Huntington's disease,
chorea, or
disorder (
HD), is a neurodegenerative
genetic disorderA genetic disorder is an illness caused by abnormalities in genes or chromosomes, especially a condition that is present from before birth. Most genetic disorders are quite rare and affect one person in every several thousands or millions....
that affects muscle coordination and leads to cognitive decline and
dementiaDementia is a serious loss of cognitive ability in a previously unimpaired person, beyond what might be expected from normal aging...
. It typically becomes noticeable in middle age. HD is the most common genetic cause of abnormal involuntary writhing movements called chorea. It is much more common in people of Western European descent than in those of Asian or African ancestry. The disease is caused by an
autosomalAn autosome is a chromosome that is not a sex chromosome, or allosome; that is to say, there is an equal number of copies of the chromosome in males and females. For example, in humans, there are 22 pairs of autosomes. In addition to autosomes, there are sex chromosomes, to be specific: X and Y...
dominant
mutationIn molecular biology and genetics, mutations are changes in a genomic sequence: the DNA sequence of a cell's genome or the DNA or RNA sequence of a virus. They can be defined as sudden and spontaneous changes in the cell. Mutations are caused by radiation, viruses, transposons and mutagenic...
on either of an individual's two copies of a
geneA gene is a molecular unit of heredity of a living organism. It is a name given to some stretches of DNA and RNA that code for a type of protein or for an RNA chain that has a function in the organism. Living beings depend on genes, as they specify all proteins and functional RNA chains...
called
HuntingtinThe Huntingtin gene, also called HTT or HD gene, is the IT15 gene which codes for a protein called the huntingtin protein...
, which means any child of an affected parent has a 50% risk of inheriting the disease. In the rare situations where both parents have an affected copy, the risk increases to 75%, and when either parent has two affected copies, the risk is 100% (all children will be affected). Physical symptoms of Huntington's disease can begin at any age from infancy to old age, but usually begin between 35 and 44 years of age. About 6% of cases start before the age of 21 years with an akinetic-rigid syndrome; they progress faster and vary slightly. The variant is classified as
juvenile,
akinetic-rigid or
Westphal variant HD.
The Huntingtin gene normally provides the genetic information for a protein that is also called "Huntingtin". The mutation of the Huntingtin gene codes for a different form of the protein, whose presence results in gradual damage to specific areas of the brain. The exact way this happens is not fully understood.
Genetic testingGenetic testing is among the newest and most sophisticated of techniques used to test for genetic disorders which involves direct examination of the DNA molecule itself. Other genetic tests include biochemical tests for such gene products as enzymes and other proteins and for microscopic...
can be performed at any stage of
developmentHuman development is the process of growing to maturity. In biological terms, this entails growth from a one-celled zygote to an adult human being.- Biological development:...
, even before the onset of symptoms. This fact raises several ethical debates: at what age is an individual considered mature enough to choose testing, do parents have the right to have their children tested, and managing confidentiality and disclosure of test results.
Genetic counselingGenetic counseling or traveling is the process by which patients or relatives, at risk of an inherited disorder, are advised of the consequences and nature of the disorder, the probability of developing or transmitting it, and the options open to them in management and family planning...
has developed to inform and aid individuals considering genetic testing and has become a model for other genetically dominant diseases.
Symptoms of the disease can vary between individuals and among affected members of the same family, but the symptoms progress predictably for most individuals. The earliest symptoms are a general lack of coordination and an unsteady gait. As the disease advances, uncoordinated, jerky body movements become more apparent, along with a decline in mental abilities and behavioral and
psychiatricPsychiatry is the medical specialty devoted to the study and treatment of mental disorders. These mental disorders include various affective, behavioural, cognitive and perceptual abnormalities...
problems. Physical abilities are gradually impeded until coordinated movement becomes very difficult. Mental abilities generally decline into
dementiaDementia is a serious loss of cognitive ability in a previously unimpaired person, beyond what might be expected from normal aging...
. Complications such as
pneumoniaPneumonia is an inflammatory condition of the lung—especially affecting the microscopic air sacs —associated with fever, chest symptoms, and a lack of air space on a chest X-ray. Pneumonia is typically caused by an infection but there are a number of other causes...
,
heart diseaseHeart disease, cardiac disease or cardiopathy is an umbrella term for a variety of diseases affecting the heart. , it is the leading cause of death in the United States, England, Canada and Wales, accounting for 25.4% of the total deaths in the United States.-Types:-Coronary heart disease:Coronary...
, and physical injury from falls reduce life expectancy to around twenty years after symptoms begin. There is no cure for HD, and full-time care is required in the later stages of the disease. Emerging treatments can relieve some of its symptoms.
Self-help supportIn a support group, members provide each other with various types of help, usually nonprofessional and nonmaterial, for a particular shared, usually burdensome, characteristic...
organizations, first founded in the 1960s and increasing in number, have been working to increase public awareness, to provide support for individuals and their families, and to promote research. The
Hereditary Disease FoundationThe Hereditary Disease Foundation aims to cure genetic disorders by supporting basic biomedical research.-History:In 1968, after experiencing Huntington's disease in his wife's family, Dr. Milton Wexler was inspired to start the Hereditary Disease Foundation, with the aim of curing genetic...
, a research group born out of the first support organization, was instrumental in finding the gene in 1993. Since that time, every few years new research discoveries have been made and understanding of the disease is improving. Current research directions include determining the exact mechanism of the disease, improving animal models to expedite research, clinical trials of pharmaceuticals to treat symptoms or slow the progression of the disease, and studying procedures such as
stem cell therapyStem cell treatments are a type of intervention strategy that introduces new cells into damaged tissue in order to treat disease or injury. Many medical researchers believe that stem cell treatments have the potential to change the face of human disease and alleviate suffering...
with the goal of repairing damage caused by the disease.
Signs and symptoms
Symptoms of Huntington's disease commonly become noticeable between the ages of 35 and 44 years, but they can begin at any age from infancy to old age. In the early stages, there are subtle changes in personality,
cognitionIn science, cognition refers to mental processes. These processes include attention, remembering, producing and understanding language, solving problems, and making decisions. Cognition is studied in various disciplines such as psychology, philosophy, linguistics, and computer science...
, and physical skills. The physical symptoms are usually the first to be noticed, as cognitive and
psychiatricPsychiatry is the medical specialty devoted to the study and treatment of mental disorders. These mental disorders include various affective, behavioural, cognitive and perceptual abnormalities...
symptoms are generally not severe enough to be recognized on their own at the earlier stages. Almost everyone with Huntington's disease eventually exhibits similar physical symptoms, but the onset, progression and extent of cognitive and psychiatric symptoms vary significantly between individuals.
The most characteristic initial physical symptoms are jerky, random, and uncontrollable movements called chorea. Chorea may be initially exhibited as general restlessness, small unintentionally initiated or uncompleted motions, lack of coordination, or slowed
saccadic eye movementsA saccade is a fast movement of an eye, head or other part of an animal's body or device. It can also be a fast shift in frequency of an emitted signal or other quick change. Saccades are quick, simultaneous movements of both eyes in the same direction...
. These minor motor abnormalities usually precede more obvious signs of motor dysfunction by at least three years. The clear appearance of symptoms such as rigidity, writhing motions or
abnormal posturingDystonia is a neurological movement disorder, in which sustained muscle contractions cause twisting and repetitive movements or abnormal postures. The disorder may be hereditary or caused by other factors such as birth-related or other physical trauma, infection, poisoning or reaction to...
appear as the disorder progresses. These are signs that the system in the brain that is responsible for movement has been affected.
PsychomotorPsychomotor retardation involves a slowing-down of thought and a reduction of physical movements in an individual. Psychomotor retardation can cause a visible slowing of physical and emotional reactions, including speech and affect...
functions become increasingly impaired, such that any action that requires muscle control is affected. Common consequences are physical instability, abnormal facial expression, and difficulties chewing,
swallowingDysphagia is the medical term for the symptom of difficulty in swallowing. Although classified under "symptoms and signs" in ICD-10, the term is sometimes used as a condition in its own right. Sufferers are sometimes unaware of their dysphagia....
and
speakingDysarthria is a motor speech disorder resulting from neurological injury of the motor component of the motor-speech system and is characterized by poor articulation of phonemes...
. Eating difficulties commonly cause weight loss and may lead to malnutrition.
Sleep disturbancesA sleep disorder, or somnipathy, is a medical disorder of the sleep patterns of a person or animal. Some sleep disorders are serious enough to interfere with normal physical, mental and emotional functioning...
are also associated symptoms. Juvenile HD differs from these symptoms in that it generally progresses faster and chorea is exhibited briefly, if at all, with rigidity being the dominant symptom.
SeizureAn epileptic seizure, occasionally referred to as a fit, is defined as a transient symptom of "abnormal excessive or synchronous neuronal activity in the brain". The outward effect can be as dramatic as a wild thrashing movement or as mild as a brief loss of awareness...
s are also a common symptom of this form of HD.
Reported prevalences of behavioral and psychiatric symptoms in Huntington's disease
| Irritability |
38–73% |
| Apathy |
34–76% |
| Anxiety |
34–61% |
| Depressed mood |
33–69% |
| Obsessive and compulsive |
10–52% |
| Psychotic |
3–11% |
Cognitive abilities are impaired progressively. Especially affected are
executive functionsThe executive system is a theorized cognitive system in psychology that controls and manages other cognitive processes. It is responsible for processes that are sometimes referred to as the executive function, executive functions, supervisory attentional system, or cognitive control...
which include planning, cognitive flexibility, abstract thinking, rule acquisition, initiating appropriate actions and inhibiting inappropriate actions. As the disease progresses,
memoryIn psychology, memory is an organism's ability to store, retain, and recall information and experiences. Traditional studies of memory began in the fields of philosophy, including techniques of artificially enhancing memory....
deficits tend to appear. Reported impairments range from
short-term memoryShort-term memory is the capacity for holding a small amount of information in mind in an active, readily available state for a short period of time. The duration of short-term memory is believed to be in the order of seconds. A commonly cited capacity is 7 ± 2 elements...
deficits to
long-term memoryLong-term memory is memory in which associations among items are stored, as part of the theory of a dual-store memory model. According to the theory, long term memory differs structurally and functionally from working memory or short-term memory, which ostensibly stores items for only around 20–30...
difficulties, including deficits in
episodicEpisodic memory is the memory of autobiographical events that can be explicitly stated. Semantic and episodic memory together make up the category of declarative memory, which is one of the two major divisions in memory...
