Overview: A hereditary degenerative disease of the central nervous system.
A hereditary degenerative disease of the central nervous system often characterized by motor deficits, cognitive decline, and psychiatric disorders. The disease is a neurologic genetic disorder associated with an abnormal Huntington’s protein gene and lacks specific treatments, including general, pharmacologic, and rehabilitative therapies.
Definition
Huntington’s chorea is a rare autosomal dominant degenerative disease of the central nervous system.
It mainly involves the nucleus accumbens and caudate nucleus in the basal ganglia region of the brain.
It is characterized by motor, cognitive and psychiatric disorders.
Classification
Adult
The usual age of onset is 30 to 50 years old, and about 10% of the cases start in old age.
Typical symptoms are choreiform movements, combined with cognitive decline and psychomotor disturbances.
Adolescent
5% to 10% of patients develop in children and adolescents.
Myoclonus, myotonia, dystonia, and seizures are usually the main manifestations, and choreiform symptoms are not prominent or may even be absent.
Cognitive deficits appear earlier and are heavier than in adults, and the disease progresses rapidly [1].
Morbidity
The disease can occur in people of all races, with the highest prevalence in Caucasians.
The global prevalence is 2.71/100,000 people, and the prevalence in Asian ethnic groups is about 2.39/100,000 people [2].
The disease is listed in the “First Rare Disease Catalog of China”, and the incidence of the disease in China has not yet been clarified.
Causes
Causes
This disease is an autosomal dominant disorder, which is caused by a mutation in the Huntington protein gene (HTT).
The mutation is a pathogenic segment of the gene, the trinucleotide (CAG) sequence, which is repeated abnormally several times and is called a copy.
Risk factors
Number of abnormal CAG copies
It is generally accepted that disease develops when the number of abnormal CAG copies on the HTT gene is ≥40.
Therefore, those whose parents or grandparents have the disease are prone to develop the disease; the higher the number of abnormal CAG copies in the parents or grandparents, the more prone the children are to develop the disease, and the earlier the age of onset of the disease, the more severe the manifestation.
Genetic Early Presence
If there are consecutive generations in the family with the disease, it will be characterized by earlier and earlier onset of the disease and more severe manifestations.
Pathogenesis
It is currently believed that the main pathogenesis of the disease is “acquisition of toxic function”.
When HTT is mutated, abnormal proteins are produced.
With the increase in the number of CAG copies, these abnormal proteins produce toxic damage to normal cells, causing them to undergo a “toxic response”, interfering with normal protein metabolic pathways, reducing protein degradation, and ultimately leading to cell death [3].
Symptoms
Main Symptoms
The clinical symptoms of Huntington’s chorea include motor, cognitive, and psychiatric disorders, as well as some nonspecific symptoms.
Motor disorders
Involuntary movements
Choreiform symptoms are the most typical manifestation, which is an involuntary, irregular, asymmetric and rapid swinging of the limbs like a dance.
Symptoms can appear in any part of the body, showing piano-like or milk-squeezing movements of the fingers, or squeezing eyebrows, making faces, or flipping and twisting of the upper and lower limbs.
Autonomous movement disorder
Clumsy limb movements, difficulty in maintaining balance, repeated falls, etc. In the late stage of the disease, there may be slurred speech, low and hoarse voice, and difficulty in swallowing.
As the disease progresses, slow movements, muscle stiffness, and limited joint movement may gradually appear.
Cognitive impairment
The most important manifestation is the decline of executive ability, and there may also be memory loss, inattention, and lack of self-awareness of the disease.
Mental Disorders
Depression is the most common, other symptoms include anxiety, agitation, obsessive-compulsive, impulsive, mania, hallucinations, and suicidal ideation in some patients.
Non-specific symptoms
Disturbances in the sleep-wake cycle, such as insomnia at night, sleeping during the day, and waking up multiple times after falling asleep.
Seizures, e.g., convulsions of limbs, upturned eyes, loss of consciousness.
