Lecture 10: Huntington’s disease Flashcards
Huntington’s disease
Sandra K. Kostyk, M.D., Ph.D.
Who was George Huntington?
George Huntington grew up on Long Island where both his father and grandfather had been physicians and had treated and followed members of several families over several generations.
George Huntington moved to Ohio and presented the first concise description of what became known as Huntington’s Disease at a medical conference in Pomeroy, Ohio in 1872.
Famous People who had Huntington’s Disease
From: Woody Guthrie: A Life by Joe Klein, 1980
Father Woody and Daughters Sue and Gwen had HD.
2 types of Huntington’s
Adult onset
Juvenile onset
HD basics
Autosomal dominant: there is a 50/50 chance of a child getting the disease if a parent has it.
HD does not skip generations:
If a person with an affected parent escapes the disease, so will all of their children.
HD is a trinucleotide repeat disorder.
(other repeat disorders include: Fragile X, Myotonic dystrophy, Kennedy’s, SCA I, Machado-Joseph, etc)
Individuals with >37 CAG (polyglutamine) repeats express the HD phenotype.
Repeat sizes from 27-36 are considered unstable for future generations. There is a tendency for “anticipation” when the gene is transmitted by the father.
There is a rough correlation between repeat size and age of onset.
anticipation
The progressively earlier appearance and increased severity of a disease from generation to generation. The phenomenon of anticipation was once thought to be an artifact, but a biological basis for it has been discovered in a number of genetic disorders, such as myotonic dystrophy and Huntington disease.
Occurrence (as of a disease or symptom) before the normal or expected time
Huntingtin is normally a
cytoplasmic protein
The disease starts insidiously and progresses continuously.
The HD CAG expansion causes a number of metabolic changes.
People with HD have decreased body mass index and over 3 years gain less weight than average Americans.
Increased 24 hr energy expenditure by11%.
Mitochondrial energy deficit found in muscle biopsy samples from pre-symptomatic and symptomatic people with HD gene expansion.
Cholesterol metabolism is abnormal in HD brain cells.
Altered glucose tolerance in people with HD, diabetes in HD mice.
HD brain
Caudate Loss in HD
Juvenile HD: Also includes
Globus pallidus and cerebellar involvement.
HD Symptoms include changes in:
Behavior
Motor function
Cognitive function
In adults, motor symptoms
include:
Chorea Motor impersistence Oculomotor changes Impaired fine motor control Balance and gait disorder Dystonia Speech/swallowing problems
Chorea
Chorea is a condition that causes involuntary, unpredictable body movements that do not have a pattern. Chorea symptoms can range from minor movements such as fidgeting to profound, uncontrolled movements of the arms and legs.
Dystonia
Dystonia is a disorder characterized by involuntary muscle contractions that cause slow repetitive movements or abnormal postures. The movements may be painful, and some individuals with dystonia may have a tremor or other neurologic features. There are several different forms of dystonia that may affect only one muscle, groups of muscles, or muscles throughout the body. Some forms of dystonia are genetic but the cause for the majority of cases is not known.
ViBE
The effect of Video game Biofeedback modulated Exercise on HD subjects on cognitive and physical symptoms.
- -Used a Variation of Dance Dance Revolution.
- -20 subjects enrolled. Two sessions per week for 6 weeks. Hand held video game control group.
Walking improved. Improved double support time, heel to heel base of support, stride length and velocity. Improved dynamic balance. Trend towards improvement in neuropsychiatric test measures.
Intellectual Difficulties In HD
Completing complex tasks Organizing and prioritizing Adapting to change Problem solving Creative thinking Word finding Memory problems
Behavioral symptoms Include:
Obsessive compulsive disorder Depression/mood swings Poor impulse control Psychosis Anxiety Apathy
Characterization of the Huntington intermediate CAG repeat expansion phenotype in PHAROS
Conclusions
In a cohort at risk for HD, the IA was associated with significant behavioral abnormalities but normal motor and cognition.
This behavioral phenotype may represent a prodromal stage of HD, with the potential for subsequent clinical manifestations, or be part of a distinct phenotype conferred by pathology independent of the CAG expansion length.
Juvenile HD
Usually a family history of relatively young onset HD.
Often inherited from the father. (~80 %)
Stiffness of legs. Scissoring gait. Walking on toes. Clumsiness of arms and legs. Decline of mental ability and milestones. Changes in behavior. Seizures ( ~25% of HD children). Swallowing & speech difficulties. Bradykinesia. Cerebellar signs.
Behavioral issues in HD juveniles
Aggression Impulsiveness Adolescence and sexuality Depression Obsessive compulsive behavior Hallucinations (rare)
Genetic testing choices and stories…..
When to get tested and why…
Choices for parents:
in vitro, adopt, coin toss, hope…
Genetic counseling is essential.
Weigh the Pros and Cons.
Why wait?
Why get tested?
1000 PHAROS ( “at risk”) study subjects elected not to be tested and have been followed clinically for 10 yrs to help identify first signs of HD.
Majority of individuals at risk for HD elect not to get pre-symptomatic testing
Dangers of premature testing
Incorrectly blaming symptoms on HD.
Discrimination (insurance, future employment).
Negative psychological & social effects.
Testing of children in the family is not encouraged.
HD Treatment:
This is a progressive disorder. Treatment plans need to be regularly reviewed.
Currently no medicine or specific treatment advised for everyone.
Symptomatic treatment:
Chorea: Benzodiazapines, amantadine, neuroleptics, valproate, tetrabenazine
Spasticity/rigidity: PT/OT, benzodiazepines, baclofen, dantrolene, tizanidine.
Speech/swallowing and dental care issues.
Behavior: Depression, Aggression, OCD.
Medical treatments.
Psychiatry and psychology input. (SSRIs, Depakote,Buspar, Anafranil…)
Seizures reportedly relatively drug resistant.
Tetrabenazine
FDA approved for use in this country for the treatment of HD related chorea in 2008.
Had been used in Europe, Canada and Australia for years.
Reversibly binds to Vesicular Monoamine Transporter Type 2 ( VMAT-2)
VMAT-2 inhibitor
Monoamine depleting agent similar to reserpine but shorter half-life and less peripheral side effects.
Decreases dopamine, seratonin, and norepineferine.
Orphan Drug
Approved with required Risk Evaluation and Mitigation Strategy (REMS)
May be obtained through a national centralized pharmacy.
Not available through general prescription
