What is Huntington’s Disease? – Causes, Symptoms, Treatment

Huntington’s disease (HD), a neurodegenerative autosomal dominant disorder, is characterized by involuntary choreatic movements with cognitive and behavioral disturbances. It occurs as a result of cytosine, adenine, and guanine (CAG) trinucleotide repeats on the short arm of chromosome 4p16.3 in the Huntingtin (HTT) gene. This mutation leads to an abnormally long expansion of the polyglutamine in the HTT protein, which leads to neurodegeneration. The expansion also causes the HTT protein to be more prone to aggregation and accumulation that mitigates protein folding. HD commonly affects patients between the ages of 30 to 50 years. However, the longer the CAG repeats, the earlier the onset of symptoms. The term juvenile HD refers to the onset of illness before the age of 20 and is characterized by learning difficulties as well as behavioral disturbances at school.

Huntington’s disease (HD) is an inherited disorder that causes nerve cells (called neurons) in parts of the brain to gradually break down and die. The disease, which gets worse over time, attacks motor control regions of the brain (those involved with movement), as well as other areas.  People with HD develop problems with behavior, emotion, thinking, and personality, along with uncontrollable dance-like movements (called chorea) and abnormal body postures.

The gene mutation that causes HD is present from birth. Symptoms of HD typically appear in middle age (adult HD), and in rare cases, they appear in children (juvenile HD).

The duration of the illness generally ranges from 10 to 30 years. HD is not fatal. The most common causes of death are infection (most often pneumonia) and injuries related to falls.

There is no cure for HD, but treatments are available to help manage its symptoms.

What are the major effects of the disease?

Early signs of the disease vary greatly from person to person, but typically include cognitive or psychiatric symptoms, difficulties with movement, and behavioral changes. Symptoms of Huntington’s disease include:

• Behavioral changes such as mood swings, irritability, apathy, inactivity, depression, or anger. These symptoms may lessen as the disease progresses or, in some individuals, may continue and include hostile outbursts, thoughts of suicide, deep bouts of depression, and psychosis. People with HD also may avoid social interaction.
• Cognitive/judgment changes may include issues with judgment, attention, other cognitive functions, problem-solving, or decision making. Other affects may include trouble with driving, prioritizing tasks, and difficulty organizing, learning new things, remembering a fact, putting thoughts into words, or answering a question.

These cognitive problems worsen as the disease progresses and affected individuals are no longer able to work, drive, or care for themselves. When the level of cognitive impairment is significant enough to impair daily functioning, it is described as dementia. Many people with HD, however, remain aware of their environment and can express emotions.

• Uncontrolled and difficult movement in the fingers, feet, face, or torso. These movements, which are signs of chorea, often intensify when the person is anxious or distracted and become more pronounced and apparent over time. HD can also begin with mild clumsiness or problems with balance.

Some people develop chorea-related movements such as problems walking, increasing the likelihood of falls. Some individuals with HD do not develop chorea; instead, they may become rigid and move very little, or not at all, a condition called akinesia. Others may start out with chorea but become rigid as the disease progresses. In addition to chorea, some individuals have unusual fixed postures, called dystonia. The two-movement disorders can blend or alternate. Other symptoms may include tremors (unintentional rhythmic muscle movement in a back-and-forth manner) and abnormal eye movements that often occur early.

• Physical changes may include slurred speech and continued decline in vital functions, such as swallowing, eating, speaking, and especially walking. Weight loss may occur due to problems with feeding, swallowing, choking, and chest infections. Other symptoms may include insomnia, loss of energy, fatigue, and seizures. Eventually, the person will be confined to a bed or wheelchair.

Other Causes

• Endocrine and metabolic – hypoglycemia, hyperthyroidism, kernicterus, hypomagnesemia
• Infectious – rheumatic fever, syphilis, subacute sclerosing panencephalitis, Lyme disease, toxoplasmosis, HIV, endocarditis
• Drugs – levodopa, oral contraceptive, neuroleptics, antihistamines, cocaine, amphetamine, tricyclics
• Toxins – CO poisoning, mercury, alcohol intoxication
• Neurologic – stroke, migraine
• Vascular – polycythemia, Churg Strauss, SLE, Behcet, Multiple sclerosis
• Malignant – primary brain tumors and metastatic lesion

How is HD inherited?

