Huntington disease and inherited dementia syndromes

At a glance

• Autosomal dominant CAG repeat expansion in HTT on chromosome 4p. Each child of a carrier has a 50% risk.
• Triad of movement disorder (chorea first), psychiatric change (depression, irritability, apathy) and subcortical dementia. Psychiatric and cognitive symptoms often come years before chorea.
• Mean onset is about 40 to 45 years; death follows 15 to 20 years after motor onset, usually from aspiration pneumonia.
• No disease-modifying treatment is approved anywhere in November 2026. Care is symptomatic and multidisciplinary.
• Predictive testing follows a set counselling protocol and is not offered to asymptomatic children.

Genetics

CAG repeats	Meaning
26 or fewer	Normal
27 to 35	Intermediate. No disease in the carrier, but can expand into the disease range in offspring, mostly paternal
36 to 39	Reduced penetrance. May develop HD late, or not at all
40 or more	Full penetrance
Over 60	Usually juvenile onset (before 20)

• Anticipation: repeats expand between generations, especially through the father, so onset is earlier in the next generation. Repeat length explains about 60% of the variation in onset age; the rest is modifier genes (DNA repair genes such as FAN1 and MSH3) and environment.
• Somatic expansion of the repeat in striatal neurons over a lifetime is now thought to drive the timing of neuronal death. This is the target of several drugs in trials.
• Prevalence in Australia is roughly 1 in 10,000, and Tasmania historically had a much higher rate, traced to one family that settled there in the 19th century.
• A negative family history doesn't exclude HD: non-paternity, early parental death, misdiagnosis (dementia, alcohol, psychiatric illness) and new expansions from an intermediate paternal allele all hide it.

Pathophysiology

• Mutant huntingtin with an expanded polyglutamine tract misfolds and aggregates, causing neuronal loss first in the caudate and putamen (medium spiny neurons of the indirect pathway).
• Loss of the indirect pathway disinhibits the thalamus, giving hyperkinetic movements (chorea). Later loss of direct pathway neurons gives rigidity and bradykinesia.
• This is why dopamine-depleting drugs reduce chorea and why levodopa can worsen it.

Recognition

Domain	Features
Motor	Chorea (fidgety, flowing, random), motor impersistence ("milkmaid grip", can't keep tongue protruded), slow and hypometric saccades with head thrusts to start them, dysarthria, dysphagia, gait instability. Late: dystonia, rigidity, bradykinesia
Psychiatric	Depression (the commonest), irritability and aggression, apathy, anxiety, obsessive-compulsive features, psychosis in about 10%
Cognitive	Executive dysfunction first: poor planning, slowed processing, lack of insight. Memory recognition is relatively spared. Aphasia and apraxia are uncommon
Other	Weight loss despite good intake, sleep disturbance

• Juvenile HD (Westphal variant): akinetic-rigid, dystonia, seizures, behavioural problems and falling school performance. Usually inherited from the father.
• Staging: the HD Integrated Staging System (HD-ISS, 2022) stages disease from the gene. Stage 0 is CAG 40 or more with no detectable change; stage 1 adds biomarker change (caudate or putamen volume loss on MRI); stage 2 adds clinical signs; stage 3 adds functional decline. It is used in research and trial enrolment. The Total Functional Capacity (TFC) score tracks function in clinic.
• Pitfall: chorea is often missed because patients incorporate it into purposeful-looking movements (parakinesia) and don't complain of it. The family usually notices first.

Investigations

• HTT CAG repeat analysis confirms the diagnosis in a symptomatic person. Pre-test counselling still applies, because the result is predictive for their children and siblings.
• MRI brain: caudate atrophy with "boxcar" frontal horns. Supportive, not diagnostic, and normal early.
• Exclude acquired chorea before or alongside testing (see table).

