Huntington’s Disease-Like Syndrome

What Causes Huntington’s Disease-Like Syndrome?

HDL is caused by an abnormal variation (a mutation) in one of several different genes that control the production of proteins. HDL1 is caused by mutations in the PRNP gene. HDL2 is caused by JPH3 gene mutations. HDL4 is caused by TBP gene mutations. The genetic cause of HDL3 is still unknown. Scientists don’t know precisely what the proteins produced by these genes do, but they appear to play an essential role in the function of the brain’s nerve cells.

The gene mutations result in an abnormally long, repeating chain of a specific segment of DNA in the gene. The abnormal chain produces an abnormal form of the protein the genes are responsible for producing. The body’s cells then process the abnormal protein into toxic compounds that bind to the brain’s nerve cells and impair their function. As the toxic compounds build up in the brain, the impairment worsens, and the nerve cells eventually die. The loss of functional nerve cells produces the symptoms of the disease.

Is Huntington’s Disease-Like Syndrome Hereditary?

HDL is almost always inherited when a parent with a mutated gene passes the gene on to their child. HDL1, HDL2, and HDL4 are passed on in an autosomal dominant pattern, meaning that the child needs only to inherit the gene from one parent to develop the disease. This is in contrast to an autosomal recessive pattern, in which the disease won’t develop unless the child inherits the gene from both parents.

The length of the gene’s repeating DNA chain seems to influence the severity and timing of the onset of the disease. Longer chains tend to produce a disease that emerges earlier and has more severe symptoms. In some cases, the chain may increase in length as it is passed from parent to child through subsequent generations.

HDL3 seems to be inherited in an autosomal recessive pattern. This means a child must inherit two copies of the gene mutation, one from each parent, to develop the disorder. People with only one copy of the mutated gene will usually not develop HDL but will be carriers who can pass the mutation on to their children. Two carrier parents have a 25 percent chance of having a child with HDL with each pregnancy. Therefore, half of their pregnancies will produce a carrier, and a quarter of them will result in a child with no mutated genes.

How Is Huntington’s Disease-Like Syndrome Detected?

HDL can be challenging to detect in its early stages because symptoms may be subtle or may look like the symptoms of some other disorder. However, early detection is important because some of the disease’s complications can be serious, even early on. For example, patients are at higher risk of suicide, most likely because of disease-associated depression, in the early stages, often before diagnosis.

Early signs of HDL include:

• Depression
• Irritability
• Problems with balance or coordination
• Small involuntary muscle movements
• Mental fogginess

How Is Huntington’s Disease-Like Syndrome Diagnosed?

If your doctor suspects HDL or Huntington’s disease may be the cause of your symptoms, the diagnostic process will typically move through a series of steps designed to rule out other possible causes. A physical exam and a medical history will be the first step, followed by expanded testing, often with the involvement of a neurologist, that includes:

• Neurological exam. This exam tests neurological functions such as balance, coordination, reflexes, muscle strength, muscle tone, and sensory perception. Other exams may test areas such as memory, reasoning, and cognitive function.
• Psychological testing. These tests will look for symptoms in the areas of mood and behavior. A psychiatrist will often administer these tests.
• Imaging. Magnetic resonance imaging (MRI) or computerized tomography (CT) may be used to examine brain structure and function. These tests may be able to spot brain activity characteristic of HDL or Huntington’s disease, or they may be used to rule out other potential disorders.
• Genetic testing. This test looks for the presence of mutated genes associated with HDL. It is the only definite way to differentiate between HDL and Huntington’s disease. The test may be used to confirm the diagnosis, but because it has no bearing on treatment, it is not always performed.

PLEASE CONSULT A PHYSICIAN FOR MORE INFORMATION.

How Is Huntington’s Disease-Like Syndrome Treated?

There is no cure for HDL, and no treatment will reverse its symptoms. However, medications are commonly used to control symptoms, and various non-drug therapies can help the sufferer maintain daily functioning for as long as possible. Because HDL and Huntington’s disease seem similar, treatments for the disorders are typically the same. Research into whether the treatments are as effective for HDL is still in progress.

