Huntington Disease
Huntington disease is an autosomal dominant neurodegenerative disorder caused by a CAG trinucleotide repeat expansion in the HTT gene, with the rare juvenile form (onset before age 20) typically presenting with rigidity, cognitive decline, and seizures rather than the classic adult chorea.
Huntington Disease (Paediatric Focus)
Huntington disease (HD) is a progressive, fatal neurodegenerative disorder inherited in an autosomal dominant (AD) pattern, caused by an expansion of CAG trinucleotide repeats in the Huntingtin (HTT) gene on chromosome 4p16.3 [1][2]. The name breaks down simply: it is named after George Huntington, who first described the condition in 1872.
HD is characterised by a triad of motor dysfunction (classically chorea), psychiatric disturbance, and progressive cognitive decline (dementia) [3]. It is a relentlessly progressive disease with no cure; the mean duration from diagnosis to death is approximately 15–20 years in adults (shorter in juvenile-onset forms).
In paediatric practice, HD manifests as Juvenile Huntington Disease (JHD), defined as onset before age 20 years (some authorities use < 21 years). JHD accounts for approximately 5–10% of all HD cases and differs substantially from adult-onset HD in its clinical presentation, being dominated by rigidity, bradykinesia, dystonia, seizures, and rapid cognitive decline rather than chorea — this is the so-called "akinetic-rigid" or "Westphal variant" [2].
Key Concept: Huntington Disease Is an Autosomal Dominant Trinucleotide Repeat Expansion Disorder
2. Epidemiology
- Prevalence: 4–8 per 100,000 in populations of European descent [2]
- Much lower prevalence in East Asian populations (including Hong Kong/China): ~0.4–0.7 per 100,000 — approximately 10-fold lower than in Caucasian populations
- Mean age of onset: ~40 years (range 2–80+ years) [2]
- Equal sex distribution (autosomal dominant inheritance — both males and females equally affected)
- Juvenile Huntington Disease (JHD, onset < 20 years): ~5–10% of all cases
- Within JHD, childhood-onset HD (< 10 years) is even rarer (~1–3% of all HD)
- HD is rare in Hong Kong and the Chinese population compared to Caucasians
- However, it is important not to dismiss the diagnosis in Chinese patients presenting with chorea, psychiatric symptoms, or a positive family history
- Lower prevalence may partly reflect under-diagnosis, social stigma, and genetic differences in CAG repeat lengths in Asian populations
- Family history: The single most important risk factor — autosomal dominant with near-complete penetrance at high repeat numbers
- Paternal transmission: Associated with greater risk of anticipation (further CAG expansion during spermatogenesis) and thus earlier onset in offspring, including JHD
- ~80% of JHD cases are inherited from the father — this is because spermatogenesis involves many more cell divisions than oogenesis, providing more opportunities for trinucleotide repeat expansion
- Number of CAG repeats: Higher repeat counts → earlier onset, more severe disease
Hong Kong Exam Point
HD is much rarer in Hong Kong/Chinese populations (~0.4–0.7/100,000) compared to Caucasians (4–8/100,000). But the principles of genetics, anticipation, and clinical features remain the same and are highly examinable [2].
3. Anatomy and Function: The Basal Ganglia and Striatum
Understanding HD requires understanding the basal ganglia circuitry, because HD selectively destroys specific neurons within the striatum.
The basal ganglia are a group of subcortical nuclei involved in motor control, cognition, emotion, and habit learning:
- Striatum (the "input station"):
- Caudate nucleus
- Putamen
- (Together = neostriatum or dorsal striatum)
- Globus pallidus (the "output station"):
- External segment (GPe)
- Internal segment (GPi)
- Subthalamic nucleus (STN)
- Substantia nigra:
- Pars compacta (SNpc) — dopaminergic
- Pars reticulata (SNpr) — GABAergic output
3.2 The Direct and Indirect Pathways
The basal ganglia modulate movement through two parallel circuits:
| Pathway | Function | Net Effect on Thalamus/Movement |
|---|---|---|
| Direct pathway | Facilitates desired movements | Disinhibits thalamus → promotes movement |
| Indirect pathway | Suppresses unwanted movements | Inhibits thalamus → suppresses movement |
Cortex → Striatum (D1 receptors) → inhibits GPi/SNpr → disinhibits thalamus → facilitates cortical motor activity → movement occurs
Cortex → Striatum (D2 receptors) → inhibits GPe → disinhibits STN → excites GPi/SNpr → inhibits thalamus → suppresses movement
The medium spiny neurons (MSNs) are the principal output neurons of the striatum. They are GABAergic (inhibitory) and are classified by the pathway they participate in:
- D1-expressing MSNs → direct pathway
- D2-expressing MSNs → indirect pathway
In HD, the D2-expressing MSNs of the indirect pathway are preferentially and selectively lost early in the disease [2]. This is the fundamental pathological event that explains the cardinal motor feature of chorea.
4. Aetiology and Pathophysiology
4.1 Genetic Basis
- Gene: HTT (previously called IT15) located on chromosome 4p16.3
- Mutation: Expansion of a CAG trinucleotide repeat in exon 1 of the HTT gene [1][2]
- CAG codes for glutamine → the expanded repeat produces a protein (mutant huntingtin, mHTT) with an abnormally long polyglutamine (polyQ) tract
- This is a "coding sequence" trinucleotide repeat expansion — the repeat is within the protein-coding region, so it directly alters the protein product [1]
CAG repeat ranges and clinical significance:
| CAG Repeat Number | Classification | Clinical Significance |
|---|---|---|
| ≤ 26 | Normal | No risk of HD; stable on transmission |
| 27–35 | Intermediate (mutable normal) | No HD phenotype, but may expand in next generation (especially paternal) |
| 36–39 | Reduced penetrance | May or may not develop HD; variable age of onset |
| ≥ 40 | Full penetrance | Will develop HD if the person lives long enough |
| ≥ 60 | Juvenile HD range | Very early onset (childhood/adolescence) |
- Autosomal dominant (AD) — only one copy of the mutant allele is needed to cause disease [1][4]
- 50% risk of transmission to each offspring
- De novo mutations: ~5–10% of HD cases have no apparent family history — these arise from expansion of intermediate alleles (27–35 repeats) in the parental germline, particularly during spermatogenesis
- Homozygosity (two copies of the expanded allele) is rare but associated with slightly more severe disease (though not dramatically worse than heterozygotes, unlike many AD conditions — this is unusual)
Anticipation is a hallmark of trinucleotide repeat disorders [1][2]:
- Definition: The phenomenon whereby the disease manifests earlier and with greater severity in successive generations
- Mechanism: The CAG repeat is unstable during DNA replication, particularly during spermatogenesis (male meiosis involves many more cell divisions than female meiosis)
- Paternal transmission → higher risk of further expansion → earlier onset in child
- This is why ~80% of JHD cases are paternally inherited
- ↑ severity upon generations (∵ triplet repeats expand between subsequent generations, i.e. anticipation) [1]
As noted in lecture materials [1]:
| Disease | Gene | Repeat | Coding/Non-coding | Key Feature |
|---|---|---|---|---|
| Huntington disease | HTT (4p16.3) | CAG | Coding | Toxic polyglutamine expansion |
| Fragile X syndrome | FMR1 (Xq27.3) | CGG | Non-coding | ↓/absent FMRP |
| Myotonic dystrophy | DMPK (19q13) | CTG | Non-coding (3'UTR) | RNA toxicity |
| Friedreich ataxia | FXN (9q21) | GAA | Non-coding (intron) | ↓frataxin |
| Spinocerebellar ataxias | Various | CAG | Coding | Polyglutamine toxicity |
Exam Pearl: Coding vs Non-Coding Trinucleotide Repeats
In coding sequence: produce protein with excess amino acid (e.g. glutamine) → toxic polyglutamine expansion → damage cells in CNS → neurodegeneration [1]
In non-coding sequence: ↓ protein production [1]
HD is a classic example of a coding sequence trinucleotide repeat disorder — the CAG repeat is translated into an abnormally long polyglutamine stretch that is directly toxic.
4.2 Pathophysiology
The expanded polyglutamine tract in mHTT causes a toxic gain of function (not simple loss of function):
- Protein misfolding and aggregation: mHTT forms intranuclear inclusions (aggregates) within neurons
- These aggregates disrupt normal cellular processes including transcription, protein degradation (proteasome/autophagy), and mitochondrial function
- Transcriptional dysregulation: mHTT interacts with transcription factors, altering gene expression profiles in vulnerable neurons
- Mitochondrial dysfunction: mHTT impairs mitochondrial complex II and III → energy depletion (the brain is highly energy-dependent)
- Excitotoxicity: Energy-depleted neurons become susceptible to glutamate-mediated excitotoxicity — even normal glutamate levels become toxic to energy-compromised cells
- Impaired BDNF (Brain-Derived Neurotrophic Factor) transport: Normal huntingtin facilitates anterograde transport of BDNF from cortex to striatum. mHTT disrupts this → striatal neurons are deprived of trophic support
- Apoptosis: All of the above converge to trigger programmed cell death of vulnerable neurons
- Loss of medium spiny neurons (MSNs) in the striatum — this is the pathological hallmark [2]
- The caudate nucleus and putamen are most severely affected → grossly visible as atrophy of the caudate nucleus with consequent enlargement of the frontal horns of the lateral ventricles ("box-car ventricles" on imaging)
- Vonsattel grading (0–4): Neuropathological severity grading based on degree of striatal atrophy
- Grade 0: No detectable neuropathological abnormality (but HD gene positive)
- Grade 4: Severe striatal atrophy with > 95% neuronal loss
Selective vulnerability: Why are MSNs preferentially lost?
- MSNs have high metabolic demands but relatively low capacity for energy generation
- They receive massive glutamatergic (excitatory) input from the cortex
- They are uniquely dependent on cortically-derived BDNF (which is disrupted by mHTT)
- D2-expressing (indirect pathway) MSNs are lost first, followed later by D1-expressing (direct pathway) MSNs
The sequential loss of MSNs explains the biphasic motor progression of HD:
Early disease: Preferential loss of indirect pathway (D2) MSNs [2]
- Loss of the indirect pathway → loss of movement suppression → involuntary hyperkinetic movements (CHOREA)
- Think of it as removing the brakes on movement
Late disease: Additional loss of direct pathway (D1) MSNs
- Loss of the direct pathway → loss of movement facilitation → akinesia, rigidity (parkinsonism)
- Parkinsonism: usually in late stage [2]
- In JHD, both pathways are destroyed rapidly and early → akinetic-rigid phenotype from the outset (Westphal variant)
5. Classification
| Classification | Age of Onset | % of Cases | Key Clinical Features |
|---|---|---|---|
| Adult-onset HD | 30–50 years (mean ~40y) | ~90% | Classic triad: chorea, psychiatric, cognitive decline |
| Juvenile HD (JHD) | < 20 years | ~5–10% | Akinetic-rigid (Westphal variant), seizures, rapid decline |
| Late-onset HD | > 60 years | ~5% | Milder phenotype, slower progression, more chorea |
| Phenotype | Pathological Basis | Typical Presentation |
|---|---|---|
| Hyperkinetic (choreiform) | Early selective loss of indirect pathway MSNs | Classic adult HD — chorea predominates |
| Akinetic-rigid (Westphal variant) | Rapid loss of both direct and indirect pathway MSNs | JHD — presents with parkinsonism rather than chorea [2] |
- Used in post-mortem classification based on degree of striatal atrophy
- Not used clinically but important for understanding disease progression
Paediatric Focus: Juvenile Huntington Disease (JHD)
JHD is defined as onset < 20 years. It is predominantly paternally inherited (anticipation via spermatogenesis) and typically has ≥ 60 CAG repeats. Unlike adult HD, JHD presents with the akinetic-rigid (Westphal variant) phenotype: rigidity, bradykinesia, dystonia, seizures (~30–50%), cerebellar signs, and rapid cognitive decline. Chorea may be minimal or absent. Progression is more rapid (mean survival ~10–15 years from onset in JHD vs 15–20 years in adult HD).
6. Clinical Features
The triad of chorea, psychiatric manifestations including depression and psychosis, and progressive dementia characterizes this fatal condition [3].
The clinical features of HD can be divided into three domains:
- Motor (neurological)
- Psychiatric (behavioural/emotional)
- Cognitive (dementia)
Importantly, psychiatric symptoms often precede motor symptoms by years — a patient may present to psychiatry long before neurological features become apparent.
