Hannan_Huntington's_DIsease

8/7/2019 Hannan_Huntington's_DIsease

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1.0 THE TRUTH

y One in every 1,000 Canadians is touched by HD for example, as an affected

individual, person at risk, friend, family member or caregiver

y One in every 10,000 Canadians has Huntington disease.

y Every child of a person with HD has a 50% risk of inheriting the disease.

y HD occurs in approximately 1 in 10,000 people in the United States.

Currently about 30,000 people in the U.S. have HD and a further 150,000 are

at risk.

y There is no cure and no effective treatment exists, but scientists are explori ng

possible treatments and caregivers are developing new approaches to care.

FIGURE : HD survival curve. Thepercentage of patients surviving as afunction of years since disease onset. Thecurve is derived from 163 patients enrolledin the Baltimore Huntingtons DiseaseCentre with a record of both age atdisease onset and age at death. (FromRoss CA, Margolis RL, Rosenblatt A, et al.Reviews in molecular medicine:Huntington disease and the relateddisorder, dentatorubral-pallidoluysianatrophy (DRPLA). Medicine (Baltimore)1997; 76:305338, with permission.)


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2 .0 OV ERVI EW

According to the Harper PS., 1996. Huntington disease (HD) is a progressive

neurodegenerative disorder with an established genetic origin and symptoms that

are preferable to specific regions of brain disease. Huntington disease (HD) is also

an inherited brain disorder that causes progressive deterioration of the physical,

cognitive and emotional self. It leads to severe incapacitation and eventual death

1040 years after the onset of the disease. Although it usually affects adults between

the ages of 30 and 45, symptoms can appear in young children and older adults.

Common symptoms are uncontrollable movements, abnormal balance when

walking, slurred speech, difficulty swallo wing, thinking difficulties, and personality

changes. Each child of an affected parent has a 50% chance of inheriting the HD

gene, which is located on chromosome four. There is no cure and no effective

treatment exists, but scientists are exploring possible treatments and caregivers are

developing new approaches to care. Cellular and molecular techniques are rapidly

elucidating the pathogenesis of the disorder and are leading to approaches designed

to develop rational treatments. Thus, HD serves as a model for the future study of

those psychiatric disorders in which to abnormal brain function is thought arise from

predominantly genetic factors.


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3 .0 IN TROD UCING: HUN TING TON S DIS EASE

Huntingtons disease (HD) is a hereditary b rain disorder that affects people

of all races all over the world. It takes its name from Dr. George Hu ntington , aLong Island physician who published a description of what he called hereditary

chorea in 1872. From the Greek word for dance, chorea refers to the

invol u ntary m ove m ents which are among the common symptoms of HD.

Huntingtons disease (HD) is an a u toso m al do m inant neurodegenerative

disorder with m idlife onset characterized by m otor, p sychiatric, and cognitive

sy mp to m s . Progressive loss of m edi um- s p iny ne u rons that produce gamma -

a m ino bu tyric acid (GABA) in the striatum and other central nervous system (CNS)structures has been considered an important phenomenon that underlies this

disease. Changes involving the cerebral cortex lead to further dysf u nction in

cortico -striatal -p allidal circ u itry .

In addition, HD is associated with a cytosine -adenine -g u anine (CAG) tri p let

re p eat expansion in the IT15 gene . The genetic mutation underlying this disorder

has been localized to the short arm of chro m oso m e 4 and was found to consist of

an expansion and instability of a polymorphic trinucleotide repeat (CAG) in geneIT15.

The decrease in cholinergic (AC h ) activity probably explains the deficit in

m e m ory retrieval observed in HD. Loss of inhi b itory GABA ergic f u nction and

increased do p a m ine (DA) tu rnover has been proposed as an explanation for the

emergence of psychotic symptoms in HD. In addition, Huntingtons disease

manifests clinically as a triad of choreic m ove m ents, cognitive decline, and

p sychiatric syndro m es .

