INTRODUCTION AND HISTORICAL PERSPECTIVES

Huntington’s disease (HD) is a neurodegenerative disorder characterized by progressive motor, psychiatric, and cognitive dysfunction, inherited in an autosomal dominant (AD) manner with age-dependent penetrance. The most prominent motor feature of HD was first described by the Renaissance alchemist, Paracelsus (1493–1541), in the 16th century and was termed “chorea naturalis.” One hundred years later, English colonists in New York, Connecticut, and Massachusetts used the term “Saint Vitus’ dance” or “that disorder” to describe people with choreiform movements (1,2). A detailed description of HD, as a form of chronic hereditary chorea, was first published by Johan Lund in 1860, but remained largely unread until its translation to English in 1959 (3). It was not until 1872 that George Huntington wrote his landmark paper describing the symptoms of “adult-onset” HD gained public recognition. Both papers stressed the hereditary nature of this disorder, and Huntington included description of the AD pattern of inheritance. He also highlighted the neuropsychiatric and cognitive manifestations of the disease and noted an elevated preponderance to suicide in this group (4).

In 1955, a concentration of HD was identified by Americo Negrette in the Lake Maracaibo region of Venezuela and this became the site for development of the US–Venezuela Huntington Disease Collaborative Research Group under the direction of Nancy Wexler (5). Through pedigree analysis of over 3,000 individuals, genetic markers of the disease were localized to chromosome 4p in 1983, and 10 years later the precise gene, “interesting transcript 15” (now called huntingtin gene), was identified (6). This was a paramount finding, as it was the first autosomal disease locus identified through genetic linkage studies (7).

The exact function of the normal gene product is unknown but is thought to be crucial for development and is conserved across species. When the gene is expanded in HD, the dysfunction of the pathologic protein leads to neuronal cell loss initially and predominantly in the striatum. Although the exact pathophysiologic mechanisms remain undetermined, the disease is postulated to arise from complex intracellular protein signaling interactions in the brain, testes, and other tissues in the body. The genetic abnormality leads clinically to a multifaceted disorder requiring an interdisciplinary and dynamic management scheme for patients who manifest HD and for those at risk for disease development.

EPIDEMIOLOGY

HD is a rare disorder, but can be found worldwide. The age at onset is typically in the third to fifth decades, but juvenile-onset (<20 years) and older-onset forms (>70 years) have been described (8). Greater than 90% of HD is considered hereditary; however, 3% to 6% of affected patients may have a sporadic mutation (9,10). The disease shows a prevalence of 5 to 10 affected individuals per 100,000 in most populations of Western European origin and slightly higher in Canada (Table 19.1) (8,11,12). The highest prevalence rates have been reported in Venezuela, Tasmania, North East of England, and Scotland and may be due to a founder effect (13–15). Curiously, HD is rare in adult African Blacks, while juvenile HD (JHD) prevalence in this population is two to four times higher than in the white population (16,17). Prevalence of HD is lowest in African Blacks, Japanese, Chinese, and Finnish populations (8,12,16–19). Despite this, there appears to be no significant difference in the number of trinucleotide repeats in affected individuals across ethnic groups and haplotype ancestry does not affect the age at the onset of disease (18,20,21). Therefore, in addition to emigration from Europe, new mutations are thought to have arisen independently in multiple locations, accounting for the geographic variations (18–20,22,23).

GENETIC BASIS OF DISEASE

PENETRANCE

HD is an AD condition caused by an expanded CAG trinucleotide repeat in the first exon of the gene on chromosome 4p16.3 (7). The age-dependent penetrance of this disease permits transmission of the deleterious allele to subsequent generations and is dictated by the CAG repeat length (Table 19.2). Greater than 40 repeats are associated with complete penetrance (24), while 26 repeats or less is considered normal in the population (7,22,25–27). Individuals with 36 to 39 repeats will have an inverse, length-dependent reduction in penetrance (27–29). Those individuals with 27 to 35 repeats are considered “mutable normal alleles” and are not thought to express the disease, although there are case reports including pathologic confirmation in this range (30–35). Nonetheless, when these “intermediate alleles” are transmitted through a paternal germ line, they are considered meiotically unstable and prone to expansion (9,27,36–38). Therefore, males with intermediate-sized alleles may confer higher risk of disease development to their offspring. Furthermore, significant behavioral abnormalities in the absence of other symptoms have been identified in this group (39). These studies suggest that individuals with intermediate alleles should be considered at risk for development of HD, although the occurrence is rare (40).

