined to the lumbosacral spinal cord region that spreads to cervical and lumbar regions
Progressive bulbar palsy	LMN	the onset of dysarthria or dysphagia with bulbar muscle atrophy and fasciculations, with progression to the limbs
Pseudobulbar palsy	UMN	the onset of dysarthria or dysphagia with emotional lability with progression to the limbs, no bulbar muscle atrophy and no fasciculations
Progressive muscular atrophy	LMN	clinically isolated LMN syndrome typically starting in distal limb muscles in an asymmetric manner and spreading over months or years; some patients develop ALS with UMN signs
Primary lateral sclerosis	UMN	typically symmetrical onset with UMN signs in the lower limbs, many patients with PLS develop lower motor neuron signs within 4 years of symptom onset
Hemiplegic form	UMN	disease onset with unilateral UMN involvement, slow progression to the contralateral side; after a variable period evolution to ALS with LMN signs
Respiratory form	UMN + LMN	respiratory involvement followed by limb weakness

Table 1.

An overview of clinical spectrum of the most important ALS phenotypes.

UMN: upper motor neuron; LMN: lower motor neuron; UE: upper extremity; LE: lower extremity; ALS: amyotrophic lateral sclerosis; and PLS: primary lateral sclerosis.

The original diagnostic criteria for ALS were defined at El Escorial in 1990 and revised multiple times [30]. In 2019, the Gold Coast criteria were developed, increasing the diagnostic sensitivity for amyotrophic lateral sclerosis [31, 32]. The diagnosis of ALS remains fundamentally clinical and relies on the medical history and physical examination. Electrodiagnostic testing with needle electromyography (EMG) and neuroimaging have been useful adjunctive tools in the diagnostic process. EMG provides evidence of LMN involvement, also at subclinical stages, revealing signs of acute denervation like fibrillation potentials, positive sharp waves, and fasciculations. Unfortunately, in cases of UMN-predominant ALS, particularly those with bulbar onset, its sensitivity is still unsatisfactory [33]. Brain and spinal cord magnetic resonance imaging is recommended in order to exclude structural lesions like infarct, cervical radiculomyelopathy, syrinx, demyelination, or neoplasm [34, 35]. Moreover, 18F-fluorodeoxyglucose positron emission tomography (18F-FDG) may reveal a typical pattern of perirolandic and prefrontal hypometabolism [36, 37]. Furthermore, several serum and cerebrospinal fluid molecules, such as neurofilament light chain (NfL) and phosphorylated neurofilament heavy chain (pNfH), are emerging as potential diagnostic and prognostic ALS biomarkers [38].

Genetics plays an important role in the pathophysiology of ALS; in fact, more than forty genes contributing to familial (fALS) and sporadic ALS (sALS) have been identified up to date [39]. The familial form of ALS constitutes up to 10% of disease cases. Familial ALS is most frequently caused by mutations in C9orf72, superoxide dismutase 1 gene (SOD1), fused of the sarcoma (FUS), and TARDBP gene [40]. The pattern of inheritance depends on the gene involved and in most cases is autosomal dominant. Mutations in the same genes are also found in sALS patients, but at considerably lower frequencies [41]. The studies of ALS at the molecular level have indicated cytoplasmic aggregation of TAR DNA-binding protein 43 (TDP-43), a protein encoded by TARDBP, as the most common ALS neuropathology, present in more than 95% of cases [42]. Except for accumulation of misfolded or aggregated proteins, other cellular processes like oxidative stress, excitotoxicity, mitochondrial dysfunction, endoplasmic reticulum stress, and inflammation can result in the loss of neurons in ALS [43]. Similar abnormalities at the genetic and molecular level have been described in patients with frontotemporal dementia (FTD) [44]. In fact, around 15% of ALS patients meet the criteria of frontotemporal dementia (FTD), and conversely, up to 15% of FTD patients develop ALS [45, 46]. In fact, ALS and FTD may be considered one disease, with ALS representing predominantly motor phenotype and FTD cognitive phenotype [47].

