---

Huntington Disease (HD)

Definition & Epidemiology

• Prevalence: ~2.71–10 per 100,000 worldwide; up to 5.7/100,000 in Europeans, as low as 0.4/100,000 in Asians
• Mean age of onset: 45 years (range: 30–55 years); 5–10% have juvenile onset before age 20
• Course: Relentlessly progressive, leading to death over ~15 years

---

Genetics & Molecular Pathogenesis

CAG Repeat Thresholds

• Anticipation: Larger repeats cause earlier onset in successive generations. CAG repeats expand preferentially during spermatogenesis (paternal transmission), so 69% of father-child pairs show expansion vs. 32% of mother-child pairs. Juvenile HD is therefore usually paternally inherited.
• HTT gene has 67 exons and encodes a 3,144 amino acid, ~350 kDa protein. Huntingtin is involved in intracellular trafficking, cytoskeletal organization, endocytosis, and transcription regulation, and is required for neuronal development.

Disease Mechanism (Toxic Gain of Function)

• Sequester transcription factors
• Disrupt protein degradation (ubiquitin-proteasome) pathways
• Perturb mitochondrial function

---

Neuropathology

• Degree of striatal degeneration correlates with motor symptom severity
• Cortical neuronal loss correlates with dementia

---

Clinical Features

1. Motor Symptoms

• Chorea (involuntary jerky, writhing movements) - predominant early
• Dystonia and parkinsonism develop later
• Westphal variant (juvenile onset): akinetic-rigid/dystonic form rather than choreic
• Oculomotor dysfunction: difficulty with refixating gaze; blinks and head thrusts to compensate

2. Cognitive Symptoms

• Bradyphrenia (slowed thinking), forgetfulness, inattention
• Executive dysfunction, impaired working memory
• Deficits in emotion recognition, smell identification, time discrimination/production
• Progresses to subcortical dementia (different from Alzheimer's cortical pattern - attention, concentration, judgment, and problem-solving are predominantly affected)
• Cognitive decline detectable decades before motor diagnosis on tests like Symbol Digit Modalities Test, Trail Making Test, Stroop

3. Psychiatric Symptoms

• Universal but widely variable
• Apathy, depression, anxiety, aggression, disinhibition
• Impulsiveness, personality changes, paranoid psychosis
• Obsessive and perseverative behaviors
• May precede motor symptoms - can be misattributed to psychotropic drugs

---

Diagnosis

• Clinical: Motor diagnosis requires an unequivocal extrapyramidal movement disorder, though cognitive and behavioral features may dominate
• Genetic testing: Confirmatory - counts CAG repeats in the IT15 gene
• MRI: Gray matter volume loss (caudate especially) detectable in premanifest and early-stage patients; useful for monitoring progression
• Biofluid markers: Mutant huntingtin protein (ultrasensitive single-molecule counting) associates with symptom onset and functional decline; NfL (neurofilament light chain) is an emerging marker

---

Treatment & Management

Chorea Management

Monitor for: depression, parkinsonism, weight gain (especially with tetrabenazine).

Psychiatric Symptoms

• Treated with standard agents for the respective condition (SSRIs for depression, antipsychotics for psychosis)

Disease-Modifying Strategies (Investigational)

• Intrathecal antisense oligonucleotides targeting mutant huntingtin mRNA - unfortunately, early trials were not helpful
• Fetal cell transplantation - not found to be helpful
• RAN proteins are potential future targets
• Genome editing approaches remain under investigation

---

Prognosis

• Inexorable decline at a relatively constant rate
• Institutionalization and death over ~15 years from symptom onset
• Prognosis varies with disease burden (CAG repeat length influences age of onset but not rate of decline once symptoms appear)

---

Differential Diagnosis of Chorea

---

---

Corpus Striatum: Anatomy, Neurons, and Receptors

1. Anatomy & Subdivisions

---

2. Neuronal Types in the Striatum

A. Medium Spiny Neurons (MSNs) - ~95% of all striatal neurons

• The dominant cell type - inhibitory, GABAergic
• Receive massive glutamatergic input from the cortex and thalamus
• Send long-range inhibitory projections to globus pallidus and substantia nigra
• Also send local axon collaterals to adjacent MSNs (mutual inhibition)
• Subdivided into two populations by their peptide co-expression and receptor profile:

B. Interneurons - ~5–10% of striatal neurons

---

3. Inputs to the Striatum

---

4. Receptors in the Corpus Striatum

Dopamine Receptors (most clinically important)

Clinical note: D2 receptor occupancy in the corpus striatum of >78% by antipsychotics is associated with extrapyramidal symptoms (EPS/parkinsonism), while <65% is associated with suboptimal antipsychotic efficacy. This window can be achieved with haloperidol doses as low as 1–5 mg/day in first-episode patients.