Significant weight loss.
Sexual dysfunction.
Complications
Complications usually occur late in the course of the disease and include dysphagia, infections, and urinary and fecal dysfunction.
Dysphagia
Disease affects the swallowing muscle groups, leading to feeding disorders and causing severe malnutrition.
Infection
Dyskinesia is further aggravated, leading to prolonged bed rest and causing symptoms such as pneumonia, urinary tract infections, and pressure sores.
Urinary and faecal dysfunction
The involvement of autonomic function is aggravated, gradually leading to difficulty in urination and severe constipation.
Consultation
Department of Medicine
Neurology
Prompt consultation is recommended when there is a clear family history of Huntington’s chorea or when motor, cognitive and psychiatric disorders typical of the disease are present.
Psychiatry
Timely consultation is recommended when there are mental and emotional disorders that affect daily life.
Preparation for medical treatment
Consultation: Registration, Preparation of documents, Frequently Asked Questions
Tips on how to get to the doctor
Neurology is usually recommended for first-time patients.
If the patient has severe mental-emotional disorders, it is recommended that he/she be treated in the psychiatric department first and then in the neurology department after stabilization.
Preparation Checklist
Symptom checklist
Pay particular attention to the time of onset of symptoms, specific manifestations, etc.
Are there any involuntary movements such as hand-waving, eye-scratching, etc.?
Is there any clumsiness in limb movement, difficulty in maintaining balance, or repeated falls?
Is there depression, anxiety, mania?
Do you choke on your food? Has the amount of food become smaller? Have you lost weight?
Are you able to urinate, defecate and sleep?
Can you take care of yourself?
When did the above symptoms start to appear?
Was the onset of symptoms acute or insidious?
List of medical history
Is there any family history of Huntington’s disease?
What medications have you been taking for a long time?
Were there any infections, poisoning, or substance abuse prior to the onset of the disease?
Checklist
Test results from the last 6 months, which can be brought with you to the doctor’s office
Cranial CT, cranial magnetic resonance imaging (MRI), EEG, genetic testing, etc.
List of medication use
Medication use in the last 3 months, if there is a pill box or package, you can bring it to the doctor
Anti-Parkinsonian symptomatic drugs: e.g. levodopa, pramipexole, etc.
Antipsychotic drugs: e.g. olanzapine, quetiapine, etc.
Antidepressant and anxiety medications: e.g., sertraline, citalopram, trazodone, etc.
Diagnosis
Diagnosis is based on
Medical history
Family history of Huntington’s chorea.
Symptoms
Presence of movement disorders with predominantly chorea-like involuntary movements, which may also manifest as dysautonomia, muscle tonus, and myoclonus.
Symptoms such as cognitive decline, psychiatric disorders, and insomnia are present.
Physical examination
Eye sweeping disorder: the eyeballs can follow the objects, but the speed is obviously slowed down when they move rapidly.
Dysarthria: It is characterized by slurred speech and a low, hoarse voice.
Changes in muscle tone: Increased resistance occurs when passively moving joints.
Difficulty in maintaining movement: inability to maintain certain simple movements, such as maintaining tongue extension.
Postural balance disorders: unsteady gait when walking, need for assistance, difficulty in maintaining balance.
Screening Tests
Unified Huntington’s Disease Rating Scale (UHDRS)
Purpose of examination: This scale is now widely used to assess motor symptoms in patients with Huntington’s chorea, and can be used not only for the assessment of movement disorders in patients with initial diagnosis, but also for long-term follow-up observation.
Common results: The scale contains standardized scores for multiple dimensions of oculomotor function, chorea, dystonia, and gait postural stability, and the total score is calculated based on each score.
Cautions: The scale should be completed by a clinician and self-assessment by the patient is not recommended. The physician may record a video for subsequent comparison [4].
Cognitive and mental function assessment
Purpose of examination: used to clarify the degree of cognitive function impairment and the degree of mental disorder of patients, and to guide the use of medication.