6.2 Motor Features (Neurological)
Chorea: The hallmark motor feature — involuntary, irregular, purposeless, non-rhythmic movements that flow from one body part to another
- Pathophysiological basis: Loss of medium spiny neurons in striatum → ↓↓ indirect pathway → dyskinesia [2]
- Loss of the indirect pathway removes the "brake" on thalamocortical excitation → excess, uncontrolled movement
- Chorea: ↑ with stress and walking, disappears during sleep [2]
- Stress activates sympathetic pathways and increases cortical excitation → amplifies the already-disinhibited motor output
- Sleep reduces cortical activity → less thalamocortical drive → chorea ceases
- Initially subtle: fidgetiness, restlessness, clumsiness, "piano-playing fingers"
- Progresses to involve face, trunk, and limbs
- Patients often incorporate chorea into voluntary movements (parakinesia) to disguise it — e.g., turning an involuntary arm jerk into a hair-smoothing gesture
- Motor impersistence: inability to sustain a voluntary contraction — e.g., cannot maintain tongue protrusion ("milkmaid's grip" when squeezing examiner's fingers, or "darting tongue" / "chameleon tongue")
- Dystonia: Sustained or repetitive muscle contractions causing abnormal postures — becomes more prominent as disease progresses
- Myoclonus: Brief, shock-like involuntary jerks — more common in JHD
- Tics: Less common but can occur
Loss of voluntary motor control: progressive, gradually causes dysarthria, dysphagia [2]
- Dysarthria (impaired speech articulation): Due to incoordination of oropharyngeal muscles → speech becomes increasingly slurred and eventually unintelligible
- Dysphagia (difficulty swallowing): Due to incoordination of swallowing mechanism → major cause of aspiration pneumonia and death
- Gait disturbance: "Dancing gait" — wide-based, lurching, with superimposed choreiform movements; falls are common
- Impaired saccadic eye movements: Slow initiation and velocity of saccades; difficulty suppressing reflexive glances — one of the earliest detectable motor signs
- Fine motor impairment: Difficulty with handwriting, buttoning, using utensils
Parkinsonism: usually in late stage [2]
- In adult HD: As the disease progresses and both direct and indirect pathway MSNs are destroyed, rigidity and bradykinesia supervene
- 'Akinetic form (Westphal variant)': presents with parkinsonism rather than chorea [2]
- This is the dominant presentation of JHD — children present with rigidity, bradykinesia, and dystonia rather than chorea
- Why? Because in JHD, the very high CAG repeat number causes rapid, widespread neuronal loss affecting both pathways simultaneously from early on
- Ataxia, intention tremor, dysmetria
- More prominent in JHD than adult-onset HD
- Due to cerebellar involvement that occurs more in juvenile cases
- Occur in 30–50% of JHD cases (rare in adult-onset HD)
- May be generalised tonic-clonic, myoclonic, or absence-type
- Reflect more widespread cortical involvement in JHD
Hung-up knee jerk ('marching the knee'): slowness in relaxation after knee jerk → repeated tapping results in rising of leg [2]
- This is a characteristic (though not pathognomonic) clinical sign of HD
- Mechanism: Reflects impaired central modulation of spinal reflexes due to basal ganglia dysfunction — the reflex arc fires normally but the dampening/relaxation phase is delayed
- Can be demonstrated by repeated tapping of the patellar tendon → the leg progressively rises ("marches") rather than returning to baseline
6.3 Psychiatric Features
Psychiatric: chronic atypical depressive states, psychosis, abnormal emotional states [2]
Psychiatric symptoms are among the earliest manifestations and may predate motor symptoms by 5–15 years. They are a major source of disability and suffering for patients and families.
- Prevalence: Up to 40–50% of HD patients
- Character: Often "atypical" — irritability, apathy, and anhedonia predominate rather than classic sadness
- Pathophysiological basis: Disruption of cortico-striato-thalamocortical circuits involved in mood regulation; loss of serotonergic and dopaminergic input to the prefrontal cortex
- Suicide risk: HD has one of the highest suicide rates of any neurological disease (~4–6× general population) — suicidality peaks around the time of genetic testing/diagnosis and when functional independence is lost
- Very common and distressing for caregivers
- Due to frontostriatal circuit dysfunction → impaired impulse control and emotional regulation
- Progressive loss of motivation, initiative, and spontaneity
- Often mistaken for depression but does not respond well to antidepressants
- Reflects dysfunction of anterior cingulate and dorsolateral prefrontal circuits
- Occurs in ~5–10% of patients
- Paranoid delusions and auditory hallucinations most common
- More common in JHD
- Rigidity of thought, perseveration, compulsive behaviours
- Due to dysfunction of orbitofrontal-striatal circuits
- In children, behavioural regression, conduct problems, school failure, social withdrawal may be the earliest signs
- Irritability, aggression, temper tantrums disproportionate to developmental stage
- Often initially attributed to ADHD, autism, or conduct disorder before the neurological diagnosis is considered
6.4 Cognitive Features
Cognitive: dementia, poor judgment, inflexibility of thought, ↓ concentration [2]
HD dementia is classified as a subcortical dementia [5]:
Subcortical dementia S/S: 'forgetfulness' (recognition > recall, improved by prompting), slowness of thought, difficulty with complex sequential tasks, impoverishment of affect and personality, flat and depressed mood, other neurological S/S (e.g. dysarthria, movement disorders) [5]
This contrasts with cortical dementia (e.g., Alzheimer's) where true amnesia, aphasia, agnosia, and apraxia predominate.
- Difficulty with planning, organising, sequencing, and mental flexibility
- Impaired judgment and decision-making
- Inflexibility of thought — difficulty shifting between tasks or adapting to new situations
- Pathophysiological basis: Disruption of dorsolateral prefrontal-striatal circuits (the "executive circuit")
- Bradyphrenia: Slowed processing speed
- Difficulty with timed tasks and complex sequential operations
- Retrieval deficit (subcortical pattern) rather than encoding deficit (cortical pattern)
- Recognition memory is relatively preserved; recall is impaired
- Performance improves with cueing and prompting
- This contrasts with Alzheimer's where encoding is fundamentally impaired and cueing does not help
- Procedural (implicit) memory is impaired early (striatum-dependent)
- Episodic (explicit) memory is impaired later
- Difficulty with spatial orientation, map-reading, construction tasks
- Due to parietal-striatal circuit involvement
- Relatively preserved in early stages (unlike AD)
- Dysarthria is a motor speech problem, not a language deficit per se
- Word-finding difficulties and reduced verbal fluency develop later
- Rapid cognitive decline — much faster than adult-onset HD
- Academic deterioration is often the first noticed feature — declining school performance, difficulty learning new material
- Global intellectual disability can develop rapidly
- Language regression may occur in very young-onset cases
6.5 Other Clinical Features
- Unintentional weight loss is a hallmark of HD, often severe and progressive
- Multifactorial: increased energy expenditure from chorea, dysphagia, hypermetabolic state, hypothalamic dysfunction
- In children with JHD, failure to thrive and growth faltering may be early features
- Disrupted circadian rhythm, insomnia, excessive daytime sleepiness
- Due to hypothalamic and brainstem involvement
- Diaphoresis (sweating), tachycardia, urinary incontinence
- Due to hypothalamic and autonomic pathway involvement
- Hypothalamic dysfunction may cause abnormal cortisol regulation, hypogonadism
- Relevant in paediatric patients for pubertal development assessment
| Feature | Adult-Onset HD | Juvenile HD (< 20y) |
|---|---|---|
| CAG repeats | 40–55 (typical) | Usually ≥ 60 |
| Inheritance | Either parent | ~80% paternal (anticipation) |
| Motor | Chorea predominates | Rigidity, bradykinesia, dystonia (Westphal variant) |
| Seizures | Rare | 30–50% |
| Cerebellar signs | Uncommon | More common |
| Cognitive | Subcortical dementia (slow) | Rapid cognitive decline, academic failure |
| Psychiatric | Depression, irritability, apathy | Behavioural regression, conduct problems |
| Progression | 15–20 years | ~10–15 years (more rapid) |
| Death | Aspiration pneumonia, suicide | Aspiration pneumonia, seizure-related |
| Sign | Description | Pathophysiological Basis |
|---|---|---|
| Chorea | Involuntary, irregular, flowing movements | Loss of indirect pathway MSNs → disinhibited thalamus |
| Motor impersistence | Cannot sustain tongue protrusion, grip | Impaired central modulation of sustained contraction |
| Hung-up knee jerk | Leg rises with repeated patellar tapping | Impaired central dampening of spinal reflexes [2] |
| Saccadic abnormalities | Slow initiation, ↓ velocity of saccades | Degeneration of frontal eye field – caudate circuit |
| Dystonia | Sustained abnormal postures | Progressive striatal degeneration |
| Rigidity / bradykinesia | Increased tone, slowness (late or JHD) | Loss of both direct and indirect pathway MSNs |
| Gait abnormality | Wide-based, lurching, "dancing gait" | Chorea + postural instability + cerebellar involvement |
| Dysarthria | Slurred, explosive speech | Motor incoordination of speech muscles |
| Cachexia | Marked weight loss, muscle wasting | Hypermetabolism + dysphagia + hypothalamic dysfunction |
In paediatric practice, think of JHD when a child presents with:
- Progressive motor disorder (especially rigidity/dystonia/bradykinesia, NOT chorea)
- Declining school performance and cognitive regression
- Behavioural changes (irritability, aggression, social withdrawal)
- Seizures of new onset
- Positive family history of HD (especially in the father)
Important: Many children with JHD are initially misdiagnosed with cerebral palsy, epilepsy, ADHD, or psychiatric conditions. A high index of suspicion is needed, especially when there is a progressive course and positive paternal family history.
HD poses unique psychosocial challenges in paediatrics:
- At-risk children: Each child of an affected parent has a 50% chance of inheriting the mutation. Predictive genetic testing in asymptomatic minors is generally NOT recommended and is ethically controversial — guidelines recommend deferring until the individual can provide autonomous informed consent (typically ≥ 18 years)
- Impact on family: Having a parent with HD is profoundly distressing for children — role reversal, grief, behavioural problems
- Genetic counselling: Essential for all families — should be offered by trained genetic counsellors
- Communication: Age-appropriate discussion with the child/adolescent about the family illness; support for caregiver/parent with HD
Ethical Consideration: Predictive Testing in Minors
Predictive genetic testing for HD in asymptomatic, at-risk minors is generally NOT recommended. Testing should be deferred until the individual is old enough to provide informed consent (usually ≥ 18 years), as there is no preventive treatment available and the psychological burden of a positive result in childhood can be devastating. Testing IS appropriate when a child is symptomatic (diagnostic testing, not predictive testing).
HD-related dementia is classified as follows [5]:
- By site: Subcortical dementia (not cortical — unlike Alzheimer's)
- Subcortical features: forgetfulness (retrieval deficit, helped by cueing), psychomotor slowing, executive dysfunction, mood changes, movement disorders
- By aetiology: Neurodegenerative — specifically a genetic/hereditary cause of dementia
- By category in dementia classification: "Anterior dementia" (frontal, motor cortex involvement) [5]
- "Includes: FTD, NPH, Huntington's disease" — characterised by "behavioural changes, disinhibition, antisocial behaviour, irresponsibility" [5]
High Yield: HD Dementia Classification
Huntington's disease dementia is classified as an anterior, subcortical dementia [5]. Key features that distinguish it from Alzheimer's (posterior, cortical dementia): retrieval memory deficit (not encoding), psychomotor slowing, early executive dysfunction, relatively preserved language, prominent movement disorder and mood changes.
High Yield Summary
-
Definition: HD is an autosomal dominant neurodegenerative disorder caused by CAG trinucleotide repeat expansion in the HTT gene (4p16.3) [1][2]
-
Genetics: CAG in coding sequence → toxic polyglutamine expansion → neurodegeneration [1]. Normal ≤ 26; intermediate 27–35; reduced penetrance 36–39; full penetrance ≥ 40 repeats
-
Anticipation: Repeats expand between subsequent generations, especially via paternal transmission [1][2]. ~80% of JHD is paternally inherited
-
Pathology: Loss of medium spiny neurons in the striatum → ↓↓ indirect pathway → chorea (early); later, ↓ direct pathway → parkinsonism [2]
-
Classic triad: Motor (chorea), psychiatric (depression, psychosis), cognitive (subcortical dementia) [2][3]
-
JHD (< 20 years): Akinetic-rigid (Westphal variant) — rigidity, bradykinesia, dystonia, seizures (30–50%), rapid decline; NOT chorea [2]
-
Key signs: Chorea ↑ with stress, disappears in sleep; hung-up knee jerk; saccadic abnormalities; motor impersistence [2]
-
Dementia type: Anterior, subcortical dementia [5] — retrieval deficit, executive dysfunction, psychomotor slowing
-
Epidemiology: Prevalence 4–8/100,000 (Caucasian); much lower in Hong Kong/Chinese populations [2]
-
No cure; progressive and fatal in 10–15 years (JHD) to 15–20 years (adult) [2]
-
Predictive testing in asymptomatic minors is NOT recommended — defer to adulthood
Active Recall - Huntington Disease (Paediatric Focus)
[1] Senior notes: Adrian Lui Pediatrics Notes.pdf (p. 495–497, Clinical Genetics: Trinucleotide Repeat Expansion, Mendelian Inheritance) [2] Senior notes: Ryan Ho Neurology.pdf (p. 127, Section 5.3 Huntington's Disease) [3] Learning Points: learning_points_output.txt (Neurology - Two Cases of Movement Disorders, Learning Point 3) [4] Senior notes: Adrian Lui Pediatrics Notes.pdf (p. 495–496, Autosomal Dominant Inheritance) [5] Senior notes: Ryan Ho Psychiatry.pdf (p. 81, 90, Classifying Dementia; Alzheimer's Disease) [6] Lecture slides: GC 169. My grandmother keeps forgetting things Geriatric psychiatry, Dementia.pdf (p. 19, AD Epidemiology) [7] Lecture slides: Neurology - Two cases of movement disorders.pdf [8] Lecture slides: GC 151. The malformed child hereditary syndromes and anomalies.pdf [9] Lecture slides: GC 148. Neurological examination in neonates, infants, and young children, including those with neurological diseases.pdf
Differential Diagnosis of Huntington Disease (Paediatric Focus)
When a child or adolescent presents with a combination of progressive motor disorder, cognitive decline, psychiatric/behavioural changes, and/or seizures, the differential diagnosis is broad. The key clinical question is: "Is this truly Huntington disease (HD/JHD), or is there another condition mimicking it?"
