Huntington disease (HD; MIM 143100) is a progressive hereditary disorder that usually

appears in adult life. It is characterized by a movement disorder (usually

chorea), dementia, and personality disorder. It was first recognized clinically by Waters
in 1842 and became accepted as a clinical entity with the comprehensive
description and interpretation of the mode of transmission by George Huntington in
1872.
Penyakit Huntington adalah gangguan herediter progresif yang biasanya muncul pada
usia dewasa. Ditandai dengan adanya gangguan gerak (biasanya korea), demensia,
dan gangguan kepribadian. Pertama kali diakui secara klinis oleh Waters pada tahun
1842 dan
Di deskripsikan kembali dengan lengkap oleh George Huntington pada tahun 1872.

Huntington's disease (HD) is a neurodegenerative disorder transmitted as an autosomal dominant

trait. Selective neuronal loss in the striatum leads to chorea and cognitive impairment. It is a
progressive disease with onset in midlife, which chronically evolves over many years and for
which no curative treatment is available today. The discovery of the underlying gene defect
helped to explain some of the clinical variability, especially the variability in age at onset and, to
a lesser extent, the disease severity.
Penyakit hungtinton merupakan gangguan neurodegenerative
Early
Symptoms of Huntington's
Middle
disease
Late
Clumsiness Unsteadiness
Chorea Dropping things
Irritability Gait disorder
Sadness Sleep disorder
Depression < ognim c
dysfunction
Decreased motivation Decreased memory
Sexual dysfunction

Awal
kikuk
Korea
Iritabilitas
kesedihan
Depresi
Kurang motivasi
Disfungsi seksual

Pertengahan
Tidak tenang
Sering menjatuhkan
barang
Gait disorder
Gangguan tidur
Penurunan kemampuan
memori

Prevalence figures for HD vary depending on the geographical

area, but the best estimate is 10 per 100,000. The
disorder is reported in all races, although it is much more
common in Scotland and Venezuela and less common in
Hnland, China, Japan, and black South Africans. HD
usually begins between the ages of 30 and 55 years,
although it has been reported to begin as early as age 2

Lanjut
Penurunan berat badan
Gangguan berbicara
Inkontinensia urine
Inkontinensia alvi

years and as late as age 92 years. About 5% of cases begin

in patients younger than 21 years; the juvenile phenotype
The mental disorder assumes several subtle
forms long before the more obvious deterioration of cognitive functions
becomes evident. In approximately half the cases, slight and
often annoying alterations of character are the first to appear. Patients
begin to find fault with everything, to complain constantly,
and to nag other members of the family; they may be suspicious,
irritable, impulsive, eccentric, untidy, or excessively religious, or
they may exhibit a false sense of superiority. Poor self-control may
be reflected in outbursts of temper, fits of despondency, alcoholism,
or sexual promiscuity. Disturbances of mood, particularly depression,
are common (almost half of the patients in some series) and
may constitute the most prominent symptoms early in the disease.
Invariably, sooner or later, the intellect begins to fail. The patient
becomes less communicative and more socially withdrawn. These
emotional disturbances and changes in personality may reach such
proportions as to constitute a virtual psychosis (with persecutory
delusions or hallucinations).
Diminished work performance, inability to manage household
responsibilities, and disturbances of sleep may prompt medical
consultation. There is difficulty in maintaining attention, in concentration,
and in assimilating new material. Mental flexibility lessens.
There is loss of fine manual skills (see further on). The performance
parts of the Wechsler Adult Intelligence Scale show
greater loss than the verbal parts. Memory is relatively spared. This
gradual dilapidation of intellectual function has been characterized
as a subcortical dementia (page 372), i.e., elements of aphasia,
agnosia, and apraxia are observed only rarely and memory loss is
not profound. Often the process is so slow, particularly in cases of
late onset, that some degree of intellectual capacity seems to be
retained for many years

Gangguan mental
Pada kira-kira setengah dari kasus, gangguan karakter adalah yang pertama
muncul. Pasien
mulai mencari-cari kesalahan, mengeluh terus-menerus,
dan mengomel kepada anggota keluarganya, mudah curiga,
mudah marah, impulsif, eksentrik, tidak rapi, atau terlalu religius, atau mungkin
menunjukkan rasa superioritas palsu. Kontrol diri yang buruk
dicerminkan dengan adanya ledakan amarah, sedih berlebihan, alkoholisme,
atau promiskuitas seksual. Gangguan mood, terutama depresi,
terjadi pada hampir semua kasus dan
mungkin merupakan gejala yang paling menonjol pada awal penyakit.

