AMYOTROPHIC LATERAL SCLEROSIS (ALS)

Amyotrophic Lateral Sclerosis (ALS) is a fatal idiopathic neurodegenerative disease that damages neural cells responsible for voluntary muscle movement. Also referred to as Lou Gehrig's disease, this atrophy of motor neurons leads to weak muscles and loss of muscle coordination. Based on the onset, ALS could either be limb-onset affecting the upper and lower motor neurons; or bulbar-onset impacting speech and swallowing. About 90 to 95 % of ALS cases are not inherited and hence, are termed Sporadic. Exposure to toxic or infectious agents, physical trauma, diet, and behavioural and occupational factors could be the potential triggers.

Figure 1. Clinical features of ALS (a) proximal muscle wasting (b) wasting of supraspinatus infraspinatus, and loss of deltoid muscle (c) split-hand feature (d) palatal elevation non-existent (Kiernan et al., 2011)

Familial ALS is closely linked to gene mutation. Studies indicate that mutations in SOD1 are highly correlated with the cases of familial ALS (20%). Besides SOD1, mutations in the C9orf72, TARDBP, ANG, OPTN and FUS genes also contribute to ALS by inducing neural apoptosis (Siddique and Ajroud-Driss, 2011). These genes can either be inherited by autosomal dominant pattern, autosomal recessive pattern, or X-linked dominant pattern. Statistically [1], the most affected age group is 40-65 with the frequency of male patients (3·0/100 000 individuals; 2.8-3.3) leading the female patients (2·4/100 000 individuals; 2.2-2.6) (Eisen, 1995).

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Figure 2. Metabolism Biomarkers of ALS. Left: non-invasive (BMI, fat-free mass, bodyweight) right: invasive (mitochondrial dysfunction, glucose metabolism) (Kirk et al., 2019)

Early symptoms of ALS could be so minor that they may be left unnoticed or untraceable. Weakness in muscles of hands, arms, legs, and speech, accompanied by difficulty in swallowing or breathing are general symptoms. Other noticeable signs include impairment in the use of arms and legs, twitching and cramping of muscles (hands and feet) and dysarthria [2]. In advanced stages, ALS leads to dysphagia [3] and difficulty in breathing, which proves to be fatal, in some cases. The pursuit of identifying a root cause of ALS is still ongoing, but recent speculations elucidate that production of inclusions in spinal and cortical motor neurons due to ubiquitinated immunoreactivity could be a characteristic neuropathological feature of ALS (Eisen, 1995).

Figure 3. The mechanisms triggering neurodegeneration in ALS- Glutamate excitotoxicity, mitochondrial dysfunction, neuroinflammation, transport defects, gene mutations, astrogliosis, to mention a few. (Kiernan et al., 2011)

Neurodegeneration in ALS is instigated from the combined interaction of glutamate excitotoxicity, generation of free radicals, protein aggregates in the cytoplasm, and mitochondrial dysfunction. Genetic mutations in TARDBP and FUS result in the formation of intracellular aggregates which damages neurons. Further activation of calcium-dependent enzymatic pathways assists neural degeneration. ALS is typically diagnosed by MRI, Corticospinal tract hyperintensity, Cerebral atrophy detection with MRI, Magnetic resonance spectroscopy, and Diffusion tensor imaging. Though an actual cure is yet to be discovered, preventive measures help patients live a decent life. These include neuroprotection, symptomatic treatments, and supportive healthcare. Anti-glutamate therapies [4] of Riluzole[5] (most efficient), lamotrigine, dextromethorphan, or gabapentin are advised. Respiratory function should be monitored by regular measurements of vital capacity or BiPAP[6]. Trophic factor replacement (DHEA, IGF-1 and BDNF) should be considered. Adaptive aids like wheelchairs, walking frames, communication aids etc. help with weakness and disability. Small doses of dermal patches are used to reduce salivation. Regular speech therapies, physiotherapies, and counselling are done to support the patients efficiently.

Reference List Eisen, A. (1995). Amyotrophic lateral sclerosis. Internal Medicine (Tokyo, Japan), 34(9), p.824-832. Kiernan, M. C., Vucic, S., Cheah, B. C., Turner, M. R., Eisen, A., Hardiman, O., Burrell, J. R., & Zoing, M. C. (2011). Amyotrophic lateral sclerosis. The Lancet (London, England), 377(9769), p.942–955. Andersen, P. M., & Al-Chalabi, A. (2011). Clinical genetics of amyotrophic lateral sclerosis: what do we really know?. Nature reviews. Neurology, 7(11), p.603–615. Kirk, S.E., Tracey, T.J., Steyn, F.J. and Ngo, S.T. (2019). Biomarkers of Metabolism in Amyotrophic Lateral Sclerosis. Frontiers in Neurology, [online], 10(191), p.1-11. Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6431787/ Siddique, T. and Ajroud-Driss, S. (2011). Familial amyotrophic lateral sclerosis, a historical perspective. Acta Myologica, [online] 30(2), pp.117–120. Available at: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3235825/ [Accessed 7 Nov. 2021]. Renton, A. E., Chiò, A., & Traynor, B. J. (2014). State of play in amyotrophic lateral sclerosis genetics. Nature neuroscience, 17(1), p.17–23. The ALS Association. (n.d.). Stages of ALS. [online] Available at: https://www.als.org/understanding-als/stages Hopkinsmedicine.org. (2019). Johns Hopkins Medicine, based in Baltimore, Maryland. [online] Available at: https://www.hopkinsmedicine.org/

[1] Population-based lifetime risk of ALS- women (1:400), and men (1:350)

[2] Difficulty in speech caused by weakened speech muscles

[3]difficulty in swallowing and chewing

[4] Inhibit glutamate release which controls glutamate-induced excitotoxicity

[5] Anti-glutamate medication; prolongs survival

[6] bi-level positive airways pressure