Twin Study Suggests Environment Modifies Genetic Risk for ALS

Twins who came to an ALS Clinic in Toronto were identical down to the repeats in their C9ORF72 genes, except one had amyotrophic lateral sclerosis and the other did not. The mismatch suggests environmental influences modified the twins’ risk for ALS, researchers concluded in the September 10 Neurology online. More studies of identical twins with C9ORF72 repeats should help scientists identify such factors, said Ekaterina Rogaeva of the University of Toronto, senior author on the report.

Co-senior author Lorne Zinman of the Sunnybrook Health Sciences Centre in Toronto examined the women, who are now 62. One developed motor neuron symptoms at age 57, although she performed normally on cognitive tests. Her sister shows no signs of ALS. However, the unaffected twin performed poorly on some cognitive tests and though her scores were not low enough to conclude she has frontotemporal dementia (FTD), they suggest she might be headed in that direction, said Rogaeva.

 

Pedigree of the study family.

One of the twins (row III) and likely their father and his sibling (row II) had ALS, as indicated by the filled diamond. The study authors also measured repeats in the C9ORF72 intron of each chromosome, indicated by a number or “exp” in the case of the lengthy expansion. [Republished with permission, © 2014 American Academy of Neurology]

 

The authors were surprised by the clinical differences between the twins. “We doubted at first that they were identical,” Rogaeva told Alzforum; she and Zinman previously came across a set of twins who believed themselves identical but were in fact fraternal. In this latest case, however, genetic testing confirmed the twins were indeed monozygotic and had similar numbers of C9ORF72 repeats. While it is difficult to count the number of repeats precisely, first author Zhengrui Xi of the University of Toronto and colleagues used Southern blotting to measure approximately 1,000 repeats in blood samples from both twins. Repeats in the first intron of C9ORF72, which codes for a gene of unknown function, predispose people to ALS, frontotemporal dementia, or a combination of both.

If the unaffected twin does go on to develop FTD, this would be the first case of identical twins with a C9ORF72 expansion developing two different diseases. Two other identical pairs with C9ORF72 expansions have been described in the literature. In one set both twins had ALS, starting at age 55, though one lived for a further two years and the other for seven (Pamphlett et al., 2013). In the other set, one twin developed ALS at age 47 and the other remained healthy until at least age 50, when both were examined. The authors of that study found that the length of the repeat was different between the two twins (Dols-Icardo et al., 2013).

Dissimilar pairs like these raise questions about how one mutation could cause disease in only one of the twins, or even a different disease in each. However, researchers cautioned that in this new case, the unaffected twin could still develop ALS. Stuart Pickering-Brown of the University of Manchester in the United Kingdom noted that the twins’ father, who was not officially diagnosed with ALS but was unable to speak for three years before he died, was neurologically healthy until the age of 76 (see image above). Pickering-Brown was not involved in the Neurology study.

“This is a very interesting finding, since it shows that inherited gene variations are not necessarily what drives ALS versus FTD,” wrote Ammar Al-Chalabi of King’s College London in an email to Alzforum. “Other explanations would include environmental exposures, epigenetic effects, somatic mutation or chance,” added Al-Chalabi, who was not involved in the study. Xi and colleagues investigated epigenetics by looking at methylation patterns just 5’ of the C9ORF72 gene, but no one in the family had any unusual modifications at that locus. Rogaeva is developing a method to look within the repeats themselves for methylation, she told Alzforum. Pickering-Brown pointed out that there still could be epigenetic modifications outside of C9ORF72 protecting the unaffected twin.

Another possible genetic explanation, Rogaeva said, could lie in the propensity of the C9ORF72 repeat region to change size over time, even in the same individual (see Jan 2013 news story). Theoretically, the twin with ALS might have larger repeats in her motor neurons than her sister, but the researchers will not be able to determine this while the woman is still alive. Zinman and colleagues will continue to monitor the women and their symptoms.

To assess possible environmental risk factors, the authors asked the twins about their lives. The two were remarkably similar, Rogaeva noted; they even had the same career, store clerk. Two differences stood out: the twin with ALS smoked for 10 years, and suffered a head injury a year before her symptoms started. Both smoking and head trauma have been potentially linked to ALS (see Aug 2010 news story; Alonso et al., 2010).

“Since this is just one case, we cannot really conclude anything,” pointed out Guy Rouleau of McGill University in Montréal, who did not participate in the work. Rogaeva told Alzforum that, at minimum, the study suggests that some environmental factor is influencing age of ALS onset in these twins, and that more studies like this are needed. She said geneticists worldwide would have to collaborate to accumulate sufficient twin pairs to identify modifiers of the C9ORF72 phenotype. “It is very important to collect not only genetic information but also details on environmental exposure, just to make sure that we are not missing potential environmental factors,” she said. Researchers have already identified two potential genetic modifiers to the C9ORF72 phenotype. Scientists determined that a variant in transmembrane protein 106B (TMEM106B) acts as a genetic modifier, protecting C9ORF72 carriers from FTD, but not ALS (see Nov 2013 news story and van Blitterswijk et al., 2014). In addition, repeats in another gene, ataxin-2, may push the phenotype in the ALS direction in C9ORF72 expansion carriers, scientists recently reported (see Sep 2014 news story). Neither of these would explain differences between identical twins.

Rouleau and Al-Chalabi agreed it should be possible to collect enough identical twins with C9ORF72 expansions to investigate the risk mechanisms. Al-Chalabi estimated that based on C9ORF72 expansion rates, about four of the 49 identical pairs in an ALS twin study he performed should be carriers (Al-Chalabi et al., 2010). Michael van Es of the University Medical Center Utrecht in the Netherlands is taking a similar approach. He and colleagues have collected 30 pairs of identical twins in which only one has ALS, though they are not C9ORF72 expansion carriers. The researchers have performed sequencing and methylation mapping on the whole genome, and are looking for more twins as they continue to analyze their data. “As always in genetics, the more the better,” van Es wrote in an email to Alzforum.

