Huntington disease is an autosomal dominant disorder characterized by chorea, neuropsychiatric symptoms, and progressive cognitive deterioration, usually beginning during middle age. Diagnosis is by genetic testing. First-degree relatives should be offered genetic counseling before genetic tests are done. Treatment is supportive.
(See also Overview of Movement and Cerebellar Disorders.)
Huntington disease is the most common cause of hereditary chorea. It affects both sexes equally. Worldwide, the prevalence is approximately 4/100,000 people (1).
Довідковий матеріал загального характеру
1. Medina A, Mahjoub Y, Shaver L, Pringsheim T: Prevalence and incidence of Huntington's disease: An updated systematic review and meta-analysis. Mov Disord 37 (12), 2327–2335, 2022.. doi: 10.1002/mds.29228 Epub 2022 Sep 26.
Pathophysiology of Huntington Disease
In Huntington disease, the caudate nucleus atrophies, the inhibitory medium spiny neurons in the corpus striatum degenerate, and levels of the neurotransmitters gamma-aminobutyric acid (GABA) and substance P decrease.
Huntington disease results from a mutation in the huntingtin (HTT) gene (on chromosome 4), causing abnormal repetition of the DNA sequence CAG, which codes for the amino acid glutamine. The resulting gene product, a large protein called huntingtin, has an expanded stretch of polyglutamine residues, which accumulate within neurons and lead to disease via unknown mechanisms. The more CAG repeats, the earlier the onset of disease and the more severe its expression (phenotype). The number of CAG repeats can increase with successive generations when the father transmits the mutation and, over time, can lead to increasingly severe phenotypes within a family (called anticipation).
Symptoms and Signs of Huntington Disease
Symptoms and signs of Huntington disease, develop insidiously, starting at about age 35 to 40, depending on phenotype severity.
Dementia or psychiatric disturbances (eg, depression, apathy, irritability, anhedonia, antisocial behavior, full-blown bipolar or schizophreniform disorder) develop before or simultaneously with the movement disorder. These symptoms predispose patients to suicidal ideation and suicide, which are much more common among patients with Huntington disease than among the general population.
Abnormal movements appear; they include chorea, athetosis, myoclonic jerks, and pseudo-tics (one manifestation of tourettism). Tourettism refers to Tourette-like symptoms that result from another neurologic disorder or use of a medication; tourettism also includes the repetitive gestural movements and/or phonatory sounds that patients with chorea make. Unlike true tics, the pseudo-tics of Huntington disease cannot be suppressed.
Typical features include a bizarre, puppet-like gait, facial grimacing, inability to intentionally move the eyes quickly without blinking or head thrusting (oculomotor apraxia), and inability to sustain a motor act (motor impersistence), such as tongue protrusion or grasping. Ataxia is an underrecognized symptom.
Huntington disease progresses, making walking impossible and swallowing difficult; it results in severe dementia. Chorea is typically replaced by akinetic-rigid features. Most patients eventually require institutionalization. Death usually occurs 13 to 15 years after symptoms begin.
Patients with Huntington disease may become depressed or anxious and/or develop obsessive-compulsive disorder.
If Huntington disease begins before age 20, it is classified as juvenile Huntington disease or Westphal variant and manifests as seizures and parkinsonism.
Diagnosis of Huntington Disease
Clinical evaluation, confirmed by genetic testing
Neuroimaging
Diagnosis of Huntington disease is based on typical symptoms and signs plus a positive family history. It is confirmed by genetic testing that measures the number of CAG repeats ([1]; for interpretation of results, see table Genetic Testing for Huntington Disease).
Neuroimaging helps identify caudate atrophy and often some frontal-predominant cortical atrophy.
Генетичне дослідження на хворобу Гантінгтона
Number of CAG Repeats | Interpretation |
|---|---|
≤ 26 | Normal |
27–35 | Normal but unstable (increased risk that children will have Huntington disease) |
36–39 | Abnormal with variable penetrance; unstable (in some studies, most patients had symptoms and signs) |
≥ 40 | Abnormal with complete penetrance and anticipation (the greater the number of repeats, the earlier the onset of symptoms) |
Довідковий матеріал щодо діагностики
1. Bean L, Bayrak-Toydemir P: American College of Medical Genetics and Genomics Standards and Guidelines for Clinical Genetics Laboratories, 2014 edition: Technical standards and guidelines for Huntington disease. Genet Med 16 (12):e2, 2014. doi: 10.1038/gim.2014.146 Epub 2014 Oct 30.
Treatment of Huntington Disease
Supportive measures
Genetic counseling for relatives
Because Huntington disease is progressive, end-of-life care should be discussed early.
Treatment of Huntington disease is supportive and symptomatic. However, researchers continue to look for ways to slow and stop disease progression.
A vesicular monoamine transporter type 2 (VMAT-2) inhibitor (tetrabenazine, deutetrabenazine) is typically used as a first-line symptomatic treatment of chorea (1). VMAT-2 inhibitors deplete dopamine and aim to lessen chorea. Doses are sequentially increased as tolerated to control symptoms. VMAT-2 inhibitors should be avoided in patients with depression because the risk of worsening depression and suicidality is increased. Other adverse effects of VMAT-2 inhibitors include excessive sedation, akathisia, and parkinsonism. VMAT-2 inhibitors are also costly. Deutetrabenazine appears to be better-tolerated than tetrabenazine.
Antipsychotics may partially suppress chorea and agitation and are an alternative first-line therapy for patients with depression. Antipsychotics include
Chlorpromazine
Haloperidol
Risperidone
Olanzapine
Clozapine
The antipsychotic dose is increased until intolerable adverse effects (eg, lethargy, parkinsonism) develop or symptoms are controlled. In patients taking clozapine, white blood cell (WBC) counts must be done frequently because agranulocytosis is a risk.
Therapies currently under study aim to reduce glutamatergic neurotransmission via the N-methyl-d-aspartate receptor and to bolster mitochondrial energy production. Treatments that aim to increase GABAergic function in the brain have been ineffective.
Selective serotonin reuptake inhibitors may help patients with depression, anxiety, or obsessive-compulsive disorder associated with Huntington disease and lessen symptoms in patients with impulse behavioral disorder.
People who have first-degree relatives with Huntington disease, particularly women of childbearing age and men considering having children, should be offered genetic counseling and genetic testing. Genetic counseling should be offered before genetic testing because the ramifications of Huntington disease are so profound.
Довідковий матеріал щодо лікування
1. Bachoud-Lévi A-C, Ferreira J, Massart R, et al: International guidelines for the treatment of Huntington's disease. Front Neurol 10:710, 2019. doi: 10.3389/fneur.2019.00710 eCollection 2019.
Ключові моменти
Huntington disease, an autosomal dominant disorder that affects either sex, usually causes dementia and chorea during middle age; most patients eventually require institutionalization.
If symptoms and family history suggest the diagnosis, provide genetic counseling before genetic testing and consider neuroimaging.
Treat symptoms and discuss end-of-life care as soon as possible.
Offer counseling before genetic testing to first-degree relatives, particularly potential parent to prepare them for possible positive findings and to reduce the risk of suicide.
