P athology related to: Mov ement The e i a i e e e a i
r
symptoms .
s n nv rs r l hip b/w repeat number and age of onset—more repeats lead to earlier
t ons
Repeat expansions occur during spermatogenesis, making paternal transmission more likely to result in
H untingtonʼs disease earlier onset in the next generation anticipation. →
Characterized by gradual onset of defects in behavior, cognition, and mvt beginning in fourth and fifth U ike a
nl m ny n eurodegenerative diseases, HD has no sporadic form.
decades of life - progressive and death within 10-20y.
e
N w mut t ons ai are rare; most sporadic cases can be explained by:
i an autosomal dominant disease caused by degeneration of striatal neurons (neurons in BG
HD s
a e i , eath of a parent before disease onset
Nonp t rn ty D
associated with motor control, reward, and addiction) and characterized by progressive mvt disorder
and dementia. A ml i dly expanded paternal allele that enlarges to a pathogenic size during spermatogenesis
Jerky, hyperkinetic, dystonic mvts involving all parts of the body are characteristics, with pts later also
P t a hophysiology and treatment of Huntingtonʼs disease
at risk of developing bradykinesia and rigidity.
Pathology:
Ep idemiology:
The b ai i
r n s small and shows striking atrophy of CN and, less markedly at early stages, the putamen. The
Frequency: lower incidence in Asian populations. In Western Europe, North America, and Australia, GP m ya atrophy secondarily, and the lateral and third ventricles are dilated. Atrophy is frequently also seen
prevalence has ↑ over past 50y. Most European countries range from 1.63-9.95 per 100,000 people, in the frontal lobe, less often in the parietal lobe, and occasionally throughout the entire cortex.
while Finland and Japan have less than 1 per 100,000 people.
The most striking neuropathology in HD occurs within the neostriatum, in which gross atrophy of CN and
Range: O nset ranges from 2y+ to older than 80y, with early or very late onset being rare. putamen is accompanied by selective neuronal loss and astrogliosis. Marked neuronal loss also is seen in
Genetics: deep layers of cerebral cortex.
her regions, including the globus pallidus, thalamus, subthalamic nucleus, substantia nigra, and
i a polyglutamine trinucleotide repeat expansion disease. CAG repeats on the huntingtin gene are
Ot
HD s
cerebellum, show varying degrees of atrophy depending on the pathologic grade. The extent of gross
normally between 6 to 35 copies. In HD, no. of repeats ↑ beyond this level, inversely related to the age
striatal pathology, neuronal loss, and gliosis provides a basis for grading the severity of HD pathology
of onset. Paternal transmission can lead to early onset in next generation due to repeat expansions
during spermatogenesis.
(grades 0-4)
athophysiology and Toxic Gain-of-Function
i a polyglutamine trinucleotide repeat expansion disorder. Caused by a mutation in HTT gene
P
HD s
located on chromosome 4p16.3, which encodes 348-kD huntingtin ptn. ci
Fun t on o f normal huntingtin is unknown, but the mutant form causes a toxic gain-of-function.
he first exon of gene, there is a CAG repeat sequence encoding a polyglutamine region near N-
In t R s e earch = silencing mutant allele as a potential therapy.
erminus of ptn.
t
e i e huntingtin being expressed in all tissues, its toxic effects are localized to certain regions of
D sp t
Norm l Ha TT ge e c
n s ain 6 to 35 CAG repeats.
ont CNS .
a h genic expansions (>35 repeats) lead to disease, with longer repeats associated with earlier
P t o Pathologic Features and Neuroprotection
ons et. A hallmark of HD is the formation of intranuclear inclusions containing huntingtin. However, these
inclusions:
Do not directly cause cellular injury.
M y a actually be neuroprotective, as neurons forming inclusions survive longer.
Poss ibly work by sequestering toxic forms of mutated huntingtin.
M echanisms of Neurodegeneration
e ea
S v r l m echanisms contribute to HD pathogenesis:
Transcriptional dysregulation:
Ant icipation and Transmission Mut nt a huntingtin binds transcriptional regulators.
Thi affec
s ts transcription factors involved in mitochondrial biogenesis and oxidative stress
prot ection, ↑ neuronal vulnerability.
