Morvan syndrome and related disorders associated with CASPR2 antibodies
Jan. 18, 2022
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Huntington disease is a genetic autosomal dominant neurodegenerative disorder caused by an expansion of a trinucleotide repeat in the gene encoding huntingtin (HTT) on chromosome 4. It is characterized by motor, behavioral, and cognitive symptoms, with the onset usually in mid-adulthood. Although the onset of disease is currently defined by its motor manifestations, the presence of cognitive and behavioral features prior to motor symptoms is increasingly recognized. A combination of nonmotor and motor symptoms inevitably progresses to produce functional impairments, important targets for symptomatic treatment, and clinical trial outcomes. Only symptomatic treatment is currently available to minimize the severity of motor and nonmotor symptoms, affecting the quality of life of patients and caregivers. The area of research to develop potentially disease-modifying therapies in Huntington disease has been growing in the past few years, with many preclinical and clinical trials underway. The development of biomarkers in Huntington disease is also an area of increasing interest that becomes even more important in the anticipation of the development of disease-modifying therapies. Predictive (prior to symptoms) genetic testing protocols take a wide range of information on Huntington disease genetics, inheritance, symptoms, and progression into account. In this article, the author explores the advances and possible therapeutic targets in the treatment of this devastating disease.
• Huntington disease is characterized by a combination of progressive motor, cognitive, and psychiatric symptoms.
• Mutant huntingtin protein that results from CAG repeat expansion affects many cellular processes including gene transcription, posttranslational modification, protein clearance, axonal trafficking, and mitochondrial function.
• Treatment of Huntington disease currently remains symptomatic but potential new therapeutic targets are being actively explored in both manifest and nonmanifest populations.
The clinical syndrome was delineated in the English literature in 1872 by George Huntington (305), who reported:
Hereditary chorea. . .confined to certain and fortunately a few families, and has been transmitted to them, an heirloom from generations away back in the dim past. It is spoken of by those in whose veins the seeds of the disease are known to exist, with a kind of horror. . . There are three marked peculiarities in this disease: 1. Its hereditary nature. 2. A tendency to insanity and suicide. 3. Its manifesting itself as a grave disease only in adult life".
The degeneration of the striatum was recognized as the essential neuropathologic feature around the turn of the century (155; 04). The genetic mutation linked to Huntington disease was found on chromosome 4 in 1983, making Huntington disease the first genetic disease mapped using DNA polymorphisms (102). In 1993, a collaborative group of researchers announced the identification of a gene with unstable trinucleotide repeat located on chromosome 4p16.3 (06). This discovery was the result of a multinational, multidisciplinary research project focused on a unique cluster of affected families in Venezuela diagnosed back in the 1950s by a local physician, Americo Negrette, author of the first monograph ever published on Huntington disease called “Corea de Huntington,” which was published in Spanish in 1963 (Hereditary Disease Foundation website) (305).
• Chorea is the most common movement disorder in Huntington disease, and it tends to slow and may be replaced by dystonia-rigidity in the end stages.
• Cognitive and behavioral changes may occur years prior to the onset of definitive motor signs, simultaneously with or after motor manifestation of the disease.
• Changes in sleep, weight loss, and autonomic dysfunction are now recognized as primary and treatable Huntington disease symptoms.
• Juvenile cases can present with prominent parkinsonism or rigidity-dystonia but no chorea; seizures are common in this population.
Huntington disease is a highly penetrant, autosomal dominant, progressive neurodegenerative disease that manifests as a movement disorder often including chorea, behavioral and cognitive symptoms, and often a constellation of other non-motor symptoms (149; 279). The mean age of onset of motor symptoms is approximately 40 years, but there are descriptions of individuals who became symptomatic as early as 2 and as late as 80 years of age (259; 216; 151).
Adult-onset Huntington disease. Currently, manifest Huntington disease is still diagnosed primarily based on motor criteria, when a clinician has 99% confidence of an “otherwise unexplained extrapyramidal movement disorder” in a person with family history of Huntington disease (242). The results of the large observational studies namely TRACK-HD, COHORT-HD, PREDICT-HD, and PHAROS (the two latter studies are discussed below) emphasized the likely onset of non-motor symptoms often years before the manifestation of the motor features of Huntington disease. Given changing view on natural history of Huntington disease, Movement Disorder Society Task Force reviewed the diagnostic criteria of Huntington disease and proposed the following modifications:
• Motor symptoms in subjects that either tested positive for CAG expansion in HTT gene or subjects with positive family history of Huntington disease are rated on 0 to 4 “diagnostic confidence” scale: 0: normal motor examination; 1: nonspecific motor symptoms; 2: possible Huntington disease with 50% probability; 3: probable Huntington disease with 90% confidence; 4: definite Huntington disease with 99% confidence.
• Manifest Huntington disease can be diagnosed if a subject has motor symptoms with confidence rate 4 even with normal cognitive function; or motor symptoms with confidence score 3 plus at least minor neurocognitive changes (excluding cognitive symptoms due to depression).
• Prodromal Huntington disease can be diagnosed if a subject has motor symptoms with confidence rate 3 even with normal cognitive function; or motor symptoms with confidence rate 2 plus at least minor neurocognitive changes.
• Presymptomatic Huntington disease can be diagnosed if a subject has known CAG expansion but has no motor signs of Huntington disease (confidence rate 0 or 1) and no cognitive changes.
• Premanifest Huntington disease includes subjects from presymptomatic and prodromal stages.
Motor manifest Huntington disease: a movement disorder. Huntington disease is classically categorized as a hyperkinetic movement disorder, with chorea and dynamic forms of dystonia as common features. Chorea, from the Greek meaning "to dance," is an involuntary movement around multiple joints. Chorea is a relatively rapid involuntary movement disorder in which the temporal and anatomic distribution of involuntary movements is normal. Dystonia is an involuntary twisting, pulling, or posturing movement. Huntington disease is also a disorder of voluntary motor control; impairments in motor control largely contribute to the progressive physical disability (79; 240). It can consist of quick jerks such as the "cigarette flicking" movements commonly seen in the fingers or fast contractions of facial muscles. More flowing and somewhat slower choreoathetotic movements also often occur with more advanced disease as do fast, large amplitude, flailing movements resembling ballism.
Other motor signs in Huntington disease include bradykinesia, rigidity, imbalance and gait impairment, oculomotor dyscontrol, fine motor incoordination, and speech disturbances. Bradykinesia and other motor symptoms generally coexist with chorea in the adult form of illness (280). Patients demonstrate impairment in the ability to produce sequences of movements or rhythmic rapid repetitions of a single movement (312). On examination, broad-based stance and gait are common, and tandem walking is often impaired. Speech and swallowing dysfunction develop midstage of the illness and ultimately lead to inability to communicate and swallow. Deep tendon reflexes are often hyperactive in Huntington disease. A bradykinetic rigid phenotype (Westphal variant), common in juvenile onset Huntington disease (see below), is observed in a minority of adults.
The movement disorder in adult-onset Huntington disease changes with time. Chorea tends to slow and may be replaced by dystonia-rigidity in the end stages. Patients can develop fixed dystonic contraction of limb and axial muscles, leading to contractures and immobility. Regular careful reviews of medications should be undertaken as the clinical picture changes to ensure that neuroleptic or other drug use is not contributing to motor dysfunction.
Nonmotor features of Huntington disease and diagnosis. Nonmotor features of Huntington disease are classically divided into cognitive and psychiatric manifestations. In addition, weight loss, dysautonomia, and sleep disturbances are areas of increasing research interest. It has long been recognized that non-motor symptoms may precede motor symptoms in Huntington disease (199). Multiple longitudinal observational studies have reported both symptoms and brain imaging changes well before motor diagnosis (64; 174; 269). Diagnosis based on nonmotor symptoms alone prior to the motor symptoms manifestation still remains debatable and challenging, even in a known mutation carrier; for example, learning from the genetic testing results, depression could be equally attributed to Huntington disease or associated with a different etiology.
Two studies provide insight into how non-motor symptoms may influence the diagnosis. The PREDICT-HD study observed mutation carriers, nonmanifest at enrollment, over several years. In addition to the UHDRS (motor) diagnostic confidence level, investigators were asked to make a diagnostic call based on all available information, ie, cognitive testing, behavioral questionnaires, motor signs, symptom reports, and overall functioning, although no specific list or criteria were provided. This multidimensional diagnosis was often simultaneous with the motor diagnosis; however, 69 (37%) of 186 participants had a multidimensional diagnosis made earlier than the motor diagnosis. Cluster analysis of the 186 participants with a motor diagnosis delineated 3 phenotype categories: primarily cognitively impaired, behaviorally impaired, and cognitively preserved (29). Multidimensional analyses, even informal, may aid in folding non-motor signs and symptoms into diagnosis. The Prospective Huntington At-Risk Observational Study (PHAROS) tracked initially nonmanifest at-risk individuals longitudinally over several years. Both research participants and investigators were blinded to mutation status. Cluster analysis of 345 participants with 37 or more CAG repeat expansions and 638 participants with fewer than 37 CAG repeats found at baseline the mutation carrier group was more impaired in motor, behavioral, and most cognitive measures with no differences in functional measures (126). Over time, the more than 37 CAG group worsened and diverged from the fewer than 37 CAG group in all categories except behavioral measures: both groups worsened in this area (126). Overall behavioral measures were the most nonspecific, with the possible exception of irritability observed more commonly in the mutation carrier group. This implies that specific cognitive or functional measures may contribute to non-motor diagnosis.
Cognitive disorder. Cognitive decline occurs in all patients, is wide ranging, and may be more disabling than the motor disorder (199). In a study, cognitive disturbances and depression were found to be determinants of quality of life (21); cognitive and behavioral symptoms may generate the greatest overall burden on families (199; 87). A predominantly choreatic motor phenotype of Huntington disease may be associated with better cognitive and general functioning than the hypokinetic-rigid motor phenotype (110; 126). Cognitive performance appears to be strongly associated with driving status (26). The cognitive profile is typically characterized by attention deficits, cognitive slowing, impaired planning and problem solving, and visuoperceptual and construction deficits. Patients tend to be disorganized and suffer from lack of initiative. There is usually a more rapid decline in visuospatial as compared to verbal skills. Variable patterns of deterioration in executive functioning in Huntington disease have been observed. In early disease, impairments in Stroop and verbal fluency tests may be detected, whereas risky decision-making appears to be spared (117). Mimic apraxia is common, and ideomotor apraxia has been reported (257). In contrast to Alzheimer disease, other cognitive deficits contribute to functional impairment in Huntington disease before the memory disturbance (204), and language is relatively preserved even into late stages (08). Awareness of memory deficits is retained in the early stages of disease but declines with disease progression (48). The Montreal Cognitive Assessment (MoCA) has been found to be able to detect cognitive impairment across a wide range of severity in Huntington disease, although it was not necessarily superior to the Mini Mental State Exam (92). Tests that appear to be sensitive to longitudinal cognitive decline across a 24-month period in early Huntington disease include Symbol Digit, Circle Tracing direct and indirect, and Stroop word reading (270). A Huntington disease-specific cognitive battery has been developed, particularly for clinical trial outcomes (269).
Psychiatric and behavioral symptoms. Psychiatric symptoms may be both disabling and treatable, mandating recognition of this important symptom area in Huntington disease. Conversely, few patients have every psychiatric symptom, and many have none. In the large European REGISTRY study, 27% of the 1993 participants had no neuropsychiatric symptoms in the last month (291).
Behavioral symptoms such as disinhibition, impulsivity, and apathy likely reflect frontal-subcortical dysfunction (199). Disabling or overwhelming apathy attributed to frontal lobe dysfunction is a common behavioral symptom in Huntington disease. Apathy was the most common neuropsychiatric symptom in a European REGISTRY cohort study of UHDRS Behavioral Scale items (291): moderate to severe apathy was reported in 28% of the 1993 mutation carriers in the study, was the most common symptom in advanced Huntington disease stages, and was had the strongest inverse correlation with the TFC score. In a 2-year prospective study, 14% of subjects who were free of apathy at baseline developed apathy at follow-up (224).
Changes in temperament or personality with irritability are common and often troublesome for family members. Apathy, irritability, and executive dysfunction are particularly common and may occur very early in disease course (174). Psychiatric disorders are prevalent in patients with Huntington disease; a variety of disturbances have been observed, including depression, mood lability, anxiety, mania, obsessive behavior, or rigidity of thought (291). Frank psychosis is relatively unusual (291), though delusions may occur. A factor analysis performed on a registry of UHDRS behavioral scores suggested the presence of distinct behavioral patterns within Huntington disease, which related to depression, executive function, irritability, and psychosis (232). Observations from the European Huntington's Disease Network's registry found that a lifetime history of behavioral symptoms was common (196). The behavioral score, however, was not related to disease burden. Severe psychiatric problems occurred in one fifth of individuals. This included suicidal ideation and attempts, irritability and aggression, and psychosis. Observational study of 1082 patients with Huntington disease reported psychosis in 17.6% of the study population (52). Patients with psychosis demonstrated lower levels of chorea but worse cognitive function and behavioral problems. A study by the Huntington Study Group reported the probability of obsessive compulsive symptoms is approximately 3 times greater in patients with clearly manifest disease than in those with no apparent motor abnormalities (24).
Depression is a very common psychiatric manifestation of Huntington disease and may be accompanied by emotional irritability with outbursts of disruptive behavior. Health-related quality of life in patients with Huntington disease is mostly determined by depressive mood and greater functional incapacity, more so than by decreased motor and cognitive functions (115). Depression in Huntington disease patients may have an outsized impact on caregivers (21). According to the data from Enroll-HD observational study of 5709 subjects, suicidal ideation was reported as current (5.8% to 10%) or present in the past (18.6% to 30.9%) in both pre- and manifest disease stages (118). History of suicidal ideation and the presence of depression were strongly associated with current suicidal ideation. For premanifest individuals, socio-demographic factors and activities of daily living were important variables influencing development of suicidal ideation, whereas for manifest patients, presence of anxiety, apathy, irritability, and psychosis played important role (303; 118). Paulsen and colleagues suggest there are 2 critical periods for increased risk of suicide in Huntington disease. The first critical period is immediately before receiving a formal diagnosis of Huntington disease, and the second is in stage 2 of the disease, when independence diminishes (201). Alcohol and drug abuse may also be predictive, as demonstrated in a subsample of Huntington disease patients with the greatest suicidal ideation. The depression subscale of the Hospital Anxiety and Depression Scale and the Depression Intensity Scale Circles were found to be good screening measures for depression in the Huntington disease population in 1 study (60). Vegetative symptoms related to sleep and appetite, as well as symptoms of agitation and irritability, appear to be poor discriminators for depressed mood in Huntington disease individuals (231).