Medications

Drugs used to treat HDL and Huntington’s disease symptoms include:

• Treatments for movement problems. Tetrabenazine can be used to control involuntary movements, but it may worsen symptoms such as depression. Amantadine, levetiracetam, and clonazepam are effective for movement symptoms but may worsen cognitive symptoms or have other side effects. Antipsychotics such as haloperidol and chlorpromazine are sometimes used, but they, too, can have significant side effects.
• Antidepressants. Citalopram, escitalopram, fluoxetine, and sertraline are often used to treat depression, OCD, and other psychological disorders.
• Antipsychotics. Quetiapine, risperidone, and olanzapine may be used to treat agitation and other more severe behavioral disorders.
• Mood stabilizers. Valproate, carbamazepine, and lamotrigine may be used to treat the symptoms of bipolar disorder.

Other Therapies

Non-drug therapies used to treat the symptoms and complications of HDL include:

• Speech therapy
• Physical therapy
• Occupational Therapy
• Psychotherapy

How Does Huntington’s Disease-Like Syndrome Progress?

The symptoms of HDL get worse over time, and treatment will not stop the progression of the disease. Eventually, the sufferer will be unable to walk or speak and will require constant care.

Death usually comes as a result of complications or circumstances arising as a result of the symptoms. Common causes of death include:

• Pneumonia
• Heart failure
• Infections
• Injuries from falls
• Choking or complications from being unable to swallow

How Is Huntington’s Disease-Like Syndrome Prevented?

There is no way to prevent HDL in someone with a genetic predisposition to develop the disease. Genetic testing can detect the mutated genes’ presence, but identifying the genes will not have any effect on whether or not the disease develops. If you think you may be at risk, a genetic counselor can help you assess whether testing is right for you.

People with a family history of HDL may be at risk of passing the disease on to their children, even if they are not showing symptoms of the disease. Again, a genetic counselor can help potential parents assess the risk and evaluate their options.

Huntington’s Disease-Like Syndrome Caregiver Tips

Caring for someone with HDL takes a toll on the caregiver. As the disease progresses, caregiving responsibilities become greater and greater, and caregivers must be sure to take care of themselves, too. If you’re caring for a loved one with the disease, remember these tips:

• Avoid isolation. The symptoms of HDL often encourage sufferers to withdraw from family and social interactions. Isolation, however, can make psychological symptoms even worse. Help your loved one to stay engaged with the broader world as much as possible.
• Know when to get help. The caregiving demands of HDL are immense, and they grow more significant as the disease progresses. Ask your medical providers for recommendations for support groups or agencies that can help you find assistance when you need it.
• Don’t hide from the disease. HDL has ramifications for the sufferer and family members who must come to terms with the risk to themselves and their children. Coping with questions about the disease can be easier with the support of professionals and peers in your situation. Ask your medical provider for a list of resources in your area, or find help online.

Many people with HDL and Huntington’s disease (HD) also suffer from other brain and mental health-related issues, a condition called co-morbidity. Here are a few of the disorders commonly associated with HD:

• About a third of people with HD also suffer from depression or an anxiety disorder.
• People with HD are at increased risk of suicidal behavior.
• HD has been associated with obsessive-compulsive behaviors.
• Alcohol abuse is sometimes associated with HD.

Huntington’s Disease-Like Syndrome Brain Science

Although scientists at least partially understand how genetic mutations trigger the development of HDL, a thorough understanding of how the associated proteins affect the brain remains elusive. Research projects aim to figure out the biochemical and neurological mechanisms at play in both normal brains and the brains of HDL patients.

Active areas of research include:

• Optogenetics. In this field of study, scientists genetically engineer brain cells to be sensitive to light. The researchers can then use light to activate and deactivate the brain cells, allowing them to study the activity of neurological circuitry more effectively. This approach could help scientists better understand how the proteins make cells behave differently in healthy and unhealthy brains.
• Biomarker identification. Earlier detection of HDL and Huntington’s disease could help scientists understand how the disease progresses, which could lead to better treatments. For that reason, some research looks at the disease’s biomarkers, measurable indicators that indicate the condition in its early stages (or even before it develops). For example, one recent project developed a test designed to detect mutant huntingtin protein in patients’ blood.