The differential diagnosis can be organised by the dominant clinical presentation:
- Chorea-predominant differentials (for the rarer child with hyperkinetic movements)
- Akinetic-rigid / dystonic differentials (the more typical JHD presentation)
- Progressive cognitive decline + movement disorder differentials
- Psychiatric presentation differentials
We will work through each systematically, always explaining why each condition can mimic HD and how to distinguish it.
The classic mnemonic for neurological differential diagnosis applies — VINDICATE (Vascular, Infectious, Neoplastic, Degenerative/genetic, Inflammatory/Immune, Congenital, Autoimmune, Toxic/Traumatic, Endocrine/metabolic) [10]. In paediatrics, we weight metabolic, genetic/degenerative, and autoimmune aetiologies more heavily than in adults.
2. Differential Diagnosis by Category
Wilson Disease: The Treatable Mimic of HD
Wilson disease is the single most important differential to exclude in any child or adolescent presenting with movement disorder + psychiatric/cognitive decline. Unlike HD, Wilson disease is treatable — missing it is catastrophic. Always check ceruloplasmin, serum copper, 24-hour urinary copper, and slit-lamp examination for Kayser-Fleischer rings.
| Feature | Huntington Disease (JHD) | Wilson Disease |
|---|---|---|
| Inheritance | Autosomal dominant [1][2] | Autosomal recessive (ATP7B gene, Ch13) |
| Mechanism | Toxic polyglutamine expansion → MSN loss | Impaired biliary copper excretion → copper accumulation in liver, brain (basal ganglia), cornea [8] |
| Age of onset | Usually > 5y (JHD) | Usually 5–35y (average 13y) [8] |
| Motor features | Rigidity, dystonia, bradykinesia (JHD) or chorea (adult) | Dysarthria (85–97%), tremor (22–55%), dystonia (11–69%), parkinsonism (19–62%), choreoathetosis [8] |
| Liver disease | Absent | Liver disease usually presents first — acute hepatitis, chronic hepatitis, cirrhosis, fulminant hepatic failure [8] |
| Eye findings | None | Kayser-Fleischer rings (60%) — greenish-brown copper deposits in Descemet's membrane; sunflower cataracts [8] |
| Psychiatric | Depression, psychosis, irritability | Depression, personality changes, psychosis [8] |
| Cognitive | Subcortical dementia | Frontal/subcortical cognitive syndromes [8] |
| Key distinguishing features | Family history of HD, genetic testing positive | Liver disease, KF rings, low ceruloplasmin, ↑ urinary copper, Coombs-negative haemolytic anaemia [8] |
| Imaging | Caudate atrophy | Basal ganglia copper deposition — "face of the giant panda" sign on MRI |
| Treatability | No cure [2] | TREATABLE — penicillamine, trientine, zinc |
Wilson disease can mimic Parkinson's — extrapyramidal deposition of copper [8].
Why Wilson mimics HD: Both cause basal ganglia dysfunction (dystonia, chorea, parkinsonism) + psychiatric symptoms + cognitive decline. But Wilson also involves the liver and has specific biochemical/ophthalmological findings. In paediatrics, any child with unexplained movement disorder must have Wilson disease excluded before concluding on other diagnoses.
- Aetiology: Post-streptococcal autoimmune process — molecular mimicry between Group A Streptococcus antigens and basal ganglia neurons → anti-basal ganglia antibodies
- Age: Typically 5–15 years — classic paediatric age group
- Why it mimics HD: Presents with chorea (the classic hyperkinetic movement), emotional lability, and sometimes psychiatric features
- How to distinguish:
- Monophasic / self-limiting (usually resolves in weeks–months) — NOT progressive
- History of recent streptococcal infection (sore throat, scarlet fever) or evidence of rheumatic fever (carditis, polyarthritis, erythema marginatum)
- Elevated ASO titre / anti-DNase B
- Often accompanied by other features of rheumatic fever (Jones criteria)
- No cognitive decline (intelligence is preserved)
- No family history of neurodegenerative disease
- Key point: This is the commonest cause of acquired chorea in children worldwide
Drug-induced parkinsonism from metoclopramide, antipsychotics, or antihistamines is particularly important to identify as it is reversible [3].
In paediatrics, common offenders include:
- Metoclopramide (anti-emetic — blocks D2 receptors → parkinsonism, acute dystonia, tardive dyskinesia)
- Antipsychotics (haloperidol, risperidone — D2 blockade)
- Anticonvulsants (valproate — can cause tremor and parkinsonism)
- Antihistamines (first-generation — anticholinergic + antihistaminic effects)
Why it mimics HD: Can cause chorea (tardive dyskinesia), dystonia, parkinsonism, akathisia How to distinguish:
- Temporal relationship to drug initiation
- Non-progressive — stabilises or improves upon drug withdrawal
- No cognitive decline (unless the drug itself is sedating)
- No family history
- Always take a thorough drug history in any child presenting with movement disorder
2.4 Autoimmune / Inflammatory Causes
- SLE can cause chorea through anti-phospholipid antibody-mediated basal ganglia vasculopathy or direct autoimmune neuronal injury
- Prevalence of chorea in paediatric SLE: ~2–5%
- How to distinguish: Look for other features of SLE (malar rash, arthritis, serositis, nephritis, oral ulcers, positive ANA/anti-dsDNA/anti-phospholipid antibodies); chorea in SLE is typically non-progressive and responsive to immunosuppression
- An increasingly recognised cause of movement disorder + psychiatric symptoms + seizures in children/adolescents — particularly important in the paediatric differential
- Why it mimics HD/JHD: Combination of dyskinesias (choreoathetosis, dystonia, orofacial dyskinesias), psychiatric features (psychosis, agitation, behavioural change), cognitive decline, and seizures
- How to distinguish:
- Subacute onset (days–weeks) rather than insidious progression over months–years
- Prominent autonomic instability (tachycardia, BP fluctuations, central hypoventilation)
- Decreased consciousness often occurs
- Anti-NMDA receptor antibodies in CSF/serum
- May be associated with ovarian teratoma (especially in adolescent females)
- Treatable with immunotherapy (IVIG, plasma exchange, rituximab) ± tumour removal
- Anti-LGI1, anti-CASPR2, anti-DPPX encephalitis can cause movement disorders but are rarer in paediatrics
2.5 Other Neurodegenerative / Genetic Conditions
- A group of rare genetic disorders characterised by progressive iron deposition in the basal ganglia
- Most common subtype: Pantothenate Kinase-Associated Neurodegeneration (PKAN) — previously called Hallervorden-Spatz disease
- Gene: PANK2 (AR inheritance)
- Onset: typically childhood (first decade)
- Features: Progressive dystonia, rigidity, spasticity, choreoathetosis, cognitive decline, retinal degeneration (pigmentary retinopathy)
- MRI: "Eye of the tiger" sign — bilateral T2 hypointensity in globus pallidus with central hyperintensity
- Why it mimics JHD: Progressive movement disorder (rigidity, dystonia) + cognitive decline in a child
- How to distinguish: AR inheritance (not AD), retinal involvement, specific MRI findings, genetic testing
- Gene: VPS13A (AR)
- Features: Chorea, orofacial dyskinesias (lip/tongue biting is characteristic), seizures, myopathy, cognitive decline
- Key finding: Acanthocytes on peripheral blood smear (spiky red blood cells)
- Why it mimics HD: Adult-onset chorea + cognitive decline + psychiatric features — very close phenocopy
- Rare in paediatrics but can present in late adolescence
- A group of conditions that phenocopy HD but have different genetic causes:
- HDL1: Prion protein gene (PRNP) octapeptide repeat insertion — AD
- HDL2: Junctophilin-3 gene (JPH3) CTG repeat expansion — AD, almost exclusively in African ancestry
- HDL3: AR, mapped to 4p15.3 — extremely rare
- HDL4/SCA17: TBP gene CAG repeat expansion — AD
- These are considered when HD genetic testing is negative but the clinical phenotype is classic for HD
- Several SCAs (especially SCA17, SCA2, SCA3) can present with chorea + cognitive decline
- Some are also trinucleotide repeat expansion disorders (CAG repeats in coding regions — same mechanism as HD) [1]
- Distinguished by prominent cerebellar ataxia and specific genetic testing
- CAG repeat expansion in ATN1 gene (AD inheritance)
- Particularly relevant in East Asian (including Hong Kong/Japanese) populations — prevalence is higher than in Caucasians
- Childhood-onset DRPLA presents with progressive myoclonus epilepsy, cerebellar ataxia, choreoathetosis, and cognitive decline — can closely mimic JHD
- Adult-onset form: chorea, ataxia, dementia, psychiatric features
- How to distinguish: Myoclonus epilepsy is prominent (more than in JHD); genetic testing
DRPLA: Important in Hong Kong Context
DRPLA is more common in East Asian populations (including Hong Kong) than in Caucasians. In a Chinese/Hong Kong child presenting with progressive myoclonus epilepsy + chorea + cognitive decline, DRPLA should be actively considered alongside JHD. Both are CAG repeat expansion disorders with anticipation.
- Mitochondrial diseases (e.g., MELAS, Leigh syndrome) can cause movement disorders (dystonia, chorea), seizures, cognitive decline, and regression in children [9]
- How to distinguish: Multisystem involvement (myopathy, cardiomyopathy, sensorineural hearing loss, lactic acidosis, stroke-like episodes), maternal inheritance pattern, specific MRI findings (e.g., bilateral basal ganglia T2 hyperintensity in Leigh syndrome)
| Condition | Key Features | How to Distinguish from JHD |
|---|---|---|
| Organic acidaemias (e.g., glutaric aciduria type 1) | Acute dystonic crises, basal ganglia necrosis on MRI, macrocephaly | Newborn screening, urine organic acids, acylcarnitine profile |
| Urea cycle disorders | Episodic encephalopathy, movement disorder | Hyperammonaemia, specific amino acid profile |
| Lipid storage disorders (e.g., Niemann-Pick type C) | Vertical supranuclear gaze palsy, ataxia, dystonia, cognitive decline, hepatosplenomegaly | Filipin staining, oxysterol levels, NPC1/NPC2 genetic testing |
| Lesch-Nyhan syndrome | Dystonia, choreoathetosis, self-mutilatory behaviour, intellectual disability | X-linked recessive, hyperuricaemia, ↑ uric acid:creatinine ratio |
Metabolic Red Flags in a Child with Movement Disorder
If the motor impairment and abnormal tone have unusual accompanying symptoms, such as unexplained hypoglycaemia, recurrent vomiting, progressively worsening seizures or there is a family history of unexplained neurological symptoms or infant deaths, one would raise the possibility of an underlying metabolic disorder [9]. Always consider metabolic workup in any child with progressive movement disorder.
2.6 Structural / Other Causes
- Basal ganglia tumours (e.g., astrocytoma, germ cell tumour) can cause contralateral movement disorders (chorea, dystonia) + cognitive decline
- How to distinguish: Typically unilateral/asymmetric at onset; raised intracranial pressure features (headache, vomiting, papilloedema); diagnosed on neuroimaging (MRI) [9]
- Classical triad of frontal dementia, apraxic gait and urinary incontinence [5]
- More common in adults (50–70y) but can occur in children (secondary to meningitis, haemorrhage, etc.)
- How to distinguish: Gait apraxia (not chorea), urinary incontinence, ALL ventricles enlarged disproportionate to sulcal effacement on imaging [5]; no family history of HD; potentially treatable with VP shunt
- Post-encephalitic parkinsonism or movement disorders (e.g., post-HSV, post-mycoplasma)
- Usually non-progressive after the acute event
- Dyskinetic CP can present with dystonia, choreoathetosis, and cognitive impairment
- How to distinguish: CP is non-progressive — the brain lesion is static (though functional manifestations may evolve with growth). History of perinatal insult (birth asphyxia, prematurity, kernicterus) [9]. Absence of progressive deterioration distinguishes CP from neurodegenerative conditions like JHD.
Since psychiatric features may predate motor features of HD/JHD by years [2], children may initially be diagnosed with:
- ADHD — inattention, hyperactivity
- Conduct disorder — aggression, irritability
- Depression — mood changes, withdrawal, school refusal
- Psychosis — hallucinations, delusions
- Autism spectrum disorder — social withdrawal, behavioural rigidity
How to distinguish: In these primary psychiatric conditions, there is no progressive motor deficit and no progressive cognitive decline. A family history of HD, progressive motor signs, or hung-up knee jerk should prompt re-evaluation.
