HUNTINGTON'S DISEASE

0193-953X/97 $0.00

NEUROPSYCHIATRY OF THE BASAL GANGLIA

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HUNTINGTON’S DISEASE MGnica Santoro Haddad, MD, MSc,

and Jeffrey L. Cummings, MD

Huntington’s disease (HD) is a heredodegenerative disease of the central nervous system (CNS) characterized by progressive motor and mental alterations. The unique neuropsychiatric characteristics of HD have fascinated researchers in the fields of neurology, psychiatry, genetics, and basic neuroscience since the beginning of this century. A great deal of knowledge about HD has accumulated worldwide, especially since the 1970s, culminating in the discovery of its genetic defect at the start of the 1990s. Current efforts are centered on the search for treatment options to change the prognosis for affected individuals and families. The key historical, epidemiologic, clinical, diagnostic, genetic, pathophysiologic, and therapeutic aspects are reviewed. HISTORICAL ASPECTS

HD was first definitively described as a distinct entity in 1872,68although genealogic studies show that the disease was present many years before this date.lz8In previous centuries, there had been little or no differentiation between HD and other conditions in which chorea is present. Despite limited attempts at nosologic classification, there was still a large degree of confusion in the 19th century concerning the cause and nomenclature of disorders with abnormal movements. This changed with the introduction of the concept that some forms of chorea might be hereditary. On April 13, 1872, George Huntington published his text ”On Chorea” in the Philadelphia Medical and Surgical Reporter, in which, after discussing the general topic of choreas, he described the familial form of the disease, and named it ”hereditary chorea.” Huntington’s description was brief but excellent

From the Department of Neurology, Hospital das Clinicas, and Movement Disorders Clinic and Study Group, University of S%oPaulo Medical School, S%oPaulo, Brazil (MSH); and the Departments of Neurology and Psychiatry, and the Alzheimer’s Disease Center, the University of California Los Angeles School of Medicine, Los Angeles, California ULC)

THE PSYCHIATRIC CLINICS OF NORTH AMERICA VOLUME 20 * NUMBER 4 . DECEMBER 1997

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in its accuracy and precision, and his name was soon associated with the disease throughout the world.61,68 Chorea, although a prominent feature, is only one of the manifestations of the disease, leading many authors to prefer the term Huntington's disease. We have adopted this term. EPIDEMIOLOGIC ASPECTS

Although HD has been reported in practically all countries and affects all races, occurring equally in both sexes, the gene apparently occurs more frequently among individuals of white origin.22Genealogic studies show that emigration from northwest Europe, particularly from France, Germany, and Holland, was primarily responsible for the spread of the disease worldwide?1 Epidemiologic studies have been conducted in several parts of the world since the 1930s, and there is general consensus that in the West, prevalence of HD is between 30 and 70 individuals per million in the population.61 In high-prevalence areas, except those where the local population is extremely small, the key factor is that these regions are isolated-such as, for example, Lake Maracaibo in VenezuelaP Isolation facilitates local mating, genetic homogeneity, and spread of the mutation throughout the local population. HD is particularly rare in Japan and among North American and African blacks?1 CLINICAL ASPECTS

The diagnosis of HD depends on a detailed clinical assessment and on establishing a positive family history, which now can be confirmed by means of molecular genetic techniques. Initial Manifestations

The most frequent initial complaint is "incoordination" and occasional involuntary jerks in different segments of the body. These abnormalities may be absent in repose and, at this stage, affected individuals may be unable to perform complex facial movements, such as blowing, whistling, and frowning. This may be a form of buccofacial apraxia, which occurs prior to the onset of obvious chorea.61A small proportion of patients never develop typical chorea, and may present with progressive generalized rigidity. This syndrome constitutes a clinical variant of HD, which is discussed later.22 Although neurologic symptoms often are described as the initial manifestations of HD, behavioral alterations may precede the movement disorder by a decade or more." Patients are excessively irritable, impulsive, unstable, or aggressive. Depression is the most common early psychiatric The first manifestation may, additionally, be psychosis.61 Symptoms of an emotional nature or personality alterations precede or coincide with the onset of choreic movements in half of the patients.46,82 Age of Onset and Duration of the D,isease

