Huntington's disease Classification and external resources
George Huntington's 1872 paper described the disorder. George Huntington ( April 9, 1850 &ndash March 3, 1916) was an American Physician.
ICD-10	G10., F02.2
ICD-9	333.4, 294.1
OMIM	143100
DiseasesDB	6060
MeSH	D006816

Huntington's disease, also called Huntington's chorea, chorea major, or HD, is a genetic neurological disorder characterized by abnormal body movements called chorea and a lack of coordination; it also affects a number of mental abilities and some aspects of behavior. The International Statistical Classification of Diseases and Related Health Problems (most commonly known by the abbreviation ICD) provides codes to classify Diseases The International Statistical Classification of Diseases and Related Health Problems 10th Revision ( ICD -10) is a coding of diseases and signs symptoms abnormal findings G00-G99 - Diseases of the Nervous system (G00-G09 Inflammatory diseases of the Central nervous system ( Bacterial meningitis The 2007 version of the ICD is available online at http//wwwwho The International Statistical Classification of Diseases and Related Health Problems (most commonly known by the abbreviation ICD) provides codes to classify Diseases The following is a list of codes for International Statistical Classification of Diseases and Related Health Problems. The Mendelian Inheritance in Man project is a Database that catalogues all the known Diseases with a genetic component, and—when possible—links them The Diseases Database is a free Website that provides information about the relationships between medical conditions Symptoms, and Medications. Medical Subject Headings ( MeSH) is a huge Controlled vocabulary (or metadata system for the purpose of indexing journal articles and books Genetics (from Ancient Greek grc-Latn genetikos, “genitive” and that from grc-Latn genesis, “origin” a discipline of Biology, is Neurodegenerative Disease ( Greek νέυρο- néuro-, "nerval" and Latin dēgenerāre, "to decline" or "to Chorea sancti viti (Latin for " St Vitus' dance " is an abnormal involuntary movement disorder one of a group of neurological disorders called Dyskinesias The name is derived from the physician George Huntington who described the disorder in 1872. George Huntington ( April 9, 1850 &ndash March 3, 1916) was an American Physician. In 1993 the gene causing HD was found, making it one of the first inherited genetic disorders for which an accurate test could be performed. A genetic disorder is a condition caused by abnormalities in Genes or Chromosomes While some diseases such as Cancer, are due to genetic abnormalities acquired Because of this, and the disorder having aspects applicable to other neurological disorders such as Alzheimer's disease, it has been extensively researched since then. Alzheimer's disease ( AD) also called Alzheimer disease or simply Alzheimer's, is the most common form of Dementia.

The gene causing the disorder is dominant and may, therefore, be inherited from a single parent. Global incidence varies, from 3 to 7 per 100,000 people of Western European descent, down to 1 per 1,000,000 of Asian and African descent. The onset of physical symptoms in Huntington's disease occur in a large range around a mean of a person's late forties to early fifties. In Mathematics and Statistics, the arithmetic Mean (or simply the mean) of a list of numbers is the sum of all the members of the list divided If symptoms are noticeable before a person is twenty, then their condition is called Juvenile HD.

Huntington's disease is one of several polyglutamine diseases caused by a trinucleotide repeat expansion. This expansion is in the Huntingtin gene, which normally codes for Huntingtin protein (Htt), producing mutant Huntingtin (mHtt). The Huntingtin Gene, also called HD ( History See also History of genetics The existence of genes was first suggested by Gregor Mendel (1822-1884 who in the 1860s studied inheritance Huntingtin (Htt is the protein coded by the gene Huntingtin, identified in 1993 The presence of this protein increases the rate of neuron cell death in select areas of the brain, and affects the functions these parts perform. Neurons (ˈnjuːɹɒn also known as neurones and nerve cells) are responsive cells in the Nervous system that process and transmit information Programmed cell-death ( PCD) is death of a cell in any form mediated by an intracellular program The brain is the center of the Nervous system in animals All Vertebrates and the majority of Invertebrates have a brain This damage itself isn't fatal, but complications caused by its symptoms reduce life expectancy. There is currently no proven cure, so symptoms are managed with a range of medications and supportive services.

