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Huntington Disease

Synonym: Huntington Chorea

, PhD, , PhD, and , MB, ChB, PhD, FRCP(C), FRSC.

Author Information
, PhD
Department of Medical Genetics
University of British Columbia
Vancouver, British Columbia, Canada
, PhD
Department of Medical Genetics
University of British Columbia
Vancouver, British Columbia, Canada
, MB, ChB, PhD, FRCP(C), FRSC
Department of Medical Genetics
University of British Columbia
Vancouver, British Columbia, Canada

Initial Posting: ; Last Update: April 22, 2010.

Summary

Disease characteristics. Huntington disease (HD) is a progressive disorder of motor, cognitive, and psychiatric disturbances. The mean age of onset is 35 to 44 years and the median survival time is 15 to 18 years after onset.

Diagnosis/testing. The diagnosis of HD rests on positive family history, characteristic clinical findings, and the detection of an expansion of 36 or more CAG trinucleotide repeats in HTT.

Management. Treatment of manifestations: Pharmacologic therapy including typical neuroleptics (haloperidol), atypical neuroleptics (olanzapine), benzodiazepines, or the monoamine depleting agent tetrabenazine for choreic movements; anti-parkinsonian agents for hypokinesia and rigidity; psychotropic drugs or some types of antiepileptic drugs for psychiatric disturbances (depression, psychotic symptoms, outbursts of aggression); valproic acid for myoclonic hyperkinesia. Supportive care with attention to nursing needs, dietary intake, special equipment, and eligibility for state and federal benefits.

Prevention of secondary complications: Attention to the usual potential complications in persons requiring long-term supportive care and the side effects associated with pharmacologic treatments.

Surveillance: Regular evaluations of the appearance and severity of chorea, rigidity, gait problems, depression, behavioral changes, and cognitive decline; routine assessment of functional abilities using the Behavior Observation Scale Huntington (BOSH) and the Unified HD rating scale (UHDRS).

Agents/circumstances to avoid: L-dopa-containing compounds (may increase chorea), alcohol consumption, smoking.

Other: Children and adolescents with a parent with HD may benefit from referral to a local HD support group for educational materials and psychological support.

Genetic counseling. HD is inherited in an autosomal dominant manner. Offspring of an individual with a mutant allele have a 50% chance of inheriting the disease-causing allele. Predictive testing in asymptomatic adults at 50% risk is possible but requires careful thought (including pretest and post-test genetic counseling) as no treatment exists. Asymptomatic at-risk individuals younger than age 18 years should not have predictive testing. Although infrequently requested, prenatal testing by molecular genetic testing is possible for pregnancies at 50% risk. Prenatal testing for pregnancies at 25% risk can be performed using linkage analysis in such a way that the genetic status of the at-risk parent is not revealed.

Diagnosis

Clinical Diagnosis

The diagnosis of Huntington disease (HD) is suspected clinically in the presence of the following:

  • Progressive motor disability featuring chorea; voluntary movement may also be affected
  • Mental disturbances including cognitive decline, changes in personality, and/or depression
  • Family history consistent with autosomal dominant inheritance

Note: The appearance and sequence of motor, cognitive, and psychiatric disturbances can be variable in HD. The test for CAG repeat size in HTT is used to determine the risk status for HD. The diagnosis and age of onset of the disease is determined clinically, usually based on motor signs.

Molecular Genetic Testing

Gene. HTT (HD) is the only gene known to be associated with Huntington disease. A trinucleotide CAG repeat expansion is the only mutation observed.

Allele sizes. Alleles in HTT are classified as normal, intermediate, or HD-causing depending on the number of CAG repeats. The disease is inherited in a dominant fashion and a single HD-causing allele is sufficient to cause the disease.

  • Normal alleles. p.Gln18(<26), 26 or fewer CAG repeats.
  • Intermediate alleles. p.Gln18(27_35), 27-35 CAG repeats. An individual with an allele in this range is not at risk of developing symptoms of HD, but because of instability in the CAG tract, may be at risk of having a child with an allele in the HD-causing range [Semaka et al 2006]. Exact estimates of risk are low, but currently unknown. Alleles in the intermediate range have also been described as "mutable alleles" [Potter et al 2004].
  • HD-causing alleles. p.Gln18(>36), 36 or more CAG repeats. Persons who have an HD-causing allele are considered at risk of developing HD in their lifetime. HD-causing alleles are further classified as:
    • Reduced-penetrance HD-causing alleles. p.Gln18(36_39), 36-39 CAG repeats. An individual with an allele in this range is at risk for HD but may not develop symptoms. In rare cases, elderly asymptomatic individuals have been found with CAG repeats in this range [Langbehn et al 2004].
    • Full-penetrance HD-causing alleles. p.Gln18(>40), 40 or more CAG repeats. Alleles of this size are associated with development of HD with great certainty.

Clinical testing

Table 1. Summary of Molecular Genetic Testing Used in Huntington Disease

Gene 1Test MethodMutations Detected 2Mutation Detection Frequency by Test Method 3
HTT (HD)Targeted mutation analysisCAG trinucleotide repeat expansion 100%

1. See Table A. Genes and Databases for chromosome locus and protein name.

2. See Molecular Genetics for information on allelic variants.

3. The ability of the test method used to detect a mutation that is present in the indicated gene

Testing Strategy

To establish the diagnosis in a proband, an HD-causing HTT allele must be identified.

Predictive testing for at-risk asymptomatic adult family members requires prior confirmation of the diagnosis in the family using molecular genetic testing.

