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Huntington’s Disease-Like 2 (HDL2)

HDL2

Huntington’s Disease (HD) has become widely recognized by both physicians and patients alike, however, patients occasionally go to the doctor with HD symptoms and, surprisingly, genetic tests show that they do not have the HD gene mutation. These patients may have what recent investigations have unveiled as a new class of Huntington Disease-Like (HDL) syndromes. There are four types of HDL syndromes, termed HDL1, HDL2, HDL3 and HDL4, and, much like HD, they are extremely rare. Although HD primarily affects those of European descent, Huntington’s Disease-Like 2 (HDL2) has been found almost exclusively in people of African heritage (those who phenotypically show predominate African ancestry) or people of African descent (individuals that descend from an ancestor of African origin).

Background & History of HDL2^

In 2001, Dr. Russell Margolis’s research team at the Johns Hopkins University School of Medicine discovered HDL2, an autosomal dominant neurological disorder that clinically and pathologically resembles HD. Its symptoms usually begin in mid-life and are characterized by irregular voluntary and involuntary movements, psychiatric ailments, dementia, and an eventual progression to death (Margolis and Rudnicki, 2008). Over 25 HDL2 pedigrees have been identified thus far, all of which have definite or probable African ancestry (Greenstein et al., 2007). Like HD which is a polyglutamine (CAG) expansion disease, HDL2 involves a trinucleotide repeat expansion caused by a chromosomal mutation in which the number of CAG/CTG repeats is expanded in the JPH3 gene which encodes the junctophilin-3 protein. Junctophilin-3 is a component of complexes that facilitate communication between the cell surface and ion channels necessary to cause cells to be activated and is primarily expressed in the brain.

Repeat expansions range from 6 to 28 triplets in unaffected populations, and range from 40 to 58 triplets in the affected population. Expansions of 40 repeats or more have been shown to cause the disease (Greenstein et al., 2007). The trinucleotide mutation originates in the CTG direction of DNA, which causes corresponding malfunctions when proteins and other structures are made from the encoded information (Rodrigues et al., 2008). JPH3 is the only known gene that is associated with HDL2, therefore diagnosis requires molecular genetic testing on JPH3. Forty-one or more CTG trinucleotide repeats is considered sufficient diagnosis with HDL2. The normal full-length junctophilin-3, does not include exon 2A with the CTG/CAG repeat (Margolis, 2009). The complete involvement in JPH3 in HDL2 pathogenesis remains unknown (Santos et al., 2008). The pathology of HDL2 manifests in striatal and cortical atrophy, as well as intranuclear protein aggregates, again showing similarities to HD. Another symptom shown in some patients is acanthocytosis, or spiny protuberances on red blood cells. The mechanism for HDL2 pathogenesis has not yet been determined, but there are some outstanding hypothesis being considered, which will be discussed below (Margolis and Rudnicki, 2008).

Hypotheses for HDL2 Pathogenesis^

As mentioned above, the mechanism of HDL2 pathogenesis is currently unknown, however there are three pertinent hypotheses along these lines.

(1) Poly-Amino Acid Toxicity^

HDL2 has strong similarities to other diseases caused by abnormal polyglutamine (CAG) expansion, such as mid-life onset of symptoms, progressive neurodegeneration, disease onset threshold of about 40 triplets, length of expansion correlating to age onset and protein aggregates (Margolis and Rudnicki, 2008). Due to these similarities, researchers initially speculated that HDL2 would fall into the category of a polyglutamine disorder. However, given that the mutation is in the CTG coding region of JPH3 this speculation is doubtful. The disease would need to originate in the corresponding CAG direction which codes for glutamine in order to surely categorize HDL2 as a polyglutamine disease. Researchers indicate that it is possible that areas containing CAG-repeats could be expressed in low levels, however there is no evidence that indicates expression of a polyglutamine protein from HDL2.

Even with this notion, protein aggregates still appear, leading scientists to question why? There are two possible explanations for this mysterious result. Firstly, the test could be marking other aggregates aside from polyglutamine. Secondly, there could be a peptide containing such low levels of polyglutamine that it is below detection in the HDL2 locus. Due to this uncertainty, researchers hypothesize that polyglutamine expression at best plays a contributing role in HDL2 pathogenesis, and is unlikely in itself to fully explain HDL2 neurotoxicity. Alternatively, HDL2 neurotoxicity could arise from expression of long tracts of other amino acids such as alanine or leucine (Margolis and Rudnicki, 2008). Expansions of these amino acids are also known to be toxic in cell cultures. Furthermore, there is at least one known neurodegenerative disease caused by polyalanine.

(2) JPH3 Loss of Function^

The second possibility is that the CAG/CTG expansion mutation leads to a loss of JPH3 expression and consequently associated neuropathology due to its loss of function. At least a partial loss of expression in the JPH3 transcript and protein was detected by studying patient’s brains. However variability among the available brains makes this data difficult for researchers to interpret. Thus, the loss of JPH3 function is an unlikely explanation for HDL2 pathogenesis, however it could contribute to neurotoxicity (Margolis and Rudnicki, 2008).

(3) RNA Gain of Function and Toxicity^

In addition to HDL2, there are eleven known diseases caused by CAG/CTG expansions (Margolis et al., 2006). Eight of those diseases are thought to promote pathogenic polyglutamine expression. However, the remaining CAG/CTG diseases have myotonic dystrophy type 1 (DM1) disorder, which has a different physical appearance. DM1 is caused by a 3’ untranslated CTG repeat expansion from 60-2,000 triplets in the DMPK gene. The CTG region of DNA is transcribed to CUG repeats in RNA. The RNA transcript with the CUG expansion is thought to be toxic to cells. Interestingly, the DM1 RNA foci greatly resembles foci that have been detected in HDL2 brains. It is unclear whether RNA foci are fundamental to the disease pathogenesis, however they do serve as markers for potentially toxic transcripts. These findings have lead researchers to the hypothesis that at least a portion of the neuronal dysfunction and death in HDL2 may be derived from toxicity of the untranslated expanded CUG repeat (Margolis and Rudnicki, 2008; & Rudnicki et al., 2007).

Clinical Presentation of HDL2^

In the context of the clinical presentation of HD and HDL2, the two diseases cannot be distinguished. However, HDL2 patients tend to have more pronounced parkinsonism symptoms than in HD. Muscle weakness, lip and tongue biting and seizures are generally not part of the typical HDL2 clinical presentation (Margolis and Rudnicki, 2008).  HDL2 has generally manifests in two types of ways, resembling: 1) juvenile-onset HD (Westphal variant) or 2) typical late-onset HD. The first HDL2 type typically correlates with longer CAG/CTG repeat expansions than the second one (Greenstein et al., 2007). Type 1 accounts for more than half of the HDL2 cases outside of South Africa and the initial reported case of HDL2 developed in the manner. In the type 1 cases, disease symptoms usually appear at 29-41 years of age. Neurological abnormalities could include parkinsonism (rigidity, bradykinesia, tremor), dysarthria, and hyperreflexia. Diminished coordination and weight loss are often observed, despite an increase in food intake. Individuals are often left in a bedridden, nonverbal state with significant dementia 10 to 15 years after disease onset. Dystonia and chorea occur in the majority of individuals and dementia and psychiatric disturbances are prominent (Margolis, 2009).

The second type of HDL2, is more variable, but generally corresponds to the typical progression of HD whereby the age of onset is generally in the 40s or beyond and the disease progresses more slowly. The definition of the phenotypical presentation of HDL2 may expand as more individuals are diagnosed and identified. In this HDL2 type, chorea may be more prominent, while dystonia, bradykinesia, tremors, hyperreflexia, and dysarthria are less prominent (Margolis, 2009).

Neuroimaging^

Neuroimaging studies have consistently shown cortical and basal ganglia atrophy in individuals afflicted with HDL2. MRI images cannot be used to distinguish HD patients from HDL2 patients. The first patient family diagnosed with HDL2 showed mild frontal, temporal, mesial parietal and occipital atrophy with serve atrophy of the caudate and putamen. Conclusions from the preliminary findings lead researchers to conclude that HDL2 and HD cannot be distinguished pathologically or clinically; however the occipital lobe and potentially the substantia nigra may be affected more in HDL2 (Margolis and Rudnicki, 2008). Neuronal loss predominately occurs in the striatum and cerebral cortex (Margolis, 2009). A clearer distinction in the neuropathology of HD as compared to HDL2 and the degree of correlation will emerge as more cases are identified and analyzed (Greenstein et al., 2007).

Protein Aggregates^

Protein aggregates in HDL2 individuals have ranged from punctate to 5μm in size. The frequency of aggregates does not appear to have any correlation with neuronal degeneration. Unlike HD, aggregates have not been found outside of the nucleus. However in all cases the aggregates were round or oval in shape, which characteristically resembles HD (Margolis and Rudnicki, 2008).