The abnormality of movement is at first slight and most evident

in the hands and face; often the patient is merely considered
to be fidgety, restless, or nervous. Slowness of movement of the
fingers and hands, a reduced rate of finger tapping, and difficulty
in performing a sequence of hand movements are early motor signs.
Gradually these abnormalities become more pronounced until the
entire musculature is implicated with chorea. The frequency of
blinking is increased (the opposite of parkinsonism), and voluntary
protrusion of the tongue is constantly interrupted by unwanted darting
movements. In the advanced stage of the disease, the patient is
seldom still for more than a few seconds. The choreic movements
are slower than the brusque jerks and postural lapses of Sydenham
chorea, and they involve many more muscles. They tend to recur
in stereotyped patterns yet are not as stereotyped as tics. In more
advanced cases, they acquire an athetoid or dystonic quality. Muscle
tone is usually decreased until late in the illness, when there may also be some
degree of rigidity, tremor, and bradykinesia,
elements suggestive of Parkinson disease (the Westphal or rigid
variant, which is more common with a childhood onset). Tendon
reflexes are exaggerated in one-third of patients, but only a few
have Babinski signs. Voluntary movements are initiated and executed
more slowly than normal, but there is no weakness and no
ataxia, although speech, which becomes dysarthric and explosive
due to incoordination between tongue and diaphragm, may convey
the impression of a cerebellar disorder. There is poor control of the
tongue and diaphragm. In late-onset cases there may be an almost
constant rapid movement of the tongue and mouth, simulating the
tardive dyskinesia that follows the use of neuroleptic drugs. DennyBrown pointed out that when the Huntington patient is suspended,
the upper limbs assume a flexed posture and the legs an extended
one, a posture that he considered to be expressive of the striatal
syndrome. The disorder of movement that characterizes Huntington
chorea has been described more fully in Chap. 4. Oculomotor function
is subtly affected in most patients (Leigh et al; Lasker et al).
Particularly characteristic are impaired initiation and slowness of
both pursuit and volitional saccadic movements and an inability to
make a volitional saccade without movement of the head. Excessive
distractibility may be noticed during attempted ocular fixation.
The patient feels compelled to glance at extraneous stimuli even
when specifically instructed to ignore them. Upward gaze is often
impaired.
DennyBrown pointed out that when the Huntington patient is suspended,
the upper limbs assume a flexed posture and the legs an extended
one, a posture that he considered to be expressive of the striatal
syndrome. The disorder of movement that characterizes Huntington
chorea has been described more fully in Chap. 4. Oculomotor function
is subtly affected in most patients (Leigh et al; Lasker et al).
Particularly characteristic are impaired initiation and slowness of