Prenatal diagnosis and preimplantation genetic diagnosis (PGD) for at-risk pregnancies require prior confirmation of the diagnosis in the family using molecular genetic testing.

Clinical Description

Natural History

At-risk individuals who have a Huntington disease-causing allele are healthy and free of detectable clinical signs or symptoms prior to onset and diagnosis of Huntington disease (HD). Preclinically, however, a phase (often referred to as 'presymptomatic' phase) exists in which people may have subtle and otherwise undetected changes in motor skills, cognition, and personality [Walker 2007].

The mean age of onset for HD is 35 to 44 years [Bates et al 2002]. About two-thirds of affected individuals first present with neurologic manifestations; others present with psychiatric changes. In the early stages following diagnosis, manifestations include subtle changes in eye movements, coordination, minor involuntary movements, difficulty in mental planning, and often a depressed or irritable mood (see Clinical Signs in HD). Affected individuals are usually able to perform most of their ordinary activities and to continue work [Bates et al 2002].

In approximately 25% of individuals with HD, the onset is delayed until after age 50 years, a few even after age 70 years. These individuals have chorea, gait disturbances, and dysphagia, but a more prolonged and benign course than the typical individual.

In the next stage, chorea becomes more prominent, voluntary activity becomes increasingly difficult, and dysarthria and dysphagia worsen. Most individuals are forced to give up their employment and depend increasingly on others for help, although they are still able to maintain a considerable degree of personal independence. The impairment is usually considerable, sometimes with intermittent outbursts of aggressive behaviors and social disinhibition.

In late stages of HD, motor disability becomes severe and the individual is often totally dependent, mute, and incontinent. The median survival time after onset is 15 to 18 years (range: 5 to >25 years). The average age at death is 54 to 55 years [Harper 2005].

Clinical Signs in HD

Early

  • Clumsiness
  • Agitation
  • Irritability
  • Apathy
  • Anxiety
  • Disinhibition
  • Delusions
  • Hallucinations
  • Abnormal eye movements
  • Depression

Middle

  • Dystonia
  • Involuntary movements
  • Trouble with balance and walking
  • Chorea, twisting and writhing motions, jerks, staggering, swaying, disjointed gait (can seem like intoxication)
  • Trouble with activities that require manual dexterity
  • Slow voluntary movements, difficulty initiating movement
  • Inability to control speed and force of movement
  • Slow reaction time
  • General weakness
  • Weight loss
  • Speech difficulties
  • Stubbornness

Late

  • Rigidity
  • Bradykinesia (difficulty initiating and continuing movements)
  • Severe chorea (less common)
  • Serious weight loss
  • Inability to walk
  • Inability to speak
  • Swallowing problems, danger of choking
  • Inability to care for oneself

Abnormalities of movement. Disturbances of both involuntary and voluntary movements occur in individuals with HD. Chorea, an involuntary movement disorder consisting of nonrepetitive, non-periodic jerking of limbs, face, or trunk, is the major sign of the disease. Chorea is present in over 90% of individuals, increasing during the first ten years. The choreic movements are continuously present during waking hours, cannot be suppressed voluntarily, and are worsened by stress.

With advancing disease duration, other involuntary movements such as bradykinesia, rigidity, and dystonia occur. Impairment in voluntary motor function is an early sign. Affected individuals and their families describe clumsiness in common daily activities. Motor speed, fine motor control, and gait are affected. Oculomotor disturbances occur early and worsen progressively. Difficulty in initiating ocular saccades, slow and hypometric saccades, and problems in gaze fixation may be seen in up to 75% of symptomatic individuals [Blekher et al 2006, Golding et al 2006]. Dysarthria occurs early and is common. Dysphagia occurs in the late stages. Hyperreflexia occurs early in 90% of individuals, while clonus and extensor plantar responses occur late and less frequently.

Abnormalities of cognition. A global and progressive decline in cognitive capabilities occurs in all individuals with HD. Cognitive changes include forgetfulness, slowness of thought processes, impaired visuospatial abilities, and impaired ability to manipulate acquired knowledge. Several studies have identified subtle but definite cognitive deficits prior to the onset of motor symptoms [Bourne et al 2006, Montoya et al 2006, Paulsen et al 2008, Rupp et al 2010, Tabrizi et al 2009]. The initial changes often involve loss of mental flexibility and impairment of executive functions such as mental planning and organization of sequential activities.

Memory deficits with greater impairment for retrieval of information occur early, but verbal cues, priming, and sufficient time may lead to partial or correct recall. Early in the disease the memory deficits in HD are usually much less severe than in Alzheimer disease.

The overall cognitive and behavioral syndrome in individuals with HD is more similar to frontotemporal dementia than to Alzheimer disease. Attention and concentration are affected early [Peinemann et al 2005], resulting in easy distractibility. Language functions are relatively preserved, but a diminished level of syntactic complexity, cortical speech abnormalities, paraphasic errors, and word-finding difficulties are common in late stages.

Neuropsychologic testing reveals impaired visuospatial abilities, particularly in late stages of the disease. Lack of awareness, especially of one's own disabilities, is common [Bates et al 2002, Ho et al 2006].

Psychiatric disturbances. Individuals with HD develop significant personality changes, affective psychosis, or schizophrenic psychosis [Rosenblatt 2007]. Prior to onset of HD, they tend to score high on measures of depression, hostility, obsessive-compulsiveness, anxiety, interpersonal sensitivity, phobic anxiety, and psychoticism [Duff et al 2007]. Unlike the progressive cognitive and motor disturbances, the psychiatric changes tend not to progress with disease severity [Anderson & Marder 2001]. Behavioral disturbances such as intermittent explosiveness, apathy, aggression, alcohol abuse, sexual dysfunction and deviations, and increased appetite are frequent. Delusions, often paranoid, are common. Hallucinations are less common.