, Red BDNF expression: Cl ni ical Features of Huntingtonʼs Disease
e e e
Low r l v ls o f brain-derived neurotrophic factor (BDNF) impact neuronal survival. Motor Dys un f ction
Imp aired protein degradation: Loss o f striatal neurons, which normally function to dampen motor activity, leads to increased motor
output .
i
D srupt on o i f proteasomal and autophagic pathways affects clearance of toxic ptns.
Thi i f en manifested as choreoathetosis, a combination of chorea (involuntary, irregular jerky
s s o t
i
Pr on L - ike Spread of Mutant Huntingtin mov ements) and athetosis (writhing movements of the extremities).
Emerging evidence suggests that mutant
The mvt disorder of HD is choreiform, characterized by:
huntingtin aggregates can transfer b/w cells,
resembling a prion-like spread of a pathogenic
↑i nvolunt ary jerky mvts of all parts of the body.
protein. W i hi g
r t n mvts of extremities, which are typical.
Co gnitive Impairment
Co gnitive changes are likely due to neuronal loss in the cerebral cortex.
a
E rly symptoms o f higher cortical dysfunction include:
Gross An atomy:
For getfulness , Cognitive dysfunction , Affective dysfunction
Atrop hy:
As t he disease progresses, it leads to severe dementia.
The b ai e hibi
r n x ts m arked overall atrophy.
Gr ading:
Str iatum:
Gr ade 0 cases have no detectable histologic neuropathology in the presence of a typical clinical
CN : Shows striking atrophy; progresses from convex to flat, and eventually concave (graded 2
p icture and positive family history suggesting HD.
to 4 based on severity).
Gr ade 1 cases have neuropathologic changes that can be detected microscopically but w/o gross
Put amen: Also shows atrophy, though typically less dramatic initially.
atrophy.
Ot her Regions:
Gr ade 2, striatal atrophy is present, but the caudate nucleus remains convex.
GP m y a atrophy secondarily.
Gr ade 3, striatal atrophy is more severe, and the caudate nucleus is flat.
The f ront al lobe is often affected, with occasional involvement of the parietal lobe and entire
Gr ade 4, striatal atrophy is most severe, and the medial surface of CN is concave
cortex.
icroscopy
Ventricular hanges: C
M
The hi stopathological hallmark is degeneration of the medium-sized spiny enkephalinergic / GABAergic
ia i
D l t on o f lateral and 3rd ventricles occurs due to loss of adjacent brain tissue.
n eurons of the striatum. Loss of these neurons leads to inhibition of the indirect basal ganglia pathway at
Microscopic Findings: its initial stage. The ensuing increased inhibition of the subthalamic nucleus leads to reduced inhibition of
the thalamic glutamatergic neurons, so that the final result is net increased activation of cortical motor
N euronal Loss and Gliosis:
neurons.
f
Pro oun d loss of medium-sized spiny neurons in striatum.
On m icroscopic examination, there is profound loss of striatal neurons; the most marked changes are
e i e astrogliosis.
Ext ns v
found in CN, esp in tail and in portions nearer the ventricle. Pathologic changes develop in a medial-to-
lateral direction in the caudate and from dorsal to ventral in the putamen. The nucleus accumbens is the
Bot h large and small neurons are affected, with smaller, spiny neurons typically lost first.
best-preserved portion of the striatum.
Intr anuclear Inclusions:
i i g neurons—both in striatum and cortex—ubiquitinated aggregates of mutant huntingtin
In surv v n
prot ein are observed.
Relative Sparing:
Som e interneurons, such as NADPH diaphorase-positive neurons (expressing nitric oxide
synt hase) and large cholinesterase-positive neurons, are relatively spared.
,Cl ni ical Features: Br ain imaging
The loss of striatal neurons, which functions to dampen motor activity, results in increased motor output, Fun ctional MRI (fMRI):
f en manifested as choreoathetosis. Symptoms begin insidiously with movement abnormalities and/or
o t
Prov ides dynamic images of the brain to elucidate neural activity.
with psychiatric and cognitive features. The course is with relentless deterioration in cognitive and motor
function. M easures haemodynamic response (blood flow) related to neural activation.