Depression is the most important mimic ('pseudodementia') when cognitive features predominate in an adolescent [5]. However, HD-related depression typically co-occurs with progressive motor signs and true subcortical cognitive deficits.
| Condition | Inheritance | Key Distinguishing Features | Treatable? |
|---|---|---|---|
| Wilson disease | AR | Liver disease, KF rings, Coombs-neg haemolytic anaemia, low ceruloplasmin [8] | YES |
| Sydenham chorea | Acquired (post-strep) | Self-limiting, Jones criteria, ASO titre | YES |
| Drug-induced | N/A | Temporal relationship to drug, reversible [3] | YES |
| Anti-NMDA receptor encephalitis | Acquired (autoimmune) | Subacute, autonomic instability, anti-NMDA Ab | YES |
| SLE chorea | Multifactorial | Other SLE features, anti-phospholipid Ab | YES |
| NBIA/PKAN | AR | "Eye of the tiger" MRI sign, retinal changes | Supportive |
| DRPLA | AD (CAG repeat) | Myoclonus epilepsy, more common in East Asians | No |
| Neuroacanthocytosis | AR | Lip-biting, acanthocytes on blood film | No |
| HDL syndromes (1–4) | AD | HD-negative genetic test, specific gene mutations | No |
| Niemann-Pick C | AR | Vertical gaze palsy, hepatosplenomegaly | Miglustat |
| Metabolic disorders | Mostly AR | Multisystem, metabolic derangements [9] | Some |
| Basal ganglia tumour | N/A | Asymmetric, raised ICP features, MRI [9] | Depends |
| NPH | N/A | Triad: dementia, gait apraxia, incontinence [5] | YES (shunt) |
| Dyskinetic CP | N/A | Non-progressive, perinatal history [9] | Supportive |
Step 1: Take a thorough history
- Family history: Three-generation pedigree — ask specifically about chorea, psychiatric illness, suicide, dementia, unexplained neurological illness. Remember HD is AD; ~5–10% may be de novo
- Drug history: Exclude drug-induced causes [3]
- Onset and progression: Acute/subacute (autoimmune, infectious) vs insidious (neurodegenerative, metabolic)
- Associated features: Liver disease (Wilson), sore throat (Sydenham), rash/arthritis (SLE), hypoglycaemia/vomiting (metabolic) [9]
Step 2: Examination
- Neurological: Characterise the movement disorder (chorea vs rigidity vs dystonia vs ataxia), saccadic eye movements, cerebellar signs, pyramidal signs, hung-up knee jerk
- Eyes: Slit-lamp for KF rings (Wilson), retinal examination (NBIA, storage disorders)
- Liver: Hepatomegaly, splenomegaly, jaundice (Wilson)
- Skin: Rash (SLE), telangiectasia (ataxia-telangiectasia)
- Growth: Failure to thrive (metabolic, mitochondrial)
Step 3: Investigations (to distinguish differentials)
- First-line "do not miss" tests:
- Ceruloplasmin, serum copper, 24-hr urinary copper → Wilson disease
- Liver function tests → Wilson disease
- Slit-lamp examination → KF rings (Wilson)
- Peripheral blood smear → acanthocytes (neuroacanthocytosis), target cells (liver disease)
- Anti-streptolysin O (ASO) titre → Sydenham chorea
- ANA, anti-dsDNA, anti-phospholipid antibodies → SLE
- Drug history review
- Genetic testing: HD genetic testing (CAG repeat analysis) — definitive for HD
- Metabolic workup (if indicated): Ammonia, lactate, urine organic acids, plasma amino acids, acylcarnitine profile, uric acid
- Neuroimaging (MRI brain): Caudate atrophy (HD), "eye of the tiger" (PKAN), basal ganglia T2 changes (Wilson, Leigh), tumour, hydrocephalus
- CSF: Anti-NMDA receptor antibodies (if subacute onset suspected)
- Neurophysiology: EEG (if seizures — JHD, DRPLA, metabolic)
The Golden Rule of Paediatric Movement Disorder DDx
Always exclude Wilson disease first — it is the treatable mimic that you cannot afford to miss. In any child or adolescent presenting with movement disorder + psychiatric features + cognitive decline, order ceruloplasmin, serum/urine copper, and arrange slit-lamp examination before anything else.
Active Recall - Differential Diagnosis of Huntington Disease
References
[1] Senior notes: Adrian Lui Pediatrics Notes.pdf (p. 497, Trinucleotide Repeat Expansion) [2] Senior notes: Ryan Ho Neurology.pdf (p. 127, Section 5.3 Huntington's Disease) [3] Learning Points: learning_points_output.txt (Neurology - Two Cases of Movement Disorders, Learning Points 2 and 3) [5] Senior notes: Ryan Ho Psychiatry.pdf (p. 81–82, Classifying Dementia, NPH) [8] Senior notes: Ryan Ho GI.pdf (p. 297, Wilson Disease Clinical Features) [9] Senior notes: MBBS Final MB (Pediatrics) (Felix PY Lai).pdf (p. 464, Differential Diagnosis of CP / Metabolic Disorders) [10] Lecture slides: CFB_Neuro clinical skills demonstration_01.08.22_file to students.pdf (p. 8, Pathological Differentials Framework)
Diagnostic Criteria, Diagnostic Algorithm, and Investigation Modalities for Huntington Disease (Paediatric Focus)
1. Diagnostic Criteria
Unlike many conditions in medicine, Huntington Disease (HD) does not rely on a clinical scoring system or consensus clinical criteria for diagnosis. Instead, the diagnosis rests on two pillars:
- Clinical features consistent with HD (motor, psychiatric, cognitive — as discussed previously)
- Genetic confirmation: Definitive detection of ≥ 36 CAG repeats in the HTT gene on chromosome 4p16.3 [2]
This makes HD relatively unique among neurodegenerative diseases — the diagnosis can be made with near-100% certainty by a single genetic test, unlike Alzheimer disease or frontotemporal dementia where diagnosis is predominantly clinical and probabilistic.
| CAG Repeat Count | Classification | Diagnostic Interpretation |
|---|---|---|
| ≤ 26 | Normal | HD excluded; repeats are stable across generations |
| 27–35 | Intermediate / Mutable normal | Not diagnostic of HD — individual will not develop disease. However, repeats are meiotically unstable and may expand into the pathogenic range in offspring (especially via paternal transmission) [1] |
| 36–39 | Reduced penetrance | Diagnostic of HD genotype — but individual may or may not develop clinical HD within a normal lifespan. Some individuals remain asymptomatic |
| ≥ 40 | Full penetrance | Diagnostic of HD — the individual will develop clinical HD if they live long enough [1][2] |
| ≥ 60 | Typically associated with Juvenile HD | Very early onset (childhood/adolescence); rapid progression |
High Yield: The Genetic Test IS the Diagnostic Gold Standard
Genetic testing (CAG repeat analysis of the HTT gene) is the definitive diagnostic test for HD [2]. There is no clinical scoring system, no biomarker panel, and no imaging finding that can substitute for this. A positive test (≥ 36 CAG repeats) in the context of compatible clinical features confirms the diagnosis.
In clinical practice, HD diagnosis is categorised as follows:
| Category | Definition |
|---|---|
| Clinically manifest HD | Compatible clinical features (motor + cognitive and/or psychiatric) AND confirmed ≥ 36 CAG repeats |
| Pre-manifest (gene-positive) | Confirmed ≥ 36 CAG repeats BUT no clinical features yet (presymptomatic carrier) |
| At-risk individual | First-degree relative of someone with confirmed HD, but not yet tested (50% prior probability) |
| Clinically suspected, genetically unconfirmed | Compatible clinical features but genetic testing not yet performed or declined |
JHD is diagnosed when:
- Clinical onset occurs before age 20 years
- ≥ 36 CAG repeats are confirmed (usually ≥ 60 in JHD)
- Progressive motor, cognitive, and/or psychiatric deterioration is documented
- Family history is present (especially paternal — ~80% of JHD) [2][3]
Paediatric Diagnostic Pitfall
JHD is frequently misdiagnosed initially because the presenting features — academic failure, behavioural problems, rigidity, seizures — overlap heavily with more common paediatric conditions (ADHD, epilepsy, cerebral palsy, psychiatric disorders). The progressive nature of symptoms and positive family history (especially paternal) should trigger genetic testing. Remember: the Westphal (akinetic-rigid) variant presents with parkinsonism rather than chorea [2], which may mislead clinicians not thinking about HD.
The diagnostic approach follows the general principle from endocrine and metabolic diagnostics: "less invasive before more invasive" — history → examination → baseline bloods → targeted biochemical/genetic testing → imaging → invasive tests [11].
For HD specifically:
Step 1 — Clinical suspicion (History + Examination) Step 2 — Exclude treatable mimics (especially Wilson disease) Step 3 — Genetic confirmation (CAG repeat analysis) Step 4 — Supportive investigations (neuroimaging, neuropsychological testing) Step 5 — Family assessment and genetic counselling
Critical Algorithm Point: Always Exclude Wilson Disease Before Genetic Testing for HD
Wilson disease can mimic Parkinson's — extrapyramidal deposition of copper [8]. Wilson disease is treatable and potentially reversible if caught early. It must be excluded in every child with progressive movement disorder before proceeding to HD genetic testing. The standard screen includes ceruloplasmin (low), serum copper (low total, high free), 24-hour urine copper (elevated), and slit-lamp examination for Kayser-Fleischer rings.
3. Investigation Modalities, Key Findings, and Interpretation
3.1 Genetic Testing — The Definitive Investigation
- Specimen: Peripheral blood (EDTA tube) — simple venipuncture
- Method: PCR-based fragment analysis of the CAG repeat region in exon 1 of the HTT gene
- Turnaround: Typically 2–4 weeks
Interpretation:
| Result | Meaning | Clinical Action |
|---|---|---|
| ≤ 26 repeats | Normal | HD excluded |
| 27–35 repeats | Intermediate | Individual unaffected, but offspring at risk of expansion — genetic counselling |
| 36–39 repeats | Reduced penetrance | May or may not develop HD; genetic counselling essential |
| ≥ 40 repeats | Full penetrance — HD confirmed | Diagnosis confirmed; initiate MDT care |
| ≥ 60 repeats | Typically Juvenile HD | Very early onset expected; anticipate rapid progression |
Why this test works from first principles: The CAG repeat is a stable, measurable length of DNA. PCR amplifies the repeat region, and fragment analysis measures the exact number of repeats. Because the relationship between repeat number and disease is well-established, a single test provides both diagnosis and prognostic information (higher repeats → earlier onset, more severe disease) [1][2].
| Type | Who Is Tested | Purpose | Ethical Considerations |
|---|---|---|---|
| Diagnostic testing | Symptomatic individual (any age, including children) | Confirm HD as the cause of symptoms | Appropriate at any age when symptoms are present |
| Predictive (presymptomatic) testing | Asymptomatic at-risk individual | Determine carrier status before symptoms appear | NOT recommended for minors (< 18 years) — should wait until individual can provide autonomous informed consent. No preventive treatment available |
| Prenatal testing | Fetus at risk | Determine fetal HD status | Complex ethical issues; genetic counselling mandatory; options include CVS (10–12 weeks) or amniocentesis (15–18 weeks) |
| Pre-implantation genetic testing | Embryo (IVF) | Select unaffected embryos | Avoids termination dilemma; available in some centres |
| Exclusion testing | At-risk individual who does NOT want to know own status | Uses linked markers to determine whether fetus inherited the "at-risk" chromosome from the affected grandparent | Preserves parent's right not to know own status |
Predictive Testing in Minors — Ethical Red Line
Predictive genetic testing for HD in asymptomatic minors is NOT recommended by international guidelines (ISGH, EHDN, ACMG). Rationale: (1) No disease-modifying therapy exists, (2) The psychological burden of a positive result in childhood can be devastating, (3) Testing removes the child's future autonomous choice. However, diagnostic testing IS appropriate when a child has symptoms consistent with JHD.
If the CAG repeat is ≤ 35 but the clinical picture strongly suggests an HD-like phenotype:
- Consider HD-like (HDL) syndromes: HDL1 (PRNP), HDL2 (JPH3), HDL4/SCA17 (TBP)
- Consider DRPLA (ATN1 gene CAG repeats) — especially important in Hong Kong/East Asian populations
- Consider other SCAs (SCA2, SCA3)
- Consider next-generation sequencing panels for hereditary chorea / movement disorders, or whole exome/genome sequencing for undiagnosed cases
3.2 Neuroimaging
Neuroimaging is supportive, not diagnostic — it cannot confirm HD but provides important information about disease stage and helps exclude structural lesions.
Key findings in HD:
| Finding | Description | Pathophysiological Basis |
|---|---|---|
| Caudate nucleus atrophy | Bilateral, symmetrical reduction in caudate volume | Loss of medium spiny neurons in the caudate (the hallmark of HD neuropathology) |
| Enlargement of frontal horns of lateral ventricles | "Box-car" or squared-off ventricle appearance | Consequence of caudate atrophy — as the caudate shrinks, the overlying ventricle expands into the space |
| Putaminal atrophy | Later finding | Putamen affected after caudate |
| Generalised cortical atrophy | Later stages | Widespread neuronal loss |
| White matter changes | T2/FLAIR signal abnormalities in white matter | Wallerian degeneration, myelin loss |
Why caudate atrophy is characteristic: The caudate nucleus forms the lateral wall of the frontal horn of the lateral ventricle. As the caudate shrinks, this wall recedes, causing the ventricle to balloon outward — producing the characteristic "box-car" configuration that is almost pathognomonic when seen in the right clinical context.
In JHD: Caudate and putaminal atrophy may be present, but cerebellar atrophy is also more prominent compared to adult-onset HD.
Volumetric MRI: Quantitative measurement of caudate volume can detect atrophy even in pre-manifest gene carriers, years before symptom onset. This is used in research settings (e.g., TRACK-HD, ENROLL-HD studies) but not routinely in clinical practice.
- Less sensitive than MRI but may show caudate atrophy and ventricular enlargement in established disease
- Useful if MRI is contraindicated or unavailable
- In paediatrics, avoid unnecessary radiation — prefer MRI
Cerebral perfusion studies (SPECT/PET) demonstrate perfusion to specific brain areas; different types of dementia typically present with different patterns of perfusion changes [12].
| Modality | Findings in HD | Utility |
|---|---|---|
| FDG-PET | ↓ glucose metabolism in the caudate and putamen (even before structural atrophy is visible on MRI) | Can detect pre-manifest disease; used in research |
| SPECT | ↓ perfusion in striatum | Less commonly used than PET |
| Dopamine transporter imaging (DaT-SPECT) | ↓ striatal dopamine transporter uptake in advanced disease | More useful for distinguishing DLB from AD [13]; limited role in HD |
In paediatric practice, functional neuroimaging is rarely needed for HD diagnosis (genetic testing is definitive) but may be used in research or atypical cases.
