Handbook of Genetic Counseling/Huntington Disease

Huntington Disease

Contracting

• What have you been told already about HD and the reason you were referred to see us?
• Wondering what questions or concerns you might like to discuss with us today?
• How has your diagnosis of a neurodegenerative disorder changed your life the most?
• Since HD is usually passed on by a parent I like to begin by taking a family medical history to see if any other family members may have had symptoms of HD. Sometimes HD can be misdiagnosed as something else like Parkinson's or Alzheimer's disease because they share some of the same symptoms and other times family members have passed away before symptoms of HD develop
• We can then discuss the cause of HD and details about the genetic testing we have to offer you.
• Dr. ____ will also be in later to perform a short physical examination and further discuss HD

HD overview

• An inherited progressive brain disease
• It often causes uncontrolled movements (chorea), problems with coordination, difficulty with memory and mental processing, and emotional or personality changes.

Incidence

• A rare disease, occurring in 3-7 people per 100,000 people in populations of western European descent
• About 1 in 10,000 in N. America
• HD is less common in Japan, China, Finland, and African Americans

Disease Manifestations

• Presently no effective therapy to halt progression of disease
• Most often symptoms develop between age 30-50
• Approximately 25% of patients with HD exhibit the first symptoms after age 50
• About 10% have juvenile Huntington disease with onset before age 20
• Epileptic seizures are common in early onset cases with 30-50% of juvenile patients being affected
• Chorea is not common in children with juvenile HD
• Early symptoms
• subtle changes in coordination
• involuntary movements (chorea)
• non-repetitive, non-periodic, jerking of limbs, face or torso
• present in over 90% of patients with HD
• continuously present during the waking hours, cannot be suppressed voluntarily and are worsened by stress
• difficulty in mental planning
• depressed or irritable mood
• memory impairments
• As HD progresses there is increased difficulty with voluntary movement
• May have outbursts of aggressive behaviors and social disinhibition
• A global decline in cognitive capabilities occurs in all HD patients
• Personality changes may develop; some develop affective psychosis or schizophrenic psychosis
• Suicide occurs in up to 12% of patients
• Behavioral disturbances such as intermittent explosiveness, apathy, aggression, alcohol abuse, sexual dysfunction and deviations, are frequent
• Delusions, often paranoid, are also common
• Hallucinations are less common
• In the late stages of HD, behavior problems are gradually lessened, but motor disability becomes severe and the patient is often totally dependent, can't speak, and can't control bladder function, weight loss often becomes a concern
• Disease usually progresses slowly over a 15-20 year period after which death occurs

What Causes Huntington Disease?

• In order to understand what causes HD and to understand the testing for HD it is helpful to review some genetics
• Review chromosomes, genes, DNA, nucleotides
• Gene IT-15 (discovered in 1993)
  • located on chromosome 4
  • area in the gene where there are tri-nucleotide repeats
  • Most individuals have between 9 and 26 repeats
  • Alleles of 27-35 CAG repeats are considered intermediate alleles. A person with an allele in the intermediate range do not develop HD, but they may have children with HD if the number of repeats increases when the gene is passed on
  • An allele in the range of 36-41 is associated with reduced penetrance for symptomatic HD (they may or may not develop symptoms of HD)
• The HD gene produces a protein (Huntingtin)
  • widely expressed
  • function unknown
  • CAG expansion causes altered structural and biochemical properties
  • The protein has been shown to accumulate in neurons within the brain
  • Uncertain if this accumulation is what causes symptoms
• Inverse correlation between CAG repeat length and the age of onset
  • Patients with adult onset of symptoms usually have an expansion that ranges from 40-55 CAG repeats
  • Patients with juvenile onset of symptoms usually have expansions about 60 repeats
  • Repeat length does not correlate with any other clinical feature, exact age of onset, or rate of progression

Inheritance

• AD inheritance
  • Homozygotes are no more severely affected clinically than heterozygotes
• Offspring of an individual with a mutant allele have a 50% chance of inheriting the disease-causing mutation
• Approximately 3% of individuals with HD have no family history of condition
• Reasons family history may be negative
  • Alternate paternity
  • Adoption
  • Early death of a parent
  • Failure to recognize symptoms or misdiagnosis
  • Late age of onset in a parent
  • Presence of intermediate allele or reduced penetrance allele in a parent
  • New mutations are rare
• Genetic anticipation
  • Disease severity or decreasing age of onset can occur in successive generations
  • Anticipation occurs more commonly in paternal transmission of the mutated allele
  • The risk of expansion of intermediate allele into the disease range is about 2.5% when transmitted by the father
  • This phenomenon arises from instability of the CAG repeat during spermatogenesis
  • Large expansions in CAG repeat size occur almost exclusively through paternal transmission