Analysis of the Enroll-HD database of 4469 manifest patients revealed that the incidence of behavioral symptoms at onset was highest in the individuals with early onset symptoms before the age 30 years (26%) as compared to the individuals with mid-adult onset, 30 to 59 years (19%), and late onset (11%) (219). Severity of all behavioral symptoms analyzed (depression, anxiety, irritability, anger, obsessive-compulsive symptoms) was also higher in the subjects with early adult onset of the disease.
Other symptom areas. Weight loss, changes in sleep and circadian rhythms, and autonomic dysfunction are reported in Huntington disease (293). Hypothalamic involvement in Huntington disease is postulated to drive many of these symptoms (85; 293), but the underlying pathophysiology is not yet clear. Given the widespread expression of huntingtin in the body, peripheral effects are also possible (41). These symptoms may have a significant impact on quality of life and on the better recognized cognitive, psychiatric, and motor features of disease.
Changes in sleep and circadian rhythms are increasingly recognized in Huntington disease, although it remains unclear what if any sleep disturbances are specific to Huntington disease versus common to Huntington disease-like or to neurodegenerative disorders in general (186). Most EEG data in Huntington disease are focused on waking states, whether to improve understanding of pathophysiology or develop biomarkers; there is a relative paucity of EEG data in sleep (206). A study plus literature review observed motor cortex dysfunction on EEG corresponding to increased motor activity in non-rapid eye movement sleep stages in Huntington disease subjects (206). Sleep in Huntington disease patients may be restless. Frequent awakening during sleep may become problematic, and sleep cycles may reverse. Disturbed night-time sleep and a delayed sleep phase can occur in Huntington disease; these may be associated with depression and lower cognitive and functional performance (13).
Weight loss was found to be directly linked to CAG repeat length and is likely to result from a hypermetabolic state (15). Huntington disease patients appear to have higher fasting energy expenditure compared with controls, and this is increased even further after insulin stimulation. Energy expenditure appears to increase with disease duration. These findings may help explain the progressive weight loss and muscle wasting in Huntington disease (14). A study of early-stage Huntington disease patients with some motor symptoms but no significant hyperkinetic movement disorder found that these individuals have a lower body mass index than age-matched controls (62). Therefore, weight loss may be an early manifestation of disease representing an intrinsic metabolic dysfunction or early neuropathology rather than solely a secondary consequence of increased movements or dysphagia.
Impaired gluconeogenesis has been described in Huntington disease patients (133). Studies also point to impaired cholesterol homeostasis in Huntington disease (158).
Autonomic dysfunction may also be seen in patients with Huntington disease (12). Heat intolerance and profuse sweating, contributing to dehydration and orthostatic hypotension, can be observed, more commonly in very young adult or juvenile onset (see below). Male sexual dysfunction may be underrecognized, significant, and progressive (148).
Functional outcomes. Motor and non-motor features often interact to create functional consequences. Functional outcomes are a key organizing principle for clinical care and are increasingly a target of clinical trials. Falls are a classic example of the combined impact of motor and non-motor symptoms. Impaired visuospatial processing and executive dysfunction creating distractibility, impulsivity, and poor planning interact with multiple movement symptoms in Huntington disease resulting in falls. Similarly, dysphagia may be a primarily motor symptom, due entirely to impulsive rapid intake, or a functional consequence of multiple impairments. Driving can be impacted by several domains: impaired ocular pursuits and saccades (poor tracking of other vehicles), motor impersistence (difficulty keeping foot on the brake or accelerator at a fixed position), impaired visuospatial processing (clipping fixed objects when trying to park), and executive dysfunction (difficultly planning a route or adjusting to detours) are some examples.
Falls are common in patients with Huntington disease; in some cohorts, up to 50% of Huntington disease patients fall more than twice a year (316; 83). In a study of 45 early- to mid-stage Huntington disease patients, falls occurred more commonly in patients with higher scores for chorea, bradykinesia, and aggression, as well as lower cognitive scores (100). In addition, Huntington disease patients had decreased gait velocity, decreased stride length, increased stride length variability, and a greater trunk sway in the mediolateral direction compared to nonfallers. In a study using a single triaxial accelerometer sensor, differences in sensor-derived velocity, step, and stride length were observed in manifest Huntington disease subjects, compared to nonmanifest mutation carriers and controls (56). Individuals with Huntington disease exhibit slower stepping response times and poorer dynamic balance, mobility, and motor performance compared with controls (95). Subtle postural deficits in the setting of changing sensory conditions have also been observed, involving not only motor manifest Huntington disease individuals but also nonmanifest and prodromal individuals up to 5 years before estimated motor diagnosis (247). Postural motor deficits have been demonstrated in Huntington disease individuals compared with controls, and these correlated with UHDRS Total Motor Score, UHDRS Total Functional Capacity, UHDRS Functional Assessment Score, and the disease burden score (228). The Tinetti Mobility Test and the Four Square Step Test may be useful tools for assessment of balance and falls risk in ambulatory motor symptomatic Huntington disease individuals (146). Huntington disease patients may be able to adjust their trunk position using auditory cues, enabling compensation in static (seated) or walking settings (138). Motor-cognitive dual task measures may be particularly useful in predicting fall rates and as functional outcomes for tracking disease progression (83), emphasizing how falls in Huntington disease are a multifactorial functional issue.
Juvenile-onset Huntington disease (Westphal variant). Juvenile cases (less than or equal to 20 years of age at onset) constitute about 5% of all cases of Huntington disease (215; 216; 84). A literature meta-analysis found a higher proportion, about 10%, in upper middle-income countries (215). Using alternative diagnosis criteria, such as cognitive decline or seizures in the setting of a high CAG repeat mutation, can increase this estimate considerably (87).
Juvenile cases and occasional young adult cases can present with prominent parkinsonism or rigidity-dystonia with little or no chorea. Oculomotor abnormalities are similar to those in adult-onset Huntington disease (99). Dominant presenting features of juvenile Huntington disease also include cognitive decline and behavioral changes in addition to nonchoreiform abnormal movements (49; 216; 87). Myoclonus is particularly common in patients with juvenile Huntington disease (216). Dysautonomia including profuse sweating and heat intolerance can be prominent in juvenile Huntington disease. As in adult-onset Huntington disease, weight loss is common; in juvenile Huntington disease this can be a very early and progressive problem. At time of diagnosis and even just prior, children with juvenile Huntington disease are on average of normal height but have significantly lower weight and BMI compared to age-matched norms (278).
Unlike in adult-onset Huntington disease, seizures are common in juvenile Huntington disease. In a retrospective review, seizures were present in 38% of juvenile Huntington disease subjects, with seizure risk increasing with younger age of onset (49). The most common seizure type was generalized tonic-clonic seizure, although multiple seizure types were often seen in the same individual.
Poor balance manifests in mid to late stages of disease for both adult and juvenile forms with frequent falling and eventual wheelchair or bed-bound state. The length of CAG expansion might affect the clinical manifestation of the disease; patients with higher expansion might have more gait disturbance as the initial motor symptom, whereas individuals with lower expansion might first present with loss of hand dexterity (84). Developmental delay and seizures are far more common in children with high expansion mutations.
Premanifest diagnosis stages. Premanifest Huntington disease includes subjects from presymptomatic (subject with no motor signs of the disease and no cognitive changes) and prodromal stages (a subject with mild motor symptoms) (242). Several motor signs may precede the onset of clinically diagnosed Huntington disease (by current motor symptom criteria): increased motor restlessness, slowing of saccadic eye movements, and slowing or dysrhythmic production of rapid, repetitive movements of the fingers or tongue (79; 205). Impairment of saccades has been demonstrated in mutation-positive individuals (246), with significant changes seen in saccadic latency from year to year (07). Oculomotor defects may be seen in individuals with a predicted time to clinical onset of up to 10 years (114). The anti-saccade performance was found to correlate with brain volume loss in the caudate and globus pallidus and with thinning of the occipital and parietal lobes. In a study, underlying gray matter loss was significantly associated with latency of vertical antisaccade performance (246). Variability in tongue protrusion forces has also been studied as a potential marker of motor dysfunction in prodromal and (motor) manifest Huntington disease (226).
Often individuals have prominent mood, thought, or personality disorders that present in the years prior to onset of definitive motor signs (174). This is true of juvenile onset Huntington disease (216) as well as adult onset. Cognitive changes may also precede the onset of motor symptoms (203). Usage of serotonergic antidepressant is higher in mutation carriers compared with controls, particularly as they approach their time to onset of motor manifest disease (243). Mild cognitive impairment may be present in nearly 40% of Huntington disease mutation carriers, with higher rates in individuals closer to the motor Huntington disease diagnosis (67). One study examining mutation carriers who were estimated to be less than 9 years from their clinical diagnosis found significantly poorer performance scores on nearly all cognitive tests compared with a control group (271). Individuals who had an estimated 9 to 15 years before their motor clinical diagnosis had poor performance scores on about half of their cognitive tests. In a study, mutation carriers appeared to demonstrate a more rapid decline in some (but not all) neurocognitive and psychomotor measures, as they approached the estimated onset of motor symptomatic disease (245). The earliest cognitive indicator of Huntington disease is emotional recognition, which may be detected in mutation carriers more than 15 years from the predicted motor diagnosis (200). Within 15 years of the predicted motor diagnosis, a number of cognitive measures may detect additional impairments, including time production and speed of processing. Mutation carriers followed over a 7-year period demonstrated a decline in memory and concentration function, as well as in motor function, as they converted to Huntington disease motor diagnosis (109). The cognitive domains of motor planning/speed and sensory-perceptual processing may predict time to clinical motor diagnosis (108). Decline in cognitive ability in mutation carriers most closely correlates to the number of trinucleotide repeats (130). Poor cognitive performance may also be affected by coexistent depression (263). Evidence suggests it is the cognitive and behavioral aspects of Huntington disease that result in the greatest burden on families and that are most strongly associated with functional decline (200). A prospective study of mutation carriers revealed that accustomed work and financial capacity were the earliest functional outcomes to decline (202). Patient concerns during the premanifest stages of Huntington disease were found to relate mostly to internal and relational issues (116). In a study of perceived stress in mutation carriers classified by estimated proximity to Huntington disease motor diagnosis, individuals in the mid group, defined as being 9 to 15 years before the diagnosis, were found to have the highest stress scores, although the precise reasons for this are unclear (66).
One challenge in assessing potential symptoms in mutation carrier premanifest individuals is the lack of validated clinical scales specifically designed to measure early changes in Huntington disease mutation carriers (287). The Unified Huntington Disease Rating Scale (UHDRS) was originally designed to measure motor signs in a motor symptomatic Huntington disease population. Although a number of items on the UHDRS appeared to discriminate between individual differences across a broad range of motor severity in one study, other items did not (286). Thus, some of the UHDRS items may have limited usefulness in assessing motor manifestations in a mutation-positive, mildly symptomatic population that does not yet have enough motor symptoms for a clinical diagnosis. The Q Motor force-transducer system is an example of attempts to develop sensitive measures for clinical trials in very early Huntington disease; comparable systems are not as yet in use clinically (225).
In another study, scores on the Trail Making Test (TMT), used to assess cognitive-motor functioning, appeared to be able to discriminate between healthy controls and mutation carriers, as far as 9 to 15 years before their time to estimated motor diagnosis (195). In prodromal individuals (early motor signs too slight for diagnosis), the TMT was found to primarily measure change in cognition and psychiatric symptoms and may, therefore, be a useful cognitive measure in these patients. Estimates of premorbid intellect, which are essential in neuropsychological test interpretation, may be complicated by early cognitive symptoms in mutation carriers (40). In a longitudinal prospective study of mutation carriers and controls, the American National Adult Reading Test (ANART) and the 2-subtest version of the Wechsler Abbreviated Scale of Intelligence (WASI) appeared to perform similarly, although there was slightly lower variability and higher test-retest reliability in the ANART compared to the WASI (40).
Subjective sleep disturbances were reported in premanifest mutation carriers in a retrospective pilot study (20). Similar to motor manifest patients in the same study, subjective sleep symptoms correlated with poorer neuropsychiatric outcomes but were not correlated with cognitive measures (20).
One study showed that caloric intake may need to be increased to maintain body mass index even in premanifest mutation carriers, suggesting increased energy expenditure due to subtle motor impairment or a hypermetabolic state (171). Children with expanded huntingtin CAG repeats and no manifest symptoms have been reported to have significant differences in growth compared to a control population (156). Measures of head circumference, weight, and body mass index were lower than that of healthy controls. In a study, growth charts of children diagnosed with juvenile Huntington disease indicated normal height but significantly decreased weight and BMI well prior to developing any Huntington disease symptoms (278). Although these data were limited to four children with prediagnosis records available, this fits with the data on presymptomatic adult mutation carriers. This suggests that Huntington disease may be a developmental (“loss-of-function”) disorder as well as a neurodegenerative (“gain-of-function”) disorder (192; 169).
Huntington disease is a progressive neurodegenerative disorder that leads to death via medical complications of the extremely debilitating neurologic condition. The illness progresses over a 15- to 25-year period. Complications during the course of illness include speech and swallowing problems, imbalance, incoordination, and falling, as well as impaired judgment and cognition. Death usually is caused by infectious complications of immobility in the late stages of the illness. Suicide remains one of the leading causes of death in the individuals with Huntington disease (118).
Juvenile-onset cases are generally more rapidly progressive than adult-onset cases; however, data are scarce, and many studies are cross-sectional, making individual prognosis challenging (216). Older adult-onset cases may be more slowly progressive based on cross-sectional studies, but longitudinal studies suggest limited differences compared to midlife onset cases (161; 151). A study comparing motor onset at 60 years or older to other adult-onset cases observed a similar prognosis in the two groups, with more gait unsteadiness and shorter average time to late-stage disease in the later onset group (151). It is possible that differences in studies reflect in part differences in “late-onset” cut-offs.
