Inherited dementia syndromes, such as Huntington disease

Description

Huntington disease - autosomal dominant trinucleotide (CAG) repeat expansion, HTT gene
Triad: movement disorder (chorea) + cognitive decline + psychiatric disturbance
Prototype of inherited early-onset dementia; other familial dementias (early-onset Alzheimer - APP/PSEN1/PSEN2; frontotemporal dementia - MAPT/GRN/C9orf72) share the autosomal dominant, mid-life-onset pattern

HD: ~5-10 per 100,000 (Western populations); much lower in Asian populations
Onset typically 30s-50s (mean ~40); juvenile HD (<20yrs) with paternal transmission and very large expansions
Autosomal dominant, full penetrance if repeat length in disease range

CAG trinucleotide repeat expansion in HTT (chr4) -> mutant huntingtin -> neuronal toxicity, striatal (caudate/putamen) atrophy predominant
Repeat length categories:
- <=26 normal
- 27-35 intermediate (not affected but unstable on transmission)
- 36-39 reduced penetrance
- >=40 full penetrance
Anticipation - repeat expands further on transmission, esp. paternal transmission -> earlier onset, more severe in successive generations
Longer repeat = earlier onset (inverse correlation)

Clinical: chorea + cognitive decline + psychiatric change (depression, irritability, psychosis) + family history
Genetic testing (CAG repeat sizing) - confirms diagnosis in symptomatic patients
Predictive testing in asymptomatic at-risk relatives - requires formal genetic counselling protocol (pre- and post-test counselling, psychological assessment) - not done as a routine blood test
MRI - caudate/striatal atrophy, generalised cerebral atrophy as disease progresses (supportive, not diagnostic)

No disease-modifying therapy - symptomatic + supportive

Chorea - vesicular monoamine transporter-2 (VMAT2) inhibitors (tetrabenazine, deutetrabenazine) first-line; antipsychotics (e.g. olanzapine, risperidone) also used, particularly if psychiatric symptoms coexist
Psychiatric symptoms - depression, irritability, psychosis managed as per standard psychiatric practice (SSRIs, antipsychotics); high suicide risk - screen actively
Cognitive decline - no proven pharmacotherapy; MDT support (OT, speech pathology for dysphagia, dietetics)
Genetic counselling - predictive testing pathway for at-risk relatives, reproductive options (PGD)
Advance care planning - progressive, discuss early given cognitive decline

Depression, irritability, psychosis, obsessive-compulsive features
Weight loss (disproportionate to intake - hypermetabolism)
Dysphagia and aspiration risk (advanced disease)
Juvenile HD variant - rigidity/bradykinesia (Westphal variant) rather than chorea, seizures, more rapid course

Relentlessly progressive over ~15-20 years from onset
Death typically from aspiration pneumonia or other complications of advanced immobility, not the disease itself
Anticipation -> earlier, more severe disease in children of affected fathers particularly
Suicide risk elevated throughout course, including in gene-positive presymptomatic individuals

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