Huntington Disease

Slide 1 · Huntington disease

A molecular-to-morphology approach

Molecular genetics • neuropathology • clinicopathologic correlation

Dr Abu Suraih Sakhri

MBBS, MD (Pathology)

www.abusuraihsakhri.com

Slide 2 · Learning objectives

Trace the HTT CAG expansion from inheritance to neuronal dysfunction.

Recognize characteristic striatal atrophy and microscopic degeneration.

Connect movement, cognitive and affective manifestations to pathology.

Explain the implications and limitations of predictive genetic testing.

Slide 3 · The defining clinicopathologic syndrome

Autosomal dominant neurodegeneration, most conspicuous in the striatum.

A progressive movement disorder accompanied by cognitive decline.

Chorea is characteristic, but later motor impairment can become hypokinetic.

HTT CAG expansion

Selective striatal neuron loss

Chorea + cognitive decline

Slide 4 · Three connected dimensions of disease

Gene

HTT CAG-repeat expansion

Tissue

Caudate and putamen degeneration

Phenotype

Motor, cognitive and affective deterioration

Slide 5 · The striatum is the primary anatomic target

Caudate nucleus and putamen constitute the dorsal striatum.

Profound neuronal loss particularly involves the caudate.

Involvement of frontal cortex provides an additional correlate of cognitive change.

Coronal schematic

Caudate

Putamen

Schematic (not a specimen)

Slide 6 · Striatal dysfunction explains hyperkinesis

Striatal neurons normally help restrain motor output.

Their loss reduces this inhibitory influence.

The clinical consequence is increased, involuntary movement.

Medium spiny neuron loss

Reduced motor suppression

Excess involuntary movement

Slide 7 · The motor phenotype evolves over time

Early movement is typically jerky, hyperkinetic and choreiform.

Writhing or dystonic components may coexist.

Bradykinesia and rigidity can emerge later in the course.

Early chorea / hyperkinesis

Variable dystonia or writhing

Later bradykinesia / rigidity

Slide 8 · The disease is autosomal dominant

A pathogenic HTT expansion can transmit disease across generations.

One affected heterozygous parent can transmit the allele to offspring.

Anticipation modifies age at onset across some generations.

Autosomal dominant transmission

Affected carrier

Unaffected

Illustrative pedigree, not patient data

Slide 9 · Pedigree reasoning: Recurrence risk

Autosomal dominant transmission gives each child of a heterozygous carrier a 1-in-2 inheritance probability.

Transmission probability does not predict age at onset.

Phenotypically unaffected relatives may carry an expansion before symptoms develop.

Each pregnancy

1 in 2

1 in 2

Inherits allele

Does not inherit

Risk is not an age-at-onset prediction

Slide 10 · HTT maps to chromosome 4p16.3

The HTT gene encodes huntingtin, a large 348-kDa protein.

The unstable repeat lies in the first exon.

The corresponding polyglutamine tract lies near the protein N-terminus.

HTT • chromosome 4p16.3

Exon 1

CAG repeats

Coding DNA

Slide 11 · The causal DNA sequence is a CAG repeat

CAG is a protein-coding trinucleotide repeat.

Each CAG codon specifies glutamine.

Expansion therefore lengthens the polyglutamine sequence in huntingtin.

CAG = glutamine codon

Unexpanded tract

CAG

CAG

CAG

CAG

CAG

Expanded tract

CAG

CAG

CAG

CAG

CAG

CAG

CAG

CAG

CAG

Schematic only: Number of boxes is not a diagnostic cutoff

Slide 12 · Expansion changes the encoded protein

DNA repeat expansion alters the translated polyglutamine tract.

The effect is a protein-structure-linked toxic gain of function.

This distinguishes HD from repeat disorders caused primarily by gene silencing.

CAG CAG CAG … (DNA)

Gln–Gln–Gln … (protein)

Lengthened polyglutamine tract

Toxic gain of function

Slide 13 · Repeat counts require precise interpretation

Unexpanded HTT

Normal-range repeat tract

No disease-causing expanded polyQ tract

Expanded HTT

Lengthened polyglutamine region

Pathogenicity / penetrance depend on repeat category

Slide 14 · Repeat length and onset are inversely related

Larger expanded repeats are associated with earlier symptom onset.