The onset of HD is insidious, and it is often difficult to state the exact age at which symptoms manifest themselves. The average age of onset varies, but is

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generally between 35 and 42 years, although it may appear at any age.3,** Juvenile HD is characterized by symptom onset before the age of 20 years, and late-onset HD by the appearance of changes after the age of 50 years.z2,97 The average age of death varies from 51.4 to 56.9 years, according to Hayden,6I who complied approximately 4000 cases from 16 demographic studies. The average survival time of HD patients ranges from 14 to 17 years after onset. There is little variation in the duration of the disease in different sbdies.86.89.107

Neurologic Manifestations Motor Signs and Symptoms

The most distinct feature of HD is the presence of involuntary choreic movements, which are present in 90% of affected individuals.61The chorea may be minimal at outset, affecting only the face or the distal portions of limbs, but becomes generalized and interferes with all the patient's voluntary movements. The choreic movements of HD are less abrupt and rapid than those of Sydenham's chorea. As the disease progresses, the nature of these movements becomes gradually more athetotic, taking on a dystonic character. Other involuntary movements, such as intention tremor and myoclonus, 125,129 rarely may be present. They are particularly uncommon among Dysarthria is prominent in HD. It appears early on in the course of the disease as a slowing down or hesitation of speech. Articulation is irregular and staccato and is broken up by long silences. Eventually, there may be complete speech disorganization and m~tisrn.9~ Dysphagia, which is common in advanced stages of HD, is frequently responsible for potentially lethal events, such as asphyxia, aspiration, and choking. Death from respiratory causes, stemming from aspiration bronchopneumonia, is reported in up to 85% of cases.39 Cerebellar signs are extremely rare in HD, although the presence of involuntary movements makes it difficult to assess HD patients have a characteristic gait, which is interrupted by choreic movements. It appears uncoordinated and patients eventually find it impossible to walk.61They also have postural instability and suffer frequent falls, which may result in fractures and cranioencephalic trauma.Iz6 Shelton and Knopman114observed ideomotor apraxia in 33% of their HD patients. Bruyn and Wentzznoted the presence of apraxia of palpebral movement, the inability either to open or close the eyelids. Dysfunction of eye movements is relatively common in HD. Starr119showed that there was slowing-down of coordinated saccadic eye movements, with preservation of pursuit movements. More refined studies using electro-oculography techniques have shown that from 60% to 80% of patients have slow saccades (increased latency and diminished speed) in all directions of gaze, as well as a reduction in the fast phase of vestibular and optokinetic nystagmus and dysmetria of saccades.8,15, These authors and others report alterations in coordinated ocular tracking and c~nvergence.~~ Although muscle tone can be normal or reduced (hypotonia), especially in the early stages, most HD patients develop hypertonia during later phases of the disease. This may present as extrapyramidal rigidity (with or without the cogwheel sign) or pyramidal hypertonia (spasticity, with or without the claspknife reflex) and occurs in three different situations, according to Hayden?

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rigidity from onset, without chorea, which occurs in roughly 5% of patients; rigidity or spasticity co-occurring with chorea (20% of patients); and choreic movements, which are gradually supplanted by spasticity, usually together with other signs of pyramidal dysfunction. Rigidity occurs most commonly at extremes of age (young and old). Pyramidal signs, including spasticity, hyperreflexia, extensor plantar responses, abolition of the abdominocutaneous reflexes, and clonus, may be present in up to one third of cases.21 Bradykinesia, associated with rigidity or not, also may be present, especially in the advanced stages of the disease, when extreme slowing-down of movements Muscular strength is preserved. Sustained contractions, however, frequently are interrupted by sudden relaxations. This reflects activation of antagonist muscles as a result of damaged reciprocal i n n e r ~ a t i o n . ~ ~ Thus in HD, apart from involuntary movements, there is also impairment of voluntary movement as a Other Neurologic Signs and Symptoms

