24 January 2012. Like many neurodegenerative conditions, amyotrophic lateral sclerosis is a disease of aging. Thus, it was unusual when a young man of 19 visited Guy Rouleau’s practice at the University of Montréal, Canada. The teen turned out to have a novel mutation in the ALS gene Fused in Sarcoma (FUS). His case corroborates previous work suggesting FUS-based ALS can hit the young, and it highlights the extraordinary variability in the disease. Rouleau was senior author on the study with first author Veronique Belzil, also at the University of Montréal.
ALS symptoms typically appear in one’s 40s and 50s, although juvenile cases in people younger than 25 do occur. In addition to the early onset, the young man in the case study was unusual in that his weakness and muscle atrophy affected mostly his right arm, shoulder and neck. However, he did have mild weakness elsewhere, convincing Rouleau that ALS was the correct diagnosis.
The team sequenced three likely candidate ALS genes: FUS, superoxide dismutase 1 (SOD1), and TAR DNA Binding Protein 43 (TDP-43). They discovered a single base pair deletion near the end of the FUS gene, causing a frameshift that swapped the final 32 correct codons for 33 new, incorrect ones. This genetic defect joins several others found previously in the carboxyl terminus of FUS, confirming the importance of that region for the protein’s function (see ARF related news story on Dormann et al., 2010).
The young man’s mother, the team found, also carried the FUS mutation, yet had no ALS symptoms at 47. Several mutations in FUS and other ALS genes have a wide range of onset (see table), causing disease in individuals as young as 13 or as old as 72 (see ARF related news story on Yan et al., 2010).
“The major message here is that there is a good deal of heterogeneity in all forms of ALS,” wrote Richard Bedlack of the Duke ALS Clinic in Durham, North Carolina, in an email to ARF (see full comment below). “This includes variability in penetrance, age and site of onset, co-morbidities (for example dementia) and progression rate.” Bedlack did not participate in the current case study.
ALS Genes Associated With Juvenile Onset
|Gene ||Age of Onset ||Reference|
|ALSIN ||3-20 ||Hadano et al., 2001; Yang et al., 2001 |
|SETX ||<25 ||Chen et al., 2004 |
|UBQLN2 ||16-71 ||Deng et al., 2011 |
|SIGMAR ||1-2 ||Al-Saif et al., 2011 |
|FUS ||20, 65 ||DeJesus-Hernandez et al., 2010 |
|17-22 ||Bäumer et al., 2010 |
|13, 21 ||Huang et al., 2010 |
|13-72 ||Yan et al., 2010 |
|20 ||Belzil et al., 2011 |
|19 ||Belzil et al., 2012 |
The variable onset, Rouleau said, could be the result of genetic or environmental factors. In the man in Montréal, the researchers used further sequencing to eliminate one potential genetic risk factor, that is, lengthy repeats in the ataxin 2 gene (see ARF related news story on Elden et al., 2010). In his case, they suspect that environmental toxins could have hastened disease. The young man had worked on farms around organophosphate fertilizers linked to neurodegeneration, as well as around heavy metals during a job in toxic waste recycling and training as a welder.
“I think we now need to focus hard on this variability... Mother Nature is trying to tell us something here!” Bedlack wrote. “We could, for example, use new tools such as whole genome microarray to compare fast and slow progressors.”—Amber Dance.
Belzil VV, Langlais JS, Daoud H, Dion PA, Brais B, Rouleau GA. Novel FUS deletion in a patient with juvenile amyotrophic lateral sclerosis. Arch Neurol. 2012 Jan 16. Abstract