Contents 1 Symptoms 1.1 Physical 1.2 Cognitive 1.3 Psychopathological 2 Genetics 2.1 Inheritance 3 Mechanism 3.1 Function 3.2 Degradation 3.3 Pathophysiology 3.3.1 Brain 3.3.2 Other systems 4 Diagnosis 5 Management 5.1 Medication 5.2 Therapies 5.3 Nutrition 6 Prognosis 6.1 Social impact 7 Epidemiology 8 History 9 Society and culture 9.1 Organizations 10 Research directions 10.1 Intrabody therapy 10.2 Gene silencing 10.3 Stem cell implants 10.4 Others 11 References 12 Sources 13 Bibliography 14 External links 14.1 Professional and research 14.2 Support and advocacy 14.3 Other

Symptoms

Symptoms increase in severity progressively, but aren't often recognised until they reach certain stages. Physical symptoms are usually the first to cause problems and be noticed, but these are accompanied by cognitive and psychiatric ones which aren't often recognized. Cognition is a concept used in different ways by different disciplines but is generally accepted to mean the process of awareness or thought Psychiatry is a medical specialty which exists to study, prevent, and treat Mental disorders in Humans Psychiatric Almost everyone with Huntington's Disease eventually exhibit all physical symptoms, but cognitive symptoms vary, and so any psychopathological problems caused by these, also vary per individual. Psychopathology is a term which refers to either the study of Mental illness or mental distress or the manifestation of behaviours and experiences which may be indicative The symptoms of juvenile HD differ in that they generally progress faster and are more likely to exhibit rigidity and bradykinesia instead of chorea and often include seizures. In Medicine ( Neurology) bradykinesia denotes "slow movement" ( Etymology: brady = slow kinesia = movement An epileptic seizure is caused by excessive and/or hypersynchronous electrical Neuronal activity and is usually self-limiting ^[1]

Physical

The most characteristic symptoms are jerky, random, and uncontrollable movements called chorea, although sometimes very slow movement and stiffness (bradykinesia, dystonia) can occur instead or in later stages. Chorea sancti viti (Latin for " St Vitus' dance " is an abnormal involuntary movement disorder one of a group of neurological disorders called Dyskinesias In Medicine ( Neurology) bradykinesia denotes "slow movement" ( Etymology: brady = slow kinesia = movement Dystonia is a neurological Movement disorder in which sustained muscle contractions cause twisting and repetitive movements or abnormal postures These abnormal movements are initially exhibited as general lack of coordination, an unsteady gait and slurring of speech. Human gait is the way Locomotion is achieved using human limbs For this article different gaits do not require changes in the geometry of motion but rather As the disease progresses, any function that requires muscle control is affected, this causes reduced physical stability, abnormal facial expression, impaired speech comprehensibility, and difficulties chewing and swallowing. Dysphagia should not be confused with the similarly pronounced Dysphasia, a language disorder Eating difficulties commonly cause weight loss. ^[2][3] HD has been associated with sleep cycle disturbances, including insomnia and rapid eye movement sleep alterations. Insomnia is a symptom of a sleeping disorder characterized by persistent difficulty falling asleep or staying asleep despite the opportunity ^[4]

Counter intuitively, there may be some health benefits as carriers of the gene are hypothesized to have higher levels of the tumor suppressor protein p53 and a better than average immune system than non-carriers. p53 (also known as protein 53 or tumor protein 53) is a Transcription factor encoded by the TP53 gene As of April 2008, neither of these hypotheses have been supported with rigorous study. ^[5]

Cognitive

Selective cognitive abilities are progressively impaired, including executive function (planning, cognitive flexibility, abstract thinking, rule acquisition, initiating appropriate actions, and inhibiting inappropriate actions), psychomotor function (slowing of thought processes to control muscles), perceptual and spatial skills of self and surrounding environment, selection of correct methods of remembering information (but not actual memory itself), short-term memory, and ability to learn new skills, depending on the pathology of the individual. --> Abstraction is the process or result of generalization by reducing the information Psychomotor retardation comprises a slowing down of Thought and a reduction of physical movements in a person In Psychology and the Cognitive sciences perception is the process of attaining awareness or understanding of sensory Information. Space is the extent within which Matter is physically extended and objects and Events have positions relative to one another In Psychology, memory is an organism's ability to store retain and subsequently retrieve information Pathology (from Greek grc πάθος pathos, "fate harm" and grc -λογία -logia) is the study and