Taking into account that both motility and psychiatric disorders have been

associated with neurochemical abnormalities that include hy p ernoradrenergic and

hy p o -GABA ergic and hy p oserotonergic activities


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Until recently, little was known or published about Huntingtons Disease. Yet

in the last 20 years, much has been learned about the causes and effects of HD and

about treatments, therapies and techniques for managing the symptoms of the

disease. In 1993, after a ten-year search, scientists found the gene that causes HD,

and important advances have flowed from this dramatic discovery. Many scientists

are actively engaged in the search for effective treatments to stop or reverse the

effects of HD, and eventually to cure it altogether.

HD also is a degenerative disease whose symptoms are caused by the loss

of cell in a part of the brain called the b asal ganglia . This damage to cells affects

cognitive a b ility (thinking, judgement, and memory), m ove m ent , and e m otional

control . Symptoms appear gradually, usually in m id -life , between the ages of 30

and 50 . However, the disease can strike yo u ng children (see Juvenile HD) and

the elderly .

In most cases, people can maintain their independence for several years after

the first symptoms of HD appear. A knowledgeable physician can prescribe

treatment to minimize the impact of symptoms. Allied health professionals, such as

social workers, occupational and physical therapists, speech-language pathologists

(speech therapists), and nutritionists can all play a useful role in maximizing abilities

and prolonging independence.


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3 .1 HUN TING TON S DIS EAS E: A FAM ILY DIS EASE

According to Folstein SE . 1989 , HD is a fa m ily disease for two reasons .

First, it is passed from one generation to the next by the transmission from parent to

child of a mu tated (altered ) gene . Each child of an affected parent has one in

two, or 50 p ercent , chance of inheriting the gene that causes HD, and is said to be

at risk. . People who carry the gene will eventually develop Huntingtons unless

they die of some other cause before the onset of symptoms.

HD occurs in approximately 1 in 10,000 p eo p le in the United States.

Currently about 30,000 p eo p le in the U.S . have HD and a further 15 0,000 are at

risk .

Males and females have an eq u al chance of inheriting the gene from an

affected parent. Those who do not inherit the gene will not develop the dis ease, nor

will their children; HD does not skip a generation. Genetic testing is available to

determine whether or not a person carries the gene for HD.

My husband Peter and I were idealistic and eager to start a family. I knewthat Peters mother was in a nursing home even though she was only in her 40s.It didnt occur to me that she might have a hereditary disease that had beenpassed on to Peter and would be passed on to our daughter. Peter was 20 and,as far as I could see, completely healthy. Brenda, Canada

HD is also a family disease because of its imp act on every fa m ily m e mb er .

As the disease progresses, the family role of the affected person will gradually

change. The spouse or partner will have to assume more and more of the

housekeeping, decision-making and parenting duties, which his/her partner may no

longer be able to fulfil. In addition the spouse or partner will most likely become the

primary care giver.


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Children and adolescents must face living with a mother or father who is ill

and whose behavior may be erratic. They may even be asked to participate in the

parents care. For p arents, telling children a b o u t HD can p ose diffic u lt

q u estions. S ho u ld a child/children b e told a b o u t HD? If so, at what age?

When is a child old eno u gh to co p e with the idea of b eing at risk for HD?

There are no easy answers, particularly since children develop at different

rates and each family situation is different. Gen erally, it is a good idea to be as open

as possible without being alarmist, and to convey the facts bit by bit. This way, a

child can develop a gradual awareness of HD rather than being suddenly

overwhelmed by information.

It is not hel p f u l to treat HD as a sha m ef u l fa m ily secret , as a child or

adolescent will find out about it eventually. Withholding the tr u th can lead to

m istr u st and resent m ent .

Though the disease is unrelentin g, pr ogressive anddebilitatin g, it is t he la ugh ter and happiness of the c hildren

and t he c ourage of the f amilies t hat I m ost recall.

Sally, Canada


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3 . 2 SYMPT O MS AND CLINI CAL FEATURES

3.2. 1 Move m ent Disorders

According P enney JB , 93 99 , the movement disorder of HD consists of two

components: involuntary m ove m ents and a b nor m al voluntary m ove m ents .

Ch orea, or choreoathetosis , is the movement abnormality most frequently

associated with HD. It consists of continuous and irregular jerky or writhing motions.