Incontinence of the urinary or anal sphincters is common, especially in the terminal stage of HD.61There is evidence of autonomic dysfunction in HD: hyperhidrosis and alterations in regulating blood pressure occasionally are reported.5,35. 73 Convulsions may be present in up to 3% of adults with HD,6l and roughly 40% of patients with early-onset HD (before 20 years of age) have seizures.22There are no accounts of prominent sensory disturbances in HD. Mental Alterations

Psychiatric and cognitive alterations may appear before, during, or after motor manifestations in HD.21,32, Io1 Cognitive Alterations

Dementia is one of the cardinal signs of HD. For many years the term dementia was used without a precise explanation of its meaning. During the last 15 years, however, classification systems for mental disorders have gained wider acceptance owing to the interest in elucidating and standardizing their diagnostic criteria.84The definition proposed in the Diagnostic and Statistical Manual of Mental Disturbances, of the American Psychiatric Association, ed 4 (DSM-IV)4 is used most widely today for identifying dementia. Another widely used system is the International Classification of Diseases (ICD-10).137A special code for dementia in HD has been included for the first time in both systems. In the first epidemiologic studies of dementia, using clinical impressions rather than systematized criteria for the diagnosis, the frequency of dementia reported varied greatly, ranging from less than one third to nearly all cases.16, There is now consensus that all HD patients eventually manifest a dementia syndrome. Dementia in HD is characterized by decline of frontal-subcortical system functions initially, with relative memory preservation until late phases of the disease. Standardized neuropsychological tests have been used during the last 20 years to assess the cognitive decline in HD. Among the most widely used tests are the Wechsler Adult Intelligence Scale (WAIS)132 and its revised version (WAIS-R),133which, by means of various subtests, allow basic patterns of cogni-

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tive impairment to be identified. In HD, there is a lowering of the overall IQ score, although there may be a slight discrepancy, with preferential impairment on the performance subscales.84Another widely used battery is the HalsteadReitan Battery, in which HD patients have major impairment on motor tasks, problem solving, memory, and c~ncentration.'~ Neuropsychological assessments have become more refined in order to explore particular facets of cognitive function; several specific tests are used with HD patients. Studies have shown that there is no dysfunction of immediate memory, but recent memory is affected significantly," 25 as is remote memory.26 Information recall is most affected, whereas recognition may be normal or only slightly impaired.17Procedural memory for motor tasks also is affected.30 Language disturbances are uncommon in HD patients and when present generally involve confrontation naming.130 Visuospatial functions also are impaired, although there are fewer studies loo It may be difficult to distinguish visuoof this neuropsychological domain.42, constructive deficits from motoric abnormalities; motor-free visuospatial tasks aid in these assessments. Difficulties in planning, organizing, and programming activities, functions ascribed to the frontal lobe and its subcortical connections, also are observed in HD patients.26,42 Patients perform poorly on tests of executive function, such as card sorting by category, verbal fluency, and response inhibition. MR imaging studies have correlated cerebral atrophy with cognitive impairment in HD patients and have provided additional evidence regarding the importance of subcortical atrophy in the genesis of these disturbance~."~ There are qualitative differences between the cognitive impairment of HD and Alzheimer's disease patients.1sThe pattern of cognitive impairment (slowing down of thought and abnormalities in problem solving, judgment, abstraction, attention, concentration, and motivation, in the presence of psychopathologic symptoms-in particular irritability and apathy) and the similarity of the pattern to that observed with Parkinson's disease, progressive supranuclear palsy, and Wilson's disease, lead to classification of the cognitive impairment of HD as a "subcortical dementia."30 Psychiatric Alterations

The presence of psychiatric symptoms among HD patients varies from 35% to 73%, and a wide range of disturbances is reported: personality alterations, mood disturbances, psychoses, as well as mixed disorders.2sMost investigators failed to find a significant association between psychiatric disturbances and the severity of cognitive impairment in HD.24, 46 Alterations of personality are the most common psychiatric symptoms, including irritability, apathy, emotional lability, impulsiveness, and aggressiveness.28 Folstein,44studying 186 HD patients, found that 30.6% of them met DSM-I11 criteria for "intermittent explosive disorder" and 5.9% had antisocial personality disorder.44Burns et al' found irritability in 58%, apathy in 48%, and aggressiveness in 59% of HD patients. Mood disorders, particularly depression, follow as the next most common psychiatric manifestation of HD. Approximately 30% of patients fit DSM criteria for major depressive episodes.28Depression is most common among patients with a later onset of the disease, may precede motor symptoms and appears to be more common in some families than in others.47The suicide rate in HD is 4 to 6 times greater than in the general population, and the rate rises to between 8 and 20 times greater in patients over the age of 50 years."O Manic episodes also may be found in HD patients, although mania is