The Unified Huntington Disease Rating Scale (UHDRS) has been developed to help assess disease and follow progression over time (120). This scale is comprised of several components used to assess motor, behavioral, cognitive, and functional status. The Total Functional Capacity (TC) Scale (a 13-point scale subcomponent of the UHDRS; 13 equals normal function) is used to stage Huntington disease; a large multicenter study showed a decline of about 0.72 points per year in those with symptomatic Huntington disease (172). An analysis of prospective longitudinal data on 334 motor manifest Huntington disease patients observed a similar 0.6-point TFC decline per year (64).
CAG repeat length influences rates of disease progression (240). Individuals with shortest CAG expansions appear to have the best prognosis. A review of clinical trial data observed statistically significant associations between CAG repeat and clinical worsening on several motor, cognitive, and functional outcomes but not behavioral outcomes (220). Ten additional CAG repeats were associated with an 81% increase in progression on the UHDRS Independence Scale.
However, caution should be used in counseling individual patients and families especially outside the extreme end of CAG repeat lengths as there is enormous individual variability in age of onset, range, and progression of symptoms. Conveying the variability and uncertainties in prognosis is an important aspect of genetic counseling.
There are obvious challenges for predicting prognosis in the setting of reduced penetrance mutations with 36 to 39 CAG repeats. As population genetic data become more available, direct penetrance estimates suggest much lower penetrance rates than assumed from clinical cohorts. A population study of British Columbia, United States, and Scottish cohorts yielded direct estimates of 0.2% penetrance for 37 CAGs and 2.0% for 38 CAGs for motor manifest Huntington disease at 65 years or older (135). Carriers of the reduced penetrance mutation who do develop manifest Huntington disease usually do so at later ages (135). As diagnoses categories have not yet expanded beyond motor signs, data on nonmotor symptom rates in reduced penetrance allele carriers remain scarce.
Intermediate alleles (CAG repeat range 27 to 35) pose increasing prognostic challenges as more data are obtained on clinical phenotypes in this group (250). Although many individuals within this group remain asymptomatic, some can develop motor and non-motor symptoms characteristic of Huntington disease with highly variable age at the onset.
This case is a fictional amalgam drawn from multiple family experiences of a new Huntington disease diagnosis.
A 32-year-old woman sought presymptomatic testing for Huntington disease. Her elderly father had recently been diagnosed with Huntington disease after developing late-life chorea. There was no family history of Huntington disease prior to her father’s diagnosis, although her father’s brother had passed away in his 60s in part due to alcoholism and an undiagnosed psychiatric disorder, and her paternal grandmother developed dementia, presumed Alzheimer disease by the family, in her 70s. She had three older adult full siblings, one of whom appeared mildly symptomatic to her but vehemently denied any issues. She worked full time as a middle school math and science teacher. She and her spouse had one healthy child. The patient spoke with a genetic counselor regarding presymptomatic genetic testing. Both the patient and her husband denied her having any abnormal movements, cognitive or behavioral changes. Patient’s initial neurologic examination was normal. She had no cognitive or mood symptoms beyond anxiety regarding her father’s diagnosis. She and her spouse started and ended her in-person pre-test visit with a genetic counselor and were given an option to go forward with a blood draw that day. They were also briefly introduced to a licensed clinical social worker and given access to patient family-oriented printed and online materials on Huntington disease.
The patient decided against having presymptomatic genetic testing at that time. She expressed feeling relief of her concern about immediate neurologic symptoms that were not identified on today’s examination. The patient also voiced understanding of hers and her child’s genetic risk status. She was provided with the information about Huntington disease support groups meetings in her geographic area.
Three years later, the patient and her spouse returned. They had made adjustments in insurance and retirement plans, made medical powers of attorney and living wills. After an initial period of simply needing to absorb her father’s diagnosis and then several months of supportive counseling and reflection, the patient and her spouse felt ready to return to their hopes for another child. They had been relieved to watch the continued normal development of their first child. In this context, the patient had decided to go forward with presymptomatic genetic testing rather than mutation status blind preimplantation genetic diagnosis (PGD) or adoption. Given the length of time that had transpired since the initial visits, a new phone interview and pre-test in person visit with the genetic counselor were arranged. The patient was ultimately found to carry a causal genetic mutation for Huntington disease with 41 CAG repeats on the expanded allele of HTT. She underwent a neuropsychological evaluation due to her own concerns regarding potential subtle cognitive symptoms, which was reassuring. She continued working. After reviewing PGD risks and costs with care providers and her spouse, she became pregnant outside of in vitro fertilization, opted against prenatal genetic testing, and delivered a healthy son. She continued counseling and initially returned annually for clinical observation for the development of signs and symptoms of Huntington disease, which dropped off as she moved on with her busy life. The patient was recently seen by the social worker at a support group meeting; she seemed in good spirits and was considering moving to part-time work to spend more time with her kids. She seemed more fidgety than in the past and was planning to re-establish care with her neurologist for monitoring of her neurologic status. The patient did not feel she needed any medications.
• Expanded CAG repeat size explains only about 60% of the individual variation in Huntington disease age at onset with other genetic modifiers accounting for the remaining variability.
• Increases in CAG repeat lengths between generations may account for the phenomenon of new mutations.
• Striatal medium spiny neurons are most vulnerable to the toxic effect of mutant huntingtin protein, although cerebral cortex can also show signs of cellular dysfunction and death.
• Several clinical, biochemical, and neuroimaging biomarkers have been identified as predictors of the disease onset and progression.
Huntington disease results from an expanded and unstable trinucleotide repeat in the IT15 gene, also termed huntingtin (HTT), on the short arm of chromosome 4 (101; 305). There is a 50% chance of inheriting an expanded HTT allele from an affected parent. Three nucleotides, cytosine-adenine-guanine, form a trinucleotide (CAG) and are normally repeated over and over in this gene. The CAG repeat is in exon 1 of HTT and is translated into a polyglutamine region of the protein, huntingtin. The normal function(s) of huntingtin remain an active area of research. The CAG repeat expansion is thought to confer mainly a toxin gain of function, with pathophysiology triggered in some way by the polyglutamine expansion, leading to neurodegeneration.
Genetics. Huntington disease is an autosomal dominant disorder: persons with more than 39 CAG repeats in 1 allele of HTT will develop Huntington disease. Homozygotes do not differ from heterozygotes in age of motor symptom onset or disease severity, and the size of the normal allele does not appear to influence age at motor symptom onset (157). Most juvenile onset cases have very large CAG repeat expansions, in the 60 to 100 range. For the 40 to 55 CAG repeat range, representing about 90% of all expanded alleles, CAG repeat length accounted for 56% of age of motor onset variability (101). Individuals with the same expanded CAG repeat length have a 40+ year range in age at motor diagnosis (307; 157). Therefore, age of motor symptoms onset and disease progression variability may be due to other contributing genetic variants or environmental factors and not due to CAG repeat length alone (307; 101; Genetic Modifiers of Huntington’s Disease Consortium 2019).
Genetic contributors outside the HTT gene itself are thought to be the main factors in the variability of disease progression in individuals with the same HTT CAG repeat length (101; 10; 273; Genetic Modifiers of Huntington’s Disease Consortium 2019). The Genetic Modifiers of Huntington’s Disease Consortium performed a genome-wide association study of 9064 affected individuals and identified few genes influencing Huntington disease onset, including DNA repair genes MLH1, FAN1, PMS1, MSH3/DHFR, PMS2, and LIG1, but additional modifier sites identified on chr 5 (TCERG1) and chr 11 (CCDC82) may not be directly connected to DNA repair process (Genetic Modifiers of Huntington’s Disease Consortium 2019).
The 36 to 39 CAG repeat range has reduced penetrance: individuals with these repeat expansions may or may not develop the disease (135). Diagnosed Huntington disease cases with reduced penetrance alleles are relatively rare, likely due to very low penetrance rates (135). Individuals with intermediate alleles (CAG repeat range 27 to 35) were traditionally associated with a normal phenotype. There is, however, increasing evidence of possibility of developing clinical disease in this group (250). About 6% of general population were estimated to have intermediate allele length of CAG repeats (53). Analysis of data from the Prospective Huntington Disease At-Risk Observational Study (PHAROS) found that, compared to individuals with normal CAG repeat lengths, individuals with intermediate CAG repeat expansions had similar motor, cognitive, and functional outcomes but worse measures of suicidal ideation and apathy (141). In addition, intermediate allele carriers had significantly worse scores on 5 UHDRS behavioral items compared to both normal allele and expanded (disease-causing) allele carriers. Subtle motor and behavioral abnormalities have also been identified in individuals with intermediate-length CAG repeats in the Cooperative Huntington’s Observational Research Trial (COHORT) (103). Severe caudate glucose hypometabolism was demonstrated in a patient with 33 CAG repeats who manifested subtle motor and cognitive findings; the patient’s son developed Huntington disease with 48 CAG repeats (267). An analysis of observations on 76 intermediate allele carriers and 581 fewer than 27 CAG repeat allele carriers (controls) in the European Huntington’s Disease Network Registry database found no significant differences between the groups in UHDRS motor, behavioral, cognitive or TFC scores, or quality of life assessments, although the intermediate allele carrier group had mildly but significantly greater cognitive decline at 1-year follow-up (53). A growing number of case reports observed frank Huntington disease signs in individuals with intermediate CAG repeat range huntingtin alleles (273); however, despite the growing case literature in this area, whether the intermediate allele itself is the cause of symptoms remains controversial (194). Nonmotor symptomatic intermediate allele carriers may not be recognized as they likely have no family history of Huntington disease and do not themselves have motor symptoms that would trigger consideration of the diagnosis.
The HTT CAG expansion was the first triplet repeat mutation identified. This discovery provided the biological basis for anticipation, in which age of onset of a disease decreases in offspring compared to prior generations (218). CAG repeat lengths are unstable when transmitted from a parent to offspring. Analysis of hundreds of parent and offspring pairs from the Venezuelan cohort observed intergenerational repeat length instability, with CAG repeat length changes from maternal to child transmission of -5 to +10 and paternal to child of -7 to +41 (308). Marked expansion of the CAG repeat length likely occurs in spermatogenesis, with larger constitutive CAG lengths more likely to further expand in spermatogenesis (308; 255). Although the same data are not directly available for oogenesis, large expansions appear less likely to occur in oogenesis than spermatogenesis (273). This explains the observation that most (90%) of juvenile onset cases inherit Huntington disease from an affected father. In the Venezuelan cohort study, repeat length instability was influenced by the sex of offspring: there was a tendency towards expansions in male offspring versus contractions in female offspring (308). This effect was significant in maternal transmission but overwhelmed by the bias to large expansions in paternal transmission.
Increases in CAG repeat lengths between generations may account for the phenomenon of new mutations. Individuals with a reduced penetrance range CAG repeat (36 to 39) who are not themselves symptomatic may have offspring with clinical Huntington disease and a more expanded CAG repeat length (188; 248). Intermediate allele carriers may also have offspring with disease-causing range CAG lengths (267; 254). The risk of expansion into the disease-causing range appears to decrease with size of parental CAG repeat, as work on intermediate (27-35) alleles demonstrates.
Overall, most intermediate alleles have a very low but non-zero chance of expanding into disease-causing mutations due to germline instability; however, the risk appears to measurably increase at 33 CAG repeats and substantially increase at 35 CAG repeats, at least for paternal transmission (255).
Specific HTT haplotypes are found at widely different frequencies in different populations, with the haplotypes common in most European populations associated with increased CAG repeat instability (266; 302; 136). Intermediate allele sizes are observed preferentially on these HTT haplotypes (266; 301). Thus, although HTT haplotypes are not thought to contribute to age of onset or disease progression variability, they do directly influence population level prevalence of Huntington disease, CAG repeat instability, and new mutation occurrence (302; 101; 22). The implications of these observations go beyond genetic epidemiology: direct gene-silencing, allele-specific therapeutic approaches could address a majority, but far from 100%, of Huntington disease cases (136).
Pathophysiology. Huntington disease is a neurodegenerative disorder. The pathogenic cause of the progressive neurodegeneration in Huntington disease is not known. The neurodegeneration affects the striatum prominently, but entire brain weight is decreased, and neuronal loss in cortex and other nuclei has been documented. In the striatum, there is predominant loss of medium spiny neurons (299), thought to generate the classic hyperkinetic movement disorder (02). Striatal atrophy levels provide a neuropathological grading of Huntington disease (299). Widespread laminar degeneration of cerebral cortex is also well accepted as a key finding in Huntington disease, and is thought to drive many symptoms, particularly cognitive (239). White matter loss is a more recent area of study, particularly in early stages or nonmanifest and prodromal mutation carriers (11). Hypothalamic involvement may produce the sleep changes, dysautonomia symptoms, and BMI pre-motor symptom changes observed in Huntington disease (293). Cerebellar degeneration is classically thought to be a juvenile onset Huntington disease feature; however, evidence of cerebellar degeneration was reported in a study of eight postmortem Huntington disease brains (244). Grey matter density differences were reported between cohorts of 26 Huntington disease and 26 controls, with increased grey matter density increases in anterior cerebellum and decreases in posterior cerebellum in the Huntington disease group (58).
Proposed pathophysiologic mechanisms in Huntington disease. How expression of an expanded polyglutamine containing huntingtin protein results in neurodegeneration is an intense area of multiple studies (22; 249; 152; 223; 274). Most work centers on toxic gain of function effects. In addition, neurodevelopmental roles for huntingtin suggest that loss of function mutation impacts and potential protective effects of normal huntingtin against the mutated protein (309).
Huntingtin is believed to play an important role in a number of biological processes including synaptic transmission, intracellular transport, gene expression, nervous system development, and brain-derived neurotrophic factor (BDNF) production (22; 249; 223; 274). Huntingtin normally interacts with many other proteins, some of which are also of unknown function (249; 223). Posttranslational modification of huntingtin has been postulated to play a major role in its subcellular localization and also in influencing its protein-protein interactions (72).
The mRNA for the HTT gene is widely expressed in all tissues (249). Huntingtin can be found in a number of subcellular compartments, including the nucleus, the Golgi complex, mitochondria, and microtubules (72). Although the vast majority of work on huntingtin has focused on the brain, consideration of huntingtin’s normal functions and pathological impact in the periphery is becoming more common (41).