Acanthocytosis^

Acanthocytosis has been identified in two unrelated families affected with HDL2. Researchers have concluded that the presence of acanthocytes in two unrelated pedigrees is unlikely coincidental. Acanthocytosis is a condition where red blood cells have many spiny cytoplasmic projections and may be caused by the JPH3 mutation, which could disrupt red blood cell membranes. Although the significance of acanthocytosis is uncertain, it appears that it may be a variable feature of HDL2 (Margolis and Rudnicki, 2008) .

Epidemiology & Association with African Ancestry^

HDL2 is very rare and thus far has been identified in about 1% of individuals with HDL disorders who tested negative for the HD mutation. There are 28 genetically documented cases of HDL2 in North America and these arise from 12 different ancestries (Margolis, et al., 2006). For geographic reference, no cases have been identified in Japan and there has been one pedigree detected in patients from Mexico. The data suggests a strong link between African ancestry and HDL2. HDL2 was first described in an African American pedigree from the southeastern region of the United States (Margolis et al., 2004). HDL2 has been found primarily in people with definite African ancestry. Even in cases where, at first, HDL2 individuals appear to have an ancestry other than African some link to Africa has later been discovered. For example, in one case in Mexico, a family identified with HDL2 originated from a region that was previously colonized by Africans, which suggests a link to African ancestry (Margolis et al., 2004). Furthermore, in a Brazilian pedigree HDL2 case where the person was presumed to be of European ancestry, a subsequent molecular analysis showed a haplotype containing an allele that has only been found in Africans. Given that JPH3 mutations may be a variable feature of HDL2, this case illustrates the importance of performing HDL2 analysis in HDL patients of ambiguous or mixed ethnic origin to account for the possibility of an indirect path to African ancestry (Rodrigues et al., 2008). The strong association with African ancestry suggests that HDL2 may have originated in Africa. In support of this, HDL2 was as common as HD in people of African descent in a South African population (Margolis and Rudnicki, 2008).

Diagnosis/Testing^

The diagnosis of HDL2 is typically suspected in individuals who present the general characteristics of HD, have a family history of an HDL disorder, but do not have the CAG repeat expansion mutation in the HD gene. To establish the diagnosis of HDL2, molecular genetic testing is required since clinical findings are not sufficient. PCR assay can determine the length of CTG trinucleotide repeats in JPH3 with an accuracy of within one to two repeats (Margolis, 2009).

Evaluations Following Initial Diagnosis^

The following evaluations are recommended by researchers to establish the extent of HDL2 once one is diagnosed. (1) Neuroimaging: this excludes other lesions or conditions which may be causing or contributing to symptoms. (2) Standardized rating instruments, such as the Unified Huntington’s Disease Rating Scale (UHDRS) or Quantitated Neurological Examination (QNE) for motor abnormalities and the Mini-Mental State Examination (MMSE) for cognition (Margolis, 2009).

Treatment and Prevention^

Like HD, there is currently no known treatment that stops or slows the progression of HDL2.

Conclusion^

While HDL2 cannot yet be clinically or pathologically distinguished from HD, it is important to recognize it as a separate disease. Although the symptoms of HDL2 and HD may converge, they are caused by two different mutations on different genes. Even though HDL2 may be exclusively present in people of African ancestry, it is important to acknowledge the possibility that anyone with a clinical presentation of HD, familial history of an HDL disorder and who tests negative for the HD mutation could potentially have HDL2. This point is especially relevant for people of mixed and/or unknown heritage. Clinical diagnosis is insufficient to make such a diagnosis given the uncanny similarity to HD, therefore genetic molecular testing is necessary to make a definitive diagnosis.

For Further Reading^

Greenstein, Penny E., et al. “Huntington’s Disease Like-2 Neuropathology.” Movement Disorder Society 22.10 (2007): 1416-423. Wiley InterScience, 21 May 2007. Web. 30 Oct. 2011.

http://ghr.nlm.nih.gov/condition/huntington-disease-like-syndrome

This quick and easy to read article describes the basis of the Huntington disease-like syndromes.

http://www.hopkinsmedicine.org/psychiatry/about/publications/newsletter/archive/06-fall/margolis_HD.html

This newsletter explains the origins of the HDL2 discovery.

Magazi, D. S., et al. “Huntington’s Disease: Genetic Heterogeneity in Black African Patients.” S Afr Med J 98 (2008): 200-03. 3 Jan. 2008. Web. 30 Oct. 2011.

Margolis, Russell L. “Huntington Disease-Like 2.” Ed. Karen Stephens. et al. GeneReviews. U of Washington, Seattle, 13 Aug. 2009. Web. 30 Oct. 2011.

Margolis, R. L., and D. D. Rudnicki. “Huntington’s Disease-Like 2.” Neuroacanthocytosis Syndromes II. Ed. Ruth H. Walker, Shinji Saiki, and Adrian Danek. Springer-Verlag Berlin Heidelberg, 2008. 59-73. 1 Jan. 2008. Web. 30 Oct. 2011. <http://www.springerlink.com/content/g8k068gu6394335p/>.

Margolis, Russell L., Dobrilla D. Rdnicki, and Susan E. Holmes. “Huntington’s Disease Like-2: Review and Update.” Acta Neurologica Taiwanica 14.1 (2005): 1-8. 19 Jan. 2005. Web. 30 Oct. 2011.

Margolis, Russell L., et al. “Huntington’s Disease-Like 2 (HDL2) in North America and Japan.” Annals of Neurology 56.5 (2004): 670-74. Wiley-Liss, 4 Oct. 2004. Web. 30 Oct. 2011.

Margolis, Russell L., et al. “Huntington’s Disease-like 2.” Genetic Instabilities and Neurological Diseases. Ed. Robert D. Wells and Tetsuo Ashizawa. 2nd ed. Amsterdam: Elsevier, 2006. 261-71.

http://www.ncbi.nlm.nih.gov/books/NBK1529/

An easy to read article that explains the different components of HDL2

Rodrigues, Guilherme G. Riccioppo, et al. “Huntington’s Disease-Like 2 in Brazil-Report of 4 Patients.” Movement Disorders 23.15 (2008): 2244-247. Wiley InterScience, 24 Sept. 2008. Web. 30 Oct. 2011.

Rudnicki, Dobrila D., et al. “Huntington’s Disease–Like 2 Is Associated with CUG Repeat-Containing RNA Foci.” Annals of Neurology 61.3 (2007): 272-82. 26 Mar. 2007. Web. 30 Oct. 2011.

Santos, C., H. et el. “Huntington Disease-like 2: the First Patient with Apparent European Ancestry.” Clinical Genetics 73.5 (2008): 480-85. 28 Jan. 2008. Web. 30 Oct. 2011.

-B. Tatum, 8/21/12

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Trinucleotide Repeat Disorders

When the cause of a disease can be traced to having too many copies of a certain nucleotide triplet in the DNA, the disease is said to be a trinucleotide repeat disorder. Today, there are 14 documented trinucleotide repeat disorders that affect human beings**. Huntington’s Disease is part of this group.

cells control nucleus refined Nis base range neuropathy

Some of these 14 trinucleotide repeat disorders are more alike than others. While the symptoms and the affected body parts vary by disease, scientists consider two illnesses to be similar if they share the same repeated codon as their cause. Six of the 14 trinucleotide repeat disorders have little or no apparent similarity to each other, or to the 8 remaining diseases. These 6 are described in brief at the end of this section. The 8 remaining disorders, one of which is Huntington’s Disease, all share the same repeated codon as their cause: CAG. Since CAG codes for an amino acid called glutamine, these 8 trinucleotide repeat disorders are collectively known as polyglutamine diseases (“poly” being the Greek word for “many”). (For background information on codons and amino acids click here.)

Polyglutamine diseases have much in common: Each of them is characterized by a progressive degeneration of nerve cells in certain parts of the body (for background info on nerve cells, click here.) In each disease, this degeneration first disrupts the function of certain group(s) of nerve cells. After 10-20 years, many of the affected nerve cells die. The major symptoms of these diseases are similar to one another and they usually affect people around the same time, in mid-life (although childhood cases have also been reported, as in the case of juvenile HD).

It deserves to be reiterated that while the polyglutamine diseases are similar to each other, they are not identical. Although they share the same repeated codon (CAG), the repeats for the different polyglutamine diseases occur on different chromosomes, and thus on entirely different segments of DNA. (For more info on chromosomes, click here.)  Despite this fact, scientists are excited about research in any of the polyglutamine diseases because finding a way to stop the CAG repeat from occurring in one disease may help lead to a cure for the other 7 as well. While this is by no means a certainty, the possibility offers wonderful incentive to be persistent in research; eight for the price of one would certainly be a great deal!