both pursuit and volitional saccadic movements and an inability to

make a volitional saccade without movement of the head. Excessive
distractibility may be noticed during attempted ocular fixation.
The patient feels compelled to glance at extraneous stimuli even
when specifically instructed to ignore them. Upward gaze is often
The first signs of the disease may appear in childhood, before
puberty (even under the age of 4), and several series of such earlyonset
cases have been described (Farrer and Conneally; van Dijk
et al). Mental deterioration at this early age is more often accompanied
by cerebellar ataxia, behavior problems, seizures, bradykinesia,
rigidity, and dystonia than by chorea (Byers et al). However,
this rigid form of the disease (Westphal variant, as it is known)
also occurs occasionally in adults, as mentioned above. Functional
decline is much faster in children than it is in adults (Young et al).
At the gene locus in Huntington disease there are normally 11
to 34 (median 19) consecutive repetitions of the CAG triplet, each
of which codes for glutamine. Individuals with 35 to 39 triplets
may eventually manifest the disease, but it tends to be late in onset
and mild in degree or limited to the below-mentioned senile chorea,
and those with more than 42 almost invariably acquire the signs of
disease if they live long enough
Pathology and Pathogenesis Gross atrophy of the head of the
caudate nucleus and putamen bilaterally is the characteristic abnormality,
usually accompanied by a moderate degree of gyral atrophy
in the frontal and temporal regions. The caudatal atrophy
alters the configuration of the frontal horns of the lateral ventricles
in that the inferolateral borders do not show the usual bulge formed
by the head of the caudate nucleus. In addition, the ventricles are
diffusely enlarged (Fig. 39-4); in CT scans, the bicaudate-cranial
ratio is increased in the majority of patients, and this finding corroborates
the clinical diagnosis in the moderately advanced case.
Chorea
is a major feature of Huntington disease (hereditary or chronic
chorea), in which the movements tend more typically to be choreoathetotic.
Also, there is an inherited form of chorea of childhood
onset without dementia that has been referred to as benign hereditary
chorea. The gene mutation is on chromosome 14, different
from the expanded gene on chromosome 4 that characterizes Huntington
disease. There may be subtle additional ataxia of gait, as
noted by Breedveld and colleagues. Not infrequently, chorea has
its onset in late life without the other identifying features of Huntington
disease. It is then referred to as senile chorea, a term that is
hardly helpful in understanding the process. Its relation to Huntington
chorea is unsettled. It may be a delayed form of the disease,
and a few such patients we have seen have had atypical depressions
or mild psychosis; but others remain for a decade with only chorea.
Genetic testing settles the issue. A number of far less common
degenerative conditions are associated with chorea, among them
dentatorubropallidoluysian atrophy
The combination of athetosis and chorea of all four limbs is
a cardinal feature of Huntington disease and of a state known as
double athetosis, which begins in childhood. Athetosis appearing
in the first years of life is usually the result of a congenital or
postnatal condition such as hypoxia or rarely kernicterus.

The biochemical defects in Huntington chorea are only beginning

to be understood. Impaired glucose metabolism in the caudate
nucleus, preceding visible atrophy, has already been noted in some
studies. Since at least a partial explanation for L-dopainduced
involuntary movements is an excess of dopamine (in contrast to
Parkinson disease, in which there is a decrease in dopamine), it has
been postulated that the abnormal movements of Huntington chorea
represent a heightened sensitivity of striatal dopamine receptors.
There are disturbances in the metabolism of other putative neurotransmitters (norepinephrine,
glutamic acid decarboxylase,
choline acetyltransferase, GABA, acetylcholine, and somatostatin),
but the significance of these biochemical disturbances is unknown.
Viewed from the molecular perspective, the pathogenesis of
this disease is a direct but still poorly understood consequence of
the aforementioned expansion of the polyglutamine region of huntingtin
(the protein product of the Huntington gene). It has been
shown that the expansion predisposes the mutant huntingtin protein
to aggregate in the nuclei of neurons. Moreover, the protein accumulates
preferentially in cells of the striatum and parts of the cortex
affected in Huntington disease. Evidence, particularly that given
by Wetz (cited in the review by Bates), suggests that these aggregates
may be toxic to neurons, either directly or in their protofibrillary
form (a situation similar to that suggested for the toxicity
of synuclein in Parkinson disease). The situation is, however, likely
to be more complex, since the bulk of huntingtin deposition is
found in cortical neurons, whereas the neuronal loss is predominantly
striatal. One theory, based on experimental data, supports
the concept that the polyglutamine expansion renders certain cell
types unduly sensitive to glutamate-mediated excitotoxicity; another
notion is that it creates an insufficiency of trophic influences
directed to the caudate from the cortex; yet another theory relates
the polyglutamine expansion to the acetylation of histones, which
leads to cell death. This finding has led to trials of inhibitors of
histone deacetylases and other therapies that modify gene expression
in transgenic mouse models of Huntington disease. Other theories
implicate mitochondrial dysfunction. As importantly, since
polyglutamine expansions are implicated in several neurodegenerative
diseases (reviewed below), treatments that block their effect
on cellular function may be broadly effective in several degenerative
diseases.