Motor symptoms and signs D t a a from manifest HD patients show:
e i i c eased motor output, chorea. Chorea is often manifested as choreoathetosis. The chorea
HD r sults n n r R ed task-activation in several subcortical and cortical regions.
becomes more florid and widespread, interfering with mvt. In later stages, chorea also affects diaphragm,
↑ ac i
t vation in different cortical areas, interpreted as compensatory mechanisms for task
pharynx, and larynx, producing dysarthria, dysphagia, and involuntary vocalizations.
performance.
ia with hyperreflexia is a feature of early disease. Dystonia (prolonged, sustained, abnormal
T
Hypoton
PE Im aging:
postur es) may be seen in the hands with such activities as walking. Mild bradykinesia is observed.
D t e ects molecular changes in the brain.
Ey e movements
i h early HD, there is delay in the initiation of volitional saccades (quick conjugate eye mvts
In pts w t
U e adi iga d
s s r ol n s to measure the distribution of radionuclide on biologically active molecules.
between points of fixation), and saccade velocity is red. This is characterized by absence of saccadic mvt E ffective for investigating in vivo abnormalities in brain metabolism and receptor distributions.
with preservation of smooth pursuit. Optokinetic nystagmus is abnormal in very early stages. In more
M agnetic Resonance Imaging (MRI):
advanced stages of HD, smooth pursuit, voluntary saccades, and refixation are all impaired.
h
S ows characteristic atrophy of CN (especially the head) and sometimes putamen.
Psy chiatric symptoms
Ve ic a di a i
ntr ul r l t on (lateral and 3rd ventricles) evident due to brain tissue loss.
i h HD may present with irritability, depression, and/or disrupted social relationships up to several
Pts w t
years prior to onset of chorea. Depression, paranoia, delusions, and hallucinations can develop at any point Genetic Testing:
in the illness. HD is associated with an ↑ risk of suicide. fi
Con rm t on o ai f HD is obtained by detecting an expanded CAG repeat in the HTT gene.
Neurologic Psychiatric Cognitive Mor e than 36 repeats are considered diagnostic.
h ea ah j dgment
a ed with control (left panel), a coronal MRI
C or Ap t y Poor u
Comp r
Dyston ia i ability
Irr t f e ibility of thought
In l x section through the brain of a patient suffering
from HD (right panel) shows marked enlargement
Ey e movement slowing e e i
D pr ss on Loss o f insight
of the lateral ventricles, caused by atrophy of the
Hyp rre eflexia e
D lus ons i D ecreased concentration neighboring caudate nucleus and putamen. Note:
shrunken cortical gyri and enlarged sulci of the
G ait abnormality Aggression e
M mory loss
patient compared with those of the brain of a
c (rare) iety bcortical dementia
healthy person.
Myo lonus Anx Su
a kinsonism (late stages)
P r Dsn i i hibition
G enetic Counseling and testing:
aa
P r no ia
If symptoms strongly suggest a diagnosis of HD, a genetic test for defective gene is recommended. Using
Co gnitive impairment and dementia a blood sample, genetic test analyzes DNA for HD mutation by counting the number of CAG repeats in the
huntingtin gene. Individuals who do not have HD usually have 28 or fewer repeats. The test can confirm
Co gnitive decline is inevitable in HD. The dominant cognitive feature of HD is executive dysfunction with
the diagnosis, and it may be valuable if there's no known family history of HD or if no other family
diminished ability to make decisions, multi-task, and switch from one set of cognitive goals to another.
member's diagnosis was confirmed with a genetic test.
Patients typically lack insight into their cognitive deficits, and may be unaware of their perceptual, motor,
and psychiatric problems related to HD. Treatment:
Common mm i ediate cause of death in HD pts is aspiration pneumonia due to discoordinated swallowing. e , here is no cure. Treatment is limited to symptom management and optimizing quality of life. The
Curr ntly t
best care is provided by an interdisciplinary team that addresses the broad physical and psychological
Diagnosis:
needs of patients and families, and manages new issues as they arise through long-term follow-up.
Based on medical history, a general physical exam, a review of the family medical history, and neurological
Neuroleptics and Tetrabenazine are used to treat the chorea in HD.
and psychiatric examinations.