Repeat count is informative, not an exact personal onset clock.

A qualitative relationship is established without assigning individual predictions.

More CAG repeats

Earlier typical onset

Association ≠ exact prediction

Slide 15 · Anticipation is a generational phenomenon

Repeat number can increase during transmission.

Greater expansion can shift onset to a younger generation.

HD is an example of genetic anticipation.

Parent: Expanded repeat

Transmission: Potential further expansion

Offspring: Earlier disease onset

Slide 16 · Paternal transmission is especially relevant

Repeat expansion can occur during spermatogenesis.

Paternal transmission is linked to anticipation in the Robbins description.

An unaffected father with a mild expansion can have an affected offspring after further expansion.

Spermatogenesis

Repeat instability / expansion

Paternal anticipation

Slide 17 · An isolated presentation need not be nongenetic

No truly nongenetic sporadic form of HD.

Apparently negative family histories may reflect death before onset or unrecognized disease.

Nonpaternity and paternal repeat expansion are additional explanations identified by the text.

Negative or unclear family history

Premature parental death / nonrecognition

Investigate inherited HTT expansion

Slide 18 · HTT expansion acts through toxic gain of function

Expansion confers deleterious properties on huntingtin.

This is not presented as simple loss of normal protein function.

Suppressing mutant HTT expression is consequently investigated as a therapeutic strategy.

Expanded polyglutamine tract

Altered interactions / cellular homeostasis

Toxic gain-of-function phenotype

Slide 19 · Normal huntingtin function remains incompletely defined

The normal protein’s biologic role as incompletely understood.

Pathogenic interpretation centers on mutant huntingtin toxicity.

A molecular diagnosis does not settle every downstream injury mechanism.

Slide 20 · Broad expression, selective neuronal injury

Huntingtin is expressed widely in tissues.

The dominant destructive effect occurs in selected central nervous system populations.

Striatal vulnerability therefore requires more explanation than expression alone.

Systemic expression

Regional vulnerability

Normal and mutant huntingtin expressed across tissues

Particularly severe CNS injury

Slide 21 · HD pathogenesis comprises parallel pathways

Mutant huntingtin perturbs transcriptional regulation and oxidative-stress responses.

Altered BDNF expression and protein clearance may amplify neuronal vulnerability.

Aggregation and possible transfer between cells complicate the mechanistic model.

Expanded mutant huntingtin

Transcription + trophic + clearance defects

Selective neurodegeneration

Slide 22 · Neuronal inclusions are a pathologic hallmark

Aggregated mutant huntingtin forms neuronal inclusions, including intranuclear deposits.

These inclusions are observed in affected striatal and cortical neurons.

Visible aggregates do not necessarily identify the most toxic molecular species.

Intranuclear protein aggregate

Neuron / nucleus diagram

Schematic (not a specimen)

Slide 23 · Inclusion burden is not synonymous with toxicity

Experimental observations challenge a directly toxic role for inclusions.

Some inclusion-bearing striatal neurons survive longer.

Sequestration of smaller toxic species is proposed as one possible explanation.

Diffusible abnormal huntingtin species

Aggregation into inclusion

Possible sequestration; Net toxicity uncertain

Slide 24 · Transcriptional dysregulation is implicated

Mutant huntingtin can associate with transcriptional regulators.

Interference with regulation may alter neuronal stress-response programs.

The pathway is implicated, not presented as the sole demonstrated cause of cell death.

Mutant huntingtin ↔ transcription factors

Altered gene regulatory activity

Reduced protective response

Slide 25 · Mitochondrial protective programs may weaken

Interacting transcription factors participate in mitochondrial biogenesis.

Reduced protective transcriptional activity may impair stress resilience.

This provides a mechanistic bridge to oxidative vulnerability.

Transcriptional regulator interactions

Reduced mitochondrial biogenesis program

Lower resistance to cellular stress

Slide 26 · Oxidative stress may accentuate degeneration

Reduced activity of protective transcription factors increases susceptibility to oxidative injury.

Oxidative stress is one contributing model of injury, not a complete explanation.

The causal network may contain interacting downstream processes.

