Huntington Disease

Clinical 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 to 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 Huntington's Disease 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 pathogenic variant have a 50% chance of inheriting the disease-causing allele. Predictive testing in asymptomatic adults at risk is available but requires careful thought (including pre- and post-test genetic counseling) as there is currently no cure for the disorder. However, asymptomatic individuals at risk may be eligible to participate in clinical trials. Predictive testing is not considered appropriate for asymptomatic at-risk individuals younger than age 18 years. Prenatal testing by molecular genetic testing and preimplantation genetic testing are possible.

Suggestive Findings

Huntington disease (HD) should be suspected in individuals with any 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 (see Clinical Description).

Establishing the Diagnosis

The diagnosis of HD is established in a proband with clinical signs and symptoms of HD by the identification of a heterozygous abnormal CAG trinucleotide repeat expansion in HTT by molecular genetic testing (see Table 1).

Note: Pathogenic (CAG)_n repeat expansions in HTT cannot currently be detected by clinical sequence-based multigene panels, exome sequencing, or genome sequencing.

CAG repeat sizes

• Normal. 26 or fewer CAG repeats
• Intermediate. Range from 27 to 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]. Risk estimates for germline CAG expansion have been established [Semaka et al 2013a, Semaka & Hayden 2014].
• Pathogenic HD-causing alleles. 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. Range from 36 to 39 CAG repeats. An individual with an allele in this range is at risk for HD but may not develop symptoms. Elderly asymptomatic individuals with CAG repeats in this range are common [Kay et al 2016].
  • Full-penetrance HD-causing alleles. 40 or more CAG repeats. Alleles of this size are associated with development of HD with increased certainty assuming a normal life span.

Molecular genetic testing relies on targeted analysis to characterize the number of HTT CAG repeats.

Note: For comprehensive recommendations pertaining to predictive genetic testing for HD, see Genetic Counseling and MacLeod et al [2013].

Clinical Description

During the prodromal phase of Huntington disease (HD) individuals may have subtle changes in motor skills, cognition, and personality (see Figure 1) [Tabrizi et al 2013, Ross et al 2014, Liu et al 2015]. These subtle changes can occur as early as 15-20 years prior to the clinical onset of manifest HD.

Figure 1.

Natural history of Huntington disease (HD). Presymptomatic individuals are free from signs and symptoms of HD. During the prodromal phase, subtle signs and symptoms may be present prior to the diagnosis of HD, which is usually based on motor symptoms. (more...)

Reilmann et al [2014] present guidelines for the diagnostic criteria of presymptomatic, prodromal, and manifest HD; see Table 2. This table can be used to place individuals into different diagnostic categories, which may have clinical management implications over time. For example, awareness of presymptomatic and prodromal HD may allow for preventive (rather than symptomatic) therapies. Note the clear differentiation of genetically confirmed HD in the classification system.

The mean age of onset for HD is approximately 45 years [Bates et al 2015]. 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 Table 3). Affected individuals are usually able to perform most of their ordinary activities and to continue working [Ross et al 2014, Bates et al 2015].

In approximately 25% of individuals with HD, the onset is delayed until after age 50 years, with some 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 [Bates et al 2015].

Abnormalities of movement. Disturbances of both involuntary and voluntary movements occur in individuals with HD. Chorea, an involuntary movement disorder consisting of nonrepetitive, nonperiodic jerking of limbs, face, or trunk, is the major sign of the disease. Chorea is present in more than 90% of individuals, and typically increases in severity 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, Tabrizi et al 2009, Rupp et al 2010]. 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 involved 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 [Ho et al 2006, Bates et al 2015].

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, and psychoticism [Duff et al 2007]. Unlike the progressive cognitive and motor disturbances, the psychiatric changes tend not to progress with disease severity [Epping et al 2016]. 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 that in 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, Pouladi et al 2009]. Suicide and suicide ideation are common in persons with HD, but the incidence rate changes with disease course and predictive testing results [Larsson et al 2006, Robins Wahlin 2007, van Duijn et al 2018]. 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, Eddy et al 2016].

