AMYOTROPHIC LATERAL SCLEROSIS (MOTOR NEURON DISEASE); ARE WE CLOSER TO A CURE?

Written by Colin Farrell, B.Sc.

Amyotrophic Lateral Sclerosis, frequently referred to under the umbrella term Motor Neurone Disease, is a neurodegenerative condition characterised by loss of skeletal, bulbar (controlling breathing, speech, and swallowing), and respiratory muscle mass, resulting in loss of voluntary neuromotor function, and progressive muscular paralysis (Tawil & Venance, 2011). ALS is fatal and death typically occurs 3-5 years after disease onset (Dickson & Weller, 2011). The leading causes of mortality in ALS are respiratory failure, breathing complications, and nutritional deficiency (Rong et al., 2011; Spataro, Lo Re, Piccoli, Piccoli, & LaBella, 2010). The majority of ALS cases occur randomly (sporadic ALS), while 5-10% of cases are inherited (familial ALS) (Wijesekera & Leigh, 2009).

Worldwide prevalence of ALS is approximately 5 per 100,000, while the male to female ratio of ALS incidence is 1.5:1. Propensity to develop the disease increases with age, with the average age of onset between 60 and 65 years of age (Talbot & Marsden, 2008). Ireland’s incidence rate is 2.7 per 100,000, with a typically lower age of onset than other European countries observed (Logroscino et al., 2010).

A multitude of potential neurobiological causes for ALS have been proposed (Figueroa-Romero et al., 2012). In familial ALS, the causal genetic factor in a substantial number of cases has been established as mutations in either the C9orf72 protein or the SOD-1 gene. The multiple genetic, developmental, and environmental factors influencing sporadic ALS are poorly understood (Turner et al., 2013), although dysfunction and degradation of TDP-43 and RNA binding proteins in the brain have been implicated (Diaper et al, 2013; Thomas et al., 2013). The degeneration of motor neurons in the brain’s primary and secondary motor areas causes reduced white matter connectivity and efficiency (Verstraete, Veldink, Mandl, van den Berg, & van den Heuvel, 2011); selective cell death also occurs in the brainstem and spinal cord (de Carvalho & Swash, 2011).

It is generally agreed that ALS is “already well on its course” when early warning signs manifest (Mitsumoto, 2010, p.41). These often include symptoms such as stumbling, poor hand grip, or slurred speech (Kinsey & Siddique, 2012). The cause of these early symptoms are weakness, thinning, and  increased tone of muscles, often in one area of the body, such as a hand, arm, leg, or the speech and swallowing muscles (Miller, Gelinas, & O’Connor, 2004). These early clinical features progress to significant and in some cases complete paralysis (Talbot & Marsden, 2008). Limb, bulbar, and respiratory onset variants of ALS exist, with the clinical features of each differing in the muscle group initially affected before disease progression. Limb onset ALS forms 75% of cases (Roth-Kaufmann & Niebauer, 2012).

While previously considered a disease which exclusively affects motor functions, ALS is now regarded as also being detrimental to cognitive and behavioural functioning in patients (Lillo, Savage, Mioshi, Kiernan, & Hodges, 2012). Significant overlap has been found between ALS and Frontotemporal lobar degeneration in presenting symptoms, such as impaired executive function and social conduct (Lagier-Tourenne, Polymenidou, & Cleveland, 2010; Phukan, Pender, & Hardiman, 2007); genetic similarities relating to the TDP-43 DNA-binding  protein have also been found in both conditions (Geser, Martinz-Lage, Kwong, Lee, & Trojanowski, 2009). ALS patients have a significantly higher risk of developing dementia, parkinsonism, and depressive symptoms (Komer et al., 2013).

While ALS currently has no cure (Yip et al., 2013), the glutamate modulating drug Riluzole has been effective in prolonging the life of patients (Vucic et al., 2013). The specific actions of Riluzole in slowing the progression of ALS remain obscure as it elicits a wide range of effects on the neuromotor system (Bellingham, 2011). Stem cell therapy for ALS has provided grounds for cautious optimism (Margakis, 2010), although the lack of understanding around the underlying disease pathogens provides a significant obstacle to its use as a treatment (Feng & Gao, 2012).

Multidisciplinary treatment is more beneficial in comparison to general neurology clinics for ALS patients (Traynor, Alexander, Corr, Frost, & Hardiman, 2003). Use of non-invasive ventilation, employment of neuropsychiatric drugs and sedatives, stretching techniques, and dietary changes can target specific symptoms of ALS. These treatments have been found to increase quality of life and reduce patient distress (Treatment of Specific Symptoms, 2009).

 

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References

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