, Trt for psychiatric manifestations. Trt for psychosis and/or disruptive behavioral symptoms without Mult idisciplinary Care:
debilitating chorea, include quetiapine. Depression is a common symptom of HD and is usually managed
erdisciplinary Approach: Involves neurologists, psychiatrists, physical and speech therapists,
Int
with selective serotonin reuptake inhibitors or tricyclic antidepressants, though the later may be more likely
genetic counselors, and social workers.
to cause adverse effects.
c i
Fo us s on m n a aging symptoms, providing supportive care, and addressing the psychological needs
Motor Symptoms (Chorea):
o f patients and their families.
Pr esynaptic VMAT2 Inhibitors (e.g., Tetrabenazine, Deutetrabenazine):
e e therapy:
G n
R ed synaptic dopamine by inhibiting the vesicular monoamine transporter type II.
Ant s ns i e e Oligonucleotides (ASOs): Synthetic strands of nucleotides designed to bind to the mutant
↓h yp erkinetic output of the basal ganglia but may exacerbate parkinsonian symptoms in later H TT mRNA, promoting its degradation and thereby reducing the production of the toxic protein.
ages.
e ference (RNAi): Utilizes small interfering RNAs (siRNAs) to target and degrade mutant HTT
st
RNA Int r
N euroleptics (e.g., Haloperidol, Chlorpromazine): mRNA , effectively silencing gene.
Ant agonize dopamine receptors to help red chorea but may lead to parkinsonism or worsen / a 9 Gene Editing: Employs the CRISPR/Cas9 system to directly edit the HTT gene, aiming to
CRISPR C s
existing symptoms. correct or disrupt the mutation responsible for HD.
P eriodic Review of Dosing: Necessary as chorea abates over time. An AAV5 vector carrying an artificial micro-RNA specifically tailored to silence the huntingtin gene has
Psy chiatric Symptoms: been prod aiming at inhibiting the production of the mutant protein.
Psy chosis: Managed with quetiapine (dopamine, serotonin antagonist). Apraxia
D epression: Treated with SSRIs or tricyclic antidepressants. Damage to premotor and supplementary motor areas leads to inability to perform learned movements
D ementia: No known effective trt for dementia associated with HD. despite normal strength.
Support v i e Therapies: :
Ex A p t a ient cannot mimic using a toothbrush despite understanding the task.
P alliative Care: Focuses on comfort, quality of life, and symptom management. Apraxia
i i e Equipment: For severe chorea (e.g., padded reclining chairs, low beds, helmets).
Ass st v Neurological disorder that affects a personʼs ability to perform purposeful mvts or gestures, despite
Dysp hagia Management: Use of thickened liquids to reduce aspiration risk. having normal muscle function and understanding of the task.
Sp eech Therapy: To manage language problems. C auses of Apraxia
P hysical Therapy: To help with gait issues and prevent falls. Stro ke, TBI, Neurodegenerative diseases (e.g., Alzheimer ʼs, Parkinsonʼs, Primary Progressive
Apr xa ia of Speech), Brain tumors, Dementia.
G ene Therapy:
Treatment:
Hunt n i gtin Gene Silencing: Aims to red huntingtin protein production to prevent damage to brain
cells. Sp eech therapy (for Apraxia of Speech).
AA V5 Vector with micro RNA: Si e ce he
l n s t ant gene.
mut
O ccupational therapy (for ideomotor, dressing, and constructional apraxia).
Sur gical Care (Experimental): h ical therapy (for gait apraxia).
P ys
Int ernal Globus Pallidotomy and Fetal Cell Transplantation: Attempted but no solid evidence e a
Comp ns tory str t a egies (alternative communication methods, visual cues).
hese approaches yet.
Type escription ommon auses ey Features
supports t
D C C K
Palliative Care: Inability to execute learned
ke, brain injury (affecting left a i i a e gestures
Ideomotor
Stro C nnot m t t
motor movements on
c e e e i g suffering and supporting quality of life throughout the diseaseʼs progression. hemisphere, especially the (e.g.,a i g, saluting), but
Apraxia
Fo us s on pr v nt n w v n
command, but can perform
parietal lobe). may do them spontaneously.
A dvance Care Planning: Helps patients express their care preferences, incl goals for trt and place of them automatically in context.
death.