Below you will find detailed descriptions for each of the polyglutamine disease, as well as a general description of all the non-polyglutamine diseases.

**Although only 14 trinucleotide repeat disorders are well-documented in medicine, genetic analysis has led researchers to believe that others exist as well. These disorders are even less common than the well-documented disorders and so have been more difficult to study, which leaves much of their story untold. They will be omitted here.

Polyglutamine Diseases:^

DRPLA (Dentatorubropallidoluysian Atrophy)^

Like other trinucleotide repeat disorders, DRPLA (Dentatorubropallidoluysian Atrophy) affects both the mind and body. It is characterized by abrupt muscle jerking, involuntary movements, and eventual dementia. Although these symptoms are common in the men and women of all ages who have DRPLA, young people with the disease may also be affected by progressive intellectual decline.

The Gene:

The gene involved in DRPLA lies on Chromosome 12 and is also named “DRPLA”. Typically, in asymptomatic individuals there are between 6 and 35 copies of CAG in the DRPLA allele. In a person with the disease, however, the allele has anywhere between 49 and 88 copies. At present, not enough data exist to fully understand the effect that alleles with between 35 and 49 copies of CAG will have on individuals. To learn more about alleles and more specifically, HD alleles, click here.

The Protein:

The protein product of the DRPLA gene is called atrophin-1. Although scientists are not sure about its function, the leading theory is that atrophin-1 is involved in the pathway that helps insulin take effect in the body’s cells. Since insulin helps determine how cells utilize their energy, it is essential that this pathway work smoothly so that cells can function efficiently. If there is a kink in the plan, it could spell disaster for an affected nerve cell.

How the Symptoms Come About:

Fig F-1: The Striatum, Globus Pallidus, & Red Nucleus

The nerve cells affected in DRPLA lie in many different parts of the brain. Understanding the functions of these different parts allows us to get a better understanding of why the symptoms of DRPLA are what they are: Take first the striatum and the globus pallidus. Together, these very important regions of the brain are collectively known as the basal ganglia. The basal ganglia are important because they help plan movements and thus have a large effect on motor control. Working with other parts of the brain such as the red nucleus and the dentate nucleus (which are also damaged in people with DRPLA), the basal ganglia help to regulate each and every movement we make. When neurons in this area are damaged due to DRPLA, it’s no wonder that muscle jerks and involuntary movements become common. (For a more detailed description of the basal ganglia – written in regards to Huntington’s Disease – click here). (See Figure F-1.)

Fig F-2: The Cerebellum

The same can be said for damage to the cerebellum, which also occurs in people with DRPLA. The cerebellum is the region of the brain where learned movements are stored. When damage occurs here, movements that were once smooth and refined become more jerky and rough since they must be constantly relearned. (See Figure F-2.)

Fig F-3: Motor and Somatosensory Cortex

The cerebral cortex also has a large effect on movement, particularly through the parts of it called the motor cortex and somatosensory cortex. Thus, the cerebral cortex is also involved in the motor symptoms of DRPLA. However, the tasks of the cerebral cortex reach far beyond motor control. Consider the many amazing capabilities we humans have: keen senses, the ability to speak and understand language, and the fact that we can create and use such things as logic and reason. All of these characteristics stem from functions of the cerebral cortex. Thus, when damage occurs to specific parts of the cerebral cortex, the tasks that these parts work to accomplish may become less refined. This loss of refinement may explain why people with DRPLA experience dementia when the nerve cells in the cerebral cortex are damaged. It may also partly explain the general intellectual decline in juvenile cases of DRPLA. (See Figure F-3).

Huntington’s Disease (HD)^

For an introduction to HD, click here.

SBMA (Spinobulbar Muscular Atrophy)^

Fig F-4: Meaning of Proximal

SBMA (Spinobulbar Muscular Atrophy) occurs predominantly in males and is characterized by weakness and atrophy of the proximal muscles. Difficulties with swallowing and articulating speech are also common symptoms of SBMA. As the first word of its name implies, the disease mainly affects the spinal cord (“spino-“) and a part of the brain called the bulbar region (“-bulbar”). (See Figure F-4.)

The Gene:

The gene involved in SBMA is called the Androgen Receptor (AR) gene. It is located on the X chromosome, which is one of the so-called sex chromosomes. (Unlike most of our chromosomes, the sex chromosomes differ between males and females and this is why SBMA occurs predominantly in males. To learn more about chromosomes, click here.) Typically, in asymptomatic individuals there are between 9 and 36 copies of CAG in the AR allele. In a person with the disease, however, the allele has anywhere between 38 and 62 copies. At present, not enough data exist to fully understand the effect that alleles with 37 copies of CAG will have on individuals.

The Protein:

Hearing the oft-repeated statement “DNA codes for proteins” might lead one to believe that it is as simple as show me DNA and poof!, you have a protein. Actually, the process is much more complex than that. In fact, the full sequence of events is broken up into several parts, one of which is called transcription. The Androgen Receptor gene codes for a protein of the same name, the Androgen Receptor (also abbreviated “AR”). Because the AR protein is a key player in transcription, it is aptly titled a transcription factor.

In its normal state, then, the AR protein helps cells carry out the instructions contained within DNA. (For more in-depth discussion of DNA and the genetic code, click here.) However, in people with SBMA, the protein has extra glutamines, resulting from the extra CAGs in the AR gene. Although scientists do not yet have a definitive explanation as to why the extra glutamines cause degeneration of the neuron, it seems likely that the extra glutamines create an altered form of the AR protein that does not perform its actions in the same way as the normal AR. This mechanism for degeneration of the neuron is much like the one for Huntington’s Disease, as illustrated in Figure A-3.

Fig F-5: Neural Inclusions (NIs)

Another theory suggests that the degeneration of the nerve cell is a result of neuronal inclusions (NIs). This theory, too, has its equivalent in the study of Huntington’s Disease. (Click here for more about nerve cell death in HD). According to the theory, the extra glutamines in the protein have a way of attracting other proteins to group together with the AR. This aggregation of proteins causes clumps, or inclusions, which may be solely responsible for damage to the nerve cell. More research in this area is necessary to find out definitively if the NIs are the true cause of damage. (See Figure F-5.)

How the Symptoms Come About:

Fig F-6: Dorsal Root Ganglion & Anterior Horn

Whatever the mechanism, once the nerve cells become damaged, the symptoms of SBMA begin to appear. As mentioned above, one of the main areas of the body that SBMA affects is the spinal cord. More precisely, it affects the parts of the cord known as the anterior horn and the dorsal root ganglion. The dorsal root ganglion is a group of nerve cell bodies that pass sensory information to other spinal cord nerve cells and on to the brain for analysis. The anterior horn is a region of the spinal cord that contains cell bodies of motor neurons, which put the brain’s decisions (based on the sensory info) into action. These two regions of the spinal cord are thus essential for control of fine muscle movements. When the dorsal root ganglion is damaged, the brain cannot receive proper input and thus cannot plan a movement of the muscle. When the anterior horn is damaged, the brain’s planned movement cannot be carried out. Thus, if either of these regions is not functioning correctly, then the muscles are not able to carry out the same motions that they had always done before. This inability to perform normal motions is why muscle weakness and atrophy are so common in SBMA. (See Figure F-6.)

Fig F-7: The Bulbar Region of the Brain

But the spinal cord is not the only body part affected by SBMA; the bulbar region of the brain is harmed as well. The bulbar region is composed of the cerebellum, the medulla and the pons. (For a tour of brain structures, including these three, click here.) An extension of the spinal cord at the base of the brain, the medulla and pons are responsible for some of the functions that keep us alive. Functions that we usually never think about, like breathing, blood circulation, and simple actions like swallowing are all in large part controlled by the medulla and pons. More complex functions, however, require use of the cerebellum. The cerebellum is where our learned movements are stored—it helps refine a great deal of motor activities, from throwing a baseball to speaking. Given the roles of the medulla, pons, and cerebellum, it’s no wonder why damage to these areas can cause difficulty swallowing and articulating speech, two more symptoms of SBMA. (See Figure F-7.)

SCA1 (Spinocerebellar Ataxia Type 1)^

SCA1 (Spinocerebellar Ataxia Type 1) is one of many closely related disorders collectively known as spinocerebellar ataxias (SCAs). Like all of the SCAs, SCA1 is characterized by atrophy of the cerebellum, a phenomenon that plays a role in the major symptoms of the disorder like loss of coordination and difficulty in articulating speech. Another common symptom of the disorder is decreased sensation in the limbs.

