A Genetic Mutation Explains Huntington’s Disease

Huntington’s disease is an inherited neurodegenerative disorder caused by an abnormality in the Huntingtin gene. This disease is characterized by involuntary movements, cognitive decline, and psychiatric and behavioral disorders. At the cellular level, it is marked by the accumulation of mutated Huntingtin protein as aggregates in the cell nucleus and a progressive loss of neurons, primarily in the striatum and cerebral cortex.

The Huntingtin gene contains a repeated sequence of three nucleotides, CAG, which codes for a series of glutamines. In a healthy individual, this sequence is repeated between 9 and 35 times. However, when this repetition exceeds 36 times, it leads to the production of an abnormal protein responsible for the disease. The higher the number of CAG repetitions, the earlier the symptoms appear. A repetition between 36 and 39 times may result in a late-onset form, while beyond 40 repetitions, the disease typically manifests in adulthood. In cases where the repetition exceeds 60 times, the disease can occur as early as childhood.

Huntington’s disease affects approximately 4.88 people per 100,000 worldwide, with a higher prevalence in Europe and North America than in Asia. Motor symptoms, such as chorea, often appear first, followed by cognitive and psychiatric disorders. Patients may also suffer from depression, anxiety, apathy, or behavioral disorders such as aggression. As the disease progresses, motor difficulties worsen, affecting walking, speech, and swallowing, which can lead to serious complications such as dysarthria and dysphagia.

At the cellular level, the mutated Huntingtin protein aggregates and disrupts many essential functions. It interferes with gene transcription, vesicle transport, mitochondrial function, and protein degradation. These disruptions lead to increased oxidative stress, excessive production of free radicals, and progressive cell death. The most affected neurons are those in the striatum, a brain region crucial for movement control.

The mechanisms of the disease also include RNA toxicity. The CAG repeats in messenger RNA form hairpin structures that trap RNA-binding proteins, thereby disrupting protein synthesis and RNA transport between the nucleus and the cytoplasm. This particularly affects neurons, where RNA plays a key role in regulating gene expression and cellular communication.

Current therapeutic approaches aim to alleviate symptoms or target the underlying mechanisms of the disease. Among symptomatic treatments, tetrabenazine and deutetrabenazine are used to reduce chorea. Antidepressants and antipsychotics may also be prescribed to manage psychiatric disorders. However, these treatments do not cure the disease and can cause significant side effects.

Recent advances include gene therapies and nucleic acid-based approaches. For example, antisense oligonucleotides can reduce the production of mutated Huntingtin protein by targeting its messenger RNA. Clinical trials are underway to evaluate the effectiveness of these treatments. Other strategies, such as gene editing with CRISPR-Cas9, allow direct correction of the defective gene. Stem cell therapies also offer hope by replacing damaged neurons with healthy cells.

Despite these advances, Huntington’s disease remains incurable. Researchers continue to explore new avenues to slow or halt the progression of the disease, targeting both neuronal mechanisms and peripheral dysfunctions, such as cardiac and metabolic disorders often associated with it. The challenges include improving the delivery of therapies to affected tissues, ensuring their long-term safety, and developing treatments capable of specifically targeting the cells or pathways involved.

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Reference Document

DOI: https://doi.org/10.1186/s13064-026-00282-5

Title: Molecular mechanisms, clinical phenotypes, and advances in Huntington’s disease therapeutics

Journal: Discover Neuroscience

Publisher: Springer Science and Business Media LLC

Authors: Athira M. Sarath; Deepti Thapliyal; Shreya Borthakur; Dipti Chakraborty; Naorem Tarundas Singh; Ritu Sarkar; Mayanglambam Dhruba Singh