Advance Directive: Incorporates pt wishes into a directive, guiding healthcare decisions when
patientʼs capacity is lost.
r
symptoms .
s n nv rs r l hip b/w repeat number and age of onset—more repeats lead to earlier
t ons
Repeat expansions occur during spermatogenesis, making paternal transmission more likely to result in
H untingtonʼs disease earlier onset in the next generation anticipation. →
Characterized by gradual onset of defects in behavior, cognition, and mvt beginning in fourth and fifth U ike a
nl m ny n eurodegenerative diseases, HD has no sporadic form.
decades of life - progressive and death within 10-20y.
e
N w mut t ons ai are rare; most sporadic cases can be explained by:
i an autosomal dominant disease caused by degeneration of striatal neurons (neurons in BG
HD s
a e i , eath of a parent before disease onset
Nonp t rn ty D
associated with motor control, reward, and addiction) and characterized by progressive mvt disorder
and dementia. A ml i dly expanded paternal allele that enlarges to a pathogenic size during spermatogenesis
Jerky, hyperkinetic, dystonic mvts involving all parts of the body are characteristics, with pts later also
P t a hophysiology and treatment of Huntingtonʼs disease
at risk of developing bradykinesia and rigidity.
Pathology:
Ep idemiology:
The b ai i
r n s small and shows striking atrophy of CN and, less markedly at early stages, the putamen. The
Frequency: lower incidence in Asian populations. In Western Europe, North America, and Australia, GP m ya atrophy secondarily, and the lateral and third ventricles are dilated. Atrophy is frequently also seen
prevalence has ↑ over past 50y. Most European countries range from 1.63-9.95 per 100,000 people, in the frontal lobe, less often in the parietal lobe, and occasionally throughout the entire cortex.
while Finland and Japan have less than 1 per 100,000 people.
The most striking neuropathology in HD occurs within the neostriatum, in which gross atrophy of CN and
Range: O nset ranges from 2y+ to older than 80y, with early or very late onset being rare. putamen is accompanied by selective neuronal loss and astrogliosis. Marked neuronal loss also is seen in
Genetics: deep layers of cerebral cortex.
her regions, including the globus pallidus, thalamus, subthalamic nucleus, substantia nigra, and
i a polyglutamine trinucleotide repeat expansion disease. CAG repeats on the huntingtin gene are
Ot
HD s
cerebellum, show varying degrees of atrophy depending on the pathologic grade. The extent of gross
normally between 6 to 35 copies. In HD, no. of repeats ↑ beyond this level, inversely related to the age
striatal pathology, neuronal loss, and gliosis provides a basis for grading the severity of HD pathology
of onset. Paternal transmission can lead to early onset in next generation due to repeat expansions
during spermatogenesis.
(grades 0-4)
athophysiology and Toxic Gain-of-Function
i a polyglutamine trinucleotide repeat expansion disorder. Caused by a mutation in HTT gene
P
HD s
located on chromosome 4p16.3, which encodes 348-kD huntingtin ptn. ci
Fun t on o f normal huntingtin is unknown, but the mutant form causes a toxic gain-of-function.
he first exon of gene, there is a CAG repeat sequence encoding a polyglutamine region near N-
In t R s e earch = silencing mutant allele as a potential therapy.
erminus of ptn.
t
e i e huntingtin being expressed in all tissues, its toxic effects are localized to certain regions of
D sp t
Norm l Ha TT ge e c
n s ain 6 to 35 CAG repeats.
ont CNS .
a h genic expansions (>35 repeats) lead to disease, with longer repeats associated with earlier
P t o Pathologic Features and Neuroprotection
ons et. A hallmark of HD is the formation of intranuclear inclusions containing huntingtin. However, these
inclusions:
Do not directly cause cellular injury.
M y a actually be neuroprotective, as neurons forming inclusions survive longer.
Poss ibly work by sequestering toxic forms of mutated huntingtin.
M echanisms of Neurodegeneration
e ea
S v r l m echanisms contribute to HD pathogenesis:
Transcriptional dysregulation:
Ant icipation and Transmission Mut nt a huntingtin binds transcriptional regulators.
Thi affec
s ts transcription factors involved in mitochondrial biogenesis and oxidative stress
prot ection, ↑ neuronal vulnerability.