Mutated huntingtin protein is found in both affected and unaffected regions of the brain (98). Thus, the regional specificity of the neuropathology is not explained by a differential expression of the HTT gene in the brain. Interaction of the mutated Htt protein with various other proteins, such as the small guanine nucleotide-binding protein Rhes, localized to the striatum, leads to cytotoxicity and may contribute to the localized neuropathology of Huntington disease (272). Additionally, there is relative loss of BDNF production and, thus, neurotrophic support due to downregulation of transcription by mutant huntingtin, which may lead to selective vulnerability in striatal neurons (320). The role of adenosine A(2A) receptors in modulating synaptic functions and maintaining BDNF levels has also been explored (277). Work on BDNF currently informs clinical trial design for a mesenchymal stem cell BDNF production therapy (210).
Neuronal intranuclear inclusions, first noted in a Huntington disease transgenic mouse model, are observed in Huntington disease patient postmortem brain tissue, other animal models, and in cell-based disease models (22). These inclusions are specific to regions of the brain affected in Huntington disease. The steps to huntingtin aggregation are likely to include huntingtin fragmentation, a nucleation process strongly influenced by CAG repeat length, formation of small aggregates, and large aggregation (22). Some posttranslational modifications may be significantly altered in the setting of a Huntington disease mutation, potentially impacting huntingtin fragmentation and aggregation processes. Investigation of protein aggregation processes and their potential impact on pathophysiology connect Huntington disease with several other neurodegenerative disorders.
Prior to the discovery of the causal mutation for Huntington disease, proposed pathophysiologic pathways included glutamate excitotoxicity and mitochondrial dysfunction. Both are still areas of continued study, particularly as they potentially interact with the abnormal huntingtin protein and with each other, although precise cause and mechanism pathways remain elusive (152; 223). Magnetic resonance spectrography (MRS) has documented an increase in brain lactate in patients with Huntington disease as might be expected in the case of mitochondrial dysfunction or increased excitatory stress (131; 107). The size of the HTT CAG repeat has been reported to affect mitochondrial function. In juvenile Huntington disease patients, MRS has documented elevated glutamate, mainly in the striatum but also in extrastriatal areas, and low striatal creatine (230). In adults, the glutamate elevations occur in nonmanifest and manifest patients, but low creatine levels were found only in nonmanifest patients (229). Trials of creatine as a neuroprotective agent yielded similar mixed results: PRECREST observed creatine treatment-related slowing of cortical and striatal atrophy neuroimaging biomarker measures in nonmanifest individuals compared to mutation-negative controls, although a large double-blind, placebo-controlled trial of creatine in symptomatic Huntington disease was halted early for lack of benefit (238).
Mitochondrial dysfunction and abnormal energy metabolism are well documented in Huntington disease. Evidence of mitochondrial dysfunction has also been demonstrated in peripheral tissue. Huntington disease patients subjected to incremental cardiopulmonary exercise were found to have a lower anaerobic threshold on ventilatory and cardiometabolic parameters associated with an increase in plasma lactate compared with controls (45). Data from a number of studies suggest the mutant huntingtin protein impairs mitochondrial function directly as well as and indirectly by dysregulation of transcriptional processes (132). The resulting defects include reduced Ca2+ uptake capacity, defects in the electron transport chain activity, and increased sensitivity of mitochondria to Ca2+-induced permeability transition pore opening. Changes in mitochondrial permeability can cause cytochrome c release and subsequent caspase activation, leading to apoptotic cell death. Genotype- and time-dependent caspase activity abnormalities have been demonstrated in peripheral blood cells of Huntington disease patients (268). The activity of certain caspases was found to be significantly increased in patients who were homozygous for CAG repeat mutations and those who were heterozygous with large CAG repeat sizes, compared to those with low mutations and controls. This was accompanied by decreased cell viability and morphological changes.
Evidence of mitochondrial respiratory chain defects has also been identified in Huntington disease tissue (284). In addition, there is evidence that mutant huntingtin protein impairs intracellular trafficking of mitochondria, providing further evidence for a possible pathogenic role of mitochondrial dysfunction in Huntington disease (160). Data on mitochondrial dysfunction, impaired calcium homeostasis, and protein trafficking related to mutant huntingtin can be taken together to make a case for synaptic dysfunction as a major end pathway in Huntington disease pathophysiology (223).
The role of peroxisome proliferator-activated receptor-coactivator alpha (PGC-1 alpha), a transcription cofactor that regulates mitochondrial biogenesis and function, may provide a link between transcription dysregulation, mitochondrial dysfunction, and striatal medium spiny neuron dysfunction in Huntington disease (223). Astrocytic nerve growth factor has also been shown to stimulate mitochondrial biogenesis via a PGC-1 alpha-medicated mechanism, in P12 neuronal cells and primary striatal neurons, suggesting methods to impact Huntington disease by targeting PGC-1 alpha (44). A PGC-1 cofactor, the peroxisome proliferator-activated receptor-delta (PPAR-delta), also interacts with huntingtin. A mouse model study of PPAR-delta and mutant huntingtin interactions suggests this as another therapeutic target for Huntington disease (223). PPAR-delta related agents are already under study for other human disease processes. Thus, the expanded CAG repeat mutation may alter huntingtin interactions with known partner proteins or allow interactions with proteins not associated with normal huntingtin. Alterations in protein-protein interactions could contribute to mutant huntingtin pathogenicity generally, and to cell specific neurodegeneration, and provide areas for testing impact of interventions or developing new therapeutics. PPAR-delta and PGC-1 alpha related compounds represent but 1 attempt at leveraging preclinical pathophysiology work into therapeutic development. Another major area of scientific work centers on the role of mutant huntingtin in gene transcription (152; 223). Proteolytic products of abnormal huntingtin containing an N-terminal fragment with the expanded polyglutamine sequences are sequestered in the nucleus where they interfere with gene regulation (22; 223). Given this role of mutant huntingtin fragments, and the relationship between load of mutant huntingtin fragments and level of neurodegeneration in animal models, disruption of autophagy is another potential contributor to neurodegeneration in Huntington disease (152).
Thus, mutant Htt protein potentially causes cell death through pathways involving decreased neurotrophic support, glutamate excitotoxicity, mitochondrial dysfunction and increased oxidative stress, dysregulation of neuronal signaling capabilities, dysregulation of gene expression, and autophagy (22; 249; 152; 223).
Animal model work has long contributed to understanding Huntingtin disease. Intrastriatal injections of quinolinic acid, a glutamate agonist, into rat brain reproduce closely the neurodegenerative changes found in Huntington disease (23), creating an excitotoxic lesion model. Intraperitoneal administration of the mitochondrial toxin 3-nitropropionic acid also causes progressive cell death in the striatum of rodents and nonhuman primates. The development of genetic based animal models in Huntington disease has greatly advanced understanding of the disease process. Transgenic mice expressing exon 1 of the mutant human HTT gene develop a progressive neurologic syndrome like that seen in humans (168). Model systems now include Drosophila, rodents, sheep, minipigs, and nonhuman primates (186; 152). Notably, absence of huntingtin causes embryonic death in mice (317), and deletions within chromosome 4 that involve the HTT gene do not cause Huntington disease, suggesting that the mutant protein exerts its effect mainly through a gain in function rather than a loss of function (01), although loss of function neurodevelopmental impacts are also documented (309). Mouse model findings influence current therapeutic development, for example, avoidance of gene silencing strategies that would shut down all huntingtin production.
Despite the advances in understanding disease pathogenesis afforded by animal models, limitations exist in translating these findings to the human condition. For example, the mouse model does not exhibit the phenotypic constellation of changes seen in the human Huntington disease brain and is unable to fully recapitulate the biological environment in which the long-term deleterious process evolves (299). Induced pluripotent stem cells (iPSCs), derived from patient fibroblasts, and embryonic stem cells retain the potential to differentiate into neurons and may hold great promise as a relevant human neural cell model of Huntington disease (94). In particular, work in iPSCs has expanded. HD-iPSCSs have reproducible CAG-repeat-expansion phenotypes on differentiation (94). iPSCs may not only provide a cellular model for studying the molecular mechanisms underlying Huntington disease but may also play a role in Huntington disease cell therapy, validation of human-specific gene therapies, and in drug discovery (94). CRISPR-Cas9 technology is being used for allele-specific genetic editing in HD-iPSCs to rescue pathology in these cell models (258; 182; 314). HD-iPSCs are also being used in preclinical development phases for viral vector-delivered RNAi gene silencing constructs (38).
Research studies have also provided further insights into possible mechanisms related to clinical manifestations of Huntington disease. Neuropathological studies have shown loss of oxytocin- and vasopressin-expressing neurons, with increases in the number of cocaine- and amphetamine-regulated transcript (CART)-expressing neurons (85). These alterations in peptide expression of hypothalamic neurons may influence the emotional and metabolic disturbances seen in Huntington disease. Studies of motor cortical plasticity in Huntington disease gene carriers (premanifest and very early manifest gene carriers) have revealed evidence of reduced inhibition to continuous theta burst stimulation (197). Early cognitive deficits are probably related to synaptic and cellular dysfunction (180). A postmortem neuropathological study found an association between motor dysfunction and cell loss in the primary motor cortex as well as between major mood symptomatology and cell loss in the anterior cingulate cortex (281). The pathological burden at autopsy, however, does not appear to correlate with cognitive and functional scores just before death (209).
Identification of a reliable and robust biomarker in Huntington disease is a growing area of research, with particular importance for future studies in disease-modifying therapies (241; 274). Clinical and neuroimaging as well as electrophysiological and biochemical parameters have been studied as potential biomarkers. Observational data collected over 24 and 36 months revealed several longitudinal changes in early Huntington disease participants, including imaging markers, cognitive measures, and quantitative motor scores, with some measures predictive of phenotypic progression (269).
The microRNA miR-34b was found to be elevated in plasma from Huntington disease gene carriers prior to the onset of clinical symptoms, potentially providing a plasma biomarker for Huntington disease (88). A significant decrease in the plasma branched-chain amino acids valine, leucine, and isoleucine has been demonstrated in Huntington disease individuals, compared with controls (181). In addition, leucine was also found to be significantly decreased in presymptomatic individuals and those at a very mild stage of disease.
The utility of MRI evaluation in nonmanifest and manifest Huntington disease has also been studied (241). Reduced intracranial volumes have been observed in preHD compared with controls (192). A meta-analysis of voxel-based morphometry studies demonstrated reductions in gray matter concentration in the left basal ganglia and prefrontal cortex of preclinical individuals (153). Impairment in tongue force, metronome tapping, and anti-saccade error rate has been associated with striatal loss in nonmanifest mutation carriers and early Huntington disease, with additional volume reduction in the occipital lobe in those with tongue force deficits and anti-saccade error (251). Using volumetric neuroimaging measurements, faster rates of atrophy in striatum, total brain, and cerebral white matter were demonstrated in prodromal individuals compared with controls (11). Klöppel and colleagues explored the usefulness of a multivariate support vector machine, using the gray matter segment of MRI scans, to automatically identify nonmanifest HTT mutation carriers in the absence of any a priori information (147). Nonmanifest HTT mutation carriers close to estimated diagnostic onset were successfully separated from controls on the basis of single anatomic MRI scans. A study of 523 prodromal Huntington disease subjects found evidence of volume decrement, particularly affecting the posterior and superior cerebral regions, even in the "midway to onset group" with an estimated proximity to clinical onset of 9 to 15 years (191). Another study demonstrated that the volumes of the caudate nucleus and putamen were reduced in nonmanifest Huntington disease far from predicted onset (greater than 10.8 years) and that atrophy of the accumbens nucleus and pallidum was also apparent in premanifest Huntington disease in individuals close to onset (0 to 10.8 years) (289). Regional cortical thinning and striatal changes were demonstrated in far-from-onset nonmanifest mutation carriers compared to controls, using cortical surface modeling and subcortical segmentation analysis (313). MRI changes in the hypothalamic region have also been demonstrated before clinical onset (264). The size of the CAG repeat lengths may also influence the rate of striatal atrophy in prodromal Huntington disease (11). In a study evaluating patterns of neuropathologic involvement in Huntington disease brains, two clusters of involvement were identified, striatal and cortical, with the striatal cluster correlating with Huntington disease repeat size (104). Research groups are currently attempting to leverage these observations in nonmanifest and prodromal groups to improve clinical prognosis and clinical trial outcome development. Investigation of multiple MRI and phenotype variables in over 1000 mutation carriers, all nonmanifest at the start of the multiyear longitudinal observational study, identified putamen volume as the best dynamic predictor of conversion to motor manifest diagnosis (159).
A study using magnetization transfer MR imaging demonstrated degeneration of the subcortical and cortical gray matter in Huntington disease mutation carriers, with correlations between regional magnetization transfer ratios and several clinical variables (91). Abnormalities in motor, associative, and limbic corticostriatal circuits on diffusion tensor MRI also correlated with several clinical signs in early Huntington disease (59). In a longitudinal study, magnetization transfer imaging-derived measures did not demonstrate a decrease in structural integrity in manifest Huntington disease individuals over a 2-year period, suggesting that these measures are not suitable for monitoring disease progression in Huntington disease (290).
Prospectively followed nonmanifest mutation carriers who developed motor symptoms after 5 years of follow-up were found to have lower caudate glucose metabolism on their initial 18F-FDG PET scan, compared to those who remained symptom-free (46). Altered levels of neural activation have been observed on functional MRI studies during tests of emotional recognition in nonmanifest individuals compared with controls (193). Cognitive decline in nonmanifest or early-stage disease has been reported to correlate with reduced levels of N-acetylaspartate and glutamate on magnetic resonance spectroscopy (285). In a small study demonstrating reduced striatal uptake of 1231-FP-CIT on SPECT, involvement of the nigrostriatal pathway has been suggested, as well as reduced substantia nigra volumes on MRI, although these did not correlate with clinical measures (140).
Elevated levels of iron have been observed in the caudate nucleus and putamen in early Huntington disease individuals, compared to nonmanifest mutation carriers and control individuals (69). MRI susceptibility and MRS studies observe progressive increases in iron and other transition metals compared to controls in nonmanifest mutation carriers and motor symptomatic Huntington disease (237; 288). These studies imply that changes in iron homeostasis could occur very early in Huntington disease pathogenesis.
Cerebrospinal fluid concentration of neurofilament light protein that is found primarily in axons and released due to neuronal damage was significantly elevated in patients with Huntington disease as compared with healthy individuals and correlated with the disease stage, motor and cognitive impairment, and brain volume loss (190; 37). Microglial-derived inflammatory mediator YKL40 was elevated in patients with Huntington disease and increased with disease progression (298). Concentration of tau protein and mHTT protein were increased in cerebrospinal fluid of the affected individuals (234; 78).