Differential of adult-onset chorea

Group	Causes
Drugs	Levodopa (dyskinesia), tardive dyskinesia from antipsychotics, oral contraceptive, phenytoin, lamotrigine, stimulants
Metabolic	Non-ketotic hyperglycaemia (hemichorea with T1 bright putamen, often in older Asian women), hyperthyroidism, hypocalcaemia, hyponatraemia correction
Vascular	Subthalamic or basal ganglia stroke (hemiballism)
Autoimmune	SLE and antiphospholipid syndrome, Sydenham chorea (and chorea gravidarum), paraneoplastic (CRMP5, anti-NMDA receptor)
Infective	HIV, toxoplasmosis, prion disease
Haematological	Polycythaemia vera
Genetic, not HD	C9orf72, SCA17, DRPLA, HDL2, neuroacanthocytosis (acanthocytes on film, raised CK), Wilson disease (under 40s)

• Pitfall: acute hemichorea in a person with diabetes is non-ketotic hyperglycaemia until proven otherwise. It resolves with glucose control.

Predictive testing

The international protocol (MacLeod 2013, from the International Huntington Association, EHDN and World Federation of Neurology) is the model for all predictive testing of untreatable adult-onset disease.

• Who can request it: adults at risk, by their own choice. Not employers, insurers, partners or family members on their behalf.
• Steps: genetic counselling, neurological examination and psychological assessment; time to reflect between counselling and the blood test; result given in person, with a support person encouraged; planned follow-up after disclosure.
• The right not to know is respected. Testing a person at 25% risk (grandchild) whose parent is untested can reveal the parent's status. Counsel both where possible.
• Minors: not tested predictively. Wait until they can choose as adults.
• Reproductive options: prenatal testing by CVS (where the couple would consider termination), preimplantation genetic testing with IVF, exclusion testing (tests whether the fetus inherited the chromosome 4 from the affected grandparent, without revealing the at-risk parent's own status), donor gametes.
• Suicidal ideation rises after a positive result and at symptom onset. Most people who test positive adapt without catastrophic events, but follow-up is part of the protocol, not an extra.
• Only about 10 to 20% of at-risk people choose predictive testing, in Australia and overseas.

Insurance and discrimination in Australia

• Commonwealth legislation passed in early 2026 (Treasury release, 1 April 2026) bars life insurers from asking for or using any genetic test results (the person's or a relative's) or whether a test was done. The only exception is a result volunteered unasked with written consent that doesn't disadvantage the person. The Act (Insurance Contracts Act s 33F to 33H) received royal assent on 8 April 2026 and applies to decisions made from 8 October 2026. It replaced the industry moratorium in place since 2019.
• Applicants can still volunteer a favourable result with written consent; it can be used only if it doesn't worsen the offer.
• Insurers can still use family history, signs, symptoms and diagnosed disease. Health insurance in Australia is community rated and unaffected.

Management

There is no disease-modifying treatment. Care is multidisciplinary: neurologist or HD clinic, psychiatry, speech pathology, dietitian, physiotherapy, occupational therapy, social work and genetic counselling, with state HD associations (such as Huntington's NSW ACT) for family support.

Chorea

Treat only if it causes falls, injury, distress or interferes with function.

Drug	Notes
Tetrabenazine	VMAT2 inhibitor. PBS Authority Required (STREAMLINED) for hyperkinetic extrapyramidal disorders. Dosing differs by label: the Australian PI starts at 25 mg twice daily, rising by 25 mg a day every 3 to 4 days to a maximum of 200 mg a day, while the US label starts at 12.5 mg daily and titrates weekly. Adverse effects: depression and suicidality, parkinsonism, sedation, akathisia, QT prolongation, neuroleptic malignant syndrome. The Australian PI contraindicates it in depression or parkinsonism, within 2 weeks of an MAOI, with levodopa or reserpine, and in breastfeeding; it advises dose reduction (not avoidance) in hepatic or renal impairment. The US label also contraindicates untreated depression or suicidality and hepatic impairment. Metabolised by CYP2D6: with fluoxetine or paroxetine, reduce the dose. The US label halves it (maximum 50 mg a day) and asks for CYP2D6 genotyping before going above 50 mg a day
Deutetrabenazine	Deuterated, longer half-life, fewer peaks. Approved for HD chorea in the US but not PBS listed, so rarely used in Australia
Antipsychotics (olanzapine, risperidone, quetiapine; haloperidol less often)	Preferred when chorea coexists with psychosis, irritability, aggression or weight loss (olanzapine)

• Valbenazine is approved for HD chorea in the US (2023) but isn't available in Australia.
• Pitfall: chorea often lessens as the disease advances and rigidity takes over. Review the need for anti-chorea drugs, which worsen parkinsonism and swallowing.