, Red BDNF expression: Cl ni ical Features of Huntingtonʼs Disease
e e e
Low r l v ls o f brain-derived neurotrophic factor (BDNF) impact neuronal survival. Motor Dys un f ction
Imp aired protein degradation: Loss o f striatal neurons, which normally function to dampen motor activity, leads to increased motor
output .
i
D srupt on o i f proteasomal and autophagic pathways affects clearance of toxic ptns.
Thi i f en manifested as choreoathetosis, a combination of chorea (involuntary, irregular jerky
s s o t
i
Pr on L - ike Spread of Mutant Huntingtin mov ements) and athetosis (writhing movements of the extremities).
Emerging evidence suggests that mutant
The mvt disorder of HD is choreiform, characterized by:
huntingtin aggregates can transfer b/w cells,
resembling a prion-like spread of a pathogenic
↑i nvolunt ary jerky mvts of all parts of the body.
protein. W i hi g
r t n mvts of extremities, which are typical.
Co gnitive Impairment
Co gnitive changes are likely due to neuronal loss in the cerebral cortex.
a
E rly symptoms o f higher cortical dysfunction include:
Gross An atomy:
For getfulness , Cognitive dysfunction , Affective dysfunction
Atrop hy:
As t he disease progresses, it leads to severe dementia.
The b ai e hibi
r n x ts m arked overall atrophy.
Gr ading:
Str iatum:
Gr ade 0 cases have no detectable histologic neuropathology in the presence of a typical clinical
CN : Shows striking atrophy; progresses from convex to flat, and eventually concave (graded 2
p icture and positive family history suggesting HD.
to 4 based on severity).
Gr ade 1 cases have neuropathologic changes that can be detected microscopically but w/o gross
Put amen: Also shows atrophy, though typically less dramatic initially.
atrophy.
Ot her Regions:
Gr ade 2, striatal atrophy is present, but the caudate nucleus remains convex.
GP m y a atrophy secondarily.
Gr ade 3, striatal atrophy is more severe, and the caudate nucleus is flat.
The f ront al lobe is often affected, with occasional involvement of the parietal lobe and entire
Gr ade 4, striatal atrophy is most severe, and the medial surface of CN is concave
cortex.
icroscopy
Ventricular hanges: C
M
The hi stopathological hallmark is degeneration of the medium-sized spiny enkephalinergic / GABAergic
ia i
D l t on o f lateral and 3rd ventricles occurs due to loss of adjacent brain tissue.
n eurons of the striatum. Loss of these neurons leads to inhibition of the indirect basal ganglia pathway at
Microscopic Findings: its initial stage. The ensuing increased inhibition of the subthalamic nucleus leads to reduced inhibition of
the thalamic glutamatergic neurons, so that the final result is net increased activation of cortical motor
N euronal Loss and Gliosis:
neurons.
f
Pro oun d loss of medium-sized spiny neurons in striatum.
On m icroscopic examination, there is profound loss of striatal neurons; the most marked changes are
e i e astrogliosis.
Ext ns v
found in CN, esp in tail and in portions nearer the ventricle. Pathologic changes develop in a medial-to-
lateral direction in the caudate and from dorsal to ventral in the putamen. The nucleus accumbens is the
Bot h large and small neurons are affected, with smaller, spiny neurons typically lost first.
best-preserved portion of the striatum.
Intr anuclear Inclusions:
i i g neurons—both in striatum and cortex—ubiquitinated aggregates of mutant huntingtin
In surv v n
prot ein are observed.
Relative Sparing:
Som e interneurons, such as NADPH diaphorase-positive neurons (expressing nitric oxide
synt hase) and large cholinesterase-positive neurons, are relatively spared.
,Cl ni ical Features: Br ain imaging
The loss of striatal neurons, which functions to dampen motor activity, results in increased motor output, Fun ctional MRI (fMRI):
f en manifested as choreoathetosis. Symptoms begin insidiously with movement abnormalities and/or
o t
Prov ides dynamic images of the brain to elucidate neural activity.
with psychiatric and cognitive features. The course is with relentless deterioration in cognitive and motor
function. M easures haemodynamic response (blood flow) related to neural activation.
