Huntington disease (HD) is an incurable, adult-onset, autosomal dominant inherited disorder associated with cell loss within a specific subset of neurons in the basal ganglia and cortex. HD is named after George Huntington, the physician who described it as hereditary chorea in 1872.[1] Characteristic features of HD include involuntary movements, dementia, and behavioral changes.[2]
The most striking neuropathology in HD occurs within the neostriatum, in which gross atrophy of the caudate nucleus and putamen is accompanied by selective neuronal loss and astrogliosis. Marked neuronal loss also is seen in deep layers of the cerebral cortex. Other regions, including the globus pallidus, thalamus, subthalamic nucleus, substantia nigra, and cerebellum, show varying degrees of atrophy depending on the pathologic grade.[1]
The extent of gross striatal pathology, neuronal loss, and gliosis provides a basis for grading the severity of HD pathology (grades 0-4).[3]
No gross striatal atrophy is observed in grades 0 and 1. Grade 0 cases have no detectable histologic neuropathology in the presence of a typical clinical picture and positive family history suggesting HD. Grade 1 cases have neuropathologic changes that can be detected microscopically but without gross atrophy. In grade 2, striatal atrophy is present, but the caudate nucleus remains convex. In grade 3, striatal atrophy is more severe, and the caudate nucleus is flat. In grade 4, striatal atrophy is most severe, and the medial surface of the caudate nucleus is concave.[4]
The genetic basis of HD is the expansion of a cysteine-adenosine-guanine (CAG) repeat encoding a polyglutamine tract in the N-terminus of the protein product called huntingtin.[5]
The function of huntingtin is not known. Normally, it is located in the cytoplasm. The association of huntingtin with the cytoplasmic surface of a variety of organelles, including transport vesicles, synaptic vesicles, microtubules, and mitochondria, raises the possibility of the occurrence of normal cellular interactions that might be relevant to neurodegeneration.
N-terminal fragments of mutant huntingtin accumulate and form inclusions in the cell nucleus in the brains of patients with HD, as well as in various animal and cell models of HD.[6]
The presence of neuronal intranuclear inclusions (NIIs) initially led to the view that they are toxic and, hence, pathogenic.[7] More recent data from striatal neuronal cultures transfected with mutant huntingtin and transgenic mice carrying the spinocerebellar ataxia-1 (SCA-1) gene (another CAG repeat disorder) suggest that NIIs may not be necessary or sufficient to cause neuronal cell death, but translocation into the nucleus is sufficient to cause neuronal cell death.[8] Caspase inhibition in clonal striatal cells showed no correlation between the reduction of aggregates in the cells and increased survival.[9]
Furthermore, postmortem studies reveal that NIIs are quite rare in the striata of patients with HD as compared to the cortex, and most of the aggregates within the striatum are observed in populations of interneurons that typically are spared in individuals with HD.
TRACK-HD is a prospective observational study that reported 12-month longitudinal changes in 116 pre-manifest individuals carrying the mutant Huntington gene (preHD), 114 patients with early HD, and 115 age- and sex-matched controls. Generalized and regional brain atrophy was higher in preHD and early HD than in controls. Voxel-based morphometry revealed grey-matter and white-matter atrophy, even in subjects furthest from predicted disease onset. The study showed change in the total functional capacity, a widely used measure of HD clinical severity, that was associated with both whole-brain and caudate atrophy rates. Compared to controls, deterioration in cognition and motor function was detectable in both preHD and early HD, as well as worsening in oculomotor function in early HD. Change in cognitive and motor measures were associated with whole-brain volume loss.[10]
The selective neuronal dysfunction and subsequent loss of neurons in the striatum, cerebral cortex, and other parts of the brain can explain the clinical picture seen in cases of HD. Several mechanisms of neuronal cell death have been proposed for HD, including excitotoxicity, oxidative stress, impaired energy metabolism, and apoptosis.
Excitotoxicity refers to the neurotoxic effect of excitatory amino acids in the presence of excessive activation of postsynaptic receptors.
Intrastriatal injections of kainic acid, an agonist of a subtype of glutamate receptor, produce lesions similar to those seen in HD.
