Nervous System & Special Senses

Huntington disease: diagnosis and counseling

Clinical Overview and When to Suspect Huntington Disease

— Mutant huntingtin causes selective neuronal loss in the striatum (caudate and putamen), then cortex

— Loss of GABAergic medium spiny neurons → disinhibited thalamocortical output → chorea

— Later, direct pathway involvement and cortical atrophy produce rigidity, bradykinesia, dementia

— <27 CAG: normal

— 27–35: intermediate; not affected but may expand in offspring (especially paternal transmission)

— 36–39: reduced penetrance

— ≥40: full penetrance

— ≥60: juvenile-onset (Westphal variant), often parkinsonian

— Adult 35–50 with insidious chorea, personality change, executive dysfunction, and family history of "early dementia," suicide, or "nervous disorder"

— Apparent psychiatric disease (depression, OCD, irritability, psychosis) preceding motor signs by years

— Unexplained falls, weight loss despite normal appetite, or worsening handwriting in middle age

— Juvenile patient with rigidity, seizures, and cognitive decline plus affected father

Huntington disease (HD) is an autosomal dominant neurodegenerative disorder caused by a CAG trinucleotide repeat expansion in the HTT gene on chromosome 4p16.3, encoding the huntingtin protein

Pathophysiology

Repeat length thresholds (memorize)

When to suspect on Step 3

Anticipation: repeat expands across generations, more pronounced with paternal transmission (spermatogenesis instability) → earlier and more severe disease in children

Epidemiology: prevalence ~5–10 per 100,000 in populations of European descent; lower in Asian/African ancestry

Board pearl: A 42-year-old with new-onset depression, subtle fidgety movements, and a father who "died in a nursing home with dementia at 55" is HD until proven otherwise — order HTT gene testing, not just an MRI

Key distinction: Sydenham chorea (post-streptococcal, children, self-limited) and drug-induced chorea (levodopa, neuroleptic withdrawal, oral contraceptives, cocaine) are reversible; HD is progressive and inherited

Mean survival from motor onset is 15–20 years; death typically from aspiration pneumonia, suicide, or trauma from falls

Presentation Patterns and Key History

— Earliest: subtle fidgetiness, motor impersistence (cannot sustain tongue protrusion or grip — "milkmaid grip"), oculomotor abnormalities (slow saccade initiation, then hypometric saccades)

— Established: generalized chorea — random, non-stereotyped, flowing, non-suppressible movements incorporated into purposeful actions ("parakinesia")

— Late: dystonia, rigidity, bradykinesia, dysarthria, dysphagia, gait instability

— Juvenile-onset: akinetic-rigid (Westphal) variant with seizures and myoclonus, less chorea

— Subcortical dementia pattern: slowed processing, executive dysfunction, impaired set-shifting and planning

— Memory retrieval affected; recognition relatively preserved (contrast with Alzheimer)

— Insight often retained early → contributes to depression and suicide risk

— Depression (up to 40%), irritability, apathy, anxiety, OCD-like behaviors, psychosis

— Suicide risk is ~5–10× general population, peaking at two windows: just before formal diagnosis and when independence is lost

— Detailed three-generation pedigree: ages of onset, cause of death, psychiatric hospitalizations, "alcoholism," suicide, early dementia

— Possibility of nonpaternity or adoption that obscures family history

— Adoption status, ancestry, consanguinity

— Medication history (neuroleptics, levodopa, stimulants) to exclude drug-induced chorea

— Functional history: driving, finances, work performance, falls, weight loss

HD evolves through three overlapping domains: motor, cognitive, and psychiatric — all three are required for a complete clinical picture

Motor features

Cognitive features

Psychiatric features (frequently the presenting complaint)

Key history elements to elicit

Step 3 management: When a patient presents with chorea + family history, do not order genetic testing in the first visit without pretest counseling; instead schedule a dedicated counseling visit and screen for suicidality, depression, and decisional capacity before drawing blood

Board pearl: Eye movement abnormalities (delayed saccade initiation, inability to suppress reflexive saccades) are among the earliest objective motor signs and can predate chorea by years

Physical Exam Findings and Functional Assessment

— Restless, fidgety, may appear to "incorporate" involuntary movements into gestures

— Weight loss disproportionate to intake (hypermetabolic state)

— Slowed initiation of saccades, often with head thrust or blink to initiate gaze

— Hypometric, slow saccades; impaired smooth pursuit

— Difficulty suppressing reflexive saccades (antisaccade task failure)

— Chorea: random, brief, non-rhythmic movements of face, tongue, limbs, trunk; worsens with distraction, disappears in sleep

— Motor impersistence:

— "Milkmaid grip" — inability to maintain steady grip

— Cannot sustain tongue protrusion >10 seconds

— Dystonia (later): sustained posturing, often truncal

— Bradykinesia and rigidity in advanced or juvenile disease

— Hyperreflexia; Babinski may be present in advanced disease

— Wide-based, lurching, "dancing" quality with superimposed chorea

— Tandem gait impaired early

— Falls common; assess with Timed Up and Go

— MoCA preferred over MMSE — better sensitivity to executive dysfunction

— Frontal release signs, verbal fluency deficits, Stroop interference

— PHQ-9 for depression, C-SSRS for suicidality at every visit

— Assess insight, capacity, and caregiver burden

— Swallowing evaluation (silent aspiration common)

— Driving safety — formal on-road testing if any concern

— Home safety: stairs, firearms (critical given suicide risk), medication management

— Unified Huntington Disease Rating Scale (UHDRS) — motor, cognitive, behavioral, functional domains; tracks progression

General appearance

Cranial nerves and oculomotor exam (high yield)