At postmortem examination, the brain is shrunken and atrophic; the caudate nucleus is
the most affected structure ( Fig. 108.1). Histologically, the cerebral cortex
shows loss of neurons, especially in layer 3. The caudate nucleus and putamen are
severely involved, with loss of neurons, particularly the medium-sized spiny
neurons, and their GABAergic striatal efferents. Those lost earliest are the efferents
(containing GABA and enkephalin) projecting to the lateral globus pallidus, which
is thought to account for chorea. With progression of the disease, the striatal efferents
projecting to the medial pallidum are lost; their loss is thought to account for the
later developing rigidity and dystonia. Dementia is attributed to changes in both the
cerebral cortex and deep nuclei (i.e., subcortical dementia).
Less marked changes occur in other structures, such as the thalamus and brainstem. A
reactive gliosis is apparent in all affected areas. In advanced cases, the

striatum may be completely devoid of cells and replaced by a gliotic process, at which
time choreic movements abate and are replaced by dystonia and an
akinetic-rigid state. Progressive striatal atrophy is the basis for staging the severity of
the disease. The age at onset is inversely correlated to the severity of striatal
degeneration

BIOCHEMISTRY
There is loss of striatal and nigral GABA and its synthesizing enzyme glutamic acid
decarboxylase, whereas the cholinergic and somatostatin striatal interneurons are
relatively spared. The receptors for dopamine and acetylcholine are decreased in the
striatum. N-methyl-D-aspartate receptors are reduced severely in the striatum
and cerebral cortex. These defects can be duplicated experimentally in animals by
striatal injection of excitotoxins, such as kainic acid, and an excitotoxic hypothesis
has been proposed as the pathogenesis of the disease. The neurochemical changes
have not yet been translated into effective therapy because trials with GABA and
acetylcholine agonists have not been beneficial. A defect in mitochondrial energy
metabolism is considered to be present in HD. This in turn can lead to oxidative
stress, which has been measured in the vulnerable regions of brain of caudate and
putamen.

GENETICS
A major discovery was the identification and characterization of the HD gene near the
tip of the short arm of chromosome 4 (4p16.3). Studies on HD families of
different ethnic origins and countries found that despite the marked variability in
phenotypic expression, there does not seem to be any genetic heterogeneity. The
abnormal gene contains extra copies of trinucleotide repeats of CAG (cytosine-adenineguanine). Normal individuals have 11 to 34 repeats; those with HD have 37 to
86 repeats. This trinucleotide repeat is unstable in gametes; change in the number of
repeats is transmitted to the next generation, sometimes with a decrease in
number but more often with an increase. Spontaneous mutations occur from expansion
of repeats from parents who have repeat lengths of 34 to 38 units, which span
the gap between the normal and HD distributions, the so-called intermediate alleles.
Spontaneous mutations in HD previously were considered rare, but this concept
has changed as more sporadic (simplex) cases are evaluated by DNA analysis
Affected mothers tend to transmit the abnormal gene to offspring in approximately the
same number of trinucleotide repeats, plus or minus about three repeats.
Affected fathers often transmit a greater increase in the length of trinucleotide repeats to
offspring, thus resulting in many more juvenile cases of HD when an
individual inherits the gene from the father. The trinucleotide repeat is stable over time
in lymphocyte DNA but is unstable in sperm DNA. This characteristic may
account for the occasional marked increase in the number of trinucleotide repeats in
offspring of affected fathers, leading to a 10:1 ratio of juvenile HD when the
affected parent is the father. This is because an inverse correlation exists between the
number of trinucleotide repeats and the age at onset of symptoms. Knowing the