(memory of one's life),
proceduralProcedural memory is memory for how to do things. Procedural memory guides the processes we perform and most frequently resides below the level of conscious awareness. When needed, procedural memories are automatically retrieved and utilized for the execution of the integrated procedures involved...
(memory of the body of how to perform an activity) and
working memoryWorking memory has been defined as the system which actively holds information in the mind to do verbal and nonverbal tasks such as reasoning and comprehension, and to make it available for further information processing...
. Cognitive problems tend to worsen over time, ultimately leading to
dementiaDementia is a serious loss of cognitive ability in a previously unimpaired person, beyond what might be expected from normal aging...
. This pattern of deficits has been called a subcortical dementia syndrome to distinguish it from the typical effects of cortical dementias e.g.
Alzheimer's diseaseAlzheimer's disease also known in medical literature as Alzheimer disease is the most common form of dementia. There is no cure for the disease, which worsens as it progresses, and eventually leads to death...
.
Reported
neuropsychiatricNeuropsychiatry is the branch of medicine dealing with mental disorders attributable to diseases of the nervous system. It preceded the current disciplines of psychiatry and neurology, in as much as psychiatrists and neurologists had a common training....
manifestations are
anxietyAnxiety is a psychological and physiological state characterized by somatic, emotional, cognitive, and behavioral components. The root meaning of the word anxiety is 'to vex or trouble'; in either presence or absence of psychological stress, anxiety can create feelings of fear, worry, uneasiness,...
, depression, a reduced display of emotions (
blunted affectBlunted affect is the scientific term describing a lack of emotional reactivity on the part of an individual. It is manifest as a failure to express feelings either verbally or non-verbally, even when talking about issues that would normally be expected to engage the emotions...
),
egocentrismEgocentrism is a personality trait which has the characteristic of regarding oneself and one's own opinions or interests as most important or valid...
,
aggressionIn psychology, as well as other social and behavioral sciences, aggression refers to behavior between members of the same species that is intended to cause humiliation, pain, or harm. Ferguson and Beaver defined aggressive behavior as "Behavior which is intended to increase the social dominance of...
, and
compulsive behaviorCompulsive behavior is behavior which a person does compulsively—in other words, not because they want to behave that way, but because they feel they have to do so....
, the latter of which can cause or worsen
addictionsBehavioral addiction is a form of addiction which does not rely on drugs or alcohol. Increasingly referred to as process addiction or non-substance-related addiction ) behavioral addiction includes a compulsion to repeatedly engage in an action until said action causes serious negative consequences...
, including
alcoholismAlcoholism is a broad term for problems with alcohol, and is generally used to mean compulsive and uncontrolled consumption of alcoholic beverages, usually to the detriment of the drinker's health, personal relationships, and social standing...
,
gamblingGambling is the wagering of money or something of material value on an event with an uncertain outcome with the primary intent of winning additional money and/or material goods...
, and
hypersexualityHypersexuality is extremely frequent or suddenly increased sexual urges or sexual activity. Hypersexuality is typically associated with lowered sexual inhibitions. Although hypersexuality can be caused by some medical conditions or medications, in most cases the cause is unknown...
. Difficulties in recognizing other people's negative expressions have also been observed. The
prevalenceIn epidemiology, the prevalence of a health-related state in a statistical population is defined as the total number of cases of the risk factor in the population at a given time, or the total number of cases in the population, divided by the number of individuals in the population...
of these symptoms is highly variable between studies, with estimated rates for lifetime prevalence of
psychiatric disordersA mental disorder or mental illness is a psychological or behavioral pattern generally associated with subjective distress or disability that occurs in an individual, and which is not a part of normal development or culture. Such a disorder may consist of a combination of affective, behavioural,...
between 33% and 76%. For many sufferers and their families, these symptoms are among the most distressing aspects of the disease, often affecting daily functioning and constituting reason for institutionalization. Suicidal thoughts and suicide attempts are more common than in the general population.
Mutant Huntingtin is expressed throughout the body and associated with abnormalities in peripheral tissues that are directly caused by such expression outside the brain. These abnormalities include
muscle atrophyMuscle atrophy, or disuse atrophy, is defined as a decrease in the mass of the muscle; it can be a partial or complete wasting away of muscle. When a muscle atrophies, this leads to muscle weakness, since the ability to exert force is related to mass...
, cardiac failure,
impaired glucose toleranceImpaired glucose tolerance is a pre-diabetic state of dysglycemia that is associated with insulin resistance and increased risk of cardiovascular pathology. IGT may precede type 2 diabetes mellitus by many years...
,
weight lossWeight loss, in the context of medicine, health or physical fitness, is a reduction of the total body mass, due to a mean loss of fluid, body fat or adipose tissue and/or lean mass, namely bone mineral deposits, muscle, tendon and other connective tissue...
,
osteoporosisOsteoporosis is a disease of bones that leads to an increased risk of fracture. In osteoporosis the bone mineral density is reduced, bone microarchitecture is deteriorating, and the amount and variety of proteins in bone is altered...
and
testicular atrophyTesticular atrophy is a medical condition in which the male reproductive organs diminish in size and may be accompanied by loss of function. This does not refer to temporary changes, such as those brought on by cold.Some medications can cause testicular atrophy...
.
Genetics
All humans have the
HuntingtinThe Huntingtin gene, also called HTT or HD gene, is the IT15 gene which codes for a protein called the huntingtin protein...
gene (
HTT), which codes for the
proteinProteins are biochemical compounds consisting of one or more polypeptides typically folded into a globular or fibrous form, facilitating a biological function. A polypeptide is a single linear polymer chain of amino acids bonded together by peptide bonds between the carboxyl and amino groups of...
Huntingtin (Htt). Part of this gene is a repeated section called a trinucleotide repeat, which varies in length between individuals and may change length between generations. When the length of this repeated section reaches a certain threshold, it produces an altered form of the protein, called mutant Huntingtin protein (mHtt). The differing functions of these proteins are the cause of pathological changes which in turn cause the disease symptoms. The Huntington's disease mutation is genetically dominant and almost fully
penetrantPenetrance in genetics is the proportion of individuals carrying a particular variant of a gene that also express an associated trait . In medical genetics, the penetrance of a disease-causing mutation is the proportion of individuals with the mutation who exhibit clinical symptoms...
: mutation of either of a person's
HTT genes causes the disease. It is not inherited according to sex, but the length of the repeated section of the gene, and hence its severity, can be influenced by the sex of the affected parent.
Genetic mutation
HD is one of several trinucleotide repeat disorders which are caused by the length of a repeated section of a gene exceeding a normal range. The
HTT gene is located on the
short armIn the fields of genetics and genetic computation, a locus is the specific location of a gene or DNA sequence on a chromosome. A variant of the DNA sequence at a given locus is called an allele. The ordered list of loci known for a particular genome is called a genetic map...
of
chromosome 4125px|rightChromosome 4 is one of the 23 pairs of chromosomes in humans. People normally have two copies of this chromosome. Chromosome 4 spans more than 186 million base pairs and represents between 6 and 6.5 percent of the total DNA in cells.Identifying genes on each chromosome is an active area...
at 4p16.3.
HTT contains a sequence of three DNA bases—cytosine-adenine-guanine (CAG)—repeated multiple times (i.e. ... CAGCAGCAG ...), known as a trinucleotide repeat. CAG is the
genetic codeThe genetic code is the set of rules by which information encoded in genetic material is translated into proteins by living cells....
for the
amino acidAmino acids are molecules containing an amine group, a carboxylic acid group and a side-chain that varies between different amino acids. The key elements of an amino acid are carbon, hydrogen, oxygen, and nitrogen...
glutamineGlutamine is one of the 20 amino acids encoded by the standard genetic code. It is not recognized as an essential amino acid but may become conditionally essential in certain situations, including intensive athletic training or certain gastrointestinal disorders...
, so a series of them results in the production of a chain of glutamine known as a
polyglutamine tractA polyglutamine tract or polyQ tract is a portion of a protein consisting of a sequence of several glutamine units. A tract typically consists of about 10 to a few hundred such units....
(or polyQ tract), and the repeated part of the gene, the
PolyQ region.
Classification of the trinucleotide repeat, and resulting disease status, depends on the number of CAG repeats
| Repeat count |
Classification |
Disease status |
| <28 |
Normal |
Unaffected |
| 28–35 |
Intermediate |
Unaffected |
| 36–40 |
Reduced Penetrance |
+/- Affected |
| >40 |
Full Penetrance |
Affected |
Generally, people have fewer than 36 repeated glutamines in the polyQ region which results in production of the cytoplasmic protein Huntingtin. However, a sequence of 36 or more glutamines results in the production of a protein which has different characteristics. This altered form, called mHtt (mutant Htt), increases the decay rate of certain types of neurons. Regions of the brain have differing amounts and reliance on these type of neurons, and are affected accordingly. Generally, the number of CAG repeats is related to how much this process is affected, and accounts for about 60% of the variation of the age of the onset of symptoms. The remaining variation is attributed to environment and other genes that modify the mechanism of HD. 36–40 repeats result in a reduced-
penetrancePenetrance in genetics is the proportion of individuals carrying a particular variant of a gene that also express an associated trait . In medical genetics, the penetrance of a disease-causing mutation is the proportion of individuals with the mutation who exhibit clinical symptoms...
form of the disease, with a much later onset and slower progression of symptoms. In some cases the onset may be so late that symptoms are never noticed. With very large repeat counts, HD has full penetrance and can occur under the age of 20, when it is then referred to as juvenile HD, akinetic-rigid, or Westphal variant HD. This accounts for about 7% of HD carriers.
