Huntington disease (HD; MIM 143100) is a progressive hereditary disorder that usually appears in adult life. It is characterized by a movement disorder (usuallychorea), dementia, and personality disorder. It was first recognized clinically by Waters in 1842 and became accepted as a clinical entity with the comprehensivedescription 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

EarlySymptoms of Huntington'sMiddlediseaseLateClumsiness UnsteadinessChorea Dropping thingsIrritability Gait disorderSadness Sleep disorderDepression < ognim cdysfunctionDecreased motivation Decreased memorySexual dysfunctionAwalPertengahanLanjut

kikukKoreaIritabilitaskesedihanDepresiKurang motivasiDisfungsi seksualTidak tenangSering menjatuhkan barangGait disorderGangguan tidurPenurunan kemampuan memori

Penurunan berat badanGangguan berbicaraInkontinensia urineInkontinensia alvi

Prevalence figures for HD vary depending on the geographicalarea, but the best estimate is 10 per 100,000. Thedisorder is reported in all races, although it is much morecommon in Scotland and Venezuela and less common inHnland, China, Japan, and black South Africans. HDusually begins between the ages of 30 and 55 years,although it has been reported to begin as early as age 2years and as late as age 92 years. About 5% of cases beginin patients younger than 21 years; the juvenile phenotypeThe mental disorder assumes several subtleforms long before the more obvious deterioration of cognitive functionsbecomes evident. In approximately half the cases, slight andoften annoying alterations of character are the first to appear. Patientsbegin 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, orthey may exhibit a false sense of superiority. Poor self-control maybe 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) andmay constitute the most prominent symptoms early in the disease.Invariably, sooner or later, the intellect begins to fail. The patientbecomes less communicative and more socially withdrawn. Theseemotional disturbances and changes in personality may reach suchproportions as to constitute a virtual psychosis (with persecutorydelusions or hallucinations).Diminished work performance, inability to manage householdresponsibilities, and disturbances of sleep may prompt medicalconsultation. 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 performanceparts of the Wechsler Adult Intelligence Scale showgreater loss than the verbal parts. Memory is relatively spared. Thisgradual dilapidation of intellectual function has been characterizedas a subcortical dementia (page 372), i.e., elements of aphasia,agnosia, and apraxia are observed only rarely and memory loss isnot profound. Often the process is so slow, particularly in cases oflate onset, that some degree of intellectual capacity seems to beretained for many yearsGangguan mental Pada kira-kira setengah dari kasus, gangguan karakter adalah yang pertama muncul. Pasienmulai 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 burukdicerminkan dengan adanya ledakan amarah, sedih berlebihan, alkoholisme,atau promiskuitas seksual. Gangguan mood, terutama depresi,terjadi pada hampir semua kasus danmungkin merupakan gejala yang paling menonjol pada awal penyakit.

The abnormality of movement is at first slight and most evidentin the hands and face; often the patient is merely consideredto be fidgety, restless, or nervous. Slowness of movement of thefingers and hands, a reduced rate of finger tapping, and difficultyin performing a sequence of hand movements are early motor signs.Gradually these abnormalities become more pronounced until theentire musculature is implicated with chorea. The frequency ofblinking is increased (the opposite of parkinsonism), and voluntaryprotrusion of the tongue is constantly interrupted by unwanted dartingmovements. In the advanced stage of the disease, the patient isseldom still for more than a few seconds. The choreic movementsare slower than the brusque jerks and postural lapses of Sydenhamchorea, and they involve many more muscles. They tend to recurin stereotyped patterns yet are not as stereotyped as tics. In moreadvanced cases, they acquire an athetoid or dystonic quality. Muscletone 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 rigidvariant, which is more common with a childhood onset). Tendonreflexes are exaggerated in one-third of patients, but only a fewhave Babinski signs. Voluntary movements are initiated and executedmore slowly than normal, but there is no weakness and noataxia, although speech, which becomes dysarthric and explosivedue to incoordination between tongue and diaphragm, may conveythe impression of a cerebellar disorder. There is poor control of thetongue and diaphragm. In late-onset cases there may be an almostconstant rapid movement of the tongue and mouth, simulating thetardive dyskinesia that follows the use of neuroleptic drugs. Denny-Brown pointed out that when the Huntington patient is suspended,the upper limbs assume a flexed posture and the legs an extendedone, a posture that he considered to be expressive of the striatalsyndrome. The disorder of movement that characterizes Huntingtonchorea has been described more fully in Chap. 4. Oculomotor functionis subtly affected in most patients (Leigh et al; Lasker et al).Particularly characteristic are impaired initiation and slowness ofboth pursuit and volitional saccadic movements and an inability tomake a volitional saccade without movement of the head. Excessivedistractibility may be noticed during attempted ocular fixation.The patient feels compelled to glance at extraneous stimuli evenwhen specifically instructed to ignore them. Upward gaze is oftenimpaired.