AGE AT ONSET VARIABILITY, ANTICIPATION, AND NATURAL COURSE OF DISEASE

Age at onset of HD can be difficult to define. In most studies, it is defined by the onset of motor signs including chorea. However, cognitive, psychiatric, and behavioral abnormalities commonly precede the emergence of motor signs. Regardless of how HD onset is defined, the largest determinate of age at onset is the length of the CAG repeat. Age at onset is inversely correlated with the repeat length, with the longer repeat lengths (>60) manifesting in the most severe, juvenile forms of this disorder (25,26). Likewise, CAG repeat size has been shown to be inversely correlated with the presence of prodromal cognitive deficits as well as with late-stage outcomes, such as age at which patients require nursing home care and feeding tubes (41,42).

The polyglutamine products of the translated CAG repeats are thought to have a toxic-gain-of-function effect that is more pronounced at longer repeat lengths. In animal models, the toxic proteins begin to accumulate after a period of latency (1). This could account for the late onset of the disease seen in humans and the correlation between CAG repeat length and age at onset. Although rate of progression of disease was also correlated to polyglutamine length in animal models, this relationship is less clear in humans (1,43–46).

Family members and individuals with the same length of CAG repeats may have markedly different ages at onset; therefore, variability in age at onset is not completely accounted for by CAG length suggesting that modifying genes and environmental factors have an influence that may be greatest at smaller repeat lengths (24,47,48).

GENETIC AND ENVIRONMENTAL AGE AT ONSET MODIFIERS

Several studies have indicated that modifying genes outside the Huntington gene or within the normal huntingtin allele could account for 38% to 56% of residual variability in the age at onset of disease (47,49,50–52). More recently, a study of >4,000 HD patients excluded the normal allele as a prominent factor in determining age at onset variability (53). Loci thought to have modifying effects include D4S10, 4p16, 6p 21-23, 6p23-24, 6p 24-26, 18q22, MSX1, and DBA/2J; however, specific genes have not been identified (49,50,52,54,55). Although 20 genetic loci have been implicated in residual age at onset variability, only the genes encoding for N-methyl-D-aspartate (NMDA) receptor subtypes (GRIN2A/B) continued to show effect when larger sample sizes were analyzed (56–60).

In addition to genetic factors, environmental influences may account for 62% of age at onset variance (47). This idea is supported by a report of monozygotic twins with a 7-year gap in the development of HD (61). Results from the PHAROS study revealed a twofold increase in phenoconversion with higher dairy consumption (62). Increased physical and emotional stress has also been linked to earlier age at onset (63,64). Evidence of these genetic and environmental modifiers provides important clues in the pathogenesis of disease and may have important implications for targeted therapies in HD.

PATHOPHYSIOLOGY

The medium spiny neurons of the striatum containing γ-aminobutyric acid (GABA) and enkephalin are the primary site of dysfunction in HD. These cells project to the globus pallidus and substantia nigra, while the interneurons within the striatum are spared. Preferential involvement of cortical and striatal neurons may have an effect on age at death (65). Both magnetic resonance imaging (MRI) abnormalities present in preclinical HD adults, and observed lower weight and smaller head circumferences of gene-positive asymptomatic children (not juvenile-onset HD) suggest that in addition to neuronal dysfunction, abnormal neural development may also be part of the disease pathogenesis (66–68).

Microglia have also been implicated in the pathogenesis of HD. Postmortem pathologic studies have reported increased numbers of activated microglia neighboring degenerating neurons (69). Positron emission tomography (PET) imaging has shown widespread microglia activation in preclinical (70) and clinical stages (71). Moreover, the intensity of the microglial reaction predicts clinical onset of disease (72) and correlates with disease severity (70,71). These studies suggest either the activation is a consequence of the mutation or there is an early inflammatory mechanism in development of disease.