Inheritance
Huntington's disease has autosomal dominant inheritance, meaning that an affected individual typically inherits one copy of the gene with an expanded trinucleotide repeat (the mutant
alleleAn allele is one of two or more forms of a gene or a genetic locus . "Allel" is an abbreviation of allelomorph. Sometimes, different alleles can result in different observable phenotypic traits, such as different pigmentation...
) from an affected parent. Since penetrance of the mutation is very high, those who have a mutated copy of the gene will have the disease. In this type of inheritance pattern, each offspring of an affected individual has a 50% risk of inheriting the mutant allele and therefore being affected with the disorder (see figure). This probability is sex-independent.
Trinucleotide CAG repeats over 28 are unstable during
replicationDNA replication is a biological process that occurs in all living organisms and copies their DNA; it is the basis for biological inheritance. The process starts with one double-stranded DNA molecule and produces two identical copies of the molecule...
and this instability increases with the number of repeats present. This usually leads to new expansions as generations pass (
dynamic mutationIn genetics, a dynamic mutation is an unstable heritable element where the probability of expression of a mutant phenotype is a function of the number of copies of the mutation. That is, the replication product of a dynamic mutation has a different likelihood of mutation than its predecessor...
s) instead of reproducing an exact copy of the trinucleotide repeat. This causes the number of repeats to change in successive generations, such that an unaffected parent with an "intermediate" number of repeats (28–35), or "reduced penetrance" (36–40), may pass on a copy of the gene with an increase in the number of repeats that produces fully penetrant HD. Such increases in the number of repeats (and hence earlier
age of onsetThe age of onset is a medical term referring to the age at which an individual acquires, develops, or first experiences a condition or symptoms of a disease or disorder...
and severity of disease) in successive generations is known as genetic
anticipationIn genetics, anticipation is a phenomenon whereby the symptoms of a genetic disorder become apparent at an earlier age as it is passed on to the next generation. In most cases, an increase of severity of symptoms is also noted. Anticipation is common in trinucleotide repeat disorders such as...
. Instability is greater in
spermatogenesisSpermatogenesis is the process by which male primary germ cells undergo division, and produce a number of cells termed spermatogonia, from which the primary spermatocytes are derived. Each primary spermatocyte divides into two secondary spermatocytes, and each secondary spermatocyte into two...
than
oogenesisOogenesis, ovogenesis or oögenesis is the creation of an ovum . It is the female form of gametogenesis. The male equivalent is spermatogenesis...
; maternally inherited alleles are usually of a similar repeat length, whereas paternally inherited ones have a higher chance of increasing in length. It is rare for Huntington's disease to be caused by a new mutation, where neither parent has over 36 CAG repeats.
Individuals with both genes affected are rare, except in large
consanguineousConsanguinity refers to the property of being from the same kinship as another person. In that respect, consanguinity is the quality of being descended from the same ancestor as another person...
families. For some time HD was thought to be the only disease for which possession of a second mutated gene did not affect symptoms and progression, but it has since been found that it can affect the
phenotypeA phenotype is an organism's observable characteristics or traits: such as its morphology, development, biochemical or physiological properties, behavior, and products of behavior...
and the rate of progression. Offspring of an individual who has two affected genes will inherit one of them and therefore definitely inherit the disease. Offspring where both parents have one affected gene have a 75% risk of inheriting HD, including a 25% risk of inheriting two affected genes. Identical
twinA twin is one of two offspring produced in the same pregnancy. Twins can either be monozygotic , meaning that they develop from one zygote that splits and forms two embryos, or dizygotic because they develop from two separate eggs that are fertilized by two separate sperm.In contrast, a fetus...
s, who have inherited the same affected gene, typically have differing ages of onset and symptoms.
Mechanism
The Htt protein interacts with over 100 other proteins, and appears to have multiple biological functions. The behavior of mutated mHtt protein is not completely understood, but it is toxic to certain types of cells, particularly in the brain. Damage mainly occurs in the
striatumThe striatum, also known as the neostriatum or striate nucleus, is a subcortical part of the forebrain. It is the major input station of the basal ganglia system. The striatum, in turn, gets input from the cerebral cortex...
, but as the disease progresses, other areas of the brain are also significantly affected. As the damage accumulates, symptoms associated with the functions of these brain areas appear. Planning and modulating movement are the main functions of the striatum, and difficulties with these are initial symptoms.
Htt function
Htt is
expressedProtein expression is a subcomponent of gene expression. It consists of the stages after DNA has been translated into polypeptide chains, which are ultimately folded into proteins...
in all mammalian cells. The highest concentrations are found in the brain and testes, with moderate amounts in the
liverThe liver is a vital organ present in vertebrates and some other animals. It has a wide range of functions, including detoxification, protein synthesis, and production of biochemicals necessary for digestion...
,
heartThe heart is a myogenic muscular organ found in all animals with a circulatory system , that is responsible for pumping blood throughout the blood vessels by repeated, rhythmic contractions...
, and
lungThe lung is the essential respiration organ in many air-breathing animals, including most tetrapods, a few fish and a few snails. In mammals and the more complex life forms, the two lungs are located near the backbone on either side of the heart...
s. The function of Htt in humans is unclear. It interacts with proteins which are involved in
transcriptionTranscription is the process of creating a complementary RNA copy of a sequence of DNA. Both RNA and DNA are nucleic acids, which use base pairs of nucleotides as a complementary language that can be converted back and forth from DNA to RNA by the action of the correct enzymes...
,
cell signalingCell signaling is part of a complex system of communication that governs basic cellular activities and coordinates cell actions. The ability of cells to perceive and correctly respond to their microenvironment is the basis of development, tissue repair, and immunity as well as normal tissue...
and intracellular transporting. In animals
genetically modifiedA genetically modified organism or genetically engineered organism is an organism whose genetic material has been altered using genetic engineering techniques. These techniques, generally known as recombinant DNA technology, use DNA molecules from different sources, which are combined into one...
to exhibit HD, several functions of Htt have been found. In these animals, Htt is important for embryonic development, as its absence is related to embryonic death. It also acts as an
anti-apoptoticApoptosis is the process of programmed cell death that may occur in multicellular organisms. Biochemical events lead to characteristic cell changes and death. These changes include blebbing, cell shrinkage, nuclear fragmentation, chromatin condensation, and chromosomal DNA fragmentation...
agent preventing
programmed cell deathProgrammed cell-death is death of a cell in any form, mediated by an intracellular program. PCD is carried out in a regulated process which generally confers advantage during an organism's life-cycle...
and controls the production of
brain-derived neurotrophic factorBrain-derived neurotrophic factor, also known as BDNF, is a protein that, in humans, is encoded by the BDNF gene. BDNF is a member of the "neurotrophin" family of growth factors, which are related to the canonical "Nerve Growth Factor", NGF...
, a protein which protects neurons and regulates their creation during
neurogenesisNeurogenesis is the process by which neurons are generated from neural stem and progenitor cells. Most active during pre-natal development, neurogenesis is responsible for populating the growing brain with neurons. Recently neurogenesis was shown to continue in several small parts of the brain of...
. Htt also facilitates
vesicularIn a neuron, synaptic vesicles store various neurotransmitters that are released at the synapse. The release is regulated by a voltage-dependent calcium channel. Vesicles are essential for propagating nerve impulses between neurons and are constantly recreated by the cell...
transport and
synaptic transmissionSynapsis is the pairing of two homologous chromosomes that occurs during meiosis. It allows matching-up of homologous pairs prior to their segregation, and possible chromosomal crossover between them. Synapsis takes place during prophase I. When homologous chromosomes synapse, their ends are...
and controls neuronal
gene transcriptionTranscription is the process of creating a complementary RNA copy of a sequence of DNA. Both RNA and DNA are nucleic acids, which use base pairs of nucleotides as a complementary language that can be converted back and forth from DNA to RNA by the action of the correct enzymes...
. If the
expressionGene expression is the process by which information from a gene is used in the synthesis of a functional gene product. These products are often proteins, but in non-protein coding genes such as ribosomal RNA , transfer RNA or small nuclear RNA genes, the product is a functional RNA...
of Htt is increased and more Htt produced,
brain cellBrain Cell is a mail art project begun by Ryosuke Cohen in June 1985. The project is basically a networked art project where individual artists create their own 30x42cm work of art with stamps, drawings, stickers and so forth. This is sent to Cohen, who prints each cell - 150 copies each - with a...
survival is improved and the effects of mHtt are reduced, whereas when the expression of Htt is reduced, the resulting characteristics are more typical of the presence of mHtt. In humans the disruption of the normal gene does not cause the disease. It is currently concluded that the disease is not caused by
inadequate productionHaploinsufficiency occurs when a diploid organism only has a single functional copy of a gene and the single functional copy of the gene does not produce enough of a gene product to bring about a wild-type condition, leading to an abnormal or diseased state...
of Htt, but by a gain of toxic function of mHtt.
Cellular changes due to mHtt
There are multiple cellular changes through which the toxic function of mHtt may manifest and produce the HD pathology. During the biological process of
posttranslational modificationPosttranslational modification is the chemical modification of a protein after its translation. It is one of the later steps in protein biosynthesis, and thus gene expression, for many proteins....
of mHtt, cleavage of the protein can leave behind shorter fragments constituted of parts of the polyglutamine expansion. The polar nature of glutamine causes interactions with other proteins when it is overabundant in Htt proteins. Thus, the Htt molecule strands will form hydrogen bonds with one another, forming a protein aggregate rather than folding into functional proteins. Over time, the aggregates accumulate, ultimately interfering with neuron function because these fragments can then misfold and coalesce, in a process called
protein aggregationProtein aggregation is the aggregation of mis-folded proteins, and is thought to be responsible for many degenerative diseases, such as Alzheimer's. It has also been implicated in CAG repeat diseases....