• Global variation in Huntington disease prevalence is partly explained by frequency of different HTT gene haplotypes in the general population.
The prevalence of Huntington disease has been reported to be 2.71 per 100,000 worldwide, based on meta-analysis (211). The prevalence based on European, North American, and Australian studies was 5.70 per 100,000 (211). A subsequent systematic review observed a tenfold difference in prevalence estimates between different populations worldwide and a clear increase in prevalence estimates especially in North American, Western European, and Australian regions (222). A review of the UK’s General Practice Research Database estimated a prevalence of 12.3 per 100,000, which had risen from 5.4 per 100,000 in 1990 (73). A direct ascertainment prevalence study in the British Columbia province of Canada estimated Huntington disease prevalence at 13.7 per 100,000 general population and 17.2 per 100,000 in the Caucasian population (77).
Incidence of Huntington disease is considered stable: a rise in incidence is not thought to be driving rising prevalence estimates (306). There are concerns that the prevalence of Huntington disease may actually be underestimated due to a variety of reasons, such as stigma associated with the disease (221; 304). Methodological differences between studies, the effect of the baby-boomer birth cohort, and the occurrence of new mutations may also contribute to increasing prevalence estimates (266; 164; 77).
Reduced penetrance 36 to 39 CAG repeat lengths represented 1 in 400 (about 0.25%) alleles in a population study of British Columbia, United States, and Scottish cohorts (135). Of these, all but 1 was on a Huntington disease-associated haplotype background (A1, A2, or A3a). The prevalence of intermediate length huntingtin alleles was about 6% in all 3 cohorts (135); a previous study of the same British Columbia cohort found 60% of intermediate length CAGs on Huntington disease associated haplotypes (256). A study of etiology of chorea in Cuban patients found intermediate alleles in 3.97% of the 63 unrelated asymptomatic control subjects (294), whereas a review of genetic data in Latin American populations reported intermediate allele frequencies of 4% to 10% in controls (42). Intermediate alleles in a Thai population were rare, only 2 of 445 chromosomes sequenced, less than 0.4% (213). As discussed above, germline expansions from intermediate alleles are a source of new mutations in the population; fewer intermediate alleles in the population likely correlates with fewer new mutations.
Although Huntington disease occurs in all populations, consistently higher frequencies are reported in populations with European ancestry; however, a low prevalence is observed in some regions, such as Finland (261). In the 2012 meta-analysis, the overall prevalence in Asia was reported as 0.40 per 100,000 (211); incidence reports in Asian populations are consistently low, regardless of study methodology (222).
A study of Huntington disease and the close genetically unrelated phenotype mimic Huntington disease-like 2 (HDL2) in South Africa generated estimates of 5.1 per 100,000 of Huntington disease alone in the white South African population versus combined Huntington disease and HDL2 prevalence estimates of 2.1 and 0.25 per 100,000 in mixed ancestry and black populations respectively (19).
The differences between Huntington disease prevalence across the globe are in large part attributed to differences in population frequencies of HTT haplotypes. Haplotypes A1 and A2 are found at high rates in most European populations (266; 302; 136), but at a relatively lower rate in Finland (261). In European populations, Huntington disease causal CAG expansions are observed primarily on haplotypes A1, A2, and (less so) A3a; intermediate alleles are also preferentially found on A haplotypes (266; 301; 302; 136). The A1 and A2 haplotypes are absent in Chinese and Japanese general populations (302) and were rare in the 192 controls in a Thai genetics study (213). Haplotypes A1 and A2 were also absent in black South African unaffected individuals but were common in self-reported Caucasian and mixed ancestry South African groups, similar to European ancestry populations (18). Similar haplotype patterns are observed in Venezuelan and Brazilian studies compared to European populations, although the Latin American population data are limited and have strong founder effects in some populations (42). In East Asian populations, Huntington disease causal CAG expansions are observed mainly on haplotype C and sometimes on haplotype A5 (302; 213). Huntington disease mutations in black South African patients were observed primarily on haplotype B (18). Overall, relatively higher population Huntington disease prevalence appears tied to the presence of higher risk A1 and A2 haplotypes with many patients of European ancestry sharing a common remote original mutation, whereas low prevalence populations have rarer multiple independent CAG expansions on a mix of other HTT haplotypes (101; 22).
Founder effects creating pockets of high prevalence are seen in some regions. A classic example is the Zulia region of Venezuela, where a single ancestor is common to the thousands of related patients making up the cohort who contributed to the discovery of the HTT mutation (307; 42). A geographical isolate of Huntington disease first reported in the Canete region of Peru in 1979 may account for the difference in haplotype distribution in Peruvian versus other Latin American populations, with 85% of Peruvian chromosomes of HTT haplotype C (42). Founder effects also likely account for wide (4-fold) variations in prevalence within European regions reported within Sweden and the United Kingdom, particularly rural versus urban populations (236).
Limited data exist for the epidemiology of juvenile-onset Huntington disease specifically. A population-based study of 20 years of patient records in the United Kingdom provides a minimal estimated incidence of 0.70 (0.36-1.22) per million patient-years and prevalence of 6.77 (5.60-8.12) per million patient-years (65). These estimates will likely increase as use of distinctive non-motor signs and symptoms in diagnosis becomes more common (87).
Length of education was suggested in a study to influence age of disease onset and clinical severity (162). Patients with longer education were found to exhibit earlier estimated age at onset; this may have been related to earlier symptom recognition. These patients also demonstrated less severe clinical scores compared to those with shorter education. Other factors that have been reported to influence age at onset include lifetime alcohol and drug abuse in women and caffeine intake, although further studies are required to confirm these findings (36; 260).
There are no proven ways to prevent the onset or the progression of Huntington disease. This remains an area of intense research.
A variety of illnesses may cause chorea or dystonia, and some are associated with dementia. Nongenetic and potentially treatable causes of chorea include systemic lupus erythematosus, neurosyphilis, multiple sclerosis, hyperthyroidism, postinfectious and infectious conditions (such as encephalitis), and stroke (112; 167). Sydenham chorea, a postinfectious disorder, is the most common cause of chorea in children. Chorea is well described as a side effect of certain drugs, including estrogens, carbamazepine, phenytoin, anticholinergics, amphetamines, and those drugs known to cause tardive dyskinesia, such as antipsychotics and antiemetics. Chorea gravidarum is a well described self-limited entity.
Other inherited disorders form the key differential diagnosis for Huntington disease (112; 167). As Huntington disease is the most common cause of chorea in adults, this workup is generally undertaken when Huntington disease has been excluded. Few features clearly distinguish Huntington disease from other causes; thus, exclusion is considered negative genetic testing (173). One comparison study found hemichorea as the only distinguishing feature between genetically diagnosed late-onset Huntington disease versus mutation-negative cases (151). As with Huntington disease itself, lack of a family history does not exclude the possibility of a genetic disorder.
Wilson disease uncommonly mimics Huntington disease in presentation, but is a key consideration as at treatable disorder, especially in young adults.
Benign hereditary chorea typically presents with an early (childhood) age at onset of a nonprogressive choreiform disorder associated with a normal life span (75). The underlying genetic etiologies are heterogeneous, including mutations in the gene for thyroid transcription factor 1. The full phenotypic range may be less benign than originally thought, with reports of learning disabilities, developmental delay, and, for some specific mutations, severe multisystem disorders of the lungs, thyroid, and central nervous system (112; 167).
Huntington disease phenocopy disorders in adults are each rare but do occur: in aggregate, in a study Mariani and colleagues accounted for 12.4% of cases with a Huntington disease-like phenotype undergoing genetic testing for diagnosis (173). In most reported cohorts, the most common cause of a Huntington disease-like presentation outside of Huntington disease in adults is the C9ORF72 expanded intronic hexanucleotide repeat mutation (111; 150). This mutation is now thought to account for nearly 2% of all Huntington disease-like cases (112; 167). This mutation was first associated with a motor neuron disease and frontotemporal dementia phenotype. The Huntington disease-like phenotype description is still expanding (111).
Huntington disease-like 2 (HDL2) is an autosomal dominantly inherited disorder due to an expansion of trinucleotide repeats in junctophilin-3, to date reported exclusively in families with African ancestry. This mutation explained 3 of the 28 cases in a study (173). HDL2 is, therefore, a key diagnostic consideration in black or mixed ethnicity population groups (19; 167). It closely resembles classic Huntington disease, including clinical features of chorea, dystonia, parkinsonism, and cognitive deficits (300; 19).
Huntington disease-like 1 (HDL1) is an extremely rare familial prion disease.
Various autosomal dominant spinocerebellar ataxia disorders can present with phenotypes similar to Huntington disease. SCA17 can present as a close mimic of Huntington disease (considered HDL4), or with a wide range of other phenotypes. Although SCA17 is considered the most classically Huntington disease-like disorder, more common spinocerebellar ataxia disorders can present with phenotypes relevant to choreic or bradykinetic rigid Huntington disease. The most common is SCA3; others include SCA1 and SCA2. Dentatorubropallidoluysian atrophy (DRLPA), although reported in families of various ethnicities, is a particular consideration in Japanese populations.
Chorea-acanthocytosis, like Wilson disease an autosomal recessive disorder, causes dementia, involuntary movements, and caudate atrophy. However, chorea-acanthocytosis also causes abnormal red cell morphology, neuropathy, myopathy, epilepsy, elevated creatine phosphokinase, self-mutilation behavior, and a peculiar eating dystonia (food is pushed out of the mouth by a dystonic tongue movement).
Other disorders that may present with Huntington disease phenotypes include forms of neurodegeneration with brain iron accumulation (NBIA), idiopathic basal ganglia calcification, Friedrich ataxia, and mitochondrial disorders (112; 167).
In a study of 285 patients with Huntington disease phenocopies with normal CAG repeats, subjects were screened for mutations causing HDL1, HDL2, DRPLA, SCA1, SCA2, SCA3, SCA17, neuroferritinopathy, and Friedreich ataxia (310). In 8 subjects, other mutations were found: 5 cases of HDL4, 1 of HDL1, 1 of HDL2, and 1 patient had Friedreich ataxia. There were no cases of DRPLA, SCA1, SCA2, SCA3, or neuroferritinopathy (NBIA3). This suggests that Huntington disease phenocopies are clinically and genetically diverse, thus, although these entities are worth including in differential diagnoses (173), obtaining a definitive genetic diagnosis in Huntington disease mutation-negative patients can be challenging.
Mutations in the HTT gene were not associated with other disorders.
• Initial genetic testing to rule out Huntington disease might be the most cost-effective way to workup adult-onset chorea given the large differential diagnosis.
• Neuropsychological testing to determine patient's degree of cognitive disability can assist a patient and family with appropriate planning of care.
• Presymptomatic and confirmatory genetic testing is best utilized with the support of genetic counseling as well as regional and international guidelines.
The diagnosis of Huntington disease may be missed or delayed even in patients with chorea without a definitive family history. This can occur if affected family members are deceased, particularly if family members died at a young age from unrelated (cancer) or possibly related but ambiguous (suicide, motor vehicle accident) causes. Due to the social stigma of the psychiatric and cognitive symptoms, family members may not divulge a Huntington disease diagnosis to others in the family. Nonpaternity and adoption are other potential reasons for a lack of family history. Finally, the CAG repeat is unstable: an increase in expansion size from parent to child can cause symptoms in the offspring prior to any symptoms in parents or other older relatives. Uncommonly, a parent carries a reduced penetrance or high intermediate range CAG repeat, which expands into the fully penetrant range in the child, causing the first symptomatic presentation of Huntington disease in the family.
These genetic considerations are especially relevant at relatively early and late-onset ages. Delays in diagnosis, some by many years, are common in juvenile onset Huntington disease as neuropsychiatric symptoms often long precede motor symptoms, making debates about clinical diagnosis categories especially acute in this group. Given the severity of the diagnosis, and the impact on the rest of the family of both psychiatric and cognitive symptoms and of the diagnosis itself, consideration of this diagnosis in cases of cognitive decline and/or progressive severe psychiatric or behavioral symptoms is warranted (216).
In a study of genetically diagnosed late-onset cases, about 30% of late-onset adult Huntington disease cases did not have a positive family history for Huntington disease, compared to about 85% of cases confirmed as negative for the Huntington disease CAG repeat expansion (151). In a late-onset Huntington disease cohort, 68% of patients represented the initial diagnosis for their family (161). Thus, lack of family history does not exclude Huntington disease as a diagnostic consideration, particularly with a classic motor symptomatic presentation. Huntington disease as a diagnosis for purely cognitive or other presentations, particularly for older individuals and for intermediate CAG repeat sizes, is an evolving area. Consideration of mixed pathologies, particularly in older Huntington disease cases with dementia, will become more acute as gene- and/or protein-specific disease modifying therapeutics come online (57).
Diagnosing symptoms as Huntington disease in a mutation carrier can be challenging, as some symptoms such as anxiety are common in the non-Huntington disease population. Consideration of other etiologies for specific symptoms is important in Huntington disease care. Conversely, less common Huntington disease motor presentations, such the bradykinetic rigid form in an adult, may be initially misdiagnosed even in the presence of family history. Although a low threshold to consider Huntington disease in the context of a positive family history is reasonable, decisions to proceed with confirmatory genetic testing in at-risk individuals (affected parent, genetic status of patient unknown) should take into account the level of uncertainty in assigning concerning symptoms specifically to Huntington disease. Etiologies from medication side effects to reactive depression to other neurologic disorders can certainly occur in patients with or at risk for Huntington disease. The clinical presentation suggestive of Huntington disease has been described in a patient with family history of Huntington disease who became convinced she had Huntington disease even though her DNA test was negative; she turned out to have a functional (psychogenic) etiology (74).
Confirmatory Huntington disease diagnosis. DNA diagnostic testing can now determine whether a patient with a suspicious clinical syndrome has Huntington disease (confirmatory genetic testing). Initial genetic testing to rule out Huntington disease is probably the most cost-effective way to workup adult-onset chorea given the large differential diagnosis and the rarity of other entities compared to Huntington disease as the underlying etiology (112). Appropriate genetic counseling should be available even in confirmatory genetic testing settings, as this diagnosis has repercussions for the entire family, and unclear results such as reduced penetrance range or intermediate alleles are possible (179). Also, Huntington disease phenocopy disorders, although each rare, are in aggregate common enough even in adults to warrant mention in genetic counseling prior to confirmatory genetic testing, particularly when there is no known genetic confirmation of the Huntington disease diagnosis in the family (173). Although confirmatory genetic testing is now the gold standard for Huntington disease diagnosis, in some regions, such as the United States, insurance coverage of genetic testing is highly variable, and families may not be able to afford confirmatory testing. Thus, a positive, genetically confirmed family history plus a high UHDRS diagnostic confidence level based on motor symptoms is still considered diagnostic even without confirmatory genetic testing.
