A life shattered by Huntington's Disease

By Dr Maria Pannell

Emily is 42 years old. She has 2 young daughters and lives with her husband of 10 years, Dan. Emily works as an architect and enjoys competitive running in her spare time. Recently, while training for the Brighton marathon, she has increasingly noticed changes in her gait, her fatigue has increased and she fell over several times during a run. She has noticed in the past few years that her performance has declined, and she has also increasingly suffered from mood swings and irritability, but blamed it on aging or perimenopause. That last run caused concern though. She went to the GP who diagnosed stress, but following an incident at home where she fell off a ladder, she privately sought a referral with a neurologist. After ruling out schizophrenia and Parkinson's, Emily was diagnosed with Huntington’s disease. Emily’s mother died aged 30 in a car crash, but her maternal grandfather had died at 57 from a mysterious condition that was never discussed within the family. Genetic testing confirmed Huntington’s, and despite undergoing physical therapy, and being prescribed medications to ease the mental and physical symptoms, 10 years later Emily uses a wheelchair. She no longer works and has difficulty speaking and swallowing. Dan helps her wash and dress. She suffers from depression, fatigue and has trouble sleeping. She often suffers from mania, outbursts and inappropriate behaviour. The impact on family life is severe. So what causes this devastating disease? Is there any hope for treatment that can reverse or at least slow the relentless rampage?

When Emily underwent genetic testing, clinicians were looking for a tiny, but disastrous error in her genetic code. The huntingtin (HTT) gene, located on chromosome 4, is responsible for HD. A repeating sequence of three DNA bases: cytosine-adenine-guanine (CAG), is found on the gene, and this sequence can occur up to 35 times in healthy individuals (1). In HD, a CAG repeat length of 36 or more is the critical threshold. While individuals with 36-41 repeats have a chance of remaining symptom-free (2), repeats of 42 or more are disastrous, with the disease inescapable (3). So how can just a small increase in these repeats result in such monumental consequences?

The HTT gene encodes a protein called huntingtin, and its normal form is essential for brain development and function (4). The repeated CAG results in the huntingtin protein to be abnormally long and misshapen, making it prone to fragmentation and aggregation. These aggregates, or clumps, are toxic to nerve cells, particularly in a region of the brain called the striatum (5), although paradoxically the formation of huntingtin inclusions within cells has been found to be neuroprotective (6,7). The loss of neurons in the striatum, an area critical for motor control, is directly responsible for the involuntary movement known as chorea and other motor symptoms.

Huntington’s, which affects 1:10,000 individuals, is an autosomal dominant disorder, meaning that only one copy of the mutated HTT gene needs to be present from either parent to develop the disease. This also means a parent with HD has a 50% chance of passing on the mutated gene to their child. This 50% inheritance rate creates an agonizing cloud of uncertainty that hangs over families for generations.

As with the case study of Emily, HD typically manifests in a person's 30s or 40s, but sometimes later. This means that individuals live a significant portion of their lives without any symptoms, often marrying, having children, and building careers, all while a genetic time bomb ticks silently within them. The disease can be roughly divided into three stages: The first is typically characterized by mood disorders, cognitive deficits, and subtle impairments in motor control. In the second, chorea, derived from the Greek word for “dance”, became dominant. Motor skills such as gait, swallowing, and speech continue to deteriorate. Cognitive capacities also continue to decline, resulting in dementia. In the third stage, weight loss, general deterioration in health, and the replacement of chorea by bradykinesia and rigidity are the final features. 15 to 20 years after disease onset, death is imminent (8).

Current treatment of HD is limited to therapies which aim to ease symptoms, rather than slow or reverse the disease progression. For example the most commonly prescribed medication is targeted at reducing the chorea. Degeneration of the basal ganglia and striatum is a hallmark of HD, and has been linked to the development of this well known feature. Tetrabenazine was one of the first drugs licensed in the UK to treat HD associated chorea (9,10). This drug, along with the similar deutetrabenazine, work by inhibiting the transporter protein vesicular monoamine transporter 2 (VMAT2), which is responsible for dopamine release, which in turn causes the excessive movements of HD. Other treatments include antipsychotic medications such as olanzapine and risperidone; SSRI antidepressants such as Fluoxetine and sertraline; and mood stabilizers such as lamotrigine which can reduce HD related behavioral symptoms such as OCD and aggression.

During the past decade, researchers have been increasingly focusing on developing therapeutics which target the root causes of HD symptoms, for example drugs which reduce the mutant huntingtin protein, thereby reducing its toxic effect on neurons. Antisense Oligonucleotide (ASO) drugs are single stranded oligonucleotide analogues, essentially short, synthetic strands of genetic material which bind to faulty mRNA or pre-mRNA, altering mutant huntingtin protein expression. A recent trial of the Roche drug Tominersen found that mutant huntingtin in the cerebral spinal fluid (CSF) was reduced by 40% (11,12). Gene editing technologies such as CRISPR-Cas9 are also being explored as a way to treat HD. Cas-9 (CRISPR associated protein 9) is a naturally occurring enzyme found in bacteria which has been used as a gene editing tool for the last decade, and induces double strand breaks in target DNA. Repair errors then deactivate the gene causing it to be permanently switched off. CRISPR-Cas9 therapies may be used to prevent the production of the mutant huntingtin protein by: removing expanded CAG repeats; targeting the mutant copy of the gene received from the affected parent; or targeting the HTT gene itself, non-specifically reducing all huntingtin protein (mutant and non-mutant). While still in the early stage of development and facing significant challenges, gene editing holds the ultimate promise of a permanent cure by fixing the root cause of HD.