, to form
inclusion bodiesInclusion bodies are nuclear or cytoplasmic aggregates of stainable substances, usually proteins. They typically represent sites of viral multiplication in a bacterium or a eukaryotic cell and usually consist of viral capsid proteins...
within cells. Neuronal inclusions run indirect interference. The excess protein aggregates clump together at axons and dendrites in neurons which mechanically stops the transmission of neurotransmitters because vesicles (filled with neurotransmitters) can no longer move through the cytoskeleton. Ultimately, over time, less and less neurotransmitters are available for release in signaling other neurons as the neuronal inclusions grow. Inclusion bodies have been found in both the
cell nucleusIn cell biology, the nucleus is a membrane-enclosed organelle found in eukaryotic cells. It contains most of the cell's genetic material, organized as multiple long linear DNA molecules in complex with a large variety of proteins, such as histones, to form chromosomes. The genes within these...
and
cytoplasmThe cytoplasm is a small gel-like substance residing between the cell membrane holding all the cell's internal sub-structures , except for the nucleus. All the contents of the cells of prokaryote organisms are contained within the cytoplasm...
. Inclusion bodies in cells of the brain are one of the earliest pathological changes, and some experiments have found that they can be
toxicNeurotoxicity occurs when the exposure to natural or artificial toxic substances, which are called neurotoxins, alters the normal activity of the nervous system in such a way as to cause damage to nervous tissue. This can eventually disrupt or even kill neurons, key cells that transmit and process...
for the cell, but other experiments have shown that they may form as part of the body's defense mechanism and help protect cells.
Several pathways by which mHtt may cause cell death have been identified. These include: effects on chaperone proteins, which help fold proteins and remove misfolded ones; interactions with
caspaseCaspases, or cysteine-aspartic proteases or cysteine-dependent aspartate-directed proteases are a family of cysteine proteases that play essential roles in apoptosis , necrosis, and inflammation....
s, which play a role in the
process of removing cellsApoptosis is the process of programmed cell death that may occur in multicellular organisms. Biochemical events lead to characteristic cell changes and death. These changes include blebbing, cell shrinkage, nuclear fragmentation, chromatin condensation, and chromosomal DNA fragmentation...
; the
toxic effects of glutamine on nerve cellsExcitotoxicity is the pathological process by which nerve cells are damaged and killed by excessive stimulation by neurotransmitters such as glutamate and similar substances. This occurs when receptors for the excitatory neurotransmitter glutamate such as the NMDA receptor and AMPA receptor are...
; impairment of energy production within cells; and effects on the expression of genes. The cytotoxic effects of mHtt are strongly enhanced by interactions with a protein called
Rhes, which is expressed mainly in the striatum. Rhes was found to induce sumoylation of mHtt, which causes the protein clumps to disaggregate—studies in cell culture showed that the clumps were much less toxic than the disaggregated form.
An additional theory that explains another way cell function may be disrupted by HD proposes that damage to mitochondria in striatal cells (numerous accounts of mitochondrial metabolism deficiency have been found) and the interactions of the altered huntingtin protein with numerous proteins in neurons leads to an increased vulnerability of glutamine, which, in large amounts, has been found to be an excitotoxin. Excitotoxins may cause damage to numerous cellular structures. Although glutamine is not found in excessively high amounts, it has been postulated that because of the increased vulnerability, even normal amounts glutamine can cause excitotoxins to be expressed. Furthermore, the increase in sensitivity turn on capases are activated by the repeat expansion of polyglutamine and the increase in sensitivity. The huntingtin protein is cleaved into tiny pieces by capases; these nuclear aggregates disrupt transcription by interfering with the production of proteins by "slipping" into the nucleus of the neuron. Unfortunately, the cellular stress caused by the interference causes more huntingtin to be broken up until apoptosis occurs.
Macroscopic changes due to mHtt
HD affects the whole brain, but certain areas are more vulnerable than others. The most prominent early effects are in a part of the
basal gangliaThe basal ganglia are a group of nuclei of varied origin in the brains of vertebrates that act as a cohesive functional unit. They are situated at the base of the forebrain and are strongly connected with the cerebral cortex, thalamus and other brain areas...
called the neostriatum, which is composed of the
caudate nucleusThe caudate nucleus is a nucleus located within the basal ganglia of the brains of many animal species. The caudate nucleus is an important part of the brain's learning and memory system.-Anatomy:...
and
putamenThe putamen is a round structure located at the base of the forebrain . The putamen and caudate nucleus together form the dorsal striatum. It is also one of the structures that comprises the basal ganglia. Through various pathways, the putamen is connected to the substantia nigra and globus pallidus...
. Other areas affected include the
substantia nigraThe substantia nigra is a brain structure located in the mesencephalon that plays an important role in reward, addiction, and movement. Substantia nigra is Latin for "black substance", as parts of the substantia nigra appear darker than neighboring areas due to high levels of melanin in...
, layers 3, 5 and 6 of the
cerebral cortexThe cerebral cortex is a sheet of neural tissue that is outermost to the cerebrum of the mammalian brain. It plays a key role in memory, attention, perceptual awareness, thought, language, and consciousness. It is constituted of up to six horizontal layers, each of which has a different...
, the
hippocampusThe hippocampus is a major component of the brains of humans and other vertebrates. It belongs to the limbic system and plays important roles in the consolidation of information from short-term memory to long-term memory and spatial navigation. Humans and other mammals have two hippocampi, one in...
,
purkinje cellFor the cells of the electrical conduction system of the heart, see Purkinje fibersPurkinje cells, or Purkinje neurons , are a class of GABAergic neurons located in the cerebellar cortex...
s in the
cerebellumThe cerebellum is a region of the brain that plays an important role in motor control. It may also be involved in some cognitive functions such as attention and language, and in regulating fear and pleasure responses, but its movement-related functions are the most solidly established...
, lateral tuberal nuclei of the
hypothalamusThe Hypothalamus is a portion of the brain that contains a number of small nuclei with a variety of functions...
and parts of the
thalamusThe thalamus is a midline paired symmetrical structure within the brains of vertebrates, including humans. It is situated between the cerebral cortex and midbrain, both in terms of location and neurological connections...
. These areas are affected according to their structure and the types of neurons they contain, reducing in size as they lose cells. Striatal spiny neurons are the most vulnerable, particularly ones with
projectionsA neural pathway, neural tract, or neural face, connects one part of the nervous system with another and usually consists of bundles of elongated, myelin-insulated neurons, known collectively as white matter...
towards the external
globus pallidusThe globus pallidus also known as paleostriatum, is a sub-cortical structure of the brain. Topographically, it is part of the telencephalon, but retains close functional ties with the subthalamus - both of which are part of the extrapyramidal motor system...
, with
interneuronAn interneuron is a multipolar neuron which connects afferent neurons and efferent neurons in neural pathways...
s and spiny cells projecting to the internal pallidum being less affected. HD also causes an
abnormal increaseAstrocytosis is an abnormal increase in the number of astrocytes due to the destruction of nearby neurons, typically because of hypoglycemia or oxygen deprivation .It usually takes place in prion infections...
in
astrocyteAstrocytes , also known collectively as astroglia, are characteristic star-shaped glial cells in the brain and spinal cord...
s.
The basal ganglia—the part of the brain most prominently affected by HD—play a key role in movement and behavior control. Their functions are not fully understood, but current theories propose that they are part of the cognitive executive system and the motor circuit. The basal ganglia ordinarily inhibit a large number of circuits that generate specific movements. To initiate a particular movement, the cerebral cortex sends a signal to the basal ganglia that causes the inhibition to be released. Damage to the basal ganglia can cause the release or reinstatement of the inhibitions to be erratic and uncontrolled, which results in an awkward start to motion or motions to be unintentionally initiated, or a motion to be halted before, or beyond, its intended completion. The accumulating damage to this area causes the characteristic erratic movements associated with HD.
Transcriptional dysregulation
CREB-binding protein (CBP), a transcription factor, is essential for cell function because as a coactivator at a significant number of promoters, it activates the transcription of genes for survival pathways. Furthermore, the amino acids that form CBP include a strip 18 glutamines. Thus, the glutamines on CBP interact directly with the increased numbers of glutamine on the Htt chain and CBP gets pulled away from its typical location next to the nucleus. Specifically, CRB contains a acetyltransferase domain that, in an experiment performed by Steffan and colleagues, showed that a Htt exon 1 with 51 glutamines binded to this domain in CBP. Autopsied brains of those who had Huntington's disease also have been found to have incredibly reduced amounts of CBP. Plus, when CBP is overexpressed, polyglutamine-induced death diminished, further demonstrating that CBP plays an important role in Huntington's disease and neurons in general.
Diagnosis
Medical diagnosisMedical diagnosis refers both to the process of attempting to determine or identify a possible disease or disorder , and to the opinion reached by this process...
of the onset of HD can be made following the appearance of physical symptoms specific to the disease. Genetic testing can be used to confirm a physical diagnosis if there is no family history of HD. Even before the onset of symptoms, genetic testing can confirm if an individual or
embryoAn embryo is a multicellular diploid eukaryote in its earliest stage of development, from the time of first cell division until birth, hatching, or germination...
carries an expanded copy of the trinucleotide repeat in the
HTT gene that causes the disease.
Genetic counselingGenetic counseling or traveling is the process by which patients or relatives, at risk of an inherited disorder, are advised of the consequences and nature of the disorder, the probability of developing or transmitting it, and the options open to them in management and family planning...
is available to provide advice and guidance throughout the testing procedure, and on the implications of a confirmed diagnosis. These implications include the impact on an individual's psychology, career, family planning decisions, relatives and relationships. Despite the availability of pre-symptomatic testing, only 5% of those at risk of inheriting HD choose to do so.
Clinical
A
physical examinationPhysical examination or clinical examination is the process by which a doctor investigates the body of a patient for signs of disease. It generally follows the taking of the medical history — an account of the symptoms as experienced by the patient...
, sometimes combined with a psychological examination, can determine whether the onset of the disease has begun. Excessive unintentional movements of any part of the body are often the reason for seeking medical consultation. If these are abrupt and have random timing and distribution, they suggest a diagnosis of HD. Cognitive or psychiatric symptoms are rarely the first diagnosed; they are usually only recognized in hindsight or when they develop further. How far the disease has progressed can be measured using the
unified Huntington's disease rating scale which provides an overall rating system based on motor, behavioral, cognitive, and functional assessments.