Depression and suicide risk. The incidence of depression in preclinical and symptomatic individuals is more than twice the general population [Paulsen et al 2005b, Marshall et al 2007]. The etiology of depression in HD is unclear; it may be a pathologic rather than a psychological consequence of having the disease [Slaughter et al 2001]. Suicide and suicide ideation are common in persons with HD, but the incidence rate changes with disease course and predictive testing results [Almqvist et al 1999, Larsson et al 2006, Robins Wahlin 2007]. The critical periods for suicide risk were found to be just prior to receiving a diagnosis and later, when affected individuals experience a loss of independence [Baliko et al 2004, Paulsen et al 2005a].

Other. Persons with HD tend to have a lower body mass index than controls [Pratley et al 2000, Stoy & McKay 2000, Djousse et al 2002, Robbins et al 2006].

Sleep cycles are disrupted in individuals with HD [Morton et al 2005], possibly as a result of hypothalamic dysfunction [Petersen & Bjorkqvist 2006].

Juvenile HD is defined by the onset of symptoms before age 20 years and accounts for 5%-10% of HD cases [Nance & Myers 2001, Gonzalez-Alegre & Afifi 2006]. The motor, cognitive, and psychiatric disturbances observed in adult HD are also observed in juvenile HD, but the clinical presentation of these disturbances is different. Severe mental deterioration, prominent motor and cerebellar symptoms, speech and language delay, and rapid decline are also characteristic of juvenile HD [Nance & Myers 2001, Gonzalez-Alegre & Afifi 2006, Squitieri et al 2006, Yoon et al 2006]. Epileptic seizures, unique to the youngest onset group, are present in 30%-50% of those with onset of HD before age ten years [Gonzalez-Alegre & Afifi 2006].

In teenagers, symptoms are more similar to adult HD, in which chorea and severe behavioral disturbances are common initial manifestations [Nance & Myers 2001].

Neuropathology. Neuropathologic features of HD primarily include a selective degeneration of neurons in the caudate and putamen [Cowan & Raymond 2006]. The preferential degeneration of medium spiny, enkephlin-containing neurons of the indirect pathway of movement control in the basal ganglia provides the neurobiologic basis for chorea [Mitchell et al 1999]. Interneurons of the striatum are generally spared. Other regions of the brain that can be affected include the substantia nigra, hippocampus, and various regions of the cortex [Van Raamsdonk et al 2005]. Pathology is also seen in peripheral tissues [Björkqvist et al 2008, van der Burg et al 2009].

Intraneuronal inclusions containing huntingtin, the protein expressed from HTT, are also a prominent neuropathologic feature of the disease. However, the expression of the huntingtin protein and the pattern and timing of huntingtin-containing inclusions in brain do not correlate with the selective degeneration of the disease and are not believed to be primary determinants of pathology [Kuemmerle et al 1999, Michalik & Van Broeckhoven 2003, Arrasate et al 2004, Slow et al 2005, Slow et al 2006].

Neuroimaging. Imaging studies including MRI, CT, SPECT, and PET provide additional support for the clinical diagnosis of HD and are valuable tools for studying progression of the disease [Biglan et al 2009, Paulsen 2009]. In addition to significant striatal atrophy in symptomatic persons, other regional and global changes have been detected [Mascalchi et al 2004, Henley et al 2006]. Neuroimaging has revealed significant changes in the striatum prior to the onset of symptoms; MRI scans have revealed significant striatal atrophy as many as 11 years prior to clinical onset of the disease [Aylward et al 2004]. Numerous studies in recent years have used neuroimaging to elucidate the pathogenesis and progress of HD, with specific interest in the use of neuroimaging for clinical trials [Paulsen et al 2006].

Genotype-Phenotype Correlations

A significant inverse correlation exists between the number of CAG repeats and the age of onset of HD [Langbehn et al 2004, Langbehn et al 2010].

  • Individuals with adult onset of symptoms usually have an HTT allele with CAG repeats ranging from 36 to 55.
  • Individuals with juvenile onset of symptoms usually have an HTT allele with CAG repeats greater than 60.

For data on the age-specific likelihood of onset by trinucleotide repeat size, see www.cmmt.ubc.ca (pdf).

A significant negative correlation also exists between CAG size and variability of onset, in which more variability in the late age of onset is associated with smaller CAG sizes, suggesting that non-CAG modifiers may have a greater effect at lower CAG sizes than larger CAG sizes [Langbehn et al 2004, Gusella & Macdonald 2009]. On average, the CAG repeat size accounts for up to 70% of the variability in age of onset, with an estimated 10%-20% of the residual variability being accounted for by heritable factors [Wexler et al 2004, Li et al 2006]. Many genes at other loci have been shown to account for small amounts of this heritable portion of the variability [Andresen et al 2007]. One large-scale genome-wide analysis study (HDMaps) found significant linkage to as-yet-unknown genetic causes mapping to 4p16 [Djousse et al 2004] and 6q23-q24 [Li et al 2006].

The rate of deterioration of motor, cognitive, and functional measures increases with larger mutant CAG repeat sizes [Rosenblatt et al 2006, Aziz et al 2009].

The progression of behavioral symptoms appears not to be related to repeat size [Ravina et al 2008].

Homozygotes for fully penetrant HD alleles appear to have a similar age of onset to heterozygotes, but may exhibit an accelerated rate of disease progression [Squitieri et al 2003].