Motor exam

Gait

Cognitive bedside testing

Psychiatric screening

Functional/safety assessment

Quantitative scale

CCS pearl: On a Step 3 CCS case of suspected HD, order neurology consult, neuropsychiatric evaluation, swallow evaluation, PT/OT, and social work in the first visit cluster — multidisciplinary care is the standard

Board pearl: Chorea that disappears during sleep distinguishes HD and most movement disorders from seizure activity or psychogenic movements

Diagnostic Workup — Initial Labs and Imaging

— CBC with peripheral smear — acanthocytes suggest neuroacanthocytosis (chorea-acanthocytosis, McLeod syndrome)

— TSH, free T4 — hyperthyroidism causes chorea

— CMP, calcium, magnesium, glucose — hypo/hyperglycemia, hypocalcemia, hypoparathyroidism

— Ceruloplasmin and 24-hour urine copper — Wilson disease in any patient <50 with movement disorder

— ANA, anti-dsDNA, antiphospholipid antibodies (lupus anticoagulant, anticardiolipin, β2-glycoprotein I) — SLE/APS chorea

— HIV, RPR — infectious causes

— ASO/anti-DNase B in younger patients — Sydenham chorea

— Vitamin B12, folate, heavy metals if exposure history

— Pregnancy test in women of reproductive age (chorea gravidarum)

— Urine toxicology — cocaine, amphetamines, levodopa metabolites

— MRI brain (preferred):

— Atrophy of caudate head → flattening or convex appearance of the lateral ventricle border, enlarging the bicaudate ratio

— Putaminal atrophy, generalized cortical atrophy in advanced disease

— Increased T2 signal in striatum (variable)

— CT acceptable if MRI contraindicated but less sensitive

— Imaging may be normal early, especially in premanifest carriers

— FDG-PET: striatal hypometabolism, often precedes structural changes

— DAT-SPECT typically normal (helps distinguish from parkinsonian syndromes)

— UHDRS motor score, MoCA, PHQ-9, weight, swallowing assessment

HD is ultimately a genetic diagnosis, but initial workup serves two purposes: (1) exclude treatable mimics and (2) establish a clinical baseline

Laboratory studies to rule out reversible chorea

Neuroimaging

Functional/specialized imaging (research or atypical cases)

Baseline evaluations to document

Step 3 management: In a 45-year-old with chorea and no family history, you must still send ceruloplasmin, TSH, HIV, ANA, and peripheral smear before genetic testing — missing Wilson disease is a costly board error because it is treatable with chelation

Board pearl: Caudate atrophy with "boxcar ventricles" on MRI is classic but not required for diagnosis — genetic testing supersedes imaging

Diagnostic Workup — Confirmatory Genetic Testing

— Detects expansion on either allele; sizes both alleles

— ≥40 repeats: diagnostic of HD in a symptomatic patient (full penetrance)

— 36–39: reduced penetrance — may or may not develop disease

— 27–35: intermediate — patient unaffected but offspring at risk due to potential expansion (paternal transmission)

— <27: normal

— Diagnostic (confirmatory) testing: in a symptomatic patient to confirm clinical suspicion

— Predictive (presymptomatic) testing: in an asymptomatic at-risk individual — requires formal multistep protocol

— Minimum two pretest counseling sessions with a genetic counselor and often a neurologist and mental health professional

— Assessment of motive, support system, current psychiatric stability, suicidality

— Informed consent documenting understanding of implications (insurance, employment, family, reproduction)

— Result disclosed in person, never by phone or mail

— Posttest follow-up at 1 week, 1 month, 6–12 months minimum

— No predictive testing in minors (<18) unless symptomatic, as it removes autonomy and provides no medical benefit

— Preimplantation genetic diagnosis (PGD) with IVF — allows selection of unaffected embryos, can preserve nondisclosure to at-risk parent

— Chorionic villus sampling (10–13 wks) or amniocentesis (15–20 wks) with option to terminate

— Exclusion (linkage) testing: tests whether fetus inherited the at-risk grandparent's haplotype without revealing parent's status

— Homozygosity (both alleles expanded) does not significantly worsen phenotype, unlike most repeat disorders

— Negative test in clinically classic case → consider HD phenocopies: C9orf72, HDL1–4, SCA17, neuroferritinopathy, neuroacanthocytosis

Definitive diagnosis: PCR-based HTT CAG repeat sizing on peripheral blood

Two distinct testing scenarios — do not confuse

Predictive testing protocol (HDSA/international guidelines)

Prenatal and reproductive options

Other confirmatory considerations

Board pearl: A patient says, "I just want to know — order the test today." Refuse and arrange counseling first. Premature predictive testing without protocol is a Step 3 ethics red flag and increases suicide risk at disclosure

Key distinction: Diagnostic testing in a symptomatic patient is straightforward; predictive testing is a months-long counseling-driven process

Risk Stratification and Overall Management Framework

— Premanifest (presymptomatic): gene-positive, no motor signs; surveillance and counseling

— Prodromal: subtle motor/cognitive/psychiatric signs not meeting diagnostic threshold

— Stage 1–2 (early manifest): independent in ADLs/IADLs; outpatient management

— Stage 3 (middle): loss of employment/finances, needs assistance with complex tasks

— Stage 4–5 (late): dependent in ADLs, often institutionalized

— Identify the most disabling symptom for the patient — not necessarily chorea

— Many patients are more disabled by depression, apathy, or irritability than by movement

— Treat one symptom at a time; minimize polypharmacy

— Reassess every 3–6 months

— Neurology (movement disorder specialist if available)

— Psychiatry — critical given suicide risk

— Genetic counseling — for patient and family planning

— PT, OT, speech-language pathology (swallow and communication)