HD is passed from parent to child through a mutation in a gene. The gene responsible for HD lies on chromosome 4. (A chromosome contains all or part of the genetic material that makes up a person or organism.)
When a parent has HD, each child has a 50 percent chance of inheriting the copy of chromosome 4 that carries the HD mutation. If a child does not inherit the HD mutation, he or she will not develop the disease and cannot pass it to subsequent generations.

People with HD have an abnormal, repetitive, greatly expanded three-letter code (or triplet) in the DNA sequence that is found in genes. DNA uses a triplet to prescribe the order and identity of amino acids—a protein’s building blocks. This three-base repeat—called a triplet repeat expansion—causes dozens of other neurological diseases, but in HD the triplet involves the excessive repeat of cytosine, adenine, and guanine (called CAG).

Most people have fewer than 27 CAG repeats in the HD gene and are not at risk for the disease. Individuals with the disease may have 36 or more repeats. People who have repeated in the intermediate range (27-35) are unlikely to develop the disease, but they could pass it on to future generations.

When HD occurs without a family history, it is called sporadic HD.

At what age does HD appear?

The rate of disease progression and the age at onset vary from person to person. Having a higher number of CAG repeats is associated with an earlier onset and faster course of the disease. Generally, the earlier the symptoms appear, the faster the disease progresses.

Adult HD

Adult-onset HD most often begins between ages 30-50. A few individuals develop HD after age 55.

There is also a related disorder called senile chorea. Some elderly individuals develop unintended, uncontrolled movements, but do not develop dementia, have a normal HD gene, and lack a family history of the disorder.

Juvenile HD

Some individuals develop symptoms of HD before age 20. This is called early-onset or juvenile HD.   Symptoms of people with juvenile HD may include:

• a rapid decline in school performance
• myoclonus (rapid involuntary muscle twitches or jerks)
• slowness
• rigidity (in which the muscles remain constantly tense)
• tremor
• seizures
• cognitive disabilities

The disease progresses most rapidly in individuals with juvenile or early-onset HD, and death often follows within 10 years.

Individuals with juvenile HD usually inherit the disease from their fathers, who typically have a later onset form of HD.

Symptoms of

Early

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

Middle

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

Late

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

How is HD diagnosed?

The disease tends to affect patients between the ages of 30 to 50. The signs and symptoms classically consist of motor, cognitive, and psychiatric disturbances. Other less common features include weight loss, sleep disturbances, and autonomic nervous system dysfunction.

1. Motor disturbances: These include the characteristic unwanted involuntary movements which initially begin in the distal extremities and are of a smaller degree but could go on to affect the facial muscles as well. The movements then spread gradually to the more proximal and axial muscles and are of greater amplitude. Motor symptoms tend to be progressive. Early in the disease, they are mostly hyperkinetic with involuntary chorea. In later stages, however, hypokinesia with bradykinesia and dystonia predominate. The balance between chorea and hypokinesia varies from patient to patient and ranges from overwhelming rigidity in the younger patients, also known as the Westphal variant to older patients being severely affected in the later stages of the disease with rigidity and contractures in the extremities leading them to be bedridden. Dysarthria and dysphagia develop during the course of the disease, which could lead to aspiration in patients, with pneumonia being a common cause of death. Dystonia, characterized by increased muscle tone with slower movements, leads to abnormal posturing such as torticollis and can be the first sign of motor involvement in HD. Other involuntary features include tics and cerebellar signs such as ataxia. Pyramidal signs such as the Babinski sign are present. The motor disturbance on daily activities progresses over time and can lead to difficulties in walking, standing, and frequent falls.
2. Behavioral and psychiatric symptoms: These are present very early in the disease, often even prior to the onset of motor symptoms. Behavioral and psychiatric symptoms are often consistent with frontal lobe dysfunction. Initially, patients may present with poor attention, impulsivity, and irritability. The irritability is often severe and leads to outbursts of anger and aggression. Later on in the disease, there is an emotional blandness with prominent apathy, loss of intuition, and creativity. The frontal lobe symptoms are likely due to frontostriatal degeneration. The most common feature of the disease is apathy, which is progressive and manifests alongside progressive motor disturbances and cognitive decline. Depression is also commonly reported, but it is unclear whether these are due to the manifestation of the disease or underlying neural pathology. Suicide may occur between the time of gene testing and when a patient’s dependence starts to increase. Psychosis can appear in later stages, which goes hand in hand with cognitive decline. Another prominent feature is the lack of insight into the nature of the symptoms they are experiencing. This includes a lack of awareness of all three domains of the disease (motor, cognitive, and psychiatric). Therefore, family members become a crucial source of information and should be involved in decision-making and assessment.
3. Cognitive disturbances: Cognitive decline is one of the main features of HD and could also be present before the onset of motor disturbances. The cognitive changes are more prominent for executive functions with patients finding difficulty in organizing, multitasking, and planning. These symptoms then progress with more cognitive deficits leading to dementia. Dementia in HD is subcortical in nature, and the memory loss originates from an inefficient search of memory rather than a deficient memory, and features such as apraxia and aphasia, which is common in cortical dementia are spared in HD. Psychomotor processes become severely slowed.