Medical imagingMedical imaging is the technique and process used to create images of the human body for clinical purposes or medical science...
, such as computerized tomography (CT) and
magnetic resonance imagingMagnetic resonance imaging , nuclear magnetic resonance imaging , or magnetic resonance tomography is a medical imaging technique used in radiology to visualize detailed internal structures...
(MRI), only shows visible
cerebral atrophyCerebral atrophy is a common feature of many of the diseases that affect the brain. Atrophy of any tissue means loss of cells. In brain tissue, atrophy describes a loss of neurons and the connections between them...
in the advanced stages of the disease.
Functional neuroimagingFunctional neuroimaging is the use of neuroimaging technology to measure an aspect of brain function, often with a view to understanding the relationship between activity in certain brain areas and specific mental functions...
techniques such as
fMRIFunctional magnetic resonance imaging or functional MRI is a type of specialized MRI scan used to measure the hemodynamic response related to neural activity in the brain or spinal cord of humans or other animals. It is one of the most recently developed forms of neuroimaging...
and
PETPositron emission tomography is nuclear medicine imaging technique that produces a three-dimensional image or picture of functional processes in the body. The system detects pairs of gamma rays emitted indirectly by a positron-emitting radionuclide , which is introduced into the body on a...
can show changes in brain activity before the onset of physical symptoms.
Genetic
Because HD follows an autosomal dominant pattern of inheritance, there is a strong motivation for individuals who are at risk of inheriting it to seek a diagnosis. The genetic test for HD consists of a
blood testGenetic testing is among the newest and most sophisticated of techniques used to test for genetic disorders which involves direct examination of the DNA molecule itself. Other genetic tests include biochemical tests for such gene products as enzymes and other proteins and for microscopic...
which counts the numbers of CAG repeats in each of the
HTT alleles. A positive result is not considered a diagnosis, since it may be obtained decades before the symptoms begin. However, a negative test means that the individual does not carry the expanded copy of the gene and will not develop HD.
A pre-symptomatic test is a life-changing event and a very personal decision. The main reason given for choosing testing for HD is to aid in career and family decisions. Over 95% of individuals at risk of inheriting HD do not proceed with testing, mostly because there is no treatment. A key issue is the anxiety an individual experiences about not knowing whether they will eventually develop HD, compared to the impact of a positive result. Irrespective of the result, stress levels have been found to be lower two years after being tested, but the risk of suicide is increased after a positive test result. Individuals found to have not inherited the disorder may experience
survivor guiltSurvivor, survivor's, or survivors guilt or syndrome is a mental condition that occurs when a person perceives themselves to have done wrong by surviving a traumatic event when others did not...
with regard to family members who are affected. Other factors taken into account when considering testing include the possibility of discrimination and the implications of a positive result, which usually means a parent has an affected gene and that the individual's siblings will be at risk of inheriting it.
Genetic counselingGenetic counseling or traveling is the process by which patients or relatives, at risk of an inherited disorder, are advised of the consequences and nature of the disorder, the probability of developing or transmitting it, and the options open to them in management and family planning...
in HD can provide information, advice and support for initial decision-making, and then, if chosen, throughout all stages of the testing process. Counseling and guidelines on the use of genetic testing for HD have become models for other genetic disorders, such as autosomal dominant cerebellar
ataxiaAtaxia is a neurological sign and symptom that consists of gross lack of coordination of muscle movements. Ataxia is a non-specific clinical manifestation implying dysfunction of the parts of the nervous system that coordinate movement, such as the cerebellum...
s.
Presymptomatic testingPredictive testing is a form of genetic testing. It is also known as presymptomatic testing. These types of testing are used to detect gene mutations associated with disorders that appear after birth, often later in life. These tests can be helpful to people who have a family member with a...
for HD has also influenced testing for other illnesses with genetic variants such as polycystic kidney disease, familial
Alzheimer's diseaseAlzheimer's disease also known in medical literature as Alzheimer disease is the most common form of dementia. There is no cure for the disease, which worsens as it progresses, and eventually leads to death...
and
breast cancerBreast cancer is cancer originating from breast tissue, most commonly from the inner lining of milk ducts or the lobules that supply the ducts with milk. Cancers originating from ducts are known as ductal carcinomas; those originating from lobules are known as lobular carcinomas...
.
Embryonic
EmbryoAn embryo is a multicellular diploid eukaryote in its earliest stage of development, from the time of first cell division until birth, hatching, or germination...
s produced using
in vitro fertilizationIn vitro fertilisation is a process by which egg cells are fertilised by sperm outside the body: in vitro. IVF is a major treatment in infertility when other methods of assisted reproductive technology have failed...
may be genetically tested for HD using
preimplantation genetic diagnosisIn medicine and genetics pre-implantation genetic diagnosis refers to procedures that are performed on embryos prior to implantation, sometimes even on oocytes prior to fertilization. PGD is considered another way to prenatal diagnosis...
. This technique, where a single cell is extracted from a 4 to 8 cell embryo and then tested for the genetic abnormality, can then be used to ensure embryos with affected
HTT genes are not implanted, and therefore any offspring will not inherit the disease. It is also possible to obtain a
prenatal diagnosisPrenatal diagnosis or prenatal screening is testing for diseases or conditions in a fetus or embryo before it is born. The aim is to detect birth defects such as neural tube defects, Down syndrome, chromosome abnormalities, genetic diseases and other conditions, such as spina bifida, cleft palate,...
for an embryo or
fetusA fetus is a developing mammal or other viviparous vertebrate after the embryonic stage and before birth.In humans, the fetal stage of prenatal development starts at the beginning of the 11th week in gestational age, which is the 9th week after fertilization.-Etymology and spelling variations:The...
in the womb.
Differential diagnosis
About 90% of HD diagnoses based on the typical symptoms and a
family historyFamily history is the systematic narrative and research of past events relating to a specific family, or specific families.- Introduction :...
of the disease are confirmed by genetic testing to have the expanded trinucleotide repeat that causes HD. Most of the remaining are called HD-like disorders. Most of these other disorders are collectively labelled HD-like (HDL). The cause of most HDL diseases is unknown, but those with known causes are due to mutations in the
prion protein geneMajor prion protein also known as CD230 is a protein that in humans is encoded by the PRNP gene...
(HDL1), the
junctophilin 3 geneJunctophilin-3 is a protein that in humans is encoded by the JPH3 gene.-External links:* -Further reading:...
(HDL2), a recessively inherited
HTT gene (HDL3—only found in one family and poorly understood), and the gene encoding the
TATA box-binding proteinThe TATA-binding protein is a general transcription factor that binds specifically to a DNA sequence called the TATA box. This DNA sequence is found about 35 base pairs upstream of the transcription start site in some eukaryotic gene promoters...
(HDL4/
SCA17Spinocerebellar ataxia is a progressive, degenerative, genetic disease with multiple types, each of which could be considered a disease in its own right.-Classification:...
). Other autosomal dominant diseases that can be misdiagnosed as HD are
dentatorubral-pallidoluysian atrophyDentatorubral-pallidoluysian atrophy is an autosomal dominant spinocerebellar degeneration caused by an expansion of a CAG repeat encoding a polyglutamine tract in the atrophin-1 protein. It is also known as Haw River Syndrome and Naito-Oyanagi disease. Although this condition was perhaps first...
and
neuroferritinopathyAdult-onset basal ganglia disease or neuroferritinopathy is a disorder caused by abnormal iron accumulation in the basal ganglia due to mutations in FTL gene...
. There are also autosomal recessive disorders that resemble sporadic cases of HD. Main examples are
chorea acanthocytosisChorea-acanthocytosis , is a rare hereditary disease caused by a mutation of the gene that directs structural proteins in red blood cells. It belongs to a group of four diseases characterized under the name Neuroacanthocytosis. When a patient's blood is viewed under a microscope, some of the red...
,
pantothenate kinase-associated neurodegenerationPantothenate kinase-associated neurodegeneration , also known as neurodegeneration with brain iron accumulation 1 and formerly called Hallervorden-Spatz syndrome Pantothenate kinase-associated neurodegeneration (PKAN), also known as neurodegeneration with brain iron accumulation 1 (NBIA1) and...
and
X-linkedSex linkage is the phenotypic expression of an allele related to the chromosomal sex of the individual. This mode of inheritance is in contrast to the inheritance of traits on autosomal chromosomes, where both sexes have the same probability of inheritance...
McLeod syndromeMcLeod syndrome is a genetic disorder that may affect the blood, brain, peripheral nerves, muscle and heart. It is caused by a variety of recessively-inherited mutations in the XK gene on the X chromosome...
.
Management
There is no cure for HD, but there are treatments available to reduce the severity of some of its symptoms. For many of these treatments, comprehensive clinical trials to confirm their effectiveness in treating symptoms of HD specifically are incomplete. As the disease progresses and a person's ability to tend to his own needs reduces, carefully managed multidisciplinary caregiving becomes increasingly necessary.
TetrabenazineTetrabenazine is a drug for the symptomatic treatment of hyperkinetic movement disorder and is marketed under the trade names Nitoman in Canada and Xenazine in New Zealand and some parts of Europe, and is also available in the USA as an orphan drug. On August 15, 2008 the U.S...
was developed specifically to reduce the severity of chorea in HD, it was approved in 2008 for this use in the US. Other drugs that help to reduce chorea include neuroleptics and
benzodiazepineA benzodiazepine is a psychoactive drug whose core chemical structure is the fusion of a benzene ring and a diazepine ring...
s. Compounds such as
amantadineAmantadine is the organic compound known formally as 1-adamantylamine or 1-aminoadamantane. The molecule consists of adamantane backbone that has an amino group substituted at one of the four methyne positions. This pharmaceutical is sold under the name Symmetrel for use both as an antiviral and an...
or
remacemideRemacemide is a drug which acts as a low-affinity NMDA antagonist with sodium channel blocking properties. It has been studied for the treatment of acute ischemic stroke and epilepsy....
are still under investigation but have shown preliminary positive results.