Disturbances of voluntary movement, however, are more highly correlated with

functional disability and disease severity, as measured by the degree of brain

disease. The disordered voluntary movements observed in HD include the following:

abnormal eye movements, such as slow, hypometric saccades and catchy pursuit;

uncoordinated, arrhythmic, and slow fine motor movements; dysphagia and

dysarthria; dysdiadochokinesis; rigidity; and gait disturbances.

According to Brandt J , 1986 , the nature of the motor symptoms changes over

time. The onset is usually insidious. Early complaints include clumsiness, difficulty

with balance, and jerky movements or tremor. In addition to limb and truncal

movements, patients may have motor tics or chorea involving respiratory, laryngeal,

pharyngeal, oral, or nasal musculature. Chorea often plateaus and even wanes in

the later stages of the disease, but disturbances involuntary movement continue to

progress. In late stage HD, patients typically become a kinetic and largely nonverbal,

with severe rigidity and joint contractures. At this point, they may have few

involuntary movements except for occasional movements of the entire body,

resembling myoclonic jerks, when disturbed. Difficulties with swallowing commonl y

lead to death in HD, either directly from suffocation or aspiration or indirectly from

starvation.

When HD begins in childhood or adolescence (juvenile onset HD), the

presentation is often somewhat different, with prominent bradykinesia, rigidity and

dystonia, and minimal chorea. Involuntary movements may take the form of tremors,

and patients may develop seizures and myoclonus.


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3.2.2 Cognitive Disorders

According Folstein MF, 1988 , c ognitive difficulties usually begin about the sa m e

tim e and p roceed at the sa m e rate as the a b nor m al m ove m ents , although some

patients may have considerable m otor imp air m ent with very little de m entia , or thereverse. Early in the course of HD, a p hasia and agnosia are usually much less

obvious than in the cortical de m entias such as Alzhei m er disease , where as

deficits in cognitive speed and flexibility are more common. In contrast to Alzheimer

disease, patients with HD seem to have trouble with retrieval rather than storage

of m e m ories . They are more apt than patients with Alzheimer disease to recognize

words from a previously memorized list or to respond to other cues to help them

recall information. This distinction has led to the classification of HD as a

s ubcortical dementia . Cognitive losses accumulate progressively. Deficits in m e m ory, vis u o s p atial a b ilities, and ju dg m ent develo p , and patients with late

stage HD demonstrate profound global impairment similar to patients with late -stage

Alzheimer disease, although their paucity of speech makes assessment difficult.


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3.2.3 P sychiatric Disorders

According to Rosen b latt A, 1999 , patients with HD frequently develop

ps yc h iatric s ym p tom s , most commonly de p ression, irrita b ility, anda p athy . The

behavioural expression of these symptoms varies considerably, and it may include

aggressive o u tbu rsts, impu lsiveness, social withdrawal, and s u icide . This

aspect of HD can be devastating to both the patient and his or her family. The

suicide rate alone, estimated at up to 12.7% , indicates the magnitude of the problem.

Yet of all the complications of HD, the psychiatric manifestations are the most

amenable to treatment.

Affective (mood) disorder is extremely common. Epidemiologic and

phenomenological evidence indicates that affective disorder in HD is a function of

the brain disease itself, rather than a reaction to changes in life circumstance. HD-

related major depression resembles the idiopathic form of major depression.

Prominent symptoms include feelings of worthlessness or guilt, self -blame, changes

in sleep and appetite, anxiety, anhedonia, loss of energy, hopelessness, and diurnal

variation of mood with more severe symptoms in the morning. Delusions and

hallucinations, when present, tend to be mood congruent: delusions of poverty,

illness, or guilt; auditory hallucinations of derogatory or threatening voices. The

diagnosis of major depression may be more difficult in patients with advanced

disease, but the condition is often signalled by a departure from baseline levels of

activity or functional capacity.

According to Ranen NG , 1996 , severe irritability is another common

symptom, present in one-third of patients in the Maryland HD survey. Irritability and

aggression may occur in patients without a prior history of a short temper, but these

symptoms are more common in patients who have had these traits all their lives.

Apathy may become evident at anytime in the course of the disease. Once present,it tends to persist or worsen. Irritability can coexist with apathy. Either apathy or

irritability may exist independently or as part of an affective syndrome.