Commonly used methods
Cognitive assessment usually includes MMSE and MOCA scales, and language fluency check and symbol-number pattern test can also be used.
Mental disorders can be assessed by anxiety and depression self-assessment scales.
Note: The test is dependent on the patient’s cooperation and is not applicable to patients with severe cognitive or psychiatric dysfunction or subjective non-cooperation.
Genetic Testing
Purpose of the test
Identify the abnormal gene locus, clarify the clinical diagnosis and genetic form, and guide the use of medication based on the type of genetic abnormality.
Evaluate the prognosis and assess the possibility of passing on the mutation to the offspring to guide eugenics.
Common results: The main test is the number of CAG repeats in the IT-15 gene, and a positive result is defined as a copy number of CAG repeats ≥40 for at least 1 allele, when all carriers develop the disease.
Cautions: Not to be used as a routine etiologic screening tool, but only for those at high risk of the disease or those with a high suspicion of the disease.
Cranial CT and magnetic resonance imaging (MRI) of the skull
Purpose of examination: To clarify intracranial structures and abnormal lesions in the brain to help clinical diagnosis.
Common findings: Atrophy of the cerebral cortex and caudate nucleus, enlarged ventricles.
Precautions
Cranial CT is radioactive and is contraindicated for women during pregnancy.
You should not wear or carry any metal objects during the MRI examination. If you have metal implants, please inform the radiologist and the doctor will decide whether the examination can be performed.
Cranial Magnetic Resonance Spectroscopy (MRS)
Purpose of the test: To reflect the metabolic changes in the brain tissue at the molecular level and to assist in diagnosis.
Common findings: Increased levels of lactic acid in the cerebral cortex and basal ganglia.
Precautions: Same as cranial MRI.
Positron Emission Tomography (PET)
Purpose of the test: “Fluorine 18-fluorodeoxyglucose” is injected into the body before the test, and the metabolism of intracranial lesions can be determined by observing the uptake of the drug by intracranial tissues, which is used to assist in the diagnosis.
Common findings: Decreased metabolism of caudate nucleus and shell nucleus.
Precautions: Fluorine 18-fluorodeoxyglucose is a glucose-like substance, the examinee should generally fast for 6 to 8 hours to avoid intake of high sugar drugs. Drink plenty of water after the test to promote drug excretion.
Electroencephalogram
Purpose of the test: to clarify the abnormal discharges in the cranium, especially for juvenile Huntington’s chorea, the importance of this test is greater.
Common findings
In adults, diffuse abnormalities are seen throughout the brain, usually without specificity.
In adolescents, abnormal intracranial discharges are seen.
Precautions
Wash your hair and scalp before the test.
For those with stiff hair, a haircut is recommended to avoid difficulty in fitting the electrode patches.
Diagnostic criteria, grading and staging
According to the 2011 edition of the Diagnostic and Therapeutic Guidelines for Huntington’s Disease, the disease can be categorized into early, middle, and late stages [5].
Early stage: predominantly mild cognitive and psychiatric disorders, still able to live on their own.
Middle stage: obvious movement disorder, may be accompanied by autonomic motor symptoms, may appear mental disorder, cognitive impairment further aggravated, social function is impaired, but life can basically take care of themselves.
Late stage: chorea-like symptoms worsen or are replaced by bradykinesia or myotonia, and the patient is mostly bedridden and needs help from others.
Differential diagnosis
Choreiform movements can be seen in a variety of diseases, this disease is mainly differentiated from hereditary diseases and acquired diseases.
Hereditary causes
Benign hereditary chorea
Similarities: both present as chorea.
Differences
Benign hereditary chorea develops in infancy or childhood, with only motor symptoms and normal cognitive and psychoemotional status. Symptoms improve on their own with age.
Imaging is unremarkable.
Neuroferritinopathy
Similarities: Clinical manifestations are very similar, with motor, cognitive, and psychiatric abnormalities.