HypokinesiaHypokinesia refers to decreased bodily movement. It is associated with basal ganglia diseases , mental health disorders and prolonged inactivity due to illness, amongst other diseases.Hypokinesia describes a spectrum of disorders:...
and rigidity can be treated with antiparkinsonian drugs, and myoclonic hyperkinesia can be treated with
valproic acidValproic acid is a chemical compound that has found clinical use as an anticonvulsant and mood-stabilizing drug, primarily in the treatment of epilepsy, bipolar disorder, and, less commonly, major depression. It is also used to treat migraine headaches and schizophrenia...
.
Psychiatric symptoms can be treated with medications similar to those used in the general population.
Selective serotonin reuptake inhibitor Selective serotonin re-uptake inhibitors or serotonin-specific reuptake inhibitor are a class of compounds typically used as antidepressants in the treatment of depression, anxiety disorders, and some personality disorders. The efficacy of SSRIs is disputed...
s and
mirtazapineMirtazapine is a tetracyclic antidepressant used primarily in the treatment of depression. It is also sometimes used as a hypnotic, antiemetic, and appetite stimulant, and for the treatment of anxiety, among other indications...
have been recommended for depression, while
atypical antipsychoticThe atypical antipsychotics are a group of antipsychotic tranquilizing drugs used to treat psychiatric conditions. Some atypical antipsychotics are FDA approved for use in the treatment of schizophrenia...
drugs are recommended for psychosis and behavioral problems.
Weight loss and eating difficulties due to
dysphagiaDysphagia is the medical term for the symptom of difficulty in swallowing. Although classified under "symptoms and signs" in ICD-10, the term is sometimes used as a condition in its own right. Sufferers are sometimes unaware of their dysphagia....
and other muscle discoordination are common, making nutrition management increasingly important as the disease advances.
Thickening agentThickening agents, or thickeners, is the term applied to substances which increase the viscosity of a solution or liquid/solid mixture without substantially modifying its other properties; although most frequently applied to foods where the target property is taste, the term also is applicable to...
s can be added to liquids as thicker fluids are easier and safer to swallow. Reminding the patient to eat slowly and to take smaller pieces of food into the mouth may also be of use to prevent choking. If eating becomes too hazardous or uncomfortable, the option of using a
percutaneous endoscopic gastrostomyPercutaneous endoscopic gastrostomy is an endoscopic medical procedure in which a tube is passed into a patient's stomach through the abdominal wall, most commonly to provide a means of feeding when oral intake is not adequate. The procedure is an alternative to surgical gastrostomy insertion, and...
is available. This is a feeding tube, permanently attached through the
abdomenIn vertebrates such as mammals the abdomen constitutes the part of the body between the thorax and pelvis. The region enclosed by the abdomen is termed the abdominal cavity...
into the stomach, which reduces the risk of
aspiratingPulmonary aspiration is the entry of material from the oropharynx or gastrointestinal tract into the larynx and lower respiratory tract...
food and provides better nutritional management.
Although there have been relatively few studies of exercises and therapies that help
rehabilitateRehabilitation of sensory and cognitive function typically involves methods for retraining neural pathways or training new neural pathways to regain or improve neurocognitive functioning that has been diminished by disease or traumatic injury....
cognitive symptoms of HD, there is some evidence for the usefulness of
physical therapyPhysical therapy , often abbreviated PT, is a health care profession. Physical therapy is concerned with identifying and maximizing quality of life and movement potential within the spheres of promotion, prevention, diagnosis, treatment/intervention,and rehabilitation...
, occupational therapy, and speech therapy. Patients with Huntington’s disease may see a physical therapist for non-invasive and non-medication ways of managing the physical symptoms of HD. Physical therapists may implement fall risk assessment and prevention, as well as strengthening, stretching, and cardiovascular exercises. The Tinetti Mobility Test has been found to be a valid outcome measure for determining whether a patient with HD is at risk for falling, as its scores correlated with the
Unified Huntington Disease Rating Scale motor scores (
r = –0.751,
p<0.0001). Patients with TMT scores below 21 are at higher risk of falling. Other valid and responsive tools for assessing risk of falling in individuals with HD include the Functional Reach Test, Berg Balance Scale, and the Timed Up and Go Test. A Berg Balance Scale score of less than 40 or Timed Up and Go Test score of greater than 14 seconds indicate increased risk of falling in individuals with HD. However, more rigorous studies are needed for health authorities to endorse the usefulness of the rehabilitation professions. A multidisciplinary approach may be important to limit disability.
The families of individuals, who have inherited or are at risk of inheriting HD, have generations of experience of HD which may be outdated and lack knowledge of recent breakthroughs and improvements in genetic testing, family planning choices, care management, and other considerations.
Genetic counselingGenetic counseling or traveling is the process by which patients or relatives, at risk of an inherited disorder, are advised of the consequences and nature of the disorder, the probability of developing or transmitting it, and the options open to them in management and family planning...
benefits these individuals by updating their knowledge, dispelling any myths they may have and helping them consider their future options and plans.
Prognosis
The length of the trinucleotide repeat accounts for 60% of the variation in the age of onset and the rate of progression of symptoms. A longer repeat results in an earlier age of onset and a faster progression of symptoms. For example, individuals with a trinucleotide repeat greater than sixty repeats often develop the disease before twenty years of age, and those with less than forty repeats may not develop noticeable symptoms. The remaining variation is due to environmental factors and other genes that influence the mechanism of the disease.
Life expectancy in HD is generally around 20 years following the onset of visible symptoms. Most of the complications that are life-threatening result from muscle coordination issues, or to a lesser extent from behavioral changes resulting from the decline in cognitive function. The largest risk is
pneumoniaPneumonia is an inflammatory condition of the lung—especially affecting the microscopic air sacs —associated with fever, chest symptoms, and a lack of air space on a chest X-ray. Pneumonia is typically caused by an infection but there are a number of other causes...
, which is the cause of death of one-third of those with HD. As the ability to synchronize movements deteriorates, difficulty clearing the lungs and an increased risk of
aspiratingPulmonary aspiration is the entry of material from the oropharynx or gastrointestinal tract into the larynx and lower respiratory tract...
food or drink both increase the risk of contracting pneumonia. The second greatest risk is
heart diseaseHeart disease, cardiac disease or cardiopathy is an umbrella term for a variety of diseases affecting the heart. , it is the leading cause of death in the United States, England, Canada and Wales, accounting for 25.4% of the total deaths in the United States.-Types:-Coronary heart disease:Coronary...
, which causes almost a quarter of fatalities of those with HD.
SuicideSuicide is the act of intentionally causing one's own death. Suicide is often committed out of despair or attributed to some underlying mental disorder, such as depression, bipolar disorder, schizophrenia, alcoholism, or drug abuse...
is the next greatest cause of fatalities, with 7.3% of those with HD taking their own lives and up to 27% attempting to do so. It is unclear to what extent suicidal thoughts are influenced by psychiatric symptoms, as they may be considered to be a response of an individual to retain a sense of control of their life or to avoid the later stages of the disease. Other associated risks include choking,
physical injury-By cause:*Traumatic injury, a body wound or shock produced by sudden physical injury, as from violence or accident*Other injuries from external physical causes, such as radiation injury, burn injury or frostbite*Injury from infection...
from falls, and malnutrition.
Epidemiology
The late onset of Huntington's disease means it does not usually affect reproduction. The worldwide
prevalenceIn epidemiology, the prevalence of a health-related state in a statistical population is defined as the total number of cases of the risk factor in the population at a given time, or the total number of cases in the population, divided by the number of individuals in the population...
of HD is 5-10 cases per 100,000 persons, but varies greatly geographically as a result of ethnicity, local migration and past immigration patterns. Prevalence is similar for men and women. The rate of occurrence is highest in peoples of Western European descent, averaging around seventy per million people, and is lower in the rest of the world, e.g. one per million people of Asian and African descent. Additionally, some localized areas have a much higher prevalence than their regional average. One of the highest prevalences is in the isolated populations of the
Lake MaracaiboLake Maracaibo is a large brackish bay in Venezuela at . It is connected to the Gulf of Venezuela by Tablazo Strait at the northern end, and fed by numerous rivers, the largest being the Catatumbo. It is commonly considered a lake rather than a bay or lagoon, and at 13,210 km² it would be the...
region of
VenezuelaVenezuela , officially called the Bolivarian Republic of Venezuela , is a tropical country on the northern coast of South America. It borders Colombia to the west, Guyana to the east, and Brazil to the south...
, where HD affects up to seven thousand per million people. Other areas of high localization have been found in
TasmaniaTasmania is an Australian island and state. It is south of the continent, separated by Bass Strait. The state includes the island of Tasmania—the 26th largest island in the world—and the surrounding islands. The state has a population of 507,626 , of whom almost half reside in the greater Hobart...
and specific regions of
ScotlandScotland is a country that is part of the United Kingdom. Occupying the northern third of the island of Great Britain, it shares a border with England to the south and is bounded by the North Sea to the east, the Atlantic Ocean to the north and west, and the North Channel and Irish Sea to the...
,
WalesWales is a country that is part of the United Kingdom and the island of Great Britain, bordered by England to its east and the Atlantic Ocean and Irish Sea to its west. It has a population of three million, and a total area of 20,779 km²...
and
SwedenSweden , officially the Kingdom of Sweden , is a Nordic country on the Scandinavian Peninsula in Northern Europe. Sweden borders with Norway and Finland and is connected to Denmark by a bridge-tunnel across the Öresund....
. Increased prevalence in some cases occurs due to a local
founder effectIn population genetics, the founder effect is the loss of genetic variation that occurs when a new population is established by a very small number of individuals from a larger population. It was first fully outlined by Ernst Mayr in 1942, using existing theoretical work by those such as Sewall...
