Huntington’s Disease

Neurology / August 28, 2026

Huntington’s Disease (HD)

Huntington’s Disease (HD) is a progressive, autosomal dominant neurodegenerative disease caused by a CAG trinucleotide repeat expansion in the HTT (IT15) gene on chromosome 4p, leading to toxic polyglutamine accumulation, striatal neuronal loss, chorea, cognitive decline, and progressive motor, cognitive, and behavioral deterioration over roughly 15–20 years.

At a Glance

Domain

Practical point

Genetics

CAG trinucleotide repeat expansion in the HTT (IT15) gene, chromosome 4p; autosomal dominant with anticipation. ≥36–40 repeats = full penetrance; ≥60 = juvenile (Westphal) onset.

Onset & course

Classical onset 30–55 years; mean survival ~17 years. Juvenile variant presents with parkinsonism + seizures, not chorea.

Motor

Chorea is the hallmark (seen in >90%), but delayed saccadic eye movement initiation is the earliest sign, preceding chorea. Bradykinesia and dystonia dominate late disease.

Cognitive

Subcortical dementia — executive dysfunction, impaired judgement/problem-solving. No aphasia or apraxia (distinguishes it from cortical dementias.)

Psychiatric

Depression in ~30% with a 6-fold increased suicide risk — screen family history of suicide/depression. Tetrabenazine can worsen suicidal ideation — use with caution.

Imaging

“Box-car” lateral ventricles from caudate and putamen atrophy; frontal horn : intercaudate distance ratio falls from 2.2–2.6 toward 1.

Treatment

No disease-modifying therapy — management is symptomatic. Tetrabenazine/deutetrabenazine for chorea; SSRIs for depression; levodopa only if parkinsonism predominates (e.g., juvenile HD).

Mimics to consider

C9ORF72 is the most common HD phenocopy (can mimic HD even on MRI); also consider HDL1–3, DRPLA, and spinocerebellar ataxias.

Genetics & Basic Facts

  • First described by: George Huntington
  • Nature: Progressive neurodegenerative disease
  • Typical age: 25–45 years (classical onset 30–55 years; mean survival ~17 years)
  • Inheritance: Autosomal dominant
    • Anticipation (earlier/more severe onset in successive generations)
    • High penetrance
  • Gene: HTT (IT15) gene → Huntingtin protein, on Chromosome 4p
  • Mutation type: Trinucleotide (CAG) repeat expansion disorder — polyglutamine repeat disorder
  • Mutant gene product: Huntingtin (toxic polyglutamine)

Etiopathogenesis

  • CAG usually codes for glutamine → expansion → formation of toxic polyglutamine
  • → Neuronal loss via:
    • Apoptosis
    • Mitochondrial dysfunction
    • Glutamate excitotoxicity
  • Loss of medium spiny neurons (MSN) in striatum → atrophy of caudate and putamen
  • Predominantly indirect pathway affected first → progresses to direct pathway later

CAG Repeat Number → Phenotype

Repeat count

Outcome

Normal

27

26–39

Intermediate/incomplete penetrance

≥36–40

Complete penetrance — disease manifests

≥60

Juvenile onset
  • Juvenile onset (Westphal variant): presents as Parkinsonism + seizures (children → Parkinsonian phenotype)
  • With very high repeats (>60): both direct and indirect pathways affected
  • Presents with hypokinetic/akinetic variant, dystonia

Pathway Physiology

  • Indirect pathway affected → Direct pathway hyperactive → hyperdynamic movements (chorea, reflection of a hyperdopaminergic state)
  • Later stages: Direct pathway also affected → bradykinesia
  • Overall: GABA-ergic transmission affected
  • Classical presentation due to defect in medium spiny neurons of caudate nucleus

Age-Related Clinical Variants

Age group

Presentation

Juvenile

Dystonic–hypokinetic variant

Middle-age

Chorea + dementia at ~same time

Older age onset

Choreiform movements = earliest symptom

>80 years

Presents with dyskinesia


  • Previously called “senile chorea” (in elderly-onset presentation)

Clinical Manifestations

A. Motor

  • Saccadic initiation — earliest sign
  • Chorea — seen in >90%; reflection of a hyperdopaminergic state
  • Fidgidity/clumsiness — can present early, before other symptoms; long-standing clumsiness
  • Bradykinesia
  • Dystonia
  • Dysphagia, dysarthria
  • Gait instability and falls
  • Hung-up pendular knee jerk

