Huntington’s Disease
Etiology/pathophysiology:
-AD; due to mutation in huntingtin gene; based on anticipation of increasing CAG repeats.
-Excess CAG repeats result in too much huntingtin proteins, causing mitochondrial toxicity,
excitotoxicity, and immune activation.
<26 repeats is normal, won’t get HD and won’t pass on HD
-27-39 is equivocal, MAY get HD and MAY pass on HD
>40 is inevitable huntington’s
>50 CAG repeats tends to be juvenile onset
-Prevalence 1/10000, but varies based on geographic location.
-Natural history: Onset ranges from infancy to 80’s, average is 50’s; patients live 15-30 years on
average from time of symptom onset.
-Younger age of onset= faster the progression.
-Medium spiny neurons most affected.
-MRI with atrophy of caudate, though putamen is actually the main site involved.
Symptoms:
-Classic triad is movement disorder (usually chorea) + psychiatric disorder + dementia
-Tend to present with chorea and personality changes first.
-Chorea (motor impersistence, pendular reflexes, semi-purposeful movements, dance-like gait);
improves as the parkinsonism worsens late in disease. Patients often unaware of debility.
-Psychosis/dementia/depression/delusions/impulsivity/euphoria/OCD/suicide
-parkinsonism (bradykinesia, rigidity)
-Dysarthria/dysphagia
-myoclonus
-Tics
-Dystonia (head, limbs, trunk)
-Oculomotor apraxia (early finding; when patient saccades eyes, also thrusts head in that direction
and blinks at same time) and square wave jerks
-Ataxia
-Anosognosia (underestimate or not acknowledge their deficits)
Diagnosis:
-Gene test; PRIOR to that, need to discuss consent, counseling, confidentiality, cost of test, and
consequences (ie, HAVE PATIENT GET GENETIC COUNSELING PRIOR TO TESTING)
-Can follow with the UHDRS (HD rating scale)
-Consider investigating for mimics if gene test is negative or equivocal:
Genetic DDx:
-HDL1, HDL2, HDL3
•DRPLA
•Neuroacanthocytosis
•SCA 2, 3, 17
•NBIA
•pantothenate kinase associated neurodegeneration (PKAN)
-neuroferritinopathy aceruloplasminemia infantile neuroaxonal dystrophy
•Benign hereditary chorea
•Wilson disease
•Mitochondrial disorders
•Ataxia with oculomotor apraxia (types 1 and 2)
•Ataxia-telangiectasia
•Dystonia-ataxia-pyramidal (OPA3)
Genetic workup for HD/mimics with chorea:
Tx:
1) Education (disease, prognosis; see below):
-Consider genetic counselors, particularly for other family members. Of note, for female HD
patients wanting to have children, in vitro methods can create embryos that are guaranteed
free of HD.
2) Symptomatic therapy: Psychiatric problems are often the most bothersome (chorea less so).
-Close Psychiatric care and treatment is KEY if any hint of psychiatric manifestations.
-SLP/PT/OT/nutrition if needed.
-Anti-dopamine drugs for chorea (only use if bothersome):
A) TETRABENAZINE: only FDA approved one (avoid if depressed or anxious, as can
worsen these symptoms).
B) Antipsychotics: Very reasonable first choice, particularly if concomitant psychiatric
issues are present; be wary if h/o significant cardiac issues or prolonged QT.
Olanzapine (start 5mg QHS, increase 7.5 10mg QHS if needed), Haldol, Risperdone.
C) Amantadine (start 100mg daily, increase to 100mg TID).
-Nothing works for neuroprotection or for dementia/cognitive symptoms (as of 2014)
HD spiel that genetics clinic gives to patients:
We explained that Huntington disease is a slowly progressive neurological
condition that affects movement, coordination and thought processes. The
symptoms of Huntington disease generally appear between 30 and 50 years of age
though individuals can develop symptoms of Huntington disease at younger or
older ages. Symptoms include involuntary movements, clumsiness, unsteady
gait, deterioration in judgment and memory and in some individuals,
personality changes, including depression and mood swings. The incidence of
alcohol abuse and suicide is increased in individuals with Huntington disease.
