How many CAG repeats cause Huntington disease?

In the HTT gene, 26 or fewer CAG repeats is normal. With 27-35 repeats (an intermediate allele) the person is not typically at risk of developing Huntington disease, but the repeat can expand into the disease range in a child. With 36-39 repeats penetrance is reduced, so symptoms may or may not develop. With 40 or more repeats the disease is expected to develop within a normal lifespan. Juvenile Huntington disease, with onset before age 20, usually involves more than 55 repeats (some sources say more than 60).

Why is anticipation in Huntington disease linked to the father?

The CAG repeat in HTT is unstable during sperm production, so it tends to lengthen when a father passes it on. According to GeneReviews, large expansions of more than 7 repeats occur almost exclusively through paternal transmission, while contractions are more common through the mother. Longer repeats cause earlier onset, so children of affected fathers can develop symptoms much earlier, and most juvenile Huntington disease is inherited from the father.

What neurotransmitter changes occur in Huntington disease?

Huntington disease destroys GABAergic medium spiny neurons in the caudate and putamen, so GABA and substance P fall, and acetylcholine synthesis in the striatum is often reduced too. Dopamine input is left relatively unopposed, which exams summarize as decreased GABA, decreased acetylcholine and increased dopamine. Loss of the indirect pathway releases the thalamus and produces chorea, which is why dopamine-depleting VMAT2 inhibitors and dopamine-blocking antipsychotics reduce it.

What does MRI show in Huntington disease?

The classic finding is atrophy of the caudate nucleus, especially the caudate head, which makes the frontal horns of the lateral ventricles look enlarged and box-shaped. The putamen also shrinks, and frontal-predominant cortical atrophy follows as the disease advances. MRI changes can appear years before symptoms. Imaging supports the diagnosis, but the confirmatory test is a genetic test that counts the CAG repeats in the HTT gene.

Which drugs are FDA-approved for chorea in Huntington disease?

Three VMAT2 inhibitors are FDA-approved for Huntington chorea: tetrabenazine (Xenazine), deutetrabenazine (Austedo and Austedo XR) and valbenazine (Ingrezza). They deplete presynaptic dopamine. All three carry a boxed warning for depression and suicidal thoughts and behavior in Huntington disease, and tetrabenazine and deutetrabenazine are contraindicated in actively suicidal patients and in untreated or inadequately treated depression. No approved treatment stops or reverses the disease itself.

How do you tell Huntington disease from Sydenham chorea and Wilson disease?

Huntington disease is an adult-onset, autosomal dominant disorder combining chorea, psychiatric change and dementia, with caudate atrophy on MRI. Sydenham chorea affects children, often months after a group A streptococcal infection as part of acute rheumatic fever, comes with emotional lability and usually resolves over months. Wilson disease is autosomal recessive copper overload from ATP7B variants, usually starting in the teens, with liver disease and Kayser-Fleischer rings.

Huntington Disease Cheat Sheet: CAG Repeats, Caudate & Drugs

Huntington disease (HD) is an autosomal dominant neurodegenerative disorder caused by an expanded CAG trinucleotide repeat in the HTT gene on chromosome 4p16.3: 40 or more repeats is fully penetrant, 36-39 shows reduced penetrance, and expansions grow mainly through the father (anticipation). Loss of GABAergic medium spiny neurons in the caudate and putamen produces chorea, psychiatric change and dementia, usually starting between 30 and 50, with caudate atrophy and enlarged frontal horns on MRI. Chorea is treated with a VMAT2 inhibitor (tetrabenazine, deutetrabenazine or valbenazine), each carrying a boxed warning for depression and suicidality in HD; no treatment stops or reverses the disease.

The one-page summary

Topic	What to know
Inheritance	Autosomal dominant: each child of an affected parent has a 50% risk
Gene	HTT (huntingtin), chromosome 4p16.3; CAG codes glutamine, so the protein carries an expanded polyglutamine tract
Mechanism	Mutant huntingtin accumulates in neurons (ubiquitinated intranuclear inclusions); excitotoxicity, mitochondrial dysfunction and protein aggregation are proposed mechanisms
Anticipation	Repeats lengthen across generations, giving earlier onset; far more common with paternal transmission
Pathology	Loss of GABAergic medium spiny neurons of the striatum (caudate, putamen), later cortex
Neurotransmitters	↓ GABA, ↓ substance P, ↓ ACh (striatal choline acetyltransferase falls in many patients); dopamine left relatively unopposed (the exam's "↑ dopamine")
Triad	Chorea + psychiatric change + cognitive decline (executive dysfunction first)
Imaging	Caudate atrophy → enlarged, box-shaped frontal horns of the lateral ventricles
Diagnosis	Genetic test counting CAG repeats (gold standard)
Chorea drugs	VMAT2 inhibitors: tetrabenazine, deutetrabenazine, valbenazine; antipsychotics
Course	Median survival 15-18 years after onset; aspiration pneumonia is the commonest cause of death, then suicide

