Most mutations are stably transmitted from parent to offspring. This reliable genetic principle does not hold, however, for dynamic mutation disorders such as Fragile X syndrome or Huntington disease (HD). In these diseases, a sequence such as a CAG repeat tract can expand during transmission, likely through mechanisms involving replication or transcription (Khristich and Mirkin, 2020). In general, the longer the repeat, the earlier the patient develops overt symptoms and the more aggressive the disease is likely to be (Koshy and Zoghbi, 1997). Thus, in HD, modest expansions of 40 repeats in huntingtin gene (HTT) are associated with the appearance of motor, cognitive, and psychiatric disturbances in mid- or late adulthood, whereas large expansions of over 80 repeats cause childhood onset with additional features such as epilepsy and a more rapidly fatal course (Bates et al., 2015b; Sun et al., 2017). Yet on an individual subject basis, we cannot predict the disease course just from the size of the repeat tract: two individuals with the same length repeat expansion in HTT may experience disease onset decades apart (Andrew et al., 1993). The inherited pathological CAG repeat size accounts for about 42–71% of the age at onset in HD (Squitieri et al., 2006), though the confidence limits narrow for tracts longer than 50 CAGs (Andrew et al., 1993; Bates et al., 2015b; Langbehn et al., 2004; Rubinsztein et al., 1997; Wexler et al., 2004).

Part of the reason for such variability could be that HD is still thought of primarily as a movement disorder, so age at onset in HD is typically defined as the point at which motor symptoms become unequivocal. But abnormalities in the brain are present from early development (Barnat et al., 2020), and mutation carriers may experience cognitive deficits, psychiatric disturbances, or even subtle motor impairments years before diagnosis (Bates et al., 2015b). It is challenging, and somewhat misleading, to pinpoint age at onset in a disease that evolves insidiously like HD.

A more interesting explanation takes into account the fact that CAG repeats do not just expand in the germline. They are also somatically unstable, such that different CAG expansions can be identified in the same sample tissue from various organs and brain regions. Somatic mosaicism occurs both in mouse models of HD (Kennedy and Shelbourne, 2000; Larson et al., 2015; Lee et al., 2010) and in humans with HD (Kennedy et al., 2003; Swami et al., 2009; Telenius et al., 1994). The greatest increases in CAG tract length have been observed in the brain regions most affected in HD, the cerebral cortex and the striatum, whose neurons can harbor repeat tract expansions in the hundreds (Gonitel et al., 2008; Kennedy et al., 2003; Møllersen et al., 2010; Mouro Pinto et al., 2020; Shelbourne et al., 2007). Repeat expansions likely result from the formation of unusual DNA structures that predispose the tract to errors in mismatch repair (Khristich and Mirkin, 2020; Tabrizi et al., 2020). In fact, variants in several different DNA repair genes are associated with somatic instability in both animal models of HD (Dragileva et al., 2009; Pinto et al., 2013; Tomé et al., 2013) and HD patients (Ciosi et al., 2019; Flower et al., 2019; Lee et al., 2019).

Mounting evidence suggests that somatic repeat lengths better explain age at onset than the germline repeat, as their propensity to expand relates to both the baseline allele length and age (Ciosi et al., 2019; Lee et al., 2019). Interestingly, these data lend support to a mathematical model put forth over a decade ago (Kaplan et al., 2007). In brief, Kaplan et al. proposed that the onset and progression of triplet repeat diseases, including HD, are determined by the rate of somatic expansion in disease-relevant cells. Symptoms manifest when a critical proportion of cells (say, 20%) pass a pathogenic threshold, which would differ for different cell types. Their modeling suggests the threshold in striatal neurons for HD would be ~115 repeats. They further posited that at birth, nearly all cells would carry just the inherited number of repeats, but that over time the mutant alleles would further expand at a rate that increased linearly with the number of repeats. The rate of expansion would thus determine how rapidly the pathological state is reached, and thus should influence disease onset and progression.

The Kaplan model is quite compelling, but to test its predictions requires longitudinal data to study the evolution of somatic instability over time within patients. Given that the HTT mutation was discovered less than thirty years ago, such a study is only now becoming feasible. Even so, there are limits to how much of the model can be tested in humans. We cannot, for example, sample neurons over the life span to see how many come to exceed 115 repeats, or tally the proportion of neurons that reach a pathogenic threshold before phenoconversion. Nevertheless, we have been able to measure somatic repeat expansions in blood samples from HD carriers and patients over a twenty-year period and examine cortical tissue from mutation-carrying fetuses and deceased adults. By characterizing the degree of somatic expansion at these different stages, we were able to analyze associations between changes in the somatic expansion, age, and inherited CAG repeat length.