— Nutrition — caloric needs often elevated due to hyperkinetic state

— Social work, palliative care, eventual hospice

— Suicide screening (C-SSRS)

— Fall risk and home safety

— Driving fitness

— Firearm access counseling

— Swallowing/aspiration risk

— Caregiver burnout and abuse screening

— Initiate early while capacity is intact — advance directives, healthcare proxy, feeding tube preferences, code status

— Reassess at each transition (loss of independence, institutionalization)

HD has no disease-modifying therapy — management is symptom-directed and multidisciplinary, organized around three domains (motor, cognitive, psychiatric) plus functional support

Disease staging (functional)

Treatment prioritization framework

Multidisciplinary team (assemble early)

Safety priorities at every visit

Goals of care discussion

Step 3 management: First-visit order set for newly diagnosed HD — psychiatry referral, genetic counseling referral, PT/OT/SLP evaluations, social work, advance directive discussion, depression and suicide screening, baseline UHDRS and MoCA

Board pearl: The single highest-yield intervention in early HD is treating depression, not chorea — depression is treatable, reversible, and the principal driver of suicide

Pharmacotherapy — Symptom-Targeted Regimens

— VMAT2 inhibitors (first-line, FDA-approved):

— Tetrabenazine — older, requires CYP2D6 genotyping if dose >50 mg/day; risks: depression, suicidality (black box), parkinsonism, QT prolongation, sedation

— Deutetrabenazine — deuterated, longer half-life, better tolerability, BID dosing

— Valbenazine — once daily, FDA-approved 2023 for HD chorea

— Atypical antipsychotics (preferred when chorea coexists with psychosis, irritability, or aggression):

— Olanzapine, risperidone, aripiprazole, quetiapine

— Dual benefit; avoid in patients with significant bradykinesia

— Typical antipsychotics (haloperidol, fluphenazine): effective but high EPS/tardive risk — reserve for refractory cases

— SSRIs first-line: sertraline, citalopram, escitalopram

— Mirtazapine if insomnia and weight loss prominent

— SNRIs (venlafaxine, duloxetine) acceptable

— Avoid bupropion — lowers seizure threshold, especially in juvenile HD

— SSRIs first; add atypical antipsychotic if needed

— Avoid benzodiazepines chronically (falls, paradoxical disinhibition)

Chorea (treat only if functionally impairing — many patients tolerate chorea well)

Depression and anxiety

Irritability/aggression

Obsessive-compulsive features: SSRIs at higher doses

Psychosis: atypical antipsychotics (olanzapine, risperidone)

Apathy: stimulants generally avoided; treat depression first

Insomnia: mirtazapine, trazodone; avoid anticholinergics (worsen cognition)

Myoclonus/seizures (juvenile): valproate, levetiracetam, clonazepam

Rigidity/bradykinesia (juvenile or late): cautious levodopa; may worsen chorea in classic HD

Sialorrhea: glycopyrrolate (peripheral, less CNS effect), botulinum toxin to salivary glands

Step 3 management: Before starting tetrabenazine, screen for depression and suicidality and obtain baseline ECG (QTc); counsel about black-box warning and document discussion

Board pearl: A patient with HD chorea plus psychosis or severe irritability → choose an atypical antipsychotic (olanzapine) over a VMAT2 inhibitor for dual benefit and to avoid worsening depression

Non-Pharmacologic and Investigational Management

— Physical therapy: balance, aerobic conditioning, fall prevention; structured exercise programs improve motor function and may slow functional decline

— Occupational therapy: ADL adaptation, home modifications, weighted utensils, grab bars

— Speech-language pathology:

— Dysarthria management, augmentative communication devices in advanced disease

— Serial swallow evaluations — modified barium swallow when clinical concern; diet texture modification

— Caloric requirements increased 20–30% due to chorea

— High-calorie, high-protein supplements; small frequent meals

— Monitor weight monthly — weight loss is an independent predictor of mortality

— PEG tube discussion before severe dysphagia — align with advance directive

— Cognitive behavioral therapy for depression/anxiety/OCD

— Support groups (HDSA), caregiver respite, palliative care integration

— Antisense oligonucleotides (ASOs) targeting HTT mRNA — tominersen failed Phase 3 in 2021; WVE-003 (allele-selective) and others in trials

— RNA interference and CRISPR-based lowering of mutant huntingtin

— Gene therapy (AMT-130) — intrastriatal AAV delivery of microRNA

— None currently approved — do not select these as answers to "best therapy" questions

— Globus pallidus internus (GPi) DBS — investigational for refractory chorea; not standard of care

— Formal on-road driving evaluation at diagnosis and at any change; revoke when unsafe

— Disability paperwork (SSDI) — HD typically qualifies under Compassionate Allowances

— Living will, healthcare proxy, POLST/MOLST

— Discuss feeding tube, antibiotics for pneumonia, hospitalization preferences before capacity is lost

Rehabilitation therapies (evidence-based, core to HD care)

Nutrition

Mental health and psychosocial

Investigational and emerging therapies (know conceptually for Step 3)

Deep brain stimulation

Driving and work

Advance care planning

CCS pearl: A complete Step 3 CCS HD case requires orders for PT, OT, SLP, nutrition, psychiatry, genetic counseling, social work, advance directive documentation, and PHQ-9/C-SSRS — omitting psychosocial orders loses points

Board pearl: Aerobic exercise is the only intervention with consistent evidence for functional benefit in HD — prescribe it explicitly

Special Populations — Elderly and Renal/Hepatic Impairment

— Typically associated with shorter CAG repeats (36–42) and slower progression

— Chorea often more prominent than cognitive decline; dementia may be mild

— Family history may be obscured (parent died before manifesting) — termed "new mutation" appearance, often from an intermediate-range paternal allele expanding