Oculomotor

  • Earliest oculomotor manifestation: delay in initiation of saccadic eye movements and their speed
  • Impaired initiation of saccade (a hallmark finding even at intermediate CAG repeat range)

B. Cognitive

  • Subcortical dementia
  • Executive dysfunction
  • Dysfunction in attention, judgement, problem-solving
  • No aphasia or apraxia (distinguishes from cortical dementia)

C. Psychiatric / Behavioural

  • Irritability, anxiety
  • Anger control issues
  • Mania/hypomania
  • Psychosis
  • Apathy
  • Depression — seen in 30%
    • Suicidal ideation — 6-fold increased
    • Evaluate for family history of suicide (rule out)
    • Evaluate family history of apathy/depression/mania
  • ⚠ Tetrabenazine (used for chorea) can worsen suicidal ideation

Imaging Findings

Classical Appearance

  • “Box-like appearance” of the frontal horns/ventricles — classical MRI/CT finding in HD
  • Gross pathology: Atrophied caudate (compare with normal specimen — enlarged/boxy lateral ventricles due to caudate atrophy)

Measurements

  • Frontal horn to frontal horn
  • Caudate to caudate distance — increases in HD
  • Inner table dimension

Key Ratios

Ratio

Normal

In HD

Frontal horn width : Intercaudate distance (FH/CC)

2.2–2.6

Approaches 1

Intercaudate distance : Inner table width (CC/IT)

0.09–0.12

Increases

Investigations

Modality

Finding

Imaging (MRI/CT)

Atrophy of caudate and putamen; “box car” ventricles — enlarged, boxy lateral ventricles

MRI (juvenile HD)

Hyperintensity in caudate and putamen

PET

Hypometabolism in caudate and putamen

SPECT

Hypoperfusion in caudate and putamen

Genetic testing

CAG repeat analysis (HTT/IT15 gene, chromosome 4p)

CAG Repeat Spectrum Summary

CAG repeats

Zone

Associated features

~27

Normal

—

Up to 36

Incomplete penetrance

—

40

Complete penetrance

Movement disorders (chorea, Parkinsonism, dystonia), neuropsychiatric symptoms, cognitive impairment, impaired saccade initiation

60+

Juvenile

Parkinsonism (Westphal variant), seizures

Treatment

Category

Detail

Disease-modifying therapy

None available — treatment is symptomatic

Tetrabenazine

Pre-synaptic dopamine depletor; inhibits VMAT-2 (vesicular monoamine transporter). Can worsen suicidal ideation

Deutetrabenazine

Deuterated form of tetrabenazine

Antipsychotics

For psychiatric/behavioural symptoms

SSRIs

For depression

Levodopa

Used if Parkinsonism features predominate (e.g., juvenile/Westphal variant)

HD Phenocopies (Mimics)

Conditions that mimic HD clinically (and sometimes on MRI):

  • C9ORF72 (most common phenocopy)
    • Mutation: GGGGCC repeat
    • Presents with chorea + motor + psychiatric manifestations
    • Can mimic HD even on MRI
  • HDL (Huntington Disease-Like) syndromes:
    • HDL1 — Prion disease
    • HDL2 — CTG/CAG repeat disease in Junctophilin 3
    • HDL3 — Very rare (only 2–3 family case reports)

Related Genetic Variants (Triplet Repeat / Polyglutamine Disorders)

  • HD
  • SMA (spinobulbar muscular atrophy — Kennedy’s disease)
  • DRPLA (Dentatorubral-pallidoluysian atrophy)
  • SCA 1, 2, 3, 6, 7, 17

DRPLA — Two Presentations

Age

Presentation

<25 years

Transitional phenotype — bridges the severe myoclonic epilepsy of youth and the prominent chorea/psychosis of later adulthood

>40 years

Ataxia + chorea

Chorea/Ataxia Differential — Other Causes

  • Spinocerebellar ataxia (SCA) 17, and SCA 1, 2, 3, 4, 8
  • Neuroacanthocytosis
  • NBIA (PKAN) — “Eye of tiger” appearance on MRI
  • Friedreich’s ataxia

References

  • Bradley and Daroff’s Neurology in Clinical Practice, 8th ed. — Chapter 96: Parkinson Disease and Other Movement Disorders
  • Harrison’s Principles of Internal Medicine, 22nd ed. — Chapter 447: Tremor, Chorea, and Other Movement Disorders

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