Understanding Key Clinical and Genetic Biomarkers in Huntington Disease Research: Sarah O'Shea, MD, MSc

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"In Huntington disease, we want to track the neuropathological and the clinical progression, and we want to make sure these are sensitive to potential disease-modifying treatments, which I'll talk about in a little bit. The most commonly used ones, not only in research but also in the clinic, are clinical."

Huntington disease (HD), a progressive neurodegenerative disorder, is caused by an abnormal expansion of CAG trinucleotide repeats in the Huntingtin (HTT) gene. Despite its primary manifestations as a result of central nervous system pathology, evidence increasingly supports the presence of peripheral disease components. The clinical presentation of HD is heterogeneous among carriers of the CAG expansion, with variability in symptom profile, age at onset, and disease severity. Although the monogenic nature of HD enables definitive genetic diagnosis, reliable biomarkers with prognostic and monitoring value remain essential for management.¹

To explore more of biomarkers in HD, NeurologyLive^® recently spoke with movement disorder specialist Sarah O'Shea, MD, MSc, an associate professor of neurology at the Icahn School of Medicine at Mount Sinai.In the interview, O’Shea described the range of biomarkers used to understand and monitor HD, emphasizing both clinical and genetic measures. She highlighted the Unified Huntington’s Disease Rating Scale and Total Functional Capacity as standard clinical tools for assessing motor, cognitive, and functional decline.

On the genetic side, O’Shea noted that the number of CAG repeats in the HTT gene and the presence of mutant HTT (mHTT) can serve as definitive indicators for diagnosis and therapeutic monitoring. During the conversation, she also emphasized the growing importance of neurofilament light chain (NfL) as a biomarker of neuronal injury, which correlates with disease severity and brain atrophy, underscoring its potential utility in clinical trials and patient management.

REFERENCES
1. Martí-Martínez S, Valor LM. A Glimpse of Molecular Biomarkers in Huntington's Disease. Int J Mol Sci. 2022;23(10):5411. Published 2022 May 12. doi:10.3390/ijms23105411