Penetrance

Alleles that contain more than 35 CAG repeats are considered HD-causing alleles and confer risk of developing the disease.

Alleles that contain from 36-39 CAG repeats, however, are incompletely penetrant and may or may not result in HD. In rare cases, elderly asymptomatic individuals have been found with CAG repeats in this range.

Alleles that contain more than 40 CAG repeats are completely penetrant. No asymptomatic elderly individuals with alleles of more than 40 CAG repeats have been reported.

Anticipation

Anticipation, the phenomenon in which increasing disease severity or decreasing age of onset is observed in successive generations, is known to occur in HD. Anticipation occurs more commonly in paternal transmission of the mutated allele. The phenomenon of anticipation arises from instability of the CAG repeat during spermatogenesis. Large expansions (i.e., an increase in allele size of >7 CAG repeats) occur almost exclusively through paternal transmission. Most often children with juvenile-onset disease inherit the expanded allele from their fathers, although on occasion they inherit it from their mothers [Nahhas et al 2005].

Nomenclature

In the premolecular genetic era there were many different names for chorea, including St. Vitus Dance and Sydenham's chorea.

Juvenile HD, or childhood-onset HD, was previously called the Westphal variant of HD.

Prevalence

The prevalence of Huntington disease (HD) is between three and seven per 100,000 in populations of western European descent. HD appears less frequently in Japan, China, and Finland, and among African blacks. The frequency of HD in Japan has been estimated at between 0.1 and 0.38 per 100,000. The prevalence of HD exceeds 15 per 100,000 in some populations, mostly of western European origin [Bates et al 2002]. The identity of the genetic change responsible for HD was first described in individuals living in the Lake Maracaibo region of Venezuela, which is believed to have the highest prevalence of HD in the world [Wexler et al 2004].

The uneven distribution of HD is at least partially explained by the distribution of specific predisposing alleles and haplotypes in the normal population of these ethnic groups [Warby et al 2009]. It is not clear whether this predisposition for CAG-expansion of specific haplotypes is simply the result of increases in background CAG size, or whether these haplotypes contain cis-elements conferring a predisposition to instability.

Intermediate HTT alleles (see Molecular Genetic Testing) are found in approximately 1%-4% of individuals in some populations [Maat-Kievit et al 2001, Semaka et al 2010].

Differential Diagnosis

Huntington disease (HD) falls into the differential diagnosis of chorea, dementia, and psychiatric disturbances. The differential diagnosis of several HD-like disorders has recently been reviewed [Semaka et al 2008, Schneider et al 2007].

Noninherited conditions are associated with chorea, but most can be excluded easily in an individual with suspected HD. Causes of chorea such as tardive dyskinesia, thyrotoxicosis, cerebrovascular disease, cerebral lupus, and polycythemia can be excluded based on associated findings and the course of illness.

Inherited conditions to be considered include the following:

  • Huntington disease-like 1 (HDL1) is an early-onset, slowly progressive prion disease with an autosomal dominant pattern of inheritance and a wide range of clinical features that overlap with HD. HDL1 is caused by a specific mutation (8 extra octapeptide repeats) in the prion protein (PrP) gene, PRNP, on chromosome 20p [Laplanche et al 1999, Moore et al 2001]. Similar mutations at this locus also result in other forms of prion disease, such as Creutzfeldt-Jakob disease (see Prion Diseases). Inheritance is autosomal dominant.
  • Huntington disease-like 2 (HDL2) is clinically indistinguishable from HD. Individuals typically present in midlife with a relentless progressive triad of movement, emotional, and cognitive abnormalities progressing to death over ten to 20 years. The causative mutation is a CTG/CAG repeat expansion in the junctophilin-3 gene (JPH3) [Holmes et al 2001, Margolis et al 2001]. The prevalence of HDL2 is highest among (and perhaps exclusive to) individuals of African descent [Margolis et al 2005]. Inheritance is autosomal dominant.
  • Chorea-acanthocytosis (ChAc) is characterized by a progressive choreiform movement disorder, a progressive distal myopathy, and acanthocytosis of the red blood cells. The movement disorder is mostly chorea, but some individuals present with a parkinsonian syndrome. Dystonia is common and affects the oral region and the tongue in particular. Progressive cognitive and behavioral changes resemble a frontal lobe syndrome. Seizures are common. Mean age of onset is about 35 years. The diagnosis of chorea-acanthocytosis depends on the presence of characteristic MRI findings and evidence of muscle disease. Acanthocytes are present in 5%-50% of the red cell population. In some cases, acanthocytosis may be absent or may appear only late in the course of the disease. VPS13A is the only gene currently known to be associated with chorea-acanthocytosis. Inheritance is autosomal recessive.
  • McLeod neuroacanthocytosis syndrome (MLS) is a multisystem disorder with central nervous system, neuromuscular, and hematologic manifestations in males. Clinical overlap with HD includes neurodegeneration in the basal ganglia as well as cognitive impairment and psychiatric symptoms. The hematologic findings in MLS are red blood cell acanthocytosis, compensated hemolysis, and the McLeod blood group phenotype. MLS is X-linked and caused by mutations in XK.
  • Spinocerebellar ataxia type 17 (SCA17) is characterized by chorea, dementia, and psychiatric disturbances. Cerebellar ataxia is common in SCA17 but not in HD [Bauer et al 2004]. Inheritance is autosomal dominant.
  • Benign hereditary chorea, an autosomal dominant condition, usually presents with non-progressive chorea without dementia.
  • Hereditary cerebellar ataxia should be distinguishable from HD on the basis of prominent cerebellar and long tract signs (see Ataxia Overview).
  • Creutzfeld-Jakob disease progresses more rapidly than HD and has myoclonus as a prominent involuntary movement (see Prion Diseases).