Less protective transcriptional activity

Greater susceptibility to oxidative stress

Slide 27 · Reduced BDNF expression is a candidate mechanism

Brain-derived neurotrophic factor is a neuronal growth/survival-related factor.

Reduced expression is implicated in HD pathogenesis.

It fits a model of declining support to vulnerable neurons.

Mutant huntingtin-associated dysregulation

Lower expression of BDNF

Potential loss of neuronal support

Slide 28 · Protein quality-control pathways are disturbed

Proteasomal degradation and autophagic pathways are reported as disrupted.

Defective clearance can increase persistence of abnormal huntingtin species.

These systems interact with, rather than replace, other pathogenic mechanisms.

Protein disposal systems

Proteasomal degradation

Autophagic degradation

Both pathways may be disrupted in HD

Slide 29 · Prion-like transfer remains an emerging hypothesis

Aggregated huntingtin may transfer between cells.

The text describes this as emerging evidence of possible prion-like spread.

Do not equate this hypothesis with transmissible human prion disease.

Possible intercellular transfer

Investigational mechanism, not infectious HD

Schematic (not a specimen)

Slide 30 · Distinguish observation from mechanistic inference

Directly described findings

Expanded HTT CAG repeat

Striatal neuronal degeneration

Neuronal huntingtin aggregates

Proposed contributors

Transcriptional disruption / oxidative stress

BDNF and proteostasis changes

Possible cell-to-cell aggregate transfer

Slide 31 · Gross examination reveals striking striatal atrophy

The brain is small, with conspicuous loss of caudate and putamen volume.

Ventricular enlargement accompanies surrounding tissue loss.

Frontal atrophy is frequent; Broader cortical atrophy is less uniform.

Normal

Huntington disease

Volume loss → relative ventricular enlargement

Schematic (not a specimen)

Slide 32 · Caudate atrophy is a defining gross clue

The caudate is particularly vulnerable among striatal structures.

Volume loss alters the walls neighboring the lateral ventricles.

A coronal-section comparison is a useful teaching approach.

Coronal schematic

Caudate

Putamen

Schematic (not a specimen)

Slide 33 · Putaminal degeneration accompanies caudate loss

The dorsal striatum consists of both caudate and putamen.

Putaminal neuronal loss contributes to basal ganglia dysfunction.

The spatial pattern of injury is not necessarily identical to the caudate.

Caudate

Putamen

Caudate degeneration

Putaminal degeneration

Slide 34 · Ventricles enlarge as tissue volume declines

Dilation of lateral and third ventricles is reported.

This is ex-vacuo enlargement associated with adjacent parenchymal atrophy.

Ventricular size is a morphologic correlate, not a stand-alone molecular diagnosis.

Normal

Huntington disease

Volume loss → relative ventricular enlargement

Schematic (not a specimen)

Slide 35 · Globus pallidus can atrophy secondarily

The pallidum may become atrophic in advanced disease.

Its involvement is described as secondary to major striatal degeneration.

Do not confuse the primary striatal lesion with secondary circuit changes.

Primary striatal atrophy

Secondary pallidal involvement

Broader basal ganglia alteration

Slide 36 · Frontal cortical atrophy is frequent

Atrophy is often seen in frontal lobes.

Parietal involvement occurs less frequently.

More diffuse cortical atrophy can occur, but is not universal.

Frequent

Variable

Frontal atrophy often described

Parietal / diffuse cortical changes less frequent

Slide 37 · Microscopy: Profound loss of striatal neurons

Neuronal depletion is a principal microscopic lesion.

The most conspicuous changes occur in the caudate.

Fibrillary gliosis accompanies the degenerative process.

Relatively preserved

HD degeneration

Neuron loss and reactive glia (conceptual)

Schematic (not a specimen)

Slide 38 · Caudate injury has regional predilection

The caudate tail and areas close to the ventricle show particularly marked changes.

Progression is described in a medial-to-lateral direction.

This anatomic gradient is distinct from the timeline of clinical symptoms.

Regional vulnerability

Directional anatomic gradient

Severe neuronal depletion + gliosis

Medial → lateral

Slide 39 · Putaminal changes follow a spatial gradient

Degeneration in the putamen is described from dorsal to ventral.

This differs from the medial-to-lateral pattern in the caudate.

Precise anatomic location matters in neuropathologic descriptions.

