HUNTINGTONs DISEASE

INTRODUCTION
Huntington's disease, chorea, or disorder (HD), is a neurodegenerative genetic disorder that affects muscle coordination and leads to cognitive decline and dementia. It typically becomes noticeable in middle age. HD is the most common genetic cause of abnormal involuntary writhing movements called chorea. The disease is caused by an autosomal dominant mutation on either of an individual's two copies of a gene called Huntingtin, Physical symptoms of Huntington's disease can begin at any age from infancy to old age, but usually begin between 35 and 44 years of age. About 6% of cases start before the age of 21 years with an akinetic-rigid syndrome; they progress faster and vary slightly. The variant is classified as juvenile, akinetic-rigid or Westphal variant HD

HISTORY

 Before the 19th century, some HD sufferers may have been thought to be possessed by spirits or persecuted as witches. In 1846 Charles Gorman observed how higher prevalence seemed to occur in localized regions. Johan Christian Lund also produced an early description in 1860. The first thorough description of the disease was by George Huntington in 1872. Examining the combined medical history of several generations of a family exhibiting similar symptoms, he realized their conditions must be linked; he presented his detailed and accurate definition of the disease as his first paper. Research into the disorder continued steadily through the 20th century, reaching a major breakthrough in 1983 when the US Venezuela Huntington's Disease Collaborative Research Project discovered the approximate location of a causal gene. In 1993 the research group isolated the precise causal gene at 4p16.3, making this the first autosomal disease locus found using genetic linkage analysis.

SYMPTOMS

 The symptoms of HD may vary in range and severity, age at onset, and rate of clinical progression from patient to patientincluding among members of the same family (kindred). The peak age of adult-onset HD is between 35 to 50 years. A small percentage of patients develop symptoms before age 20; this is a juvenile variant of the disease. Evidence suggests that early onset is associated with increased severity as well as more rapid disease progression. HD is classically associated with progressive emotional, cognitive, and motor disturbances. Early, relatively subtle symptoms (prodromal phase) may precede outright disease onset by several years.

 Initial characteristic signs may include: Slight personality changes Forgetfulness Clumsiness Gradual development of random, brief, "fidgeting" movements of the fingers or toes

Complications
Lack of physical activity, dietary problems, and eating and swallowing problems can cause constipation, incontinence, and weight loss Psychiatric and cognitive problems can lead to social isolation and deep depression

Cause and Risk Factors

Having a parent with Huntington's is the risk factor. A child of an affected parent has a 50% chance of inheriting the disease The genetic mutation that occurs in gene IT-15, located on chromosome 4, alters the huntington protein, which is present in all human beings, and causes Huntington's disease. How the mutation of gene IT-15 alters the function of the protein is not well understood
10

Prognosis
The bedridden patient in the final stages of Huntington's disease often dies from complications such as heart failure or pneumonia
Juvenile Huntington's disease (16%) runs it course comparatively fast, with death typically occurring in about 10 years

11

What is Juvenile HD?

10% of Huntingtons cases. Usually 80-100 CAG repeats stiffness or rigidity in joints as opposed to chorea for adult-onset HD 1/3 of Juvenile HD patients have recurring seizures. Believed to inherit large numbers of repeats from father.

PREVELANCE

 Huntington's disease affects an estimated 3 to 7 per 100,000 people of European ancestry. The disorder appears to be less common in some other populations, including African Americans and Japanese. In the United States alone, about 30,000 people have Huntington's disease; estimates of its prevalence are about 1 in every 10,000 people. At least 150,000 others have a 50 percent risk of developing Huntington's disease, and thousands more of their relatives live with the possibility that they, too, might develop Huntington's diseas

The Genetics of Huntingtons

Huntingtons Disease is a Tri-nucleotide Repeat Disorder CAG Repeats on specific gene It is an Autosomal Dominant disease Not sex-linked HD onset is found generally in adults around the age of 40 HD is caused by a faulty gene on the 4th chromosome which is responsible for producing the protein Huntingtin

Structure of the Huntington disease gene

Short vertical bars represent exons.

Huntington disease - a triplet repeat disease

CAG CAG CAG CAG CAG CAG CAG CAG CAG CAG CAG ... CAG

11-34 CAG triplet repeats are normal: encodes a run of 11-34 glutamine amino acid residues in the protein.