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less common than depression. Patients may present with bipolar disorder or hyp0mania.3~. 45 The mood abnormalities in HD evolve similarly to primary mood disord e r ~ Kurlan ?~ et a177found positive correlations between the severity of depression and levels of corticotrophin release factor in the cerebrospinal fluid of HD patients. This factor also is increased in patients with primary major depression. The early onset of depression in HD patients suggests that the medial portion of the caudate nucleus and its cortical connections, affected in the beginning phase of the disease, are probably the neuropathologic sites of the HD-related mood disorders.45As a matter of fact, many disorders associated with caudate nucleus dysfunction have a high rate of depression, implying that this nucleus plays a key role in mediating mood disturbances (see elsewhere in this Schizophreniform psychosis is not unusual in HD, with frequency estimates This disorder is characterized by paranoid sympvarying from 6% and 25y0.~ toms, with delusions of persecution and jealousy, as well as auditory hallucinations. These psychotic manifestations may precede or co-occur with motor manifestations of HD, although they appear to be more common among early-onset patients (see elsewhere in this issue).61 Obsessive-compulsive disorder (OCD) is not commonly reported in HD. Cummings and C ~ n n i n g h a mreported ~~ two HD patients with classic OCD features and noted that OCD is associated with basal ganglia disease more commonly than with lesions elsewhere in the nervous system. The occurrence of OCD in HD implies that the caudate nuclei may play a role in the pathophysiology of OCD (see elsewhere in this Other psychiatric disturbances occasionally are reported in HD patients, including psychosomatic complaints, anxiety, alterations of sexual behavior, and paraphilias.28 General Manifestations

Severe weight loss is a striking characteristic in many HD patients. The reason for this weight loss, which borders on cachexia in advanced stages, is unclear.'n8 Clinical Variants

The concept of clinical variants in HD was introduced in 1916, when Davenport and M u n ~ e yused ~ ~ the term "biotype" to describe affected families that could be distinguished in terms of differences in age of onset and the type and degree of motor and mental disorder. Since that time several attempts to classify the clinical presentations of HD have been made. In 1973, StevenslZn proposed a clinical classification for cases with alternate manifestations. The traditional distinction between the typical choreiform type, the Westphal type adult (hypokinetic-rigid), and the juvenile type (choreatic or rigid) was rejected, and cases were classified according to only the predominant type of clinical symptomatology: the hyperkinetic-hypo/normotonic type and the hypokinetichypertonic (rigid) type. This differentiation has been corroborated by other authors.Iz7Because the terms juvenile HD, Westphal variant, and subchoreatic state are still in use, however, we describe the specific clinical characteristics of

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these variants. These variants contrast with the classic form of the illness described previously. Westphal's Variant

This term refers to patients in whom the predominant clinical manifestation is rigidity.61The first case showing these clinical characteristics was described by Westphal in 1883.134 HD can present as a rigid-hypokinetic syndrome or develop these characteristics secondarily, with patients initially exhibiting a typical choreic disorder that gradually gives way to dystonia and eventually becomes rigid-akinetic (the secondary form of Westphal).22 Among adults, fewer than 5% initially manifest the rigid form of the disease (adult type Westphal).z2Among juvenile cases, however, this form is much more common, and up to half of all patients develop it primarily or secondarily.21 Juvenile Huntington's Disease