Motor symptoms and signs D t a a from manifest HD patients show:
e i i c eased motor output, chorea. Chorea is often manifested as choreoathetosis. The chorea
HD r sults n n r R ed task-activation in several subcortical and cortical regions.
becomes more florid and widespread, interfering with mvt. In later stages, chorea also affects diaphragm,
↑ ac i
t vation in different cortical areas, interpreted as compensatory mechanisms for task
pharynx, and larynx, producing dysarthria, dysphagia, and involuntary vocalizations.
performance.
ia with hyperreflexia is a feature of early disease. Dystonia (prolonged, sustained, abnormal
T
Hypoton
PE Im aging:
postur es) may be seen in the hands with such activities as walking. Mild bradykinesia is observed.
D t e ects molecular changes in the brain.
Ey e movements
i h early HD, there is delay in the initiation of volitional saccades (quick conjugate eye mvts
In pts w t
U e adi iga d
s s r ol n s to measure the distribution of radionuclide on biologically active molecules.
between points of fixation), and saccade velocity is red. This is characterized by absence of saccadic mvt E ffective for investigating in vivo abnormalities in brain metabolism and receptor distributions.
with preservation of smooth pursuit. Optokinetic nystagmus is abnormal in very early stages. In more
M agnetic Resonance Imaging (MRI):
advanced stages of HD, smooth pursuit, voluntary saccades, and refixation are all impaired.
h
S ows characteristic atrophy of CN (especially the head) and sometimes putamen.
Psy chiatric symptoms
Ve ic a di a i
ntr ul r l t on (lateral and 3rd ventricles) evident due to brain tissue loss.
i h HD may present with irritability, depression, and/or disrupted social relationships up to several
Pts w t
years prior to onset of chorea. Depression, paranoia, delusions, and hallucinations can develop at any point Genetic Testing:
in the illness. HD is associated with an ↑ risk of suicide. fi
Con rm t on o ai f HD is obtained by detecting an expanded CAG repeat in the HTT gene.
Neurologic Psychiatric Cognitive Mor e than 36 repeats are considered diagnostic.
h ea ah j dgment
a ed with control (left panel), a coronal MRI
C or Ap t y Poor u
Comp r
Dyston ia i ability
Irr t f e ibility of thought
In l x section through the brain of a patient suffering
from HD (right panel) shows marked enlargement
Ey e movement slowing e e i
D pr ss on Loss o f insight
of the lateral ventricles, caused by atrophy of the
Hyp rre eflexia e
D lus ons i D ecreased concentration neighboring caudate nucleus and putamen. Note:
shrunken cortical gyri and enlarged sulci of the
G ait abnormality Aggression e
M mory loss
patient compared with those of the brain of a
c (rare) iety bcortical dementia
healthy person.
Myo lonus Anx Su
a kinsonism (late stages)
P r Dsn i i hibition
G enetic Counseling and testing:
aa
P r no ia
If symptoms strongly suggest a diagnosis of HD, a genetic test for defective gene is recommended. Using
Co gnitive impairment and dementia a blood sample, genetic test analyzes DNA for HD mutation by counting the number of CAG repeats in the
huntingtin gene. Individuals who do not have HD usually have 28 or fewer repeats. The test can confirm
Co gnitive decline is inevitable in HD. The dominant cognitive feature of HD is executive dysfunction with
the diagnosis, and it may be valuable if there's no known family history of HD or if no other family
diminished ability to make decisions, multi-task, and switch from one set of cognitive goals to another.
member's diagnosis was confirmed with a genetic test.
Patients typically lack insight into their cognitive deficits, and may be unaware of their perceptual, motor,
and psychiatric problems related to HD. Treatment:
Common mm i ediate cause of death in HD pts is aspiration pneumonia due to discoordinated swallowing. e , here is no cure. Treatment is limited to symptom management and optimizing quality of life. The
Curr ntly t
best care is provided by an interdisciplinary team that addresses the broad physical and psychological
Diagnosis:
needs of patients and families, and manages new issues as they arise through long-term follow-up.
Based on medical history, a general physical exam, a review of the family medical history, and neurological
Neuroleptics and Tetrabenazine are used to treat the chorea in HD.
and psychiatric examinations.