Neuropsychological testing can be helpful in delineating the patient's degree of cognitive disability and suggesting nonmedication interventions for continued independence. Clinical interview by neuropsychology, neurology, or psychiatry is important in identifying treatable mood and other neuropsychiatric changes, whether these are centered around coping with a new diagnosis or part of the disease itself.
MRI and CT scans show prominent caudate atrophy in young patients with moderate disability, but these may be within the normal range in patients with early signs of Huntington disease. In elderly patients with Huntington disease, caudate atrophy may not stand out as conspicuous in comparison to the degree of cortical atrophy. Pragmatically, imaging is currently used in clinical care to explore potential non-Huntington disease contributions to symptoms rather than for diagnosis or staging of Huntington disease itself.
Seizures are well reported in juvenile-onset Huntington disease, particularly the youngest onset group (49). Thus, EEG is a key part of the workup in these cases.
Juvenile-onset Huntington disease presents special complications for confirmatory genetic testing decisions. Children who present under 10 years of age should be considered for confirmatory testing if they have a positive history of Huntington disease (usually the father) and at least two of the following: declining school performance, seizures, oral motor dysfunction, rigidity, or a gait disorder (216). Studies propose confirmatory genetic testing in potential juvenile-onset cases with a positive family history, seizures, or declining school performance and decreasing cognition even without motor symptoms (87). Caution must be used in considering CAG repeat lengths under 60 as diagnostic for juvenile Huntington disease; although lower CAG repeat lengths can cause juvenile Huntington disease, nonspecific symptoms in these cases including seizures, cognitive symptoms, and especially psychiatric symptoms may be due to other etiologies. Similarly, juvenile onset Huntington disease without known positive family history is uncommon but well reported; thus, it is important to consider in the differential diagnosis even in the absence of family history, but caution must be applied in considering and interpreting confirmatory genetic testing in these circumstances.
Presymptomatic genetic testing. The term “at risk” has long been used in the Huntington disease community to indicate that a person has an affected relative but does not know their own genetic status. The risk level depends on the family relationship; for example, an individual with an affected grandparent is 25% at risk of inheriting the Huntington disease causal mutation. This is in contrast to clinical genetics language, where a mutation carrier is also considered “at risk” for developing the clinical disorder at some point in their life: for HTT CAG repeats over 39, the risk level is 100%. This discussion uses current common terms of at risk as unknown mutation status. Similarly, “presymptomatic” and “predictive” are both used to describe genetic testing in nonmanifest individuals, either with no possible Huntington disease-related symptoms or no motor diagnosis.
Prior to available genetic testing, about 50% to 80% of at-risk individuals indicated interest in presymptomatic testing; however, worldwide uptake of presymptomatic genetic testing averages about 10% to 20% (282). A substantial number of at-risk patients do not come forward for testing until symptomatic (185). One study indicated that women who are at risk from their mothers are the most likely to go through testing (93); multiple subsequent studies show a higher uptake of predictive genetic testing in women compared to men, and in offspring of affected mothers versus fathers, but the underlying reasons for gender associated differences in predictive genetic testing remain unclear (128). Reducing uncertainty is in some cohorts a more frequently cited reason for undergoing presymptomatic genetic testing than reproductive decision making (93; 68). Uptake of presymptomatic genetic testing is likely to shift as attitudes towards genetic information change, legal protections against genetic discrimination increase, and disease modifying therapeutics become available.
Presymptomatic DNA testing for the Huntington disease mutation is a complex procedure with a variety of medical, psychological, ethical, and financial implications for the person tested, their partner, and relatives. International guidelines are available and are very helpful in structuring the case-by-case approach (282). Referral to an experienced genetic counselor is strongly recommended. Pre-test discussion of the full range of potential genetic results and their known implications, including the uncommon reduced penetrance and intermediate alleles, is warranted. Current guidelines suggest at least three points of contact through the testing process: an initial phone interview, and pre- and post-test in-person visits. Genetic testing guidelines were revised in 2016 and are available on the website of Huntington Disease Society of America: www.hdsa.org. Identification of a support person, a friend or relative, to accompany the at-risk individual is recommended, as is identifying a trained counselor for use if needed. The phone interview can help determine whether a neurologic or psychiatric exam needs to be part of the initial in-person visit or if the individual needs more time before making an in-person appointment. An in-person pre-test visit may include blood draw for genetic testing, or the patient may decide to defer genetic testing at that point. The care team may recommend delay in genetic testing particularly if any concerns are raised regarding untreated or undertreated psychiatric or medical disorders that could impact decision-making and increase risk of negative consequences of genetic testing. Finally, in-person post-test results delivery of any result, mutation-positive or -negative, is considered the care gold standard, both for reducing risk of adverse consequences of presymptomatic genetic testing and for adequately conveying complex genetic information. Some individuals who seek genetic testing will voluntarily withdraw after blood testing has been completed but before the in-person post-test visit, presumably because after personal reflection and counseling they determine that obtaining a genetic test result is not in their best interest. Gradually telemedicine options are becoming available to decrease travel burden for the “in-person” visits. The Huntington disease approach to predictive testing has been adopted for other disorders (96).
Use of this cautious approach is associated with few adverse events (03; 93; 283). It also provides at-risk people multiple points for decision making and decision changes. A prospective German study examined outcomes a year out from undergoing at least 1 step in a predictive genetic testing protocol, ie, patients who did and did not choose to go forward with the genetic testing (128). Initially 79% of participants expressed clear interest in genetic testing, but 61% went forward with actual testing. One patient never returned for results during the 4-year follow-up period (128).
In people completing genetic testing protocols and receiving results, serious adverse events such as suicidality and acute psychiatric illness appear to be rare (03; 68). Patient experiences, assessed at 5 years after acquiring the knowledge of their carrier status, were found to be varied in their long-term impact: one study found that the knowledge could potentially play both motivating and obstructive roles in decisions to pursue further education, career, or investment in personal health (105). In another study, the prevalence of major depression 1 year after predictive testing in mutation carriers was found to be 6% as compared to 3% in mutation-negative individuals (50). However, in a multiyear longitudinal study, mutation carriers who at pre-test had more intrusive thoughts, avoidance reactions, low self-esteem, and worse sense of well-being were more likely to be lost to follow-up after receiving a mutation-positive result, implying a possible systematic underestimation of adverse events (283). Feelings of hopelessness in mutation carriers decreased after an initial spike but then rose again 7 to 10 years after genetic testing (283). Longitudinal studies of 1 year (51) or 7-to-10-year post-test follow-up (283) provide some insights on potential indicators of adverse impacts of presymptomatic genetic testing. Hopelessness and depressive symptoms were more common at 1 year or less and in the 1- to 5-year range in individuals with a mutation-positive result, with no children, who were married at time of genetic testing, and who were close to their estimated age of motor symptom onset (51; 283). Mutation-negative individuals can also have negative and even serious post-test reactions, emphasizing the need for a common in-person results pathway for all individuals (03; 93).
Genetic counseling of the individuals with low penetrance alleles (36 to 39 CAG repeats) and intermediate alleles is challenging (179). Considering the unpredictability of age at onset and of clinical prognosis in Huntington disease in those patient groups, the accurate interpretation, a proper psychological support, and a scientifically sound and compassionate communication of the genetic test result are crucial. Individuals carrying an intermediate or low penetrance allele should be carefully counseled on the potential risk of genetic transmission to children, even if they are asymptomatic at the time of genetic counseling.
Presymptomatic genetic testing in children and juveniles at risk for Huntington disease is not recommended.
• Management of Huntington disease involves an interdisciplinary whole-family approach utilizing expertise in neurology, psychiatry, neuropsychology, rehabilitation and wellness, and nutrition, in addition to genetic and social issues.
• Despite advances in understanding pathophysiology of Huntington disease made in the past decade and multiple clinical trials of potential disease-modifying therapies, current treatment remains symptomatic.
An interdisciplinary approach is invaluable in the initial diagnosis and continued care of Huntington disease (22; 279). Periodic consultation at a subspecialty center can support community providers. Treatment of patients with Huntington disease requires a coordinated effort on the part of a medical, psychiatric, social service, and physical or occupational therapy team. Treatment is tailored to the treatable symptoms and cannot be generalized to all patients or to an individual patient over all stages of the illness. Although only symptomatic treatment is currently available, disease-modifying therapy, aimed at slowing disease progression, is an area of active research (296; 139; 17; 176; 275).
Symptomatic pharmacological therapy. Chorea in Huntington disease decreases functional capacity (25), increases falls risk (100), and worsens weight loss (166). The symptomatic treatment of chorea is an important part of Huntington disease management (09), although consideration should be given to the risk of potential side effects, the likelihood of benefit, and the presence of other symptoms and comorbidities (112). Evidence-based guidelines from the American Academy of Neurology were published in 2012 and recommended tetrabenazine, amantadine, or riluzole (Level B) for varying degrees of expected benefit of chorea in Huntington disease (09). However, as these guidelines are based on arbitrarily chosen anchors in the Unified Huntington’s Disease Rating Scale, which do not reflect validated or generally accepted levels of clinical relevance, there are concerns that recommendations based on these guidelines are not directly translatable into clinical practice and are not consistent with treatment recommendations by experts (225). In particular, the use of riluzole, or treatment with amantadine as a “first-line” agent, remains controversial (177). In a randomized trial, amantadine hydrochloride treatment at doses of 300 mg/day had no significant effect on the mean chorea score compared to placebo, although most patients felt subjectively better (198). In a multicenter, placebo-controlled trial, riluzole 200 mg/day decreased the intensity of chorea without improving functional capacity (121). It caused reversible liver transaminase abnormalities that require long-term monitoring. Another randomized controlled trial using riluzole 50 mg twice daily did not demonstrate a change in UHDRS chorea scores after 3 years of treatment (154). Thus, expert opinion-based therapeutic recommendations may provide more practical guidance than strict evidence-based reviews in the absence of strong clinical evidence (112).
Recommendations for neuroleptic medications to treat chorea are not included in evidence-based reviews due to the paucity of high-quality studies. However, they remain a core feature of clinical practice. Risperdal and haloperidol are both used based mainly on titrating extrapyramidal side effects to benefit chorea; caution must be used in judging this tradeoff. In a small study of 6 patients with Huntington disease, aripiprazole was compared to tetrabenazine (34). Both had similar effects on UHDRS chorea scores, but aripiprazole was associated with less sedation and was better tolerated. There was a slight trend for improvement in depression with the aripiprazole-treated patients, but this was not significant. A prospective open-label study reported improvement in motor scores with high-dose olanzapine (30 mg/day) (31).
Tetrabenazine was the first drug licensed in North America and some European countries for treatment of Huntington disease chorea (129). It is now recommended as a first-line treatment of chorea by the International Guidelines for the Treatment of Huntington Disease (17). The exact mechanism of the anti-chorea effect is unknown, but it is believed to be related to monoamine depletion by reversibly binding to the type 2 vesicular monoamine transporter (122). Tetrabenazine has more than 75% bioavailability and is 82% to 85% protein bound. In the pivotal clinical trial, 84 patients were randomized to either tetrabenazine up to 100 mg/day or placebo for 12 weeks (122). Tetrabenazine effectively lessened chorea in ambulatory patients. The treatment effect was 3.5 UHDRS points, with 69% having at least a 3-point decline in total chorea score and 19% having at least a 10-point decline (28-point maximum). The clinical global improvement scores showed 44% of active treatment and 7% of placebo were much improved or much improved. Serious adverse events included suicide and restlessness. The FDA suggests CYP2D6 genotyping when considering doses of more than 50 mg/day (see package insert). In clinical practice, cautious dose titration regardless of CYP2D6 allelic status is recommended (225), which may obviate the clinical need for costly genetic testing. In a withdrawal study, 30 patients treated with tetrabenazine were assigned to be withdrawn in a double-blind, staggered fashion (80). The chorea scores of subjects withdrawn from tetrabenazine treatment increased by 5.3, whereas the scores of the group with partial or no withdrawal of tetrabenazine treatment increased by 3.0 units (P = 0.0773). A post hoc analysis of the linear trend was positive for reemergent chorea (P = 0.0486). No serious adverse events were reported after abrupt withdrawal of tetrabenazine treatment; thus, abrupt withdrawal is possible and likely safe when medically required, although in practice down titration is recommended in nonurgent situations. The trend for reemergence of chorea supports the effectiveness of tetrabenazine in reducing chorea.
New VMAT2 inhibitors have been approved for clinical use in the United States. These new agents have different pros and cons compared to tetrabenazine itself (129).
Valbenazine is FDA-approved for use in tardive dyskinesia, and a phase 3 clinical trial of the drug in chorea associated with Huntington disease has completed enrollment (235). Valbenazine, a prodrug of the tetrabenazine (+)-alpha isomer, has the longest half-life of the group, allowing once a day dosing (129). Its pharmacokinetics also mitigate dose-related side effects such as somnolence.
Deutetrabenazine (SD-809), a novel molecule containing 2 trideuteromethoxy groups (-OCD3) installed at the 9- and 10-positions instead of the 2 methoxy groups (-OCH3) at the corresponding positions in the tetrabenazine molecule, was FDA-approved for treatment of chorea associated with Huntington disease in April 2017 (233). It is the first deuterium-containing therapeutic in human use in any disorder. Deuterium atoms at key positions, in this case CYP2D6 enzymatic breakdown targets, prolong plasma half-life and reduce metabolic variability relative to nondeuterated tetrabenazine metabolites. This reduces the impact of CYP2D6 variants on drug metabolism, and potentially reduces limiting peak dose side effects while maintaining efficacy level with lower total daily doses and fewer dose times per day. In a pivotal trial, there was a larger effect on patient global impression of change (PGIC) compared to clinician global impression of change (CGIC): PGIC was much or very much improved in 51% of the deutetrabenazine group versus 20% of placebo, whereas CGIC was much or very much improved in 42% of the deutetrabenazine group versus 13% of placebo (123). Although there are currently no head-to-head studies to adequately compare safety and efficacy profiles between tetrabenazine and deutetrabenazine, an indirect comparison study suggested that both medications can produce a statistically significant improvement in chorea compared with placebo, whereas adverse effects of deutetrabenazine were similar to those of placebo (123). In an open-label study, 37 Huntington disease patients converted overnight from tetrabenazine to deutetrabenazine using a conversion formula of approximately 2 to 1; they were then evaluated over a 4-week period. Switching to deutetrabenazine allowed to increase the dosage to achieve greater improvement of chorea without dose-limiting adverse effects (81; 233). Favorable adverse effect profile was observed up to the maximally allowed dose of 72 mg per day, well above the FDA-recommended limit of 48 mg per day.