Glutamate Receptors

GABA Receptors

Acetylcholine Receptors

• Predominantly muscarinic (M1–M5) on striatal interneurons and MSNs
• Mediate both excitatory and inhibitory effects
• Balanced against dopamine (dopamine inhibits, ACh excites striatal output)

Adenosine Receptors

• A2A receptors are co-localized with D2 receptors on GABAergic D2-MSNs in the indirect pathway
• A2A and D2 receptors have antagonistic interactions; A2A antagonists are under development for Parkinson disease

Cannabinoid Receptors

• CB1 receptors are particularly abundant in the basal ganglia/striatum
• Endogenous ligands: anandamide and 2-arachidonoylglycerol (2-AG)
• Modulate dopaminergic effects; role in motor control still being characterized

Serotonin Receptors

• Multiple subtypes present: 5-HT1, 5-HT2, 5-HT3 (ligand-gated), 5-HT4, 5-HT6, 5-HT7

---

5. The Direct and Indirect Pathways

Direct Pathway (facilitates movement)

• D1-MSNs use GABA + Substance P + Dynorphin
• Dopamine on D1 receptors excites this pathway (cAMP ↑)
• Net effect: movement facilitation

Indirect Pathway (suppresses movement)

• D2-MSNs use GABA + Enkephalin
• Dopamine on D2 receptors inhibits this pathway (cAMP ↓)
• Net effect: movement suppression

---

6. Functional Territories

---

7. Three Balanced Biochemical Systems

---

---

Point 4: Corpus Striatum - Interneurons & Neurons

---

🔵 Interneurons release ACh (Acetylcholine)

• These are only ~5% of striatal neurons
• They fire continuously (tonically) and keep a baseline level of ACh in the striatum
• ACh has an excitatory effect on striatal output neurons
• They act as a counterbalance to dopamine

---

🔵 Spiny Neurons release GABA

• Inhibitory - release GABA
• Have dendrites covered in spines (hence "spiny")
• Receive glutamate input from the cortex and dopamine from the substantia nigra
• They are the ones that carry information OUT of the striatum

---

The 50/50 Split - D1 vs D2 Receptors

✅ 50% express D1 receptor → Direct Pathway

Cortex (Glu) → Striatum D1-MSNs → GPi + SNr pars reticulata
                                          ↓ (GABA - inhibits)
                                        Thalamus (disinhibited)
                                          ↓ (Glu - excites)
                                        Cortex → MOVEMENT

• D1 neurons project to GPi (globus pallidus internal) and SNr (substantia nigra pars reticulata)
• D1 is an excitatory receptor - it is Gs-coupled → increases cAMP
• When dopamine hits D1 → it activates/excites these neurons
• These activated neurons then inhibit GPi/SNr (via GABA)
• GPi/SNr normally suppress movement - when they are inhibited, movement is released (facilitated)
• Co-express Substance P and Dynorphin

D1 + Dopamine = Direct pathway ON = Movement facilitated

---

✅ 50% express D2 receptor → Indirect Pathway

Cortex (Glu) → Striatum D2-MSNs → GPe (external)
                                         ↓ (GABA - inhibits GPe)
                                    GPe normally inhibits STN
                                    STN disinhibited → excites GPi
                                         ↓ (Glu)
                                        GPi/SNr more active
                                         ↓ (GABA - suppresses)
                                        Thalamus suppressed
                                         ↓
                                        Cortex → MOVEMENT SUPPRESSED

• D2 neurons project to GPe (globus pallidus external)
• D2 is an inhibitory receptor - it is Gi-coupled → decreases cAMP
• When dopamine hits D2 → it inhibits/suppresses these neurons
• This means GPe is less inhibited → GPe can now inhibit the STN
• STN activity drops → GPi/SNr suppression → thalamus freed → movement facilitated
• Co-express Enkephalin

D2 + Dopamine = Indirect pathway OFF = Movement facilitated

---

The Big Picture: How Dopamine Promotes Movement

---

ACh vs Dopamine Balance

---

Simple Memory Aid

D1 = Direct = Do movement D2 = inDirect = Dopamine inhibits this to allow movement ACh = brakes on movement; Dopamine = accelerator

Corpus Striatum - Short Summary

---

Two types of neurons:

---

Spiny neurons split 50/50:

• Dopamine hits D1 → excites → facilitates movement ✅

• Dopamine hits D2 → inhibits → also facilitates movement ✅

Dopamine promotes movement via BOTH pathways simultaneously.

---

Key balance:

• Dopamine = accelerator (pro-movement)
• ACh = brake (anti-movement)
• Both must be balanced for normal movement