The Gene:

The gene involved in SCA1 lies on Chromosome 6 and is also called SCA1. Typically, in asymptomatic individuals there are between 6 and 44 copies of CAG in the SCA1 allele. In alleles with more than 20 copies (but still less than 44), the codon CAT interrupts the string of CAGs 1-4 times in a way that adds stability to the CAG chain. In a person with the disease, however, these stabilizing CATs are not present and the allele has anywhere between 39 and 81 copies of CAG. Thus, especially in the 39-44 CAG repeat range (where one may or may not be at risk for the disease), the CATs are very important—their existence can make the difference between having the illness and not.

The Protein:

The protein product of the SCA1 gene is called ataxin-1. Many studies of ataxin-1 have led scientists to believe that its major function may be to facilitate the maneuvering of nerve cell connections to allow learning. However, it is important to note that the symptoms of SCA1 are not directly caused by the loss of normal ataxin-1 function. Instead, it is believed that the cause of disease lies in the interaction between ataxin-1 and another protein called LANP. Scientists believe that LANP has a major effect on cell communication, which is needed for the survival of a nerve cell. When the ataxin-1 is altered, its interaction with LANP is also altered. The ataxin-1 is said to “sequester” the LANP and thus interfere with its normal activity. After a time, the sequestering of LANP appears to cause degeneration of the nerve cell.

How the Symptoms Come About:

To best explain how the symptoms of SCA1 come about, it is helpful to have an understanding of the cerebellum. (For more on the cerebellum, click here.)

Add to the equation a loss of pyramidal nerve cells (cells of a different pathway that are also involved in performing highly-skilled motions) and one can see why SCA1 can have such a large effect on one’s ability to perform movements.

The decreased sensation in the limbs of people with SCA1 is known as peripheral neuropathy. This condition comes about when the nerve cells that pass information from the limbs to the spinal cord (and on up to the brain) are damaged. Since they cannot do their jobs to maximum effectiveness, some of the sensory information is lost and this results in the decreased sensation.

SCA2 (Spinocerebellar Ataxia Type 2)^

SCA2 (Spinocerebellar Ataxia Type 2) is characterized by a general slowing of some of the body’s normal processes. In addition to the loss of coordination that is common to all SCAs, people with SCA2 often develop slow or nonexistent reflexes and tend to shift the focus of their eyes from one point to another in a very deliberate manner. Partial paralysis of the eyes has even been described in some cases.

The Gene:

The gene involved in SCA2 lies on Chromosome 12 and is also named SCA2. Typically, in asymptomatic individuals there are between 14 and 31 copies of CAG in the SCA2 allele. In a person with the disease, however, the allele has anywhere between 36 and 64 copies. Individuals with between 31 and 36 copies of CAG may or may not develop the symptoms of the disease (individual results vary).

The Protein:

Fig F-9: Function of Ataxin-2

The protein product of SCA2 is called ataxin-2. So far, although the exact function of this protein is unknown, scientists believe that it may be involved in aiding protein-protein interaction within the cell. This would make it something of a “mediator” of communications within the cell. If this theory is correct, then when the protein is in its altered form in people with SCA2, it cannot do the same mediation that the normal form does. This loss of normal function means that essential protein-protein interactions cannot be as efficient as they were with the normal ataxin-2 involved. The end result is that the health of the cell is compromised. (See Figure F-9.)

How the Symptoms Come About:

Fig F-10: Midbrain & Cerebellum

The mechanism for the loss of coordination experienced in SCA2, due primarily to damage to the cerebellum, is more-or-less the same as the mechanism described for SCA1. (Read more about the cerebellum by clicking here.) The symptoms involving the eyes, however, result from SCA2’s effect on a different part of the brain. This region is called the midbrain. The primary function of the midbrain is to control the movement of the eyes. When neurons in this area are damaged, the eye’s movements become slower than normal and even partial eye paralysis can occur. Both of these phenomena are symptoms of SCA2. (See Figure F-10.)

Fig F-11: Granule Cells

The effect of SCA2 on the reflexes is explained by the damage it inflicts on the granule cells. A granule cell is a specific type of nerve cell that forwards a great deal of information on to the cerebellum. Much of this information involves the positions and movements of the limbs, as well as what parts of the skin are being stimulated at any given time. In terms of reflexes, all of this information is very important. As an example, suppose that someone is burned by a hot plate: The person must know not only what body part this sensation is coming from, but also where this part is located in space and what direction to move it in order to stop the pain. If this information is slow in getting to the brain, it can delay the reflex that is needed to deal with the pain. This slower flow of information occurs when the granule cells are damaged, causing people with SCA2 to develop slower reflexes. (See Figure F-11.)

SCA3 (Spinocerebellar Ataxia Type 3 or Machado-Joseph Disease)^

SCA3 (Spinocerebellar Ataxia Type 3) is also known as Machado-Joseph Disease. In addition to the loss of coordination that is common to all SCAs, the most common symptoms of SCA3 include bulging eyes, small contractions of the facial muscles, and general rigidity.

The Gene:

The gene involved in SCA3 lies on Chromosome 14 and is also named SCA3 (although the name “MJD1″ is sometimes used instead). Typically, in asymptomatic individuals there are between 12 and 43 copies of CAG in the SCA3 allele. In a person with the disease, however, the allele has anywhere between 56 and 86 copies. At present, not enough data exist to fully understand the effect that alleles with between 43 and 55 copies of CAG will have on individuals.

The Protein:

Fig F-12: Location of Ataxin-3

The protein product of SCA3 is called ataxin-3. Although scientists do not know the exact function of the protein, they do know that it normally resides in the cytoplasm of the cell. In people who have SCA3, however, ataxin-3 is known to aggregate in the nucleus. Researchers suspect that this change of place may be key in understanding the initiation of the disease. (See Figure F-12.)

How the Symptoms Come About:

Of all the polyglutamine disorders, SCA3 is perhaps the most perplexing with regard to the relationship between the affected brain regions and the symptoms of the disease. Damage commonly occurs in the cerebellum, basal ganglia, brain stem, and spinal cord. While damage to these areas commonly affects a wide range of movements, it does not seem to explain why such things as bulging eyes and general rigidity would occur. Hopefully, more research in this area will soon uncover the mystery.

SCA6 (Spinocerebellar Ataxia Type 6)^

SCA6 (Spinocerebellar Ataxia Type 6) is probably the simplest of all the SCAs in terms of its symptoms: People with SCA6 predominantly experience random episodes of ataxia or slowly progressing ataxia.

The Gene:

The gene involved in SCA6 lies on Chromosome 19 and is also named SCA6. Typically, in asymptomatic individuals there are between 4 and 18 copies of CAG in the SCA6 allele. In a person with the disease, however, the allele has anywhere between 21 and 33 copies. This is the smallest number of trinucleotide repeats known to cause disease. At present, not enough data exist to fully understand the effect that alleles with 19 copies of CAG will have on individuals. Individuals with 20 copies of CAG may or may not be at risk of developing SCA6. To learn more about alleles and more specifically, HD alleles, click here.

The Protein:

Fig F-13: Alpha-1 Subunit

Instead of its own separate protein product, the SCA6 gene codes for a subunit of the calcium channels that exist in all nerve cells. This subunit, called Alpha-1A, creates a pore in the membrane of the nerve cell, allowing calcium to enter the cell and have an excitatory effect. The excited cell can then process the inputs it has received (due to calcium’s effect) and decide whether or not it should relay this information on to other nerve cells. In this way, Alpha-1A appears to play a significant role in nerve cell communication. (For more information about how nerve cells communicate, click here). In their altered form, however, Alpha-1A subunits tend to leave the membrane and aggregate in the cytoplasm inside the cell, where they clump together and do not perform their normal duties. This movement from the membrane hinders the nerve cell’s ability to receive and process messages from other nerve cells. Since communication is essential to the survival of nerve cells, the clumping of the altered Alpha-1A subunits in the cytoplasm may play a significant role in nerve cell degeneration. (See Figure F-13.)

How the Symptoms Come About:

Fig F-14: Cerebellar Information Pathways

In SCA6, the areas most affected by nerve cell damage are the cerebellum and the Purkinje cells. Given their roles in refining motions (as mentioned in the discussion of the cerebellum), one can see how damage to these areas esults in loss of coordination. Also contributing to the symptoms is degeneration of the granule cells and the nerve cells of the inferior olive. Since these structures are involved in the input of information to the cerebellum – and likewise the Purkinje cells are involved in its output – we can see that both input and output are quite important in creating smooth, precise motions. At any given time, some nerve cells may be less affected by SCA6 than others, and this may account for the random episodes of ataxia: one group of cells may be affected one day, and another group a different day. (See Figure F-14.)

SCA7 (Spinocerebellar Ataxia Type 7)^

SCA7 (Spinocerebellar Ataxia Type 7) is the last of the SCAs to fall under the category of polyglutamine diseases. Like the other SCAs, the most common symptom of SCA7 is loss of coordination. In addition to this, people with SCA7 often have difficulties with vision.