Psychopathological

Psychopathological symptoms vary more than cognitive and physical ones, and may include anxiety, depression, a reduced display of emotions (blunted affect) and decreased ability to recognize negative expressions like anger, disgust, fear or sadness in others,^[6] egocentrism, Aggression, and Compulsive behavior. Anxiety is a physiological and psychological state characterized by Cognitive, Somatic, Emotional and Behavioral components Major depressive disorder, also known as major depression, unipolar depression, unipolar disorder, clinical depression, or simply depression Blunted affect is the scientific term describing a lack of Emotional reactivity on the part of an individual In Psychology, egocentrism is defined as a the incomplete differentiation of the self and the world including other people and b the tendency to perceive understand and interpret In Psychology and other social and Behavioral sciences aggression refers to behavior that is intended to cause harm Compulsive behavior is behavior which a person does "compulsively" i The latter can cause, or worsen, hypersexuality and addictions such as alcoholism and gambling. Hypersexuality is the desire to engage in Human sexual behavior at a level high enough to be considered clinically significant The term " addiction " is used in many contexts to describe an obsession compulsion or excessive Physical dependence or psychological dependence such as Alcoholism is a term with multiple and sometimes conflicting definitions

Genetics

See also: Trinucleotide repeat disorders

The gene involved in Huntington's disease, called Huntingtin (HTT), or Interesting Transcript 15 (IT15) gene, known historically as the HD gene, is located on the short arm of chromosome 4 (4p16. The Huntingtin Gene, also called HD ( Chromosome 4 is one of the 23 pairs of Chromosomes in Humans People normally have two copies of this chromosome 3). In the first part, called the 5' end of the gene, is a sequence of three DNA bases—cytosine-adenine-guanine (CAG)— repeated multiple times (i. Directionality, in Molecular biology, refers to the end-to-end chemical orientation of a single strand of Nucleic acid. Deoxyribonucleic acid ( DNA) is a Nucleic acid that contains the genetic instructions used in the development and functioning of all known Structure The "skeleton" of adenine Cytosine is one of the five main bases found in DNA and RNA. It is a Pyrimidine derivative with a Heterocyclic Aromatic ring Adenine is a Purine with a variety of roles in Biochemistry including Cellular respiration, in the form of both the energy-rich Adenosine Guanine is one of the five main Nucleobases found in the Nucleic acids DNA and RNA, the others being Adenine, Cytosine, e. . . . CAGCAGCAG. . . ) and known as a trinucleotide repeat. CAG is the genetic code for the amino acid glutamine; thus a series of CAG forms a chain of glutamine known as polyglutamine (polyQ). The genetic code is the set of rules by which information encoded in genetic material ( DNA or RNA sequences is translated into Proteins In Chemistry, an amino acid is a Molecule containing both Amine and Carboxyl Functional groups In Biochemistry, this Glutamine (abbreviated as Gln or Q; the abbreviation Glx or Z represents either glutamate or Glutamic acid) is one of the 20 ^[7]

Effect	classification	repeat count
unaffected	normal	< 27
	intermediate	27 - 35
affected	Reduced Penetrance	36 - 39
	Full Penetrance	> 39

A polyQ length of less than 36 glutamines produces a cytoplasmic protein called huntingtin protein (Htt), whereas a sequence of 36 or more produces an erroneous form of Htt, mHtt (standing for mutant Htt), this causes certain neurons, in select areas of the brain, to have an increased mortality. The cytoplasm is the contents of a cell that is enclosed within the Plasma membrane. Proteins are large Organic compounds made of Amino acids arranged in a linear chain and joined together by Peptide bonds between the Carboxyl Huntingtin (Htt is the protein coded by the gene Huntingtin, identified in 1993 As the number of neurons reduces in these areas their functionality is impaired. Generally, the number of CAG repeats is related to the rate that these neurons die, affecting the age at onset and progression of symptoms. ^[8] Counts of 36-39 repeats result in later onset and slower progression of symptoms termed "reduced penetrance". Penetrance is a term used in Genetics describing the proportion of individuals carrying a particular variation of a Gene (an Allele or genotype that also No case of HD has been diagnosed with a count of less than 36. ^[9]