Nabilone, a synthetic cannabinoid, was shown to improve motor symptoms in a pilot study involving 44 patients (54). Further studies are required to evaluate its use in Huntington disease and to assess its safety and addiction potential (09).
An open-label pilot study suggested that levetiracetam may be efficacious in reducing Huntington disease chorea in doses up to 3000 mg/day (318).
Levodopa may be used to relieve bradykinesia and rigidity, particularly in juvenile-onset cases or in some adults where those are the predominant motor symptoms.
Dystonia and rigidity may complicate disease. If these symptoms are uncomfortable or interfere with hygiene or care of the patient, then excessive tone can be treated with local injections of botulinum toxin.
Surgical treatment. Deep brain stimulation (DBS) of bilateral globus pallidus may have the potential to optimize motor response in Huntington disease, improving chorea without worsening bradykinesia (184; 315). In a small report of two patients with Huntington disease who underwent pallidal deep brain stimulation, sustained improvement in chorea was seen after 2 years follow-up. However, one patient had returned to his preoperative level of functioning due to progressive deterioration in gait, bradykinesia, and dystonia. In addition, both patients experienced further decline in neurocognitive functioning (134). Sustained improvement in chorea has also been reported 4 years after GPi deep brain stimulation, although no significant improvement in total functional capacity score was demonstrated (265). There is a case report of a patient with bradykinetic rigid Huntington disease who showed temporary improvement in UHDRS Total Motor Score after bilateral GPi DBS (47). One study has reported a better outcome of deep brain stimulation for one dystonia-predominant Huntington disease case compared to one chorea-predominant case (295). A prospective open-label study of GPi deep brain stimulation on seven patients over a 3-year period reported a sustained reduction in chorea in all patients, with maximal reduction in chorea, specifically orolingual and upper limbs, noted 1 year postoperatively (97). This transient effect was complicated by worsening of bradykinesia and dystonia, attributed to both disease progression and complications of deep brain stimulation. Bradykinesia was treated with pulse width reduction and levodopa therapy. Although there was improvement in swallowing, a dose reduction or discontinuation of neuroleptics, and no significant decline in cognitive function, there was an overall functional decline in multiple measures including the UHDRS Total Functional Capacity score. A different 3-year follow-up study reported sustained benefit for chorea but not dystonia in three patients with Huntington disease after bilateral GPi DBS, with variable increases in bradykinesia (319). Cognitive changes were described as heterogeneous. In contrast, 5-year follow-up of a bilateral GPi DBS case observed initial benefit for chorea and dystonia but progressive gait impairment, dysarthria, cognitive impairment, loss of benefit for dystonia, and severe functional decline despite sustained benefit for chorea (163). Analysis of 39 patients treated with GPi DBS from 18 studies concluded that this treatment had a stable effect on chorea even after 30 months of follow-up but no improvement of functional assessment after 12 months following surgery (315). Westphal variant of the disease showed no motor benefits after 6 months of therapy. The rate of stimulation-related adverse effects was estimated as 87.2%. Overall, maintaining long-term benefit for Huntington disease motor symptoms after deep brain stimulation may be challenging, and relative benefit of deep brain stimulation may be outweighed by potential adverse effects and functional decline. Despite these obstacles, attempts to prove efficacy and improve safety of GPi DBS for Huntington disease are underway. There is an ongoing prospective, randomized, double-blinded parallel treatment group trial comparing on and off stimulator settings over 12 weeks, ie, patients will either have stimulators on or off for the 3 months immediately post-operative (clinicaltrials.gov NCT02535884).
Rehabilitation. Rehabilitation and wellness approaches are important components of individualized Huntington disease symptomatic care, although clinical trial data are scarce. Improvement in gait has been reported following physical therapy (30). A small prospective study in Norway with 10 early- to mid-stage patients with Huntington disease utilized a 2-year intensive multidisciplinary rehabilitation program (208). Outcome measures included evaluation of gait, balance, cognition, anxiety and depression, activities of daily living, and quality of life. In the 6 patients who completed the study, there was a nonsignificant trend of decline in gait and balance, no significant improvement in quality of life or mood outcomes but also no significant cognitive decline (208). An open-label study of 26 weeks of endurance training in 12 Huntington disease and 12 control participants observed stabilization of motor deficits in the Huntington disease group compared to the 6 months prior to intervention, and significant increases in peak oxygen intake in both groups (82). Exercise interventions can be creative and successful. A study of Dance Dance Revolution video game play in Huntington disease found this intervention to be motivating and observed improvements in walking balance in participants (145). Patients with Huntington disease are able to participate in physical activity interventions: a randomized, controlled feasibility trial observed 82% of participants meeting minimum adherence criteria in the physical activity coaching intervention arm compared to 100% in the social interaction arm, with excellent retention rates in both arms, encouraging data regarding self-management of physical activity by patients with Huntington disease (35).
Speech therapy for both communication and dysphagia treatment is strongly recommended during the full range of Huntington disease symptom severity. In end stage patients, changing the shape of cups and stable posture, in consult with a speech therapist, may lessen chance of aspiration (106). Occupational therapy may cover a wide range of needs, from driving assessments to basic safety. Medical assist device experts may also contribute to symptomatic care. For example, because of impulsivity and excessive involuntary movements some patients will need to be placed in modified floor beds at night and may need special chairs (eg, Broda chair) for daytime seating.
Treatment of associated nonmotor symptoms. Sleep disturbances can occur in Huntington disease and may be associated with depression and lower cognitive and functional performance (13). Sleep disruption may have a particularly negative impact on neuropsychiatric symptoms (20). Recognition and modification of disrupted sleep, whether the sleep disruption is intrinsic to Huntington disease (206) or from other etiologies, is, therefore, important in overall Huntington disease symptomatic treatment. Avoidance of daytime sleeping and other basic good sleep hygiene practices are important in Huntington disease symptomatic treatment. Use of medications such as melatonin or sedating antidepressants such as trazodone, mirtazapine or amitriptyline at bedtime can help modify sleep disturbances. Consideration of relative benefits versus side effects is important when utilizing medication interventions. Identification and treatment of entities such as obstructive sleep apnea is recommended.
Psychiatric symptoms should be addressed. Although this is an area of very scarce Huntington disease specific data, it is also an area relatively rich in available symptomatic interventions. For a review of the medication management of Huntington disease symptoms, see Eddy and colleagues (71). Non-medication interventions are also feasible in this population, particularly early in disease course. Depression often responds partially to treatment with standard antidepressants. Obsessive ideation is common and may respond to selective serotonin reuptake inhibitors. Carbamazepine or valproate may improve patients with a manic disorder. Delusions and paranoia often respond to neuroleptics, although isolated fixed delusions may be particularly intractable. Neuroleptics also decrease chorea, but care is needed not to increase to doses that impair the individual's functional level. Low doses of neuroleptics are often well-tolerated, whereas high doses are rarely helpful and may impair motor function, such as swallowing and cognitive function. Behavioral modification on the part of the patient and caregiver can alleviate such stressful situations. Carbamazepine, selective serotonin reuptake inhibitors, clonazepam, propranolol, valproate, aripiprazole, and clomipramine are just some of the medications that may be helpful. Irritability and emotional dyscontrol are common in patients with Huntington disease and can cause great disturbance in their families or living situation. A phase 2 placebo-controlled trial of the vasopressin 1a receptor antagonist SRX246 has completed recruitment: clinicaltrials.gov NCT02507284. A phase 3 clinical trial evaluating the efficacy of dextromethorphan/quinidine in treating irritability in Huntington disease is currently underway: clinicaltrials.gov NCT03854019.
There are no data supporting medication interventions for cognitive symptoms in Huntington disease. Treatment of sleep disturbances, psychiatric symptoms, and unrelated primary sensory losses (hearing, vision) and regular review of medications to change out or discontinue any no longer necessary agents are recommended to best support cognitive function. Supportive symptomatic care also includes neuropsychology and rehabilitation and wellness interventions to maximize coping with cognitive symptoms. The 2008 self-published book “Hurry Up and Wait! A Cognitive Care Companion Huntington’s Disease in the Middle and More Advanced Years” by Jimmy Pollard provides pragmatic strategies for handling cognitive changes in Huntington disease. Trials in other neurodegenerative disorders are demonstrating measurable impacts on symptoms and brain structure from nonmedication cognitive interventions, such as mindfulness training (207). Cognitive intervention may delay cognitive decline in Huntington disease; this type of therapy may, therefore, be disease-modifying as well as of symptomatic use (05).
A phase 3 trial of latrepirdine failed to meet its primary cognitive outcome of improvement in minimental status exam (119). A phase 2b double-blind, placebo-controlled crossover trial testing bupropion for apathy in Huntington disease showed no treatment effect for bupropion; however, symptoms of apathy lessened in all trial participants, implying aspects of the closely structured and supportive environment of the clinical trial itself as a foundation for nonmedication interventions for apathy (89).
Nutrition is important in patients with Huntington disease as their caloric requirements may be increased even in very early motor manifest or nonmanifest and prodromal stages. Increases in total caloric intake in nonmanifest and symptomatic stages, modifications in food consistency for dysphagia, and pragmatic accommodations for motor incoordination may all be required. Diet modifications may need to take into account changing patient preferences with age, particularly in pediatric populations, and impact of cognitive and psychiatric symptoms on food enjoyment (183). Nutritional interventions, including weight loss prevention, can help improve motor symptoms and maximize functional status (321).
In advanced stages, enteral nutrition via gastric or jejunal tubes may be utilized, depending on patient and family wishes (321). Longer CAG repeat lengths are associated with earlier age at nursing home placement as well as earlier age at percutaneous endoscopic gastrostomy placement, but the interval from the onset of Huntington disease symptoms to either of these endpoints is similar regardless of CAG repeat length (170).
Palliative care is an understudied yet crucial area of symptomatic intervention in Huntington disease (276). The patient's wishes regarding late-stage treatment should be ascertained well in advance and in an ongoing fashion whenever possible. Open discussions between patients and current or potential caregivers along with care team members well ahead of medical crises are recommended. New quality-of-life measures are attempting to capture prodromal and motor manifest Huntington disease patient concerns about end of life in order to improve care and research in this area (39).
There are excellent free downloadable resource guides for patient management distributed by the Huntington Disease Society of America, the U.S. national support organization for Huntington disease. Publications cover a wide range of symptom topics including motor, non-motor, nutritional support, and advanced directives, and a wide range of readers including medical professionals, first responders, long-term care facilities staff, and caregivers. Some are available in both English and Spanish.
Minocycline at 200 mg/day demonstrated no meaningful slowing of the rate of functional decline; a futility study showed that although futility was not supported by the primary analysis, the data provided insufficient evidence to justify a larger and longer trial of minocycline in Huntington disease (124).
Cysteamine is thought to increase availability of brain-derived neurotrophic factor (BDNF) and, therefore, potentially slow Huntington disease progression (32). Initial studies established tolerability but not clear efficacy in Huntington disease (212). A phase II/III 36-month trial of delayed-release cysteamine (RP103) in 96 early motor manifest Huntington disease patients using an 18-month blinded, placebo-controlled phase reported a negative efficacy result (297).
Pridopidine belongs to a novel class of dopaminergic stabilizers, which act primarily at dopamine type 2 receptors (61). An initial small-scale study focused primarily on cognitive outcomes was negative but reported potential improvement in voluntary motor symptoms in patients receiving pridopidine (165); a subsequent phase III study using doses up to 90 mg/day did not demonstrate any difference in the modified motor score after 26 weeks compared with placebo. Additional analyses revealed an improvement in the tertiary endpoint of UHDRS total motor score (UHDRS-TMS) at a dose of 90 mg/day (61). A subsequent, randomized, double-blind, placebo-controlled trial also demonstrated no significant treatment-associated improvement in the modified motor score after 12 weeks, although a modest beneficial effect was again observed in the UHDRS-TMS with the 90 mg/day dosage (125). A large-scale multicenter multinational phase 2/3 double-blind placebo-controlled trial of pridopidine including higher dose arms and TMS as the prespecified primary endpoint, PRIDE-HD, reported negative top-line data in 2016. Subgroup analyses detected slower than predicted decline in functional status in early-stage manifest Huntington disease patients. A planned phase 3 study was terminated by the drug manufacturer (139). Another phase 3, placebo-controlled clinical trial of pridopidine in the early stages of Huntington disease (PROOF-HD) is currently underway: clinicaltrials.gov NCT04556656.
A phase 2 study of the green tea polyphenon (2)-epigallocatechin-3-gallate (EGCG) testing cognitive outcome measures in Huntington disease was completed in 2015; results are not yet available, but more information can be accessed at the following website:clinicaltrials.gov NCT01357681.
Multiple pilot studies of intracerebral fetal cell transplantation have reported limited amount and duration of benefit, although some studies including autopsy reports (months to years after transplantation) demonstrate graft survival and integration (16). An ongoing multicenter European trial proposes to increase understanding of how and whether to employ this potential treatment strategy in Huntington disease (16). Forty-five patients have undergone surgery so far. A German extension of the main study has reported data on 10 of its 22 patients, with improvement in one patient. This treatment approach remains experimental, with many of the same concerns that have faced human fetal cell transplantation in other neurologic conditions. Graft overgrowth in a patients with Huntington disease receiving fetal neural transplantation resulting in a symptomatic mass was described (137).
Novel applications of deep brain stimulation in Huntington disease, particularly for cognitive symptoms, are under investigation (28; 189).
Disease-modifying therapy. There is no known disease-modifying therapy to date. Large multicenter, multinational, double-blind, placebo-controlled trials of CoQ10 and creatine were terminated early for lack of benefit on interim analyses (113; 175). New approaches to disease-modifying therapeutics are under active investigation (139; 176; 142).
