What is Huntington's disease?

Huntington's disease is an inherited neurodegenerative disorder — caused by a CAG repeat expansion in the HTT gene — that causes progressive deterioration of motor function (chorea), cognition (dementia) and psychiatric health, leading to complete dependence and death typically 15-20 years after symptom onset. It affects approximately 30,000 Americans and 200,000+ people globally. HD is autosomal dominant (one mutated copy causes disease), meaning each child of an affected parent has a 50% chance of inheriting the mutation.

What causes HD and who gets it?

HD is caused by an expanded CAG repeat (>36 copies) in the Huntingtin (HTT) gene on chromosome 4. The resulting abnormal huntingtin protein misfolds and accumulates as toxic aggregates — particularly damaging striatal medium spiny neurons and cortical neurons. There is no environmental cause — HD is purely genetic. Age of onset typically ranges from 30-50 years for the most common repeat lengths; longer repeats cause earlier onset. Juvenile HD (onset 55).

What are the symptoms?

HD has three domains of symptoms that are often present simultaneously: Motor: chorea (involuntary, irregular, dance-like movements) in early HD; later rigidity, bradykinesia (slowness), dystonia, and dysphagia. Cognitive: attention and executive function decline initially; progressing to severe dementia. Psychiatric (often earliest manifestations, years before motor symptoms): depression, irritability, anxiety, obsessive-compulsive symptoms, apathy, and — less commonly — psychosis and suicidal ideation. Suicide is a leading cause of death in HD (20x elevated risk vs general population).

Is there treatment for HD?

No approved disease-modifying treatment. Symptomatic treatments: Chorea: tetrabenazine (Xenazine) or deutetrabenazine (Austedo) — FDA-approved for HD chorea; both reduce movements but can cause depression and sedation. Psychiatric symptoms: antidepressants, antipsychotics (particularly for irritability and psychosis), anxiolytics. Cognitive symptoms: no specific pharmacotherapy; occupational therapy and cognitive rehabilitation. Swallowing: speech and language therapy; PEG tube when aspiration risk is high. End-stage care: multidisciplinary palliative care.

What happened with tominersen?

Tominersen (formerly IONIS-HTTRx/RG6042, Roche/IONIS) was an antisense oligonucleotide targeting HTT mRNA — designed to reduce total huntingtin protein (both mutant and wild-type) by approximately 40-50%. It reached Phase 3 (GENERATION HD1) with great hope. In 2021, the trial was halted at interim analysis after higher-dose participants showed worse functional outcomes than placebo. The failure was a major setback — highlighting that non-selective huntingtin lowering in manifest HD may be harmful. Possible explanations: lowering both mHTT and wild-type HTT (which has neuroprotective functions) may be harmful in manifest HD; allele-selective approaches (lowering only mHTT without affecting the healthy allele) are now in development.

Should people at risk of HD get tested?

Predictive genetic testing for HD is available — it can determine with certainty whether an at-risk person will develop HD. Whether to test is a deeply personal decision with profound implications: a positive result means certain disease, with no disease-modifying treatment available; it affects decisions about family (having children — preimplantation genetic diagnosis is available), career, relationships and life planning. Comprehensive genetic counselling (multiple sessions, with psychological support) is mandatory before predictive testing. Most at-risk individuals (approximately 80%) choose NOT to be tested. Testing of minors is not recommended.

What is the research outlook for HD?

Despite tominersen's failure, the HD therapeutic landscape continues to evolve: allele-selective ASOs and RNAi (targeting only the mutant HTT allele): multiple programmes in development; early clinical trials (PRECISION-HD1/HD2 — WAVE Life Sciences); CRISPR gene editing for permanent mHTT gene correction; neuroinflammation targeting (microglia activation is prominent in HD); and biomarker development (neurofilament light chain — NfL — tracking neurodegeneration; mHTT CSF quantification). The focus is shifting to pre-manifest HD intervention before neurodegeneration accrues.

How does GMJ News cover HD?

GMJ News covers WHO HD data, tominersen Phase 3 failure analysis, HTT lowering approaches, predictive testing ethics, tetrabenazine evidence and the HD research pipeline. Huntington's disease exemplifies the challenge of neurodegenerative disease where genetics is clear but treatment remains elusive — relevant to PHIG's neurological health priorities.

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Huntington's Disease

GMJ News knowledge hub · last reviewed September 2026 · Georgian Medical Journal

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Huntington's disease — a devastating autosomal dominant neurodegenerative disorder caused by CAG trinucleotide repeat expansion in the HTT gene — affects approximately 30,000 people in the USA and 200,000+ globally, causing relentless progressive deterioration in motor function (chorea), cognition and psychiatric health, with invariable fatal outcome typically 15-20 years after symptom onset (WHO). Huntington's has no approved disease-modifying treatment — the highest-profile attempt (tominersen, an antisense oligonucleotide) failed Phase 3 in 2021, a major setback for the field. The primary therapeutic hope remains RNA-targeting approaches — lowering mutant huntingtin protein through ASOs, RNAi or CRISPR gene editing.