The Gene:

The gene involved in SCA7 lies on Chromosome 3 and is also named SCA7. Typically, in asymptomatic individuals there are between 4 and 19 copies of CAG in the SCA7 allele. In a person with the disease, however, the allele has anywhere between 37 and 306 copies. At present, not enough data exist to fully understand the effect that alleles with between 19 and 29 copies of CAG will have on individuals. Individuals with 30-36 copies of CAG are considered to be in the intermediate zone; they may or may not develop the symptoms of SCA7. If they do develop symptoms, the symptoms are likely to be milder and to appear later in life than they would for people with 37 or more copies of CAG.

The Protein:

Fig F-5: Neuronal Inclusions (NIs)

The protein product of the SCA7 gene is called ataxin-7. Currently, the normal function of this protein is unknown. Scientists suspect that when ataxin-7 proteins are altered, they tend to clump together in the nucleus, producing what are called neuronal inclusions, or NIs (NIs have also been found in certain nerve cells of people with SBMA, HD, and some other SCAs). These inclusions have been associated with degeneration of the nerve cell, but whether or not they are in fact the direct cause of degeneration is yet to be determined. (See Figure F-5.)

How the Symptoms Come About:

The loss of coordination that people with SCA7 experience results from damage to the cerebellum. This mechanism is more-or-less the same as that of SCA1. (For a more detailed explanation of this mechanism, click here.)

Fig F-15: Visual Pathway

The effect that SCA7 has on one’s vision is a little more complicated because vision is a process that involves many players. Contrary to popular belief, humans do not literally “see” with their eyes. Instead, the eyes are simply the first stop on a pathway for visual information that will eventually lead to the processing of this information in the brain. After light from an image comes into the eye, the information it contains is encoded into nerve impulses by the retina. (For a discussion of nerve impulses, click here.) These impulses are then sent down the optic tract to a part of the brain called the lateral geniculate body. Here the information undergoes something like a preliminary inspection, which involves a categorization of the data. The newly categorized info is then sent on to the visual cortex, which is part of the cerebral cortex of the brain. It is in the cerebral cortex where the brain assembles a processed image and we actually “see” what is in front of us. To see an image clearly and accurately, then, all pieces in this visual puzzle must be in good working order. In SCA7, however, there is noticeable damage to all parts of the visual pathway. While this by no means implies that people with SCA7 go blind, some problems with vision are likely to occur. (See Figure F-15.)

Non-Polyglutamine Diseases^

As noted in the introduction to this chapter, polyglutamine diseases are only a subset of the trinucleotide repeat disorders. As of this writing (summer 2001), researchers have identified six non-polyglutamine diseases that also fall under the category of trinucleotide repeat disorders. Because each disease involves a unique repeated codon, the six non-polyglutamine diseases show relatively little resemblance to one another. More importantly, none of them appear to have any strong similarity to Huntington’s Disease or the other polyglutamine diseases. For this reason, we provide only brief descriptions of these non-polyglutamine disorders. The descriptions follow below.

Fragile X Syndrome^

Fragile X Syndrome (often abbreviated “FRAXA”) is a disorder involving the CGG codon (contrast this with the CAG codon involved in the polyglutamine diseases). The affected gene is called FMR1 and it lies on the X chromosome (hence the name “Fragile X Syndrome”). In asymptomatic individuals, the FMR1 allele has between 6 and 53 CGG repeats. In people with the disorder, the FMR1 allele has over 230 repeats. At present, not enough data exist to fully understand the effect that alleles with between 53 and 230 copies of CGG will have on individuals. Common symptoms of FRAXA include mental retardation, long and prominent ears and jaws, stereotypic hand movements (like flapping and biting one’s hands), hyperactivity, and others. The disease typically affects males.

Fragile XE Mental Retardation^

Fragile XE Mental Retardation (often abbreviated “FRAXE”) is a disorder involving the GCC codon. The affected gene is called FMR2 and, like the gene causing Fragile X Syndrome, FMR2 lies on the X chromosome. In asymptomatic individuals, the FMR2 allele has between 6 and 35 copies of GCC. In people with the disorder, however, the allele has over 200 copies of GCC. At present, not enough data exist to fully understand the effect that alleles with between 35 and 200 copies of GCC will have on individuals. Common symptoms of FRAXE include mild mental retardation, learning deficits, and possible developmental delays.

Friedreich’s Ataxia^

Friedreich’s Ataxia (often abbreviated “FRDA”) is a disorder involving the GAA codon. The affected gene is called X25 (also known as “frataxin”). In asymptomatic individuals, the frataxin allele has between 7 and 34 GAA repeats. In people with the disorder, the allele has 100 or more repeats. At present, not enough data exist to fully understand the effect that alleles with between 34 and 100 copies of GAA will have on individuals. There are many common symptoms of FRDA, some of which include slurred speech, heart disease, and diminished reflexes of the tendons. The name “ataxia” describes a loss of coordination, and this is typical in the limbs and trunk of those who have FRDA. The typical age of onset for this disorder is early childhood.

Myotonic Dystrophy^

Myotonic Dystrophy (often abbreviated “DM”, not “MD”) is a disorder involving the CTG codon. The affected gene is called DMPK. In asymptomatic individuals, the DMPK allele has between 5 and 37 CTG repeats. In people with the disorder, the allele has at least 50 repeats in adult-onset cases, and can go up to several thousand in congenital cases. At present, not enough data exist to fully understand the effect that alleles with between 37 and 50 copies of CTG will have on individuals. Common symptoms of adult-onset DM include muscle weakness and degeneration, while such symptoms as kidney failure, facial dysmorphology, heart problems, premature balding, cataracts, and, in males, atrophy of the testicles are less common. The congenital form of DM is the most severe and its symptoms include diminished muscle tone, problems with respiration at birth, and developmental abnormalities. The term “myotonic” comes from “myotonia”—a condition characterized by frequent muscle spasms. Obviously, myotonia is quite common in DM.

Spinocerebellar Ataxia Type 8^

Like Myotonic Dystrophy, SCA8 (Spinocerebellar Ataxia Type 8) is a disorder involving the CTG codon. The affected gene is also called SCA8. Asymptomatic individuals possess between 16 and 37 repeats of CTG in the SCA8 allele, while people with the disorder have between 110 and 250 repeats. At present, not enough data exist to fully understand the effect that alleles with between 37 and 110 copies of CTG will have on individuals. SCA8 is a slowly progressive disorder and its symptoms include decreased sense of vibration, sharp reflexes, and atrophy of the cerebellum, which has a large amount of control over the body’s learned movements. (For a more detailed description of the cerebellum, click here.)

Spinocerebellar Ataxia Type 12^

Much like the polyglutamine diseases discussed above, SCA12 (Spinocerebellar Ataxia Type 12) is a disorder involving the CAG codon. But unlike the polyglutamine diseases, which have CAG repeats that occur in what is known as the “translated region” of DNA, the CAG repeats in SCA12 occur in what is called an “untranslated region” of DNA. In what basically amounts to an exception to the normal rule, the chemical information of an untranslated region of DNA is not used as instructions for making proteins. None of the codons in the untranslated region of DNA produce any amino acids at all (a realization that has prompted some scientists to refer to the untranslated region as “junk DNA”). This exception means that the CAG codons of SCA12 actually do not produce the amino acid called glutamine. Because of this fact, SCA12 is not considered a polyglutamine disorder.

The affected gene in SCA12 is also called SCA12. Asymptomatic individuals possess between 7 and 28 repeats of CAG in the SCA12 allele, while people with the disorder have between 66 and 78 repeats. At present, not enough data exist to fully understand the effect that alleles with between 28 and 66 copies of CAG will have on individuals. SCA12 is the most recent addition to the group of spinocerebellar ataxias. Since there are relatively few cases to date, the full effects of the disorder are not yet fully known. Given that it is a spinocerebellar ataxia, however, it is likely that some of the general symptoms include slurred speech and loss of coordination of some parts of the body.