number of repeats in an at-risk offspring can fairly well predict the age at onset of
symptoms. The rate of pathologic degeneration also correlates with the number of
repeats
HD is a true autosomal dominant disease in that homozygotes do not differ clinically
from heterozygotes. Overexpression of the normal protein could explain why an
individual with a double dose of the gene (i.e., the HD gene was transmitted to the
offspring by each affected parent) does not differ phenotypically from
heterozygotes with only one abnormal gene.
The protein product of the normal gene is called huntingtin. The trinu- cleotide CAG
codes for glutamine, and the increase in polyglutamine appears to prevent the
normal turnover of the protein, resulting in aggregation of the protein with accumulation
in the cytoplasm and the nucleus. Other genetic disorders with expanded
trinucleotide repeats of CAG include the Kennedy syndrome (X-linked spinal and bulbar
muscular atrophy), myotonic dystrophy, many of the spinocerebellar
atrophies, and dentatorubral-pallidoluysian atrophy. A similar pathogenesis for these
disorders has been proposed.
One-third of individuals with HD share a common haplotype, thus implying a common
ancestor. The other two-thirds appear to derive HD through a spontaneous
mutation in the distant or near past. For the time being, without directly testing for the
gene, lack of a positive family history raises questions of paternity or
misdiagnosis. A diagnosis of HD can be established by testing for the gene in patients
with adult-onset chorea without a clear positive family history. Preclinical and
prenatal testing can also be carried out, but appropriate genetic counseling is required.
Diagnosis is still uncertain in those with a borderline number of trinucleotide
repeats (i.e., between 34 and 37); for them, the diagnosis is inconclusive.
Disclosure of positive results of the HD gene in asymptomatic individuals often leads to
transient symptoms of depression, but suicidal ideation has been rare.
Because of the ethical and legal implications that arise with DNA identification of a gene
carrier, predictive testing must be performed by a team of clinicians and
geneticists who not only are knowledgeable about the disease and the genetic
techniques but also are sensitive to the psychosocial issues and counseling that
precede and follow testing.
Symptoms usually appear between 35 and 40 years of age. The range of age at onset
is broad, however, with cases recorded as early as age 5 and as late as age
70. The three characteristic manifestations of the disease are movement disorder,
personality disorder, and mental deterioration. The three may occur together at
onset or one may precede the others by a period of years. In general, the onset of
symptoms is insidious, beginning with clumsiness, dropping of objects, fidgetiness,
irritability, slovenliness, and neglect of duties, progressing to frank choreic movements
and dementia. Overt psychotic episodes, depression, and irresponsible
behavior may occur. The disease tends to run its course over a period of 15 years, more
rapidly in those with an earlier age at onset.

OTHER NEUROLOGIC MANIFESTATIONS

Cranial nerves remain intact except for rapid eye movements, which are impaired in a
large percentage of patients. Patients often blink during the execution of a
saccadic eye movement. Sensation is usually unaffected. Tendon reflexes are usually
normal but may be hyperactive; the plantar responses may be abnormal.
Muscle tone is hypotonic in most patients except for those with the so-called akineticrigid variety ( Westphal variant). With childhood onset (approximately 10% of
cases), the akinetic-rigid state usually occurs instead of chorea and in conjunction with
mental abnormalities and convulsive seizures. This form of the disease is
rapidly progressive with a fatal outcome in less than 10 years. The observation that 90%
of all patients with childhood onset inherit the disease from their father stems
from the greater likelihood of a large increase in the number of CAG repeats in sperm
cells. In the terminal stages of the more classic form of HD, muscular rigidity
and dystonia tend to replace chorea, and seizures are not unusual
The most striking and diagnostic feature of the disease is the appearance of involuntary
movements that seem purposeless and abrupt but less rapid and
lightning-like than those seen in myoclonus. The somatic muscles are affected in a
random manner, and choreic movements flow from one part of the body to another.
Proximal, distal, and axial muscles are involved. In the early stages and in the less
severe form, there is slight grimacing of the face, intermittent movements of the
eyebrows and forehead, shrugging of the shoulders, and jerking movements of the
limbs. Pseudopurposeful movements ( parakinesia) are common in attempts to
mask the involuntary jerking. As the disease progresses, walking is associated with
more intense arm and leg movements, which cause a dancing, prancing, stuttering
type of gait, an abnormality that is particularly characteristic of HD. Motor impersistence
or inhibitory pauses during voluntary contraction probably account for
milkmaid grips, dropping of objects, and inability to keep the tongue steadily protruded.
Ocular movements become impaired with reduced saccades and loss of
smooth pursuit. The choreic movements are increased by emotional stimuli, disappear
during sleep, and become superimposed on voluntary movements to the point
that they make volitional activity difficult. With increased severity, the routine daily
activities of living become difficult, as do speech and swallowing. Terminally,
choreic movements may disappear and be replaced by muscular rigidity and dystonia.