Intrastriatal injections of quinolinic acid, an N -methyl-D-aspartate (NMDA) receptor agonist, selectively affect medium-sized GABA-ergic spiny projection neurons, sparing the striatal interneurons and closely mimicking the neuropathology seen in HD.
NMDA receptors are depleted in the striata of patients with HD, suggesting a role of NMDA receptor-mediated excitotoxicity, but no correlation exists between the distribution of neuronal loss and the density of such receptors.
The theory that reduced uptake of glutamate by glial cells may play a role in the pathogenesis of HD also has been proposed.
Oxidative stress is caused by the presence of free radicals (ie, highly reactive oxygen derivatives) in large amounts. This may occur as a consequence of mitochondrial malfunction or excitotoxicity and can trigger apoptosis.
Striatal damage induced by quinolinic acid can be ameliorated by the administration of spin-trap agents, which reduce oxidative stress, providing indirect evidence for the involvement of free radicals in excitotoxic cell death.
Impaired energy metabolism reduces the threshold for glutamate toxicity and can lead to activation of excitotoxic mechanisms as well as increased production of reactive oxygen species.
Nuclear magnetic resonance spectroscopy studies have shown elevated lactate levels in the basal ganglia and occipital cortex of patients with HD.
Patients with HD have an elevated lactate-pyruvate ratio in the cerebrospinal fluid.
A reduction in the activity of the respiratory chain complex II and III (and less in complex IV) of mitochondria of caudate neurons in patients with HD has been reported.
In rats, intrastriatal injections of 3-nitroproprionic acid (3-NP), an inhibitor of succinate dehydrogenase or complex II of the respiratory chain, cause dose-dependent ATP depletion, increased lactate concentration, and neuronal loss in the striatum. Systemic injections of 3-NP into rats produce a selective loss of medium spiny neurons in the striatum.
Apoptosis is the programmed cell death that is activated normally in the nervous system during embryogenesis to remove supernumerary neurons as part of natural development.
Morphological features of apoptosis have been well characterized. Oxidative stress, excitotoxicity, and partial energy failure can lead to apoptosis.
A subset of neurons and glia in the neostriata of patients with HD appears to undergo apoptosis, as shown by in situ DNA nick end labeling (TUNEL) staining, but clear morphological evidence for an apoptotic process in HD is still missing.
One theory is that expanded polyglutamine repeats cause neuronal degeneration through abnormal interactions with other proteins containing short polyglutamine tracts. Recent work suggests that polyglutamine interference with transcription of CREB binding protein (CBP), a major mediator of survival signals in mature neurons, may constitute a genetic gain of function underlying polyglutamine disorders including HD.[8]
The role of caspases (a class of highly specific proteases) in apoptosis involves cleavage of target proteins at different sites. In humans with HD and in animal models of HD, the intracellular accumulation of N-terminal huntingtin fragments is one of the neuropathological features. Caspases, among other proteins, cleave huntingtin within the N-terminal region. To address the question of a potential in vivo neuroprotective effect of inhibition of caspases, a YAC mouse model expressing mutant huntingtin, along with selective mutations of the caspase-3 and caspase-6 cleavage sites, was studied. Selective elimination of the caspase-6, but not caspase-3, cleavage site in mutant huntingtin resulted in protection from neuronal dysfunction and neurodegeneration in vivo. These results suggest that preventing caspase-6 cleavage of huntingtin may be of therapeutic interest.[9]
Estimates of the prevalence of HD in the United States range from 4.1-8.4 per 100,000 people.[11] Accurate estimates of the incidence of HD are not available.
The frequency of HD in different countries varies greatly. A few isolated populations of western European origin have an unusually high prevalence of HD that appears to have resulted from a founder effect. These include the Lake Maracaibo region in Venezuela (700 per 100,000 people)[12] , the island of Mauritius off the South African coast (46 per 100,000 people), and Tasmania (17.4 per 100,000 people).[13] The prevalence in most European countries ranges from 1.63-9.95 per 100,000 people. The prevalence of HD in Finland and Japan is less than 1 per 100,000 people.[14]
Most studies show a mean age at onset ranging from 35-44 years. However, the range is large and varies from 2 years to older than 80 years. Onset in patients younger than 10 years and in patients older than 70 years is rare. The Venezuelan kindreds manifest an earlier mean age of onset (34.35 years) when compared with Americans (37.47 years) and Canadians (40.36 years). Modifying genes and environmental factors are thought to influence the age of onset in these different populations.