Key messages

Invariably fatal — no disease-modifying treatment

Huntington's disease is an autosomal dominant neurodegenerative disorder — invariably fatal, typically 15-20 years after symptom onset — with no approved disease-modifying treatment. The highest-profile attempt (tominersen, an antisense oligonucleotide) failed Phase 3 in 2021 (WHO).

CAG repeat expansion — predictable genetic cause

HD is caused by CAG trinucleotide repeat expansion in the HTT gene (>36 repeats) — with 100% penetrance above 40 repeats. The number of repeats inversely correlates with age of onset. The mutation can be detected decades before symptom onset — raising profound ethical questions about predictive genetic testing.

Progressive triad — motor, cognitive, psychiatric

HD causes a characteristic triad: motor disturbances (chorea — involuntary dance-like movements; later rigidity/bradykinesia); cognitive decline (dementia); and psychiatric symptoms (depression, irritability, anxiety, obsessive symptoms, psychosis). Psychiatric symptoms often precede motor symptoms by years.

200,000+ affected globally — genetic risk in families

Approximately 30,000 Americans and 200,000+ people globally have HD; each child of an affected parent has a 50% chance of inheriting the mutation. Genetic counselling and predictive testing are available — but profound ethical, psychological and social complexities surround presymptomatic testing.

HTT lowering — the primary therapeutic hope

Lowering mutant huntingtin (mHTT) protein production — through antisense oligonucleotides (ASOs), RNA interference (RNAi) or CRISPR gene editing targeting the HTT gene — remains the primary therapeutic strategy. Despite tominersen's failure (ASO — worsened outcomes possibly due to mHTT lowering not benefiting manifest HD), research in pre-manifest HD continues.

Tetrabenazine/deutetrabenazine for chorea

Tetrabenazine (VMAT2 inhibitor) and deutetrabenazine (longer-acting) are approved for chorea management in HD — reducing involuntary movements, though not affecting underlying disease progression.

Key statistics

~30K

HD patients in USA; ~200K+ globally

WHO/HDSA

50%

lifetime risk for each child of HD parent

WHO

15-20yr

typical survival from symptom onset

WHO

>36

CAG repeats in HTT gene diagnostic of HD

WHO

approved disease-modifying treatments

WHO 2024

2021

year tominersen Phase 3 failed (major setback)

Roche/IONIS

Huntington's disease — typical symptom progression timeline

Source: Published clinical data. Prodromal/pre-HD phase may last 15+ years before formal diagnosis.

Glossary of key terms

HTT gene and CAG repeat
WHOThe Huntingtin (HTT) gene on chromosome 4 — containing a CAG (cytosine-adenine-guanine) trinucleotide repeat. Normal: ≤35 repeats. Intermediate (35-36): reduced penetrance. HD: 37-40 reduced penetrance; 41+ full penetrance. Longer repeats = earlier onset. The mutant huntingtin (mHTT) protein accumulates as toxic aggregates.

Chorea
WHO/ClinicalInvoluntary, brief, random-appearing, non-rhythmic movements — the hallmark early motor sign of HD. Derived from Greek for "dance." Chorea arises from striatal neuronal loss disrupting the balance of direct and indirect basal ganglia pathways. Later replaced by rigidity and bradykinesia as HD progresses.

Tetrabenazine (Xenazine)
FDA/WHOA vesicular monoamine transporter type 2 (VMAT2) inhibitor — the first FDA-approved treatment specifically for HD chorea (2008). Depletes presynaptic dopamine → reduces choreiform movements. Deutetrabenazine (Austedo) is a deuterium-stabilised version with better tolerability and twice-daily dosing.

Tominersen
Roche/IONISAn antisense oligonucleotide (ASO) designed to lower total huntingtin (both mutant and wild-type) by degrading HTT mRNA — delivered by intrathecal injection. Phase 3 (GENERATION HD1) halted in 2021 after interim analysis showed higher-dose groups had worse outcomes. The mechanism of failure is debated — possibly highlighting that total HTT lowering in manifest HD is harmful; allele-selective approaches (lowering only mHTT) are in development.

Predictive genetic testing
WHO/ISADTesting asymptomatic adults at-risk of HD (with an affected parent) for CAG repeat expansion. A positive result means HD is certain if the person lives long enough. This requires comprehensive genetic counselling both pre- and post-test. Protocols: the International Huntington Association recommends multiple counselling sessions; testing minors is not recommended; testing in pregnancy (for fetal HD) raises profound ethical issues.

Juvenile Huntington's disease
WHOHD with onset before age 20 — typically with very high CAG repeat counts (usually >55). Juvenile HD accounts for approximately 5-10% of HD cases and has different clinical features: rigidity predominates over chorea; seizures are common; cognitive decline and psychiatric symptoms are prominent. Faster progression than adult HD.

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