Diagnostic Testing

• Diagnosis of HD rests on a positive family history, characteristic clinical findings, and molecular DNA testing the reveals an expansion of the CAG repeat in the HD gene
• Imaging studies including MRI, CT, SPECT, and PET may provide additional support for the clinical diagnosis. (used mainly to determine whether other conditions are contributing to the neurologic dysfunction)

Direct DNA testing

• Blood test
• Measures number of CAG repeats
• 98.8% sensitive, 100% specificity
• Sometimes results are uninformative, but if CAG repeat is within the normal range likely that your symptoms are due to a different neurodegenerative disorder
• Cost of testing is approximately $270
• Insurance - already symptomatic

Psychosocial Considerations

• Probably beyond initial reaction to diagnosis of progressive neurodegenerative disorder
• Encourage to carry on normally as long as possible
• Others with HD have said it helps to try and live in the moment
• Families should expect to deal with a variety of emotions
• Realizing that this may be genetic and if children will inherit it
• Watching things you used to do slowly slip away
• Family members having to watch as loved one slowly looses their motor and cognitive skills
• Moodiness, aggressiveness, emotional outbursts can be difficult for caregiver
• Plans and potential concerns for the future
  • • How are you coping with the likelihood that you will have to eventually give up work
    • Legal, financial, health insurance
    • Being dependent on others
    • Caregivers having time for themselves (not being selfish)
• What have you told other family members?
• How is the rest of the family reacting?
  • • Do they know it could be genetic?
    • Different family members react differently based on their personalities, fears, and types of coping strategies
• If testing were to come back showing you have HD how do you think you will react?
• Would this be different if it came back showing you don't have HD
• If positive for HD there is a support group
• Don't be too reassuring, but provide hope that a lot of research is ongoing to try and understand the disease better
• HD can provide challenges to family relationships
  • • Roles and family dynamics may change
    • Have you come across any of these challenges
    • How have you dealt with problems in the past
    • Changes in sexual activity

Differential Diagnosis

• Differential diagnosis include other conditions that involve chorea, dementia, and psychiatric disturbances
• Many non-inherited conditions are associated with chorea
• These include tardive dyskinesia, thyrotoxicosis, cerebrovascular disease, cerebral lupus, and polycythemia
• Usually be excluded by other clinical features in a patient with suspected HD
• Neuroancanthocytosis -- considered if muscle wasting, absent lower limb tendon reflexes, and signs of neuropathy are present
• Benign hereditary chorea usually presents with nonprogressive chorea without dementia
• Creutzfeld-Jakob disease progresses more rapidly then HD and has myoclonus as a prominent involuntary movement
• For children, Hallervorden-Spatz syndrome, Lesch-Nyhan syndrome, and other metabolic diseases must be excluded when there is no known family history of HD
• SCA

Management

• Limited to symptomatic treatment
  • Choreic movements can be partially suppressed by neuroleptics
  • Anti-Parkinsonian agents may ameliorate hypokinesia and rigidity
  • Psychiatric disturbances such as depression, psychotic symptom, and outbursts of aggression may respond well to psychotropic drugs
• Cognitive impairment is not amenable to treatment
• There is no effective therapy to slow down disease progression

Reproductive Options

• There are alternative reproductive options for those not wishing to risk transmitting the disorder to offspring
  • Prenatal testing is possible using DNA that has been extracted via amniocentesis or chorionic villus sampling (CVS).
  • Preimplantation genetic diagnosis (PGD) is also available. This technology uses in vitro fertilization (IVF) to produce embryos, which are tested for the HD mutation. Only embryos without the CAG expansion are implanted into the uterus.
    • You can have this procedure done without knowing if you actually carry the mutation
    • Consider cost per IVF cycle and success rates

Resources

• Huntington's Disease Society of America

158 West 29th Street, 7th Floor

New York, NY 10001-5300

Phone: 212-242-196; 800-345-HDSA

Fax: 212-239-3430

Email: hdsainfo@hdsa.org

www.hdsa.org

• Huntington Society of Canada

151 Frederick Street, Suite 400

Kitchener, Ontario N2H 2M2

Phone: 519-749-7063 or 1-800-998-7398

Fax: 519-749-8965

Email: info@hsc-ca.org

www.hsc-ca.org

References

• NORD
• GeneClinics
• HDSA
• Huntington Society of Canada

Notes

The information in this outline was last updated in 2003.