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Patients with HD occasionally develop classic obsessive compul sive disorder,

with typical symptoms such as fear of contamination or excessive hand washing.

More commonly, however, patients may display an obsessive preoccupation with

particular ideas or plans (e.g., obtaining cigarettes, getting are fill of coffee) an d

maybe come irritable when these requests are not honoured. Rarely, patients

develop a schizophrenia-like syndrome, with prominent delusions, hallucinations, or

thought disorder in the absence of an abnormal mood.

My son Keith was a happy-go-lucky, mischievous little boy who was verygood in sports during his first few years at school. He won lots of ribbons onsports day. Then, when he entered Grade 3, he started having behavioural problems. He ran away from school a lot we still dont know why. He wasabout eight years old. I began to notice he wasnt very coordinated at times, but I just thought it was a clumsy age he was going through. La ura, Canada


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3 . 3 THE STAG ES O F HUN TING TON S DS EASE

According to Hayden MR, 1981 , though the pattern and severity of symptoms

vary from person to person, the course of HD can be roughly divided into three

stages.

Early in the disease, m anifestations incl u de s ub tle changes in

coordination, p erha p s so m e invol u ntary m ove m ents, diffic u lty thinking

thro u gh p ro b le m s, and often, a de p ressed or irrita b le m ood . At this stage,

medications are often effective in treating depression and other emotional

symptoms. It is a good time to begin planning for the future. F inancial plans should

be made and legal documents (a Living Will, for example) drawn up. HDSA chapter

social workers and family service coordinators can help to determine what is needed.

In the m iddle stage, invol u ntary m ove m ents (chorea ) may become more

pronounced. A staggering gait can sometimes be mistaken for drunkenness (it can

be helpful to carry documentation that clearly refers to a diagnosis of Huntingtons

Disease). Speech and swallowing will begin to be affected. It is important to consult

a speech-language pathologist (speech therapist) who will be able to offer

suggestions and strategies for improving communication and swallowing abilities.

Likewise, occupational and physical therapists can develop programs to help

maintain the highest level of functioning and thereby improve the quality of life.

Thinking and reasoning skills will also gradually diminish. At this stage it may

become increasingly difficult to hold a job and to carry out household responsibilities.

Here again, simple strategies may be employed to help decrease frustration,

increase functioning, and prolong independence. For example, disorientation and

short-term memory loss can be addressed by labelling drawers, maintaining a daily

routine and posting a calendar listin g appointments and events.

People with late -stage HD m ay have severe chorea , but more often have

become rigid. Choking on food becomes a major concern, as does weight loss. At

this stage people with HD are totally dependent on others for all aspects o f care, can


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no longer walk, and are not able to speak. Although cognitive abilities are severely

impaired, it is important to remember that the person is generally still aware of

his/her environment, remains able to comprehend language, and retains an

awareness of loved ones and others. He/she may continue to enjoy looking at

photographs and hearing stories of family and friends.

People do not die from HD itself but rather from a complication of the

disease, such as choking or infection. Death generally occurs about 15 to 20 years

after onset.


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3 .4 JUVENIL E HUN TING TON S DIS EASE

According to Hayden MR, 1981 , Juvenile Huntington's disease (JHD) refers

to anyone who develops signs or symptoms of HD before they are 20 years old. It is

a relatively rare condition and only about 5 -10% of people affected with HD will

develop symptoms this young. This can make it quite an isolating experience for the

person affected by HD, their family, and any professionals that are helping them .

HD in young people can present differently to HD in adults, although this is

not always the case. Children, and to a lesser extent teenagers, with HD are more

likely to show rigidity of the muscles. It is less common for them to show the chorea

(involuntary movements) that is often seen in adults with HD. Epilepsy can occur insome people with JHD, and this occurs more commonly than in adults with HD.

Ms. Knight was very helpful. On the first day of school, sheintroduced Jodie to the class, and explained to the other

children that Jodie was a little different than they were. Shedidnt walk quite as well or print her letters quite as neatly.The children responded very favorably and many becamegood friends with Jodie, helping her and playing with her at recess. Brenda, Canada


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4.0 SY MPT O MAT IC TREATMEN T

According to Rosen b latt A, 1996 , there are no c u rrently acce p ted s p ecific

treat m ents to slow the rate of clinical progression of HD. However, sy mp to m atic

m anage m ent of both movement and emotional disturbances is possible.