Huntington’s Disease-Like Syndrome Research

Title: Preparing for Prevention of Huntington’s Disease (PREVENT-HD) (PREVENT-HD)

Stage: Not Yet Recruiting

Contact: Jane S. Paulsen, PhD

University of Wisconsin, Madison

Madison, WI 

This is a prospective investigation that aims to address key challenges to the design of clinical trials to prevent the onset of Huntington’s disease (HD). The project will provide necessary psychometric data for clinical outcome assessments (COAs) and biomarkers (BMs) in the cerebral spinal fluid (CSF) to address questions of central importance to the success of these measures for premanifest clinical trials. Of the 258 participants: 52 will be at low risk of motor diagnosis, 102 at high risk of motor diagnosis, 52 with diagnosed HD (stages I or II), and 52 healthy controls. Participants can expect to be on study for up to 2 years.

Title: Neurobiological Predictors of Huntington’s Disease (PREDICT-HD) (PREDICT-HD)

Stage: Recruiting

Principal investigator: Jane S Paulsen, PhD

University of Iowa

Iowa City, IA 

Huntington’s Disease (HD) is an inherited disease that causes changes in a person’s ability to control movements, thinking, and feelings. This study intends to learn more about the beginning changes in thinking skills, emotional regulation, and brain structure and function as a person transitions from health to HD.

Preliminary studies indicate that people with HD may have a marked decline before an actual diagnosis. This study will help reveal the earliest indicators of the disease and what factors influence the age at which a person carrying the gene develops the disease. It is necessary to get information on the early stages of HD to develop drugs that can slow or postpone HD’s onset. The investigators hope this study will provide essential information for future trials of experimental drugs for HD.

During this study, participants will undergo several detailed tests, including MRI scans of the brain, cognitive assessments, physical exams, biospecimen (blood, urine, cerebral spinal fluid) collection, and neurological and psychiatric testing.

Title: Child to Adult Neurodevelopment in Gene Expanded Huntington’s Disease (ChANGE HD)

Stage: Recruiting

Principal investigator:  Peggy C Nopoulos, MD

University of Iowa

Iowa City, IA

Huntington’s Disease (HD) is an autosomal dominant disease manifested in a triad of cognitive, psychiatric, and motor signs and symptoms. HD is caused by a triplet repeat (CAG) expansion in the gene Huntingtin (HTT). This disease has classically been conceptualized as a neurodegenerative disease. However, recent evidence suggests that abnormal brain development may play an important role in HD’s etiology. Huntingtin (HTT)is expressed during development and through life. In animal studies, the HTT gene has been shown to be vital for brain development. This suggests that a mutant form of HTT (gene-expanded or CAG repeats of 40 and above) would affect normal brain development. In addition, studies in adults who are gene-expanded for HD but have not yet manifested the illness (pre-HD subjects) have significant changes in the structure of their brain, even up to 20 years before the onset of clinical diagnosis. How far back these changes are evident is unknown. One possibility is that these brain changes are present throughout life due to changes in brain development, though initially associated with only subtle functional abnormalities.

In an effort to better understand the developmental aspects of this brain disease, the current study proposes to evaluate brain structure and function in children, adolescents, and young adults (ages 6-30) who are at risk for developing HD – those who have a parent or grandparent with HD. Brain structure will be evaluated using Magnetic Resonance Imaging (MRI) with quantitative measures of the entire brain, cerebral cortex, and white matter integrity via Diffusion Tensor Imaging. Brain function will be assessed by cognitive tests, behavioral assessment, and physical and neurologic evaluation. Subjects that are gene-expanded (GE) will be compared to subjects who are gene-non-expanded (GNE). Changes in brain structure and/or function in the GE group compared to the GNE group would lend support to the notion that this disease has an important developmental component.