Purpose: To objectively document and characterise the pattern and severity of cognitive deficits
Key domains assessed (linking to HD cognitive profile):
| Domain | Expected Pattern in HD | Test Examples |
|---|---|---|
| Executive function | Impaired early — difficulty with planning, sequencing, mental flexibility | Trail Making Test B, Wisconsin Card Sorting Test, verbal fluency |
| Processing speed | Slowed (bradyphrenia) | Symbol Digit Modalities Test (SDMT) — considered the single most sensitive cognitive measure in HD |
| Memory | Retrieval deficit (recognition > free recall; improved by cueing) | CVLT, Hopkins Verbal Learning Test |
| Visuospatial | Impaired in moderate-advanced disease | Clock drawing, Rey complex figure copy |
| Language | Relatively preserved early | Boston Naming Test, verbal fluency |
In children (JHD): Use age-appropriate neuropsychological batteries (e.g., WISC-V for IQ, NEPSY-II for neurodevelopmental domains). Document serial decline — the trajectory is more informative than any single score.
Clinical utility: Neuropsychological testing helps:
- Establish baseline cognitive function at diagnosis
- Monitor disease progression (serial assessments)
- Differentiate HD-type subcortical dementia from other dementia types
- Guide educational and supportive interventions for children
These are performed to:
- Exclude treatable mimics (the "do not miss" investigations)
- Establish baseline for monitoring
- Assess for comorbidities and nutritional status
| Investigation | Purpose / What to Look For |
|---|---|
| Ceruloplasmin, serum copper, 24-hr urinary copper | Exclude Wilson disease [8] — ceruloplasmin low (< 0.2 g/L), 24-hr urine copper elevated (> 100 μg/day), free copper elevated |
| Liver function tests | Hepatic involvement in Wilson disease; baseline for future medication monitoring |
| CBC | Baseline; acanthocytes on blood film (neuroacanthocytosis) |
| Peripheral blood smear | Acanthocytes (neuroacanthocytosis); target cells (liver disease) |
| TFT | Exclude thyroid disease as cause of psychiatric/cognitive symptoms |
| Serum B12, folate | Exclude nutritional causes of cognitive impairment [5] |
| Renal function, electrolytes | Baseline; exclude metabolic encephalopathy |
| Calcium, glucose | Exclude metabolic causes of neuropsychiatric symptoms [5] |
| ESR, CRP | Inflammatory/autoimmune markers if subacute presentation suspected |
| ANA, anti-dsDNA, anti-phospholipid Ab | Exclude SLE chorea |
| ASO titre | Exclude Sydenham chorea (post-streptococcal) |
| Anti-NMDA receptor antibodies (CSF + serum) | Exclude autoimmune encephalitis (if subacute onset) |
| Metabolic screen (if < 10y or atypical features) | Ammonia, lactate, urine organic acids, plasma amino acids, acylcarnitine [14] — exclude inborn errors of metabolism |
In a case of suspected acutely presenting metabolic disease: basic metabolic investigations should include ABG and plasma electrolytes, plasma glucose, plasma lactate, plasma ammonium, urine and blood ketones, CK. Special metabolic investigations: acylcarnitine on dried blood spots, plasma amino acids, urinary organic acids [14]
- In adult HD: EEG shows non-specific changes (diffuse slowing, loss of alpha rhythm in advanced disease)
- In JHD: EEG is more clinically relevant because of the high prevalence of seizures (30–50%)
- May show epileptiform discharges (generalised or focal)
- Important for characterising seizure type and guiding anticonvulsant choice
- Helps distinguish from other seizure disorders (e.g., progressive myoclonus epilepsy as in DRPLA)
- Purpose: To detect Kayser-Fleischer (KF) rings — greenish-brown discolouration at corneal margin due to granular copper deposits in Descemet's membrane [8]
- Usually only seen with slit lamp (consult Ophthalmology) [8]
- Interpretation: If KF rings are present → strongly suggests Wilson disease (present in 50% of hepatic Wilson, 98% of neurological Wilson) [8]
- In HD: Slit-lamp examination will be normal — its role is purely to exclude Wilson disease
3.7 Clinical Signs with Diagnostic Value
Hung-up knee jerk ('marching the knee'): slowness in relaxation after knee jerk → repeated tapping results in rising of leg [2]
- Technique: With the patient's leg hanging freely, tap the patellar tendon repeatedly at a regular rhythm. In HD, instead of the leg returning to its resting position after each tap, it progressively rises ("marches upward")
- Mechanism: Reflects impaired central modulation of spinal reflexes due to basal ganglia and corticospinal pathway dysfunction — the normal central dampening of the stretch reflex is delayed
- Specificity: Not pathognomonic for HD (can occur in other basal ganglia disorders, cerebellar disease, hypothyroidism) but is a useful bedside clue
- Darting tongue / chameleon tongue: Ask the patient to protrude the tongue and hold it out — in HD, the tongue darts in and out involuntarily because the patient cannot sustain the contraction
- Milkmaid's grip: When the patient squeezes the examiner's fingers, grip pressure fluctuates rhythmically
- These signs reflect the core HD deficit of inability to maintain sustained voluntary contraction
- Slow saccade initiation: Latency before saccades begin
- Decreased saccade velocity: Saccades are slow when they do occur
- Difficulty with antisaccades: Cannot suppress reflexive glances toward stimuli
- These are among the earliest detectable motor signs — the frontal eye field → caudate circuit is affected early
| Investigation | Category | Key Finding in HD | Role |
|---|---|---|---|
| HTT CAG repeat analysis | Genetic | ≥ 40 repeats = full penetrance | DIAGNOSTIC (gold standard) [2] |
| MRI brain | Imaging | Caudate atrophy, enlarged frontal horns | Supportive; staging; exclude structural lesions |
| FDG-PET | Functional imaging | ↓ Caudate/putamen metabolism | Research / pre-manifest detection |
| Neuropsychological testing | Cognitive | Executive dysfunction, retrieval deficit, bradyphrenia | Baseline; monitoring; characterisation |
| EEG | Neurophysiology | Epileptiform discharges (JHD); diffuse slowing | Seizure characterisation in JHD |
| Ceruloplasmin / copper | Blood | Normal in HD (abnormal in Wilson) | Exclude Wilson disease |
| Slit-lamp examination | Ophthalmology | Normal in HD (KF rings in Wilson) | Exclude Wilson disease |
| Peripheral blood film | Haematology | Normal in HD (acanthocytes in neuroacanthocytosis) | Exclude neuroacanthocytosis |
| Metabolic screen | Biochemistry | Normal in HD (abnormal in IEM) [14] | Exclude metabolic causes |
| Hung-up knee jerk | Clinical examination | Positive (leg "marches") [2] | Supportive clinical sign |
4. Approach to Diagnosis in Special Paediatric Scenarios
A child presenting with progressive motor disorder + cognitive decline ± psychiatric features ± seizures and a positive family history of HD (especially paternal):
- Exclude treatable mimics first (Wilson, drug-induced, autoimmune, metabolic)
- Obtain HTT CAG repeat analysis — if ≥ 36 repeats, diagnosis confirmed
- MRI brain to document baseline and exclude structural lesions
- Neuropsychological testing for baseline
- EEG if seizures are present
- Initiate MDT care: neurology, psychiatry, genetics, psychology, social work, school/education liaison
- Genetic counselling for the family — siblings, parents
- International guidelines (ISGH/EHDN) recommend against predictive testing in minors
- Offer genetic counselling to the family and the adolescent
- Support the young person to make an autonomous decision when they reach adulthood (typically ≥ 18 years)
- Provide psychosocial support — growing up with an at-risk status and an affected parent is profoundly challenging
- Available for families who wish to prevent transmission
- Prenatal: CVS at 10–12 weeks or amniocentesis at 15–18 weeks; direct CAG repeat analysis
- Pre-implantation genetic testing (PGT-M): IVF + embryo biopsy → select unaffected embryos
- Exclusion testing: Uses linked markers without revealing the at-risk parent's status — an option for parents who do not wish to know their own HD status
- All require extensive pre-test genetic counselling
High Yield Summary: Diagnosis of HD
-
Gold standard diagnostic test: HTT gene CAG repeat analysis — ≥ 40 = full penetrance, 36–39 = reduced penetrance [1][2]
-
Genetic testing is definitive — no clinical criteria score is needed [2]
-
Always exclude Wilson disease first in any child with progressive movement disorder + psychiatric/cognitive features: ceruloplasmin, copper studies, slit-lamp [8]
-
MRI brain: Caudate atrophy with enlarged frontal horns — supportive, not diagnostic
-
Neuropsychological testing: Subcortical pattern — executive dysfunction, retrieval deficit, bradyphrenia
-
Key clinical signs: Hung-up knee jerk, motor impersistence (darting tongue, milkmaid's grip), saccadic abnormalities [2]
-
Predictive testing in asymptomatic minors is NOT recommended — diagnostic testing in symptomatic children IS appropriate
-
JHD: Usually ≥ 60 CAG repeats, ~80% paternal inheritance [2][3]
-
If HD genetic test is negative but clinical suspicion persists: Consider HDL syndromes, DRPLA (important in East Asian populations), other SCAs, metabolic/genetic panels
-
Metabolic screen (ammonia, lactate, organic acids, amino acids, acylcarnitine) should be performed in young children with atypical features [14]
Active Recall - Diagnosis of Huntington Disease
References
[1] Senior notes: Adrian Lui Pediatrics Notes.pdf (p. 495–497, Clinical Genetics: Trinucleotide Repeat Expansion, Mendelian Inheritance) [2] Senior notes: Ryan Ho Neurology.pdf (p. 127, Section 5.3 Huntington's Disease) [3] Learning Points: learning_points_output.txt (Neurology - Two Cases of Movement Disorders, Learning Point 3) [5] Senior notes: Ryan Ho Psychiatry.pdf (p. 82, Approach to Potential Case of Dementia — Investigations) [8] Senior notes: Ryan Ho GI.pdf (p. 297, Wilson Disease Clinical Features) [11] Senior notes: Block A - Introduction to Endocrine investigations.pdf (p. 3, Sequence of Investigations Principle) [12] Senior notes: Ryan Ho Diagnostic Radiology.pdf (p. 69, Cerebral Perfusion Study for Dementia) [13] Lecture slides: GC 241. Reference (3) - Patel dementia with lewy bodies.pdf (p. 6–8, Dopamine Transporter Imaging, DLB Diagnostic Criteria) [14] Senior notes: Ryan Ho Chemical Path.pdf (p. 56, Investigations of IEM)
Management of Huntington Disease (Paediatric Focus)
The single most important fact about managing HD is stated clearly in lecture materials:
No cure: progressive and fatal in 10–15y [2]
No treatment. Multidisciplinary supportive care [15]
There is no disease-modifying therapy for HD as of 2026. All management is therefore:
- Symptomatic — treating specific symptoms (chorea, psychiatric features, seizures, dystonia)
- Supportive — maintaining function, quality of life, nutrition, and safety
- Multidisciplinary — requiring a coordinated team approach
- Family-centred — especially critical in paediatrics, where the child's care is inseparable from the family context (and the family is often simultaneously coping with a parent who has HD)
Core Exam Point: HD Management
3. Symptomatic Pharmacological Treatment
3.1 Treatment of Chorea
Chorea is the cardinal motor feature of adult-onset HD and may also occur (though less prominently) in JHD. Treatment should only be initiated when chorea is functionally disabling — mild chorea that does not impair function does not require pharmacological intervention.
Clonazepam or tetrabenazine for control of chorea [15]
Chorea: neuroleptics (risperidone/sulpride), tetrabenazine [2]
What is tetrabenazine?
- The name gives a clue: "tetra-" (four) + "benazine" — it is a synthetic benzoquinolizine derivative
- Mechanism: Vesicular monoamine transporter 2 (VMAT2) inhibitor — it blocks the packaging of monoamines (dopamine, serotonin, norepinephrine) into synaptic vesicles in presynaptic neurons
- Net effect: Depletes presynaptic dopamine in the striatum → reduces the dopaminergic "drive" on the already-disinhibited direct pathway → suppresses chorea
- Why it works in HD specifically: In HD, loss of indirect pathway MSNs causes excessive thalamocortical activation (chorea). Tetrabenazine reduces dopaminergic input to the remaining striatal circuits, dampening this excessive activation
Dosing in paediatrics:
- Start low, titrate slowly: typically begin at 12.5 mg once daily, increase by 12.5 mg every 3–5 days
- Usual dose range: 25–75 mg/day in divided doses (2–3 times daily)
- Maximum: generally 75–100 mg/day (lower in children; titrate to effect)
- CYP2D6 metabolism: Tetrabenazine is metabolised by CYP2D6. Poor metabolisers (CYP2D6 PM) have higher plasma levels → increased risk of side effects → some centres recommend CYP2D6 genotyping before prescribing
Side effects (directly predictable from the mechanism — dopamine depletion):
| Side Effect | Mechanism | Clinical Significance |
|---|---|---|
| Depression, suicidality | Serotonin and dopamine depletion | Most serious — HD patients already have high baseline suicide risk; tetrabenazine can worsen this. Contraindicated in actively suicidal patients |
| Parkinsonism (rigidity, bradykinesia) | Excessive dopamine depletion | Dose-limiting; can worsen JHD Westphal variant |
| Akathisia (inner restlessness) | Dopamine depletion | Distressing; may be mistaken for worsening chorea |
| Sedation, somnolence | Central monoamine depletion | Common; may impair school performance |
| Dysphagia | Worsened oropharyngeal motor control | Dangerous — can increase aspiration risk |
| QTc prolongation | Direct cardiac effect | Check baseline ECG; avoid in long QT syndrome |
Tetrabenazine: Key Safety Warning in Paediatrics
Tetrabenazine can worsen depression and increase suicidality — both major concerns in HD patients who already have a 4–6× elevated suicide rate. In children and adolescents, this risk is compounded by the general increased vulnerability to antidepressant/mood-altering drug effects in youth. Monitor mood closely after initiation. Contraindicated in patients with active suicidal ideation or untreated/inadequately treated depression.