Mortality/morbidity
HD is a relentlessly progressive disorder, leading to disability and death, usually from an intercurrent illness.
The mean age at death in all major series ranges from 51-57 years, but the range may be broader. Duration of illness varies considerably, with a mean of approximately 19 years. Most patients survive for 10-25 years after the onset of illness. In a large study, pneumonia and cardiovascular disease were the most common primary causes of death.
Juvenile HD (ie, onset of HD in patients younger than 20 years) accounts for approximately 5-10% of all affected patients. Most patients with juvenile HD inherit the disease from their father, whereas patients with onset of the disease after age 20 years are more likely to have inherited the gene from their mother. Inheritance through the father can lead to earlier onset through succeeding generations, a phenomenon termed anticipation. This is caused by greater instability of the HD allele during spermatogenesis. CAG repeat length correlates inversely with age of onset, and the correlation is stronger when the onset of symptoms occurs earlier.
The length of the CAG repeat is the most important factor in determining age of onset of HD, although substantial variability remains after controlling for repeat length. Both genetic and environmental components account for this variability. The US-Venezuela Collaborative Research Project studied Venezuelan HD kindreds, the world's largest genetically related HD community (18,149 individuals spanning 10 generations) since 1979, collecting genetic and clinical data.[3]
A small number of homozygotes for the HD mutation have been identified, and they seem to be phenotypically indistinguishable from heterozygotes, making HD a truly autosomal dominant disorder.[4]
With the increasing amount of genetic/hereditary information available in HD, the question of whether patients and/or family members should be made aware of the genetic risks is becoming an increasingly important issue.
For excellent patient education resources, visit eMedicineHealth's Brain and Nervous System Center. Also, see eMedicineHealth's patient education article Huntington Disease Dementia.
Huntington disease mutation carriers who have yet to develop clinical symptoms are most concerned with internal and relational issues (social, emotional, and self concerns) that are associated with the disease. These concerns remain throughout and do not increase in the subsequent stages of HD. Patients with HD stages 1-5 are most concerned with physical and functional issues caused by HD, with these concerns increasing as the disease progresses. Patients with early HD (stages 1 and 2) have increasing concerns about cognitive issues, and these concerns remain constant during moderate HD (stages 3 and 4). Patients with late-stage HD (stage 5) have a lack of cognitive concerns, presumably due to impaired insight.[5]
The clinical features of Huntington disease (HD) include a movement disorder, a cognitive disorder, and a behavioral disorder. Patients may present with one or all disorders in varying degrees.
Chorea (derived from the Greek word meaning to dance) is the most common movement disorder seen in HD.
Initially, mild chorea may pass for fidgetiness. Severe chorea may appear as uncontrollable flailing of the extremities (ie, ballism), which interferes with function.
As the disease progresses, chorea coexists with and gradually is replaced by dystonia and parkinsonian features, such as bradykinesia, rigidity, and postural instability, which are usually more disabling than the choreic syndrome per se.
In advanced disease, patients develop an akinetic-rigid syndrome, with minimal or no chorea. Other late features are spasticity, clonus, and extensor plantar responses.
Dysarthria and dysphagia are common. Abnormal eye movements may be seen early in the disease. Other movement disorders, such as tics and myoclonus, may be seen in patients with HD.
Juvenile HD (Westphal variant), defined as having an age of onset of younger than 20 years, is characterized by parkinsonian features, dystonia, long-tract signs, dementia, epilepsy, and mild or even absent chorea.
Cognitive decline is characteristic of HD, but the rate of progression among individual patients can vary considerably. Dementia and the psychiatric features of HD are perhaps the earliest and most important indicators of functional impairment.
The dementia syndrome associated with HD includes early onset behavioral changes, such as irritability, untidiness, and loss of interest. Slowing of cognition, impairment of intellectual function, and memory disturbances are seen later. This pattern corresponds well to the syndrome of subcortical dementia, and it has been suggested to reflect dysfunction of frontal-subcortical neuronal circuitry. (The so-called cortical dementias primarily involve the cerebral cortex and are associated with aphasia, agnosia, apraxia, and severe amnesia.)