The distinction between juvenile and adult HD is potentially valuable, although it is somewhat arbitrary. The term juvenile H D conventionally is used to designate patients whose clinical manifestations began before the age of 20 years. This group additionally may be subdivided into onset during childhood (before the age of 10 years) and onset in An estimated 5% to 10% of HD cases appear before 20 years of age,Z1and 3% occur before age 15 years.82The motor disorders begin with alterations of gait and frequent falls. The predominant motor symptom is rigidity-, which is present in up to 60% of cases, often accompanied by pyramidal tract signs, with hyperreflexia and extensor responses.61There also may be tremor in rigid cases, as well as bradykinesia, which often leads to misdiagnosis of juvenile Parkinson's disease.22The chorea may be very slight or even absent, and may be supplanted by dystonic or athetotic movements. There are juvenile cases, however, in which chorea is the predominant motor manifestation, as in adults.22 Dysarthria and oculomotor alterations are also prominent in patients with juvenile HD.21 Intellectual deterioration, with a drop in school performance, is found in nearly all patients, and is often the initial manifestati~n.~~ Other symptoms of behavioral alteration, including psychoses, may be the presenting abnormality.20 Convulsions occur in from 30% to 50% of cases6] These seizures, which usually are generalized tonic-clonic spasms, appear late in the evolution of the disease and are difficult to control. Refractory grand ma1 epilepsy is common.22 Cerebellar signs, such as dysmetria, dysdiadochkinesia, and tremors of intention, are more common in juvenile than in adult cases.61 Juvenile HD, especially of the rigid type, tends to evolve more rapidly than adult HD, whether the rigid or the choreic type.41,63, Io7 Many studies have drawn attention to the fact that heredity in juvenile HD cases is generally ~aterna1.l~. 21, 83 Indeed, 80% of juvenile rigid-form HD patients inherited the gene from an affected father.96Adult rigid-form HD patients do not display this disproportion of patrilineal inheritance or the rapid advance of the disease.lZ7 Variations of phenotype observed between adults and children with HD probably stem from differences in the pattern of reaction to the degenerative process between the developing brain and the adult brain.61

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Subchoreatic State

This term is used both to designate cases in which the onset of clinical manifestations occurs late in life, and those in which the choreic manifestations are extremely discreet.22Some patients present clinically at an advanced age, between the sixth and eighth decades. In these late-onset cases, the progress of the disease is usually slower, and the clinical symptoms may be limited to choreic movements and minimal intellectual decline.82,87 In some cases, the clinical evolution of late-onset patients may be as serious as in younger patients.61 COMPLEMENTARY TESTS Electroencephalography The most commonly encountered abnormality is a low-voltage electroencephalogram (EEG).II1 This is not specific for HD, however. Neuroimaging In the past, pneumoencephalography showed enlargement of the ventricular system and widening of the cortical and cisternal s ~ l c i CT . ~ ~studies of the cranium have enabled more accurate assessments of the size of the caudate nucleus to be performed. Objective measurements in millimeters assess the span of the frontal horns (FH line) and the bicaudate diameter (CC line), which is the smallest transverse distance between the medial edges of the caudate nuclei at the level of Monro's foramen.61Terrence et al, in 1977,'22 were the first to study the tomographic aspects of HD patients. The CC line increases in HD, owing to the degeneration of the corpus striatum. As a result, the FH/CC ratio decreases. Barr et all1proposed using another measurement, the bicaudate ratio, which significantly distinguishes HD patients from normal subjects, or from patients with cortical atrophies of different causes. It appears that severer dilatation occurs in more advanced cases, although there is no strict correlation between the radiologic findings and the clinical symptoms.118 MR imaging shows a volumetric decrease of the striatal structures, as well as of the thalamus and cortical areas.'", 71 Additionally, several authors report the presence of a hyperintense signal on T,-weighted images in the putamen and caudate nucleus in patients with the rigid form of the disease, although this may be present in some chorea-type cases as well.'", 92, Io9, In 1982 the first studies of HD involving positron emission tomography (PET) were performed. The local glucose metabolic rate was noticeably reduced in the basal ganglia of these patients.76This functional abnormality was present both in patients with marked atrophy of the caudate on CT scan, as well as in those patients without evidence of structural abnormalitie~.~~ Differences in cortical metabolic activity between HD patients and controls were not found, but significant decreases were observed in the caudate nucleus and putamen of HD patients.139 Several studies also have been performed with people at risk for HD. Some have shown that asymptomatic carriers of the gene have levels of glucose 65 These findings, along with metabolism in the caudate nucleus below the neurologic tests for people at risk for the disease, suggest that the abnormali-

