This paper details 3 subtypes of sporadic motor neuron disease (MND): Amyotrophic Lateral Sclerosis, Primary Lateral Sclerosis, and Progressive Muscular Atrophy. We discuss these diseases in depth, investigating the clinical, neuropathological, and genetic characteristics of each.
The term ‘clinical’ refers to the range of symptoms being exhibited by the patient, which aid in diagnosis and classification. Neuropathological sections explain the physical damage/pathology being done to the nervous system tissue by the disease, which is the cause for the outwardly observable clinical symptoms. Genetic aspects of the disease identify the key mutations in the genome that cause the specific pathology of each disease.
There is ongoing debate within the MND research field, as to whether each of these subtypes are distinct from one another, or exist on a continuous spectrum. As many clinical aspects appear to overlap, it is important to gain a deeper understanding of the neuropathological and genetic traits of these variants, to aid in correct specific diagnosis and treatment of patients.
The human nervous system has many neuron types, which are diverse cells that connect and enable communication between tissues across the body, through the transmission of electrical impulses along the neuronal axon, using a complex system of electrochemical gradients caused by the movement of anions and cations (McDermott & Shaw, 2008) (Feher, 2017) (Fig.1).
Two key types of neuron work together to control our skeletal muscles, which enable both voluntary and involuntary movements, from walking to breathing: sensory neurons provide afferent signals, with inputs from receptors in the body sending information towards the central nervous system; in comparison, motor neurons transmit efferent signals which originate from the nervous system towards the muscles and associated tissues, to initiate movement (McDermott & Shaw, 2008). Within these types, subtypes of motor neuron also exist. Upper motor neurons (UMNs) are located in the cerebral cortex and brainstem, with key regions being in the basal ganglia, cerebellum, superior colliculus, reticular formation, and vestibular nuclei (Garg & et al., 2017). Lower motor neurons (LMNs) are mainly found in the Peripheral nervous system, such as the spinal cord, but also exist in the brainstem centres (Statland & et al. , 2015).
This paper will discuss 3 diseases that affect the motor neurons, causing neurodegeneration of these cells and tissues, but impact UMN and LMN to varying extents (Leigh & et al. , 1994). The subtypes of motor neuron disease (MND) in this investigation are: Amyotrophic Lateral Sclerosis, Primary Lateral Sclerosis, and Progressive Muscular Atrophy. These MNDs are classed as primarily sporadic (Fig.2).
Sporadic motor neuron diseases typically have no familial/hereditary causation and appear to occur at random. However, this does not mean there is no genetic involvement, as random mutations to the genotype have been associated with the development of MND (Leigh & et al. , 1994).
During the analysis of each MND subtype, we aim to identify the defining characteristics of each disease. This is of significance, as there is ongoing debate on the distinctiveness of each disorder, with some arguing that their crossover in neuropathological symptoms (Grad & et al. , 2017) as well as genetic markers (Chen, et al., 2013) indicates that these diseases are more accurately described on a spectrum (as illustrated in Fig.2). So, the aim is to classify the symptoms, pathology, and genetics of each, in order to determine the existence of distinct qualities.
Amyotrophic Lateral Sclerosis (ALS)
Clinical aspects of ALS:
The symptoms of ALS can be summarised by rapid loss of motor control, due to both upper and lower motor neuron involvement (Arthur, et al., 2016), and the average life expectancy after initial onset is 2-4 years (Arthur, et al., 2016). It is the most common type of MND, with 90% of cases being sporadic, with no apparent familial cause (Chen, et al., 2013), while the remaining 10% of cases can be attributed to inherited mutations. Due to the lack of a singular definitive test to diagnose ALS, a series of eliminations must be carried out to rule out similar diseases (Winhammar & et al. , 2005).
Symptoms characteristic of ALS include mostly limb effects in 80% of cases, limb-onset is therefore the most common exhibition of ALS. Figure 3 displays typical muscle wastage in a limb-onset patient with both UMN and LMN involvement; the most common symptoms accompanying this condition are weakness, spasticity, and fasciculations (Chen, et al., 2013).
The other 20% of ALS cases present bulbar-onset clinical symptoms. This form involves more neurological symptoms, such as slow/slurred speech (dysarthria), difficulty with hand-eye coordination, such as a loss of writing ability, and the wasting of facial/tongue muscles (Fig. 4) (Kiernan & et al, 2011).