Our longitudinal study provides data that support the Kaplan model in several ways (Kaplan et al., 2007). First, the model predicts that at the beginning of life, all disease-relevant cells begin with the inherited repeat and negligible somatic instability. This turns out to be the case: we found almost no somatic mosaicism at the fetal stage. One might have expected that the high number of mitoses at this stage of brain development would make neural precursors sensitive to double-strand breaks and replication errors (Leija-Salazar et al., 2018; Schwer et al., 2016), but somatic expansions occur through different mechanisms than germline expansions (Khristich and Mirkin, 2020; Tabrizi et al., 2020). Although we did not have samples from embryos at later stages, there is such data for other diseases caused by repeat expansions. For instance, in Friedreich ataxia, which is caused by an expanded GAA repeat in the first intron on both alleles of the FXN gene, levels of instability found in tissues from an 18-week-old fetus were very low compared to adult-derived tissues (De Biase et al., 2007). In myotonic dystrophy, caused by a non-coding CTG repeat expansion in the DMPK gene, repeat instability was not observed at 13 weeks in fetal tissues, but a difference between tissues became detectable after 16 weeks (Martorell et al., 1997). All these studies suggest that, early in life, somatic instability is minimal.

Second, Kaplan et al. posited that somatic expansions should progress with age, even prior to disease onset. This also turns out to be correct: the presymptomatic carrier parents of fetal mutation carriers already showed somatic instability in the blood at the time of the pregnancy. It is remarkable, in fact, that increases in ER were evident despite our limited sample size and despite the fact that we had to derive this calculation from blood cells, which are not involved in HD pathogenesis and completely change over every six months or so. Unfortunately, for this very reason, the EI from the blood is not sufficient to predict AO, which is influenced by not only repeat length and somatic instability but other factors such as variants in DNA repair factors (see below).

Third, the model predicts the rate of allele expansion should increase with time and be a function of the repeat length at that time. This is indeed what we found: not just greater somatic expansions with age and reference repeat length (as represented by EI), but a greater propensity to expand with age (as represented by ER).

One prediction of the Kaplan model we could not test is that there should be different thresholds of somatic expansions that must be reached for different brain regions to become pathological. It is hard to imagine how this particular prediction of the model could be tested, other than by performing extensive neuropathological studies on a great many mice at many different disease stages. In terms of correlation between somatic instability and disease progression, we did find group-level differences in EI and ER between the premanifest and manifest state. We could not establish a correlation at the individual subject level, however, likely because of the limited sample size as well as the difficulty of pinpointing phenoconversion in a disease that continues to unfold over many years. Stronger evidence on this point came from a large study of nearly 750 HD mutation carriers, which showed that larger somatic expansions are associated with worse clinical outcomes (earlier AO, higher motor and progression scores) in HD (Ciosi et al., 2019).

The most interesting questions that remain to be answered have to do with what drives somatic instability. The brain regions that have the greatest repeat expansions in HD, the striatum and cortex, are hypermetabolic from early in the disease course (Tereshchenko et al., 2020), and neurons show greater somatic instability than glial cells in models and post mortem brains (Gonitel et al., 2008; Shelbourne et al., 2007). Metabolic stress may also lead to mitochondrial dysfunction and energy deficit in HD (Mochel et al., 2012; Roze et al., 2008; Tabrizi et al., 1999). An excess of excitatory glutamatergic inputs and NMDA receptor activation creates energy demands that are not sustainable in a context of diminished energy capacity, and may lead to cell death (Milnerwood et al., 2010; Mochel and Haller, 2011).

In fact, an excitotoxicity model of neurodegeneration was proposed for HD many years before the discovery of the genetic basis of the disease (Coyle and Schwarcz, 1976; Mcgeer and Mcgeer, 1976). The medium spiny neurons of the caudate and putamen, which are the most vulnerable in HD, receive their main input from cortical glutamatergic neurons; they are thus particularly susceptible to excitation and, in fact, HD can be mimicked by administering glutamate analogues to the striatum (Coyle and Schwarcz, 1976; Estrada Sánchez et al., 2008; Mcgeer and Mcgeer, 1976). In this context it is worth noting that variants in the GluR6 kainate receptor locus were found to account for 13% of variation in AO that was not provided by CAG repeat number (Rubinsztein et al., 1997). Along similar lines, a recent study showed that absence of the aryl hydrocarbon receptor (AhR), which protects mice from excitotoxicity, greatly reduced behavioral deficits in the R6/1 transgenic model of HD (Angeles-López et al., 2021).

Hypermetabolism would also contribute to oxidative stress, which can cause DNA damage (Iyer and Pluciennik, 2021; Leija-Salazar et al., 2018). Large-scale studies have linked somatic CAG expansions in patients’ blood to the presence of variants in DNA repair genes, not just in HD (Ciosi et al., 2019; Lee et al., 2019) but in other polyglutamine diseases as well (Bettencourt et al., 2016). In HD, somatic instability is influenced by polymorphisms in MSH3, MLH1, MlH3, and FAN1, which are all involved in DNA repair (Ciosi et al., 2019). Counterintuitively, loss of function of some DNA repair factors can be protective: knockout of Msh2 or Msh3 in a knock-in model of HD prevents CAG expansions in the striatum (Pinto et al., 2013). The reason for this may be that transcriptionally active genes elicit mismatch repair activity to guard genomic integrity, but long repeat tracts are difficult to repair accurately (Iyer and Pluciennik, 2021). A different mechanism is at work for FAN1, which actually stabilizes the CAG repeat in HD (Goold et al., 2019); loss of FAN1 function increases repeat instability (Kim et al., 2020; Loupe et al., 2020). Interestingly, there is evidence that double-strand break repair is dysregulated in HD: ATM (ataxia-telengiectasia mutated) is upregulated in brain tissue from HD mice and patients, and its heterozygous loss of function is protective in both mouse and Drosophila models of HD (Lu et al., 2014). It could be that the decline in DNA repair capacity or efficiency that comes with age (Gorbunova et al., 2007) contributes to the increasing somatic instability in blood cells, which, as we noted above, seem too short-lived to accumulate expansions as they do. An extended longitudinal study of the effect of DNA repair gene variants on somatic instability would be of great interest.

