Dreaded Anticipation: ALS Strikes Earlier in Successive Generations

While each new generation hopes to live better than the last, the reality may be different in families stricken with hexanucleotide repeat expansions in the C9ORF72 gene—the most common genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). A study published February 13 in JAMA Neurology reported that with each successive generation that inherits the expansions, disease symptoms start earlier in life. Piecing together clinical histories in 36 families, researchers led by Christine Van Broeckhoven of the VIB Center for Molecular Neurology at the University of Antwerp in Belgium found that over four generations, the average age at onset slid from 62 to 49. Even though tools to accurately size long repeat tracts still elude scientists, they now think ballooning expansions underlie this effect.

“These findings provide an indirect confirmation that the size of the expansion is important in human disease,” commented Johnathan Cooper-Knock of the University of Sheffield in the U.K. He added that while the study is the largest one so far to look at disease anticipation in C9ORF72 expansion carriers, larger studies are still needed to confirm the effect.

Called “disease anticipation,” the phenomenon has been documented in other degenerative diseases caused by run-on repeat sequences in the DNA, including Huntington’s disease, spinocerebellar ataxia, and muscular dystrophy (see Duyao et al., 1993; Albuquerque et al., 2015; and Savić Pavićević et al., 2013). Due to their inherent instability during DNA replication, repeat expansions tend to increase in length from one generation to the next, and can expand further in different tissues throughout life (see Jones et al., 2017). The age at onset of these disorders varies markedly, and researchers suspect that expansion length could be responsible.

In the case of GGGGCC repeat expansions in C9ORF72, age at onset can range from the 20s to 80s, and pathological expansions range from as few as 45 repeats to several thousand. However, repeat length is difficult to measure and can even vary between tissues in a given person. Hence scientists still debate whether the size of the expansion dictates onset or severity of disease (see van Blitterswijk et al., 2013; Nov 2013 conference news; and Cooper-Knock et al., 2014).

In a previous study, Van Broeckhoven and colleagues tried to cross this technical hurdle by using methylation as a proxy for repeat length. They reported that, in a Belgian cohort, longer expansions were more heavily methylated, and also that people harboring the longer repeats were younger at onset than people with shorter expansions (see Nov 2014 conference news and Gijselinck et al., 2016). In 13 pairs of parent-child transmission, they found that the child’s repeat tended to be longer, as inferred by methylation. In a subset of these pairs, age at onset also dropped. Because there were few parents with available genetic data, the number of parent-child pairs was insufficient to prove disease anticipation occurred.

For the current study, first author Sara Van Mossevelde and colleagues leveraged ongoing and historical clinical data on 36 multigenerational families in whom C9ORF72 expansions triggered FTD, ALS, or both. Age at onset data was as ascertained by clinical records or by asking living family members, and was available for two generations in 21 families, three generations in 13 families, and four generations in two families. The researchers found that among the 111 affected people, symptoms popped up in the oldest generations at a later age—62.5 years of age, on average. Successive generations had average ages at onset of 57.1, 54.6, and 49.3.

While men were younger than women when symptoms began, the sex of the affected parent did not influence the age at onset of his or her offspring. This suggested that differences in the stability of expansions in sperm versus egg did not significantly factor into onset age.

In addition to earlier onset, could the course of the disease also change from one generation to the next? Not according to this study. Among 124 affected people, there were no significant differences in age at death among the generations. In 87 of those for whom age at onset was available, the researchers found no significant differences in disease duration between generations. While people within any generation had shorter disease spans if they became symptomatic at an older age, this was likely due to the fact that they were older and more vulnerable to comorbidities, the researchers speculated. Unsurprisingly, people with ALS had shorter disease spans than those with FTD.

Cooper-Knock told Alzforum that the findings add weight to the predominant hypothesis— supported primarily by tissue culture experiments—that longer repeats have more toxic effects than shorter ones. He pointed out that the continued lack of adequate tools for accurately sizing large expansions prevents researchers from drawing this conclusion directly. That said, rough estimates hint that the length of expansions generally increases from one generation to the next. Why expansion size might influence disease onset but not duration remains to be seen, Cooper-Knock said. He proposed that perhaps long repeats hasten disease onset, but after that point, different processes govern the rate of progression.

