Jennifer K. Ocasio Biol. 3095-142

A Comprehensive Comparison of Motor and Behavioral Symptoms of Adult-Onset and Juvenile Huntington's Disease

Table of Contents

I. Abstract.......................................................................................................................1

II. Introduction.................................................................................................................2

III. Adult-Onset and Juvenile Huntington's Disease.........................................................3

A. Common Aspects.............................................................................................3

1. Shared Symptoms................................................................................3

B. Prevalent Differences......................................................................................4

1. Overview of Symptoms.......................................................................4

2. Abnormalities in Juvenile Behavioral and Motor Symptoms.............5

3. Effects..................................................................................................7

IV. Conclusion...................................................................................................................8

A. Frequency........................................................................................................8

B. Possible importance of knowledge..................................................................8

V. References..................................................................................................................9

Abstract

Huntington’s Disease, described in 1872 by George Huntington, is a neurodegenerative

disease caused by a repetition of the CAG trinucleotide on chromosome 4. The severity of the

disease depends on the amount of repetitions present in the brain and can be divided into two

major classifications: Juvenile Huntington’s Disease and Adult-Onset Huntington’s Disease.

Although they are one disease and the causes are the same, there are marked differences in the

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behavioral and motor problems. Since this is a hereditary disease, measures must be taken to

understand these manifestations and their symptoms more accurately

Introduction

Huntington's disease was first officially described in 1872 by George Huntington, an

American physician that called the illness "an heirloom from generations away back in the dim

past," (National Institute of Neurological Disorders and Stroke, 2009), for even though he

recently described it, it was a disease that had been observed since the Middle Ages. It was not,

however, named Huntington's disease at first. Instead it was given the name chorea from the

Greek word choreia meaning dance, so named because of the involuntary movements made from

patients ailing from this. The name St. Vitus' Dance was used long ago while the names

Hereditary chorea (which gave mention to the fact that it can be passed on through generations)

and Chronic progressive chorea (which described how the disease became worse over time in

patients), are more recent but are not given much usage either. Instead, Huntington's disease

remains the name most utilized by modern physicians and others.

Though Huntington's disease (HD) was described by Huntington in 1872, it was not until

1993 that the exact gene responsible for the illness was found. Once it was discovered, scientists

realized that HD is categorized by an excessive repetition of CAG (glutamine) on the short arm

of chromosome 4. The normal CAG repetition in that particular chromosome is supposed to be

less than 28. When it reaches more than 28 but less than 35, the patient technically has HD but is

unaffected. Thirty-six to 40 repetitions signify HD with symptoms that typically manifest

themselves at 40 years and more than 40 repetitions cause juvenile HD, a much more severe

manifestation. Adult-onset and juvenile Huntington's (JHD) have many differences: from the

CAG repetition typical of the disease to the symptoms presented in each.

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Common Aspects

Though Juvenile Huntington's disease and Adult-Onset Huntington's Disease are

essentially very different from each other in terms of symptoms, they are the same disease and

therefore strongly similar. The symptoms may vary between the two but they both present the

same characteristic involuntary movements associated with the disease. As demonstrated by

Squiteri (2006), adult-onset and juvenile HD usually present the following symptoms: behavioral

abnormalities, depression and psychosis, clumsiness, cognitive alteration, eye movement

abnormalities, chorea and tourettisms, dysphagia, dysarthria, memory loss, gait disturbances,

hyperreflexia, bradykinesia, rigidity, dystonia and incontinence. The grand majority of these

symptoms are significant problems affecting motor and cognitive functions that will steadily

progress and become worse as time passes.

The excessive CAG repetitions presented in the short arm of chromosome 4 cause an

excess of mutant huntingtin protein to be present in the body. This in turn negatively affects the

brain by causing neurodegeneration of the striatum (Fig. 1 and Fig. 2), which is responsible for a

wide variety of cognitive functions. This degeneration is what causes the characteristic physical

symptoms of both instances of the disease and therefore causes various behavioral problems that

will affect both young people and legal adults.

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Fig 1: On the left is a section of an HD brain demonstrating the damage to the striatum. On the right is the brain of a normal person (National Research Roster for Huntington Disease Patients & Families, 2004)

Fig 2: Neurodegeneration of the striatum caused by Huntington’s disease. There are few neurons left and reactive gliosis (neuroinflammation)

Unaffected brain with neurons and no inflammation (National Research Roster for Huntington Disease Patients & Families, 2004)

Prevalent Differences

Although there are many aspects in common between both instances of the disease, there

are still fundamental differences in the same. The symptoms presented vary wildly between the

two as do the overall exact causes. For, although they are fundamentally caused by the same

CAG repetitions and excessive mutant huntingtin protein, there are differences between the two

that cause these to appear at different ages and have different behavioral symptoms.

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CAG repetitions present in juvenile HD can span up to 150 CAG repetitions while adult-

onset can have as little as 36 repetitions. According to Aronin et al. (1995), these repetitions

have an effect on mutant huntingtin present in the disease. Using immunoblots to track the

presence of the protein in various cases of repetitions, researchers demonstrated that those cases

with larger repetitions also had increased numbers of the protein. This is supported by Squiteri

et al. (2006), who also believes that other pathological mechanisms could be responsible for the

variety between the two types of the same disease. He sustains that the CAG repetitions are not

the only factors influencing differences found for some of the instances of JHD were found in

subjects with fewer CAG repetitions than normal. However, the most common idea is that the

mutant huntingtin is what is responsible for the symptoms presented in Huntington's disease.