For further reading^

  1. Cummings, C. J. and Zoghbi, H.Y. “Trinucleotide Repeats: Mechanisms and Pathophysiology.” Annu. Rev. Genomics Hum. Genet. 2000. 1:281-328.
    A fairly technical paper explaining the symptoms of each trinucleotide repeat disorder, as well as a breakdown of the codon involved and the amount of repeats in people with and without the disease (as of the publishing, however, updated and slightly different data regarding the numbers are available; see next entry in bibliography). Also discussed are theories regarding the function of the altered proteins.
  2. GeneClinics. Online.
    An in-depth site with very recent information about all of the SCAs (and DRPLA). A wonderful resource to find out more about each disorder. (Look up the any of the SCA’s by using the search feature.)
  3. Online Mendelian Inheritance in Man (OMIM). Online.
    A compilation of abstracts from a multitude of different studies on HD. From case studies regarding inheritance to new methods of diagnosing HD, this is an excellent site for all the various types of HD research going on today. (Look up any of the trinucleotide repeat disorders using the search feature.)
  4. Silverthorn, Dee Unglaub. “Human Physiology.” Upper Saddle River, NJ: Prentice Hall, 2001. pp. 256-263, 396.
    Written for college students, this textbook has excellent explanations of all aspects of human physiology, as well as wonderful pictures to increase one’s understanding. The pages noted are excellent in teaching the functions of various parts of the nervous system.
  5. Thompson, Richard F. “The Brain.” New York: Worth Publishers, 2000. pp. 11-16, 296-303, 308-309, 451.
    An introduction to neuroscience. Very clearly explains the functions of the various parts of the nervous system. Also gives insight into current research going on in neuroscience.

-M. Stenerson, 9-25-01

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Huntington's Disease Comparisons

The following chapter aims to compare Huntington’s disease to other neurological diseases such as Alzheimer’s disease and Parkinson’s disease.

Risk Factors^

HD is caused by a mutation in the Huntington gene, which lies on chromosome 4. A certain sequence of DNA (C-A-G) of the Huntington gene is repeated multiple times. Generally, if a person has 35 or fewer copies of CAG on a particular segment of the Huntington gene, the person will not get HD. However, if he or she has 40 or more copies, he or she will get the disease. The greater the number of repeats, the more likely it is that the person will develop symptoms and the greater the chance that these symptoms will occur at a younger age. Every child of a parent with HD has a 50% chance of inheriting the disease, and the disease may occur earlier and more severely in each succeeding affected generation because the number of repeats canincrease. For more info on inheritance, click here.

gene altered neurons base ganglia control nucleus

Like Huntington’s disease, family genetics present a significant risk factor for inheriting Alzheimer’s disease. A study performed by Erasmus University Medical School in The Netherlands found that the risk of developing Alzheimer’s disease for those with at least one affected immediate relative was 3.5 times greater than those with no affected relatives. The study also showed a significant association between Alzheimer’s disease and family history of Down’s Syndrome, as well as an increased risk in with a family history of Parkinson’s disease. Perhaps the most significant risk factor of Alzheimer’s disease is age. Although there is variability in the age ofHD symptom onset, the incidence of Alzheimer’s increases with age, doubling every five years from 1% at 60 years to as many as 50% for those over 85 years of age. This is because normal aging is associated with altered protein metabolism, a process that often leads to the degradation of brain cells and the formation of abnormal clumps of protein in the brain over time. Other risk factors for Alzheimer’s disease include Down’s syndrome, untreated chronic hypertension, high cholesterol, and sustained head injuries.

Age is also the main risk factor for developing Parkinson’s disease. A subtype of Parkinson’s disease called young-onset Parkinson’s disease affects those younger than 40; however, most of those affected do not experience symptoms until after age 55. Although controversial, researchers now think genetics may play a rolein the development of the disease. The recent discovery of an abnormal protein called a-synuclein in an Italian family with many Parkinson’ssufferers has contributed to the understanding of Parkinson’s disease. As of early 2002, there were nine genetic abnormalities that had beenassociated with Parkinson’s disease. New studies show that having one close relative with Parkinson’s may increase the chances of developing Parkinson’s three or four-fold, and having two or more relatives may increase the chances ten-fold. However, most often a definite family history is not present for most patients. In these sporadic cases, agenetic predisposition may still play a role by increasing the chance of getting the disease when patients are exposed to possible environmental risk factors such as certain pesticides and herbicides. Other risk factors that may contribute to Parkinson’s disease include reduced estrogen levels and low folate levels (see section onnutrition).

Neurobiology: Neuromotor Comparisons^

As addressed in the HD Neurobiology chapter, the part of the brain most affected by HD is a group of nerve cells (neurons) at the base of the brain known collectively as the basal ganglia. The basal ganglia is responsible for the muscle-driven, motor movements of the body. As the cells in this area die, a person with HD experiences uncontrollable muscular movements likened to fidgetiness or nervous restlessness.

Similarly, Parkinson’s disease patients experience uncontrollable movements due to the disease’s effects on a specific area of the basal ganglia called the substantia nigra. The substantia nigra produces a chemical called dopamine, which is a neurotransmitter. Neurotransmitters are special chemicals that help neurons communicatewith each other. Dopamine and another neurotransmitter, acetycholine help to control our movements. In Parkinson’s disease, the neurons inthe substantia nigra gradually die off, which causes less dopamine to be made. With less dopamine than normal, there is an imbalance between dopamine and acetylcholine (see figure). This imbalance causes the nerve cells to fire out of control, leaving patients unable to direct their movement in a normal manner.

In Alzheimer’s disease, neurons in the brain and the spaces between them become clogged with protein deposits called beta amyloid plaques and neurofibrillary tangles. Even in people who don’t have AD, plaques and tanglesdevelop as part of the normal aging process. However, in people with Alzheimer’s disease, there are many more plaques and tangles. Plaques are dense, mostly insoluble (cannot be dissolved) deposits of protein and cellular material outside and around the neurons. Tangles are insoluble twisted fibers that build up inside the nerve cell. When neurons are clogged with tangles, and the spaces between neurons are clogged with plaques, the transmission of nerve impulses from one neuron to the next does not happen properly. As a result, the brain cannot perform mental functions such as remembering and thinking. There are other senile dementias (like Multi-infarct Dementia) that present like Alzheimer’s disease but have very different causes and are not comparable to HD. Though they many share certain neurobiological properties, these are distinctive conditions.

Though Huntington’s, Parkinson’s, and Alzheimer’s disease are caused by unique cellular processes, all three diseases are facilitated by the inability of neurons to communicate with each other. Gradual neuron death in people with HD hinders the ability of neurons to communicate. For people with PD, neurons die, causing an imbalance of dopamine and acetylcholine and the uncontrolled firing of nerve cells. Finally, in people with AD, plaques and tangles inhibit neurons’ ability to communicate.

Neurobiology: Emotional/Cognitive Comparisons^

Disclaimer: Despite many similarities, these cognitive and emotional signs present at different stages of the disease in different people. A person with HD may very well maintain healthy cognitive functioning throughout the remainder of his/her life.

The symptoms of Huntington’s disease are both behavioral and cognitive. Symptoms are the direct result of neurological changes in the brain. Apathy is one of the most common behavioral symptoms of HD due the death of nerve cells controlling “emotions” in the brain. Deterioration of a certain area of the brain called the caudate nucleus causes HD sufferers to be unable to control intensities of emotion, and makes them more likely to experience frustration, irritability, and aggression. For more on behavioral symptoms associated with HD go here.

In addition to behavior symptoms associated with HD, many cognitive changes also arise with the onset of Huntington’s disease due to neuronal damage. A patient’s ability to initiate a conversation and to communicate is altered due to degeneration in the brain. Furthermore, an individual suffering from the cognitive symptoms of HD may have memory, problem solving, and judgment difficulties. Tasks that were once simple are difficult for an HD patient to perform efficiently. An HD patient also experiences difficulty with visual spatial impairment, awareness, and organization. For more on the cognitive symptoms associated with HD, go here.

Similarly, patients of Alzheimer’s disease may experience both behavioral and cognitive changes at different stages of their disease process, many which are similar to HD. Difficulty with the acquisition of new information is generally the most salient symptom to emerge in patients with AD. Whereas learning new information for HD patients is disorganized and slow, Alzheimer’s patients experience rapid forgetfulness and an inability to store information. Several studies have demonstrated that people with AD lose more information over a brief delay than other patients with disorders that involve amnesia or dementia. Though at first their symptoms may be mild, people in the later stages of AD may forget how to perform simple tasks, like brushing their teeth or combing their hair. They neglect to bathe, or wear the same clothes over and over again while insisting that they have taken a bath or that their clothes are still clean. They can become lost on their own street, forget where they are and how they got there, and not know how to get back home. Eventually, patients need total care because they are unable to think clearly and perform tasks for daily living.

Another similarity to HD is that Alzheimer’s patients lose their initiative to perform normal activities or to engage in activities they used to enjoy. They often become very passive, sitting in front of the television for hours and sleeping more than usual. Furthermore, Alzheimer’s patients can experience rapid mood swings for no apparent reason, and their personality can vary from becoming extremely confused and suspicious to being fearful or dependent on a family member. They also may see, hear, smell, or taste things that are not there. Finally, like those with HD, Alzheimer’s patients sometimes exhibit poor judgment, which creates safety issues when left alone. They may wander and risk exposure, accidental poisoning, falls, self-neglect, or exploitation.