LABORATORY DATA
Routine studies of blood, urine, and cerebrospinal fluid show no abnormalities. Diffuse
abnormalities are seen in the electroencephalogram. Radiographs of the skull
are normal, but computed tomography and magnetic resonance imaging show enlarged
ventricles with characteristic butterfly appearance of the lateral ventricles, a
result of degeneration of the caudate nucleus ( Fig. 108.2). Patients with the akineticrigid form of HD are likely to show striatal hyperintensity on T2-weighted
magnetic resonance imaging. Positron emission tomography using fluorodeoxyglucose
has shown hypometabolism in the caudate and the putamen in affected
patients. Abnormalities in striatal metabolism may precede caudate atrophy, but positron
emission tomography is not sufficiently sensitive to detect the disease in

presymptomatic persons

DIAGNOSIS AND DIFFERENTIAL DIAGNOSIS

HD can be diagnosed without difficulty in an adult with the clinical triad of chorea,
dementia, and personality disorder and family history of the disease. Difficulties
arise when the family history is lacking. The patient may be ignorant of the family history
or may deny that history.
Other conditions in which choreic movements are a major manifestation can often be
excluded on clinical grounds. The most common other adult-onset choreic
disorder is neuroacanthocytosis. It is manifested by mild chorea, tics, tongue biting,
peripheral neuropathy, feeding dystonia, increased serum creatine kinase, and
red cell acanthocytes. It is also common for these patients to have had a few seizures.
Dentatorubral-pallidoluysian atrophy can also mimic HD. Besides chorea, it can
present with myoclonus, ataxia, seizures, and dementia. Differentiation is by gene
testing. Sydenham chorea has an earlier age at onset, is self-limited, and lacks the
characteristic mental disturbances. Chorea and mental disturbances occurring as
manifestations of lupus erythematosus are usually more acute in onset, the chorea
is more localized and often periodic, and there are characteristic serologic and clinical
abnormalities. Involuntary movements occurring in psychiatric patients on
long-term treatment with neuroleptic agents (the so-called tardive dyskinesia)
occasionally pose a diagnostic problem. Such movements, however, are usually
repetitive (stereotypy), in contrast to the nonrepetitive and random nature of chorea.
Oral-lingual-buccal dyskinesia is the most common feature of tardive dyskinesia.
Gait is usually normal in tardive dyskinesia and is abnormal in HD (see Table 116.1 for
more distinguishing differences). The presenile dementias (Alzheimer and Pick
diseases) are similar in the mental disorder, but language is more often involved;
aphasic abnormalities are not seen early in HD. Myoclonus, rather than chorea,
occasionally occurs. The peculiarities of the childhood disorder with rigidity, convulsive
seizures, and mental retardation require differentiation from other heritable
disorders, such as the leukodystrophies and gangliosidosis. Tics, particularly those of
the Gilles de la Tourette syndrome, usually pose little problem in view of the
complex nature of the involuntary movements, the characteristic vocalizations, and their
suppressibility. Hereditary nonprogressive chorea begins in childhood, does
not worsen, and is not associated with dementia or with personality disorder.
There is at present no known means of altering the disease process or the fatal
outcome. Attempts to replace the deficiency in GABA by using GABA-mimetic agents
or inhibitors of GABA metabolism have been unsuccessful. Symptomatic treatment of
depression and psychosis can be achieved with antidepressants and typical or
atypical (i.e., clozapine and quetiapine) antipsychotic agents. The choreic movements
can be controlled by the use of neuroleptic agents, including dopamine receptor
blockers, such as haloperidol and perphenazine, and presynaptic dopamine depleters,
such as reserpine and tetrabenazine. Using these drugs combined with
supervision of the patient's daily activities allows management at home during the early
stages of the disorder. As the disease advances, however, confinement to a

psychiatric facility is often necessary.