Lesley Jones of Cardiff University in the U.K. added that a different, less satisfying, phenomenon could explain the generational effect: “As the authors note, small changes from generation to generation could be a result of ascertainment bias—that once a disease is known to segregate in a family, then it is more likely to be diagnosed earlier as family members and clinicians are primed to spot it,” Jones wrote. Without the means to accurately size the expansions, it is difficult to rule out the influence of ascertainment bias completely, she wrote. However, Van Mossevelde and colleagues did attempt to control for this in a separate analysis, in which they only included ages at onset determined by a physician, rather than hearsay from family members, and still saw a significant generational effect. While they could not completely account for the effect of improved diagnostic protocols over time, Van Broeckhoven said that relying on emergence of symptoms, rather than a formal diagnosis, helps lessen that issue.

Jones added that beyond size and stability of the repeat expansions, age at onset could also be modified by other genes, as has been documented in Huntington’s and other repeat disorders. Van Broeckhoven told Alzforum that her lab is currently in search of such genetic modifiers, as they could point the way to therapeutic targets.

The researchers are monitoring C9ORF72 expansion carriers who are still asymptomatic, Van Broeckhoven added. She said that while the current data suggests they will get the disease earlier than their parents did, larger studies are still needed to confirm the effect.

References

Van Mossevelde S, van der Zee J, Gijselinck I, Sleegers K, De Bleecker J, Sieben A, Vandenberghe R, Van Langenhove T, Baets J, Deryck O, Santens P, Ivanoiu A, Willems C, Bäumer V, Van den Broeck M, Peeters K, Mattheijssens M, De Jonghe P, Cras P, Martin JJ, Cruts M, De Deyn PP, Engelborghs S, Van Broeckhoven C, Belgian Neurology (BELNEU) Consortium. Clinical Evidence of Disease Anticipation in Families Segregating a C9orf72 Repeat Expansion. JAMA Neurol. 2017 Feb 13; PubMed.

Duyao M, Ambrose C, Myers R, Novelletto A, Persichetti F, Frontali M, Folstein S, Ross C, Franz M, Abbott M. Trinucleotide repeat length instability and age of onset in Huntington’s disease. Nat Genet. 1993 Aug;4(4):387-92. PubMed.

Albuquerque MV, Pedroso JL, Braga Neto P, Barsottini OG. Phenotype variability and early onset ataxia symptoms in spinocerebellar ataxia type 7: comparison and correlation with other spinocerebellar ataxias. Arq Neuropsiquiatr. 2015 Jan;73(1):18-21. PubMed.

Savić Pavićević D1, Miladinović J, Brkušanin M, Šviković S, Djurica S, Brajušković G, Romac S. Molecular genetics and genetic testing in myotonic dystrophy type 1. Biomed Res Int. 2013;2013:391821. PubMed.

Jones L, Houlden H, Tabrizi SJ. DNA repair in the trinucleotide repeat disorders. Lancet Neurol. 2017 Jan;16(1):88-96. PubMed.

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. PubMed.

Cooper-Knock J, Shaw PJ, Kirby J. The widening spectrum of C9ORF72-related disease; genotype/phenotype correlations and potential modifiers of clinical phenotype. Acta Neuropathol. 2014 Mar;127(3):333-45. Epub 2014 Feb 4 PubMed.

Gijselinck I, Van Mossevelde S, van der Zee J, Sieben A, Engelborghs S, De Bleecker J, Ivanoiu A, Deryck O, Edbauer D, Zhang M, Heeman B, Bäumer V, Van den Broeck M, Mattheijssens M, Peeters K, Rogaeva E, De Jonghe P, Cras P, Martin JJ, de Deyn PP, Cruts M, Van Broeckhoven C. The C9orf72 repeat size correlates with onset age of disease, DNA methylation and transcriptional downregulation of the promoter. Mol Psychiatry. 2015 Oct 20; PubMed.


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