Huntington disease is fundamentally a monogenic, single-mutation disorder. The level of mutated huntingtin protein expression is one factor likely influencing the rate and amount of huntingtin-driven pathogenic processes (22). Thus, many current areas of investigation in disease-modifying therapeutics involve methods to impact the level of mutant huntingtin (mHTT), some directly targeting the HTT gene (311; 178; 176; 76). This approach shifts the field from potentially general mechanisms of neurodegeneration to very huntingtin- and HTT-specific approaches (178). A few approaches to target DNA and RNA to reduce mHTT expression have been evaluated as potential therapy in Huntington disease, including non-allele specific gene silencing (producing simultaneous reduction of both wild-type and mutant HTT) and allele-specific silencing (targeting only mutant HTT) (76). Although the reduction of wild-type HTT, along with the reduction of mHTT, did not result in any adverse outcomes in animal studies, the function of HTT is not yet fully understood; therefore, the effects of lowering wild-type HTT production should be considered in non-allele specific genetic therapy approaches. The first safety study of antisense oligonucleotides against mHTT in humans with early motor symptomatic Huntington disease completed enrollment in 2019: (clinicaltrials.gov NCT02519036). Antisense oligonucleotides, an example of the non-allele-specific gene silencing approach, pair with target mRNA and recruit RNase to degrade mutant mRNA or DNA-RNA duplex. Preclinical and clinical trials with antisense oligonucleotide IONIS-HTTRx showed a reduction of mutant huntingtin in animal models and humans (275; 76). Allele-specific gene silencing approaches are under development (262; 136; 178; 76). Several different RNA interference strategies (non-allele specific and allele specific) are under active basic science and preclinical investigation (38; 178; 76).
The PRECISION-HD1 (WVE-120101) and PRECISION-HD2 (WVE-120102) placebo-controlled trials assessing the safety and tolerability of WVE-120101 and WVE-120102 allele-specific oligonucleotides targeting mHTT were terminated due to lack of efficacy: clinicaltrials.gov NCT03225833.
PBT2, a metal-protein attenuating compound acting as a synthetic chaperone designed to disrupt interactions between biological metals such as copper and zinc, was thought to reduce copper-induced aggregation of mHTT based on the results of preclinical studies. It has been assessed in the Reach2HD study, a 26-week phase 2 randomized, double-blind, placebo-controlled study in 109 patients with early to mid-stage Huntington disease. Although the change in the main composite cognitive score was not different in the PBT2 groups and placebo, the change in the Trail Making Test improved (127). The FDA issued a partial clinical hold in 2015 due to safety concerns raised by nonclinical data.
Laquinimod, an orally administered carboxamide derivative studied as a disease-modifying treatment for multiple sclerosis was suggested to have therapeutic potential in Huntington disease by the observation that mHTT can be associated with a hyperactivation status of monocytes and microglia. LEGATO-HD study, a phase 2 12-month multicenter randomized, placebo-controlled, double-blind trial has released the preliminary results: primary endpoint (change in the Total Motor Score (TMS) of the Unified Huntington Disease Rating Scale (UHDRS) was not met, but the MRI outcome of the caudate volume was met. More information is available at the following website:https://www.activebiotech.com/en/media/pressreleases/?id=2208124&date=1533024900.
The target for immunotherapy in Huntington disease currently being assessed is not HTT but semaphorin 4D (SEM4D), a transmembrane signaling molecule that can exist in a soluble dimer form and plays a role in cellular trafficking. VX15/2503 is a humanized monoclonal antibody targeting SEM4D currently being assessed in Huntington disease in the SIGNAL study, which is a phase 2 multicenter, randomized, double-blind, placebo-controlled study in subjects with late prodromal and early manifest Huntington disease: clinicaltrials.gov NCT02481674. The study completed recruitment in 2020, and results have not yet been published.
Other studies are also examining the plant-based phenol resveratrol. Although this type of food-based “nutraceutical” holds a great deal of appeal, data on its impact in human neurodegeneration, particularly in Huntington disease, remain scarce (55).
Testing of many of these agents, which are of unknown efficacy and safety, is occurring in nonmanifest, prodromal, and very early symptomatic Huntington disease populations. Work in these groups creates particular scientific considerations, such as development of surrogate biomarker measures (241; 22).
Studies in nonmanifest populations are important for several reasons. Including nonmanifest individuals in clinical trials may reveal disease-modifying therapeutics that are effective early on but do not impact disease progression in symptomatic stages. For example, PRECREST observed creatine treatment-related slowing of cortical and striatal atrophy neuroimaging biomarker measures in nonmanifest individuals compared to mutation negative controls, although trials of creatine in symptomatic Huntington disease were halted early for lack of benefit (238).
In January 2019, the FDA approved the first trial of an HTT-lowering gene therapy, AMT-130, an adeno-associated virus (AAV5) delivered, nonallele selective HTT miRNA: clinicaltrials.gov. Noncoding miRNA form hairpin structures that guide the RNA-induced silencing complex to bind to an mRNA target leading to mRNA cleavage.
Huntington disease is a progressive disorder leading to disability in most manifest patients. The current goals of treatment are symptomatic: to reduce the effect of motor and nonmotor symptoms on quality of life.
Side effects of the medications used for symptomatic pharmacological and surgical therapies were discussed in the Management section.
There are no concerns regarding pregnancy or delivery due to Huntington disease. Genetic counseling is suggested for at-risk individuals to support informed decision making regarding reproductive options; however, genetic testing is not considered clinically necessary in nonmanifest at risk or mutation carrier fertile men or women prior to or during pregnancy. At-risk individuals make highly individual decisions regarding reproduction (214).
Prenatal diagnostic testing is available. Although undergoing prenatal diagnostic testing does not carry any obligation for terminating pregnancy, prenatal diagnostic testing is strongly discouraged except when abortion is under serious consideration. Current guidelines recommend against presymptomatic (predictive) genetic testing in patients under age 18 years, including use of prenatal diagnostic testing as purely presymptomatic testing. Prenatal testing is, therefore, offered as part of a decision-making process that includes possible pregnancy termination.
Although uptake and results of prenatal testing vary widely between geographical regions, a review from the Netherlands provides some insights. Of 216 prenatal genetic tests for Huntington disease over a 10-year period in the Netherlands, 91 generated mutation-positive results of 36 or greater CAG repeats in HTT (292). Of these, 13% were carried to term and 82% were terminated; a small number were miscarried spontaneously. Prenatal diagnostic testing was a consideration for mutation carrier parents, at-risk (mutation status unknown) parents, and intermediate allele carriers (292). A report on a French clinic cohort includes prenatal genetic testing requests from 61 prospective parents, evenly split between male and female mutation carriers (33). Of 51 pregnancies with mutation carrier results, one was carried to live birth term, one miscarried, and the rest were terminated. Many families underwent more than ` pregnancy with prenatal testing, resulting in 101 genetic tests. Eighty-three percent of women with an initial negative prenatal genetic testing pregnancy went on to a subsequent pregnancy, compared to 38% of those with an initial mutation carrier pregnancy. Interestingly, 10% of interviewed couples went on to have an untested pregnancy and, thus, an at-risk child. Many families had children before the initial prenatal genetic testing experience; thus, overall, 33% of interviewed families had a mix of siblings from tested and untested pregnancies. At the time of the study, 12 women had disclosed the (negative) prenatal genetic test results to their child, generally after age 7 (33). More study of the impact of this and other reproductive technologies on Huntington disease families is warranted.
Preimplantation genetic diagnosis (PGD), in which a woman undergoes in vitro fertilization and only mutation-negative embryos are implanted, is also available. This gives mutation-positive parents a means of ensuring mutation-negative biological children. At-risk prospective parents can remain blinded to their own mutation status by using PGD and opting to not be informed of whether any mutation-positive embryos were generated. Given the increased risks of multiple gestations and deliveries, both maternal and to offspring, minimizing the number of embryos implanted per cycle is recommended. The in vitro fertilization process itself carries medical risk for the woman involved, generating special ethical considerations in the use of PGD for at-risk mutation status unknown women, men with normally fertile female partners, and particularly in the use of PGD for at-risk men who may be mutation-negative. For many couples, terminating an established pregnancy is a more wrenching decision than coping with PGD; however, the ethics of PGD and the differences in uptake of prenatal genetic testing versus PGD are evolving areas (27; 292).
Pediatric age group. Presymptomatic genetic testing of children and juveniles under age 18 at risk for Huntington disease is not recommended. Special considerations in confirmatory genetic testing are discussed above. Juvenile cases of Huntington disease are often treated with antiparkinsonian medications, most often levodopa, to reduce prominent bradykinesia, posture abnormalities, rigidity, and dystonia (217). Antipsychotics and antidepressants are also commonly used, although data supporting care choices are extremely limited (217). Similarly, antiepileptic medications are required for seizure control in some juvenile Huntington disease cases, but data on best Huntington disease-specific choices are not available (49). Pediatric palliative care is increasingly available for late-stage juvenile Huntington disease (143). There are excellent free downloadable resource guides for juvenile Huntington disease patient management distributed by the Huntington Disease Society of America, the United States national support organization for Huntington disease. Publications cover a wide range of symptom topics and are targeted at medical professionals, teachers, and caregivers. The HDSA is the parent organization for the National Youth Alliance; similar youth-oriented groups exist in other regions. The international nonprofit Huntington Disease Youth Organization provides age-appropriate information on Huntington disease through their website http://en.hdyo.org and support by and for young people impacted by Huntington disease. Information for kids, young adults, parents, friends, and professionals is translated by volunteers into 10 different languages.
Intermediate alleles. Given the level of uncertainty in both their own potential symptomatic range and in transmission of novel mutations, individuals who receive an intermediate allele result may have difficulty understanding and interpreting the result (252). An evidence-based approach to pre-test genetic counseling, including information on the potential of an intermediate allele results and its implications, is strongly recommended (253; 179).
Premanifest individuals and clinical trials. Exposing presymptomatic or prodromal patients to risk in clinical trials is ethically possible, and arguably necessary to fully test potential disease-modifying therapeutics but carries unique ethical and scientific considerations. The PREQUEL study evaluated safety of CoQ10 in 90 premanifest mutation carriers, providing the first evidence that clinical trials could be safely and successfully carried out in this population (43). The PRECREST trial was a phase 3 double-blind placebo-controlled study of creatine to alter neuroimaging biomarker progression in nonmanifest Huntington disease (238). Blinding included mutation status: 19 known mutation carriers and 45 at-risk individuals of unknown mutation status were included, with the biostatistician the only team member aware of participant genetic status. Of the 45 at-risk individuals, 17 were mutation-negative; this group was used as an internal control comparison of the natural history of the study biomarkers. This study demonstrated feasibility of clinical trial participation for at-risk individuals who do not wish to know their mutation status.
At-risk individuals, nonmutation carrying. Predictive genetic testing can have long-term impacts on individuals without an expanded CAG repeat, not all positive (03; 93). Although intrusive thoughts and avoidance drop immediately after receiving a mutation-negative presymptomatic testing result, they peak again after a few years before another decline (283). In another study, 27% of mutation-negative individuals did not cope well in the long term with their results, and 24% were depressed some many years after genetic testing (86). A definitely nonexpanded result (< 29 CAG repeats) can be highly positive, reducing uncertainty and allowing more confident forward decision making. It can also present significant challenges of survivor guilt, regret over past decisions or behaviors that may have been driven by an assumption of mutation carrier status, and major shifts in self-image.
In the current era of no proven disease-modifying interventions, individuals often reasonably refrain from presymptomatic genetic testing. At-risk individuals who are in fact mutation negative may, thus, take on unnecessary medical or research risk. Although the PRECREST study demonstrated the feasibility and scientific importance of including at-risk mutation-negative individuals in a clinical trial, creatine was not entirely benign: 15 subjects (2 placebo) dropped out of the study (238). At-risk individuals may take supplements such as high-dose creatine in the hopes of positive benefit, although these agents may carry medical risk, in the case of creatine potential impact on renal function. PGD for at-risk parents maintains individual autonomy in choosing to remain blinded to one’s own mutation status, at the cost of increasing the risks around conceiving a mutation-free child, including direct medical risks of in vitro fertilization, financial risks, and emotional impacts of the process such as the low live birth rate for in vitro fertilization cycles. Weighing the pros and cons of presymptomatic genetic testing includes considering the relative risk-benefit scenarios for choices under nonexpanded allele carrier circumstances.
Partners and caregivers. Given the severity and inherited nature of Huntington disease, nonmanifest mutation status results, confirmatory diagnosis, and ongoing care burdens directly impact partners and caregivers. After presymptomatic genetic testing, partners of causal mutation carriers have a similar trajectory of hopelessness compared to the mutation carriers themselves, with an initial spike, decline, then another rise in hopelessness 7 to 10 years after genetic testing to higher levels than prior to testing (283). Predictors for partners’ poor response in the 1- to 5-year range included having no children and age of the mutation carrier close to predicted motor symptom onset. Partners of mutation carriers had more intrusive thoughts than partners of nonexpanded allele carriers; partners of individuals who did not carry an expanded CAG repeat allele were also less distressed in the long run than the tested individuals themselves (283). Partners of both at-risk status and mutation carriers often fold knowledge of Huntington disease into reproductive decisions, including decisions that confer added medical risk to themselves or potential offspring, as discussed above.
Caregiver impacts include issues similar to other neurodegenerative disorders and unique to Huntington disease (63). Depression and motor disturbance have been reported as predictors of caregivers’ burden (21). Limited data on juvenile Huntington disease caregiver experiences are available (70).
A retrospective review of 11 patients with Huntington disease reported normal responses to induction and maintenance of anesthesia without adverse effects (144). Increased aspiration risk due to bulbar dysfunction and potential drug interactions with psychiatric medications should be considered. Unusual sensitivity to anesthetic agents has also been reported. As with any potentially cognitively impaired patient population, cognitive recovery from anesthesia may be slowed, and patients may be vulnerable to cognitive and psychiatric side effects of anesthetics and narcotic pain medications in the postoperative recovery period.
Olga Waln MD
Dr. Waln of Houston Methodist Neurological Institute has no relevant financial relationships to disclose.See Profile
Robert Fekete MD
Dr. Fekete of New York Medical College received consultation fees from Acadia, Acorda, Adamas, Amneal/Impax, Kyowa Kirin, Lundbeck, Neurocrine, and Teva.See Profile
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Jan. 18, 2022
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Behavioral & Cognitive Disorders
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Behavioral & Cognitive Disorders
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