Early stages of HD are characterized by deficits in short-term memory, followed by motor dysfunction and a variety of cognitive changes in the intermediate stages of dementia.[6, 7] These deficits include diminished verbal fluency, problems with attention, executive function, visuospatial processing, and abstract reasoning. Language skills become affected in the final stages of the illness, resulting in a marked word-retrieval deficit.
The behavioral disorder of HD is represented most commonly by affective illness.
Depression is more prevalent, with a small percentage of patients experiencing episodic bouts of mania characteristic of bipolar disorder.
Patients with HD and persons at risk for HD may have an increased rate of suicide.
Patients with HD also can develop psychosis, obsessive-compulsive symptoms, sexual and sleep disorders, and changes in personality.
Most patients with HD have a mixed pattern of neurological and psychiatric abnormalities. Understanding of the clinical signs must take into account the fact that signs change during the course of the illness and that different patterns may be observed, depending on the age of onset.
Chorea is a characteristic feature of HD and, until recently, the disorder commonly was called Huntington chorea. Chorea, as defined by the World Federation of Neurology, is a state of excessive, spontaneous movements, irregularly timed, randomly distributed, and abrupt.
Severity of chorea may vary from restlessness with mild intermittent exaggeration of gesture and expression, fidgeting movements of the hands, and unstable dancelike gait to a continuous flow of disabling violent movements. Chorea in cases of HD usually is generalized.
Patients may incorporate involuntary choreiform movements into apparently purposeful gestures, a phenomenon referred to as parakinesia.
Ballism is characterized by large amplitude, usually proximal, flinging movements of a limb or body part. Ballism is considered to be a severe form of chorea by most authors.
Chorea may coexist with slower, distal, writhing, sinuous movements called athetosis; it then is described as choreoathetosis.
Chorea is less prominent in juvenile HD and in advanced stages of the illness.
Bradykinesia and akinesia are frequent features of HD and may explain some of the abnormalities of voluntary movement observed clinically.
Bradykinesia may be a major source of disability of voluntary movement, though it commonly is overshadowed by the hyperkinetic movement disorder.
Other parkinsonian signs, such as rigidity and postural instability, may be seen. Patients may become akinetic and rigid in the terminal stages of the illness.
Dystonia is defined as a syndrome of sustained muscle contractions, frequently causing twisting and repetitive movements or abnormal postures.
Mild dystonia, in combination with chorea, may give the writhing appearance of choreoathetosis.
Sustained dystonic posturing may result in contractures, immobility, and breakdown of skin.
Dystonia may be prominent in juvenile HD.
Eye movement abnormalities can be seen early in the disease.
Initiation of saccadic movements is slow and uncoordinated. Patients have difficulty suppressing head movements or blinking in order to break fixation and generate saccadic movements.
Smooth pursuit is interrupted by saccadic intrusions.
Patients are unable to inhibit saccades toward a peripheral stimulus when instructed to look in the opposite direction.
Tendon reflexes are variable in HD, ranging from reduced in some patients to pathologically brisk with clonus in other patients. The plantar response usually is flexor, but it may be extensor in advanced stages of the illness.
Other hyperkinesias, such as tics and myoclonus, may be seen in HD.
Dementia, depression, and other psychiatric manifestations may be seen at the time of examination as well.
No single imaging technique is necessary or sufficient for diagnosis of Huntington disease (HD). Measurement of the bicaudate diameter (ie, the distance between the heads of the 2 caudate nuclei) by CT scan or MRI is a reliable marker of HD.[10]
Abnormalities in positron emission tomography (PET) scanning and proton MR spectroscopy have been reported; however, their use in clinical practice is limited.
Genetic testing (reported as the CAG repeat number for each allele) is now commercially available.
Genetic testing may not be necessary in a patient with a typical clinical picture and a genetically proven family history of HD.
In the absence of a family history of HD, patients with a suggestive clinical presentation should undergo genetic testing to exclude or confirm HD.
Persons at risk for HD who request presymptomatic testing should undergo extensive genetic counseling and neurologic and psychiatric evaluation, given the implications of receiving a positive (or negative) result for an untreatable, familial, progressive, neurodegenerative disease. Most testing centers follow strict protocols, such as the one put forth by the Huntington's Disease Society of America (HDSA).[15]
If the genetic test is negative for HD, then testing for systemic lupus erythematosus (SLE), antiphospholipid antibody syndrome, thyroid disease, neuroacanthocytosis, DRPLA, Wilson disease, and other less common causes of chorea may be reasonable, depending on the individual case.