— Differential broadens: senile chorea, vascular chorea, tardive dyskinesia, drug-induced movements

— Start low, go slow with all psychoactive medications

— Tetrabenazine and deutetrabenazine: increased risk of parkinsonism, sedation, orthostatic hypotension, depression, falls — often start at half the usual dose

— Antipsychotics carry FDA black-box warning for increased mortality in elderly with dementia-related psychosis — document risk/benefit; prefer atypicals at lowest effective dose

— Anticholinergic burden: avoid TCAs, diphenhydramine, oxybutynin — worsen cognition and increase falls

— QTc monitoring essential with VMAT2 inhibitors and antipsychotics; baseline and after dose changes

— Polypharmacy review at every visit

— Tetrabenazine and deutetrabenazine are primarily hepatically metabolized — no specific renal dose adjustment required, but accumulation of metabolites possible in severe CKD

— Valbenazine: avoid in severe renal impairment (CrCl <30)

— Many SSRIs (citalopram, sertraline) acceptable in CKD; avoid lithium

— Tetrabenazine contraindicated in hepatic impairment — use deutetrabenazine or valbenazine cautiously

— Deutetrabenazine: avoid in hepatic impairment

— Valbenazine: dose reduction in moderate-severe hepatic impairment

— SSRI choice: sertraline preferred in mild-moderate liver disease; avoid duloxetine in significant impairment

— CYP2D6 inhibitors (fluoxetine, paroxetine, bupropion) significantly increase tetrabenazine levels — genotype or avoid combination

— MAOIs contraindicated with VMAT2 inhibitors (washout 14 days)

— Reserpine washout 20 days before starting tetrabenazine

Late-onset HD (onset >60 years)

Pharmacologic considerations in the elderly

Renal impairment

Hepatic impairment

Drug-drug interactions to flag

Step 3 management: Before starting tetrabenazine in any patient, check baseline ECG, LFTs, depression/suicide screen, and review for CYP2D6 inhibitors; in elderly, start at 12.5 mg daily and titrate weekly

Board pearl: A 70-year-old with new chorea and no family history is more likely tardive dyskinesia or vascular chorea than late-onset HD — review medication list first

Special Populations — Pregnancy, Pediatrics, and Reproductive Counseling

— HD itself does not significantly worsen during pregnancy in most cases, but chorea may transiently increase

— Distinguish from chorea gravidarum (idiopathic or associated with prior Sydenham/APS, resolves postpartum)

— Pharmacologic caution:

— Tetrabenazine, deutetrabenazine, valbenazine: limited human data — generally avoid unless symptoms severe

— SSRIs: sertraline preferred in pregnancy; avoid paroxetine (cardiac malformations)

— Antipsychotics: if needed, quetiapine or olanzapine are commonly used; avoid in third trimester due to neonatal EPS/withdrawal

— Valproate contraindicated (neural tube defects, neurodevelopmental risk)

— Breastfeeding generally compatible with sertraline; VMAT2 inhibitors not recommended

— Each child of an affected parent has a 50% risk of inheriting the expanded allele

— Options to discuss before conception:

— Natural conception with prenatal testing (CVS or amnio) ± termination

— Preimplantation genetic diagnosis (PGD) with IVF — selects unaffected embryos

— Exclusion (linkage) testing — for at-risk parent who does not want to know own status; tests only whether fetus inherited the at-risk grandparental haplotype

— Donor gametes or adoption

— Genetic counseling is mandatory before any reproductive testing

— Typically paternal inheritance with CAG repeats ≥60

— Presentation: rigidity, bradykinesia, dystonia (Westphal variant), seizures, myoclonus, cognitive decline, behavioral problems

— Chorea less prominent

— School performance decline often the first sign

— Management:

— Antiepileptics for seizures (valproate, levetiracetam)

— Cautious levodopa for rigidity

— Antipsychotics for behavior

— Avoid stimulants

— Predictive testing in minors is not recommended unless symptomatic

— Defer predictive testing until age 18 and capable of informed consent

— Address emotional and identity issues; refer to support resources

Pregnancy in known HD carriers

Reproductive counseling (Step 3 high-yield)

Juvenile HD (onset <20 years, ~5–10% of cases)

Adolescents at risk

Step 3 management: A 28-year-old woman whose father has HD asks about pregnancy. Order referral to genetic counseling and discuss PGD, prenatal diagnosis, and exclusion testing; do not order HTT testing on the patient as the first step

Board pearl: Juvenile HD = paternal transmission + large CAG repeat + rigidity/seizures, not chorea

Complications and Adverse Outcomes

— Progressive dementia → loss of decision-making capacity, eventually mutism

— Severe dysarthria → loss of communication

— Dystonia and rigidity → contractures, immobility

— Seizures (especially juvenile HD)

— Sleep disturbance — fragmentation, REM behavior disorder

— Suicide — leading non-pneumonia cause of death; risk highest at:

— Time of diagnostic disclosure

— Loss of functional independence (driving, employment)

— Transition to long-term care

— Major depression, psychosis, severe irritability, homicidal ideation

— Substance use as self-medication

— Progressive weight loss despite normal/increased intake (hypermetabolism + dysphagia)

— Cachexia in late disease

— Dehydration

— Aspiration pneumonia is the most common cause of death

— Silent aspiration common; serial swallow evaluations essential

— Choking events

— Falls → fractures, head injury, subdural hematoma

— Burns and household accidents from impaired coordination and cognition

— Increased cardiovascular mortality

— QT prolongation from VMAT2 inhibitors and antipsychotics

— Autonomic dysfunction (orthostasis)