The diagnosis of HD in children is straightforward in a family with a history of HD. In simplex cases (an affected individual with no known family history of HD), ataxia-telangiectasia, pantothenate kinase-associated neurodegeneration (previously known as Hallervorden-Spatz syndrome), Lesch-Nyhan syndrome, Wilson disease, progressive myoclonic epilepsy [Gambardella et al 2001], and other metabolic diseases must be excluded.

Note to clinicians: For a patient-specific ‘simultaneous consult’ related to this disorder, go to Image SimulConsult.jpg, an interactive diagnostic decision support software tool that provides differential diagnoses based on patient findings (registration or institutional access required).

Management

Evaluations Following Initial Diagnosis

To establish the extent of disease in an individual diagnosed with Huntington disease (HD), the following evaluations are recommended:

  • Physical examination
  • Neurologic assessment
  • Assessment of the full range of motor, cognitive, and psychiatric symptoms associated with HD. Among a range of clinical scoring systems that have been described, the Unified Huntington's Disease Rating Scale (HDRS) provides a reliable and consistent assessment of the clinical features and progression of HD.

Treatment of Manifestations

Pharmacologic therapy is limited to symptomatic treatment [Mestre et al 2009].

  • Choreic movements can be partially suppressed by typical and atypical neuroleptics such as haloperidol and olanzapine respectively, benzodiazepines, or the monoamine-depleting agent tetrabenazine [de Tommaso et al 2005, Bonelli & Wenning 2006, Huntington Study Group 2006].
  • Anti-parkinsonian agents may ameliorate hypokinesia and rigidity, but may increase chorea.
  • Psychiatric disturbances such as depression, psychotic symptoms, and outbursts of aggression generally respond well to psychotropic drugs or some types of antiepileptic drugs.
  • Valproic acid has improved myoclonic hyperkinesia in Huntington disease [Saft et al 2006].

Supportive care with attention to nursing, diet, special equipment, and eligibility for state and federal benefits is much appreciated by individuals with HD and their families. Numerous social problems beset individuals with HD and their families; practical help, emotional support, and counseling can provide relief [Williams et al 2009].

Prevention of Secondary Complications

Significant secondary complications of HD include the following:

  • The complications typically observed with any individual requiring long-term supportive care
  • The side effects associated with various pharmacologic treatments. Drug side effects are dependent on a variety of factors including the compound involved, the dosage, and the individual; but with the medications typically used in HD, side effects may include depression, sedation, nausea, restlessness, headache, neutropenia, and tardive dyskinesia. For some individuals, the side effects of certain therapeutics may be worse than the symptoms; such individuals would benefit from being removed from the treatment, having the dose reduced, or being 'rested' regularly from the treatment. Current medications used to treat chorea are particularly prone to significant side effects. Individuals with mild to moderate chorea may be better assisted with non-pharmacologic therapies such as movement training and speech therapy.
  • Standard treatment for depression is appropriate when indicated [Paulsen et al 2005b, Phillips et al 2008]

Surveillance

Regular evaluations should be made to address the appearance and severity of chorea, rigidity, gait problems, depression, behavioral changes, and cognitive decline [Anderson & Marshall 2005, Skirton 2005].

The Behavior Observation Scale Huntington (BOSH) is a scale developed for the rapid and longitudinal assessment of functional abilities of persons with HD in a nursing home environment [Timman et al 2005]. For longitudinal studies, the Unified HD Rating Scale is used (UHDRS) [Huntington Study Group 1996, Siesling et al 1998].

Agents/Circumstances to Avoid

L-dopa-containing compounds may increase chorea.

Alcohol and smoking are discouraged.

Evaluation of Relatives at Risk

See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.

Therapies Under Investigation

A wide range of potential therapeutics are under investigation in both animal models of HD and human clinical trials. This diversity reflects the variety of cellular pathways that are known to be perturbed in HD [Bonelli et al 2004, Rego & de Almeida 2005, Borrell-Pages et al 2006, Graham et al 2006, Bonelli & Hofmann 2007].

Numerous human clinical trials are planned or underway for HD and are listed at www.huntington-study-group.org.

Search ClinicalTrials.gov for access to information on clinical studies for a wide range of diseases and conditions.

Other

Children and adolescents living with a parent affected with HD, sometimes in very deprived conditions, can have special problems. Referral to a local HD support group for educational material and needed psychological support is helpful (see Resources).

Cognitive impairment is not amenable to treatment.

Donepezil, a drug used to treat Alzheimer disease, has not improved motor or cognitive function in HD [Cubo et al 2006].

Genetic Counseling

Genetic counseling is the process of providing individuals and families with information on the nature, inheritance, and implications of genetic disorders to help them make informed medical and personal decisions. The following section deals with genetic risk assessment and the use of family history and genetic testing to clarify genetic status for family members. This section is not meant to address all personal, cultural, or ethical issues that individuals may face or to substitute for consultation with a genetics professional. —ED.

Mode of Inheritance

Huntington disease (HD) is inherited in an autosomal dominant manner.

Risk to Family Members

Parents of a proband

  • Although most individuals diagnosed with HD have an affected parent, the family history may appear to be negative for one of the following reasons:
    • Failure to recognize the disorder in family members
    • Early death of the parent before the onset of symptoms
    • The presence of an intermediate allele (range: 27-35 CAG repeats) or an HTT allele with reduced penetrance (range: 36-39 CAG repeats) in an asymptomatic parent
    • Late onset of the disease in the affected parent
  • Molecular genetic testing is recommended for the parents of a proband with an apparent de novo mutation.