, Trt for psychiatric manifestations. Trt for psychosis and/or disruptive behavioral symptoms without Mult idisciplinary Care:
debilitating chorea, include quetiapine. Depression is a common symptom of HD and is usually managed
erdisciplinary Approach: Involves neurologists, psychiatrists, physical and speech therapists,
Int
with selective serotonin reuptake inhibitors or tricyclic antidepressants, though the later may be more likely
genetic counselors, and social workers.
to cause adverse effects.
c i
Fo us s on m n a aging symptoms, providing supportive care, and addressing the psychological needs
Motor Symptoms (Chorea):
o f patients and their families.
Pr esynaptic VMAT2 Inhibitors (e.g., Tetrabenazine, Deutetrabenazine):
e e therapy:
G n
R ed synaptic dopamine by inhibiting the vesicular monoamine transporter type II.
Ant s ns i e e Oligonucleotides (ASOs): Synthetic strands of nucleotides designed to bind to the mutant
↓h yp erkinetic output of the basal ganglia but may exacerbate parkinsonian symptoms in later H TT mRNA, promoting its degradation and thereby reducing the production of the toxic protein.
ages.
e ference (RNAi): Utilizes small interfering RNAs (siRNAs) to target and degrade mutant HTT
st
RNA Int r
N euroleptics (e.g., Haloperidol, Chlorpromazine): mRNA , effectively silencing gene.
Ant agonize dopamine receptors to help red chorea but may lead to parkinsonism or worsen / a 9 Gene Editing: Employs the CRISPR/Cas9 system to directly edit the HTT gene, aiming to
CRISPR C s
existing symptoms. correct or disrupt the mutation responsible for HD.
P eriodic Review of Dosing: Necessary as chorea abates over time. An AAV5 vector carrying an artificial micro-RNA specifically tailored to silence the huntingtin gene has
Psy chiatric Symptoms: been prod aiming at inhibiting the production of the mutant protein.
Psy chosis: Managed with quetiapine (dopamine, serotonin antagonist). Apraxia
D epression: Treated with SSRIs or tricyclic antidepressants. Damage to premotor and supplementary motor areas leads to inability to perform learned movements
D ementia: No known effective trt for dementia associated with HD. despite normal strength.
Support v i e Therapies: :
Ex A p t a ient cannot mimic using a toothbrush despite understanding the task.
P alliative Care: Focuses on comfort, quality of life, and symptom management. Apraxia
i i e Equipment: For severe chorea (e.g., padded reclining chairs, low beds, helmets).
Ass st v Neurological disorder that affects a personʼs ability to perform purposeful mvts or gestures, despite
Dysp hagia Management: Use of thickened liquids to reduce aspiration risk. having normal muscle function and understanding of the task.
Sp eech Therapy: To manage language problems. C auses of Apraxia
P hysical Therapy: To help with gait issues and prevent falls. Stro ke, TBI, Neurodegenerative diseases (e.g., Alzheimer ʼs, Parkinsonʼs, Primary Progressive
Apr xa ia of Speech), Brain tumors, Dementia.
G ene Therapy:
Treatment:
Hunt n i gtin Gene Silencing: Aims to red huntingtin protein production to prevent damage to brain
cells. Sp eech therapy (for Apraxia of Speech).
AA V5 Vector with micro RNA: Si e ce he
l n s t ant gene.
mut
O ccupational therapy (for ideomotor, dressing, and constructional apraxia).
Sur gical Care (Experimental): h ical therapy (for gait apraxia).
P ys
Int ernal Globus Pallidotomy and Fetal Cell Transplantation: Attempted but no solid evidence e a
Comp ns tory str t a egies (alternative communication methods, visual cues).
hese approaches yet.
Type escription ommon auses ey Features
supports t
D C C K
Palliative Care: Inability to execute learned
ke, brain injury (affecting left a i i a e gestures
Ideomotor
Stro C nnot m t t
motor movements on
c e e e i g suffering and supporting quality of life throughout the diseaseʼs progression. hemisphere, especially the (e.g.,a i g, saluting), but
Apraxia
Fo us s on pr v nt n w v n
command, but can perform
parietal lobe). may do them spontaneously.
A dvance Care Planning: Helps patients express their care preferences, incl goals for trt and place of them automatically in context.
death.
Advance Directive: Incorporates pt wishes into a directive, guiding healthcare decisions when
patientʼs capacity is lost.