Other. Persons with HD tend to have a lower body mass index than controls [Pratley et al 2000, Stoy & McKay 2000, Djoussé et al 2002, Robbins et al 2006], which may be related to altered metabolism [Duan et al 2014] and could represent a biomarker of clinical progression [van der Burg et al 2017]. Individuals with HD also demonstrate disturbed cholesterol metabolism [Valenza & Cattaneo 2006, Wang et al 2014]. It is also common for persons with HD to demonstrate increased appetite and energy expenditure [Pratley et al 2000, Trejo et al 2004, Gaba et al 2005].

Sleep and circadian rhythms are disrupted in individuals with HD [Goodman & Barker 2010, Morton 2013], possibly as a result of hypothalamic dysfunction [Petersén & Björkqvist 2006] and/or alterations in melatonin secretion [Kalliolia et al 2014]. Insomnia and daytime somnolence may also be present, although this is more commonly due to psychiatric changes, depression, or chorea [Videnovic et al 2009].

Neuropathology. The primary neuropathologic feature of HD is degeneration of neurons in the caudate and putamen as well as the cerebral cortex [Waldvogel et al 2015]. The preferential degeneration of enkephalin-containing, medium spiny neurons of the indirect pathway of movement control in the basal ganglia provides the neurobiologic basis for chorea [Galvan et al 2012]. The additional loss of substance P-containing medium spiny neurons of the direct pathway results in akinesia and dystonia [Galvan et al 2012]. There is also evidence for loss of neurons in the globus pallidus, subthalamic nucleus, thalamus, hypothalamus, substantia nigra, and hippocampus [Vonsattel et al 1985, Vonsattel & DiFiglia 1998, Heinsen et al 1999, Petersén et al 2005, Guo et al 2012, Domínguez et al 2013, Singh-Bains et al 2016]. Region-specific patterns of neuronal loss in the basal ganglia and cortex may underlie the most evident symptoms in affected individuals and could contribute to the phenotypic variability among individuals [Thu et al 2010, Hadzi et al 2012, Kim et al 2014, Waldvogel et al 2015, Mehrabi et al 2016]. Pathology is also observed 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 the 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 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, Tabrizi et al 2011, Tabrizi et al 2012, Tabrizi et al 2013]. In addition to significant striatal atrophy in symptomatic individuals, regional and whole-brain gray and white matter changes have been detected [Majid et al 2011, Tabrizi et al 2011, Tabrizi et al 2012, Tabrizi et al 2013]. Furthermore, MRI studies have revealed progressive gray and white matter atrophy many years prior to predicted disease onset [Tabrizi et al 2011, Tabrizi et al 2012, Tabrizi et al 2013]. Numerous studies in recent years have used neuroimaging to elucidate the clinical progression of HD, with the specific interest of using these objective measures in clinical trials for testing efficacy of experimental therapeutics [Tabrizi et al 2012, Tabrizi et al 2013].

Juvenile HD is defined by the onset of symptoms before age 20 years and accounts for 5%-10% of individuals with HD [Gonzalez-Alegre & Afifi 2006, Quarrell et al 2013]. 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].

Intermediate alleles (IA). An individual with a CAG repeat in the 27-35 range is not believed to be at risk of developing HD but, because of instability in the CAG tract, may be at risk of having a child with an allele in the pathogenic CAG range [Semaka et al 2006, Kay et al 2018]. Limited data suggest that individuals with IAs may exhibit behavioral changes as well as motor and cognitive impairments, although more research is required in this regard [Killoran et al 2013, Cubo et al 2016].

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]. See Molecular Genetics.

• 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.
• Intermediate alleles (ranging from 27 to 35 CAG repeats) usually have not been associated with disease but are prone to CAG repeat instability [Semaka et al 2013b].

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

In addition to age at clinical onset, CAG repeat length has also been shown to predict age at death, but not the duration of the illness [Keum et al 2016].