Sibs of a proband

  • The risk to the sibs of a proband depends on the genetic status of the proband's parent.
  • If a parent is affected or has an HTT allele with CAG length of 40 or greater, the risk to the sibs is 50%.
  • If the father has an intermediate HTT allele, the risk to the sibs of inheriting a mutant allele (i.e., ≥36 CAG repeats) is estimated to be as high as 5% (50% x 10%).
  • A sib who inherits an HTT allele with reduced penetrance may or may not develop symptoms of HD.

Offspring of a proband

  • At conception, each child of an individual with HD as a result of heterozygosity for the HTT allele has a 50% chance of inheriting the disease-causing mutation.
  • Each child of an affected individual who is homozygous for CAG repeat expansion in HTT will inherit an HD-causing allele.

Other family members. The risk to other family members depends on the genetic status of the proband's parents. If a parent is affected or has a CAG expansion in HTT, his or her family members are at risk.

Related Genetic Counseling Issues

Intermediate alleles (IA): 27-35 CAG. Individuals who have an intermediate allele are not at risk of developing HD. However, children of such individuals are at risk for HD because the instability of the CAG repeat as it is passed between generations can result in CAG repeat expansion [Semaka et al 2006]. The risk to a child of inheriting a CAG expansion greater than 35 repeats or a "new mutation for HD" from a parent with an intermediate allele depends on a variety of factors, including the following:

  • The CAG size of the allele. Larger CAG sizes are more prone to expansion.
  • The sex and age of the transmitting parent. Paternally inherited intermediate alleles are more prone to CAG expansion than maternally inherited intermediate alleles; there has never been a documented case of maternal intermediate allele expansion into the HD range, and thus it remains a theoretical risk. Expanded intermediate alleles are preferentially transmitted by males with advanced paternal age.
  • The DNA sequence in cis configuration with the CAG expansion. CAG tracts interrupted with CCG trinucleotides are more stable.

The risk of inheriting an HTT allele with CAG size of 35 has been estimated at 6%-10%. (Previous estimates of the likelihood for expansion of alleles between 28 and 34 CAG repeats were lower than these estimates.)

Testing of asymptomatic at-risk adults. Testing of asymptomatic adults at risk for HD is possible. Testing for the disease-causing mutation in the absence of definite symptoms of the disease is predictive testing. Such testing is not useful in accurately predicting age of onset, severity, type of symptoms, or rate of progression in asymptomatic individuals. However, data reported by Langbehn et al [2004] concerning the likelihood that an individual with a particular size CAG repeat will be affected by a specific age may be useful. See also Supplementary Tables at www.cmmt.ubc.ca/hayden (pdf). When testing at-risk individuals for HD, it is helpful to test for the CAG expansion in HD in an affected family member to confirm that the disorder in the family is HD.

At-risk asymptomatic adult family members may seek testing in order to make personal decisions regarding reproduction, financial matters, and career planning. Others may have different motivations including simply the "need to know." Testing of asymptomatic at-risk adult family members usually involves pretest interviews in which the motives for requesting the test, the individual's knowledge of HD, the possible impact of positive and negative test results, and neurologic status are assessed. Those seeking testing should be counseled about possible problems that they may encounter with regard to health, life, and disability insurance coverage, employment and educational discrimination, and changes in social and family interaction. Interestingly, a recent study has found that genetic testing does not increase the risk for discrimination; perceived genetic discrimination is more likely due to the family history of HD regardless of gene status, rather than due to the specific results of the HD genetic test [Bombard et al 2009]. Other issues to consider include implications for the at-risk status of other family members. Depression and suicide ideation are issues to be addressed as part of the predictive testing program for HD [Robins Wahlin et al 2000, Robins Wahlin 2007]. Informed consent should be obtained and records kept confidential. Individuals with a mutant allele need arrangements for long-term follow-up and evaluations.

Short-term follow-up of the participants in the Canadian Predictive Testing Program has revealed that predictive testing for HD may maintain or even improve the psychological well-being of at-risk individuals even though some had negative experiences. About 10% of the group who were determined to be at decreased risk had serious difficulties adapting to their new status. The major issue for these individuals is the realization that they are facing an unplanned future. Overall the demand for testing of at-risk asymptomatic adults has been lower than expected in studies conducted before the availability of direct molecular genetic testing. Consistent with use of medical services and genetic testing in general, women are more likely than men to undergo predictive testing for HD [Taylor 2005].

In their study of psychological distress in the partners of asymptomatic individuals who had inherited a mutant HTT allele, Decruyenaere et al [2005] found that partners have at least as much distress as the individuals found to have the mutant allele yet their grief tends to be "disenfranchised" or not socially recognized.

Testing of asymptomatic at-risk individuals during childhood. Requests from parents for testing of asymptomatic at-risk individuals younger than age 18 years require careful counseling. Consensus holds that asymptomatic individuals younger than age 18 years should not have testing. The principal arguments against testing such individuals are that it removes their choice to know or not know this information, it raises the possibility of stigmatization within the family and in other social settings, and it could have serious educational and career implications. Duncan et al [2005] reported on the testing and outcome of 49 asymptomatic minors at risk for adult-onset disorders for which no treatment exists.

See also the National Society of Genetic Counselors position statement on genetic testing of minors for adult-onset conditions and the American Society of Human Genetics and American College of Medical Genetics points to consider: ethical, legal, and psychosocial implications of genetic testing in children and adolescents.