Denny-Brown pointed out that when the Huntington patient is suspended,the upper limbs assume a flexed posture and the legs an extendedone, a posture that he considered to be expressive of the striatalsyndrome. The disorder of movement that characterizes Huntingtonchorea has been described more fully in Chap. 4. Oculomotor functionis subtly affected in most patients (Leigh et al; Lasker et al).Particularly characteristic are impaired initiation and slowness ofboth pursuit and volitional saccadic movements and an inability tomake a volitional saccade without movement of the head. Excessivedistractibility may be noticed during attempted ocular fixation.The patient feels compelled to glance at extraneous stimuli evenwhen specifically instructed to ignore them. Upward gaze is often

The first signs of the disease may appear in childhood, beforepuberty (even under the age of 4), and several series of such earlyonsetcases have been described (Farrer and Conneally; van Dijket al). Mental deterioration at this early age is more often accompaniedby 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. Functionaldecline is much faster in children than it is in adults (Young et al).

At the gene locus in Huntington disease there are normally 11to 34 (median 19) consecutive repetitions of the CAG triplet, eachof which codes for glutamine. Individuals with 35 to 39 tripletsmay eventually manifest the disease, but it tends to be late in onsetand mild in degree or limited to the below-mentioned senile chorea,and those with more than 42 almost invariably acquire the signs ofdisease if they live long enough

Pathology and Pathogenesis Gross atrophy of the head of thecaudate nucleus and putamen bilaterally is the characteristic abnormality,usually accompanied by a moderate degree of gyral atrophyin the frontal and temporal regions. The caudatal atrophyalters the configuration of the frontal horns of the lateral ventriclesin that the inferolateral borders do not show the usual bulge formedby the head of the caudate nucleus. In addition, the ventricles arediffusely enlarged (Fig. 39-4); in CT scans, the bicaudate-cranialratio is increased in the majority of patients, and this finding corroboratesthe clinical diagnosis in the moderately advanced case.

Choreais a major feature of Huntington disease (hereditary or chronicchorea), in which the movements tend more typically to be choreoathetotic.Also, there is an inherited form of chorea of childhoodonset without dementia that has been referred to as benign hereditarychorea. The gene mutation is on chromosome 14, differentfrom the expanded gene on chromosome 4 that characterizes Huntingtondisease. There may be subtle additional ataxia of gait, asnoted by Breedveld and colleagues. Not infrequently, chorea hasits onset in late life without the other identifying features of Huntingtondisease. It is then referred to as senile chorea, a term that ishardly helpful in understanding the process. Its relation to Huntingtonchorea is unsettled. It may be a delayed form of the disease,and a few such patients we have seen have had atypical depressionsor mild psychosis; but others remain for a decade with only chorea.Genetic testing settles the issue. A number of far less commondegenerative conditions are associated with chorea, among themdentatorubropallidoluysian atrophy

The combination of athetosis and chorea of all four limbs isa cardinal feature of Huntington disease and of a state known asdouble athetosis, which begins in childhood. Athetosis appearingin the first years of life is usually the result of a congenital orpostnatal condition such as hypoxia or rarely kernicterus.