, a historical migration of carriers into an area of geographic isolation. Some of these carriers have been traced back hundreds of years using
genealogicalGenealogy is the study of families and the tracing of their lineages and history. Genealogists use oral traditions, historical records, genetic analysis, and other records to obtain information about a family and to demonstrate kinship and pedigrees of its members...
studies. Genetic
haplotypeA haplotype in genetics is a combination of alleles at adjacent locations on the chromosome that are transmitted together...
s can also give clues for the geographic variations of prevalence.
Until the discovery of a genetic test, statistics could only include clinical diagnosis based on physical symptoms and a family history of HD, excluding those who died of other causes before diagnosis. These cases can now be included in statistics and as the test becomes more widely available, estimates of the prevalence and incidence of the disorder are likely to increase.
History
The first definite mention of HD was in a letter by Charles Oscar Waters, published in the first edition of
Robley DunglisonRobley Dunglison was an English physician who moved to America to join the first faculty of the University of Virginia. He was personal physician to Thomas Jefferson and considered the "Father of American Physiology".-Biography:...
's
Practice of Medicine in 1842. Waters described 'a form of chorea, vulgarly called magrums', including accurate descriptions of the chorea, its progression, and the strong heredity of the disease. In 1846 Charles Gorman observed how higher prevalence seemed to occur in localized regions. Independently of Gorman and Waters, both students of Dunglison at Jefferson Medical College in Philadelphia, Johan Christian Lund also produced an early description in 1860. He specifically noted that in Setesdalen, a secluded area in
NorwayNorway , officially the Kingdom of Norway, is a Nordic unitary constitutional monarchy whose territory comprises the western portion of the Scandinavian Peninsula, Jan Mayen, and the Arctic archipelago of Svalbard and Bouvet Island. Norway has a total area of and a population of about 4.9 million...
, there was a high prevalence of dementia associated with a pattern of jerking movement disorders that ran in families.
The first thorough description of the disease was by
George HuntingtonGeorge Huntington was an American physician who contributed a classic clinical description of the disease that bears his name -- Huntington's disease....
in 1872. Examining the combined medical history of several generations of a family exhibiting similar symptoms, he realized their conditions must be linked; he presented his detailed and accurate definition of the disease as his first paper. Huntington described the exact pattern of inheritance of autosomal dominant disease years before the rediscovery by scientists of
Mendelian inheritanceMendelian inheritance is a scientific description of how hereditary characteristics are passed from parent organisms to their offspring; it underlies much of genetics...
.
"Of its hereditary nature. When either or both the parents have shown manifestations of the disease ..., one or more of the offspring almost invariably suffer from the disease ... But if by any chance these children go through life without it, the thread is broken and the grandchildren and great-grandchildren of the original shakers may rest assured that they are free from the disease.".
Sir
William OslerSir William Osler, 1st Baronet was a physician. He was one of the "Big Four" founding professors at Johns Hopkins Hospital as the first Professor of Medicine and founder of the Medical Service there. Sir William Osler, 1st Baronet (July 12, 1849 – December 29, 1919) was a physician. He was...
was interested in the disorder and chorea in general, and was impressed with Huntington's paper, stating that "In the history of medicine, there are few instances in which a disease has been more accurately, more graphically or more briefly described." Osler's continued interest in HD, combined with his influence in the field of medicine, helped to rapidly spread awareness and knowledge of the disorder throughout the medical community. Great interest was shown by scientists in Europe, including
Louis Théophile Joseph LandouzyLouis Théophile Joseph Landouzy was a French neurologist from Reims, and whose father and grandfather were also physicians. He studied medicine in Reims and Paris, earning his doctorate in 1876...
,
Désiré-Magloire BournevilleDésiré-Magloire Bourneville was a French neurologist born in Garencières. He studied medicine in Paris, and was an intern at the Salpêtrière and Bicêtre Hospitals....
,
Camillo GolgiCamillo Golgi was an Italian physician, pathologist, scientist, and Nobel laureate.-Biography:Camillo Golgi was born in the village of Corteno, Lombardy, then part of the Austrian Empire. The village is now named Corteno Golgi in his honour. His father was a physician and district medical officer...
, and
Joseph Jules DejerineJoseph Jules Dejerine , was a French neurologist.Joseph Jules Dejerine was born to French parents in Geneva, Switzerland, where his father was a carriage proprietor. During the Franco-Prussian War Dejerine worked as a volunteer in a Geneva Hospital and in the spring of 1871 decided to pursue his...
, and until the end of the century, much of the research into HD was European in origin. By the end of the 19th century, research and reports on HD had been published in many countries and the disease was recognized as a worldwide condition.
During the rediscovery of Mendelian inheritance at the turn of the 20th century, HD was used tentatively as an example of autosomal dominant inheritance. The English biologist
William BatesonWilliam Bateson was an English geneticist and a Fellow of St. John's College, Cambridge...
used the pedigrees of affected families to establish that HD had an autosomal dominant inheritance pattern. The strong inheritance pattern prompted several researchers, including
Smith Ely JelliffeSmith Ely Jelliffe . American neurologist, psychiatrist, and psychoanalyst who lived and practiced in New York City nearly his entire life. Originally trained in botany and pharmacy, Jelliffe switched first to neurology in the mid-1890s then to psychiatry, neuropsychiatry, and ultimately to...
, to attempt to trace and connect family members of previous studies. Jelliffe collected information from across New York State and published several articles regarding the genealogy of HD in
New EnglandNew England is a region in the northeastern corner of the United States consisting of the six states of Maine, New Hampshire, Vermont, Massachusetts, Rhode Island, and Connecticut...
. Jelliffe's research roused the interest of his college friend,
Charles DavenportCharles Benedict Davenport was a prominent American eugenicist and biologist. He was one of the leaders of the American eugenics movement, which was directly involved in the sterilization of around 60,000 "unfit" Americans and strongly influenced the Holocaust in Europe.- Biography :Davenport was...
, who commissioned Elizabeth Muncey to produce the first field study on the
East Coast of the United StatesThe East Coast of the United States, also known as the Eastern Seaboard, refers to the easternmost coastal states in the United States, which touch the Atlantic Ocean and stretch up to Canada. The term includes the U.S...
of families with HD and to construct their pedigrees. Davenport used this information to document the variable age of onset and range of symptoms of HD; he claimed that most cases of HD in the USA could be traced back to a handful of individuals. This research was further embellished in 1932 by P. R. Vessie, who popularized the idea that three brothers who left
EnglandEngland is a country that is part of the United Kingdom. It shares land borders with Scotland to the north and Wales to the west; the Irish Sea is to the north west, the Celtic Sea to the south west, with the North Sea to the east and the English Channel to the south separating it from continental...
in 1630 bound for
BostonBoston is the capital of and largest city in Massachusetts, and is one of the oldest cities in the United States. The largest city in New England, Boston is regarded as the unofficial "Capital of New England" for its economic and cultural impact on the entire New England region. The city proper had...
were the progenitors of HD in the USA. The claim that the earliest progenators had been established and eugenic bias of Muncey's, Davenport, and Vessie's work contributed to misunderstandings and prejudice about HD. Muncey and Davenport also popularized the idea that in the past some HD sufferers may have been thought to be possessed by spirits or victims of
witchcraftWitchcraft, in historical, anthropological, religious, and mythological contexts, is the alleged use of supernatural or magical powers. A witch is a practitioner of witchcraft...
, and were sometimes
shunnedShunning can be the act of social rejection, or mental rejection. Social rejection is when a person or group deliberately avoids association with, and habitually keeps away from an individual or group. This can be a formal decision by a group, or a less formal group action which will spread to all...
or
exileExile means to be away from one's home , while either being explicitly refused permission to return and/or being threatened with imprisonment or death upon return...
d by society. This idea has not been proven. Researchers have found contrary evidence; for instance, the community of the family studied by George Huntington openly accommodated those who exhibited symptoms of HD.
Research into the disorder continued steadily through the 20th century, reaching a major breakthrough in 1983 when the US–
VenezuelaVenezuela , officially called the Bolivarian Republic of Venezuela , is a tropical country on the northern coast of South America. It borders Colombia to the west, Guyana to the east, and Brazil to the south...
Huntington's Disease Collaborative Research Project discovered the approximate location of a causal gene. This was the result of an extensive study begun in 1979, focusing on the populations of two isolated Venezuelan villages, Barranquitas and Lagunetas, where there was an unusually high prevalence of the disease. Among other innovations, the project developed
DNADeoxyribonucleic acid is a nucleic acid that contains the genetic instructions used in the development and functioning of all known living organisms . The DNA segments that carry this genetic information are called genes, but other DNA sequences have structural purposes, or are involved in...
-marking methods which were an important step in making the
Human Genome ProjectThe Human Genome Project is an international scientific research project with a primary goal of determining the sequence of chemical base pairs which make up DNA, and of identifying and mapping the approximately 20,000–25,000 genes of the human genome from both a physical and functional...
possible. In 1993 the research group isolated the precise causal gene at 4p16.3, making this the first autosomal disease
locusIn the fields of genetics and genetic computation, a locus is the specific location of a gene or DNA sequence on a chromosome. A variant of the DNA sequence at a given locus is called an allele. The ordered list of loci known for a particular genome is called a genetic map...
found using genetic linkage analysis. In the same time frame, key discoveries concerning the mechanisms of the disorder were being made, including the findings by
Anita HardingAnita Harding was a British neurologist. She was born in Birmingham and educated at the King Edward VI High School for Girls and the Royal Free Hospital Medical School, where she qualified in 1975. She married neurology professor P.K...
's research group on the effects of the gene's length.
Modelling the disease in various types of animals, such as the transgenic mouse developed in 1996, enabled larger scale experiments. As these animals have faster
metabolismMetabolism is the set of chemical reactions that happen in the cells of living organisms to sustain life. These processes allow organisms to grow and reproduce, maintain their structures, and respond to their environments. Metabolism is usually divided into two categories...
s and much shorter lifespans than humans, results from experiments are received sooner, speeding research. The 1997 discovery that mHtt fragments
misfoldProtein folding is the process by which a protein structure assumes its functional shape or conformation. It is the physical process by which a polypeptide folds into its characteristic and functional three-dimensional structure from random coil....
led to the discovery of the
nuclear inclusionsInclusion bodies are nuclear or cytoplasmic aggregates of stainable substances, usually proteins. They typically represent sites of viral multiplication in a bacterium or a eukaryotic cell and usually consist of viral capsid proteins...
they cause. These advances have led to increasingly extensive research into the proteins involved with the disease, potential drug treatments, care methods, and the gene itself.
