Unusual ALS Case Highlights Variable Onset

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, comorbidities (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

Comments

  1. In my opinion the major message here is that there is a good deal of heterogeneity in all forms of ALS, even in specific subtypes of familial ALS such as this. This includes variability in penetrance, age and site of onset, comorbidities (for example dementia) and rate of progression. There are several possible reasons for this type of variability, including the specific site of each person's mutation within a given gene, possible modifier genes (for example kifap 3), and also possible environmental influences (for example exercise, lipid status).

    Personally I think we now need to focus hard on this variability between patients....mother nature is trying to tell us something here! We could for example use new tools such as whole-genome microarray to compare fast and slow progressors. If we can understand this variability we may be able to shift patients' systems over to a more favorable phenotype even if we don't fully understand why it works.

    View all comments by Richard Bedlack

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References

News Citations

  1. Going Nuclear: First Function for FUS Mutants
  2. Research Brief: FUS Rears Its Head in Juvenile ALS, Too
  3. New ALS Genes Implicate Protein Degradation, Endoplasmic Reticulum
  4. New Gene for ALS: RNA Regulation May Be Common Culprit
  5. ALS—A Polyglutamine Disease? Mid-length Repeats Boost Risk

Paper Citations

  1. Dormann D, Rodde R, Edbauer D, Bentmann E, Fischer I, Hruscha A, Than ME, Mackenzie IR, Capell A, Schmid B, Neumann M, Haass C. ALS-associated fused in sarcoma (FUS) mutations disrupt Transportin-mediated nuclear import. EMBO J. 2010 Aug 18;29(16):2841-57. PubMed.
  2. Yan J, Deng HX, Siddique N, Fecto F, Chen W, Yang Y, Liu E, Donkervoort S, Zheng JG, Shi Y, Ahmeti KB, Brooks B, Engel WK, Siddique T. Frameshift and novel mutations in FUS in familial amyotrophic lateral sclerosis and ALS/dementia. Neurology. 2010 Aug 31;75(9):807-14. Epub 2010 Jul 28 PubMed.
  3. Hadano S, Hand CK, Osuga H, Yanagisawa Y, Otomo A, Devon RS, Miyamoto N, Showguchi-Miyata J, Okada Y, Singaraja R, Figlewicz DA, Kwiatkowski T, Hosler BA, Sagie T, Skaug J, Nasir J, Brown RH, Scherer SW, Rouleau GA, Hayden MR, Ikeda JE. A gene encoding a putative GTPase regulator is mutated in familial amyotrophic lateral sclerosis 2. Nat Genet. 2001 Oct;29(2):166-73. PubMed.
  4. Yang Y, Hentati A, Deng HX, Dabbagh O, Sasaki T, Hirano M, Hung WY, Ouahchi K, Yan J, Azim AC, Cole N, Gascon G, Yagmour A, Ben-Hamida M, Pericak-Vance M, Hentati F, Siddique T. The gene encoding alsin, a protein with three guanine-nucleotide exchange factor domains, is mutated in a form of recessive amyotrophic lateral sclerosis. Nat Genet. 2001 Oct;29(2):160-5. PubMed.
  5. Deng HX, Chen W, Hong ST, Boycott KM, Gorrie GH, Siddique N, Yang Y, Fecto F, Shi Y, Zhai H, Jiang H, Hirano M, Rampersaud E, Jansen GH, Donkervoort S, Bigio EH, Brooks BR, Ajroud K, Sufit RL, Haines JL, Mugnaini E, Pericak-Vance MA, Siddique T. Mutations in UBQLN2 cause dominant X-linked juvenile and adult-onset ALS and ALS/dementia. Nature. 2011 Sep 8;477(7363):211-5. PubMed.
  6. Al-Saif A, Al-Mohanna F, Bohlega S. A mutation in sigma-1 receptor causes juvenile amyotrophic lateral sclerosis. Ann Neurol. 2011 Dec;70(6):913-9. PubMed.
  7. Bäumer D, Hilton D, Paine SM, Turner MR, Lowe J, Talbot K, Ansorge O. Juvenile ALS with basophilic inclusions is a FUS proteinopathy with FUS mutations. Neurology. 2010 Aug 17;75(7):611-8. PubMed.
  8. Huang EJ, Zhang J, Geser F, Trojanowski JQ, Strober JB, Dickson DW, Brown RH, Shapiro BE, Lomen-Hoerth C. Extensive FUS-immunoreactive pathology in juvenile amyotrophic lateral sclerosis with basophilic inclusions. Brain Pathol. 2010 Nov;20(6):1069-76. PubMed.
  9. Elden AC, Kim HJ, Hart MP, Chen-Plotkin AS, Johnson BS, Fang X, Armakola M, Geser F, Greene R, Lu MM, Padmanabhan A, Clay-Falcone D, McCluskey L, Elman L, Juhr D, Gruber PJ, Rüb U, Auburger G, Trojanowski JQ, Lee VM, Van Deerlin VM, Bonini NM, Gitler AD. Ataxin-2 intermediate-length polyglutamine expansions are associated with increased risk for ALS. Nature. 2010 Aug 26;466(7310):1069-75. PubMed.

External Citations

  1. ALSIN
  2. 3-20
  3. Chen et al., 2004
  4. DeJesus-Hernandez et al., 2010
  5. Belzil et al., 2011
  6. Belzil et al., 2012

Further Reading

Papers

  1. Hanson KA, Kim SH, Tibbetts RS. RNA-binding proteins in neurodegenerative disease: TDP-43 and beyond. Wiley Interdiscip Rev RNA. 2011 Oct 25; PubMed.
  2. Fiesel FC, Kahle PJ. TDP-43 and FUS/TLS: cellular functions and implications for neurodegeneration. FEBS J. 2011 Oct;278(19):3550-68. PubMed.
  3. Strong MJ, Volkening K. TDP-43 and FUS/TLS: sending a complex message about messenger RNA in amyotrophic lateral sclerosis?. FEBS J. 2011 Oct;278(19):3569-77. PubMed.
  4. Sproviero W, La Bella V, Mazzei R, Valentino P, Rodolico C, Simone IL, Logroscino G, Ungaro C, Magariello A, Patitucci A, Tedeschi G, Spataro R, Condino F, Bono F, Citrigno L, Monsurrò MR, Muglia M, Gambardella A, Quattrone A, Conforti FL. FUS mutations in sporadic amyotrophic lateral sclerosis: Clinical and genetic analysis. Neurobiol Aging. 2011 Nov 3; PubMed.
  5. Talbot K, Lowe J, Ansorge O, Hilton D, Bäumer D, Paine S, Turner M. PATU5 Characterisation of fused in sarcoma pathology and FUS mutations in juvenile amyotrophic lateral sclerosis with basophilic inclusions. J Neurol Neurosurg Psychiatry. 2010 Nov;81(11):e25. PubMed.
  6. Orlacchio A, Babalini C, Borreca A, Patrono C, Massa R, Basaran S, Munhoz RP, Rogaeva EA, St George-Hyslop PH, Bernardi G, Kawarai T. SPATACSIN mutations cause autosomal recessive juvenile amyotrophic lateral sclerosis. Brain. 2010 Feb;133(Pt 2):591-8. PubMed.

Primary Papers

  1. 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 May;69(5):653-6. PubMed.

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