The biochemical defects in Huntington chorea are only beginningto be understood. Impaired glucose metabolism in the caudatenucleus, preceding visible atrophy, has already been noted in somestudies. Since at least a partial explanation for L-dopainducedinvoluntary movements is an excess of dopamine (in contrast toParkinson disease, in which there is a decrease in dopamine), it hasbeen postulated that the abnormal movements of Huntington chorearepresent 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 ofthis disease is a direct but still poorly understood consequence ofthe aforementioned expansion of the polyglutamine region of huntingtin(the protein product of the Huntington gene). It has beenshown that the expansion predisposes the mutant huntingtin proteinto aggregate in the nuclei of neurons. Moreover, the protein accumulatespreferentially in cells of the striatum and parts of the cortexaffected in Huntington disease. Evidence, particularly that givenby Wetz (cited in the review by Bates), suggests that these aggregatesmay be toxic to neurons, either directly or in their protofibrillaryform (a situation similar to that suggested for the toxicityof synuclein in Parkinson disease). The situation is, however, likelyto be more complex, since the bulk of huntingtin deposition isfound in cortical neurons, whereas the neuronal loss is predominantlystriatal. One theory, based on experimental data, supportsthe concept that the polyglutamine expansion renders certain celltypes unduly sensitive to glutamate-mediated excitotoxicity; anothernotion is that it creates an insufficiency of trophic influencesdirected to the caudate from the cortex; yet another theory relatesthe polyglutamine expansion to the acetylation of histones, whichleads to cell death. This finding has led to trials of inhibitors ofhistone deacetylases and other therapies that modify gene expressionin transgenic mouse models of Huntington disease. Other theoriesimplicate mitochondrial dysfunction. As importantly, sincepolyglutamine expansions are implicated in several neurodegenerativediseases (reviewed below), treatments that block their effecton cellular function may be broadly effective in several degenerativediseases.

At postmortem examination, the brain is shrunken and atrophic; the caudate nucleus is the most affected structure ( Fig. 108.1). Histologically, the cerebral cortexshows loss of neurons, especially in layer 3. The caudate nucleus and putamen are severely involved, with loss of neurons, particularly the medium-sized spinyneurons, and their GABAergic striatal efferents. Those lost earliest are the efferents (containing GABA and enkephalin) projecting to the lateral globus pallidus, whichis 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 thelater 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, thestriatum may be completely devoid of cells and replaced by a gliotic process, at which time choreic movements abate and are replaced by dystonia and anakinetic-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 striataldegeneration

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

GENETICSA 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 ofdifferent ethnic origins and countries found that despite the marked variability in phenotypic expression, there does not seem to be any genetic heterogeneity. Theabnormal gene contains extra copies of trinucleotide repeats of CAG (cytosine-adenine-guanine). Normal individuals have 11 to 34 repeats; those with HD have 37 to86 repeats. This trinucleotide repeat is unstable in gametes; change in the number of repeats is transmitted to the next generation, sometimes with a decrease innumber 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 spanthe gap between the normal and HD distributions, the so-called intermediate alleles. Spontaneous mutations in HD previously were considered rare, but this concepthas 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 anindividual inherits the gene from the father. The trinucleotide repeat is stable over time in lymphocyte DNA but is unstable in sperm DNA. This characteristic mayaccount 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 theaffected 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 thenumber 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 ofrepeats

HD is a true autosomal dominant disease in that homozygotes do not differ clinically from heterozygotes. Overexpression of the normal protein could explain why anindividual 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 fromheterozygotes 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 thenormal turnover of the protein, resulting in aggregation of the protein with accumulation in the cytoplasm and the nucleus. Other genetic disorders with expandedtrinucleotide repeats of CAG include the Kennedy syndrome (X-linked spinal and bulbar muscular atrophy), myotonic dystrophy, many of the spinocerebellaratrophies, 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 spontaneousmutation 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 ormisdiagnosis. 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 andprenatal testing can also be carried out, but appropriate genetic counseling is required. Diagnosis is still uncertain in those with a borderline number of trinucleotiderepeats (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 andgeneticists who not only are knowledgeable about the disease and the genetic techniques but also are sensitive to the psychosocial issues and counseling thatprecede 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 age70. The three characteristic manifestations of the disease are movement disorder, personality disorder, and mental deterioration. The three may occur together atonset 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 irresponsiblebehavior 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 MANIFESTATIONSCranial nerves remain intact except for rapid eye movements, which are impaired in a large percentage of patients. Patients often blink during the execution of asaccadic 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 akinetic-rigid variety ( Westphal variant). With childhood onset (approximately 10% ofcases), the akinetic-rigid state usually occurs instead of chorea and in conjunction with mental abnormalities and convulsive seizures. This form of the disease israpidly 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 stemsfrom 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 rigidityand 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 andlightning-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 theeyebrows and forehead, shrugging of the shoulders, and jerking movements of the limbs. Pseudopurposeful movements ( parakinesia) are common in attempts tomask the involuntary jerking. As the disease progresses, walking is associated with more intense arm and leg movements, which cause a dancing, prancing, stutteringtype of gait, an abnormality that is particularly characteristic of HD. Motor impersistence or inhibitory pauses during voluntary contraction probably account formilkmaid grips, dropping of objects, and inability to keep the tongue steadily protruded. Ocular movements become impaired with reduced saccades and loss ofsmooth pursuit. The choreic movements are increased by emotional stimuli, disappear during sleep, and become superimposed on voluntary movements to the pointthat 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 DATARoutine studies of blood, urine, and cerebrospinal fluid show no abnormalities. Diffuse abnormalities are seen in the electroencephalogram. Radiographs of the skullare normal, but computed tomography and magnetic resonance imaging show enlarged ventricles with characteristic butterfly appearance of the lateral ventricles, aresult of degeneration of the caudate nucleus ( Fig. 108.2). Patients with the akinetic-rigid form of HD are likely to show striatal hyperintensity on T2-weightedmagnetic resonance imaging. Positron emission tomography using fluorodeoxyglucose has shown hypometabolism in the caudate and the putamen in affectedpatients. Abnormalities in striatal metabolism may precede caudate atrophy, but positron emission tomography is not sufficiently sensitive to detect the disease inpresymptomatic persons