Considerations in families with an apparent de novo mutation. When neither parent has an HD-causing HTT allele (>35 CAG repeats) or an intermediate allele (27-35 repeats), possible non-medical explanations including alternate paternity or maternity (e.g., with assisted reproduction) or undisclosed adoption could be explored.

Family planning. The optimal time for determination of genetic risk and discussion of the availability of prenatal testing is before pregnancy. Similarly, decisions about testing to determine the genetic status of at-risk asymptomatic family members are best made before pregnancy.

DNA banking is the storage of DNA (typically extracted from white blood cells) for possible future use. Because it is likely that testing methodology and our understanding of genes, mutations, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals.

Prenatal Testing

For fetuses at 50% risk. Prenatal diagnosis for pregnancies at 50% risk is possible by analysis of DNA extracted from fetal cells obtained by amniocentesis usually performed at about 15 to 18 weeks' gestation or chorionic villus sampling (CVS) at about ten to 12 weeks' gestation. The presence of the disease-causing allele in the affected parent or in an affected relative of the at-risk parent should be confirmed before prenatal testing is performed.

Note: Gestational age is expressed as menstrual weeks calculated either from the first day of the last normal menstrual period or by ultrasound measurements.

Requests for prenatal testing for typically adult-onset conditions such as HD are not common. Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing when the testing is being considered for the purpose of pregnancy termination or for early diagnosis. Although most centers would consider decisions about prenatal testing to be the choice of the parents, discussion of these issues is appropriate.

Preimplantation genetic diagnosis (PGD) may be an option for some families in which the disease-causing mutations have been identified in an affected family member. Existing PGD exclusion protocols allow for testing of the embryo for couples in an at-risk family who do not wish to undergo presymptomatic mutation testing themselves [Sermon et al 2002, Stern et al 2002, Moutou et al 2004, Jasper et al 2006].

Resources

GeneReviews staff has selected the following disease-specific and/or umbrella support organizations and/or registries for the benefit of individuals with this disorder and their families. GeneReviews is not responsible for the information provided by other organizations. For information on selection criteria, click here.

  • HDBuzz
  • Huntington Society of Canada
    151 Frederick Street
    Suite 400
    Kitchener Ontario N2H 2M2
    Canada
    Phone: 800-998-7398 (toll-free); 519-749-7063
    Fax: 519-749-8965
    Email: info@huntingtonsociety.ca
  • Huntington's Disease Society of America (HDSA)
    505 Eighth Avenue
    Suite 902
    New York NY 10018
    Phone: 800-345-4372 (toll-free); 212-242-1968
    Fax: 212-239-3430
    Email: hdsainfo@hdsa.org
  • International Huntington Association
    Callunahof 8
    Harfsen 7217 ST
    Netherlands
    Phone: +31 573 431 595
    Fax: +31 573 431 719
    Email: iha@huntington-assoc.com
  • National Library of Medicine Genetics Home Reference
  • NCBI Genes and Disease
  • Testing for Huntington Disease: Making an Informed Choice
    Booklet providing information about Huntington disease and genetic testing
    University of Washington Medical Center
    Seattle WA
  • Hereditary Disease Foundation
    3960 Broadway
    6th Floor
    New York NY 10032
    Phone: 212-928-2121
    Fax: 212-928-2172
    Email: cures@hdfoundation.org
  • European Huntington's Disease Network (EHDN) Registry
    Germany
  • Huntington Study Group (HSG)
    University of Rochester, HSG Administrative Office
    1351 Mount Hope Avenue
    Suite 223
    Rochester NY 14620
    Phone: 800-487-7671 (toll-free)
  • Predict HD Registry
    University of Iowa Carver College of Medicine
    200 Newton Road
    1185A-1 Westlawn
    Iowa City IA 52242
    Phone: 319-353-4307
    Fax: 319-353-4438
    Email: predict-hd@uiowa.edu

Molecular Genetics

Information in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED.

Table A. Huntington Disease: Genes and Databases

Gene SymbolChromosomal LocusProtein NameLocus SpecificHGMD
HTT4p16​.3HuntingtinHTT homepage - Mendelian genesHTT

Data are compiled from the following standard references: gene symbol from HGNC; chromosomal locus, locus name, critical region, complementation group from OMIM; protein name from UniProt. For a description of databases (Locus Specific, HGMD) to which links are provided, click here.

Table B. OMIM Entries for Huntington Disease (View All in OMIM)

143100HUNTINGTON DISEASE; HD
613004HUNTINGTIN; HTT

Gene structure. HTT encompasses 67 exons and spans over 200 kb. It is ubiquitously expressed as two transcripts, 10.3 kb and 13.6 kb in length, that differ in the size of the 3' UTR.

Normal allelic variants. The gene contains a trinucleotide repeat (CAG) that is expanded within HTT on at least one chromosome of individuals with Huntington disease (HD). The CAG repeat length is highly polymorphic in the population and unaffected alleles have CAG repeat size ranges from ten to 35 (p.Gln18(10_35). The median size allele is p.Gln18(18). The most common alleles in all populations contain repeats of 15-20 CAG in length [Warby et al 2009].

Pathogenic allelic variants. The mutation underlying HD is an expansion of a CAG trinucleotide (or polyglutamine) tract in the first exon. The CAG repeat length in individuals with HD is 36 or more (p.Gln18(>36)). Individuals with adult-onset HD usually have a CAG expansion from 40 to 55 (p.Gln18(40_55)) whereas those with juvenile onset have CAG expansions greater than 60 (p.Gln18(>60)) that are often inherited from the father. A well-established inverse correlation between CAG repeat length and age of onset exists. However, penetrance of alleles with a CAG repeat range of 36-39 is reduced.