Inheritance

Huntington's disease is autosomal dominant, needing only one affected allele from either parent to inherit the disease. An allele (ˈæliːl (UK /əˈliːl/ (US (from the Greek αλληλος allelos, meaning each other) is one member of a pair or series of different forms Although this generally means there is a one in two chance of inheriting the disorder from an affected parent, the inheritance of HD is more complex due to potential dynamic mutations, where DNA replication doesn't produce an exact copy of itself. In Genetics, a dynamic mutation is an unstable heritable element where the probability of mutation is a function of the number of copies of the mutation DNA replication is the process of copying a double-stranded DNA molecule to form two double-stranded molecules This can cause the number of repeats to change in successive generations. This can mean that a parent with a count close to the threshold, may pass on a gene with a count either side of the threshold. Repeat counts maternally inherited are usually similar, whereas paternally inherited ones tend to increase. ^[10] This potential increase in repeats in successive generations is known as anticipation. In 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

New mutations, in which neither parent has HD, are rare. In biology mutations are changes to the Nucleotide sequence of the Genetic material of an organism

Most dominant disease exhibit more severe symptoms for Homozygous individuals, who's both parents both have the same disease gene, but HD is one of the first documented who's prognosis isn't altered. Zygosity refers to the genetic condition of a Zygote. In genetics zygosity describes the similarity or dissimilarity of DNA between Homologous ^[11]

Mechanism

See also: Huntingtin protein

Like all proteins, Htt and mHtt are translated, perform or affect biological functioning, and are finally dissolved in a process called biodegradation. Huntingtin (Htt is the protein coded by the gene Huntingtin, identified in 1993 Translation is the first stage of Protein biosynthesis (part of the overall process of Gene expression) Foundations of modern biology There are five unifying principles Biodegradation is the process by which organic substances are broken down by the enzymes produced by living organisms The exact role mHtt has in DNA replication and its influence in programmed cell death is unknown. Research focuses on identifying the functioning of Htt, how mHtt differs or interferes with it, and the detrimental effects of remnants of mHtt left after biodegradation (Proteopathy). Proteopathy (Proteo- protein -pathy disease proteopathies pl.

Function

The Htt protein is involved in vesicle trafficking as it interacts with HIT1, a clathrin binding protein, to mediate endocytosis, the absorption of materials into a cell. A vesicle is a small bubble of liquid within a cell A more formal definition in Cell biology, would be that a vesicle is a relatively small intracellular membrane-enclosed Clathrin is a Protein that is the major constituent of the 'coat' of the clathrin- Coated pits and coated Vesicles formed during Endocytosis Endocytosis is a process where cells absorb material ( Molecules such as proteins from the outside by engulfing it with their Cell membrane. ^[12][13]

The mHtt protein reduces the production of brain-derived neurotrophic factor (BDNF). Brain-derived neurotrophic factor also known as BDNF is a Protein encoded by the BDNF Gene. BDNF protects neurons and regulates the neurogenesis of new ones, but the precise way it does this is unknown, but a reduction in its level increases neuron cell death and creation, leading to atrophy of areas of the brain. Neurogenesis ( birth of Neurons ' is the process by which neurons are created ^[14][15][16]