DIAGNOSIS AND DIFFERENTIAL DIAGNOSISHD can be diagnosed without difficulty in an adult with the clinical triad of chorea, dementia, and personality disorder and family history of the disease. Difficultiesarise 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 choreicdisorder is neuroacanthocytosis. It is manifested by mild chorea, tics, tongue biting, peripheral neuropathy, feeding dystonia, increased serum creatine kinase, andred 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 canpresent with myoclonus, ataxia, seizures, and dementia. Differentiation is by gene testing. Sydenham chorea has an earlier age at onset, is self-limited, and lacks thecharacteristic mental disturbances. Chorea and mental disturbances occurring as manifestations of lupus erythematosus are usually more acute in onset, the choreais more localized and often periodic, and there are characteristic serologic and clinical abnormalities. Involuntary movements occurring in psychiatric patients onlong-term treatment with neuroleptic agents (the so-called tardive dyskinesia) occasionally pose a diagnostic problem. Such movements, however, are usuallyrepetitive (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 Pickdiseases) 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 heritabledisorders, such as the leukodystrophies and gangliosidosis. Tics, particularly those of the Gilles de la Tourette syndrome, usually pose little problem in view of thecomplex nature of the involuntary movements, the characteristic vocalizations, and their suppressibility. Hereditary nonprogressive chorea begins in childhood, doesnot 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 agentsor inhibitors of GABA metabolism have been unsuccessful. Symptomatic treatment of depression and psychosis can be achieved with antidepressants and typical oratypical (i.e., clozapine and quetiapine) antipsychotic agents. The choreic movements can be controlled by the use of neuroleptic agents, including dopamine receptorblockers, such as haloperidol and perphenazine, and presynaptic dopamine depleters, such as reserpine and tetrabenazine. Using these drugs combined withsupervision of the patient's daily activities allows management at home during the early stages of the disorder. As the disease advances, however, confinement to apsychiatric facility is often necessary.

Depression is one of the most commonconcerns for individuals and families with HD, occurringin up to 3>% of patients. It has been suggested thatdepression can precede the onset of neurological symptomsin HD by 2 to 20 years, although large-scale empiricalresearch has been minimal. Recent data from the HSGindicate that depression is most common immediatelybefore diagnosis, when neurological soft signs and othersubtle abnormalities become evident. Following a definitediagnosis of HD, however, depression is most prevalent inthe middle stages of the disease (i.e., Shoulson-Fahn stages2 and 3) and may diminish in the later stages. Positronemission 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 CounselingThe 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 4PHD 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 EpilepsyThe 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 3HD 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 AtrophyChorea 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 17Dementia 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 StageAnjuran perawatan pada penyakit Huntington menurut perjalanan penyakit

Figure 4: Life cycle in Huntingtons diseaseThis 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 timelineshows events that might occur in diff erent sequences for diff erent individuals; irrespective of timing, such events can have clinically signifi cant implications.