The rate of deterioration of motor, cognitive, and functional measures increases with larger CAG repeat sizes [Aziz et al 2009, Chao et al 2017].

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 2011, Lee et al 2012].

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 at 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 [Li et al 2006, Gusella & Macdonald 2009]. Many genes at other loci have been shown to account for small amounts of this heritable portion of the variability [GeM-HD Consortium 2015].

Significant progress has been made in recent years in the identification of these additional genomic modifiers, both at the HTT locus and throughout the genome.

• Cis-acting factors. The most common CAG repeat tract (>95% of alleles) has a CAA interruption in the penultimate repeat [(CAG)n-CAA-CAG]. Uninterrupted CAG repeats [(CAG)n] are associated with decreased age of onset in HD and increased somatic instability of the repeat [Ciosi et al 2019, GeM-HD Consortium 2019, Wright et al 2019] (GeM-HD 2019 full text). These findings suggest that uninterrupted CAG length is more predictive than polyglutamine length in estimating HD age of onset.
• Trans-acting factors. Genome-wide association studies have identified other candidate modifier genes for HD [GeM-HD Consortium 2015, Moss et al 2017]. These analyses have shown the important role of biologic pathways involved in DNA repair, mitochondrial fission, and oxidoreductase activity with regard to this phenotype, and have identified candidate modifier genes for future study (e.g., FAN1, MLH1, MTMR10, MSH3, and RRM2B).

Penetrance

Alleles with 36 to 39 CAG repeats are considered HD-causing alleles, but exhibit incomplete penetrance. Elderly asymptomatic individuals with CAG repeats in this range are common [Kay et al 2016].

Disease risk varies for the common [(CAG)n-CAA-CAG] interrupted repeat, observed in more than 95% of alleles, and the rare [(CAG)n] uninterrupted repeat, observed in about 1% of alleles [Ciosi et al 2019, GeM-HD Consortium 2019, Wright et al 2019] (GeM-HD 2019 full text):

• 36-39 repeats. Approximately one third of symptomatic individuals have a pure [(CAG)n] repeat.
• 36 and 37 repeats. The majority of symptomatic individuals have a pure [(CAG)n] repeat.

The loss of the CAA repeat has been termed the loss of interruption (LOI) variant [Wright et al 2019] and will be useful in modifying the probability of disease in individuals with 36-39 CAG repeats.

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 far more commonly in paternal transmission of the mutated allele. The phenomenon of anticipation arises from instability of the CAG repeat during spermatogenesis [Semaka et al 2013a]. 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 pre-molecular-genetic era, there were many different names for chorea, including St. Vitus's dance and Sydenham's chorea.

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

Individuals who do not yet show symptoms are in the premanifest phase of HD. Individuals who have been diagnosed with chorea and/or other validated signs of the disorder have manifest HD.

Prevalence

HD prevalence varies across world regions. Populations of European ancestry display an average prevalence of 9.71:100,000 [Rawlins et al 2016], but estimates as high as 17:100,000 have been reported [Fisher & Hayden 2014, Baig et al 2016]. In contrast, HD appears much less frequently in Japan, China, Korea, and Finland, as well as in indigenous African populations from South Africa, with estimated prevalence values ranging from 0.1:100,000 to 2:100,000 [Pringsheim et al 2012, Sipilä et al 2015, Xu & Wu 2015].

Individuals living in the Lake Maracaibo region of Venezuela are 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 general population of these ethnic groups [Warby et al 2009, Warby et al 2011, Kay et al 2018]. For example, a recent study of 15 diverse global populations demonstrated that the mean CAG size in a population, as well as intermediate allele frequency, correlates with HD prevalence and contributes to differences in disease prevalence across major ancestry groups [Kay et al 2018].

Reduced-penetrance HTT alleles (see Establishing the Diagnosis, CAG repeat sizes) have recently been shown to occur at a high frequency in the general population, with as many as one in 400 individuals having these alleles – although the penetrance rate was determined to be lower than previously reported (i.e., 0.2%-2% for 36-38 CAG alleles) [Kay et al 2016].