Significant discoveries in genetics research has brought a better understanding of ALS pathogenesis over recent years, which is crucial for the development of disease-modifying and curative therapies in the future [48]. At this point, riluzole remains the only widely approved drug for the treatment of ALS. Riluzole exerts inhibitory effects on the glutamatergic system, which prevents neuronal dysfunction and death called “excitotoxicity.” Unfortunately, the benefit is very limited, and riluzole can extend the average survival time by only 3 months [49]. Another drug, edaravone, is a free radical scavenger that reduces oxidative stress. The first clinical trials conducted in Japan and in the USA have shown that the treatment with edaravone may prolong survival up to 6 months, leading to the approval of the drug by several countries [50, 51]. Unfortunately, its beneficial clinical effects have not been confirmed in European cohorts [52, 53]. The third available drug, AMX0035, is a combination of two compounds—tauroursodeoxycholic acid (TUDCA) and sodium phenylbutyrate (PB)—and is believed to increase the threshold for cell death by blocking key cell death pathways. After promising results of the first randomized, placebo-controlled, phase 2 trial of AMX0035 in ALS (CENTAUR), in which the treatment with AMX0035 led to both functional and survival benefits in ALS patients, the drug has been approved in the USA and Canada [54]. The collaborative research efforts do not stop, and there are many experimental therapies in development, targeting, among others, excitotoxicity, oxidative stress, mitochondrial dysfunction, protein homeostasis, and neuroinflammation [55]. Furthermore, cannabis-based medicine has been gaining increasing attention as a potential therapeutic agent for many neurological conditions, including ALS [56, 57, 58].

4. Upper motor neuron (UMN) syndromes

Pure upper motor neuron (UMN) syndromes comprise PLS, which as a phenotype of ALS was mentioned above, and hereditary spastic paraplegia (HSP). PLS clinically overlaps with (UMN)-predominant ALS and HSP, posing a diagnostic challenge to the clinicians. Nevertheless, HSP compared to PLS is more frequently associated with the presence of a family history, the earlier and symmetric onset of the disease, diminished vibratory sensation, the absence of bulbar involvement, and slower disease progression [59].

4.1 Hereditary spastic paraplegia (HSP)

Hereditary spastic paraplegia (HSP) describes a heterogeneous group of neurodegenerative diseases with a complex genetic background of more than 70 genetic variants recognized, with all possible patterns of inheritance reported [39]. Between 13 and 40% of cases occur, however, with no family history [60]. Clinically, the “pure” form of HSP is marked by progressive spasticity of the lower limbs, whereas “complex” variants of HSP encompass additional disturbances, including dementia, cognitive delay, epilepsy, neuropathy, and others. The disease can present in infancy, childhood, adolescence, or adulthood. Nonetheless, the more common autosomal-dominant types manifest between the second and third decades [61].

Autosomal dominant hereditary spastic paraplegia 4 (SPG4) is the most prevalent form of HSP. Among the autosomal-recessive forms, SPG11 is the most frequent and associated with a “complex” phenotype [62]. Disease progression in HSP individuals is overall slow. Late disease onset and SPG11 form are associated with a higher disease severity and earlier loss of independent walking. The diagnosis of HSP is made based on clinical features, genetic testing, and neuroimaging. Despite the wide attainability of the next-generation sequencing-based HSP gene panels, a genetic diagnosis is not made in up to 71% of all suspected cases of HSP [60].

Up to this date, no specific HSP modifying therapy is available [63]. Oral antispasmodics, including baclofen and tizanidine, have an established role in the management of spasticity; another promising oral treatment option is fampridine (4-aminopyridine) [64]. In more severe cases, the administration of intrathecal baclofen may be used to alleviate spasticity and improve gait [65]. Sadly, despite great progress in unraveling the genetics of HSP, no substantial advances in developing gene-specific therapy have been achieved [39].

5. Conclusions

Over the last decades, considerable efforts have been made to unfold the underlying pathophysiology of MNDs and find novel therapeutic modalities. Yet MNDs present a unique challenge to researchers and clinicians. The approval of three efficacious and safe therapies (nusinersen, risdiplam, and onasemnogene abeparvovec) led to a breakthrough in the management of SMA. With regard to ALS, diagnostic and prognostic procedures have remained relatively unchanged, apart from genetic testing. Neurofilament light chain and phosphorylated neurofilament heavy chain have emerged as possible diagnostic and prognostic biomarkers in serum and cerebrospinal fluid of the ALS patients. On the other hand, as NfL and pNfH levels are elevated in many neurodegenerative diseases, their clinical utility might be insufficient. Available treatment options for ALS are limited and not curative. Three disease modifying drugs have been approved by the US Food and Drug Administration (FDA), including riluzole, edaravone, and AMX0035. Due to contradictory results in clinical trials, edaravone and AMX0035 have not been approved in most of the European countries. Currently, the multidisciplinary supportive care provided by medical practitioners in neurology, pulmonology, gastroenterology, rehabilitation, and palliative care continues to be the core stone of MND management. Our book aims to discuss the latest developments in the field of MNDs.