A run of > 34 glutamine residues causes the protein to aggregate in the brain cells and cause progressive cell death.

Runs of >34 CAG repeats in the HD gene expand further (particularly during male meiosis) causing earlier age of onset in children of men who have the gene anticipation.

1 ttg ggg 61 gca tgc 121 cgc gga 181 cgg tgc 241 att cgg 301 ggg aag 361 tcc cag 421 cag ccg

ctg gcg gag tgg ggc cgc gtc ttt gcc ccc cgg ctg ttc cag cag ccg

tgt ggc tcc ccg ccc aag caa tac ccg gag gag atg cag cag cag ccg

gag tgg gca gcg gcc gcg gat ctg gtg gcc acc aag cag cag caa ccg

gca ttc ggc tgg tcc ccg gga cgg ctg tcc gcc gcc cag cag cag cct

gaa cct tag ccc gcc tgg cgg ccc agc ggg atg ttc cag cag ccg cct

cct ggc ggc cgc ggc ggg ccg aga ggc gac gcg gag cag cag cca cag

gcg cag tgt ctc gca ctg ctc gcc gcc tgc acc tcc cag cag ccg ctt

ggg cca caa cgc cgt ccg agg cca gcg cgt ctg ctc cag cag ccg cct

gca ttg tca cgg ctg gga ttc ttc agt gcc gaa aag cag cag ccg cag

21 CAG repeats in a normal/usual Huntington disease gene

Tri-nucleotide Repeat
CAG Repeats are found on the HD gene on Chromosome
>40 repeats you develop HD, children 50% chance of developing disease 36-39 repeats Grey Zone May develop HD, children may or may not develop HD 29-35 repeats the individual will not develop HD, children may <29 repeats, the individual will not develop HD, children will not develop HD

The Gene and its Normal Function

The HD Gene was specifically located in 1993 by researchers at MIT, on the 4th Chromosome It is responsible for producing the protein Huntingtin Researchers are not completely sure what Huntingtin does, however they do know that it is somehow very important for the normal functioning of Brain Cells

Huntingtin
Huntingtins exact function is not known but it is known that:
It serves a vital in cellular function, acting as a housekeeper Not required for immediate survival and function of the cell Is required for the survival and function of the organism as a whole

The transcripts from normal and the disease allele are both expressed in the cells and tissues of Heterozygous HD patients.

Even More Huntingtin

The mutated Huntingtin in cells follows same pattern as normal protein Produces embryos that fail during gastrulation 7.5 days before they form a nervous system

What does all this mean?

This suggests that the pattern of neuronal cell death in the striatum is due to the relatively high levels of Huntingtin expression found in medium sized neurons
But this doesnt explain why neuronal cell types in other regions of the brain that also express high levels of huntingtin are not affected by the disease

In neurons, huntingtin immunoreactivity is found in cytoplasm throughout the body, axons, dentrites, and perikarya.
Suggesting a role in trafficking or neurotransmission from Huntingtin

Types of Testing
Presymptomatic Testing: Testing for people who are genetically at risk for getting HD. Confirmatory Testing: Testing that determines whether people who are showing symptoms actually have HD. Prenatal Testing: Testing used to determine whether a fetus is at risk for HD.

Prenatal Testing
Amniocentesis involves testing a sample of amniotic fluid from the womb. Usually done when woman is between 16 and 20 weeks. Chronic Villi Sampling: performed earlier than amniocentesis between the 10th and 12th weeks of pregnancy. In CVS, a catheter or thin needle is inserted into the womb to extract some of the chorionic villi - cells from the tissue that will become the placenta. The chorionic villi contain the same chromosomes as the fetus.

Presymptomatic Testing
Usually includes sessions devoted to: genetic counseling, a neurological exam, a psychological interview, discussion of the results, and follow-up. Neurological exam is meant to determine whether the patient has any symptoms, in which case they may choose to discontinue testing procedure. Sessions are meant to ensure that the person about to undergo testing understands the implications of the knowledge of the results

There are generally two types of tests used in diagnosing Huntington's disease: genetic testing and imaging tests

Imaging Tests
The physician may also ask the individual to undergo a brainimaging test. Computed tomography (CT scan) and magnetic resonance imaging (MRI) provide excellent images of brain structures. Patients with HD often show shrinkage in two areas of the brain - the caudate nuclei and putamen - and enlargement of cavities within the brain called ventricles Positron Emission Tomography (PET) uses injected tracers like flumazenil or raclopride to test the reduction in dopamine D1 and D2 receptors in the brain regions called basal ganglia. PET is used only to support the diagnosis and research of HD, since these changes could occur in other brain diseases as well.