Beyond these cutting-edge therapies, researchers are also exploring a range of other strategies, including antibody therapies that can clear out the toxic protein aggregates, drugs to protect and support nerve cells, and stem cell research aimed at replacing neurons lost to HD, improve regeneration and provide pro-survival factors (13).

While the science is fascinating, it is crucial to remember the individuals suffering at the hands of this disease. The progressive nature of HD demands a constant recalibration of expectations and a profound resilience. Support groups, advocacy organizations such as the Huntington's Disease Association (HDA), and a growing community of families and researchers are working together to raise awareness, provide support, and accelerate the search for a cure. A diagnosis of HD marks the beginning of a bleak and arduous journey for everyone involved. Yet, the power of science and its potential, means that with every new piece of research published or clinical trial completed, effective therapies move closer, offering a beacon of hope for patients, their families, and future generations.

References

1. Jimenez-Sanchez M, Licitra F, Underwood BR, Rubinsztein DC. Huntington’s Disease: Mechanisms of Pathogenesis and Therapeutic Strategies. Cold Spring Harb Perspect Med. 2017 July;7(7):a024240.
2. Rubinsztein DC, Leggo J, Coles R, Almqvist E, Biancalana V, Cassiman JJ, et al. Phenotypic Characterization of Individuals with 30–40 CAG Repeats in the Huntington Disease (HD) Gene Reveals HD Cases with 36 Repeats and Apparently Normal Elderly Individuals with 36–39 Repeats. Am J Hum Genet. 1996 July;59(1):16–22.
3. Brinkman RR, Mezei MM, Theilmann J, Almqvist E, Hayden MR. The likelihood of being affected with Huntington disease by a particular age, for a specific CAG size. Am J Hum Genet. 1997 May;60(5):1202–10.
4. Nasir J, Floresco SB, O’Kusky JR, Diewert VM, Richman JM, Zeisler J, et al. Targeted disruption of the Huntington’s disease gene results in embryonic lethality and behavioral and morphological changes in heterozygotes. Cell. 1995 June;81(5):811–23.
5. Goel F, Dobhal V, Kumar D, Rai SN, Yadav DK. Evidence based molecular pathways, available drug targets, pre- clinical animal models and future disease modifying treatments of huntington’s disease. Mol Biol Rep. 2025 July 25;52(1):754.
6. Takahashi T, Kikuchi S, Katada S, Nagai Y, Nishizawa M, Onodera O. Soluble polyglutamine oligomers formed prior to inclusion body formation are cytotoxic. Hum Mol Genet. 2008 Feb 1;17(3):345–56.
7. Ramdzan YM, Trubetskov MM, Ormsby AR, Newcombe EA, Sui X, Tobin MJ, et al. Huntingtin Inclusions Trigger Cellular Quiescence, Deactivate Apoptosis, and Lead to Delayed Necrosis. Cell Rep. 2017 May 2;19(5):919–27.
8. Blumenstock S, Dudanova I. Cortical and Striatal Circuits in Huntington’s Disease. Front Neurosci. 2020 Feb 6;14:82.
9. Ovid [Internet]. [cited 2025 Sept 7]. Tetrabenazine for the treatment of chorea and... : Expert Review of Neurotherapeutics. Available from: https://www.ovid.com/journals/exneu/fulltext/10.1586/ern.11.149~tetrabenazine-for-the-treatment-of-chorea-and-other
10. Hayden MR, Leavitt BR, Yasothan U, Kirkpatrick P. Tetrabenazine. Nat Rev Drug Discov. 2009 Jan;8(1):17–8.
11. Dhuri K, Bechtold C, Quijano E, Pham H, Gupta A, Vikram A, et al. Antisense Oligonucleotides: An Emerging Area in Drug Discovery and Development. J Clin Med. 2020 June 26;9(6):2004.
12. Tabrizi SJ, Leavitt BR, Landwehrmeyer GB, Wild EJ, Saft C, Barker RA, et al. Targeting Huntingtin Expression in Patients with Huntington’s Disease. N Engl J Med. 2019 June 13;380(24):2307–16.
13. Ferguson MW, Kennedy CJ, Palpagama TH, Waldvogel HJ, Faull RLM, Kwakowsky A. Current and Possible Future Therapeutic Options for Huntington’s Disease. J Cent Nerv Syst Dis. 2022 May 21;14:11795735221092517.