Differences: decreased serum ferritin concentration, iron deposition on cranial MRI, different types of gene mutations.
Echinococcosis
Similarities: both may present as chorea, head atrophy of caudate nucleus visible on cranial CT.
Differences
Echinococcosis is a recessive disease, cognitive impairment is not obvious, and may be combined with peripheral neuropathy and myasthenia gravis.
Echinocytosis is seen on peripheral blood smear.
Other neurodegenerative diseases
C9orf72, DRPLA, HDL2 are several types of neurodegenerative disorders caused by mutations in genes that are very similar to the Huntington’s chorea phenotype, with no significant difference in clinical presentation and requiring genetic testing to identify.
Acquired causes
Motor and psychiatric abnormalities caused by non-genetic factors such as drugs and infections.
Chorea minor
Also known as rheumatic chorea or Sydenham chorea.
Similarities: involuntary movements, dysarthria and dysphagia.
Differences
History of streptococcal infection or rheumatic fever, involuntary movements are predominantly sudden jerk-like episodes, cognitive impairment is rare.
Serology and pharyngeal swabs may reveal inflammation and streptococcal infection, and cranial CT/MRI shows enlarged caudate nucleus, shell nucleus, and pallidum, and edema.
Drug-related dyskinesias
Includes delayed-onset dyskinesia and pharmacogenetic chorea.
Pharmacogenetic chorea: develops as a result of long-term use of tricyclic antidepressants and antiepileptic drugs.
Delayed-onset dyskinesia: usually develops after initiation of treatment for Huntington’s chorea and is associated with the use of dopamine receptor blocking drugs.
Treatment
Aims of treatment: to control symptoms and improve quality of life.
Principles of treatment: Drugs and psychotherapy are the mainstay, with nursing, social and environmental support.
General treatment
Choose a quiet environment with fall prevention measures and avoid aggravating factors as much as possible.
In the advanced stage of the disease, it is necessary to provide full monitoring and round-the-clock nursing care to prevent the following complications.
Lung infections: Turn and pat the back frequently to prevent pneumonia and use antibiotics if necessary.
Urinary tract infection: prolonged bed rest and urinary retention after indwelling urinary catheter increase the risk of urinary tract infection, attention should be paid to the skin around the urethral opening cleaning and care.
Pressure ulcers: turn over frequently, add air cushion or soft cushion.
Lower extremity venous thrombosis: use long compression stockings and inflatable compression devices.
Dysphagia: For patients who have difficulty eating by mouth or cannot meet nutritional needs, a gastric tube should be left in place to give enteral nutrition.
Medication
Start with small doses and avoid combinations of drugs.
Treatment of movement disorders
Purpose of medication: Improvement of chorea-like symptoms in the early stage of the disease, and improvement of muscle ankylosis and postural gait disorders in the late stage of the disease.
Buprenazine and Deuterobuprenazine
are currently the main drugs used to treat Huntington’s chorea.
Common adverse effects are drowsiness and upright hypotension.
They may aggravate depression and suicidal tendencies and are therefore contraindicated in patients with psychiatric symptoms [6].
Improvement of motor symptoms in patients
Commonly used drugs: levodopa, pramipexole, etc.
Improvement of “Parkinson-like” symptoms such as bradykinesia, myotonia, and postural balance disorders. Common adverse effects are nausea, palpitations, postural hypotension.
In patients with psychiatric disorders, delirium may be induced.
Other drugs
Baclofen and haloperidol may be effective in the treatment of movement disorders of the disease.
Intramuscular injections of botulinum toxin are effective for localized spasms.
Treatment of mental disorders
Purpose of medication: to improve anxiety, depression, obsessive-compulsive and other psychiatric symptoms.
Improvement of mood and sleep disorders
Commonly used drugs: citalopram, paroxetine, sertraline, trazodone and so on.