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ties in the basal ganglia begin before a clinical diagnosis of HD is possible. It 98 remains unclear how early this DIFFERENTIAL DIAGNOSIS

Differential diagnosis of HD includes conditions that may appear with a prominent choreic clinical picture. Thus, all symptomatic choreas are diagnostic consideration^?^, 94 In practice, most of these conditions are clearly distinguishable, enabling relatively simple differentiation with respect to HD. Therefore, those diseases in which there is a hereditary or familial component besides choreic manifestations must be most distinguished carefully.z2These include benign hereditary chorea, paroxysmal familial choreoathetosis, choreoacanthocytosis, and dentato-rubro-pallido-luysianatrophy, among others.* The various means of inheritance, the clinical course and prognosis, as well as the findings of complementary tests in some of these diseases make differentiation possible. Among nonhereditary diseases, the differential diagnosis between HD and late-onset dyskinesia may be somewhat difficult. HD patients whose presentation is predominantly psychiatric initially may be diagnosed as suffering from schizophrenia or depression. The advent of involuntary movements may be interpreted incorrectly as a complication of therapy (i.e., tardive dyskinesia). This situation, which is not rare, illustrates the importance of obtaining a detailed family history.61 GENETIC ASPECTS

Understanding of Mendelian genetics has shown that HD is an autosomal dominant hereditary disease. The penetrance of HD, defined as the percentage of individuals that possess the gene who actually will display the disease, is loo%, assuming that the individual does not die prematurely from other causes.8z Mapping and Cloning the HD Gene

The search for the HD gene intensified in 1979, when efforts were concentrated on identifying appropriate families for DNA linkage analysis, with a view to isolating polymorphic markers. A cooperative study group, led by Wexler, was set up between the United States and Venezuela and, in 1981, blood samples from a large Venezuelan family and from a large American family were collected and studied.97,135, 138, I4O Genetic analysis of this material initially was performed by the group led by G~sella,5~ using DNA recombination techniques. These researchers used a DNA probe to locate the HD gene on the short arm of chromosome 4. The precise site was named D4S10.57The area began to be mapped by means of refined molecular genetics techniques and indicated a proximal region on chromosome 4 known as 4 ~ 1 6 . 3At . ~ the ~ beginning of the 1990s, Gusella and the Huntington's Disease Collaborative Research Group (THDCRG) discovered that this region contained approximately 250,000 base pairings.56,96 The region was cloned entirely and efforts were focused on identi*References 19, 43,58, 60, 69, 85, 104, 116, 121, 131, and 136.

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fying the different genes within it to discover which one contained the HD mutation.’05,lz3 Gusella and c o - ~ o r k e r sIz3~ ~selected , 15 interesting transcripts (IT) before finding the abnormality for HD on the 15th IT. Close to the fifth region of IT15, they discovered an area in which the three nucleotide bases cytosine-adenine-guanine(CAG), which codifies a glutamine, repeated a variable number of times. In people without HD, the number of repetitions is usually around 20, whereas HD patients typically have at least 37 repetitions of the CAG triplicate at this site. The gene for HD finally had been The gene encodes a 300-kilodalton protein, “huntingtin,” which is unrelated to any other known protein.96Huntingtin is located within cells, in the cytoplasm of somatic cells, and in the cytoplasm and nucleus of neurons.67The normal function of the gene and how the mutated gene produces HD are not known. It has been suggested that many glutamines in series would produce changes in the nature of the codified protein, which would thus receive a new function or a new scope for its normal f~nction.~’ Since the gene was discovered, polymerase chain reaction (PCR) tests have been developed and make it possible to specify the number of repetitions in any sample containing DNA in order to confirm an HD diagnosis. The analysis of CAG repetitions in many patients from ethnically different populations throughout the world has shown that the mutational mechanism is always the increase in repetitions of the three nucleotide bases, and that there are no significant differences in the number of repetitions among the different populations of HD patients that have been studied.” Comparison between the age of onset of HD and the number of repetitions of the three nucleotide base have shown there to be a significant inverse correlation between these parameter^.^, 90, 91, At the extreme end of the spectrum, patients with more than 60 repetitions almost invariably present with juvenileonset HD. The stability of the number of CAG repetitions between generations in HD has been examined. When the mother passes the gene to the child, there is a slight instability in the number of repetitions, which either increase or decrease by only three or four. When it is the father who passes on the gene, however, there may be a marked increase in the number of repetition^.^^,"^ It is this substantial increase occurring in some paternal transmissions that explains why in the majority of juvenile cases the gene was inherited from the father.7,81This increase in the number of CAG repetitions in paternal transmission also accounts for the appearance of “spontaneous mutations” in HD.5ZThe rate of mutation per generati0r1.l~~ in HD is extremely low: roughly 1 X Additionally, the phenomenon known as anticipation may occur in HD, in which the disease appears earlier and progresses faster from generation to generation.lo3

