Genetics

• Autosomal dominant — chromosome 4p16.3, HTT gene encoding huntingtin protein
• Trinucleotide repeat: CAG expansion in exon 1
  • <27 repeats → normal
  • 27–35 → intermediate (unaffected, may expand in offspring)
  • 36–39 → reduced penetrance
  • ≥40 repeats → full penetrance
• Anticipation: Earlier onset in successive generations — CAG expansion especially with paternal transmission (spermatogenesis instability)

Clinical Features

Motor

• Chorea: Involuntary, irregular, non-repetitive, flowing movements — hallmark of adult-onset HD
• Progressive: chorea worsens, then transitions to rigidity and akinesia in advanced stages
• Motor impersistence: Cannot sustain tongue protrusion or grip (“milkmaid’s grip”)
• Dystonia, impaired saccades, dysarthria, dysphagia in later disease

Psychiatric & Cognitive

• Psychiatric symptoms often precede motor by years — depression (most common), high suicide risk, irritability, impulsivity, psychosis
• Subcortical dementia: Executive dysfunction, slowed processing; recognition > recall (unlike Alzheimer)

Westphal Variant (Juvenile HD)

• Onset <20 years; >60 CAG repeats — almost always paternal inheritance
• Rigidity and akinesia predominate (NOT chorea) — parkinsonian phenotype
• Seizures, cerebellar ataxia, rapid cognitive decline; more aggressive course

Imaging & Pathology

• MRI: Bilateral caudate atrophy → “boxcar ventricles” (frontal horn dilation)
• Pathology: Loss of medium spiny neurons (GABA/enkephalin) in caudate and putamen
• Intranuclear inclusion bodies with mutant huntingtin aggregates

Treatment

• Chorea — VMAT2 inhibitors (first-line):
  • Tetrabenazine: First FDA-approved for HD chorea; BLACK BOX warning for depression/suicidality; CYP2D6 genotyping required for doses >50 mg/day (to identify poor metabolizers) — NOT universal
  • Deutetrabenazine: Better tolerability, longer half-life; FDA-approved for HD chorea; shares boxed warning for depression/suicidality (same as tetrabenazine)
  • Valbenazine (Ingrezza): FDA-approved Aug 2023 for HD chorea; 40–80 mg/day; once-daily dosing
• Antipsychotics if chorea + psychiatric features (haloperidol, risperidone, olanzapine) — use with caution: may worsen depression/suicidality and parkinsonism in advanced HD; consider pimozide as alternative
• Depression: SSRIs/SNRIs; screen regularly given high suicide risk
• No disease-modifying therapy currently available

• Post–Group A strep infection — latency of 2–6 months after pharyngitis
• Mechanism: Anti–basal ganglia antibodies (molecular mimicry — streptococcal M protein vs. basal ganglia antigens)
• Part of rheumatic fever — one of the major Jones criteria
• Most common acquired chorea in children; peak age 5–15; female predominance, especially post-pubertal
• Features: Generalized chorea (often starts unilateral), emotional lability, hypotonia, motor impersistence (milkmaid’s grip, darting tongue)
• May have concurrent carditis — always get echocardiogram

Diagnosis & Treatment

• Elevated ASO titer or anti-DNase B confirms recent streptococcal infection (ESR/CRP may be normal by the time chorea appears)
• Natural history: Usually resolves within weeks to months; ~20–50% have persistent or recurrent chorea; psychiatric features (OCD, tics) may persist long-term; recurrences possible with re-infection or pregnancy
• PANDAS (Pediatric Autoimmune Neuropsychiatric Disorders Associated with Streptococcal infections): post-streptococcal autoimmune disorder with abrupt-onset OCD, tics, and behavioral changes; overlaps with Sydenham spectrum but remains controversial as a distinct entity
• Symptomatic: Valproate (first-line), carbamazepine, or dopamine blockers if severe
• Penicillin prophylaxis: Long-term secondary prophylaxis to prevent recurrent rheumatic fever

Anti-NMDAR Encephalitis

• Young women (peak 20s) — associated with ovarian teratoma (~50% of cases in women)
• Prodrome: Often a viral-like illness (headache, fever, malaise) days to weeks before neuropsychiatric onset
• Staged presentation: Psychiatric (psychosis, agitation) → orofacial/limb dyskinesias → seizures → decreased consciousness → autonomic instability → central hypoventilation
• Diagnosis: CSF anti-NMDAR antibodies (more sensitive than serum)
• Treatment: Tumor removal + immunotherapy (steroids, IVIG, PLEX; rituximab/cyclophosphamide if refractory)

Anti-LGI1 Encephalitis

• Older adults (>50 years); male predominance
• Faciobrachial dystonic seizures (FBDS) — brief, frequent face+arm contractions; pathognomonic; may precede full encephalitis
• Limbic encephalitis with memory loss, confusion, temporal lobe seizures; hyponatremia (SIADH)
• Treatment: Immunotherapy (responds poorly to antiseizure medications alone)

Other Autoimmune Choreas

• Anti-CASPR2: Neuromyotonia/Morvan syndrome, chorea, limbic encephalitis; associated with thymoma
• Anti-IgLON5: Sleep disorder (parasomnia, sleep apnea), gait instability, chorea, bulbar dysfunction; tauopathy on pathology

• Definition: Large-amplitude, violent, flinging/throwing proximal limb movements — most severe form on the chorea spectrum
• Unilateral — contralateral to lesion; bilateral (biballism) is rare