Common adverse reactions include nausea, constipation, diarrhea, increased sweating, postural hypotension and so on.
Do not stop the medication abruptly after use. If there is a need to reduce or stop the medication, it should be done under the guidance of a doctor.
Antipsychotic drugs
Improve mania, hallucinations and other mental symptoms.
Commonly used drugs: olanzapine, risperidone.
Common adverse effects include increased appetite, weight gain, drowsiness, dizziness and postural hypotension.
Surgical treatment
Deep brain electrical stimulation (DBS) surgery has improved choreiform movements in patients with Huntington’s chorea, but is ineffective for cognitive function and psychiatric symptoms.
Therapeutic Advances
Gene therapy
AMT-130 carries a nucleotide sequence that specifically recognizes the mutated region of the disease gene, which reduces the formation of toxic proteins and reduces “toxic acquisition.
AMT-130 therapy was the first gene therapy to enter clinical trials and has shown promising results, but has yet to enter the clinic.
Antisense Oligonucleotide Therapy
Including Tominersen therapy and WVE-003 therapy, which are currently in clinical studies.
Rehabilitation
Although Huntington’s disease currently lacks specific treatment, rehabilitation of neurological symptoms can be carried out throughout the course of the disease to improve patient symptoms and quality of life [10].
Limb function training
Mainly for patients with combined postural gait disorder, balance function and gait training can be carried out to correct gait and prevent repeated falls.
At the same time, it can prevent lower limb venous thrombosis and lower limb disuse atrophy.
Swallowing function training
Swallowing disorders can be relieved by changing the eating posture and adjusting the character of food.
The strength of swallowing muscles can be improved by swallowing without food or with small amounts of food.
Voice training
Improve the clarity and smoothness of pronunciation by training the movement of muscles in the face and throat.
Cognitive function training
Memory, calculation and thinking skills are trained by memorizing numbers, doing math and reasoning problems.
Prognosis
Cure
The disease cannot be cured, but the progression of the disease can be slowed by supportive therapy and medication. The duration of the disease is about 10 to 25 years, with an average of 19 years [1].
The prognosis is mainly related to the age of onset; the earlier the onset of the disease, the relatively more severe the symptoms and the relatively worse the prognosis.
Harmfulness
Once the disease is diagnosed, it is an irreversible process, usually with a long duration, which brings a huge burden to the patients, their families and the society.
Early and mid-stage patients can still take care of themselves, but the quality of life is seriously reduced.
In the late stage, patients often need round-the-clock care, which increases the burden on the family and leads to complications such as serious infections, severe malnutrition, and deep vein thrombosis in the lower limbs, which may lead to death.
Daily
Daily Management
Dietary management
Balanced nutrition, pay attention to supplement foods rich in protein, phospholipids and calories, such as eggs and lean meat.
Eat fiber-rich food appropriately to prevent constipation.
For those with dysphagia. Patients who are seriously affected by eating should be left with gastric tube for nasal feeding diet.
Life management
Take medication regularly, do not adjust medication or stop medication on your own.
Provide patients with a quiet and safe living environment, equipped with handrails, guardrails and fall prevention equipment.
Help bedridden patients to turn over every 2 to 3 hours to avoid prolonged skin pressure.
Advanced patients may need long-term indwelling urinary catheter, need to pay attention to the perineum clean; for those who have difficulty in defecation, often massage the abdomen, outlining constipation.
Disease monitoring and follow-up
Daily attention to changes in motor, cognitive, and psychiatric symptoms, and to temperature, skin, and bowel conditions.
Follow-up visits as recommended by the physician, usually once every 1 to 3 months. Follow-up of disease progression is often done at follow-up visits using the Unified HD Rating Scale (UHDRS).
Prevention
The disease is hereditary and the main prevention method is to avoid the birth of children with the disease-causing gene.
Genetic counseling and genetic testing are recommended for family members of diagnosed patients.
Family members of diagnosed patients should undergo prenatal diagnosis before giving birth.