This is very well what could be causing the disease to present itself so early on in JHD as

compared to adult HD and cause the different aspects in behavior.

Graeme et al. (1999) demonstrated the effects that such numbers of mutated protein could

have with his experiments using yeast artificial chromosome (YAC) transgenic mice. In this

case, Graeme and his collaborators developed these mice to display the exact mutation

characteristic of Huntington's Disease. There were mice with as little as 18 repetitions, mice

with 46 repetitions and mice with 72 repetitions, plus mice that had been unaffected and were

used as control. The YAC46 mice demonstrated the usual symptoms of adult-onset

Huntington's, showing the same electrophysiological abnormalities and cytoplasmic toxicity.

YAC72 mice, on the other hand, showed these same symptoms but additionally demonstrated

selective neurodegeneration shortly afterwards. Besides this, behavioral abnormalities were

obviously present in YAC72 mice, demonstrating strange behavior such as rapid circling; most

of these changes in behavior started at five months of age and continued for the rest of their

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lives. They were also easily susceptible to confusion, unable to complete a beam-crossing test

soon after being picked up by their tails. There was also a slight increase in hyperactivity that

contributed to the abnormal circling. It was obvious that significant differences existed between

the control, YAC18, YAC46 and YAC72, with the most marked differences displayed in the

YAC72 mice. This signified that juvenile HD was much more severe and detrimental to

behavioral patterns in comparison with adult cases.

A similar experiment was carried out by Laforet et al. (2001) where 474 transgenic mice

were observed for abnormalities in both electrophysiological properties and behavior. Through

four neurological tests, it was found that there were abnormalities in gait, hyperactivity levels,

balance and clasping, such as those found by Graeme. It sustained that there was indeed a

marked difference between the behavioral patterns of mice with adult HD and JHD. The JHD

mice, which had 100 CAG repetitions, were more easily disorientated, had more frequent

circling motions, were more hyperactive, had unusual gaits, would clasp their forepaws or hind

paws when picked up by their tails and had very poor balance.

Squiteri (2006) demonstrated that the other symptoms demonstrated in JHD as opposed to

adult-onset HD are much more severe (Table 1) and demonstrates the differences in symptoms.

Due to the fact that there are more CAG repetitions, it makes sense that there is also a higher

concentration of mutant huntingtin and this in turn in causing more advanced neurodegeneration

as proved by Graeme (1999). The excessive number of this protein could cause it to not only

affect the striatum as it does so normally to also affect the cerebellum and other areas of the brain

that HD does not usually affect. This could account for the different symptoms additionally

found only in juvenile. For instance, juveniles will sometimes present autism, learning problems

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(which will in turn cause scholastic failure) and spasticity. These different behavioral problems

could cause a severe problem in young people with the disease.

Increased motor problems in JHD more severely affect the behavior of young adults who

suffer from the disease. Besides the obvious behavioral problems already found, psychological

problems such as obsessive compulsive disorder (OCD), depression and others will also affect

patient behavior. The behavior of JHD patients definitely differs from adult HD patients,

according to the tests conducted by various researchers. HD with a baseline of 46 CAG

repetitions didn't show any behavioral abnormalities until after 12 months, compared with the

JHD time of approximately 5 months. Clearly, JHD behavioral abnormalities outstrip adult HD

problems, indicating a pressing need to understand these more accurately.

Symptoms manifested from adult and juvenile HD

Additional symptoms predominantly manifested in infantile HD

Behavioural abnormalities Autism, severe behavioural changes

Depression and psychosis Seizures and myoclonic epilepsy

Clumsiness Predominant cerebellar features

Cognitive alteration Learning problems

Eye movement abnormalities EEG abnormalities

Chorea and tourettisms School failure

Dysphagia Spasticity

Dysarthria

Memory loss

Gait disturbances

Hyperreflexia

Bradykinesia

Table 1: Squiteri (2006) presents the most common symptoms representative of the disease and compares the symptoms shared by both occurrences with those found only in juvenile HD. As demonstrated, JHD patients have more severe symptoms that set them apart from the adult-onset.Conclusion

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There are roughly 4 to 8 people per 100,000 that will present with this disease, varying in

different parts of the world. Out of this number, approximately 5 to 10% are juvenile cases.

Although the number may seem low, Huntington's disease is a dominant disorder which means

that it will continue spreading. Not only this but juvenile HD is a very severe disease and causes

the people presenting it to die rather quickly due to complications of the same.

Understanding the differences between the two instances of the same disease will be

detrimental in understanding the manner with which to treat and perhaps try to find a cure for

each. The fact that juveniles present with more severe behavioral symptoms suggests that there

should be a different treatment to be able to effectively target the additional problems faced by

patients under twenty years old with Huntington's. First and foremost, however, more must be

studied and discovered about this disease before there can be many significant breakthroughs in

combating the same. Therefore, the behavioral problems caused by HD should be studied to be

able to try to combat such a disease.

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