Other secondary symptoms include

• Ataxia: Rarely occurs. Patients might exhibit mild degrees of cerebellar atrophy, and the presence of more severe cerebella dysfunction is suggestive of an alternate diagnosis.
• Gait abnormalities
• Eye movement abnormalities: Patients exhibit slow and hypermetric gaze with a superimposed dysfunctional gaze. A mild form of oculomotor apraxia can also be seen.
• Seizures: these are only present in the juvenile variant, occurring in 30 to 50% of patients before the age of 10.

Clinical course and classification

• 1) Presymptomatic HD – (if genetically confirmed and clinically at risk if not confirmed): there are no signs or symptoms of motor or cognitive disturbances. These patients might exhibit changes in imaging. Generally, no symptomatic treatment is indicated.
• 2) Prodromal HD – (if genetically confirmed and clinically prodromal HD if not confirmed): Patients start to exhibit subtle motor and cognitive disturbance. Behavioral changes, such as apathy and depression, might be present. The changes in imaging are seen. Patients may require symptomatic treatment. Initiating disease-modifying treatments may be appropriate.
• 3) Manifest HD – (if patients are genetically confirmed and clinically manifest HD if they are not genetically confirmed): Prominent motor and/or cognitive disturbances that interfere with the quality of life are seen. Start symptomatic and disease-modifying treatments.

A diagnosis of HD is generally based on findings from neurological, psychological, and genetic testing.

Neurological exam and patient history – A neurologist will conduct an in-depth interview to obtain the medical history (including any family history, called a pedigree or genealogy) to rule out other conditions. Neurological and physical exams may review reflexes, balance, movement, muscle tone, hearing, walking, and mental status. Laboratory tests may also be ordered, and individuals with HD may be referred to specialists such as psychiatrists, genetic counselors, clinical neuropsychologists, or speech pathologists for specialized management and/or diagnostic clarification.

Diagnostic imaging – In some cases, especially if a person’s family history and genetic testing are inconclusive, the physician may recommend brain imaging, such as computed tomography (CT) or, more likely, magnetic resonance imaging (MRI). As the disease progresses, these scans typically reveal shrinkage in parts of the brain and enlargement of fluid-filled cavities within the brain called ventricles. These changes do not necessarily indicate HD, because they can occur in other disorders. A person can have early symptoms of HD and still have normal findings on a structural CT or MRI scan.

Genetic tests – Genetic testing can confirm or rule out a suspected genetic condition or help determine a person’s chance of developing or passing on a genetic disorder. Genetic testing makes it possible to predict with a higher degree of certainty if someone will develop HD.

• The most effective and accurate method of testing for HD—called the direct genetic test—counts the number of CAG repeats in the HD gene, using DNA taken from a blood sample. The presence of 36 or more repeats supports a diagnosis of HD. A test result of 26 or fewer repeats rules out HD.
• An older genetic test, called linkage testing (also called prenatal exclusion testing) requires a sample of DNA from a closely related affected relative, preferably a parent, to identify markers close to the HD gene and to determine if a fetus has inherited a chromosome 4 mutation from an affected grandparent. A version of the linkage method is sometimes used for prenatal testing.

Prenatal testing is an option for people who have a family history of HD and are concerned about passing the disease to a child. Prenatal testing can be done using either the direct method or the linkage method. As with adult testing, the direct method provides higher certainty.

What treatments are available for HD?

Medications may be prescribed to help control emotional and movement problems associated with HD. It is important to remember, however, that while medicines may help keep these clinical symptoms under control, there is no treatment to stop or reverse the course of the disease.