Psychiatric and cognitive symptoms

• Depression: SSRI or mirtazapine. Ask about suicide at every visit; HD has several times the population rate, peaking just before formal diagnosis and again when independence is lost (TFC stage 2).
• Pitfall: fluoxetine and paroxetine inhibit CYP2D6 and raise tetrabenazine levels. Prefer sertraline, citalopram or mirtazapine, or reduce the tetrabenazine dose.
• Irritability and aggression: SSRIs, antipsychotics; mood stabilisers in some.
• Apathy is the symptom most linked to functional decline and responds poorly to drugs.
• No drug improves cognition. Cholinesterase inhibitors haven't helped in trials.

Function, nutrition and planning

• Weight loss is common and predicts faster decline. High-energy diet (energy needs can exceed 4,000 kcal a day with severe chorea), texture modification, speech pathology for dysphagia.
• PEG feeding is an individual decision, ideally discussed early through advance care planning while capacity remains.
• Driving: executive dysfunction and chorea both impair driving. Under Austroads 2022, assess cognition and motor function, and the licensing authority may grant a conditional licence with periodic review. Patients often lack insight, so involve the family.
• Discuss enduring power of attorney, guardianship and the NDIS (people must apply before age 65).

Disease-modifying trials

• Tominersen (antisense oligonucleotide lowering huntingtin): GENERATION HD1 stopped in 2021 for no benefit and worse outcomes at the higher dose. Roche went on to test it in younger, earlier-stage patients (GENERATION HD2).
• AMT-130 (AAV5 gene therapy delivering a microRNA against huntingtin, injected into the striatum by neurosurgery): the phase 1/2 high-dose group showed 75% slower progression on the composite UHDRS at 36 months against a matched Enroll-HD external control (2025). Regulatory review turns on whether an external control is acceptable evidence, so check its current status. It isn't available in Australia outside trials.

Other inherited dementias

The genetic medicine curriculum groups HD with other inherited dementias. Suspect one with onset before 65, a dominant family history, or unusual features. Refer to genetics before testing; the same predictive testing principles apply.

Condition	Gene	Clues
Early-onset familial Alzheimer disease	APP, PSEN1 (commonest), PSEN2	Onset often in the 40s or 50s; PSEN1 can add spastic paraparesis, myoclonus and seizures. People with Down syndrome carry an extra APP copy
Frontotemporal dementia	C9orf72, MAPT, GRN	Behavioural or language variant; C9orf72 also causes MND and psychosis (see Dementia syndromes)
CADASIL	NOTCH3	Migraine with aura, recurrent subcortical strokes, mood disorder, white matter change in the anterior temporal poles and external capsules
Familial prion disease	PRNP	Familial CJD, Gerstmann-Straussler-Scheinker (ataxia), fatal familial insomnia
Spinocerebellar ataxias	SCA1, 2, 3, 17 and others	Ataxia with cognitive decline; see Cerebellar disorders

• APOE ε4 raises Alzheimer risk (one copy about 3-fold, two copies about 10- to 12-fold) but isn't deterministic, so it isn't used for predictive testing. It now matters for anti-amyloid antibody eligibility, because ε4 homozygotes have the highest ARIA risk.

Pitfalls

• Testing a symptomatic patient without counselling. The result tells their children and siblings their own risk.
• Missing depression and suicide risk, which can precede chorea by years and peaks just before diagnosis and again with loss of independence.
• Starting tetrabenazine in someone who is depressed. Treat the depression first, or choose an antipsychotic.
• Adding fluoxetine or paroxetine to tetrabenazine without reducing the dose (CYP2D6 inhibition).
• Assuming no family history rules HD out. Intermediate paternal alleles, early deaths and misattributed diagnoses hide inheritance.
• Testing a child at a parent's request. Defer until adulthood.
• Calling hemichorea in a person with diabetes HD. Check glucose.
• Treating chorea that doesn't bother the patient. The drugs cause depression, parkinsonism and dysphagia.