The expanded trinucleotide repeat results in an elongated polyglutamine product near the N terminus of the Huntingtin protein, htt (7). The function of htt is unknown. Likewise, the mechanism by which the mutant protein product causes neuronal dysfunction and eventual death is largely undiscovered. One proposed pathologic mechanism occurs when the expanded polyglutamine repeat undergoes conformational change, thereby interfering with cell trafficking, and after getting cleaved, the fragments adopt an oligomeric-β confirmation. These toxic oligomers may inhibit intracellular chaperones, preteosomes, and autophagy, permitting further buildup of toxic fragments within cells (73). There is debate whether the aggregates themselves execute a toxic effect on the cell or whether aggregation of potentially toxic monomers and oligomers is a protective neuronal pathway. Giant aggregates eventually become intranuclear neuronal inclusions seen diffusely throughout the cortex and striatum in HD (74). htt fragments have been localized to these intranuclear inclusions (75).

CLINICAL FEATURES AND DIAGNOSIS

PREMANIFEST HD

Diagnosis of HD can be made clinically based on the classic motor, cognitive, and neuropsychiatric manifestations. Subtle signs in these domains, however, are often present 15 to 20 years prior to the diagnosis (11,76–78). Up to 7% of at-risk HD participants or presymptomatic HD gene carriers may have motor abnormalities, including irregularities in saccadic eye movements and optokinetic nystagmus, difficulty with tongue protrusion, hyperreflexia, impaired fine finger or rapid alternating movements, and increased variation in stride length (45,46,77–81). During emotional stress, excessive or inappropriate movements of the fingers and toes have been described and are likely the early signs of chorea (45,82).

Cognitive dysfunction in premanifest HD groups has been demonstrated on psychometric testing and is partly explained by disruption of striatal–frontal pathways (77,78,82–86). Odor identification is also impaired (77,78). Likewise, rates of apathy, irritability, depression, anxiety, obsessive–compulsiveness, interpersonal sensitivity, and psychosis are higher in premanifest HD groups when compared to controls. The severity of these neuropsychiatric symptoms increases as one approaches the diagnosis, which may explain why there is one peak of suicide just prior to diagnosis (39,76,78,87).

These cognitive changes may be associated with imaging abnormalities seen in persons at risk for HD and are present 16 to 20 years prior to diagnosis. Striatal volume loss is seen early in the disease course and is most notable in the putamen initially (77,78,81). Cortical gray matter thinning is demonstrated in the posterior frontal regions initially and progresses to the occipital, parietal, superior temporal, and superior frontal lobes by the time of diagnosis. White matter atrophy also begins in the frontal regions, but is widespread at diagnosis (78,81). These gray and white matter abnormalities directly correlate with estimated years to the onset of disease (88). The subtle clinical and imaging characteristics exhibited in preclinical HD gene carriers likely represent the prodromal stage of HD. This stage may be recognized by an astute clinician and therefore should be the target stage to initiate novel therapeutics in the future.

EARLY HD

Onset of chorea, incoordination, and positive family history bring most patients to a diagnosis, which may be later confirmed using genetic testing (11,89). Genetic testing identifies the CAG repeat expansion and differentiates HD from other neuropsychiatric conditions with high sensitivity and specificity (22,90). Age at diagnosis is typically 25 to 45 years with a median survival of 15 to 20 years (46,91). The progressive course in the earlier stages of the disease can be followed clinically with the Unified Huntington Disease Rating Scale (UHDRS), which tracts motor and cognitive dysfunction, behavioral abnormalities, and functional capacity of the patient (89).

Chorea (L., Gr. choreia = dance) is the distinguishing motor feature in HD and is characterized by continuous, irregular, and unpredictable involuntary movements that flow from one body part to another. Mild chorea may be confused with restlessness, agitation, or “fidgetiness,” and early on, patients may be able to temporarily suppress the movements by camouflaging them into semipurposeful activities (i.e., parakinesia). Interestingly, patients often have reduced awareness of their chorea (i.e., anosognosia) independent of any cognitive dysfunction (92). Movements of the trunk and limbs affect gross and fine motor skills (46). Postural instability and worsening of chorea with walking impair gait even in early stages of the disease (93). Stress and mental distraction also worsen the movements. Facial involvement leads to abnormal facial expressions with involuntary elevation of the eyebrows and a look of astonishment. Motor impersistence is a common feature. This inability to maintain tone leads to the characteristic handshake (“milkmaid’s grip”) and difficulty with tongue protrusion (“flycatcher’s tongue”). In addition to chorea, other hyperkinetic movements, such as dystonia, myoclonus, and tics (tourettism), as well as parkinsonism (rigidity, lack of voluntary movements) may also be present.