Anatomy & Etiology

• Classic localization: Contralateral subthalamic nucleus (STN)
• Most common cause: Stroke (lacunar infarct or hemorrhage in STN)
• Also: caudate, putamen, or thalamic lesions; hyperglycemia; tumors; demyelination
• Mechanism: Loss of STN glutamatergic output to GPi → reduced thalamic inhibition → excessive thalamocortical drive

Course & Treatment

• Usually self-limiting — vascular cases improve over days to weeks
• Symptomatic: Neuroleptics (haloperidol, risperidone) first-line; tetrabenazine for persistent cases; benzodiazepines as adjunct
• Nonketotic hyperglycemia: T1-hyperintense contralateral putamen on MRI (often with caudate involvement); correct glucose → movements resolve

Chorea Gravidarum

• Chorea during pregnancy (usually first trimester); most cases linked to prior Sydenham chorea or antiphospholipid syndrome
• Self-limiting; resolves after delivery; avoid teratogenic agents

SLE / Antiphospholipid Chorea

• Antiphospholipid antibodies (anticardiolipin, lupus anticoagulant, anti-β2-glycoprotein I) — most common cause of chorea in SLE
• Mechanism is thought to be direct antibody binding to basal ganglia neurons (immune-mediated), not purely thrombotic — hence response to immunosuppression even without stroke
• May be presenting feature; treatment: anticoagulation, immunosuppression, symptomatic dopamine blockers

Metabolic & Drug-Induced Choreas

• Thyrotoxicosis: Resolves with thyroid treatment
• Polycythemia vera: Hyperviscosity/basal ganglia microvascular changes
• Drug-induced: Levodopa (peak-dose dyskinesias — most common iatrogenic chorea), dopamine agonists (pramipexole, ropinirole, apomorphine), OCPs (estrogen-related, especially with prior Sydenham), stimulants, anticonvulsants at toxic levels

Benign Hereditary Chorea

• NKX2-1 (TITF1) mutation — AD; “Brain-Lung-Thyroid” syndrome: Chorea + pulmonary disease + congenital hypothyroidism
• Childhood onset; non-progressive (unlike HD); normal cognition

Neuroacanthocytosis (Chorea-Acanthocytosis)

• AR (VPS13A gene, encodes chorein); orofacial dyskinesias with lip/tongue biting (self-mutilation) — pathognomonic
• Chorea, dystonia, parkinsonism, seizures, neuropathy
• Acanthocytes on blood smear; elevated CK; caudate atrophy on MRI
• Comparator — McLeod syndrome: XK gene (X-linked); absent Kx antigen + weakened Kell antigens on RBCs; elevated CK; cardiomyopathy; acanthocytes; chorea, neuropathy, psychiatric features — clinically overlaps with chorea-acanthocytosis but distinguished by X-linked inheritance and Kell antigen testing

Huntington Disease–Like (HDL) Syndromes

• HDL1: PRNP gene (prion protein, octapeptide insertion); AD; HD-like phenotype with psychiatric and cognitive features
• HDL2: JPH3 (junctophilin-3), 16q24; CTG/CAG expansion; AD; almost exclusively African descent; phenocopies HD including caudate atrophy and acanthocytes
• HDL3: AR, childhood onset, chromosome 4p; rare, gene not identified
• HDL4 = SCA17: TBP gene CAG/CAA expansion; AD; chorea, ataxia, dementia, psychiatric features

McLeod Syndrome

• XK gene (Xp21); X-linked recessive — males affected, female carriers may have mild features
• RBC phenotype: Absent Kx antigen with weakened Kell antigens (diagnostic)
• Chorea, orofacial dyskinesias, neuropathy, myopathy; elevated CK; cardiomyopathy (dilated, arrhythmias); acanthocytes on smear
• Onset 4th–5th decade; psychiatric/cognitive features common

C9orf72 (FTD–ALS–Chorea Overlap)

• C9orf72 hexanucleotide (GGGGCC) repeat expansion — most common genetic cause of FTD and ALS
• Can present with chorea or other movement disorders as part of FTD–ALS spectrum; rare HD phenocopy
• Consider when HD genetic testing is negative but family history is consistent with AD dementia/ALS/movement disorder

Lesch-Nyhan Syndrome

• HGPRT (HPRT1) deficiency — X-linked recessive purine salvage defect on Xq26-q27 → massively elevated serum and urinary uric acid (hyperuricemia, gouty arthritis, urate nephrolithiasis “orange sand” in diapers).
• Triad: (1) severe self-mutilation — compulsive lip/finger biting and head-banging despite intact pain perception (pathognomonic), (2) dystonia & choreoathetosis (onset 8–12 months after early hypotonia), (3) intellectual disability with hyperreflexia/spasticity.
• Treatment: allopurinol (controls uric acid, prevents nephropathy; does NOT improve neurologic features), physical restraints/dental extraction for self-mutilation, benzodiazepines/baclofen for dystonia.
• Comparator: Lesch-Nyhan = elevated uric acid; chorea-acanthocytosis (above) = normal uric acid with acanthocytes and elevated CK — classic board distractor pair.

Senile Chorea

• Sporadic, late-onset (typically >60 years) generalized chorea without dementia, psychiatric features, or family history
• Diagnosis of exclusion — HTT genetic testing negative; rule out HDL2, C9orf72, structural/metabolic causes
• Typically slowly progressive or non-progressive; symptomatic treatment with VMAT2 inhibitors or dopamine blockers