Funded by the NIH • Developed at the University of Washington, Seattle
Funded by the NIH • Developed at the University of Washington, Seattle
[Huntington Chorea]
|
Authors:
|
Simon C Warby, PhD
Rona K Graham, PhD Michael R Hayden, MB, ChB, PhD, FRCP(C), FRSC |
|
Initial Posting:
|
Last Update:
|
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 the HD gene.
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 available 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 available for fetuses at 50% risk. Prenatal testing for fetuses 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.
The diagnosis of Huntington disease (HD) is suspected clinically in the presence of the following:
Note: The appearance and sequence of motor, cognitive, and psychiatric disturbances can be variable in HD. The test for CAG repeat size in the HD gene 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.
GeneReviews designates a molecular genetic test as clinically available only if the test is listed in the GeneTests Laboratory Directory by either a US CLIA-licensed laboratory or a non-US clinical laboratory. GeneTests does not verify laboratory-submitted information or warrant any aspect of a laboratory's licensure or performance. Clinicians must communicate directly with the laboratories to verify information. —ED.
Gene. HD (IT15) is the only gene associated with Huntington disease.
A trinucleotide CAG repeat expansion is the only mutation observed.
Allele sizes. Alleles in the HD gene 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: 26 or fewer CAG repeats
Intermediate alleles: 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]. Alleles in the intermediate range have also been described as "mutable alleles" [Potter et al 2004].
HD-causing alleles: 36 or more CAG repeats. Persons who have an HD-causing allele are considered at risk for developing HD in their lifetime. HD-causing alleles are further classified as:
Reduced-penetrance HD-causing alleles: 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 [Rubinsztein et al 1996 , McNeil et al 1997 , Langbehn et al 2004].
Full-penetrance HD-causing alleles: 40 or more CAG repeats. Alleles of this size are associated with development of HD with great certainty.
Clinical testing
Table 1
summarizes molecular genetic testing for this disorder.
|
||||||||
|
1. Proportion of affected individuals with a mutation(s) as classified by test method
|
To establish the diagnosis in a proband, an HD-causing allele must be identified.
Predictive testing for at-risk asymptomatic adult family members requires prior confirmation of the diagnosis in the family.
Prenatal diagnosis and preimplantation genetic diagnosis (PGD) for at-risk pregnancies require prior confirmation of the diagnosis in the family.
No other phenotypes are associated with mutations in the HD gene.
At-risk individuals who have a Huntington disease (HD) allele are healthy and free of detectable clinical signs or symptoms prior to onset and diagnosis of Huntington disease. Preclinically, however, a phase (often referred to as 'presymptomatic' phase or period of phenoconversion) 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 become increasingly dependent 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 [Hayden 1981 , Harper 1996 , Harper 2005].
Early
Middle
Late
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. Although cognitive deficits occur very early in the disease, it is unknown whether neuropsychologic deficits appear before other clinical signs [Diamond et al 1992]. Several studies have identified subtle but definite cognitive deficits prior to the onset of motor symptoms [Hahn-Barma et al 1998 , Lawrence et al 1998] although others have not [de Boo et al 1997]. The initial changes often involve loss of mental flexibility and impairment of executive functions such as mental planning and organization of sequential activities [Morris 1995].
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 [Morris 1995].
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 (72%), affective psychosis (20%-90%), or schizophrenic psychosis (4%-12%) [Mendez 1994 , Cummings 1995]. Unlike the progressive cognitive and motor disturbances, the psychiatric changes tend not to progress with disease severity. 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, Nehl et al 2005 ; Marshall et al 2007]. The etiology of depression in HD is unclear; it may be a pathologic rather than psychological consequences of having the disease [Slaughter et al 2001]. Suicide and suicide ideation is 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]. 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, Hoth et al 2005].
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 21 years and accounts for 5%-10% of HD cases [Nance & Myers 2001 , Gonzalez-Alegre et al 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 et al 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 et al 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].
Intraneuronal inclusions containing huntingtin, the protein expressed from the HD gene, are also a prominent neuropathologic feature of the disease [DiFiglia et al 1997 , Gourfinkel-An et al 1998]. 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 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. 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].
A significant inverse correlation exists between the number of CAG repeats and the age of onset of HD [Andrew et al 1993 , Andrew et al 1997].
For data on the age-specific likelihood of onset by trinucleotide repeat size, see www.cmmt.ubc.ca/clinical/hayden (pdf).
A significant negative correlation exists between CAG size and variability of onset, suggesting that non-CAG modifiers may have a greater effect at lower CAG sizes [Langbehn et al 2004].
On average, the CAG repeat size accounts for about 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 6q23-24 [Li et al 2006].
The evidence concerning the relationship between CAG repeat length and progression is conflicting. Some studies have identified a correlation between age of onset or CAG size and disease progression [van Dijk et al 1986 , Brandt et al 1996 , Aylward et al 1997 , Mahant et al 2003 , Rosenblatt et al 2006] while others have not [Kieburtz et al 1994 , Claes et al 1995 , Marder et al 2000].
Homozygotes for HD appear to have a similar age of onset to heterozygotes, but may exhibit an accelerated rate of disease progression [Squitieri et al 2003].
Alleles that contain more than 35 CAG repeats are considered HD-causing alleles and confer risk for developing the disease.