Genetic Testing: family-based linkage studies

In 1983, before identification of the IT15 gene, investigators characterized DNA that is closely linked to the gene and typically inherited with it as a unit (haplotype). Known as a genetic marker, this discovery enabled researchers to map the gene to the short arm (p) of chromosome 4. This led to the development and availability of testing for HD before symptom onset (presymptomatic testing). Numerous DNA markers closely linked to the HD gene have since been identified in different families (kindreds) affected by the disease. It is important to note that such testing, called DNA linkage analysis, detects the inheritance of DNA potentially linked to the gene as opposed to the presence of the mutated gene itself. Therefore, such testing is much less specific than the direct mutation analysis previously described. DNA linkage testing necessitates the analyses of blood samples from multiple unaffected and affected family members (preferably from two generations)and may have only a certain degree of accuracy (e.g., depending on the population investigated). Linkage analysis is no longer used for diagnosis of HD.

Genetic Testing: direct mutation analysis

HD is usually inherited as an autosomal dominant trait, meaning that each child of an affected parent has a 50% risk of inheriting the mutated gene for the disease. Those who do not inherit a copy of the disease gene (or have a spontaneous mutation in that gene) do not develop HD and cannot pass the disease trait on to future generations. The discovery of the IT15 gene in 1993 facilitated the development of specialized testing that may help to confirm the diagnosis of HD in patients with an affected parent or characteristic symptoms of the disease. During such testing, blood samples are taken from patients and DNA is directly analyzed for HD mutations. The DNA is studied through a series of tests known as Polymerase chain reactions or PCR testing. During this testing, the number of CAG repeats within the IT15 gene region is estimated. Additional blood samples may be obtained from close or firstdegree relatives (e.g., mother or father) with HD to help confirm the results.

Treatment
There is NO CURE for Huntington's disease Collaborative goals focus on:

- Reducing symptoms - Preventing complications - Providing support and assistance to the patient and significant others

31

Medication
Antipsychotics (hallucinations, delusions, violent outbursts): haloperidol, chlorpromazine, olanzapine (contraindicated if patient has dystonia)

Antidepressants (depression, obsessive-compulsive behavior): fluoxetine, sertraline hydrochloride, nortriptyline

Tranquilizers (anxiety, chorea): benzodiazepines, paroxetine, venlafaxin, beta-blockers Mood-stabilizers (mania, bipolar disorder): lithium, valproate, carbamazepine Botulinum toxin (dystonia, jaw clenching)
32

Nutrition
Some HC patients need a lot of time for meals because the loss of coordinated movement makes it difficult for them to swallow or feed themselves Minimize Risk of Choking
- Cut food into small pieces, softened, or pureed to make swallowing easier - Swallowing therapy can help if started before there is serious difficulty - Avoid dairy products because they tend to increase the secretion of mucus, which can increase the risk for choking

33

 Important to consume enough calories to maintain adequate body weight

- Number of daily meals may have to be increased - Vitamins and nutritional supplements recommended - If eating and dietary problems become severe, may need feeding tube

Requires large quantities of fluids (especially during hot weather to avoid dehydration)
- Bendable straws make drinking easier - Liquids may have to be thickened with additives to the consistency of syrup before drinking is possible
34

Physical Activity
Should walk as much as possible, even if assistance is necessary
Daily exercise promotes physical and mental well-being Falls are always a risk, keep surroundings free of hard, sharp objects Wearing special padding during walks helps protect against injury from falls Small weights worn around the ankles and sturdy, well-fitting shoes that slip on and off easily can improve a patient's stability

35

Social Activity
Unless and until the disease's progression prohibits it, should participate in outside activities, socialize, and pursue hobbies and interests These activities also give family members and caregivers valuable time for themselves

36

ORGANIZATIONS
Huntington's Disease Society of America Japan's Huntington's Disease Network Baltimore Huntington's Disease Center Australian Huntington's Disease Association