NEUROPATHOLOGIC AND PATHOPHYSIOLOGIC ASPECTS

The most striking anatomic and pathologic characteristic of HD is the degeneration of the basal ganglia.59,106 The caudate nucleus and the putamen are the most affected regions. There is intense progressive atrophy and gliosis of these structure^.^^^ Io6 Atrophy and gliosis of the pallidal regions (medial and lateral globus pallidus, substantia nigra pars reticulata) are also observable, but there is no obvious neuronal Alterations in the cerebral cortex, thalamus, and subthalamic nucleus also may be observed, although less in tens el^.^^,'^ The

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loss of cortical mass and white matter appears to be responsible for the cerebral atrophy seen in some HD patients.96 There is a noticeable loss of gamma-aminobutyric acid (GABA) and its synthesis enzyme, as well as decreases in enkephalin (enk), substance P (SP), and the conversion enzyme for angiotensin.12 Each type of cell in the corpus striatum differs in vulnerability to the degenerative process that occurs in HD. The medium-sized "spiny" cells that contain GABA and a peptide (enk or SP) are the most sensitive and are the first to disappear.= The "nonspiny" interneurons (which contain somatostatin/nitric oxide/neuropeptide Y) appear to be spared in HD, and maintain their normal numbers in the putamen, whether in adult or childhood HD.2 It has been shown that early in the course of HD there is selective loss of striatal neurons containing GABA/enk.', Io2 These affected neurons usually give rise to the indirect striatopallidal pathway (see elsewhere in this issue). The resulting loss of inhibition of globus pallidus externa (GPe) neurons causes excessive inhibition of the subthalamic nucleus. This functional deactivation of the subthalamic nucleus (NST) results in a decrease in pallidal-thalamic inhibition, increasing thalamic-cortical excitation and generating the choreic movements of HD. The additional loss of the striatal neurons containing GABA/SP, which give rise to the direct pathway, leads to an increase in the release of globus pallidus interna/substantia nigra reticulata (GPi/SNr), resulting in increased inhibition of the thalamus, with a breakdown in cortical activation. This would explain the rigidity and bradykinesia, signs that are seen later in the evolution of HD.2 In HD patients with the primary rigid form of the disease, both pathways, the medial pallidal-striatal and the lateral pallidal-striatal, would be affected to the same extent from the outset.2 This model, albeit speculative, provides an explanation for the coexistence of chorea and bradykinesia, characteristic of HD patient^.'^^ Much less is known about the underlying pathophysiologic mechanisms for the cognitive and psychiatric alterations found in HD. Damage to the frontalstriatal connections (especially with anterior portions of the caudate nucleus) may underlie alterations in cognition.99 TREATMENT