Alleles in the 36-39 CAG range, however, are incompletely penetrant and may or may not result in development of HD. In rare cases, elderly asymptomatic individuals have been found with CAG repeats in this range [Rubinsztein et al 1996 , McNeil et al 1997].
Alleles with more than 40 CAG repeats are completely penetrant. No asymptomatic elderly individuals with alleles of more than 40 CAG repeats have been reported.
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 [Duyao et al 1993 , Telenius et al 1995]. Large expansions (i.e., an increase in allele size >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].
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.
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 uneven distribution of HD is at least partially explained by the distribution of predisposing alleles and haplotypes in the normal population of these ethnic groups [Kremer et al 1994 , Squitieri et al 1994 , Almqvist et al 1995 , Watkins et al 1995]. The most common alleles in all populations contain 15 to 20 CAG repeats; in western European populations, the distribution is skewed towards longer alleles within the normal range, whereas these longer alleles are less common in African and Asian populations [Squitieri et al 1994 , Watkins et al 1995 , Rubinsztein et al 1996], suggesting that the expanded alleles in the disease range arise from long normal alleles, which are more prevalent in western European populations.
Intermediate alleles (see Molecular Genetic Testing) are found in approximately 1%-4% of individuals in some populations [Goldberg et al 1995 , Maat-Kievit et al 2001].
For current information on availability of genetic testing for disorders included in this section, see GeneTests Laboratory Directory. —ED.
Huntington disease (HD) falls into the differential diagnosis of chorea, dementia, and psychiatric disturbances.
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 (eight extra octapeptide repeats) in the prion protein (PrP) gene, PRNP, on chromosome 20p [Xiang et al 1998 , 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) [van Gool et al 1995]. 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 (JPH3) gene [Holmes et al 2001 , Margolis et al 2001]. The prevalence of HDL2 is highest among (and perhaps exclusive to) individuals of African decent [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 upon 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. CHAC 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 the XK gene.
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).
Familial frontotemporal dementia with parkinsonism-17 (FTDP-17)
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.
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 [Huntington Study Group 1996].
Pharmacologic therapy is limited to symptomatic treatment.
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 help.
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 dependant 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 dsykinesia. 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 anti-choretic medications 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.
Depression. Treatment is appropriate [Paulsen, Nehl et al 2005].
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]
L-dopa-containing compounds may increase chorea.
Alcohol and smoking are discouraged.
See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.
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].
Pharmacologic agents being investigated include inhibitors of apoptosis, excitotoxicity, huntingtin aggregation, huntingtin proteolysis, inflammation, oxidative damage, and transglutaminase activity as well as compounds that modulate mitochondrial function and transcriptional activity.
Therapeutics that have shown improvements in mouse models of HD and are in preliminary trials include coenzyme Q10, minocycline, sodium butyrate, essential fatty acids, racemide, creatine, cystamine, and riluzole [Walker & Raymond 2004 , Bender et al 2005 , Puri et al 2005 , Bonelli & Wenning 2006 , Hersch et al 2006].
Longitudinal studies of persons at risk for HD are underway to form a basis for future therapeutic trials [Paulsen et al 2006 , Huntington Study Group PHAROS Investigators 2006].
Neural transplantation studies in HD have shown variable results with small numbers of individuals [Furtado et al 2005 , Bachoud-Levi et al 2006 , Farrington et al 2006].
Search ClinicalTrials.gov for access to information on clinical studies for a wide range of diseases and conditions.
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].
Genetics clinics are a soure of information for individuals and families regarding the natural history, treatment, mode of inheritance, and genetic risks to other family members as well as information about available consumer-oriented resources. See the GeneTests Clinic Directory.
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. To find a genetics or prenatal diagnosis clinic, see the GeneTests Clinic Directory. —ED.
Huntington disease (HD) is inherited in an autosomal dominant manner.
Parents of a proband
Sibs of a proband
Offspring of a proband
Other family members. The risk to other family members depends on the genetic status of the proband's parents. If a parent is found to be affected or to have a CAG expansion in the HD gene, his or her family members are at risk.
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 [Kremer et al 1995]. Expanded intermediate alleles are preferentially transmitted by males with advanced paternal age [Goldberg et al 1993 , Goldberg et al 1995].
The DNA sequence in cis configuration with the CAG expansion. CAG tracts interrupted with CCG are more stable.
The risk of inheriting a CAG size of 35 has been estimated at 6%-10% [Chong et al 1997]. (Previous estimates for 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 has been available for over ten years. 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 link at www.cmmt.ubc.ca/hayden .) When testing at-risk individuals for HD, it is helpful to test for the CAG expansion in the HD gene 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. 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 [Lawson et al 1996 , 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 [Bloch et al 1992] even though some had negative experiences [Lawson et al 1996]. 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 the psychological distress in the partners of asymptomatic individuals who had inherited a mutant HD 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 [Bloch & Hayden 1990]. 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 resolution on genetic testing of children 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 (pdf; Genetic Testing).
Considerations in families with an apparent de novo mutation. When neither parent has an HD-causing allele (>35 CAG repeats) or an intermediate allele (27-35 repeats), possible non-medical explanations including alternate paternity 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. 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. See DNA Banking for a list of laboratories offering this service.
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 15-18 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, careful discussion of these issues is appropriate.
Preimplantation g