Most of the medications available for HD symptoms work by modulating neurotransmitters—the chemical messages that shuttle between neurons.

Tetrabenazine, which causes depletion of the neurotransmitter dopamine, is prescribed for treating Huntington’s-associated involuntary movements, as is deutetrabenazine.

Antipsychotic drugs, such as risperidone, olanzapine, or haloperidol, or other drugs such as clonazepam, may help to lessen chorea and may also be used to help control hallucinations, delusions, and violent outbursts. Antipsychotic drugs, however, typically do not help with the muscle contractions associated with involuntary muscle contractions and may in fact worsen the condition, causing stiffness and rigidity.

For depression, physicians may prescribe citalopram, fluoxetine, sertraline, nortriptyline, or other compounds. Tranquilizers can help control anxiety and lithium may be prescribed to combat pathological excitement and severe mood swings.

Drugs used to treat the symptoms of HD may have side effects such as fatigue, sedation, decreased concentration, restlessness, or hyperexcitability, and should be only used when symptoms create problems for the individual. For those on medication, it may be difficult to tell if a particular symptom, such as apathy or memory loss, is a sign of the disease or a drug reaction.

What research is being done?

The mission of the National Institute of Neurological Disorders and Stroke (NINDS) is to seek fundamental knowledge about the brain and nervous system and to use that knowledge to reduce the burden of neurological disease. NINDS is a component of the National Institutes of Health (NIH), the leading supporter of biomedical research in the world. NINDS-funded research has played a key role in our understanding of HD—helping to localize the HD-causing gene to chromosome 4 and identifying the mutation that causes HD.

HD strikes individuals at different ages and it is hard to predict the age of disease onset. Researchers are focusing on discovering and studying factors that hasten or delay the disease onset, which would provide clues for strategies to slow or stop the progression of the disease before symptoms even begin.

Understanding Huntington’s disease mechanisms

NINDS-funded researchers are trying to better understand the cellular and molecular mechanisms involved in the neurodegenerative processes of HD by investigating, for instance, how the mutant Huntingtin protein affects cell signaling and how its altered structure can contribute to disease. Among research efforts:

• A new avenue of NINDS-supported research is asking whether additional changes to the mutant Huntington gene during development and in adulthood impact disease onset and severity, and whether the mutant Huntington gene affects the brain’s overall ability to maintain healthy, undamaged DNA.  This work is a promising area for identifying new modifiers of HD onset and progression that may be attractive drug targets.
• Excessive chemical signaling between cells in the brain may lead to chronic overexcitation (overactivation of neurons to turn on), which is toxic to neurons. Several labs are investigating whether drugs that counteract excitotoxicity might help against HD.
• Cutting-edge methods such as optogenetics (where neurons are activated or silenced in the brains of living animals using light beams) are being used to probe the cause and progression of cell circuit defects in HD.

Biomarkers

The NINDS-funded PREDICT-HD study and several international studies seek to identify and validate biomarkers for HD. Biomarkers are biological changes that can be used to predict, diagnose, or monitor disease. One goal of PREDICT-HD is to determine if the progression of the disease correlates with changes in brain scan images, or with chemical changes in blood, urine, or cerebrospinal fluid. Another goal is to find measurable changes in personality, mood, and cognition that typically precede the appearance of motor symptoms of HD. The third phase of PredictHD is ongoing.

A related NINDS-supported study aims to identify additional human genetic factors that influence the course of the disease. Finding genetic variants that slow or accelerate the pace of disease progression promise to provide important new targets for disease intervention and therapy.

Stem Cells

Scientists can take adult blood or skin cells and return them to a pluripotent state (called iPS, cells), where they can become most cells of the body. Through an NINDS-funded consortium, researchers are using cultures of these cell lines (created from people with HD who have donated skin and blood samples for research) to understand why neurons malfunction and die in HD and to rapidly test potential new drugs. Another approach may be to mobilize stem cells that are already there and can move into damaged tissue.

Turning research into treatment

Testing investigational drugs may lead to new treatments and at the same time improve our understanding of the disease process in HD. Classes of drugs being tested include those that control symptoms, slow the rate of progression of HD, block the effects of excitotoxins, provide support factors that improve neuronal health, or suppress metabolic defects that contribute to the development and progression of HD.

Several groups of scientists are using gene-editing or specific molecules that can interfere with the production of Htt in cells or animals to reduce or eliminate the production of Htt.

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