— Tetrabenazine: depression, suicidality (black box), parkinsonism, akathisia, QT prolongation, neuroleptic malignant syndrome

— Antipsychotics: tardive dyskinesia (masked by underlying chorea), metabolic syndrome, EPS

— Polypharmacy — sedation, falls, anticholinergic cognitive decline

— Caregiver burnout, depression, and increased suicide risk in caregivers

— Financial devastation; loss of insurance

— Domestic conflict, divorce, child welfare concerns

— 1. Aspiration pneumonia

— 2. Suicide

— 3. Trauma (falls)

— 4. Cardiovascular disease

— 5. Cachexia/inanition

Neurologic complications

Psychiatric complications

Nutritional and metabolic

Aspiration and respiratory

Trauma

Cardiac

Iatrogenic

Social and family

Causes of death (memorize order)

Board pearl: A patient with HD on tetrabenazine presents with fever, rigidity, altered mental status, and elevated CK → consider neuroleptic malignant syndrome; stop the drug, supportive care, dantrolene/bromocriptine

Step 3 management: At every visit, document C-SSRS, weight, fall history, swallowing status, and medication review — these are the modifiable drivers of mortality

When to Escalate Care — Hospitalization and Consults

— Active suicidal ideation with plan or intent → psychiatric hospitalization, often involuntary if capacity impaired

— Aspiration pneumonia, sepsis, severe dehydration

— Fall with head injury, fracture, or syncope

— New seizures (especially juvenile HD)

— Neuroleptic malignant syndrome suspicion (VMAT2 inhibitor or antipsychotic)

— Acute psychosis with agitation endangering self/others

— Severe weight loss requiring nutritional rehabilitation or PEG placement

— Status dystonicus (rare, life-threatening sustained dystonia with rhabdomyolysis)

— Rule out infection (CXR, UA, blood cultures, COVID/flu PCR seasonal)

— Metabolic panel, CK, troponin if NMS suspected

— Aspiration precautions, NPO until swallow evaluation

— Medication reconciliation — pause QT-prolonging agents if QTc >500

— Telemetry if on VMAT2 inhibitor or antipsychotic

— Neurology — for any HD admission

— Psychiatry — suicidality, psychosis, capacity assessment

— Speech-language pathology — swallow evaluation before any oral intake

— Nutrition — caloric assessment, PEG discussion

— Palliative care — symptom management, goals of care

— Social work — disposition planning, caregiver support

— Ethics consult — when capacity, advance directive, or feeding tube decisions are contested

— Aspiration with respiratory failure requiring intubation

— Status dystonicus or NMS with autonomic instability

— Severe overdose (intentional or accidental)

— Goals of care must guide intensity — many advanced HD patients have DNR/DNI preferences

— Stable swallowing or feeding plan in place

— Psychiatric stabilization confirmed

— Caregiver capable and educated; home health/PT arranged

— Outpatient neurology and psychiatry follow-up scheduled within 1–2 weeks

— Suicide means restricted (firearms removed, medication lockbox)

Indications for emergency department or inpatient evaluation

Inpatient workup priorities

Consults to order

ICU triage

Discharge readiness

CCS pearl: In a CCS case of an HD patient with pneumonia, order swallow evaluation BEFORE allowing oral intake, continue aspiration precautions, assess capacity for code status, and schedule outpatient neurology follow-up before discharge — these are the highest-leverage orders

Board pearl: A safe discharge from an HD admission is not complete without psychiatric reassessment, caregiver education, and 1–2 week follow-up — Step 3 frequently tests transitions-of-care gaps

Key Differentials — Other Inherited and Neurodegenerative Choreas

— C9orf72 expansion — most common HD phenocopy; also causes ALS/FTD; family history of ALS or early dementia

— HDL1 (PRNP) — prion-related, autosomal dominant

— HDL2 (JPH3) — predominantly African ancestry; clinically indistinguishable

— SCA17 (TBP) — ataxia plus chorea and cognitive decline

— DRPLA — common in Japanese populations; myoclonus, ataxia, epilepsy, dementia

— Neuroferritinopathy (FTL1) — adult-onset, orofacial dyskinesia, low ferritin, iron deposition in basal ganglia

— Chorea-acanthocytosis (VPS13A) — autosomal recessive, orofacial dyskinesia, lip/tongue biting, seizures, axonal neuropathy, elevated CK, acanthocytes on smear

— McLeod syndrome (XK gene, X-linked) — males, acanthocytes, absent Kell antigens (Kx), myopathy, cardiomyopathy

— PKAN (PANK2) — "eye of the tiger" sign on MRI; dystonia > chorea; pediatric onset

— Autosomal recessive ATP7B; always test in patients <50 with movement disorder

— Kayser-Fleischer rings, hepatic dysfunction, low ceruloplasmin, high urine copper, hemolytic anemia

— Treatable — chelation (penicillamine, trientine) and zinc

— Childhood onset, non-progressive chorea, often with thyroid and pulmonary abnormalities ("brain-lung-thyroid syndrome")

— CAG repeat in ATN1; ataxia, chorea, myoclonus, epilepsy

— Predominant ataxia → SCA17, DRPLA

— Family history of ALS/FTD → C9orf72

— African ancestry → HDL2

— Orofacial self-mutilation, elevated CK → chorea-acanthocytosis

— Iron deposition on MRI → neuroferritinopathy, PKAN

HD phenocopies (clinically identical, HTT-negative; <1% of cases combined)

Neuroacanthocytosis syndromes

Wilson disease

Friedreich ataxia and other SCAs — ataxia dominant, chorea variable

Benign hereditary chorea (NKX2-1)

Dentatorubral-pallidoluysian atrophy (DRPLA)