Degradation

Both Htt and mHtt are cleaved (the first step in degradation) by caspase-3, which removes the protein's amino end (the N-terminal). Caspases, or c ysteine- asp artic acid prote ases, are a family of Cysteine proteases which play essential roles in Apoptosis (programmed The N-terminus (also known as the amino-terminus, NH2-terminus, N-terminal end or ^[17] Caspase-2 then further breaks down the amino terminal fragment (the part with the CAG repeat) of Htt, but cannot process all of the mHtt protein. ^[18] The unprocessed pieces left in the cell are called aggregates, or N-fragments, and are able to affect genetic transcription. Transcription is the synthesis of RNA under the direction of DNA ^[19] Specifically, mHtt binds with TAF_II130, a coactivator to CREB dependent transcription. TAF4 RNA polymerase II TATA box binding protein (TBP-associated factor 135kDa, also known as TAF4, is a human Gene. CREB ( cAMP response element-binding Proteins are Transcription factors which bind to certain DNA sequences called CAMP response ^[20] The aggregates also interact with the transcription factor protein SP₁, preventing it from binding to DNA. In the field of Molecular biology, a transcription factor (sometimes called a sequence-specific DNA binding factor is a Protein that binds to specific sequences See also SP1. Sp1 is a human Transcription factor involved in gene expression in the early development of an organism Deoxyribonucleic acid ( DNA) is a Nucleic acid that contains the genetic instructions used in the development and functioning of all known ^[21]

In transgenic mice neurodegeneration caused by mHtt is related to the caspase-6 enzyme cleaving the Htt protein, as they did not show effects of HD in experiments. Caspases, or c ysteine- asp artic acid prote ases, are a family of Cysteine proteases which play essential roles in Apoptosis (programmed ^[22]

In genetically altered "knockin" mice, the extended CAG repeat portion of the gene is all that is needed to cause disease. ^[23] Aggregates of mHtt are present in the brains of people and mice with HD,^[24][25] and are most prevalent in cortical pyramidal neurons, less so in striatal medium-sized spiny neurons and almost absent in most other brain regions including the hippocampus and cerebellum. A pyramidal cell (or pyramidal neuron, or projection neuron) is a multipolar Neuron located in the Hippocampus and Cerebral The medium spiny neurons are a special type of inhibitory cells representing approximately 90% of the Neurons within the Corpus striatum of the Basal ganglia The hippocampus is a part of the Forebrain, located in the medial Temporal lobe. The cerebellum ( Latin: "little brain" is a region of the Brain that plays an important role in the integration of sensory perception ^[24][26][27] These aggregates consist mainly of the amino terminal end of mHtt (CAG repeat), and are found in both the cytoplasm and nucleus of neurons. The cytoplasm is the contents of a cell that is enclosed within the Plasma membrane. In Cell biology, the nucleus (pl nuclei; from Latin la ''nucleus'' or la ''nuculeus'' "little nut" or kernel is a membrane-enclosed ^[28] The presence of these aggregates however does not correlate with cell death. ^[29] Thus mHtt acts in the nucleus but does not cause apoptosis through aggregation. ^[30]

Pathophysiology

Brain

Studies on physiopathology are mainly focused on the brain because most notable symptoms are related to it.

Profound neuronal degeneration in the striatum with some additional atrophy of the frontal and temporal cortices. Neurons (ˈnjuːɹɒn also known as neurones and nerve cells) are responsive cells in the Nervous system that process and transmit information The striatum is a subcortical (ie inside rather than on the outside part of the Telencephalon. The frontal lobe is an area in the Brain of Mammals It is located at the front of each Cerebral hemisphere and positioned anterior to (in front of the The temporal lobes are parts of the cerebrum that are involved in speech, Memory, and Hearing. ^[31] There is also astrogliosis and loss of medium spiny neurons. Astrocytosis ( astrogliosis) is an abnormal increase in the number of Astrocytes due to the destruction of nearby Neurons, typically because of Hypoglycemia ^[32]

The brain initiates motion by sending a signal down the spinal cord from the external globus pallidus. The globus pallidus ( Latin for "pale globe" is a sub- cortical structure of the Brain. At the same time that the stimulus is being sent down the spinal cord, the subthalamic nuclei of the striatum excite the internal globus pallidus, which inhibits the thalamus and modulates motion. The subthalamic nucleus is a small lens-shaped nucleus in the Brain where it is a part of the Basal ganglia system The striatum is a subcortical (ie inside rather than on the outside part of the Telencephalon. The thalamus (from Greek θάλαμος = room chamber, IPA= /ˈθæləməs/ is a pair and symmetric part of the brain

In Huntington's disease the external globus pallidus over-inhibits the flow of excitation from the subthalamic nuclei, which interferes with the initiation of motion. The subthalamic nuclei also generate reduced excitation to the internal globus pallidus, resulting in a weak inhibitory signal to the thalamus. The thalamus in turn then sends a strong excitatory signal to the putamen resulting in unmodulated motion. "Putamen" is also a botanical term for the stone in a Fruit, such as a Peach.