Neuropathological aspects of ALS:
The structural neuropathology of this disease impacts the UMN in the motor cortex, specifically the pyramidal Betz cells in the 5th layer of grey matter (Hirano, 1996), as well as the LMN in the motor nuclei in the brainstem, and in the anterior horn of the spinal cord, causing degradation and loss of these cells through a process called ubiquitination (Hirano, 1996) (Al-Chalabi , et al., 2012). Ubiquitin is a small protein molecule, and acts in the process of cellular degradation (Neumann & et al. , 2006). Ubiquitin attaches to short-lived proteins, when they have fulfilled their purpose, to act as a signal to the transport-machinery organelles within the cell, to move the protein to a proteasome or lysosome, to be broken down (Neumann & et al. , 2006). Malfunctions to normal ubiquitination processes in ALS occur commonly in the LMNs of the spine (Al-Chalabi , et al., 2012). A second pathological hallmark of ALS is the TAR DNA binding protein, TDP-43, and has been linked to the abnormal ubiquitinated cytoplasmic inclusions (Mackenzie & et al. , 2007). TDP-43 abnormalities are observed in 97% of all ALS cases, meaning there is no doubt this is a key neuropathological aspect of the disease (Scotter, et al., 2015). These TDP-43 factors are often found in aggregation with Bunina bodies (small eosinophilic intraneuronal inclusions) (Okamoto, 2007), which occur most commonly in the LMNs.
No single cause has been defined for ALS, and the symptoms are most likely the result of the sum of many neuropathological aspects.
Genetic aspects of ALS:
The genetic causes (aetiology) of 11% of ALS cases are known and are attributed to specific genes or gene combinations (Fig.5) (Renton, et al., 2013). The most heavily implicated genetic mutation is C9orf72 (shown in green in Fig.5) (Renton, et al., 2013) (Nguyen, et al., 2018), and this protein is found in many regions of the central nervous system, from neuronal cytoplasm, to presynaptic terminals. The gene C9orf72 is also thought to be closely associated with the ubiquitin-binding process, and partial production of TDP-43 (Nguyen, et al., 2018). Additionally, a GGGGCC hexanucleotide repeat mutation in C9orf72 is now seen as the potentially predominant genetic factor in ALS (Turner & et al. , 2017).
Furthermore, the TARDBP gene, which accounts for 2% of sporadic ALS cases, also has strong associations with the coding of TDP-43 (Mackenzie & Rademakers, 2008). So overall, genes involved in the production of TDP-43 make the most contribution to ALS cases, proving the importance of the protein in this disease. Additionally, the FUS gene causes a mutation with strong similarities to TDP-43, in the form of cytoplasmic inclusions, further showing the significance of this mechanism in ALS (Kamelgarn & et al. , 2018). The final large genetic contributor to ALS – SOD1 – has mechanisms also linked to molecular aggregations (Forsberg, et al., 2011).
Genetic aspects of ALS are hugely complex, and little understood, but it is clear that multiple DNA regions are implicated (Nguyen, et al., 2018) (Al-Chalabi , et al., 2012).
Primary Lateral Sclerosis (PLS)
Clinical aspects of PLS:
High degrees of variation exist in the symptoms of PLS. Most commonly, clinical symptoms begin with limb-onset, including leg weakness, joint stiffness, and hyperactive reflexes (Tartaglia & et al. , 2009) (Fournier, et al., 2016).
PLS typically affects the UMN alone, specifically the corticospinal pathway, (Kuipers-Upmeijer & et al. , 2001) (Statland & et al. , 2015). However, as PLS is a non-fatal, and slower progressive subtype of MND, some cases develop to involve the LMN, therefore potentially transitioning into ALS. For this reason, diagnosis of PLS involves the criteria of a 3-year window, in which only UMN impacts are seen (Fournier, et al., 2016).
Neuropathological aspects of PLS:
Patients with PLS display severe atrophy in specific brain regions, such as the precentral cortex and gyrus (Tartaglia & et al. , 2009) – a factor absent in ALS cases, therefore aiding their differentiation (Kolind & et al., 2013). A second distinguishing factor in PLS is the vast degeneration of Betz cells (Kolind & et al., 2013).
A further hallmark aspect of PLS is the loss of neurons in the motor cortex and degeneration of the descending corticospinal tracts (Statland & et al. , 2015).
However, similarities can be seen between PLS and ALS, as both have been found to involve TDP-43 ubiquitinated inclusions in the cortex and also the existence of Bunina bodies in the LMNs (despite not being degraded) (Kosaka & et al. , 2011).