Key distinction: When HTT testing is negative in a classic HD picture →

Board pearl: Always order peripheral smear, ceruloplasmin, and CK as part of the chorea workup — these three labs catch chorea-acanthocytosis, Wilson, and McLeod

Key Differentials — Acquired and Secondary Choreas

— Levodopa, dopamine agonists — Parkinson disease overtreatment

— Neuroleptic withdrawal → tardive dyskinesia (orofacial > limb)

— Stimulants — cocaine, amphetamines, methylphenidate

— Oral contraceptives, estrogens

— Anticonvulsants — phenytoin, carbamazepine, lamotrigine, valproate

— Lithium

— Anticholinergics

— Step 3 management: Stop the offending agent before pursuing extensive workup

— Sydenham chorea — post-streptococcal, children 5–15, often hemichorea, "milkmaid grip," emotional lability; treat underlying strep, consider IVIG/steroids for severe cases

— SLE chorea — usually associated with antiphospholipid antibodies

— Antiphospholipid syndrome — chorea may precede thrombosis

— Anti-NMDA receptor encephalitis — orofacial dyskinesia, psychosis, autonomic instability, often paraneoplastic (ovarian teratoma)

— CRMP5, LGI1, CASPR2 antibodies — paraneoplastic

— Behçet disease, sarcoidosis

— Hyperthyroidism — diffuse chorea, weight loss; resolves with treatment

— Hyperglycemia (nonketotic) — hemichorea-hemiballism, T2 hyperintensity in contralateral putamen on MRI; resolves with glucose control

— Hypocalcemia, hypomagnesemia, hyponatremia

— Hypoparathyroidism with basal ganglia calcifications

— Hepatic encephalopathy (acquired hepatocerebral degeneration)

— HIV — direct or opportunistic (toxoplasmosis in basal ganglia)

— Neurosyphilis, viral encephalitis, prion disease (CJD — rapid dementia, myoclonus)

— Striatal stroke → hemichorea/hemiballism, classically subthalamic nucleus lesion

— Polycythemia vera — chorea in elderly

— Tumors, AVMs of the basal ganglia

— Chorea gravidarum — often associated with prior Sydenham or APS; resolves postpartum

Drug-induced chorea (most common acquired cause)

Autoimmune/inflammatory

Metabolic

Infectious/post-infectious

Vascular

Structural/neoplastic

Pregnancy

Key distinction: Acute, asymmetric, or hemichorea → think vascular, hyperglycemic, or autoimmune, not HD. Chronic, bilateral, with cognitive/psychiatric decline and family history → HD

Board pearl: A diabetic with acute hemichorea and contralateral putaminal T1 hyperintensity = nonketotic hyperglycemic chorea — check glucose and HbA1c, treat hyperglycemia

Long-Term Plan, Secondary Prevention, and Care Coordination

— Stable early disease: neurology every 6 months, psychiatry every 3 months if on psychotropics

— Active symptoms or new medication: every 4–6 weeks until stable

— Annual comprehensive multidisciplinary review (PT, OT, SLP, nutrition, social work)

— Reassess every visit: still needed? Still effective? Side effects?

— Deprescribe sedating, anticholinergic, or QT-prolonging agents when possible

— Maintain single prescriber for psychotropics to avoid duplication

— Age-appropriate cancer screening (mammography, colonoscopy, cervical, lung CT if eligible)

— Vaccinations: annual influenza, pneumococcal (PCV20 or PCV15+PPSV23), COVID-19, RSV (≥60), Tdap, shingles (≥50)

— Cardiovascular risk: BP, lipids, diabetes screening; statin per ASCVD risk

— Bone health: DEXA in those at risk; calcium/vitamin D

— Dental care (often neglected; affected by chorea and cognition)

— Each first-degree relative is at 50% risk if patient is heterozygous

— Refer interested relatives to genetic counseling — never test relatives' samples without their own informed consent and counseling protocol

— Address children: when and how to disclose family history

— Capacity reassessment annually or with cognitive change

— Update healthcare proxy, living will, POLST/MOLST

— Discuss feeding tube, antibiotics, hospitalization preferences

— Hospice eligibility in late disease (functional decline, weight loss, recurrent aspiration)

— Genetic Information Nondiscrimination Act (GINA) — protects against health insurance and employment discrimination based on genetic testing, but does NOT cover life, disability, or long-term care insurance

— Counsel patients to consider these policies before predictive testing

— Assist with SSDI application (HD qualifies under Compassionate Allowances)

Longitudinal care framework — HD is chronic and progressive; the "discharge plan" is lifelong

Outpatient visit cadence

Medication stewardship

Health maintenance (do not neglect — Step 3 loves this)

Counseling family members

Advance care planning revisited at each transition

Insurance and legal

Step 3 management: At each follow-up, address the "HD 5" — mood/suicide, swallow/weight, falls, medications, advance directives

Board pearl: Patients often ask about life insurance after a positive predictive test — explain that GINA does not protect life or long-term care insurance, so policies should ideally be obtained before testing

Follow-Up Monitoring, Rehab, and Counseling Detail

— UHDRS — motor, cognitive, behavioral, functional subscales; track annually

— Total Functional Capacity (TFC) score — used for staging (13 = normal, 0 = fully dependent)

— MoCA — annually or with cognitive complaint

— PHQ-9 every visit; C-SSRS every visit

— Weight every visit; >5% loss over 3 months triggers nutrition referral

— UHDRS dysphagia subscale or formal SLP swallow eval every 6–12 months or with symptoms

— Tetrabenazine/deutetrabenazine/valbenazine: ECG (QTc) at baseline, after dose changes; mood/suicide screen every visit; LFTs as indicated