Other systems

Huntington's disease appears to affect non nervous physiological functions. One study in humans highlighted a systemic, early hypermetabolic state and a lower level of branched chain amino acids in the plasma as the disease progresses;^[33] this seems to originate from the brain's own need for energetic substrates. The phrase branched-chain amino acids or BCAA is sometimes used to refer to the Amino acids having Aliphatic side-chains that are non-linear

In a murine model, heart restricted expression of amyloid-forming polyglutamine fragments resulted in heart failure. ^[34]

Diagnosis

Further information: Genetic testing

To determine whether initial symptoms are evident, a physical and/or psychological examination is required. Genetic testing allows the genetic Diagnosis of vulnerabilities to inherited Diseases, and can also be used to determine a person's Ancestry. The uncontrollable movements are often the symptoms which cause initial alarm and lead to diagnosis; however, the disease may begin with cognitive or emotional symptoms, which are not always recognized. Pre-symptomatic testing is possible by means of a blood test which counts the number of repetitions in the gene. Genetic testing allows the genetic Diagnosis of vulnerabilities to inherited Diseases, and can also be used to determine a person's Ancestry.

A negative blood test means that the individual does not carry the expanded copy of the gene, will never develop symptoms, and cannot pass it on to children. A positive blood test means that the individual does carry the expanded copy of the gene, will develop the disease, and has a 50% chance of passing it on to children. A pre-symptomatic positive blood test is not considered a diagnosis, because it may be decades before onset.

Because of the ramifications on the life of an at-risk individual, with no cure for the disease and no proven way of slowing it, several counseling sessions are usually required before the blood test. Unless a child shows significant symptoms or is sexually active or considered to be Gillick competent, children under eighteen will not be tested. Gillick competence is a term originating in England and is used in medical law to decide whether a child (16 years or younger is able to consent to his or her own medical treatment The members of the Huntington's Disease Society of America strongly encourage these restrictions in their testing protocol. Huntington's Disease Society of America is a national non-profit organization committed to finding a cure for Huntington's disease. A pre-symptomatic test is a life-changing event and a very personal decision. Embryonic screening is also possible, giving HD carriers or at-risk individuals the option of ensuring their children will not inherit the disease if abortion is acceptable to them. It is possible to test an embryo either in the womb (prenatal diagnosis) or to ensure a child will not have HD by utilising in vitro fertilisation and testing before implantation. Prenatal testing is Testing for diseases or conditions in a Fetus or Embryo before it is born In vitro fertilisation ( IVF) is a process by which

A full pathological diagnosis can only be established by a neurological examination's findings and/or demonstration of cell loss in the areas affected by HD, supported by a cranial CT or MRI scan findings. Computed tomography (CT is a Medical imaging method employing Tomography.

Management

There is no treatment to fully arrest the progression of the disease, but symptoms can be reduced or alleviated through the use of medication and care methods. Huntington mice models exposed to better husbandry techniques, especially better access to food and water, lived much longer than mice that were not well cared for. Animal husbandry, also called Animal science, stockbreeding or simple husbandry, is the agricultural practice of breeding

Medication

Other standard treatments to alleviate emotional symptoms include the use of antidepressants and sedatives, with antipsychotics (in low doses) for psychotic symptoms. An antidepressant is a Psychiatric medication used for alleviating major depression or Dysthymia ('milder' depression Antipsychotics are a group of Psychoactive drugs commonly but not exclusively used to treat Psychosis, which is typified by Schizophrenia.