CAG repeat ranges

CAG repeats	Category (GeneReviews)	Meaning
26 or fewer	Normal	No HD
27-35	Intermediate	The person is not typically at risk of HD, but the allele is unstable and can expand into the HD range in a child
36-39	Reduced penetrance	May or may not develop HD
40 or more	Full penetrance	Develops HD, assuming a normal lifespan
Very large (usually >55; some sources say >60)	Juvenile HD (onset before 20)	Prominent rigidity, slowness and falls; seizures in 30-50% of those with onset before age 10; faster course (disease duration about 8-12 years)

Longer repeat = earlier onset. Typical adult-onset HD starts at 30-50; prevalence is about 1 in 10,000 people of European ancestry.
Each additional generation can add repeats, so an affected father with onset at 50 can have a son with onset in his 30s, or a child with juvenile HD. See the trinucleotide repeat disorders table for the other repeat diseases.

Anticipation: why the father matters

Mechanism: CAG repeats are unstable during spermatogenesis, so they expand mainly when the father transmits the gene.
GeneReviews: large expansions (more than 7 repeats) occur almost exclusively on paternal transmission, while contractions are more common on maternal transmission. Most juvenile HD comes from the father.
Contrast the repeat diseases: in fragile X (CGG, FMR1) the dangerous expansion happens in the mother's eggs; Friedreich ataxia (GAA, FXN) is autosomal recessive. Practice the concept with this anticipation question.

Why chorea happens

The striatum's GABAergic medium spiny neurons degenerate; over the disease more than 90% of them are lost, and caudate atrophy appears early.

Indirect pathway: medium spiny neurons carrying D2 receptors project to the external globus pallidus (GPe) and normally brake movement. HD interrupts the indirect pathway, so the thalamus is released and movement becomes hyperkinetic. A subthalamic lesion (hemiballismus) knocks out the same pathway.
Chain to memorize: striatal neurons lost → GPe overactive → subthalamic nucleus suppressed → less GPi output → less thalamic inhibition → chorea. Drill it with the basal ganglia pathways question.
Neurotransmitters: GABA and substance P levels fall, striatal acetylcholine synthesis (choline acetyltransferase activity) is often reduced, and dopamine input is left relatively unopposed. That is why drugs that deplete or block dopamine reduce chorea.
Late disease: the picture shifts toward bradykinesia, rigidity and dystonia as degeneration spreads.

Clinical picture

Psychiatric (often first): depression (about 40%), irritability, apathy, anxiety, impulsivity and aggression; psychosis can occur. About 25% attempt suicide; risk peaks just before diagnosis and again when independence is lost.
Cognitive: executive dysfunction (planning, organizing, multitasking) progressing to dementia.
Motor: chorea that starts in the distal limbs and spreads to proximal and axial muscles; motor impersistence (can't keep the tongue protruded or sustain a grip, the "milkmaid" grip); slow voluntary saccades (needs a blink or head thrust to shift gaze); a puppet-like gait; dysarthria and dysphagia.
Body: marked weight loss and reduced muscle mass.

Diagnosis and counseling

Clinical diagnosis is possible with typical motor, cognitive or behavioral signs and an affected parent; the gold standard is a targeted genetic test that counts CAG repeats.
MRI or CT: atrophy of the caudate head (and putamen) makes the frontal horns enlarged and box-like; frontal cortical atrophy follows. MRI changes appear years before symptoms.
Predictive testing of at-risk relatives follows genetic counseling with pretest interviews; prenatal and preimplantation testing are options.

Treatment

No treatment stops or reverses HD (NINDS, 2026); therapy targets symptoms. Huntingtin-lowering therapies remain investigational: uniQure submitted a Biologics License Application for its one-time gene therapy AMT-130 (ifezuntirgene inilparvovec, a microRNA that silences HTT, injected into the caudate and putamen) in September 2026, and it is not FDA-approved.

Drug (brand)	FDA-labeled uses	Label points
Tetrabenazine (Xenazine)	Chorea of HD	CYP2D6 genotyping before doses above 50 mg/day; contraindicated in hepatic impairment and with MAOIs, reserpine, deutetrabenazine or valbenazine
Deutetrabenazine (Austedo, Austedo XR)	Chorea of HD; tardive dyskinesia	Contraindicated in hepatic impairment and with MAOIs, reserpine, tetrabenazine or valbenazine
Valbenazine (Ingrezza, Ingrezza Sprinkle)	Tardive dyskinesia; chorea of HD	Somnolence is the most common adverse reaction

How they work: reversible VMAT2 inhibition stops monoamines being packed into vesicles, depleting dopamine (and serotonin, norepinephrine and histamine).
Boxed warning (all three): increased depression and suicidality in patients with HD. Tetrabenazine and deutetrabenazine are contraindicated in patients who are actively suicidal or have untreated or inadequately treated depression.
Other label warnings: QT prolongation, neuroleptic malignant syndrome, parkinsonism and sedation; akathisia and restlessness with tetrabenazine and deutetrabenazine.
Antipsychotics (such as risperidone and olanzapine) suit chorea with psychosis, irritability or aggression; review typical vs atypical antipsychotics. SSRIs treat depression, anxiety and obsessive-compulsive symptoms.
Support: physical therapy, speech and swallow therapy, nutrition for weight loss, psychotherapy and safety planning.

