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Amyotrophic lateral sclerosis (ALS) is a rapidly progressive neurodegenerative disorder resulting in loss of motor neurons within the motor cortex and bulbospinal regions. The worldwide prevalence is around 4–6 per 100 000, and the disease generally carries a poor prognosis with respiratory failure and death usually within 3 years, although the disease course can be highly variable.1 At present, there is no proven effective treatment for ALS aside from riluzole, a modulator of glutaminergic and Na+ pathways, which confers at most a modest improvement in survival by about 3 months through its disease modifying effects.2 ,3 The heterogeneity in clinical presentation, natural history and prognosis combined with the lack of definitive diagnostic tools, and hence considerable diagnostic delays contribute to the challenges in establishing effective drug trials in ALS.
Currently, the pathogenesis of ALS remains poorly understood, but is likely to be a complex interplay between polygenetic, environmental and lifestyle factors that influence the development of the disease and its onset as well as mediate progression of the condition. Large epidemiological studies allow for the identification of geographical clusters and information pertaining to the disease characteristics and natural history, thereby providing valuable insight into genetic and environmental influences governing ALS.
In their JNNP paper, Chen et al4 contribute to this expanding knowledge by providing a unique account of ALS in China. The manuscript examined the natural history and prognostic factors in a cohort of 1624 sporadic Chinese patients with ALS diagnosed and followed up 3-monthly between 2003 and 2012. The authors further subdivide their analyses according to clinical phenotypes, baseline demographics and potential environmental factors. The authors report a mean age of onset as 49.8 years, significantly lower than the reported 65 years in European countries.5 On the whole, their study also demonstrated a median survival of 71 months, again vastly different from most European and American countries that average 2–3 years. Despite this earlier age of onset and longer survival, the Chinese cohort in the study had a reportedly lower proportion using riluzole and non-invasive ventilation. The earlier onset may suggest a time-dependent exposure to either/or a combination of genetic and environmental risk factors, but at the same time, these very factors may have also influenced the natural history of the disease in this cohort.
Of interest is the authors identified that living in rural regions as well as exposure to pesticides were both associated with poorer prognosis, supporting links to environmental influences and toxins in the aetiology and pathogenesis of ALS, although a clearly larger scale epidemiological data that study exposure to cigarette smoking, heavy metals, radiation, physical activity and manual labour have not been conclusive.6–11 Furthermore, a likely consequence of rural dwelling may be restricted access to medical care as well as differences in comorbidities that ultimately resulted in poorer prognosis. Further, incorporation of genetic information into the study would perhaps have been more insightful and may, in time, explain the discrepancies in onset age, survival time, and clinical phenotypes between this population and others of different ethnic background. For instance, a novel G41D mutation in the SOD1 gene has just been demonstrated in a Chinese family with ALS of whom the affected members exhibited a protracted disease course with relatively early age of onset,12 supporting a potential genotype–phenotype correlation in ALS presentation among certain ethnic cohorts.13
Over recent years, rapid advances in the genetics of ALS have led to the discovery of over 20 mutant genes and loci, with about two-thirds of familial cases attributed to mutations in C9ORF72, SOD1, TARDBP, and FUS.14 ,15 Genetic mutations are also responsible for up to 11% of apparently sporadic cases.16 The most remarkable discovery was that of the C9ORF72 mutation which causes repeat expansion in the GGGGCC hexanucleotide sequence, present in about 40% and 7% of familial and sporadic cases, respectively, is rarely identified in the Asian population.17 This suggests that both sporadic and familial forms of ALS share potentially similar molecular pathological mechanisms. Our current knowledge relating to this will likely be in its juvenile stages, with many questions still remaining unanswered, such as factors impacting penetrance of high-effect genes, epigenetic, polygenetic and other modifying factors.
Complex analyses combining geographical and genetic information will continue to provide insight into the genetic–environmental interactions. Further understanding and knowledge into this interaction, and contrasts across ethnic representations will not only facilitate diagnostic and prognostic algorithms, but more importantly will pave the way to the development of effective novel disease-modifying therapies that we so desperately lack.
Competing interests None declared.
Provenance and peer review Commissioned; internally peer reviewed.
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