4.1 Treatment of Movement Abnormalities

Chorea may be a disabling symptom, leading to bruises, fractures, or falls a nd

impairing the ability of patients to feed themselves. Other patients find the chorea of

major cosmetic concern. Treatment with high -p otency ne u role p tics , such as

halo p eridol and flup henazine , maybe indicated in such cases, but with importantcaveats. These medicines may exacer b ate the dist u r b ance of vol u ntary

m ove m ent , which, as noted earlier, correlates best with functional disability.

Furthermore, neuroleptics increase m or b idity by making patients more rigid,

sedated, and apathetic.

If pharmacologic treatment for chorea is initiated, starting doses of

ne u role p tics sho u ld b elow 10m g , for example, 0.5 to 1mg of haloperidol or

fluphenazine per day. Doses higher than 10mg per day of haloperidol yield little or no b enefit over lower doses . If patients experience unacceptable rigidity, akathisia

or dystonic reactions to high-potency neuroleptics, lower -p otency agents such as

thioridazine maybe better tolerated. However,use of lower -potency neuroleptics

increases the risk of sedation, anticholinergic side effects, and p ost u ral

hy p otension .

Do p a m ine -de p leting agents such as reser p ine and tetra b enazine

represent another option in the treatment of chorea. Reserpine is a known cause of

drug-induced depression, and the affective state of patients receiving this agent

should be monitored carefully. The b enzodiaze p ine clonaze p a m may also be

useful in the treat m ent of chorea , and it may be of benefit in the later stages of the

disease, when neuroleptic medication often has little effect.


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4. 3 Treatment of Psychiatric Abnormalities

Major depression in HD responds to the same treatments used in idiopathic

depression. In general, depression in HD is under diagnosed and undert reated,perhaps because of the propensity of clinicians to see it as an understandable

reaction to having the disease. Although no controlled studies exist, our experience

is that both tricyclic antide p ressants and selective serotonin re up take inhi b itors

are effective. As with any neuropsychiatric disorder, patients should be started on

low doses that are slowly increased while the patientis closely monitored for adverse

effects, particularly delirium. It is important to remain with a medication for a full

therapeutic trial at adequate d oses and blood levels. Depressed patients should

always be questioned about thoughts of suicide. When suicide is a concern, thepatient should receive as few pills as possible, especially if they are to be kept in the

patients care.

The addition of antipsychotic (neuroleptic) medication is indicated as an

adjunct to antidepressant treatment in depressed patients with hallucinations or

delusions. Clozapine and other a typical neuroleptics may have the advantage over

traditional neuroleptic medications, such as haloperidol, of causing fewer

extrapyramidal side effects and therefore not worsening aspects of the voluntarymovement disturbance. Electroconvulsive therapy is indicated for depressed patients

who are refractory to treatment with medication, for patients with delusions, for those

who are not eating or drinking because of their depression, or for those who are at

high risk of suicide. For patients with bipolar disorder, carbamazepine, divalproex

sodium,or lithium may the initial treat ment of choice; again, it is prudent to start with

low doses that are gradually increased until symptoms respond, side effects make

further dose increases counterproductive, or therapeutic blood levels have been

reached.


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In treating irritability, it i s important to attempt to identify and to minimize

precipitants such as hunger, pain, inability to communicate, frustration with failing

capabilities, boredom, difficult interpersonal relationships, and minor unexpected

changes in routine. Pharmacologic treatment can be very effective. We have had

success using selective serotonin reuptake inhibitors and divalproex. Sexual

disorders in HD, particularly aggressive hyper sexuality, can be treated with anti

androgenic medications. Obsessive-compulsive disorder in HD can be treated with

standard anti obsessional agents, such as selective serotonin reuptake inhibitors and

clomipramine.

