Long before Huntington's disease: what matters most?
Authors: Anne-Catherine Bachoud-Lévi
Journal: The Lancet Neurology (2020)

Huntington's disease is an inherited, autosomal dominant, neurodegenerative disease. It manifests in adults through motor, cognitive, and psychiatric symptoms, typically leading to death in approximately 20 years from symptom onset. Because of its full penetrance, carriers of the mutated huntingtin gene with more than 40 CAG repeats will inevitably develop the disease. This predictability might provide an opportunity for early intervention with the emergence of disease-modifying therapies to lower mutant huntingtin protein concentrations. In The Lancet Neurology, Rachael Scahill and colleagues1Scahill RI Zeun P Osborne-Crowley K et al.Biological and clinical characteristics of gene carriers far from predicted onset in the Huntington's disease Young Adult Study (HD-YAS): a cross-sectional analysis.Lancet Neurol. 2020; 19: 502-512Summary Full Text Full Text PDF PubMed Scopus (25) Google Scholar report results from the Huntington's disease Young Adult Study (HD-YAS), in which they aimed to determine the best biomarkers for use in studies of disease-modifying therapies in young adult gene carriers (premanifest Huntington's disease [preHD]) far from predicted clinical symptom onset. Predicted age at clinical onset (defined by the appearance of motor symptoms) was estimated through the disease burden score combining age and number of CAG repeats. The investigators enrolled 64 participants with preHD (mean age 29·0 years [SD 5·6]) who were 23·6 years (SD 5·8) from predicted clinical onset, and 67 healthy controls matched for age, education, and sex. Controls either had a family history of Huntington's disease but a negative genetic test, or no known family history of Huntington's disease. Participants underwent neuropsychiatric and cognitive assessments, imaging (for those without contraindications), and assessment of biofluid markers from samples of blood and CSF collected from 83% of participants. There were no differences between preHD participants and controls in planning, flexibility, inhibition, attention, memory, learning, emotion recognition, or social cognition. PreHD participants self-reported similar levels of depression, anxiety, apathy, sleep, impulsivity, obsessive compulsion, and frontal behaviour to controls. Multimodal brain imaging identified slightly smaller putamen volumes in preHD individuals but this was not correlated with CAG repeats. Among the biomarkers assessed, YKL-40 and neurofilament light protein (NfL) concentrations were elevated in preHD CSF with only NfL being associated with CAG repeats and predicted age to onset. Despite the detection of mutant huntingtin in the CSF of preHD participants, the concentration was too low for reliable quantification in 53% of participants. Scahill and colleagues concluded that NfL is a sensitive biomarker in preHD participants approximately 24 years before predicted clinical onset. Combining an identified biomarker with the lack of subclinical symptoms, they propose this timepoint as optimum for initiating potential future preventive disease-modifying therapy. The comprehensiveness and rigor of HD-YAS is likely to make the study an important reference for future preHD studies. Huntingtin is essential for brain development and its total absence induces death. 10% of the normal huntingtin concentration can support survival and partial brain development in mice.2Kordasiewicz HB Stanek LM Wancewicz EV et al.Sustained therapeutic reversal of Huntington's disease by transient repression of huntingtin synthesis.Neuron. 2012; 74: 1031-1044Summary Full Text Full Text PDF PubMed Scopus (455) Google Scholar Lower weight, lower body-mass index, and smaller head circumference has been noted in preHD children aged 7–18 years compared with controls.3Lee JK Mathews K Schlaggar B et al.Measures of growth in children at risk for Huntington disease.Neurology. 2012; 79: 668-674Crossref PubMed Scopus (48) Google Scholar Gene carriers display cerebellar-striatal hyperconnectivity as early as age 6 years.4Tereshchenko AV Schultz JL Bruss JE Magnotta VA Epping EA Nopoulos PC Abnormal development of cerebellar-striatal circuitry in Huntington disease.Neurology. 2020; (published online April 7.)DOI:10.1212/WNL.0000000000009364Crossref PubMed Scopus (12) Google Scholar HD-YAS is therefore particularly important since the absence of any subclinical symptoms in preHD individuals far from onset shows that the abnormal developmental aspect of Huntington's disease has no substantial effect on adults' clinical pattern. This finding provides hope for the future of preventive therapy by focusing on the degenerative facet of Huntington's disease, and might relieve psychological burden in affected families. Whereas some symptoms were previously observed 15 years before disease onset,5Paulsen JS Long JD Johnson HJ et al.Clinical and biomarker changes in premanifest huntington disease show trial feasibility: a decade of the PREDICT-HD Study.Front Aging Neurosci. 2014; 6: 78Crossref PubMed Scopus (135) Google Scholar, 6Quaid KA Eberly SW Kayson-Rubin E et al.Factors related to genetic testing in adults at risk for Huntington disease: the prospective Huntington at-risk observational study (PHAROS).Clin Genet. 