As Huntington disease progresses, involuntary movements, known as chorea,
become more pronounced. Over time, speech and swallowing difficulties develop
and the ability to think and remember events deteriorates. Once symptoms of
Huntington disease have developed, generally an individual will survive 10-25+
years. Unfortunately, at the present time, there is no cure for Huntington
disease. There are medications that can be taken to help with some of the
symptoms but these medications cannot alter the course of Huntington disease.
We also discussed the genetics of Huntington disease. We explained that our
genetic information is contained in structures called chromosomes.
Chromosomes are found in nearly all the cells in our bodies. Humans have 46
chromosomes which are organized into 23 pairs; one chromosome from each pair
is inherited from each parent. Chromosomes are numbered 1-22, with the 23rd
pair determining sex. Females have two X chromosomes; males have an X and a Y
chromosome. Chromosomes contain thousands of genes. Genes are what determine
physical traits, diseases and how our bodies function. The gene that is
altered in individuals who have Huntington disease is located on chromosome
number 4. Huntington disease is inherited in an autosomal dominant manner
[autosomal-not related to gender so both males and females are affected;
dominant-one altered copy of the gene required to have the condition]. Almost
all individuals who have inherited the gene alteration for Huntington disease
will develop Huntington disease.
We explained that there is genetic testing available to determine if an
individual has inherited the gene alteration for Huntington disease. The cost
of the genetic testing is approximately $300 per sample and analysis can be
performed on a blood sample. The Huntington disease gene contains a region of
CAG repeats; individuals with Huntington disease usually have more than 39
copies of the CAG repeat on one of their two number 4 chromosomes though there
is some variation between laboratories. Laboratories generally request that a
blood sample from a family member with Huntington disease be analyzed first to
confirm the presence of this CAG expansion prior to testing a family member at
risk for Huntington disease. We emphasized that genetic testing
for Huntington disease will not provide information on age of onset, type of
symptoms, severity or disease progression. We also explained that in some
cases genetic testing will not yield a definitive result. If the number of
CAG repeats is in the inconclusive range, it will not be possible to predict
whether or not an individual will develop Huntington disease.
The Huntington Disease Society of America recommends that individuals at risk
for Huntington disease have the following prior to testing: 1) genetic
counseling 2) neurological evaluation and 3) psychological evaluation. Once
these evaluations are completed and provided that there are no significant
concerns, a blood sample can be drawn for genetic testing. If you decide to
proceed with genetic testing, you will need to return to the Medical Genetics
Clinic to have the blood sample drawn and to obtain your test results.
Follow-up counseling sessions would be available. It is recommended that
genetic testing be performed at a time of low stress when you are not
experiencing major life changes. In addition, it is recommended that a
"support person" such as a spouse, relative or a close friend be present when
results are received and throughout the other evaluations if possible, and
that a counselor in your community be identified for local support. The
Huntington Disease Society of America has developed the guidelines for
presymptomatic testing described above based on the experience of other at
risk individuals for Huntington disease.
We discussed the potential psychological implications of genetic testing for
Huntington disease. Some individuals decide to be tested to make informed
life decisions while others just feel a need to know their carrier status.
Other individuals at risk for Huntington disease decide not to proceed with
genetic testing because they do not want the burden of finding out that they
will later develop a disease for which there currently is no cure. It is
important that individuals take the time to carefully think through their
decision about whether to proceed with genetic testing.
It is not clear what the implications of being a carrier of Huntington disease
could have on insurance coverage and employability. We discussed that it is
important that you make sure that your health insurance, life insurance and
disability insurance are up to date prior to undergoing genetic testing for
Huntington disease. We also discussed the option of self-paying for the
evaluations and testing. We explained that there will be a University of
Michigan medical chart record of your visit to the Medical Genetics Clinic and
discussed confidentiality issues.
We provided you with information from the Huntington Disease Society of
America. The phone number for the Huntington Disease Society of America is
(800) 345-HDSA. There are Huntington disease support groups in Michigan that
provide support for individuals with Huntington disease, their family members
and caregivers. The phone numbers for the Michigan chapters are: Lansing(517) 321-6511; Mt. Clemens- (810) 465-7550. There are also Support Groups
in: Kalamazoo-(616) 381-7725, Grand Rapids-(616) 949-9275 and Saginaw-(517)
835-9933. The Mid-Michigan HDSA chapter also sponsors a Help Line, which is
coordinated by Janet Howes, MSW [(800) 909-0073], and has information about
community resources. There is also a lot of information about Huntington
disease on the Internet