— Antipsychotics: metabolic panel, lipids, HbA1c annually; AIMS (Abnormal Involuntary Movement Scale) every 6 months for tardive dyskinesia

— SSRIs: monitor for suicidality (especially first 4 weeks), GI side effects, hyponatremia in elderly, sexual dysfunction

— Routine repeat MRI not required unless clinical change suggests alternative diagnosis or stroke

— PT: aerobic exercise program — 150 min/week moderate intensity if tolerated; balance and gait training

— OT: home safety assessment annually; adaptive equipment (weighted utensils, shower bench, raised toilet)

— SLP: dysarthria therapy, communication aids, swallow strategies (chin tuck, thickened liquids)

— Driving evaluation at diagnosis, then annually or with any change

— Newly diagnosed: disease education, family planning, advance directives, support groups (HDSA), employment/disability planning

— Middle stage: capacity transitions, power of attorney, transition from work, home modifications, caregiver support

— Late stage: hospice, feeding tube revisited, dignity-preserving care, bereavement preparation for family

— Screen caregivers for depression (PHQ-9), burden (Zarit scale)

— Respite care referral

— Caregivers at-risk are often gene-positive children themselves — offer them counseling resources

Quantitative monitoring tools

Medication monitoring

Imaging follow-up

Rehab milestones

Counseling content at each stage

Caregiver support

Step 3 management: Document at every follow-up: UHDRS or TFC, MoCA, PHQ-9, C-SSRS, weight, falls, medication review, advance directive status, caregiver assessment

Board pearl: Total Functional Capacity (TFC) < 7 marks transition to middle-stage HD and typically signals loss of employment and need for in-home assistance

Ethical, Legal, and Patient Safety Considerations

— Autonomy: the at-risk individual alone decides; never coerced by family, employer, or insurer

— Minimum-age standard: no predictive testing of asymptomatic minors — preserves their future autonomy

— Two-visit minimum counseling, in-person result disclosure, scheduled follow-up — non-negotiable protocol

— Suicide risk peaks around disclosure — screen and arrange support before and after

— Right not to know must be respected

— Result belongs to the tested individual; clinician may not disclose to relatives without consent

— Encourage but do not require the patient to share with at-risk relatives

— If patient refuses to inform spouse/children, the clinician's duty is generally to counsel the patient, not breach confidentiality (no "duty to warn" override for genetic information in most jurisdictions, unlike Tarasoff)

— Discuss PGD, prenatal testing, exclusion testing, donor gametes, adoption non-directively

— Exclusion testing preserves the at-risk parent's right not to know

— GINA (2008) prohibits discrimination by health insurers and employers based on genetic information

— GINA does NOT cover:

— Life insurance

— Disability insurance

— Long-term care insurance

— Employers with fewer than 15 employees

— Active military (TRICARE separate)

— Counsel patients to purchase these policies before predictive testing if desired

— Formal capacity assessment when cognition declines

— Activate durable power of attorney for healthcare — established early, while capacity intact

— Re-evaluate capacity at each major decision (consent for procedures, treatment changes)

— Many states have physician reporting requirements for unsafe drivers — know your jurisdiction

— Counsel on firearm removal given high suicide risk; document discussion

— Both should be addressed at diagnosis and revisited every visit

— Feeding tube decisions should align with previously expressed wishes; surrogate cannot override a valid advance directive

— Withholding/withdrawing artificial nutrition is ethically permissible with appropriate consent and is not euthanasia

— Informed consent must account for cognitive decline; reconsent if capacity changes

Predictive (presymptomatic) testing ethics

Confidentiality and family

Reproductive ethics

Insurance and employment

Capacity and surrogate decision-making

Driving and firearms (transition-of-care safety, Step 3 favorite)

End-of-life care

Research participation

Step 3 management: A patient with HD scores 18/30 on MoCA and wants to change their advance directive to "full code, full feeding tube." First step: formal capacity assessment with psychiatry consultation — capacity is decision-specific, not global

Board pearl: GINA protects health insurance and employment, not life/disability/long-term care insurance — this is the single most-tested HD ethics fact

High-Yield Associations and Rapid-Fire Facts

— HTT gene, chromosome 4p16.3, CAG repeat, autosomal dominant, full penetrance ≥40 repeats

— Anticipation, worse with paternal transmission

— Juvenile HD: paternal, ≥60 repeats, rigid/akinetic Westphal variant

— Homozygosity does not worsen phenotype

— Caudate atrophy first, then putamen, then cortex

— Loss of GABAergic medium spiny neurons (indirect pathway first)

— Intranuclear inclusions of mutant huntingtin

— "Boxcar ventricles" from caudate atrophy

— FDG-PET: striatal hypometabolism precedes atrophy

— Motor (chorea) + cognitive (subcortical dementia) + psychiatric (depression, OCD, psychosis)

— Mean onset 35–45 years; survival 15–20 years from onset

— Slow saccade initiation, motor impersistence (milkmaid grip, tongue), subtle fidgetiness

— Chorea: VMAT2 inhibitors (tetrabenazine, deutetrabenazine, valbenazine) or atypical antipsychotic

— Depression: SSRI (sertraline, citalopram); avoid bupropion (seizures)

— Psychosis/irritability: atypical antipsychotic (olanzapine)

— Juvenile rigidity/seizures: valproate, levetiracetam, levodopa

— No disease-modifying therapy approved

— Aspiration pneumonia > suicide > trauma

— Tetrabenazine: depression and suicidality

— Antipsychotics in elderly with dementia: increased mortality

— C9orf72 (most common phenocopy)

— Wilson disease (treatable, always test <50)

— Sydenham chorea (post-strep, kids)