2017; 91: 824-831Crossref PubMed Scopus (11) Google Scholar the findings from Scahill and colleagues1Scahill RI Zeun P Osborne-Crowley K et al.Biological and clinical characteristics of gene carriers far from predicted onset in the Huntington's disease Young Adult Study (HD-YAS): a cross-sectional analysis.Lancet Neurol. 2020; 19: 502-512Summary Full Text Full Text PDF PubMed Scopus (25) Google Scholar showing their absence 24 years before clinical onset raises questions about therapeutic strategies. Yet, by enrolling 131 participants out of the 314 screened, and excluding individuals with psychiatric disorders or medication, low compliance, and a disease burden score of less than 240, might constitute a methodological limitation. First, the investigators might have excluded preHD individuals with measurable cognitive and psychiatric disorders. Reducing the variability of the preHD group limits the generalisability of the findings. Second, cognitive assessments used in the study might not have been optimum because they did not include some relevant domains. For example, language7Hinzen W Rossello J Morey C et al.A systematic linguistic profile of spontaneous narrative speech in pre-symptomatic and early stage Huntington's disease.Cortex. 2018; 100: 71-83Crossref PubMed Scopus (19) Google Scholar and calculation,8Nanetti L Contarino VE Castaldo A et al.Cortical thickness, stance control, and arithmetic skill: an exploratory study in premanifest Huntington disease.Parkinsonism Relat Disord. 2018; 51: 17-23Summary Full Text Full Text PDF PubMed Scopus (10) Google Scholar which showed capacity to discriminate controls from preHD close to onset in fewer than 20 participants, were not included. Ideally, more sensitive cognitive tasks including these domains should be designed for preHD participants. However, if reliable biomarkers are identified, the absence of clinical markers will not be a prerequisite for treatment initiation. The trade-off between decades of use of a disease-modifying therapy and potential detrimental and irreversible effects remains the key issue in Huntington's disease. Administering early treatment to people with substantial concentrations of relevant biomarkers but with no discomfort in real life might be tempting, but would it be beneficial for them? By contrast with spinal muscular atrophy, in which gene carriers die in childhood because of a loss-of-function effect of the survival of motor neuron gene,9Groen EJN Talbot K Gillingwater TH Advances in therapy for spinal muscular atrophy: promises and challenges.Nat Rev Neurol. 2018; 14: 214-224Crossref PubMed Scopus (102) Google Scholar Huntington's disease manifests mainly in adulthood, combining both toxicity and function loss of mutant huntingtin. Thus, the optimum period for initiating a disease-modifying therapy might not be as early in Huntington's disease as in spinal muscular atrophy, because the optimum calibration of huntingtin concentrations might be of more importance and cannot be controlled over decades with currently available strategies. The best window for treatment should instead target the time when a detectable subclinical slope of cognitive performance allows for predicting disease onset within a few years. Turning to machine learning methodology, such as that in oncology, might also permit combining the best window and the best disease-modifying therapy for individuals with preHD. For example, this approach would allow the inclusion of additional information, such as modifiers of disease evolution (eg, the COMT polymorphism).10de Diego-Balaguer R Schramm C Rebeix I et al.COMT Val158Met polymorphism modulates Huntington's disease progression.PLoS One. 2016; 11e0161106Crossref PubMed Scopus (11) Google Scholar Altogether, the most robust findings of HD-YAS1Scahill RI Zeun P Osborne-Crowley K et al.Biological and clinical characteristics of gene carriers far from predicted onset in the Huntington's disease Young Adult Study (HD-YAS): a cross-sectional analysis.Lancet Neurol. 2020; 19: 502-512Summary Full Text Full Text PDF PubMed Scopus (25) Google Scholar are the sensitiveness of NfL compared with mutant huntingtin in CSF of individuals with preHD, and that degenerative rather than developmental disorders are clinically relevant. Therapeutic intervention in preHD is likely to rely mostly on biomarkers at this stage. A-CB-L reports grants and personal fees from Roche, and grants from the French Ministry of Health and Direction de la Recherche Clinique. Biological and clinical characteristics of gene carriers far from predicted onset in the Huntington's disease Young Adult Study (HD-YAS): a cross-sectional analysisWe report normal brain function yet a rise in sensitive measures of neurodegeneration in a preHD cohort approximately 24 years from predicted clinical onset. CSF NfL appears to be a more sensitive measure than plasma NfL to monitor disease progression. This preHD cohort is one of the earliest yet studied, and our findings could be used to inform decisions about when to initiate a potential future intervention to delay or prevent further neurodegeneration while function is intact. Full-Text PDF Open Access