Regional vulnerability

Directional anatomic gradient

Severe neuronal depletion + gliosis

Dorsal → ventral

Slide 40 · Medium spiny neurons are especially vulnerable

Medium-sized, spiny striatal neurons are preferentially affected.

They provide inhibitory signaling within motor circuits.

Preferential neuronal loss offers a cellular basis for the motor phenotype.

Schematic medium spiny neuron

Schematic (not a specimen)

Slide 41 · Affected neurons use GABA and neuropeptides

The principal inhibitory transmitter identified is γ-aminobutyric acid (GABA).

Enkephalin, dynorphin and substance P are also associated with these neurons.

Loss of these neurons disrupts the functional output of striatal circuits.

GABA

Primary inhibitory transmitter

Enkephalin

Associated peptide

Dynorphin / substance P

Associated peptides

Slide 42 · Reactive gliosis exceeds simple background change

Fibrillary gliosis is prominent at sites of neuronal loss.

The reaction is more extensive than usual for comparable neuronal loss,.

Gliosis is a secondary tissue response, not a disease-specific molecular assay.

Surviving neurons

Reactive glia

Schematic (not a specimen)

Slide 43 · Huntingtin aggregates localize to affected regions

Protein inclusions are detectable in striatum and cerebral cortex.

The published textbook figure uses ubiquitin immunohistochemistry to highlight an intranuclear inclusion.

No authentic textbook photomicrograph is reproduced in this presentation.

Intranuclear protein aggregate

Neuron / nucleus diagram

Schematic (not a specimen)

Slide 44 · Integrating morphology and phenotype

Striatal loss weakens the motor-suppressing influence of basal ganglia circuits.

Cortical neuronal loss contributes to progressive cognitive dysfunction.

Different manifestations can therefore emerge from one molecular cause.

Striatal neuron loss → hyperkinesis

Cortical neuron loss → cognitive change

Progression → combined disabilities

Slide 45 · Adult onset is most typical

Initial manifestations are most commonly observed in the fourth or fifth decade.

Age at onset varies with expanded CAG length.

This typical age distribution does not substitute for a molecular definition.

Typical onset

Fourth–fifth decades

Variation depends in part on repeat length

Slide 46 · Chorea is a recognizable motor manifestation

Movements are involuntary, brief, jerky and hyperkinetic.

Different body regions may be affected.

Chorea reflects disordered motor control rather than increased voluntary strength.

Loss of striatal inhibitory neurons

Failure to dampen movement

Irregular involuntary jerks

Slide 47 · Choreoathetosis includes a writhing component

Writhing movements of the extremities.

Jerky and flowing involuntary movements may coexist.

The phenotype must be distinguished clinically from tremor or isolated rigidity.

Chorea

Athetotic component

Brief, irregular, jerky movements

Writhing movements of extremities

Slide 48 · Rigidity and bradykinesia may appear later

Hyperkinetic manifestations dominate the classic description.

Later disease may feature slow movement and increased muscle tone.

The phase of illness changes what the clinician observes.

Early chorea / hyperkinesis

Variable dystonia or writhing

Later bradykinesia / rigidity

Slide 49 · Cognitive dysfunction has a cortical correlate

Degeneration extends beyond the striatum in many patients.

Cortical neuronal loss is implicated in cognitive decline.

The pathologic process is therefore not exclusively a movement disorder.

Cortical neuronal involvement

Higher cortical dysfunction

Progressive cognitive impairment

Slide 50 · Early neurobehavioral symptoms may be subtle

Forgetfulness may appear early.

Cognitive and affective disturbances can accompany motor symptoms.

Neurologic assessment should not focus only on involuntary movements.

Memory: Forgetfulness

Cognition: Higher cortical dysfunction

Affect: Emotional / behavioral changes

Slide 51 · Progression can culminate in severe dementia

Cognitive deficits intensify during the course.

Severe dementia may develop in advanced disease.

Behavioral and cognitive changes are central components of the illness.

Early forgetfulness

Progressive cognitive and affective decline

Severe dementia in advanced illness

Slide 52 · Motor manifestations often precede cognition

That motor symptoms commonly precede cognitive impairment.

The sequence is not a rigid diagnostic requirement.

A history of progressive change across multiple domains is informative.