Table 2. Selected HTT Allelic Variants

Class of Variant AlleleDNA Nucleotide Change
(Alias 1)
Protein Amino Acid ChangeReference Sequences
Normalc.52CAG(<26)
(<26 CAG repeats)
p.Gln18(<26)NM_002111​.6
NP_002102​.4
Intermediatec.52CAG(27_35) 2
(27 to 35 CAG repeats)
p.Gln18(27_35)
Pathogenicc.52CAG(36_39) 3
(36 to 39 CAG repeats)
p.Gln18(36_39)
c.52CAG(>40) 4
(>40 CAG repeats)
p.Gln18(>40)

Note on variant classification: Variants listed in the table have been provided by the authors. GeneReviews staff have not independently verified the classification of variants.

Note on nomenclature: GeneReviews follows the standard naming conventions of the Human Genome Variation Society (www​.hgvs.org). See Quick Reference for an explanation of nomenclature.

1. Variant designation that does not conform to current naming conventions

2. Intermediate HTT alleles

3. Reduced-penetrance HD-causing HTT alleles

4. Full-penetrance HD-causing HTT alleles

Normal gene product. Huntingtin is a protein of 3144 amino acids with a predicted molecular mass of 348 kd. Huntingtin is widely expressed with no obvious differences in the regional distribution of the mutant and wild-type protein. The polyglutamine tract starts at residue 18 and is followed by a polyproline region. The region downstream of the polyglutamine tract contains a HEAT repeat, a motif consisting of 40 loosely conserved amino acids repeated multiple times in tandem, proposed to be involved in protein-protein interactions [Palidwor et al 2009].

Abnormal gene product. The CAG repeat in HTT is translated into an uninterrupted stretch of glutamine residues that when expanded may have altered structural and biochemical properties.

References

Published Guidelines/Consensus Statements

  1. American College of Medical Genetics/American Society of Human Genetics Huntington Disease Genetic Testing Working Group; Laboratory guidelines for Huntington disease genetic testing. Am J Hum Genet. 1998;62:1243–7. [PMC free article: PMC1377103] [PubMed: 9545416]
  2. American Society of Human Genetics and American College of Medical Genetics. Points to consider: ethical, legal, and psychosocial implications of genetic testing in children and adolescents. Available online. 1995. Accessed 7-21-14. [PMC free article: PMC1801355] [PubMed: 7485175]
  3. International Huntington Association and the World Federation of Neurology Research Group on Huntington's Chorea; Guidelines for the molecular genetics predictive test in Huntington's disease. Neurology. 1994;44:1533–6. [PubMed: 8058167]
  4. International Huntington Association and World Federation of Neurology; Guidelines for the molecular genetic predictive test in Huntington's disease. J Med Genet. 1994;31:555–9. [PMC free article: PMC1049979] [PubMed: 7966192]
  5. National Society of Genetic Counselors. Position statement on genetic testing of minors for adult-onset conditions. Available online. 2012. Accessed 7-21-14.
  6. World Federation of Neurology Research Committee Research Group on Huntington's Chorea; Ethical issues policy statement on Huntington's chorea molecular genetics predictive test. J Neurol Sci. 1989;94:327–32. [PubMed: 2533250]

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Suggested Reading

  1. Hayden MR, Kremer B. Huntington disease. In: Valle D, Beaudet AL, Vogelstein B, Kinzler KW, Antonarakis SE, Ballabio A, Gibson K, Mitchell G, eds. The Online Metabolic and Molecular Bases of Inherited Disease (OMMBID). New York, NY: McGraw-Hill. Chap 223. Available online. 2014. Accessed 7-21-14.
  2. Imarisio S, Carmichael J, Korolchuk V, Chen C, Saiki S, Rose C, Krishna G, Davies JE, Ttofi E, Underwood BR, Rubinsztein DC. Huntington's disease: from pathology and genetics to potential therapies. Biochem J. 2008;412:191–209. [PubMed: 18466116]

Chapter Notes

Author Notes

Booklets available through the Huntington Society of Canada:

  • Loss and Grief, Coping with the Death of a Loved One and with Other Losses Related to Huntington Disease
  • A Physician's Guide to the Management of Huntington Disease
  • Caregiver's Handbook for Advanced-Stage Huntington Disease
  • Juvenile Huntington Disease: A Resource for Families, Health Professionals and Caregivers
  • Understanding Behaviour in Huntington Disease: A practical guide for individuals, families, and professionals coping with HD
  • Personal Perspectives on Genetic Testing for Huntington Disease
  • Understanding Huntington Disease: A Resource for Families

Author History

Rona K Graham, PhD (2007-present)
Brendan Haigh, PhD; University of British Columbia (1998-2007)
Michael R Hayden, MB, ChB, PhD, FRCP(C), FRSC (1998-present)
Mahbubul Huq, PhD; University of British Columbia (1998-2007)
Simon C Warby (2007-present)

Revision History

  • 22 April 2010 (me) Comprehensive update posted live
  • 19 July 2007 (me) Comprehensive update posted to live Web site
  • 30 August 2005 (cd) Revision: correction of CAG repeat ranges
  • 15 February 2005 (me) Comprehensive update posted to live Web site
  • 25 May 2004 (cd) Revisions
  • 23 October 1998 (pb) Review posted to live Web site
  • 16 May 1998 (mh) Original submission
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