Chorea and its look-alikes

Condition	Clues	Key difference
Huntington disease	Adult; autosomal dominant family history; chorea + psychiatric change + dementia	Caudate atrophy; CAG 36 or more
Sydenham chorea	Child, often months after group A strep (acute rheumatic fever); emotional lability, milkmaid grip	Post-infectious autoimmunity with antineuronal antibodies, the same post-infectious logic as Guillain-Barré syndrome after Campylobacter; resolves over months, recurs in about a third
Wilson disease	Usually teens to young adults; liver disease, tremor, psychiatric change, Kayser-Fleischer rings	ATP7B, autosomal recessive copper overload; see Wilson disease
Tardive dyskinesia	After long-term dopamine-blocking drugs	Drug history; valbenazine and deutetrabenazine are labeled for it
Parkinson disease	Older adult; bradykinesia, rigidity, resting tremor	Hypokinetic; loss of substantia nigra dopaminergic neurons
Creutzfeldt-Jakob disease	Rapidly progressive dementia (death usually within 6 months), myoclonus	Periodic sharp waves on EEG, cortical ribboning on diffusion MRI, CSF RT-QuIC

How USMLE tests it: a pedigree with earlier onset in the son of an affected father (paternal anticipation); "which neurons are lost" (striatal GABAergic medium spiny neurons); the neurotransmitter trio (↓ GABA, ↓ ACh, relative ↑ dopamine); the MRI (caudate atrophy, big frontal horns); and the drug for chorea (a VMAT2 inhibitor, with the depression and suicide warning).

Practice question

A 42-year-old man is brought in by his partner for 18 months of personality change and clumsiness. He has become irritable and impulsive and was disciplined at work for poor judgment. He has brief, nonrhythmic, flowing movements of the face and hands and cannot keep his tongue protruded. His father died in his 50s after years of progressive neurologic decline. MRI shows atrophy of both caudate nuclei with enlarged frontal horns of the lateral ventricles. Which best explains his condition?

A. Expanded CAG repeat in HTT on chromosome 4 B. Expanded CGG repeat that silences FMR1 C. Expanded GAA repeat in FXN that reduces frataxin D. Biallelic ATP7B variants causing copper accumulation E. Degeneration of dopaminergic neurons in the substantia nigra pars compacta F. Accumulation of misfolded prion protein

Answer: A. Midlife chorea, motor impersistence and psychiatric change, an affected father (autosomal dominant) and caudate atrophy are Huntington disease: an expanded polyglutamine-coding CAG repeat in HTT.

B: fragile X (CGG, X-linked) causes intellectual disability from childhood with a long face, large ears and, after puberty, macroorchidism, not midlife chorea.
C: Friedreich ataxia (GAA, autosomal recessive) begins at ages 5-15 with ataxia, sensory loss, hypertrophic cardiomyopathy, diabetes and scoliosis.
D: Wilson disease is autosomal recessive, usually begins in the teens, and adds liver disease and Kayser-Fleischer rings; an affected parent would be unusual.
E: loss of nigral dopaminergic neurons is Parkinson disease, a hypokinetic disorder (bradykinesia, rigidity, resting tremor) without caudate atrophy.
F: Creutzfeldt-Jakob disease causes a rapidly progressive dementia with myoclonus, usually fatal within about 6 months, not an 18-month illness with chorea and caudate atrophy.

Key takeaways

HD = autosomal dominant CAG expansion in HTT (chromosome 4), polyglutamine huntingtin.
Cut-offs: 26 or fewer normal; 27-35 intermediate (not typically at risk themselves; the risk is to children); 36-39 reduced penetrance; 40 or more full penetrance; juvenile HD usually above 55.
Anticipation is mainly paternal: repeats expand during spermatogenesis.
Striatal GABAergic medium spiny neuron loss interrupts the indirect pathway → chorea; ↓ GABA, ↓ ACh, relative ↑ dopamine.
Caudate atrophy with enlarged frontal horns on MRI; confirm with a CAG repeat test.
VMAT2 inhibitors (tetrabenazine, deutetrabenazine, valbenazine) treat chorea; all carry a boxed warning for depression and suicidality in HD.