For patients with Parkinson’s disease, the most prominent symptom is tremor. Tremor often starts in one extremity and worsens with precipitating factors such as stress, fatigue, and cold weather. The tremor associated with PD occurs predominantly at rest, and results in the slowness of a patient’s movement (also known as Bradykinesia) A delay in initiating movements develops due to the brain’s inability to transmit necessary instructions to the body at a normal rate. Parkinson’s patients often report difficulties in performing activities of daily life, such as dressing, walking, and doing household chores. Symptoms that appear later in the progression of the disease include poor balance and the inability to swallow. Upon walking, a Parkinson sufferer has a decreased or non-existent arm swing, short shuffling, and difficulty negotiating turns. Another major symptom is rigidity, characterized by increased tone and stiffness in the muscles; rigidity is responsible for a Parkinson patient’s sometimes mask-like facial expressions and stooped posture.

As with HD and AD, depression is commonly seen in the early stages of Parkinson’s disease. It is estimated that about half of people with Parkinson’s may suffer from depression. This is thought to be not only a reaction to the diagnosis, but rather an intrinsic part of the disease process. Also, as with HD, Parkinson’s disease causes anxiety and can cause panic attacks. Symptoms of anxiety include breathlessness, sweating, chest discomfort, choking, and dizziness. In severe cases, patients may have feelings such as the fear of dying or the fear of going insane. Also, about 15-25% of individuals with Parkinson’s disease will suffer from memory and cognitive deficits similar to those of Huntington’s disease patients. Mild cognitive deficits are common in Parkinson’s and are characterized by a lack of flexibility in thought, difficulty in learning new information, and impaired visual-spatial skills. Short-term memory deficits are common and may progress to more severe memory deficits. Language skills are relatively spared although some studies have found a mild impairment in naming. Higher executive function (abstract thinking, planning abilities, judgment, and initiative) is often affected in patients with Parkinson’s disease as well.

Treatments^

Currently there exists no cure for any three of the neurological diseases. As with Huntington’s Disease, treatments for Alzheimer and Parkinson’s can be split into two distinct categories: treatments that target the specific mechanism of the disease, and palliative treatments (eg those that lessen symptoms but do not cure). For HD, mechanisms which are targeted include protein aggregation, inflammation, and free radical damage (See treatments section).

As of this writing (Jan 04), there are five FDA-approved drugs that can control symptoms and slow the progression of Alzheimer’s disease. Four of these drugs, Cognex, Aricept, Exelon, and Reminyl belong to a class of drugs known as cholinesterase inhibitors. Each drug acts in a different way to slow the metabolic breakdown of acetylcholine, an important brain chemical involved in nerve cell communication, and to make more available for communication between cells. Those suffering from AD have low levels of acetylcholine, and the medication helps to slow the progression of cognitive impairment and is most effective for patients in the early to middle stages of AD. The fifth drug, Namenda (memantine), is the first drug approved for the treatment of moderate to severe AD. Namenda shields brain cells from overexposure to another brain chemical called glutamate, excess levels of which contribute to the death of brain cells in people with Alzheimer’s. Although all five drugs have all been shown to modestly slow the progression of cognitive symptoms and reduce problematic behaviors in some people, at least half of the people who take these drugs do not respond to them. While the overall treatment effect of these medications is modest, studies show that, when they do work, they can make a significant difference in a person’s quality in life and day-to-day functioning.

Research is now focused upon prevention trials which try to stop the disease process from happening in the first place, and a number of studies are underway to test the effectiveness of various therapies in people without symptoms or who have only slight memory problems. Some of these studies are examining estrogen and various classes of anti-inflammatory and antioxidant chemicals. Research has shown that vitamin E and other antioxidants may slow the progression of AD in some people, although the overall impact is minimal. Research also suggests that ginkgo biloba, an extract made from the leaves of the ginkgo tree, may be of some help in treating AD symptoms. However, there is no evidence that ginkgo will cure or prevent AD. (For more on ginkgo biloba, click here.)

Palliative medications that can control depression, anxiety, agitated behavior (including aggression, hyperactivity and combativeness) and psychotic symptoms can help patients in the middle stages of AD. The medications prescribed for these symptoms are not specifically designated for AD, but they may be considered as part of the treatment plan by the supervising physician. Generally, medications for these symptoms are considered when non-medicated alternatives have failed and/or these symptoms put the AD patients, or others, in danger.

The purpose of all medicines for Parkinson’s disease is to help control tremor, movement, and balance to maintain daily activities. One of the mechanisms targeted by Parkinson’s medications includes the interactions of dopamine, a neurotransmitter (chemical messenger) that affects brain processes by allowing nerve cells to communicate with one another in the brain. Scientists have determined that people with late PD have lost more than 80 percent of dopamine-producing cells in the substantia nigra, an area deep within the brain. Normally, these cells communicate with other brain cells in the nearby striatum via dopamine. Thus, without dopamine, the striatum can’t send out certain messages and the symptoms of Parkinson’s ensue. Levodopa, also called L-dopa, was the earliest treatment discovered for Parkinson’s disease. L-dopa is a method of dopamine replacement therapy; it is turned into dopamine in the brain to supplement the cells that are producing less.

Another group of medications fit into the category of dopamine antagonists, drugs that bind but don’t stimulate dopamine receptors. Antagonists can prevent or reverse the actions of dopamine by keeping dopamine from attaching to receptors; they help improve control of various body movements, which begin to slow or become irregular in early Parkinson’s disease. Dopamine antagonists work by copying the effect of the neurotransmitter dopamine, proving effective in people with Parkinson’s disease who are losing their dopamine-producing cells. By doing this, dopamine antagonists can help people maintain their daily activities. Furthermore, anticholinergic drugs can be used to treat mild symptoms of Parkinson’s disease. Anticholinergic drugs block a neurotransmitter that affects dopamine so that more dopamine is available in the brain. Other pharmacological medications exist to treat Parkinson’s, and they too usually involve the mimicking or replacement of dopamine.

Prognosis^

As discussed elsewhere in this website, HD is a progressively debilitating disease with no known cure. The person with Huntington’s disease may be able to maintain a job for several years after diagnosis, despite the increase in disability. Loss of cognitive functions and increase in motor and behavioral symptoms eventually prevent the person with HD from continuing employment. Ultimately, severe motor symptoms prevent mobility. HD is usually fatal within15 to 20 years. Progressive weakness of respiratory and swallowing muscles leads to increased respiratory infection and choking, the most common causes of death. (For more information about the complications of HD, click here.) However, not all patients with Huntington’s disease progress at the same pace and are equally affected. The number of repeats may determine severity. There are people with a low number of repeats that have mild abnormal movements later in life and progression is slow whereas others with a large repeat length who are severely affected at a young age.

Although different in many ways, Alzheimer’s disease is also an incurable and progressively debilitating disease that can vary widely in its progression. Some people have a very precipitous course and go downhill rapidly, while others remain stable for a long time. For some, the disease only for the last 5 years of life; others may have it for as many as 20 years. A study of the prognosis of AD at the University of Massachusetts Medical School suggests that initial degree of severity (“how far”) rather than the variation in the rate of progression (“how fast”) best predicts prognosis in the early to intermediate stages of Alzheimer’s disease. Total disability is common in people with Alzheimers, and the most common cause of death is infection or a failure of other body systems.

Predicting disease progression for Parkinson’s disease is difficult because of the wide spectrum of disease types. Again, the course and prognosis of this disease vary according to the individual. Without treatment, PD causes severe disability or death in 25% of patients within 5 years, 65% of survivors after 10 years, and 89% of survivors after 15 years. However, with treatment, the life expectancy of people with PD without an accompanying dementia is nearly normal. The mean time from diagnosis to death in treated PD is 14 years. Death is usually due to complications of immobility, such as pulmonary embolism (blood clot in the lungs) or aspiration pneumonia (lung infection from regurgitated stomach contents).

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Dementia in Huntington's Disease

Dementia refers to neurodegeneration that results in loss of mental abilities. Neurodegeneration is the loss of mental abilities that can be caused by brain damage and/or neuron death. For this reason, dementia is common in neurodegenerative disorders such as Alzheimer’s Disease. While Huntington’s Disease (HD) is commonly thought of as a motor disorder, cognitive symptoms can be present which can progress to dementia. To learn more about some of these cognitive symptoms, click here. Interestingly, many cognitive symptoms appear in HD patients before motor deficits appear.

Although a formal clinical diagnosis of HD depends on unequivocal signs of motor impairment, recent research has shown the importance of neuropsychological analysis and the evaluation of dementia in determining the condition of HD patients. There are several tests that clinicians administer to evaluate a patient’s cognitive abilities and degree of dementia. For physicians, it is important for these tests to recognize the subtle differences between different neurodegenerative diseases, particularly HD, Alzheimer’s disease and Parkinson’s Disease, which show similar cognitive symptoms.