Contraindications:
- Active suicidal ideation or untreated depression
- Hepatic impairment (hepatic metabolism)
- Co-administration with MAO inhibitors (risk of hypertensive crisis)
- Co-administration with reserpine (additive monoamine depletion)
- A deuterated form of tetrabenazine (hydrogen atoms replaced with deuterium)
- Advantage: Slower metabolism (deuterium–carbon bonds are harder to break) → longer half-life → more stable plasma levels, fewer daily doses (twice daily vs three times daily), and potentially fewer side effects (less peak-trough fluctuation)
- FDA-approved for HD chorea in adults (2017); used off-label in paediatrics
- Same mechanism and similar side effect profile as tetrabenazine but generally better tolerated
- Another VMAT2 inhibitor, primarily approved for tardive dyskinesia
- Limited evidence specifically for HD chorea; not routinely used as first-line
Chorea: neuroleptics (risperidone/sulpride), tetrabenazine [2]
If tetrabenazine is insufficient, not tolerated, or contraindicated (e.g., significant depression), antipsychotics that block D2 dopamine receptors can reduce chorea:
| Drug | Class | Key Points in Paediatrics |
|---|---|---|
| Risperidone | Atypical antipsychotic (D2 + 5-HT2A antagonist) | Commonly used; effective for chorea AND psychiatric symptoms (irritability, psychosis). Start 0.25–0.5 mg daily, titrate slowly. Watch for weight gain, metabolic syndrome, prolactin elevation, EPS |
| Sulpride | Atypical antipsychotic (selective D2/D3 antagonist) | Used in Hong Kong practice; less sedating; risk of hyperprolactinaemia |
| Olanzapine | Atypical antipsychotic | Effective for chorea + psychosis; significant weight gain and metabolic effects — problematic in HD patients who are already losing weight |
| Haloperidol | Typical antipsychotic (potent D2 antagonist) | Effective but high risk of EPS, tardive dyskinesia, parkinsonism — generally avoided in HD, especially JHD |
Why antipsychotics work for chorea: They block D2 receptors in the striatum, counteracting the excessive dopaminergic drive that contributes to choreiform movements. Essentially, they are doing pharmacologically what the lost indirect pathway MSNs should be doing physiologically.
Paediatric considerations: Antipsychotics in children carry additional risks of metabolic syndrome, weight gain, sedation, and endocrine effects (prolactin elevation → galactorrhoea, menstrual disturbance). Monitor BMI, waist circumference, fasting glucose, lipid profile, and prolactin regularly.
Psychiatric: benzodiazepines (clonazepam), antidepressants [2]
Clonazepam or tetrabenazine for control of chorea [15]
- Clonazepam: Enhances GABAergic inhibition → reduces chorea and also helps with anxiety/agitation and myoclonus
- Paediatric dosing: Start 0.01–0.03 mg/kg/day in 2–3 divided doses; titrate slowly
- Advantages: Also treats associated anxiety, sleep disturbance, and myoclonus (relevant in JHD)
- Disadvantages: Sedation, cognitive blunting (worsens already-declining cognition), dependency, paradoxical agitation in children, tolerance with chronic use
- Role: Adjunctive therapy — rarely sufficient as monotherapy for chorea
This is the predominant motor phenotype of JHD — the akinetic-rigid (Westphal) variant [2]. Treatment is challenging because:
- VMAT2 inhibitors (tetrabenazine) can WORSEN rigidity and bradykinesia — they deplete the very dopamine that is needed to drive the remaining direct pathway
- D2-blocking antipsychotics similarly worsen parkinsonism
Management options for the rigid/dystonic JHD child:
| Modality | Mechanism | Paediatric Considerations |
|---|---|---|
| Baclofen | GABA-B receptor agonist → reduces spasticity and rigidity | Oral or intrathecal (ITB pump). Start oral: 5 mg TDS in older children, titrate. Intrathecal baclofen for severe generalised dystonia/spasticity |
| Botulinum toxin injections | Blocks acetylcholine release at neuromuscular junction → focal muscle relaxation | Useful for focal dystonia (e.g., cervical dystonia, limb dystonia). Requires repeated injections every 3–4 months |
| Levodopa trial | Dopamine precursor → replenishes dopamine in the nigrostriatal pathway | Response is variable and often modest in JHD (unlike idiopathic PD where it is excellent). Worth a trial in cases with prominent parkinsonism. Start low-dose levodopa/carbidopa |
| Trihexyphenidyl | Anticholinergic → reduces cholinergic/dopaminergic imbalance | May help rigidity and dystonia; side effects: dry mouth, urinary retention, cognitive impairment, constipation — problematic in patients with cognitive decline |
| Clonazepam | GABAergic → reduces rigidity and myoclonus | Adjunctive; see benzodiazepine section above |
Critical JHD Management Point
In JHD (Westphal variant), the dominant phenotype is rigidity, not chorea. Therefore, dopamine-depleting agents (tetrabenazine) and D2-blocking antipsychotics should be used with extreme caution or avoided as they will worsen rigidity and bradykinesia. Treatment focuses on baclofen, botulinum toxin, cautious levodopa trial, and supportive therapies.
3.3 Treatment of Psychiatric Symptoms
Psychiatric: benzodiazepines (clonazepam), antidepressants [2]
- SSRIs are first-line: fluoxetine, sertraline, citalopram, escitalopram
- Why SSRIs? They increase synaptic serotonin availability, counteracting the serotonergic depletion seen in HD (both from striatal circuit disruption and, if tetrabenazine is used, from pharmacological monoamine depletion)
- Paediatric dosing: Use lower starting doses than adults; monitor for behavioural activation and suicidality (black box warning for SSRIs in under-18s, though the benefit generally outweighs risk in HD-related depression)
- E.g., Fluoxetine 10 mg daily initially, increase to 20 mg after 1–2 weeks if tolerated
- E.g., Sertraline 25–50 mg daily initially
- Mirtazapine: NaSSA (noradrenergic and specific serotonergic antidepressant) — has the added benefit of appetite stimulation and sedation (helpful for HD patients with weight loss and insomnia)
- Venlafaxine (SNRI): Useful for comorbid depression + anxiety; risk of hypertension at higher doses
- Avoid: TCAs (anticholinergic effects worsen cognition; cardiac toxicity risk in overdose)
- Electroconvulsive therapy (ECT): Reserved for severe, treatment-refractory depression with active suicidality — rarely used in paediatrics
- Low-dose atypical antipsychotics: olanzapine, quetiapine, risperidone
- These also help control chorea (dual benefit)
- Start at very low doses and titrate slowly
- Avoid typical antipsychotics (haloperidol) — high EPS risk in an already-compromised basal ganglia
- SSRIs (if co-existing depression)
- Low-dose atypical antipsychotics (risperidone, quetiapine)
- Behavioural strategies: structured routines, environmental modification, caregiver education
- Benzodiazepines (short-term only) for acute agitation
- Most challenging symptom to treat pharmacologically
- SSRIs may paradoxically worsen apathy
- Stimulants (methylphenidate) — limited evidence; used cautiously by some movement disorder specialists
- Environmental and behavioural strategies are mainstay
- SSRIs at higher doses (as for OCD)
- Cognitive-behavioural strategies where developmentally appropriate
Seizures occur in 30–50% of JHD and require standard anticonvulsant therapy:
| Anticonvulsant | Advantages | Cautions in HD |
|---|---|---|
| Valproate (sodium valproate) | Broad-spectrum; effective for generalised seizures, myoclonic seizures | Weight gain (problematic in HD with weight loss → may actually be helpful); hepatotoxicity (monitor LFTs); teratogenic (relevant for adolescent females) |
| Levetiracetam | Broad-spectrum; few drug interactions; generally well-tolerated | Psychiatric side effects (irritability, aggression) — may worsen HD behavioural symptoms |
| Lamotrigine | Broad-spectrum; mood-stabilising properties (dual benefit) | Slow titration required (risk of Stevens-Johnson syndrome); may be less effective for myoclonic seizures |
| Clonazepam | Effective for myoclonus and seizures | Sedation, cognitive worsening, tolerance |
Avoid: Carbamazepine and phenytoin (enzyme inducers that may worsen chorea; less effective for generalised/myoclonic seizures)
Loss of voluntary motor control: progressive, gradually causes dysarthria, dysphagia [2]
Dysphagia is a major cause of morbidity and mortality in HD — aspiration pneumonia is the most common cause of death.
| Stage | Intervention |
|---|---|
| Early: Mild swallowing difficulty | Speech and language therapy (SLT) assessment; postural advice during meals (upright, chin-tuck position); texture modification (soft diet, thickened fluids) |
| Moderate: Frequent coughing/choking with meals | Intensive SLT input; further dietary modification; consider supplemental high-calorie drinks/snacks to maintain weight; regular weight monitoring |
| Severe: Unable to maintain adequate nutrition/hydration orally; recurrent aspiration | Enteral feeding — nasogastric tube (NG, temporary) or percutaneous endoscopic gastrostomy (PEG) |
PEG feeding in paediatric HD:
- Decision to place a PEG should involve the child (if they have capacity/assent), family, neurologist, SLT, dietitian, and gastroenterologist
- Should be considered early — before the child becomes too nutritionally depleted to tolerate the procedure
- This is an important advance care planning discussion
Weight loss management:
- High-calorie diet: HD patients have increased energy expenditure (from hyperkinetic movements + hypermetabolic state)
- Nutritional supplements: Energy-dense oral supplements
- Dietitian involvement: Essential throughout the disease course
- Growth monitoring: In children — plot weight, height, and BMI on growth charts at every visit. Failure to thrive or crossing centiles downward should trigger nutritional intervention
- SLT: Exercises to maintain speech clarity as long as possible
- Augmentative and alternative communication (AAC): As dysarthria progresses, introduce AAC devices (picture boards, tablet-based communication apps, eye-gaze technology)
- Family/caregiver communication training: Teach strategies to facilitate communication (yes/no questions, patient pacing, reducing background noise)
4. Non-Pharmacological and Supportive Management
Multidisciplinary supportive care [15]
In a child with JHD, the MDT should include:
| Team Member | Role |
|---|---|
| Paediatric neurologist | Overall medical management; motor and seizure treatment |
| Child and adolescent psychiatrist | Psychiatric symptom management; suicide risk assessment |
| Clinical psychologist | Neuropsychological assessment; psychological support for child and family |
| Clinical geneticist / Genetic counsellor | Genetic counselling for family; predictive testing discussions for siblings/relatives |
| Physiotherapist | Maintain mobility; prevent contractures; gait training; falls prevention |
| Occupational therapist | Adaptive equipment; daily living skills; environmental modification |
| Speech and language therapist | Swallowing assessment; communication strategies; AAC |
| Dietitian | Nutritional assessment; high-calorie dietary planning; enteral feeding guidance |
| Social worker | Family support; financial/social resources; child protection considerations |
| School liaison / Educational psychologist | Modified educational plans (EHCP/IEP); school support |
| Palliative care team | Advance care planning; symptom management; end-of-life care |
- Goals: Maintain mobility, prevent contractures, improve balance, reduce falls
- Approaches: Active stretching, strengthening exercises, gait training, postural management
- As disease progresses: Wheelchair assessment and provision; seating clinic referral; pressure area care
- In JHD: Physiotherapy must be adapted to the child's developmental stage and interests — play-based therapy for younger children, gym/sports-based for adolescents
- Adaptive equipment: Modified cutlery, non-slip mats, adapted writing tools, computer access devices
- Environmental modification: Bathroom adaptations, bed rails, wheelchair accessibility
- Daily living skills: Breaking tasks into smaller steps; teaching compensatory strategies
- Educational Health Care Plan (EHCP) or equivalent: Formal documentation of the child's needs
- Classroom adaptations: Extra time for tasks; scribe for exams; modified curriculum; reduced homework load
- Special educational provision: As cognitive decline progresses, the child may need transfer to a school with specialist support or home tutoring
- Peer support: Facilitating social inclusion; addressing bullying; peer education about the condition (with family consent)
- For the child: Age-appropriate psychoeducation about their condition; managing grief and anxiety; coping strategies; therapeutic play
- For siblings: Sibling support groups; addressing feelings of guilt, fear, and "survivor's guilt" (especially if they are at-risk)
- For parents/caregivers: Coping with dual burden (often one parent has HD while the child has JHD); carer fatigue; respite care; support groups (e.g., HDYO — Huntington's Disease Youth Organisation)
- For parents: Clarify recurrence risk (50% for each offspring); discuss reproductive options (prenatal testing, PGT-M)
- For siblings: At-risk siblings should be supported and offered counselling; predictive testing when they are adults and wish it
- For the affected child: Age-appropriate communication about their diagnosis
- Ethical framework: Non-directive counselling; respect for autonomy; confidentiality
HD is a progressive, life-limiting condition. In paediatrics, palliative care should be introduced early — not as a marker of "giving up" but as part of comprehensive management.