The doctor has prescribed a few different medications over the years. He explained that we were just trying them that nothing could take away Jodies symptoms, but we could tryto make them slightly better. Some medications were helpful in making her less stiff. One or two that we tried just zonked her out, to the point where she was really tired or unaware of her surroundings. The doctor always listened to my input. At my suggestion, we tried a lower dose, or a higher dose of certain medications, if I felt it was helping. Brenda


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5 .0 DI FFEREN TIAL DI AGNOSIS

According to Z ogh b i HY, 2000 , the clinical features of HD are often

characteristic, and the diagnosis is not diffic u lt in a p atient with a known fa m ily

history , ty p ical choreifor m m ove m ents , and cognitive dysf u nction . The

diagnosis is less clear in patients with uncharacteristic presentations or a lack of

family history. For instance, patients may present with very little chorea or with

movements that are predominantly athetoid, dystonic, or even tic like. All the

affected members of a pedigree may manifest a typical feature of the disorder, such

as prominent brain stem involvement, a finding contributing to diagnostic confusion.

Occasional patients (particularly with late onset) may have only subtle movement

abnormality and relatively little cognitive disorder. Fortunately, with the availability of

the HD gene test , it is now possible to establish the diagnosis of HD definitively

even in patients with no family history or an atypical presentation. Most patients

thought to have HD on clinical examination but who do not have the triplet repeat

expansion appear to have atypical features, more characteristic of spinocerebellar

ataxias or other multisystem atrophies.

I took Keith to the doctor several times but was told that it was all in my imagination. Finally, I asked for an appointment with a neurologist because, by then, I knew there wassomething wrong with him. Thank God my mother was withme when we learned the news. I dont know what I would have done without her support. Deep down I had known all along that he had the disease but to hear those words...it washard to take. Keith was 13 years old when he was diagnosed.

He took it really well, though. It seemed as though he knew all along. Laura, Canada


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According to Ross CA , 199 7 , HD is now recognized as part of a family of

related neurodegenerative disorders, all ca u sed b y ex p ansions of CAG re p eats

encoding gl u ta m ine . The diseases share certain clinical features, especially ataxia

and dementia, and can be confused with each other. Among these diseases,

Machado J ose p h disease and dentator ub ral p allidol u ysian atro p hy are most

like HD. Various other diseases may also present with HD like symptoms, including

Wilson disease , Cre u tzfeldt J ako b disease , forms of ceroid neuronal

lipofuscinoses, chorea with red blood cell acanthocytosis, hereditary non progressive

chorea, paroxysmal choreoa thetosis, mitochondrial disorders, co rtico basal

degeneration, basal ganglia calcification, forms of hereditary dystonia, Sydenham

chorea, vitamin E deficiency, and cerebral vascular disease.


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6 .0 SEARCHING FO R THE LIG HT

The key to better treatments and an eventual cure for HD is research. There

have been several exciting breakthroughs in recent years, notably the HD gene

discovery of 1993. Since then, certain brain proteins have been discovered which

appear to interact with huntingtin, the protein expressed by the HD gene. Research

is under way to determine how these substances combine to cause the symptoms of

HD, and to find ways of stopping this interaction as a possible means of treatment.

After the gene discovery, an international coalition of scientists, known as

the Huntington Study Group (HSG), was formed to conduct basic and clinical

research in a coordinated fashion. HSG sites combine research facilities with teams

of doctors with expertise in treating HD. The group has begun to test new drugswhich could potentially lead to effective treatments for Huntingtons disease.

In 1997, the Huntingtons disease Society of America established the HDSA

Coalition for the Cure, a consortium of 14 top laboratories in North America and

Europe. Coalition investigators focus on four key areas of study: animal models, cell

models, biochemistry and cell biology. Through HDSA funding, semi -annual

meetings and the sharing of data and ideas, the Coalition is accelerating the pace of

HD research.

The Huntington Society of Canada is a national network of volunteers and

professionals united in the fight against HD since 1973.The Huntington Society of

Canada aspires to a world free from Huntington disease. The Society maximizes th e

quality of life of people living with HD by, delivering services, enabling others to

understand the disease and, furthering research to slow and to prevent Huntington

disease


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I guess many of the feelings I experienced, and still

experience, are common to any parent who has seen the life of a child end prematurely. I wonder what each of them would have grown to be, and the experiences we missed together.When death comes, it is both the deepest of sorrows and thegreatest of releases.Rebecca, Canada

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