Other commonly associated findings include progression of saccadic eye movement abnormalities (with increased saccade latency), “hung-up” or “pendular” reflexes, mixed dysarthria, and progressive dysphagia (45,46,93). Dysphagia can be worsened with a phenomenon common in HD of quickly putting food in the mouth without adequate chewing or swallowing. The huntingtin protein is expressed ubiquitously in cells throughout the body and is associated with nonneurologic complications as well. These include skeletal muscle atrophy, cardiac failure, endocrine dysfunction (with testicular atrophy, thyroid abnormalities, and alterations in glucose metabolism), osteoporosis, and dysfunction of blood-derived cells (94). Weight loss in HD is pervasive and is thought to partly be due to alterations in digestion and fat storage. Even in premanifest HD, gene carriers weigh less despite a higher caloric intake (86,94,95).

A significant proportion of patients report nonphysical difficulties as their presenting symptoms. These include mounting anxiety and depression, irritability, memory loss, and apathy (78,93,96). Nearly all patients with HD report neuropsychiatric symptoms, which are independent of the cognitive and motor manifestations of the disease (85). This may be biased by the fact that patients are more often aware of their emotional state than their motor symptoms. Behavioral changes are evident early on with impulsivity and hygienic neglect.

Cognitive changes include loss of mental flexibility, organization of sequential tasks, advanced planning, working memory, attention, and processing speed. Disorders of the caudate interfere with connections to the prefrontal cortex. However, this disconnect does not explain all the cognitive disturbances seen in HD. In fact, MRI is often free of the characteristic caudate atrophy early in the disease course. The putamen, however, can show volume reductions of up to 50% and correlates with neurologic examination abnormalities (97).

MODERATE HD

As the disease progresses from premanifest to advanced HD, motor scores on the UHDRS worsen as indicated by a higher total score (86). More specifically, abnormalities in saccades (including increased antisaccadic error rates and saccadic latency, and slowing of saccade velocity), motor impersistence (difficulty with tongue protrusion), and self-paced finger tapping precision show a stepwise decline (78,98,99). Increased saccade latency correlates with worsening of chorea, while motor impersistence is independent (98,99). Chorea is actually a poor marker of disease progression as it can be a transient phenomenon in some patients (100). In many, chorea progresses to interfere with activities of daily living, walking, and coordination, and leads to increasing falls (45,81,100). The rate of decline in motor abilities and total functional capacity (as measured by the UHDRS) is most rapid in the early and middle stages of disease (45,46). Many patients lose the ability to drive or maintain gainful employment during this time.

The loss of independence patients experience in this stage of disease correlates with the second peak in suicide rates (87). Overall, suicide rates are four times higher in HD than in the general population. Suicide is the third leading cause of death in HD (101,102). Patient agitation, anxiety, impulsivity, and lack of insight, in addition to more traditional risk factors such as social isolation and family history of suicide, contribute to the high suicide rates in this group. Likewise, cognition continues to worsen and speech production becomes more difficult over time leading to further patient frustration. Whole brain atrophy rates on MRI correlate with this stepwise decline in cognition, as does caudate and putamen volume loss (78,81).

Sleep disturbances can also become a major concern for patients and caregivers alike. Reversal of day–night activity patterns, sleep-onset latency, increased interspersed wakefulness, and reduced sleep efficiency have all been noted in the HD population (103). Poor sleep likely worsens the cognitive, psychiatric, behavioral, and motor features of the disease.

ADVANCED HD

In later stages of HD, the development of parkinsonism and dystonia accelerates (46). Bradykinesia and rigidity often coexist with chorea throughout the disease course, but in later stages, these become the prominent features (11,81,104). Parkinsonism is slowly worsened by the cumulative use of antichoreic treatment, while chorea may actually diminish (45,100). Dystonia is widespread and can affect the face (with blepharospasm and bruxism), neck, trunk, and limbs. Gait continues to deteriorate with almost cerebellar qualities (i.e., ataxia), and loss of ability to maintain head and trunk upright posture leads to significant increases in falls. Saccadic eye movements become increasingly impaired and insuppressible eye blinks and head movements are required to initiate saccades (99). Hyperreflexia continues through late stages with or without clonus and occasionally with extensor plantar responses (11).

