Presented by: Veronica Santini, MD, MA
Clinical Assistant Professor, Neurology and Neurological Sciences
October 1, 2015
Huntington’s disease (HD) is a hereditary disease causing progressive degeneration of nerve cells in the brain characterized as a movement disorder, a cognitive disorder, and a neuropsychiatric disorder. Its most notable physical symptom is a dancelike, involuntary movement called chorea, though it also can cause tics, muscle jerks, abnormal eye movements, difficulty swallowing, inability to maintain muscle contractions, and impaired gait and balance. It also leads to cognitive impairment with slowed processing speed, poor concentration, impulsiveness, and lack of insight. Many people with HD suffer from depression, anxiety, irritability, and apathy, which can often lead to social isolation. There is a significantly increased risk of suicide in this population.
HD has been recognized and documented for hundreds of years. In the 16th century, Paraclesus first noted the characteristic movements, which he termed chorea naturalis, and a century later it was called “that disease” or St. Vitus Dance. In 1872 George Huntington wrote a landmark paper describing the hereditary nature of the disease and the specific disease symptoms. A hundred years later, the responsible gene was localized to chromosome 4 after genetic analysis of more than 3,000 people.
Huntington’s disease is an autosomal dominant disorder, meaning that the disease will affect each generation in the family. The abnormality of the gene is due to the repeated expansion of three proteins in our DNA, called CAG (cytosine-adenine-guanine), that lead to an abnormal structure of the huntington protein, which is believed to be essential for development. Because of the abnormal protein structure, the cell cannot function or communicate properly and this leads to gradual brain cell dysfunction and death. The result is clinical triad of abnormal movements, cognitive decline, and psychiatric problems, said Veronica Santini, MD, MA, Clinical Assistant Professor of Neurology and Neurological Sciences, who spoke at a presentation sponsored by the Stanford Health Library. Dr. Santini co-directs the Stanford Multidisciplinary Huntington’s Disease and Genetic Ataxia Clinic.
The number of CAG repeats an individual has determines their risk of developing the disease. A person with 40 repeats has a 100 percent chance of developing HD, while someone with 36-39 repeats has an elevated risk of disease development. Individuals with 27 to 35 repeats may not develop the disease though their offspring may be at risk. A person with 26 or fewer repeats will not develop the disease. Additionally, scientists believe that other genes and environmental factors may play a role in disease development. The CAG repeat length also seems to correlate with age at onset of disease.
A diagnosis of Huntington’s disease is suspected when a patient has any of the above symptoms and has a family history of disease, though family history is not always known. Diagnosis is confirmed with genetic testing and can be done pre-symptomatically if a patient choses. Physical symptoms can begin at any age, but usually begin between 35 and 55 years of age.
“It’s hard to say when exactly Huntington’s disease arises,” Dr. Santini said. “Some say it’s when the motor signs—chorea—appear. But the cognitive and behavioral changes may manifest much earlier.”
Disease symptoms are tracked based on motor, behavioral, cognitive, and functional assessments. Its progression is measured through five stages:
- “Prodromal” or “premanifest” stage— mild but progressive cognitive and psychiatric symptoms (such as irritability, apathy, and anxiety) may appear up to 15 to 20 years before motor symptoms arise; some subtle motor symptoms such as eye movement abnormalities, hand coordination, reduced sense of smell, and gait changes; first peak in suicide rates is just before diagnosis
- Early stage—subtle changes in coordination; mild chorea; mood changes such as impulsiveness or obsessions; memory loss, reduced attention and processing speed; trouble swallowing; weight loss
- Moderate stage—worsening chorea; falling and loss of motor control; decline in motor skills; impaired thinking; poor sleep patterns; apathy, irritability. This phase is the second peak in suicide rates—five times higher than in the general population.
- Advanced stage—chorea calms and parkinsonism increases, including stiffness, slowness, and abnormal muscle contractions; inability to stay upright, increased falls; speech is difficult; swallowing loss makes it unsafe to eat by mouth; cognition levels out and behavior symptoms abate; some episodes of screaming
Therapy is designed to address all aspects of care to improve daily life, said Dr. Santini, and includes services movement and memory disorder specialists, psychiatrists, genetic counselors, social workers, nutritionists, speech, physical, and occupational therapists, and hospice care team members.
There is no cure for HD, and no medications can slow or stop its progression. Dr. Santini administers medications only when needed and prefers to use one medication (when possible) for combined therapy to treat mood, involuntary movements, weight loss, and fatigue.
Several medications address both the physical and psychological symptoms at all stages of HD. Early-stage options include memantine for memory loss; tetrabenzine, a dopamine depleter; antipsychotic medications that calm involuntary movements; selective serotonin re-uptake inhibitors (SSRIs) for depression; and mood stabilizers like lamotrigine and valproic acid for mania and irritability.
Studies are showing some benefit of rivastigmine to treat cognitive and memory symptoms, though other drugs, including donepezil, show no benefit and cause unwanted side effects.
Advanced-stage therapy may involve withdrawal of medications to avoid the worsening slowness, stiffness, and abnormal muscle contractions that appear later in the disease, she said. The patient eventually becomes totally dependent on others for care and speech output and cognition becomes more impaired, although the person can still understand. Dr. Santini suggested that end-of-life decisions become part of an ongoing conversation between patient and physician and between patient and caregivers and that the topic is introduced early, so patients can properly express their desires.
About the Speaker
Veronica Santini, MD, is a Clinical Assistant Professor of Neurology and Neurological Sciences, specializing in the diagnosis and management of movement disorders, including Parkinson’s disease, Huntington’s disease, tremor, and ataxia. She is co-director of the Stanford Multidisciplinary Huntington’s Disease and Genetic Ataxia Clinic, which has been designated as a 2015 Huntington’s Disease Society of America, Center of Excellence. She received her MD at Boston University School of Medicine, where she completed her residency in neurology and a fellowship in movement disorders. Dr. Santini is also committed to medical education and global health, and started multiple educational initiatives and programs bringing multidisciplinary medical teams to Haiti to provide neurologic care. She serves as the associate neurology clerkship director and was appointed as an ambassador to the St. Luke Foundation in Port-au-Prince and visiting professor at the Université d’Etat d’Haiti. She joined the Stanford faculty in 2014.
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