Amyotrophic Lateral Sclerosis - Cause


Where no family history of the disease is present – i.e., in around 95% of cases – there is no known cause for ALS. Potential causes for which there is inconclusive evidence includes head trauma, military service, and participation in contact sports. Many other potential causes, including chemical exposure, electromagnetic field exposure, occupation, physical trauma, and electric shock, have been investigated but without consistent findings.

There is a known hereditary factor in familial ALS (FALS), where the condition is known to run in families. Recently, a genetic abnormality known as a hexanucleotide repeat was found in a region called C9ORF72, which is associated with ALS combined with frontotemporal dementia ALS-FTD, and accounts for some 6% of cases of ALS among white Europeans. The high degree of mutations found in patients that appeared to have "sporadic" disease, i.e. without a family history, suggests that genetics may play a more significant role than previously thought and that environmental exposures may be less relevant.

A defect on chromosome 21 (coding for superoxide dismutase) is associated with approximately 20% of familial cases of ALS, or about 2% of ALS cases overall. This mutation is believed to be autosomal dominant, and has over a hundred different forms of mutation. The most common ALS-causing SOD1 mutation in North American patients is A4V, characterized by an exceptionally rapid progression from onset to death. The most common mutation found in Scandinavian countries, D90A, is more slowly progressive than typical ALS and patients with this form of the disease survive for an average of 11 years.

Mutations in several genes have also been linked to various types of ALS, and the currently identified associations are shown in the table below.

Type OMIM Gene Locus Remarks
ALS1 105400 SOD1 21q22.1
ALS2 205100 ALS2 2q33.1
ALS3 606640 ? 18q21
ALS4 602433 SETX 9q34.13
ALS5 602099 ? 15q15.1–q21.1 Juvenile onset
ALS6 608030 FUS 16p11.2
ALS7 608031 ? 20p13
ALS8 608627 VAPB 20q13.3
ALS9 611895 ANG 14q11.2
ALS10 612069 TARDBP 1p36.2
ALS11 612577 FIG4 6q21
ALS12 613435 OPTN 10p13
ALS13 183090 ATXN2 12q24.12
ALS14 613954 VCP 9p13.3 Very rare, described only in one family
ALS15 300857 UBQLN2 Xp11.23–p11.1 Described in one family
ALS16 614373 SIGMAR1 9p13.3 Juvenile onset, very rare, described only in one family
ALS17 614696 CHMP2B 3p11 Very rare, reported only in a handful of patients
ALS18 614808 PFN1 17p13.3 Very rare, described only in a handful of Chinese families

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