Due to this range of neuropathological features, both sides of the argument can be understood, that although ALS and PLS are officially classified as distinct subtypes of MND, they may actually exist on a spectrum. The weight of evidence on each side must be continually assessed, when new information emerges.
Genetic aspects of PLS:
PLS is generally seen as entirely sporadic (Statland & et al. , 2015) (McDermott & Shaw, 2008), and currently has no known genetic indicators.
However, there is a rare form, called juvenile PLS, that has genetic inheritance in autosomal recessive transmission (Gómez-Tortosa & et al. , 2017). Mutations in the genes ALS2 and ERLIN2 have been implicated, suggesting the role of their proteins is a pathogenetic mechanism for disease (Panzeri & et al. , 2006) (Al-Saif, et al., 2012). These mutations seen in juvenile PLS are also seen in individuals diagnosed with juvenile ASL, a common genetic means can be seen in these familial pathogeneses.
Progressive Muscular Atrophy (PMA)
Clinical aspects of PMA:
This final subtype of MND is characterised by pure LMN symptoms (Statland & et al. , 2015); the LMN involvement causes advancing exponential progression of weakness, muscle degeneration, and muscle fasciculations (Liewluck & Saperstein, 2015). Further definitive clinical features are the later onset age, high prevalence in males, and long life-expectancy (Kim & et al. , 2009). However, as with PLS, it can develop with time to involve both UMN and LMN damage, and associated symptoms (spasticity, hyperactive reflexes) (Garg & et al., 2017), and therefore is also included in the scientific debate on the distinctiveness of each MND disease. Approximately 70% of individuals diagnosed with PMA, develop UMN as the disease advances (Winhammar & et al. , 2005) (Rowland, 2010). In these cases, PMA is re-diagnosed as an LMN-onset presentation of ALS (Pinto & et al. , 2019).
Neuropathological aspects of PMA:
Typical LMN damage can be seen in autopsy examinations of PMA patients (Geser & et al., 2011), such as damage/degeneration of the brainstem and spinal cord neurons (Liewluck & Saperstein, 2015). However, there are also several neuropathological features that are commonalities with ALS, even in patients who present purely LMN clinical symptoms (Ince & et al., 2003); corticospinal tract degradation, cytoplasmic inclusions with pathological TDP-43, and evidence of Bunina bodies, have all been recorded through post-mortem histopathology (Rowland, 2010) (Kim & et al. , 2009). These factors support the argument that PMA is a form of ALS, or a step in the disease’s progression.
Genetic aspects of PMA:
Despite being a sporadic MND, specific genotype mutations have been identified with the development of PMA (Garg & et al., 2017): SOD1 (Cervenkova, et al., 2000), VAPB, DCTN1 genes, and others with less evidence (Pinto & et al. , 2019), are all associated with the occurrence of PMA, even in patients displaying only LMN presentation (Pinto & et al. , 2019). It is important to note that the majority of genes linked to PMA diagnosis, can also be seen in the ALS research (Garg & et al., 2017), which contributes further information and evidence that suggests these diseases share a pathological pathway/mechanism, and exist on a diagnostic spectrum.
In review, each of the diseases, Amyotrophic Lateral Sclerosis, Primary Lateral Sclerosis, and Progressive Muscular Atrophy, can be defined as primarily sporadic subtypes of adult-onset Motor Neuron Disease. These diseases affect the motor neurons to varying extents, with ALS causing damage to the Lower and Upper motor neurons, PLS impacting mainly the UMN, and PMA presenting in the LMN. From here, finer classifications can be made through examining the clinical, neuropathological, and genetic features of each type. The observable clinical symptoms of each subtype tend to overlap, making diagnosis without genetic or histopathological examinations and testing increasingly complex, and for this reason, accurate diagnosis can take many years, to rule out other disorders, as patients with PLS and PMA often have symptoms advance into ALS, with both UMN and LMN involvement, despite starting with only type.
An additional layer of evidence that these diseases are one and the same, is the number of neuropathological commonalities, where pathological inclusions of TPD-43 seen in all 3 subtypes, as well as the number of shared genotypic mutations found, further suggesting a common pathogenesis mechanism.
On the other hand, there are clear distinctive features observed in only one subtype, such as the fatality of ALS compared to PLS and PMA, and the acute brain atrophy observed in PLS.
However, in conclusion I believe the weight of evidence suggests that, although pure UMN and LMN forms of motor neuron disease exist, the most common pathway of progression for MND is to eventually involve both neuron types, which is a clear feature of ALS, meaning it may be more useful to understand these diseases as part of a spectrum, rather than existing in isolation.
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