Huntington’s Disease — Discovery and Treatment

Huntington’s disease (HD) is a rare, adult-onset, autosomal dominant, progressive neurodegenerative disease named after George Huntington, who described it among East Hampton, Long Island residents in 1872. Genetic disorders are characterized by autosomal dominant inheritance patterns. The term “autosomal” means that the gene is located on a numbered, or non-sex linked, chromosome. A mutated gene (from one parent) can cause the disorder if it is only present in one copy. HD is also referred to as Huntington’s chorea (involuntary movements). George Huntington provided a comprehensive description of adult-onset HD in 1872; he was only 22 years old at the time. More than 100 years later, JF Gusella et al., in 1983 identified the Huntingtin (HTT) gene. This was the first gene associated with HD to be molecularly mapped to a human chromosome. A decade later (1993), MacDonald et al., uncovered its DNA sequence and the exact mutation causing HD in HTT. It is known that HTT has a section with several repeated triplet nucleotides- CAG. In addition, the number of CAG repeats within this gene determines whether an individual will develop HD. People with 6 to 35 CAG repeats will not be affected; those with 36–39 are at greater risk; 40 or more CAG repeats guarantee the expression of disease characteristics. It is now known that a person with Huntington’s disease has a single defective gene on chromosome 4 — one of 23 chromosomes that carry all their genetic information.

Although a precise determination of one’s risk for HD can be established through molecular genetics, no cure or successful treatment has been found to deter or reverse the condition. Nevertheless, medical remedies and lifestyle approaches exist that can alleviate the symptoms and enhance the quality of life for those with Huntington’s disease. Additionally, research into the affliction is ongoing to potentially find more effective management options. Scientists are also focusing on the normal function of the huntingtin protein and how a handful of extra sequences in its genetic code led to the agonizing signs of Huntington’s. If successful, this may promulgate a greater understanding of an array of other brain pathologies, such as Alzheimer’s, Parkinson’s and, amyotrophic lateral sclerosis (ALS).

For clarity, the defective gene codes for a protein called huntingtin, which scientists have identified as the cause of Huntington’s disease. Scientists do not yet know the normal function of this protein.

Clinically, HD is characterized by uncontrollable movements of the arms, legs, head, face, and upper body, and usually develops between the ages of 30 and 50 but can occur as young as 2 or as old as 80. As well as deteriorating memory, concentration, judgment, and planning and organizing skills, HD also causes a decline in reasoning abilities. As a result of HD, brain changes affect mood, particularly depression, anxiety, and uncharacteristic anger and irritability. Another common symptom is obsessive-compulsive behavior, which involves repeating the same question or activity constantly. While not knowing the normal function, it is clear a defective huntingtin protein causes abnormal involuntary movements, a severe decline in thought and reasoning skills, and irritability, depression, and other mood changes in the brain.

In addition to not being able to cure HD, there is no way to slow or stop its brain changes. Three of the disease’s most critical indications have the following recommended treatments:

· Some healthcare providers recommend starting treatment with atypical antipsychotics like olanzapine and risperidone. Tetrabenazine, a drug recently approved by the Food and Drug Administration (FDA) for Huntington’s, is another type of medication used to control symptoms.

· It is recommended to try selective serotonin reuptake inhibitors (SSRIs), an antidepressant, first for less severe, nonthreatening irritability. As a standard treatment for obsessive-compulsive thoughts and behaviors, experts also recommend SSRIs.

As well as treating Huntington’s symptoms, generally accepted guidelines should be followed for anxiety, depression and insomnia. People with Huntington’s are encouraged to keep all their medical appointments and not get discouraged if their health care team takes a while to find the right medications and dosages.

As HD has multiple genetic components, there are many potential therapeutic targets. There are also a number of novel treatment options being studied, including:

· Pharmacological agents being studied are those that inhibit apoptosis, excitotoxicity, HTT aggregation, proteolysis, phosphorylation, and oxidative stress. In addition, compounds that affect transcription, mitochondria, and chaperone activity are being investigated.

· Treatment options that have shown promise in preclinical animal models and have advanced to clinical trials include minocycline, memantine, sodium butyrate, and phosphodiesterase 10a inhibitors.

· Minocycline, memantine, sodium butyrate, and phosphodiesterase 10a inhibitors have shown improvement in preclinical animal models.

· Experimental therapies include pridopidine, laquinimod, and semaphorin-4D neutralizing antibodies.

· Several preclinical animal studies have demonstrated the safety of gene silencing to target the cause of HD. These aim to silence, nonselectively, all HTT expression or selectively target the mutated HTT allele as a treatment for HD.

Studies have found variable results in cell transplantation and safety, as well as the effectiveness of intravenously injecting mesenchymal stem cells. According to recent studies the mutated HTT gene can extend into allografted (not from the same person) neural tissue.

As well as studying the development and progression of Huntington’s disease, researchers are also looking at lifestyle choices and environmental factors. As part of their research, they examine ways to improve quality of life for people with HD and their families by studying factors such as diet, exercise, and stress. HD research aims to develop effective treatments and ultimately find a cure.

Huntington’s disease (HD) is a debilitating inherited illness. It results in the gradual breakdown and death of nerve cells in certain parts of the brain, impairing voluntary movement as well as other functions. Johns Hopkins researchers have long been recognized as pioneers in HD gene discovery and genetic testing, leading to enhanced accuracy when providing information about age of onset and other pertinent aspects to individuals impacted by this condition. While testing for the gene that causes HD offers a means of detection, researchers continue to work on treatments that may mitigate some of the neurological effects of the disease.

Written By: Lawrence D. Jones, Ph.D.

Keywords: HD, Huntington’s, neurological disorders