Movement disorder often first

Cognitive and affective impairment progresses

Combined late-stage disability

Slide 53 · The clinical course is relentlessly progressive

The textbook gives an average disease course of about 15 years.

Progression affects movement, cognition and functional capacity.

The quoted duration is a population-level summary, not a personal prognosis.

Initial movement / neurobehavioral changes

Progression across neurologic domains

Advanced disability and complications

Slide 54 · Pneumonia is a major terminal complication

Pneumonia is identified as the most common immediate cause of death.

It often occurs during advanced disease.

The terminal event should be distinguished from the underlying inherited neurodegeneration.

Inherited neurodegeneration

Advanced progressive disability

Pneumonia as immediate cause of death

Slide 55 · Psychiatric safety is clinically consequential

Elevated suicide risk in HD.

Affective dysfunction deserves attention throughout the disease course.

Discuss risk without reducing the illness to a psychiatric stereotype.

Affective dysfunction + elevated suicide risk

Clinical vigilance is necessary throughout disease

Slide 56 · Genetic testing establishes the molecular lesion

A test targeting the HTT CAG-repeat expansion can identify a disease-associated allele.

Phenotypic assessment and family history still provide clinical context.

Interpretation of borderline categories and predictive testing requires specialized counseling.

Clinical suspicion + pedigree

HTT CAG-repeat analysis

Molecular confirmation and counseling

Slide 57 · Testing an unaffected relative is different

Presymptomatic identification may provide genetic information before clinical manifestations.

The result may have major personal and family consequences.

The textbook explicitly raises ethical concerns about routine predictive screening.

Asymptomatic at-risk adult

Informed choice + counseling

Potential genetic knowledge; Uncertain onset

Slide 58 · Counseling must address genetic uncertainty

Autosomal dominant inheritance and anticipation alter family discussions.

Repeat size is associated with onset but does not fix an exact future date.

Autonomy and informed decision-making are critical in predictive testing.

Transmission risk

Meaning and limits of repeat result

Voluntary informed decision

Slide 59 · Case: Progressive involuntary movements

A 44-year-old develops progressive generalized jerky movements.

Family members describe increasing forgetfulness and personality change.

A parent had an incompletely characterized progressive neurologic illness.

Which anatomic structure and molecular lesion best unify the findings?

Slide 60 · Case reasoning: Phenotype to genotype

Chorea suggests disinhibition of motor output from striatal damage.

Cognitive and affective changes suggest additional cortical involvement.

An inherited HTT CAG expansion unifies the motor, familial and cognitive features.

Progressive chorea

Striatal degeneration

Familial HTT CAG expansion

Slide 61 · Case: A healthy adult requests prediction

An asymptomatic adult has a parent with genetically confirmed HD.

The adult requests a test predicting precisely when symptoms will develop.

The question includes medical, psychological and familial dimensions.

What can a repeat-expansion result establish—and what can it not?

Slide 62 · Predictive testing: Answer the right question

Genetic testing may identify an HTT repeat expansion.

Repeat length cannot provide a precise individual onset date.

Pretest counseling and respect for the person’s decision are essential.

Allele categorization

No exact onset prediction

Counseling-centered decision-making

Slide 63 · Distinguishing HD from another degeneration

Huntington disease

HTT CAG polyglutamine expansion

Striatal neuronal degeneration

Chorea with cognitive and affective decline

Multiple system atrophy

Oligodendroglial α-synuclein inclusions

Striatonigral / autonomic / cerebellar systems

Parkinsonism, autonomic failure or ataxia

Slide 64 · Integrating the disease in one causal model

HTT CAG expansion → mutant huntingtin toxic gain of function.

Multiple cellular stress pathways → selective striatal / cortical degeneration.

Caudate–putamen atrophy → chorea; Cortical involvement → cognitive change.

Expanded CAG → abnormal polyQ

Mutant huntingtin toxicity

Striatal + cortical degeneration

Motor + cognitive + affective disease

Slide 65 · References and interpretive boundaries

Robbins, Cotran & Kumar: Pathologic Basis of Disease, 11th edition (2026).

Content follows the Huntington disease section and the general repeat-expansion discussion.

Morphology illustrations are original editable schematics—not clinical photographs or textbook figures.