—Amber Dance

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References

News Citations

  1. Chicago—Dynamic Repeats: C9ORF72 Expands and Shrinks in ALS
  2. TDP-43 and Tau Entangle Athletes’ Nerves in Rare Motor Neuron Disease
  3. Researchers Revel in C9ORF72 Advances at RNA Symposium
  4. Ataxin 2 Variants Take Aim at Motor Neurons, Not Frontal Cortex

Paper Citations

  1. Pamphlett R, Cheong PL, Trent RJ, Yu B. Can ALS-associated C9orf72 repeat expansions be diagnosed on a blood DNA test alone?. PLoS One. 2013;8(7):e70007. Print 2013 PubMed.
  2. Dols-Icardo O, García-Redondo A, Rojas-García R, Sánchez-Valle R, Noguera A, Gómez-Tortosa E, Pastor P, Hernández I, Esteban-Pérez J, Suárez-Calvet M, Antón-Aguirre S, Amer G, Ortega-Cubero S, Blesa R, Fortea J, Alcolea D, Capdevila A, Antonell A, Lladó A, Muñoz-Blanco JL, Mora JS, Galán-Dávila L, Rodríguez de Rivera FJ, Lleó A, Clarimón J. Characterization of the repeat expansion size in C9orf72 in amyotrophic lateral sclerosis and frontotemporal dementia. Hum Mol Genet. 2013 Oct 8; PubMed.
  3. Alonso A, Logroscino G, Hernán MA. Smoking and the risk of amyotrophic lateral sclerosis: a systematic review and meta-analysis. J Neurol Neurosurg Psychiatry. 2010 Nov;81(11):1249-52. PubMed.
  4. van Blitterswijk M, Mullen B, Nicholson AM, Bieniek KF, Heckman MG, Baker MC, DeJesus-Hernandez M, Finch NA, Brown PH, Murray ME, Hsiung GY, Stewart H, Karydas AM, Finger E, Kertesz A, Bigio EH, Weintraub S, Mesulam M, Hatanpaa KJ, White CL 3rd, Strong MJ, Beach TG, Wszolek ZK, Lippa C, Caselli R, Petrucelli L, Josephs KA, Parisi JE, Knopman DS, Petersen RC, Mackenzie IR, Seeley WW, Grinberg LT, Miller BL, Boylan KB, Graff-Radford NR, Boeve BF, Dickson DW, Rademakers R. TMEM106B protects C9ORF72 expansion carriers against frontotemporal dementia. Acta Neuropathol. 2014 Mar;127(3):397-406. Epub 2014 Jan 3 PubMed.
  5. Al-Chalabi A, Fang F, Hanby MF, Leigh PN, Shaw CE, Ye W, Rijsdijk F. An estimate of amyotrophic lateral sclerosis heritability using twin data. J Neurol Neurosurg Psychiatry. 2010 Dec;81(12):1324-6. Epub 2010 Sep 22 PubMed.

External Citations

  1. C9ORF72
  2. TMEM106B
  3. ataxin-2

Further Reading

Papers

  1. van Blitterswijk M, DeJesus-Hernandez M, Niemantsverdriet E, Murray ME, Heckman MG, Diehl NN, Brown PH, Baker MC, Finch NA, Bauer PO, Serrano G, Beach TG, Josephs KA, Knopman DS, Petersen RC, Boeve BF, Graff-Radford NR, Boylan KB, Petrucelli L, Dickson DW, Rademakers R. Association between repeat sizes and clinical and pathological characteristics in carriers of C9ORF72 repeat expansions (Xpansize-72): a cross-sectional cohort study. Lancet Neurol. 2013 Oct;12(10):978-88. Epub 2013 Sep 5 PubMed.
  2. Fang F, Kamel F, Lichtenstein P, Bellocco R, Sparén P, Sandler DP, Ye W. Familial aggregation of amyotrophic lateral sclerosis. Ann Neurol. 2009 Jul;66(1):94-9. PubMed.
  3. McDade E, Boeve BF, Burrus TM, Boot BP, Kantarci K, Fields J, Lowe VJ, Peller P, Knopman D, Baker M, Finch N, Rademakers R, Petersen R. Similar clinical and neuroimaging features in monozygotic twin pair with mutation in progranulin. Neurology. 2012 Apr 17;78(16):1245-9. PubMed.
  4. Brown RC, Lockwood AH, Sonawane BR. Neurodegenerative diseases: an overview of environmental risk factors. Environ Health Perspect. 2005 Sep;113(9):1250-6. PubMed.
  5. Migliore L, Coppedè F. Genetics, environmental factors and the emerging role of epigenetics in neurodegenerative diseases. Mutat Res. 2009 Jul 10;667(1-2):82-97. PubMed.
  6. Al-Chalabi A, Hardiman O. The epidemiology of ALS: a conspiracy of genes, environment and time. Nat Rev Neurol. 2013 Nov;9(11):617-28. Epub 2013 Oct 15 PubMed.

Primary Papers

  1. Xi Z, Yunusova Y, van Blitterswijk M, Dib S, Ghani M, Moreno D, Sato C, Liang Y, Singleton A, Robertson J, Rademakers R, Zinman L, Rogaeva E. Identical twins with the C9orf72 repeat expansion are discordant for ALS. Neurology. 2014 Oct 14;83(16):1476-8. Epub 2014 Sep 10 PubMed.

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