Given that somatic instability influences disease progression, targeting the repeat instability is a very appealing disease-modifying strategy (Khristich and Mirkin, 2020). One possibility is to introduce DNA-stabilizing interruptions into the repeat tract via gene editing (Ciosi et al., 2019). Another is to modulate DNA repair activity in HD to retard somatic expansions (Dragileva et al., 2009; Pinto et al., 2013), but this might also run the risk of increasing overall genomic instability. A recent approach using a small molecule that specifically binds CAG slip-out structures was able to contract the expansions and reduce protein aggregates in the striatum of R6/2 mice (Nakamori et al., 2020). Further efforts to stabilize or contract somatic expansions are warranted, particularly if expansions within brain tissue can be reduced. Last but not least, there is much more work to be done to understand the mechanisms that trigger somatic expansions, whether they relate to excitotoxicity, and how they lead to neurodegeneration.

All patient data generated and analyzed are included in the manuscript and available in Tables 1, 2 and 3.

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Author details

1. Radhia Kacher

   1. Sorbonne Université, Paris Brain Institute (ICM Institut du Cerveau), AP-HP, INSERM, CNRS, University Hospital Pitié-Salpêtrière, Paris, France
   2. Univ. Grenoble Alpes, INSERM, U 1216, Grenoble Institut Neurosciences, Grenoble, France

   Contribution

   Conceptualization, Resources, Data curation, Formal analysis, Investigation, Methodology, Writing - original draft, Writing - review and editing

   Competing interests

   No competing interests declared

   "This ORCID iD identifies the author of this article:" 0000-0003-4679-7361

2. François-Xavier Lejeune

   1. Sorbonne Université, Paris Brain Institute (ICM Institut du Cerveau), AP-HP, INSERM, CNRS, University Hospital Pitié-Salpêtrière, Paris, France
   2. Paris Brain Institute’s Data and Analysis Core, University Hospital Pitié-Salpêtrière, Paris, France

   Contribution

   Software, Formal analysis, Methodology, Writing - original draft

   Competing interests

   No competing interests declared

3. Sandrine Noël

   Neurogenetics Laboratory, Department of Genetics, Assistance Publique–Hôpitaux de Paris, University Hospital Pitié-Salpêtrière, Paris, France

   Contribution

   Resources, Software, Methodology

   Competing interests

   No competing interests declared

4. Cécile Cazeneuve

   Neurogenetics Laboratory, Department of Genetics, Assistance Publique–Hôpitaux de Paris, University Hospital Pitié-Salpêtrière, Paris, France

   Contribution

   Conceptualization, Resources, Methodology

   Competing interests

   No competing interests declared

5. Alexis Brice

   Sorbonne Université, Paris Brain Institute (ICM Institut du Cerveau), AP-HP, INSERM, CNRS, University Hospital Pitié-Salpêtrière, Paris, France

   Contribution

   Validation, Investigation, Writing - original draft

   Competing interests

   No competing interests declared

6. Sandrine Humbert

   Univ. Grenoble Alpes, INSERM, U 1216, Grenoble Institut Neurosciences, Grenoble, France

   Contribution

   Conceptualization, Supervision, Funding acquisition, Validation, Investigation, Writing - original draft, Writing - review and editing

   For correspondence

   sandrine.humbert@univ-grenoble-alpes.fr

   Competing interests

   No competing interests declared

   "This ORCID iD identifies the author of this article:" 0000-0002-9501-2658

7. Alexandra Durr

   1. Sorbonne Université, Paris Brain Institute (ICM Institut du Cerveau), AP-HP, INSERM, CNRS, University Hospital Pitié-Salpêtrière, Paris, France
   2. Neurogenetics Laboratory, Department of Genetics, Assistance Publique–Hôpitaux de Paris, University Hospital Pitié-Salpêtrière, Paris, France

   Contribution

   Conceptualization, Resources, Supervision, Funding acquisition, Validation, Investigation, Methodology, Writing - original draft, Project administration, Writing - review and editing

   For correspondence

   alexandra.durr@icm-institute.org

   Competing interests

   serves on the advisory boards of Triplet Therapeutics. and holds partly a Patent B 06291873.5, "Anaplerotic therapy of HD and other polyglutamine diseases."

   "This ORCID iD identifies the author of this article:" 0000-0002-8921-7104

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