Depression is one of the most common
concerns for individuals and families with HD, occurring
in up to 3>% of patients. It has been suggested that
depression can precede the onset of neurological symptoms
in HD by 2 to 20 years, although large-scale empirical
research has been minimal. Recent data from the HSG
indicate that depression is most common immediately
before diagnosis, when neurological soft signs and other
subtle abnormalities become evident. Following a definite
diagnosis of HD, however, depression is most prevalent in
the middle stages of the disease (i.e., Shoulson-Fahn stages
2 and 3) and may diminish in the later stages. Positron
emission tomography (PET) studies indicate that patients

HD is rare but exists worldwide, with cases in Europe, North America, South America, and
Australia, mostly in Caucasian populations. It has the highest prevalence rates in the region of
Lake Maracaibo in Venezuela and the Moray Firth region of Scotland, and it is relatively rare in
African blacks and almost absent in Asia (Harper, 2002; Hayden, 1980). Throughout Europe, the
prevalence ranges from 5 to 10 per 100,000 (Harper, 2002). Genetic heterogeneity was suspected
in a very small proportion of clinical HD cases, 5% to 10%. The HD gene involved in the disease
is responsible for more than 90% of HD in Caucasian populations, and another gene (JPH3 or
HDL2) is responsible for 40% of clinical HD in South Africa (Table 18.1) In Japan HD is very
rare, with 0.11 and 0.45 per 100,000. It is believed that the mutation for HD arose independently
in multiple locations and that its uneven distribution is due to founder effects (Kremer, 1994;
Squitieri, 1994; Almqvist, 1995; Watkins, 1995).
Genes and Their Mutations Involved in Huntington's Disease

Genetic Counseling
The HD gene is the major gene associated with Huntington's disease. A translated trinucleotide
CAG repeat expansion is the only mutation observed in the HD gene. There are other more rare
genes associated with clinical HD, with a very similar phenotype, especially in the case of HDL2
(Table 18.1).
Prior genetic counseling is needed before DNA analysis confirms the diagnosis. It is important to
inform patients and their relatives of the potential implications before blood sampling for DNA
testing.
The Huntington's Disease Gene on Chromosome 4P
HD was the first inherited disorder whose defect was mapped to a chromosomal region using
linkage studies with DNA markers. The successful positional-cloning strategy finally allowed the
identification of the IT15 or HD gene located on chromosome 4p16.3 and its mutation
(Huntington's Disease Collaborative Research Group, 1993). The HD gene contains a CAG
trinucleotide repeat
in its first exon, which is expanded above the threshold of 36 in a heterozygous state in patients
(Fig. 18.1). The mutation is called unstable because the expansion may vary in size upon
transmission. Although contractions or stable transmission may occur, in most instances the size

of the expansion further increases during transmission, resulting in a mean increase of the
expansion size in successive generations. There are, however, differences according to the sex of
the transmitting parent, paternal transmissions being associated with the greatest instability, and
tendency to increase in size.
The diagnosis of sporadic HD is a difficult counseling issue because the sudden
discovery of a dominant disease frightens. However, the absence of a positive
family history with no known cases in the elder generations is due more often to
censured family histories, such as early death, adoption, or false paternity (Durr,
1995). The discovery of the mutation in apparently isolated cases has important
consequences for all family members since they were not aware of an inherited
disorder until the genetic testing. This has to be taken into account and explained to
the sporadic HD patient and to relatives before blood sampling and testing