Testing for Dementia^

When dementia is suspected in patients, physicians will administer tests before giving a formal diagnosis. For patients, whether they are at risk for HD or other diseases associated with dementia, the Mini-Mental State Examination (MMSE) is the most common test that is administered. The MMSE is convenient to administer to patients because it is relatively short, but can still help determine whether a patient’s cognitive functions are declining.

In addition to the MMSE, physicians also use other neuropsychological tests that usually involve several mental tasks that require the use of different areas of the brain. For example, the striatum, the brain area most affected in HD, has been implicated in sequence and procedure learning. Since the neuropsychological tasks test different regions of the brain, physicians can use the results to determine what regions of the brain have been affected. When patients are tested for dementia using these tests, their performance is compared to that of healthy individuals on the same tasks. Researchers are still determining which neuropsychological tests are most suitable for evaluating certain regions of the brain.

How are dementias classified?^

After a patient is diagnosed with dementia, it is important to determine the kind of dementia that is present. Dementias are often classified by the region of the brain that is affected. One of the main classifications divides dementias into two main groups: cortical and sub-cortical based on the area of the brain where degeneration occurs. The cortical region consists of the cerebral cortex while the sub-cortical region is comprised of the other structures of the brain including the thalamus, hypothalamus, cerebellum and brain stem (See Figure 1). To learn more about the brain click here for the HOPES Brain Tutorial. Whether cortical and subcortical dementias should be considered separately is still controversial among researchers and physicians. In general, studies have shown that some differences do exist, but there is disagreement on the degree to which the two dementias differ.

Figure 1: The brain can be divided into the cortical and subcortical regions. The cortical region consists of the cerebral cortex while the sub-cortical region consists of the thalamus, hypothalamus, cerebellum and brain stem.

To more clearly define the two types of dementia, researchers have studied whether their effects on memory differ. Alzheimer’s patients are often used as a model for cortical dementia because patients with this disease have large amounts of degeneration in the cerebral cortex. Clinical studies of Alzheimer’s patients have shown that cortical dementias have difficulty performing tasks that require semantic memory. Semantic memory is what we use to store facts without respect to the setting where we learned the facts (See Figure 1). To evaluate this type of memory, patients are asked to perform tasks such as matching pictures and generating definitions of words. To a lesser degree, cortical dementia can also affect episodic memory, which is used to remember experiences and the setting in which facts are learned. For example, after a boy bumps his head in a bike accident, semantic memory would enable him to remember that wearing a helmet is important when riding bikes, while episodic memory would enable him to recollect the specific time when the accident occurred.

Sub-cortical dementias have a slightly different effect on memory than cortical dementias in that they have a smaller effect on semantic memory. HD and Parkinson’s disease are considered sub-cortical dementias. In HD, patients instead find it challenging to accomplish cognitive tasks that require retrieval and synthesis of known facts, such as forming abstractions. Unlike patients with Alzheimer’s, however, those with HD can accomplish tasks that require semantic memory under the right conditions. For example, one study tested patients on a category fluency task in which patients were asked name as many items as possible from certain categories (e.g. foods, animals, plants) within an allotted time period. Under what scientists call “cued” conditions in which patients were given hints or clues that help with the task, HD and Parkinson’s patients improved their scores. Alzheimer’s patients, however, did not perform better under “cued” conditions. This suggests that patients with HD or other types of sub-cortical dementia have not experienced degradation of semantic memory per se, but instead have difficulty retrieving facts from their memory.

Sub-cortical dementias like HD do not affect memory following a time-dependent gradient. Memories and knowledge obtained recently are not more susceptible to degeneration than those from the distant past, as is the case in Alzheimer’s Disease. To learn more about the effects of HD on memory click here.

Figure 2: Our brains use different types of memory. Cortical dementia is thought to affect semantic memory to a greater degree than episodic memory. Sub-cortical dementia, as in HD, is thought to affect semantic memory to a lesser degree than cortical dementias.

Although memory is one of the leading areas of interest in the study of cortical and subcortical dementias, other differences between the two dementias exist. Sub-cortical dementias almost always result in motor disorders. Chorea in HD patients and tremors in Parkinson’s tremors are examples of motor impairment that accompany sub-cortical dementias. In terms of other cognitive effects, differences between dementias are still being studied.

Criticisms of the Dementia Differentiation^

Some researchers and physicians consider the differentiation between cortical and sub-cortical dementia important for patient diagnosis, but others remain skeptical that a significant difference exists. The major criticism of the studies that show variation between cortical and sub-cortical dementias is that there is pathological overlap between the sample groups that are used to model the two categories. These studies often assume that Alzheimer’s patients mostly have cortical dementia and HD or Parkinson’s patients preferentially exhibit subcortical dementia. Necropsies have shown, however, that the brains of both Alzheimer’s and HD patients exhibit a certain degree of both categories of dementia.

If in fact both cortical and subcortical dementia occur in Alzheimer’s, HD, and Parkinson’s patients, then these studies may be problematic. As a result, physicians are still trying to learn more about the differences between the pathologies of the diseases in hopes of finding a more reliable way of differentiating dementias. The ability to differentiate dementias may lead researchers and physicians to better diagnose and treat neurodegenerative diseases.

Further Reading^

  • Langbehn, Douglas R. et al. “Predictors of diagnosis in Huntington disease.” Neurology. 2007; 68: 1710-1717.
    Researchers and The Huntington Study Group performed a longitudinal study to identify early clinical symptoms that arise in HD patients. Findings showed that psychological performance can be used in diagnosis along with motor impairment. There is a thorough discussion of clinical evaluation of neurological performance in HD patients and the types of tests administered to patients.
  • Rosser, Anne and John R. Hodges. “Initial letter and semantic category fluency in Alzheimer’s disease, Huntington’s disease and progressive supranuclear palsy.” Journal of Neurology, Neurosurgery and Psychiatry 1994; 57: 1389-1394.
    This study examined symptoms related to semantic and episodic memory in three different neurodegenerative diseases. Several neuropsychological tests were administered to patients and the results suggested that semantic memory is more heavily influenced in cortical dementias like Alzheimer’s disease.
  • Sadek, Joseph R. et al. “Retrograde Amnesia in Dementia: Comparison of HIV-Associated Dementia, Alzheimer’s Disease, and Huntington’s Disease.” Neuropsychology, 2004; 18.4: 692-699.
    This study tested how three different types of dementia affect memory. The findings show that overall dementia is equally severe in all three types, but memory impairment differs. Time-dependent memory loss was not found in HD patients and HD patients were able to improve on memory tasks under “cued” conditions. The authors discuss their findings in the context of the debate on how cortical and subcortical dementias differ.
  • Wedderburn, C et al. “The utility of the Cambridge Behavioural Inventory in neurodegenerative disease.” Journal of Neurology, Neurosurgery, and Psychiatry. 2008; 79: 500-503.
    A review of a new test that is used to evaluate the mental condition of patients with neurodegenerative diseases. It includes helpful information about cognitive and psychological symptoms in HD, Parkinson’s and Alzheimer’s patients and how these symptoms differ between the diseases.

Additional Resources:

  • Ho AK, Sahakian BJ, Brown RG, Barker RA, Hodges JR, Ane MN, Snowden J, Thompson J, Esmonde T, Gentry R, Moore JW, Bodner T (2003) “Profile of cognitive progression in early Huntington’s disease.” Neurology 61:1702-1706.
  • Kirkwood SC, Siemers E, Hodes ME, Conneally PM, Christian JC, Foroud T (2000) “Subtle changes among presymptomatic carriers of the Huntington’s disease gene.” J Neurol Neurosurg Psychiatry 69:773-779.
  • Lawrence A, Hodges J, Rosser A, Kershaw A, French-Constant C, Rubinsztein D, Robbins T, BJ S (1998) “Evidence for specific cognitive deficits in preclinical Huntington’s disease.” Brain Pathol 121:1329-1341.
  • Lemiere J, Decruyenaere M, Evers-Kiebooms G, Vandenbussche E, Dom R (2004) “Cognitive changes in patients with Huntington’s disease (HD) and asymptomatic carriers of the HD mutation—a longitudinal follow-up study.” J Neurol 251:935-942.
  • Meade, Catherine E. “Diagnosing Dementia: mental status testing and beyond.” Australian Prescriber, 2005 (28): 11-13.
  • Savla, Gauri Nayak and Barton W. Palmer. “Neuropsychology in Alzheimer’s disease and other dementia research.” Current Opinions in Psychiatry, 2005 (18): 621-627.

– T. Wang, 5/17/09

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