The extent of gross striatal pathology, neuronal loss, and gliosis provides a basis for grading the severity of HD pathology (grades 0-4). See Pathophysiology.
Ablative surgical procedures and fetal cell transplantation have been attempted in patients with HD. Currently, enough data to support this type of treatment are not available. It is still experimental.
Consider general safety measures and nonpharmacologic interventions first in the management of Huntington disease (HD).
If chorea is severe enough to interfere with function, consider treatment with benzodiazepines, such as clonazepam or diazepam; valproic acid; dopamine-depleting agents (eg, reserpine, tetrabenazinem deutetrabenazine); and finally, neuroleptics.
The drug tetrabenazine, a central acting vesicular monoamine transporter 2 (VMAT2) inhibitor, has shown positive effects in the treatment of chorea, for patients with HD. It selectively depletes central monoamines by reversibly binding to VMAT2.
Results from a phase III clinical study showed that this investigational drug is an effective treatment for chorea associated with HD. The dosing range that proved effective was 12.5-100 mg/d.[16] Its manufacturer has been granted fast track and orphan drug status by the FDA. It was the first treatment approved for chorea in patients with HD in the United States. Always weigh potential adverse effects against the benefits of each drug.
A second VMAT2 inhibitor, deutetrabenazine, was approved by the FDA in April 2017. Approval was based on a double-blind multicenter trial conducted in 90 ambulatory patients at 34 centers in the United States and Canada, with 45 patients randomly assigned to deutetrabenazine and 45 to placebo. Deutetrabenazine or placebo was titrated to optimal dose level over 8 weeks and maintained for 4 weeks, followed by a 1-week washout.
Baseline total maximal chorea score was 8 or higher in study participants. Results showed improvement in the Unified Huntington Disease Rating Scale total maximal chorea scores for patients taking deutetrabenazine of 4.4 units from baseline to the maintenance period (average of week 9 and week 12), compared with approximately 1.9 units for patients taking placebo. The treatment effect of –2.5 units was statistically significant (P < .0001).[17]
Patients who have HD and predominant features of bradykinesia and rigidity may benefit from treatment with levodopa or dopamine agonists.[18]
Depression in patients with HD is treatable and should be recognized promptly. Selective serotonin reuptake inhibitors (SSRIs) should be considered as first-line therapy. Other antidepressants, including bupropion, venlafaxine, nefazodone, and tricyclic antidepressants, also can be used. Electroconvulsive therapy (ECT) can be used in patients with refractory depression.
Antipsychotic medications may be necessary in patients with hallucinations, delusions, or schizophrenia-like syndromes. Newer agents, such as quetiapine, clozapine, olanzapine, and risperidone, are preferred to older agents because of the lower incidence of extrapyramidal side effects and the decreased risk for tardive syndromes.
Irritability may be treated with antidepressants, particularly the SSRIs; mood stabilizers, such as valproic acid or carbamazepine; and, if needed, atypical neuroleptics.
Other less frequent aspects of HD that may require pharmacologic treatment are mania, obsessive-compulsive disorder, anxiety, sexual disorders, myoclonus, tics, dystonia, and epilepsy.
Guidelines for treating neuropsychiatric symptoms of Huntington’s disease (HD) were published in November 2018 in the Journal of Huntington’s Disease.[19, 20]
Guidelines for Agitation in HD
Guidelines for Anxiety in HD
Guidelines for Apathy in HD
Guidelines for Psychosis in HD
Guidelines for Sleep Disorders in HD
Although no therapy is currently available to delay the onset of symptoms or prevent the progression of the disease, symptomatic treatment of patients with Huntington disease (HD) may improve the quality of life and prevent complications. As is the case with other neurological diseases, HD makes individuals more vulnerable to side effects from medications, particularly cognitive adverse effects. Avoid polypharmacy if possible. Symptomatic treatment for HD can be divided into drugs to treat the movement disorder and drugs to treat psychiatric or behavioral problems.