Differential diagnosis has to be considered either in isolated cases of HD-like phenotypes or in

familial ones. The most common cause of isolated chorea is tardive dyskinesias due to the use of
neuroleptics but also due to L- dopainduced dyskinesias in patients with Parkinson's disease,
noradrenergic drugs such as cocaine, or oral contraceptives. Other causes includes
thyreotoxicosis, cerebrovascular disease, lupus erythematosus, and polycythemia rubra vera.
HIV infection is also a cause of chorea, and AIDS-related disease should be considered in young
patients presenting without a family history of movement disorders (Piccolo, 2003). None of
those resemble HD closely enough because of the absence of behavior and cognitive changes.
The only exception is Sydenham's chorea, which is associated with prominent psychiatric
changes, occurs in children, and is known as an autoimmune disorder associated with
streptococcal infections. Several autosomal recessive diseases, such as cerebellar ataxia with
ocular apraxia type 1, also can exhibit chorea as an associated feature (Le Ber, 2004), Wilson
disease, or choreoacanthocytosis. The latter is characterized by chorea, parkinsonism, dystonia,
distal myopathy, and acanthocytes of red blood cells. ChAc is the associated responsible gene
(Rubio, 1997; Rampoldi, 2001).
The following diseases can be considered as a differential diagnosis in familial HD-like
phenotypes.
HDL1 with Epilepsy
The HDL1 locus was identified using linkage analysis in a single family with an HD-like
phenotype, including 4 out of 6 patients with chorea and 3 with epileptic features (Xiang, 1998).
Consecutively, a 192bp insertion in the octapeptide-coding region in the PRPN gene encoding
the Prion protein was found (Moore, 2001).
HDL2 Gene, Junctophilin 3
HD was thought to be monogenetic par excellence with one responsible gene and one single
mutation in the HD gene. Nevertheless, the involvement of HDL2 or Junctophilin 3 located on
chromosome 16q proved genetic heterogeneity (Table 18.1). The responsible mutation is an
expanded CTG/CAG repeat. The pathological repeat ranges from 44 to 57 CTG/CAG repeats.
Several studies have showed that the HDL2 gene is rarely involved (Margolis, 2001; Margolis,
2004; Stevanin, 2002). The frequencies reported are 1% (6/538) in North America (Margolis,
2004), and 0% (0/44) in Japan (Margolis, 2004), 3% (2/60) in France (Stevanin, 2002), but 35%
(7/20) in South Africa (Krause, 2002). Interestingly, this indicates that HDL2 might be frequent
in populations from black African ancestry.

Dentatorubro-Pallidoluysian Atrophy
Chorea is part of the clinical spectrum of dentatorubro-pallidoluysian atrophy (DRPLA)
(Ikeuchi, 1995). DRPLA is included in the classification of autosomal dominant cerebellar
ataxias (SCA) because cerebellar ataxia is often the prominent sign. It is more frequent among
Japanese patients (Le Ber, 2003; Ikeuchi, 1995). As in HD and other SCA subtypes (SCA1, 2, 3,
6, 7, 17), the causal mutation is an expanded CAG repeat in the coding region. The phenotype is
an association of cerebellar signs, movement disorders, and cognitive impairments. In cases with
predominant dystonic and choreic features, the phenotype may be similar to HD.
SCA 17 Spinocerebellar Ataxia 17
Dementia and movement disorders, including chorea, are observed in patients with
spinocerebellar ataxia 17 (SCA17), due to a CAG repeat expansions in the Tata-binding protein
gene (Fujigasaki, 2001). The occurrence of HD phenotypes due to TBP/SCA17 expansions
highlights the clinical overlap between HD and some forms of spinocerebellar ataxias (Stevanin,
2003).
Care Proposal in Huntington's Disease According to Disease Stage
Anjuran perawatan pada penyakit Huntington menurut perjalanan
penyakit

Figure 4: Life cycle in Huntingtons disease

This figure depicts the sequential evolution of events and ultimately recurrent nature of
Huntingtons disease from the perspective of a child born to an aff ected parent. The
family events timeline
shows events that might occur in diff erent sequences for diff erent individuals;
irrespective of timing, such events can have clinically signifi cant implications.