| Domain | Content |
|---|---|
| Advance care planning | Discuss goals of care with family (and child, if developmentally appropriate); document preferences regarding resuscitation, intubation, ICU admission, PEG feeding |
| Symptom management | Pain, spasticity, seizures, secretion management, agitation at end-of-life |
| Location of care | Home care vs hospice vs hospital — family preference should guide |
| Bereavement support | Anticipatory grief support for family; bereavement counselling after death |
| Transition planning | For adolescents surviving into adulthood — transition to adult neurology, psychiatry, palliative care |
While no treatment [15] is currently available that modifies the disease course, several approaches are in clinical trials:
| Approach | Mechanism | Status (2026) |
|---|---|---|
| Antisense oligonucleotides (ASOs) targeting HTT mRNA (e.g., tominersen) | Reduce production of mutant huntingtin protein by degrading its mRNA | Phase III trial (GENERATION HD1) halted due to unfavourable risk-benefit ratio (2021). Next-generation allele-selective ASOs in development |
| RNA interference (RNAi) | Small interfering RNA to silence mutant HTT expression | Phase I/II trials ongoing |
| Gene editing (CRISPR/Cas9) | Direct editing of the expanded CAG repeat | Preclinical stage |
| Small molecule splicing modulators (e.g., branaplam) | Alter HTT mRNA splicing to reduce mutant protein | Clinical trials; safety signals under investigation |
| Stem cell therapy | Replace lost striatal neurons | Very early research; not yet in clinical trials for HD |
| Neuroprotective agents | Various targets (mitochondrial support, anti-excitotoxicity, BDNF supplementation) | Multiple agents in preclinical/early clinical stages |
Research Update: Huntingtin-Lowering Therapies
The most promising disease-modifying approach is huntingtin-lowering therapy — reducing the production of the toxic mutant protein. Although the first-generation ASO tominersen did not succeed in Phase III trials, next-generation allele-selective approaches that target only the mutant allele (sparing normal huntingtin, which has important physiological roles) are in active development. These therapies may eventually transform HD from a uniformly fatal disease to a manageable condition. Paediatric patients with JHD may eventually be the most important target group, as early intervention could prevent the worst neurodegeneration.
| Symptom | First-Line Treatment | Alternatives | Paediatric Cautions |
|---|---|---|---|
| Chorea | Tetrabenazine [2][15] | Risperidone, sulpride [2]; deutetrabenazine; clonazepam [15] | Depression/suicidality monitoring with tetrabenazine; avoid in JHD Westphal variant |
| Rigidity/dystonia (JHD) | Baclofen; botulinum toxin | Cautious levodopa trial; trihexyphenidyl | Avoid tetrabenazine and D2 blockers — they worsen rigidity |
| Depression | SSRIs (fluoxetine, sertraline) | Mirtazapine (appetite benefit), venlafaxine | SSRI black box warning in under-18s; monitor suicidality |
| Psychosis | Low-dose atypical antipsychotics (olanzapine, quetiapine, risperidone) | — | Low doses; monitor metabolic effects |
| Irritability/agitation | SSRIs; behavioural strategies | Low-dose antipsychotics; short-term benzodiazepines | Avoid typical antipsychotics |
| Apathy | Environmental/behavioural strategies | Cautious stimulant trial | Limited evidence |
| Seizures (JHD) | Valproate; levetiracetam | Lamotrigine; clonazepam | Levetiracetam may worsen irritability; valproate: hepatotoxicity, teratogenicity |
| Dysphagia | SLT; dietary modification | PEG feeding when oral intake fails | Early PEG discussion; growth monitoring |
| Dysarthria | SLT; AAC devices | — | Age-appropriate communication aids |
| Weight loss | High-calorie diet; nutritional supplements | PEG feeding | Plot growth charts; dietitian involvement |
| Overall care | Multidisciplinary supportive care [15] | — | Family-centred; genetic counselling; palliative care integration |
High Yield Summary: Management of Huntington Disease
-
Multidisciplinary supportive care is the cornerstone [15]
-
Chorea treatment: Tetrabenazine (VMAT2 inhibitor) — first line; clonazepam; neuroleptics (risperidone/sulpride) [2][15]
-
JHD Westphal variant (rigidity/dystonia): Avoid dopamine-depleting agents — use baclofen, botulinum toxin, cautious levodopa trial
-
Psychiatric: Antidepressants (SSRIs first-line); benzodiazepines (clonazepam) for anxiety/chorea [2]; low-dose atypical antipsychotics for psychosis
-
Seizures in JHD: Valproate or levetiracetam
-
Dysphagia/nutrition: SLT assessment, dietary modification, PEG when oral intake fails; growth monitoring in children
-
Suicide risk: HD has one of the highest suicide rates of any neurological disease — actively screen and manage
-
Genetic counselling for entire family; predictive testing in asymptomatic minors NOT recommended
-
Palliative care: Introduce early as part of comprehensive care, not as an endpoint
-
Emerging therapies: Huntingtin-lowering strategies (ASOs, RNAi) are the most promising disease-modifying approaches in development
Active Recall - Management of Huntington Disease
References
[2] Senior notes: Ryan Ho Neurology.pdf (p. 127, Section 5.3 Huntington's Disease — Management) [3] Learning Points: learning_points_output.txt (Neurology - Two Cases of Movement Disorders, Learning Point 3) [15] Lecture slides: Neurology - Two cases of movement disorders.pdf (p. 13, Huntington's Disease — No treatment, Multidisciplinary supportive care, Clonazepam or tetrabenazine)
Complications of Huntington Disease (Paediatric Focus)
HD is a relentlessly progressive, multisystem neurodegenerative disorder. Its complications arise directly from the three core domains of the disease — motor, psychiatric, and cognitive — and from the treatment itself. In paediatrics, many complications are amplified because the disease disrupts a still-developing brain and body.
The complications can be logically organised into:
- Motor-related complications
- Psychiatric and behavioural complications
- Cognitive complications
- Nutritional and metabolic complications
- Treatment-related (iatrogenic) complications
- Psychosocial and family complications
- Terminal complications and causes of death
1. Motor-Related Complications
Loss of voluntary motor control: progressive, gradually causes dysarthria, dysphagia [2]
Why does this happen?
- The progressive loss of medium spiny neurons in the striatum, combined with cortical and brainstem degeneration, disrupts the exquisitely coordinated sequence of pharyngeal and oesophageal muscular contractions required for safe swallowing
- Chorea superimposes involuntary movements on the swallowing mechanism, making timing unpredictable
- In late-stage disease (and in JHD's rigid variant), bulbar dysfunction becomes severe — the cough reflex weakens, and the patient can no longer clear aspirated material from the airway
- Result: chronic microaspiration → recurrent lower respiratory tract infections → aspiration pneumonia
In paediatrics specifically:
- Children with JHD may develop dysphagia earlier and more rapidly than adults due to the more aggressive disease course
- Aspiration pneumonia is the single commonest cause of death in HD, accounting for ~40–50% of mortality
- Monitoring: Regular speech and language therapy (SLT) swallowing assessments (videofluoroscopy or fibreoptic endoscopic evaluation of swallowing, FEES); serial chest X-rays if recurrent infections
Prevention:
- Upright positioning during and after meals; chin-tuck swallowing technique
- Texture-modified diet and thickened fluids
- Oral hygiene (reduces bacterial load in oropharyngeal secretions → reduces severity of aspiration events)
- Timely PEG insertion when oral feeding becomes unsafe
- Vaccination: influenza and pneumococcal vaccines (standard paediatric immunisation schedule, plus additional at-risk scheduling)
Why?
- Chorea → unpredictable, irregular movements that throw the patient off balance
- Postural instability → impaired righting reflexes (basal ganglia and brainstem circuits)
- Gait abnormality → wide-based, lurching "dancing gait" with superimposed choreiform or dystonic movements
- In JHD: progressive rigidity and dystonia also impair safe ambulation
- Cognitive decline → impaired judgment and spatial awareness compound fall risk
Consequences:
- Fractures (especially hip, wrist, skull)
- Subdural haematoma (from head injury — important in any child with unexplained neurological deterioration on a background of HD)
- Soft tissue injuries, burns (falls near hot surfaces/water)
Prevention:
- Physiotherapy: gait training, balance exercises, strengthening
- Environmental modification: remove trip hazards, install grab rails, non-slip surfaces
- Protective equipment: padded helmets for children with frequent falls
- Early wheelchair provision when ambulation becomes unsafe (not a defeat — a safety measure)
Why?
- In JHD (Westphal variant): progressive rigidity and dystonia cause sustained abnormal posturing of limbs and trunk
- Immobility in advanced disease further promotes periarticular fibrosis and muscle shortening
- Without active range-of-motion exercises and positioning, joints become fixed in flexion contractures
Common patterns:
- Flexion contractures of hips, knees, elbows, wrists
- Equinovarus foot deformity (from sustained ankle plantarflexor dystonia)
- Scoliosis (from asymmetric truncal dystonia and prolonged wheelchair use)
Prevention and management:
- Regular physiotherapy with passive and active stretching
- Orthotic devices (splints, ankle-foot orthoses)
- Botulinum toxin injections for focal dystonia
- Serial casting for established contractures
- Seating clinic assessment for wheelchair users (posture-supporting seating systems)
- Develop in advanced/immobile stages of disease
- Due to prolonged pressure on bony prominences (sacrum, heels, greater trochanters) + nutritional depletion + incontinence
- Prevention: pressure-relieving mattresses and cushions; regular repositioning; skin inspection; optimised nutrition
2. Psychiatric and Behavioural Complications
Psychiatric manifestations: chronic atypical depressive states, psychosis, abnormal emotional states [15]
- HD carries one of the highest suicide rates of any neurological disease — approximately 4–6× the general population
- Critical periods: Around the time of genetic diagnosis/disclosure, and when functional independence is lost
- In adolescents with JHD, suicidal ideation may co-exist with the developmental stresses of adolescence, compounding risk
- Risk factors: Depression (present in ~40–50%), psychosis, social isolation, loss of autonomy, family history of suicide, tetrabenazine use (dopamine/serotonin depletion)
Management:
- Active screening for suicidal ideation at every clinical encounter (age-appropriate questioning)
- Psychiatric review and treatment of depression (SSRIs first-line)
- Safety planning; reduce access to means
- Family education about warning signs
- Crisis intervention planning documented in care plan
Suicide Risk in HD: Never Forget
HD has a suicide rate 4–6× higher than the general population. In adolescents with JHD, this risk intersects with the already-elevated adolescent suicide vulnerability. Tetrabenazine can worsen depression and suicidality. Screen actively at every visit. Untreated depression in HD is a medical emergency.
- Paranoid delusions can lead to aggressive behaviour, treatment refusal, self-harm
- Hallucinations may cause distress, agitation, unsafe behaviour
- May require inpatient psychiatric admission (with careful medication choice — avoid typical antipsychotics that worsen motor symptoms)
- Aggression and violent behaviour: Profoundly distressing for families and carers; may cause injury to caregivers or the child themselves
- Self-injurious behaviour: Can occur, particularly in severe JHD
- Safeguarding: If a child with HD is also being cared for by a parent with HD, there may be child protection/safeguarding concerns — the affected parent's judgment, impulse control, and capacity may be compromised. Social work involvement is essential.
3. Cognitive Complications
Cognitive features: dementia, poor judgment, inflexibility of thought, ↓concentration [2]
- Progressive executive dysfunction → inability to manage daily activities (dressing, bathing, feeding) independently
- Impaired judgment → unsafe decisions (crossing roads, handling sharp objects, medication self-administration)
- In children: loss of previously acquired skills (regression) — a particularly distressing feature for families
- Declining school performance is often the earliest noticed feature of JHD
- Loss of ability to follow the standard curriculum → need for modified educational plans → eventual inability to attend school
- Impact: Social isolation, loss of peer relationships, self-esteem damage, grief
- Combined dysarthria (motor speech impairment from basal ganglia/bulbar dysfunction) + cognitive decline → severe communication difficulty in advanced disease
- Patient may become effectively non-verbal — requires augmentative and alternative communication (AAC) devices
- Frustration from inability to communicate can worsen behavioural disturbance
4. Nutritional and Metabolic Complications
Why does weight loss occur?