Experimental therapies for HD currently are being tested in animal models and human trials. Awareness of ongoing research to find an effective cure for HD must be a part of the care plan of an individual patient and the patient's family.
Therapeutic options include dopamine-depleting agents (eg, reserpine, tetrabenazine) and dopamine-receptor antagonists (eg, neuroleptics). Long-term use of these drugs may carry a high risk of adverse effects. Choreic movements in patients with HD should be treated pharmacologically only if they become disabling to the patient. Neuroleptics may worsen other features of the disease, such as bradykinesia and rigidity, leading to further functional decline.
Results of some studies have suggested that valproic acid and clonazepam may be effective in the treatment of chorea, while results of other studies have been less conclusive. In the authors' experience, using valproic acid and clonazepam first may be worthwhile because of their safer adverse-effect profiles.
Tetrabenazine is a dopamine-depleting agent was approved by the FDA in August 2008. It may be more effective than reserpine in the treatment of chorea and less likely to cause hypotension. The dose is titrated slowly and may be increased over several weeks to a maximum 75-100 mg/d in divided doses.
Clinical Context: Depletes neurotransmitter stores of dopamine, serotonin, and noradrenaline within nerve cells in the brain, thereby altering transmission of electric signals from the brain that control movement by reversibly inhibiting vesicular monoamine transporter 2 (VMAT2).
Efficacy and safety established in a randomized, double-blind, placebo-controlled, multicenter study. Patients treated with tetrabenazine had significant improvement in chorea compared with those treated with placebo. Additional studies support this effect. Indicated for chorea associated with Huntington disease.
Clinical Context: Orally administered VMAT-2 inhibitor. It is indicated for chorea associated Huntington disease.
Clinical Context: Dopamine-depleting agent. Used in past to treat hypertension.
Antichorea effect of central monamine-depleting agents is believed to be related to its effect on reversible depletion of monoamines (eg, dopamine, serotonin, norepinephrine) from nerve terminals.
Clinical Context: Carboxylic acid commonly used as antiepileptic drug, mood stabilizer in mania, and prophylactic agent for migraine. When combined with sodium valproate in 1:1 molar relationship, called divalproex sodium. Mechanism by which valproate exerts its antiepileptic effects has not been established; its activity may be related to increased brain levels of GABA. No large clinical trials exist to support its use for hyperkinetic movement disorders, but it may be effective, as suggested by a few small studies in patients with chorea of different etiologies.
Daily maximum dose of 2000 mg in divided doses (bid or tid) is enough to determine whether drug is going to be effective for individual patient.
Clinical Context: Belongs to benzodiazepine class of drugs. Enhances activity of GABA, major inhibitory neurotransmitter in CNS. Used commonly as antiepileptic drug. May be useful in treatment of chorea, but no large clinical trials exist to support its use. Does not induce parkinsonism or carry risk of tardive syndromes, as neuroleptics do; therefore, an adequate trial with this medication is reasonable before using dopamine antagonists.
Maximum daily dose of 2-4 mg divided bid/tid usually is enough to determine effectiveness for individual patient.
Clinical Context: Antipsychotic agent that belongs to new chemical class, benzisoxazole derivatives.
Antagonist of type 2 dopamine and serotonin receptors.
Less likely than typical neuroleptics to cause parkinsonism.
Clinical Context: First of butyrophenone class of major tranquilizers. Typical neuroleptics, such as haloperidol, are potent dopamine-receptor antagonists and should be used only as last resort to treat chorea.
Clinical Context: SSRI that can be used once daily. Most patients should take it in morning because can be stimulating and may cause insomnia. If sedation occurs, drug should be taken at bedtime. A few patients develop sexual problems, such as decreased libido, anorgasmia, or ejaculatory delay.
Depression is relatively common in patients with HD and should be treated pharmacologically as soon as diagnosis of depression is made. Depression in patients with HD can be treated with the same agents used for treatment of depression of any other cause. SSRIs may be used as first-line therapy because of their low adverse-effect profile, convenient dosing, and safety in the event of overdose. Other antidepressants can be used, including bupropion, venlafaxine, nefazodone, and the tricyclic antidepressants. Electroconvulsive therapy can be effective if an immediate intervention is required and in patients who do not respond to several good trials of medication.