Treatment is directed at symptomatic relief. Dopaminergic antagonists are used in the treatment of chorea, given that at least a relative dopaminergic hyperfunction would be contributing to the choreic movements in HD. These agents include phenothiazines, butyrophenones, benzoquinolones, and rauwolfia alkoloids. None of these drugs is particularly superior in controlling the choreic movements of HD patients.61 Depression in HD is treated using conventional tricyclic antidepressant drugs (imipramine, nortriptyline, or amitriptyline) or selective serotonin reuptake inhibitors. Generally speaking, most patients respond satisfactorily to these In resistent cases, electroconvulsive therapy may be ~sefu1.4~ Mania in HD responds better to treatment with carbamazepine than with lithium. Clonazepam and valproic acid are possible alternatives.28 Psychotic symptoms also can be treated with neuroleptic medications, but there are persuasive data that the response to these conventional antipsychotic agents is not optimal.24Doses are generally higher than those used for motor symptoms. Anxiety, like excessive irritability, may be treated with benzodiazepines.

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Aggressive patients may benefit from the use of neuroleptic, antidepressant, or beta-blocking agents.28 Surgical treatment is not indicated in HD. Supportive treatment, such as physiotherapy, occupational therapy, nutritional guidance, and family psychotherapy, also may be considered as part of the comprehensive approach to the HD patient. FUTURE DIRECTIONS

If HD produces a defect in oxidative metabolism, which leads to the pathologic alterations described, then it should be possible to detect this metabolic defect. Recent MR imaging spectroscopic studies were performed on the basis of this assumption, which enabled the levels of lactic acid in the brain to be meas~red.’~ Levels of lactate increase when oxidative metabolism cannot cope with metabolic demand. HD patients exhibit detectable quantities of lactic acid in the occipital cortex and the basal ganglia, whereas normal control patients do not. These findings are present only in symptomatic patients and not in individuals who possess the gene but are not yet symptomatic.” Preliminary studies suggest that treatment with metabolic stimulators (such as ubiquinone) reduces the production of lactic acid in the brain of HD patients.74It remains to be defined whether this will produce any long-term clinical benefit for patients. The pathogenesis of HD will be understood thoroughly only when the abnormality produced by the gene is explained. References 1. Albin RL, Reiner A, Anderson KD, et al: Preferential loss of striato-external pallidal projection neurons in presymptomatic Huntington’s disease. AM Neurol31:425,1992 2. Albin RL, Reiner A, Anderson KD, et al: Striatal and nigral neuron subpopulations in rigid Huntington’s disease: Implications for the functional anatomy of chorea and rigidity-akinesia. Ann Neurol 27357, 1990 3. Alter M, Myrianthoupoulos N: Chronic progressive hereditary chorea of Huntington. In Goldensohn ES, Appel SH (eds): Scientific Approaches to Clinical Neurology. Malvern, PA, Lea & Febiger, 1977, p 1091 4. American Psychiatry Association: Diagnostic and Statistical Manual of Mental Disorders, ed 4. Washington, American Psychiatric Association, 1994 5. Aminoff MJ, Gross M: Vasoregulatory activity in patients with Huntington’s chorea. J Neurol Sci 21:33, 1974 6. Aminoff MJ, Marshall J, Smith EM, et al: Pattern of intellectual impairment in Huntington’s chorea. Psycho1 Med 5:169, 1975 7. Andrew SE, Goldberg YP, Kremer B, et al: The relationship between trinucleotide (CAG) repeat length and clinical features of Huntington’s disease. Nature Genet 4:398, 1993 8. Avanzini G, Girotti F, Caraceni T, et al: Oculomotor disorders in Huntington’s chorea. J Neurol Neurosurg Psychiatry 42:581, 1979 9. Avili-Girbn R Medical and social aspects of Huntington’s chorea in the state of Zulia, Venezuela. ln Barbeau A, Chase TN, Paulson GW (eds): Huntington’s Chorea. (Advances in Neurology, Vol 1). New York, Raven Press, 1973, p 261 10. Barbosa ER, Haddad MS, Bacheschi LA, et al: Magnetic resonance imaging (MRI) of the brain in Huntington’s disease. Mov Disord ll(suppl):llO, 1996 11. Barr AN, Heinze WJ, Dobben GD, et al: Bicaudate index in computerized tomography of Huntington disease and cerebral atrophy. Neurology 28:1196, 1978 12. Bird ED Huntington’s chorea: Etiology and pathogenesis. In Vinken PJ, Bruyn GW,

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