- Increased energy expenditure: Constant involuntary movements (chorea) burn significant calories — like running a marathon every day without eating enough to compensate
- Hypermetabolic state: Hypothalamic dysfunction disrupts metabolic regulation → increased basal metabolic rate
- Dysphagia: Difficulty swallowing reduces oral intake
- Apathy and depression: Reduce motivation to eat
- Executive dysfunction: Inability to plan and prepare meals (in adolescents who would otherwise be gaining independence)
In paediatric patients:
- Failure to thrive and growth faltering — weight and height should be plotted on growth charts at every visit
- Delayed puberty may occur (hypothalamic-pituitary dysfunction)
- Nutritional deficiencies: Iron, folate, vitamin D, protein — can compound neurological decline
- Cachexia in advanced disease → muscle wasting, immunocompromise, poor wound healing
Management:
- Dietitian involvement from diagnosis
- High-calorie, nutrient-dense diet; oral nutritional supplements
- Consider PEG feeding early (as discussed in management section)
- Monitor growth parameters, BMI, and nutritional markers (albumin, pre-albumin, iron studies, vitamin levels)
- Dysphagia → reduced fluid intake
- Autonomic dysfunction → impaired thirst regulation
- May present with acute kidney injury, electrolyte disturbance, confusion (though distinguishing delirium from baseline cognitive decline is challenging)
| Medication | Complication | Mechanism |
|---|---|---|
| Tetrabenazine | Depression, suicidality | Serotonin and dopamine depletion |
| Tetrabenazine | Worsened parkinsonism (especially in JHD Westphal) | Excessive dopamine depletion in already-damaged striatum |
| Tetrabenazine | Dysphagia worsening | Further impairs oropharyngeal motor control |
| Tetrabenazine | QTc prolongation | Direct cardiac effect → risk of arrhythmia |
| Antipsychotics (risperidone, olanzapine) | Metabolic syndrome (weight gain, dyslipidaemia, insulin resistance) | Metabolic effects of D2/5-HT2A blockade |
| Antipsychotics | Hyperprolactinaemia | D2 blockade in tuberoinfundibular pathway → galactorrhoea, menstrual disturbance, bone density effects |
| Antipsychotics | EPS, tardive dyskinesia | D2 blockade in nigrostriatal pathway — already compromised in HD |
| Antipsychotics | Sedation | Histaminergic blockade → impairs school performance and participation |
| SSRIs | Behavioural activation, suicidality (in under-18s) | Complex serotonergic effects in developing brain — black box warning |
| Valproate (for seizures) | Hepatotoxicity, pancreatitis | Mitochondrial toxicity; idiosyncratic |
| Valproate | Teratogenicity | Neural tube defects — critically important counselling for adolescent females |
| Levetiracetam | Psychiatric side effects (irritability, aggression) | Unknown mechanism; may worsen pre-existing HD behavioural problems |
| Benzodiazepines | Sedation, cognitive blunting, tolerance, paradoxical agitation | GABA-A receptor modulation; tolerance with chronic use |
6. Psychosocial and Family Complications
These are often the most impactful complications in paediatric HD — sometimes more so than the medical complications themselves.
- Dual disease burden: Often, one parent has adult-onset HD while the child has JHD → the family is simultaneously managing TWO progressive neurodegenerative illnesses
- Caregiver burnout: Physical exhaustion, emotional distress, financial strain, social isolation
- Sibling impact: At-risk siblings live with the knowledge that they have a 50% chance of developing HD; they may experience anticipatory grief, anxiety, and "survivor's guilt" if they test negative while their sibling is affected
- Guilt: The transmitting parent (usually the father in JHD) may experience profound guilt
- Predictive testing dilemmas: At-risk siblings or relatives face agonising decisions about whether to be tested
- Privacy and disclosure: The child's diagnosis inherently reveals the family's HD status — this may affect insurance, employment, and social relationships
- Stigma: HD (especially the psychiatric and cognitive features) carries significant social stigma
- If the caregiving parent has HD with impaired judgment, impulse control, or capacity, the child may be at risk — both the affected child and unaffected siblings
- Social work involvement and safeguarding assessment should be part of routine care
- Respite care and supported living arrangements may be needed
- As motor, cognitive, and behavioural symptoms progress, the child becomes increasingly isolated from peers
- Bullying may occur (due to visible chorea, speech changes, cognitive slowness)
- Loss of friendships compounds depression and reduces quality of life
Progressive and fatal in 10 to 15 years [15]
| Cause of Death | Frequency | Mechanism |
|---|---|---|
| Aspiration pneumonia | ~40–50% (commonest) | Progressive dysphagia → chronic aspiration → recurrent/overwhelming pulmonary infection |
| Suicide | ~5–8% | Depression + impulsivity + loss of autonomy |
| Cardiovascular disease | ~20–25% | Autonomic dysfunction; physical inactivity; possibly direct cardiac involvement (cardiomyopathy has been reported) |
| Sepsis (other infections) | Variable | Immobility → pressure ulcers → cellulitis/osteomyelitis; urinary tract infections from catheterisation; immunocompromise from cachexia |
| Seizure-related death (JHD) | Uncommon but recognised | Status epilepticus; SUDEP (sudden unexpected death in epilepsy) |
| Inanition | Advanced disease | Severe cachexia + refusal or inability to accept nutrition |
In JHD specifically:
- Mean survival from onset: ~10–15 years (shorter than adult-onset HD's 15–20 years)
- Death typically occurs in adolescence or early adulthood
- Aspiration pneumonia remains the commonest cause, but seizure-related death is a more prominent contributor than in adult-onset HD
| Category | Key Complications | Pathophysiological Basis | Prevention/Management |
|---|---|---|---|
| Respiratory | Aspiration pneumonia | Dysphagia → aspiration | SLT, PEG, oral hygiene, vaccination |
| Musculoskeletal | Falls, fractures, contractures | Chorea/rigidity + postural instability + immobility | PT, environmental modification, helmets, orthotics |
| Nutritional | Weight loss, cachexia, FTT | Hyperkinesis + hypermetabolism + dysphagia + apathy | Dietitian, high-calorie diet, PEG |
| Psychiatric | Suicide, psychosis, aggression | Corticostriatal circuit disruption; medication effects | Active screening, SSRIs, antipsychotics, safety planning |
| Cognitive | Dementia, educational failure, communication breakdown | Subcortical neurodegeneration | Neuropsychological support, educational adaptations, AAC |
| Iatrogenic | Depression (tetrabenazine), metabolic syndrome (antipsychotics), seizure drug side effects | Drug mechanisms as above | Careful drug selection; monitoring; dose titration |
| Psychosocial | Family burden, caregiver burnout, sibling impact, stigma, safeguarding | Genetic nature of disease; progressive disability | MDT support, genetic counselling, social work, respite |
| Terminal | Aspiration pneumonia, suicide, cardiovascular, seizure-related | Progressive multisystem failure | Palliative care, advance care planning |
High Yield Summary: Complications of Huntington Disease
-
Leading cause of death: Aspiration pneumonia (~40–50%) — due to progressive dysphagia from loss of voluntary motor control [2][15]
-
Suicide: 4–6× general population rate; peaks at diagnosis and loss of independence; tetrabenazine worsens risk
-
Progressive and fatal in 10–15 years [15]; JHD is more rapidly progressive (~10–15 years from onset)
-
Falls and injuries: From chorea, rigidity, postural instability, and impaired judgment — fractures, subdural haematoma
-
Contractures and deformity: From rigidity and dystonia (JHD Westphal) + immobility — prevented by physiotherapy, orthotics, botulinum toxin
-
Weight loss / cachexia / failure to thrive: Multifactorial — hyperkinesis, hypermetabolism, dysphagia, apathy; growth monitoring essential in children
-
Iatrogenic complications: Tetrabenazine → depression/suicidality/worsened parkinsonism; antipsychotics → metabolic syndrome, EPS; valproate → hepatotoxicity/teratogenicity
-
Psychosocial: Dual family burden, caregiver burnout, sibling at-risk anxiety, safeguarding concerns, educational failure, social isolation
-
Seizure-related death: More relevant in JHD (30–50% have seizures) — status epilepticus, SUDEP
-
Palliative care and advance care planning should be integrated from early in the disease course
Active Recall - Complications of Huntington Disease
References
[2] Senior notes: Ryan Ho Neurology.pdf (p. 127, Section 5.3 Huntington's Disease) [3] Learning Points: learning_points_output.txt (Neurology - Two Cases of Movement Disorders, Learning Point 3) [15] Lecture slides: Neurology - Two cases of movement disorders.pdf (p. 13, Huntington's Disease — Progressive and fatal in 10–15 years; No treatment; Multidisciplinary supportive care)
High Yield Summary
-
Definition: HD is an autosomal dominant neurodegenerative disorder caused by CAG trinucleotide repeat expansion in the HTT gene (4p16.3) [1][2]
-
Genetics: CAG in coding sequence → toxic polyglutamine expansion → neurodegeneration [1]. Normal ≤ 26; intermediate 27–35; reduced penetrance 36–39; full penetrance ≥ 40 repeats
-
Anticipation: Repeats expand between subsequent generations, especially via paternal transmission [1][2]. ~80% of JHD is paternally inherited
-
Pathology: Loss of medium spiny neurons in the striatum → ↓↓ indirect pathway → chorea (early); later, ↓ direct pathway → parkinsonism [2]
-
Classic triad: Motor (chorea), psychiatric (depression, psychosis), cognitive (subcortical dementia) [2][3]
-
JHD (< 20 years): Akinetic-rigid (Westphal variant) — rigidity, bradykinesia, dystonia, seizures (30–50%), rapid decline; NOT chorea [2]
-
Key signs: Chorea ↑ with stress, disappears in sleep; hung-up knee jerk; saccadic abnormalities; motor impersistence [2]
-
Dementia type: Anterior, subcortical dementia [5] — retrieval deficit, executive dysfunction, psychomotor slowing
-
Epidemiology: Prevalence 4–8/100,000 (Caucasian); much lower in Hong Kong/Chinese populations [2]
-
No cure; progressive and fatal in 10–15 years (JHD) to 15–20 years (adult) [2]
-
Predictive testing in asymptomatic minors is NOT recommended — defer to adulthood
High Yield Summary: Diagnosis of HD
-
Gold standard diagnostic test: HTT gene CAG repeat analysis — ≥ 40 = full penetrance, 36–39 = reduced penetrance [1][2]
-
Genetic testing is definitive — no clinical criteria score is needed [2]
-
Always exclude Wilson disease first in any child with progressive movement disorder + psychiatric/cognitive features: ceruloplasmin, copper studies, slit-lamp [8]
-
MRI brain: Caudate atrophy with enlarged frontal horns — supportive, not diagnostic
-
Neuropsychological testing: Subcortical pattern — executive dysfunction, retrieval deficit, bradyphrenia
-
Key clinical signs: Hung-up knee jerk, motor impersistence (darting tongue, milkmaid's grip), saccadic abnormalities [2]
-
Predictive testing in asymptomatic minors is NOT recommended — diagnostic testing in symptomatic children IS appropriate
-
JHD: Usually ≥ 60 CAG repeats, ~80% paternal inheritance [2][3]
-
If HD genetic test is negative but clinical suspicion persists: Consider HDL syndromes, DRPLA (important in East Asian populations), other SCAs, metabolic/genetic panels
-
Metabolic screen (ammonia, lactate, organic acids, amino acids, acylcarnitine) should be performed in young children with atypical features [14]
High Yield Summary: Management of Huntington Disease
-
Multidisciplinary supportive care is the cornerstone [15]
-
Chorea treatment: Tetrabenazine (VMAT2 inhibitor) — first line; clonazepam; neuroleptics (risperidone/sulpride) [2][15]
-
JHD Westphal variant (rigidity/dystonia): Avoid dopamine-depleting agents — use baclofen, botulinum toxin, cautious levodopa trial
-
Psychiatric: Antidepressants (SSRIs first-line); benzodiazepines (clonazepam) for anxiety/chorea [2]; low-dose atypical antipsychotics for psychosis
-
Seizures in JHD: Valproate or levetiracetam
-
Dysphagia/nutrition: SLT assessment, dietary modification, PEG when oral intake fails; growth monitoring in children
-
Suicide risk: HD has one of the highest suicide rates of any neurological disease — actively screen and manage
-
Genetic counselling for entire family; predictive testing in asymptomatic minors NOT recommended
-
Palliative care: Introduce early as part of comprehensive care, not as an endpoint
-
Emerging therapies: Huntingtin-lowering strategies (ASOs, RNAi) are the most promising disease-modifying approaches in development
High Yield Summary: Complications of Huntington Disease
-
Leading cause of death: Aspiration pneumonia (~40–50%) — due to progressive dysphagia from loss of voluntary motor control [2][15]
-
Suicide: 4–6× general population rate; peaks at diagnosis and loss of independence; tetrabenazine worsens risk
-
Progressive and fatal in 10–15 years [15]; JHD is more rapidly progressive (~10–15 years from onset)
-
Falls and injuries: From chorea, rigidity, postural instability, and impaired judgment — fractures, subdural haematoma
-
Contractures and deformity: From rigidity and dystonia (JHD Westphal) + immobility — prevented by physiotherapy, orthotics, botulinum toxin
-
Weight loss / cachexia / failure to thrive: Multifactorial — hyperkinesis, hypermetabolism, dysphagia, apathy; growth monitoring essential in children
-
Iatrogenic complications: Tetrabenazine → depression/suicidality/worsened parkinsonism; antipsychotics → metabolic syndrome, EPS; valproate → hepatotoxicity/teratogenicity
-
Psychosocial: Dual family burden, caregiver burnout, sibling at-risk anxiety, safeguarding concerns, educational failure, social isolation
-
Seizure-related death: More relevant in JHD (30–50% have seizures) — status epilepticus, SUDEP
-
Palliative care and advance care planning should be integrated from early in the disease course
Friedreich Ataxia
Friedreich ataxia is an autosomal recessive neurodegenerative disorder, typically presenting in childhood or adolescence (usually before age 25), caused by GAA trinucleotide repeat expansions in the frataxin gene, leading to progressive gait and limb ataxia, dysarthria, loss of deep tendon reflexes, and hypertrophic cardiomyopathy.
Prader-willi Syndrome
Prader-Willi syndrome is a genetic disorder caused by loss of function of genes on chromosome 15q11-q13 (paternal deletion), presenting in infancy with hypotonia and feeding difficulties, followed in early childhood by hyperphagia, obesity, intellectual disability, short stature, and hypogonadism.