— Chorea-acanthocytosis (orofacial self-mutilation, acanthocytes, ↑CK)

— McLeod (X-linked, absent Kx antigen)

— SLE/APS chorea; nonketotic hyperglycemia hemichorea

— GINA protects health insurance + employment; NOT life/disability/long-term care

— No predictive testing in minors

— In-person result disclosure only

Genetics

Neuropathology

Imaging

Clinical triad

Earliest motor signs

Treatment quick-recall

Causes of death (in order)

Black boxes and warnings

Mimics to remember

Legal/ethics

Reproductive options: PGD, prenatal testing, exclusion testing

Functional staging: TFC score (13 = normal, 0 = dependent)

Board pearl: "Father died at 50 with dementia, patient has depression and clumsiness at 42" → HD until proven otherwise

Board Question Stem Patterns

— 45-year-old with 2-year history of irritability, divorce, mild fidgeting; father had "Alzheimer at 55"; exam shows slow saccades, milkmaid grip, brief jerky movements

— Best next step: Pretest genetic counseling, then HTT CAG testing

— Distractor: "Order MRI" — useful but not diagnostic; "Start tetrabenazine" — premature

— 25-year-old asymptomatic woman whose mother has HD requests testing today

— Best next step: Refer to genetic counseling for multistep predictive testing protocol

— Distractors: order test; reassure; recommend against testing

— HD patient with disabling chorea AND psychosis/irritability

— Best therapy: Atypical antipsychotic (olanzapine or risperidone) — dual benefit

— Distractor: tetrabenazine — worsens depression

— HD patient started on tetrabenazine develops worsening sadness and passive suicidal ideation

— Best next step: Discontinue tetrabenazine, psychiatric evaluation, consider valbenazine or atypical antipsychotic

— 30-year-old gene-positive woman wants child but doesn't want her child to inherit HD

— Best option to discuss: Preimplantation genetic diagnosis (PGD) with IVF

— Exclusion testing if she doesn't want to know her own status

— 14-year-old boy, father has HD, presents with school decline, rigidity, seizures

— Diagnosis: Juvenile HD (Westphal variant); CAG repeat likely ≥60 from paternal transmission

— Order HTT testing (symptomatic minor — permitted)

— 22-year-old with chorea, dysarthria, mild hepatitis, family history negative

— Order ceruloplasmin, 24-hour urine copper, slit-lamp before HTT

— Elderly diabetic with sudden unilateral chorea, glucose 480, MRI T1 hyperintensity in putamen

— Diagnosis: Nonketotic hyperglycemic hemichorea; treat hyperglycemia

— HD-affected patient asks whether his gene-positive daughter should buy life insurance now

— Answer: Yes, before further testing/disclosure — GINA does not cover life insurance

— Advanced HD patient with recurrent aspiration pneumonia; advance directive declines feeding tube; family insists

— Best step: Honor advance directive; involve palliative care/ethics; surrogates cannot override valid directive

— Patient on fluoxetine started on tetrabenazine, develops parkinsonism and somnolence

— Cause: CYP2D6 inhibition by fluoxetine → tetrabenazine accumulation; dose-reduce or switch

Stem 1 — Classic diagnostic

Stem 2 — Predictive testing request

Stem 3 — Treatment selection with comorbid psychiatry

Stem 4 — Tetrabenazine safety

Stem 5 — Reproductive counseling

Stem 6 — Juvenile HD

Stem 7 — Wilson disease mimic

Stem 8 — Acute hemichorea in diabetic

Stem 9 — Insurance ethics

Stem 10 — End-of-life

Stem 11 — Drug interaction

Board pearl: When the stem mentions family history of dementia and suicide together, think HD before Alzheimer

One-Line Recap

Huntington disease is an autosomal dominant CAG-repeat (HTT, chromosome 4) neurodegenerative disorder presenting in midlife with the triad of chorea, subcortical dementia, and psychiatric disease, diagnosed by genetic testing after counseling, managed symptomatically with VMAT2 inhibitors or atypical antipsychotics plus aggressive treatment of depression and suicide risk, with no disease-modifying therapy currently available.

High-yield recap bullets:

Genetics: HTT CAG expansion; ≥40 = full penetrance; paternal anticipation → juvenile Westphal variant ≥60 repeats; each child has 50% risk

Diagnosis: Symptomatic patient → HTT testing after pretest counseling; always exclude Wilson disease, hyperthyroidism, SLE/APS, chorea-acanthocytosis, and drug-induced chorea before settling on HD when family history is absent; MRI shows caudate atrophy / boxcar ventricles

Predictive testing: Multistep counseling protocol, in-person disclosure, never in asymptomatic minors; address life/disability/long-term care insurance BEFORE testing because GINA does not cover them

Treatment priorities: Treat the most disabling symptom — often depression, not chorea; SSRIs (avoid bupropion); chorea → VMAT2 inhibitor (screen mood, QTc, CYP2D6) or atypical antipsychotic (preferred if comorbid psychosis/irritability); juvenile HD → valproate/levetiracetam, cautious levodopa

Multidisciplinary care: Neurology, psychiatry, genetic counseling, PT/OT/SLP, nutrition, social work, palliative care; assess suicide, swallowing, weight, falls, advance directives every visit

Reproductive options: PGD with IVF, prenatal CVS/amnio, exclusion testing for those wishing not to learn their own status

Mortality drivers: Aspiration pneumonia > suicide > trauma; modifiable through swallow evaluations, mood treatment, fall and firearm safety

Ethics/Step 3: Honor advance directives even against family wishes; capacity is decision-specific; counsel on driving and firearms at diagnosis

Board pearl: Midlife chorea + family history of "early dementia or suicide" = HD until HTT testing proves otherwise