Ethics
Huntington's disease, particularly the application of the genetic test for the disease, has raised several ethical issues. The issues for genetic testing include defining how mature an individual should be before being considered eligible for testing, ensuring the confidentiality of results, and whether companies should be allowed to use test results for decisions on employment, life insurance or other financial matters. There was controversy when
Charles DavenportCharles Benedict Davenport was a prominent American eugenicist and biologist. He was one of the leaders of the American eugenics movement, which was directly involved in the sterilization of around 60,000 "unfit" Americans and strongly influenced the Holocaust in Europe.- Biography :Davenport was...
proposed in 1910 that
compulsory sterilizationCompulsory sterilization also known as forced sterilization programs are government policies which attempt to force people to undergo surgical sterilization...
and
immigrationImmigration is the act of foreigners passing or coming into a country for the purpose of permanent residence...
control be used for people with certain diseases, including HD, as part of the
eugenicsEugenics is the "applied science or the bio-social movement which advocates the use of practices aimed at improving the genetic composition of a population", usually referring to human populations. The origins of the concept of eugenics began with certain interpretations of Mendelian inheritance,...
movement. In vitro fertilization has some issues regarding its use of embryos. Some HD research has ethical issues due to its use of animal testing and embryonic stem cells.
The development of an accurate diagnostic test for Huntington's disease has caused social, legal, and ethical concerns over access to and use of a person's results.
Many guidelines and testing procedures have strict procedures for disclosure and confidentiality to allow individuals to decide when and how to receive their results and also to whom the results are made available.
Financial institutionIn financial economics, a financial institution is an institution that provides financial services for its clients or members. Probably the most important financial service provided by financial institutions is acting as financial intermediaries...
s and businesses are faced with the question of whether to use genetic test results when assessing an individual, such as for life insurance or employment. Although the United Kingdom's insurance companies have agreed that until 2014 they will not use genetic information when writing most insurance policies, Huntington's is explicitly excluded from this agreement. As with other untreatable genetic conditions with a later onset, it is ethically questionable to perform pre-symptomatic testing on a child or adolescent, as there would be no medical benefit for that individual. There is consensus for testing only individuals who are considered cognitively mature, although there is a counter-argument that parents have a right to make the decision on their child's behalf. With the lack of an effective treatment, testing a person under legal age who is not judged to be
competentGillick competence is a term originating in England and is used in medical law to decide whether a child is able to consent to his or her own medical treatment, without the need for parental permission or knowledge....
is considered unethical in most cases.
There are ethical concerns related to
prenatal genetic testingPrenatal diagnosis or prenatal screening is testing for diseases or conditions in a fetus or embryo before it is born. The aim is to detect birth defects such as neural tube defects, Down syndrome, chromosome abnormalities, genetic diseases and other conditions, such as spina bifida, cleft palate,...
or
preimplantation genetic diagnosisIn medicine and genetics pre-implantation genetic diagnosis refers to procedures that are performed on embryos prior to implantation, sometimes even on oocytes prior to fertilization. PGD is considered another way to prenatal diagnosis...
to ensure a child is not born with a given disease. For example, prenatal testing raises the issue of selective abortion, a choice considered unacceptable by some. Using preimplantation testing for HD requires twice as many embryos to be used for in vitro fertilization, as half of them will be positive for HD. As it is a dominant disease, there are difficulties in situations in which a parent does not want to know his or her own diagnosis. This would require parts of the process to be kept secret from the parent.
Support organizations
In 1968, after experiencing HD in his wife's family, Dr. Milton Wexler was inspired to start the
Hereditary Disease FoundationThe Hereditary Disease Foundation aims to cure genetic disorders by supporting basic biomedical research.-History:In 1968, after experiencing Huntington's disease in his wife's family, Dr. Milton Wexler was inspired to start the Hereditary Disease Foundation, with the aim of curing genetic...
(HDF), with the aim of curing genetic illnesses by coordinating and supporting research. The foundation and Dr. Wexler's daughter,
Nancy WexlerNancy Wexler FRCP is a geneticist and the Higgins Professor of Neuropsychology at Columbia University, best known for her discovery of the location of the gene that causes Huntington's disease . Despite having an AB and PhD in clinical psychology, Wexler instead chose to work in genetics...
, were key parts of the research team in Venezuela which discovered the HD gene. At roughly the same time as the HDF formed,
Marjorie GuthrieMarjorie Mazia Guthrie was for a time the wife of folk musician Woody Guthrie, and was the mother of folk musician Arlo Guthrie and Woody Guthrie archivist Nora Guthrie....
helped to found the Committee to Combat Huntington's Disease (now the
Huntington's Disease Society of AmericaHuntington's Disease Society of America is a national non-profit organization committed to finding a cure for Huntington's disease. Huntington's disease is an incurable degenerative disease of the nervous system that affects movement, thinking, and some aspects of personality. The disease is...
), after her husband
Woody GuthrieWoodrow Wilson "Woody" Guthrie is best known as an American singer-songwriter and folk musician, whose musical legacy includes hundreds of political, traditional and children's songs, ballads and improvised works. He frequently performed with the slogan This Machine Kills Fascists displayed on his...
died from complications of HD. Since then, support and research organizations have formed in many countries around the world and have helped to increase public awareness of HD. A number of these collaborate in umbrella organizations, like the International Huntington Association and the EuroHD network. Many support organizations hold an annual HD awareness event, some of which have been endorsed by their respective governments. For example, June 6 is designated "National Huntington's Disease Awareness Day" by the
US SenateThe United States Senate is the upper house of the bicameral legislature of the United States, and together with the United States House of Representatives comprises the United States Congress. The composition and powers of the Senate are established in Article One of the U.S. Constitution. Each...
.
Research directions
Research into the mechanism of HD has focused on identifying the functioning of Htt, how mHtt differs or interferes with it, and the brain pathology that the disease produces. Most research is conducted in animals. Appropriate animal models are critical for understanding the fundamental mechanisms causing the disease and for supporting the early stages of
drug developmentDrug development is a blanket term used to define the process of bringing a new drug to the market once a lead compound has been identified through the process of drug discovery...
. Mice and monkeys, chemically induced to exhibit HD-like symptoms were initially used, but they did not mimic the progressive features of the disease. Since the Huntingtin gene was identified, transgenic animals (mice,
DrosophilaDrosophila melanogaster is a species of Diptera, or the order of flies, in the family Drosophilidae. The species is known generally as the common fruit fly or vinegar fly. Starting from Charles W...
fruit fliesDrosophila melanogaster is a species of Diptera, or the order of flies, in the family Drosophilidae. The species is known generally as the common fruit fly or vinegar fly. Starting from Charles W...
, and more recently monkeys) exhibiting HD-like syndromes can be generated by inserting a CAG repeat expansion into the gene.
NematodeThe nematodes or roundworms are the most diverse phylum of pseudocoelomates, and one of the most diverse of all animals. Nematode species are very difficult to distinguish; over 28,000 have been described, of which over 16,000 are parasitic. It has been estimated that the total number of nematode...
worms also provide a valuable model when the gene is expressed.
Genetically engineered
intracellularNot to be confused with intercellular, meaning "between cells".In cell biology, molecular biology and related fields, the word intracellular means "inside the cell".It is used in contrast to extracellular...
antibody fragments called intrabodies have been shown to prevent mortality during the development stages of
Drosophila models. Their mechanism of action was an inhibition of mHtt aggregation. As HD has been conclusively linked to a single gene,
gene silencingGene silencing is a general term describing epigenetic processes of gene regulation. The term gene silencing is generally used to describe the "switching off" of a gene by a mechanism other than genetic modification...
is potentially possible and by using
gene knockdownGene knockdown refers to techniques by which the expression of one or more of an organism's genes is reduced, either through genetic modification or by treatment with a reagent such as a short DNA or RNA oligonucleotide with a sequence complementary to either an mRNA transcript or a gene...
in mouse models, researchers have shown that when the influence of mHtt is reduced, symptoms improve.
Stem cell therapyStem cell treatments are a type of intervention strategy that introduces new cells into damaged tissue in order to treat disease or injury. Many medical researchers believe that stem cell treatments have the potential to change the face of human disease and alleviate suffering...
is the replacement of damaged neurons by transplantation of
stem cellThis article is about the cell type. For the medical therapy, see Stem Cell TreatmentsStem cells are biological cells found in all multicellular organisms, that can divide and differentiate into diverse specialized cell types and can self-renew to produce more stem cells...
s into affected regions of the brain. Experiments have yielded some positive results using this technique in animal models and preliminary human
clinical trialClinical trials are a set of procedures in medical research and drug development that are conducted to allow safety and efficacy data to be collected for health interventions...
s.
Numerous drugs have been reported to produce benefits in animals, including
creatineCreatine is a nitrogenous organic acid that occurs naturally in vertebrates and helps to supply energy to all cells in the body, primarily muscle. This is achieved by increasing the formation of Adenosine triphosphate...
, coenzyme Q10 and the antibiotic
minocyclineMinocycline is a broad-spectrum tetracycline antibiotic, and has a broader spectrum than the other members of the group. It is a bacteriostatic antibiotic, classified as a long-acting type...
. Some of these have then been tested by humans in clinical trials, and as of 2009 several are at different stages of these trials. In 2010, minocycline was found to be ineffective for humans in a multi-center trial.
External links
- Huntington's Disease links directory at the Open Directory Project
The Open Directory Project , also known as Dmoz , is a multilingual open content directory of World Wide Web links. It is owned by Netscape but it is constructed and maintained by a community of volunteer editors.ODP uses a hierarchical ontology scheme for organizing site listings...