The illness progresses slowly over many years until the patient becomes completely physically dependent, mute, and requires 24-hour care. Worsening dysphagia often leads to nonoral feeding mechanisms, if the patient or family chooses this option. Death typically occurs 10 to 20 years from disease onset and is often due to secondary illness (i.e., aspiration pneumonia), suffocation, or sequelae of accidents and falls (i.e., subdural hematoma) (11). Patients often have an autonomic storm with fluctuations in blood pressure and temperature along with delirium and screaming in the near-death period. Although suicide is the third leading cause of death in this population, it is not a major concern during the final stages as behavioral disturbances, aggression, and violence are generally less prominent (87).

JUVENILE HD

Seven percent to 10% of HD cases are of juvenile-onset, with presentation at 20 years or prior (1,105). Although the triad of motor, cognitive, and neuropsychiatric abnormalities occurs in JHD, the clinical features differ from the later-onset form. The younger the patient’s age at presentation, the more distinct the clinical characteristics and rapid progression of the disease. Those who present in the first decade of life typically have a positive family history (frequently paternal) as well as seizures, oral motor dysfunction (dysarthria, dysphagia, or drooling), rigidity of limbs or trunk, gait disorder, and display a decline in school performance (106–108). Seizures are usually generalized and of tonic–clonic or myoclonic type (105,107,108). Chorea is uncommon in young children, however may be the first symptom in adolescence. Likewise, young children exhibit less conduct changes and mental deterioration, while teenagers may present with severe behavioral disturbances, including arson, suicide, sexually aggressive or inappropriate behavior, and significant drug and alcohol abuse (105,108). Tremor and dystonia, which can be severe and refractory to treatment, become more apparent over time, often causing substantial pain. Eye movement abnormalities and mild cerebellar signs as seen in adults can also be found in the juvenile form (45,105,108). Children also exhibit psychomotor regression and poor school performance (107). All affected individuals lose the ability to walk, communicate, or eat and become completely physically dependent by young adulthood. The presentation of JHD (discrete from HD) often leads to misdiagnosis or delay in diagnosis. The distinctive phenotype of JHD could reflect the effect of the mutant allele on brain development and may provide clues to HD pathogenesis.

DIFFERENTIAL DIAGNOSIS

HD shares phenotypic and genotypic characteristics with other neurodegenerative disorders (Table 19.3). Huntington disease–like 1 (HDL1) is AD (109), while Huntington disease–like 2 (HDL2), dentatorubral–pallidoluysian atrophy (DRPLA), spinal and bulbar muscular atrophy, and spinocerebellar ataxias (SCA) 1, 2, 3, 6, 7, and 17 are all AD caused by trinucleotide repeat expansions and lead to an expanded polyglutamine product (110–121). Some of these are considered clinically indistinguishable from HD and are called “Huntington disease–like” when huntingtin gene testing is negative.

In HDL1, affected individuals have seizures with parkinsonism predominating the motor features. As a familial prion disorder, the natural history of HDL1 shows rapid progression to dementia, dependence, and death (109,122). HDL2, however, is due to a mutated CTG/CAG expansion in the junctophilin-3 gene and accounts for approximately 2% of the genetic heterogeneity in HDL patients (110). The disease was thought only to be present in families of African descent until more recent reports of Brazilian kinships have emerged (123–126). HDL2 is clinically similar to HDL1; however, seizures are absent and peripheral acanthocytes can occasionally be found (110,127,128). Significant clinical overlap also exists with the AD SCAs and HD, since these disorders all demonstrate cognitive impairment, cerebellar signs, and movement disorders. SCA 17 (also called Huntington disease–like 4) is due to a CAG expansion in the TATA-binding protein and can appear clinically identical to HD (110,121). DRPLA is due to an expanded CAG repeat in the atrophin 1 gene and age at onset is inversely correlated to CAG repeat length. The disorder is seen more frequently in Japanese, but is otherwise clinically analogous to HD (112

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