Therapies

Speech therapy helps by improving speech and swallowing methods; this therapy is more effective if started early on, as the ability to learn is reduced as the disease progresses. Speech-language pathology is the study of disorders that affect a person's Speech, Language, cognition voice swallowing ( Dysphagia) and the rehabilitative A two-year pilot study, of intensive speech, pyschiatric and physical therapy, applied to inpatient rehabilitation, showed motor decline was greatly reduced. ^[35]

Nutrition

Nutrition is an important part of treatment; most third and fourth stage HD sufferers need two to three times the calories of the average person to maintain body weight. This article is about the unit of energy For its use in Nutrition and Food labelling regulations, see the article on Food energy. ^[36] Healthier foods in pre-symptomatic and earlier stages may slow down the onset and progression of the disease. High calorie intake in pre-symptomatic and earlier stages has been shown to speed up the onset and reduce IQ level.

Thickening agent can be added to drinks as swallowing becomes more difficult, as thicker fluids are easier and safer to swallow. Thickening agents, or thickeners, are substances which when added to an aqueous mixture increase its Viscosity without substantially modifying its other properties The option of using a stomach PEG is available when eating becomes too hazardous or uncomfortable; this greatly reduces the chances of aspiration of food, and the subsequent increased risk of pneumonia, and increases the amount of nutrients and calories that can be ingested. A percutaneous endoscopic gastrostomy ( PEG) is an endoscopic procedure for placing a tube into the Stomach. Aspiration pneumonia is Bronchopneumonia that develops due to the entrance of foreign materials that enter the bronchial tree usually oral or gastric contents (including food

EPA, an Omega-3 fatty acid, may slow and possibly reverse the progression of the disease. Eicosapentaenoic acid (EPA or also icosapentaenoic acid is an Omega-3 fatty acid. ^[37] As of April 2008, it is in FDA clinical trial as ethyl-EPA, (brand name Miraxion), for prescription use. Clinical trials utilise 2 grams per day of EPA. In the United States, it is available over the counter in lower concentrations in Omega-3 and fish oil supplements. Results of the first Phase III trial showed an improvement in motor function scores over the control group, but the small sample size render the result inconclusive. A larger trial is near completion and will be more statistically robust when results are posted.

Prognosis

Development of Huntington’s disease is highly dependent on how many times CAG is repeated. The genetic code is the set of rules by which information encoded in genetic material ( DNA or RNA sequences is translated into Proteins Usually, CAG is repeated between 7 and 35 times; more than this, however, will cause the disease. ^[38] The age of onset (and to a degree the severity of the disease) and hence the age at death, are inversely correlated with the length of the expanded CAG repeat, such that those with longer repeats develop the disease earlier. Individuals with greater than approximately 60 CAG repeats often develop juvenile Huntington's disease. ^[39] There is a large variation in age of onset for any given CAG repeat length within the intermediate range (40-50 CAGs). For example, a repeat length of 40 CAGs leads to an onset ranging from 40 to 70 years of age in the North American and Canadian population. This variation means that, although logarithmic algorithms have been proposed for predicting the age of onset,^[40][41] in reality predicting the precise age of onset can be generalised, but not precisely predicted with confidence. In Mathematics, the logarithm of a number to a given base is the power or Exponent to which the base must be raised in order to produce In Mathematics, Computing, Linguistics and related subjects an algorithm is a sequence of finite instructions often used for Calculation

Following the onset of obvious physical diagnosis of the disorder, life expectancy is generally a further 15 to 20 years. ^[42] Mortality is not caused by Huntington’s disease directly, but by associated complications, these include pneumonia (which causes one third of fatalities), heart failure (although heart disease, cerebrovascular disease and atherosclerosis show no increase), choking and nutritional deficiencies. Pneumonia is an inflammatory illness of the Lung. Frequently it is described as lung Parenchyma / alveolar inflammation and abnormal Heart failure is a Cardiac condition that occurs when a problem with the structure or function of the Heart impairs its ability to supply Heart disease is an Umbrella term for a variety for different diseases affecting the Heart. Atherosclerosis is a Disease affecting arterial Blood vessels It is a chronic inflammatory response in the walls of arteries in large part due to the accumulation ^[43] Suicide is an associated risk, with suicide rates of up to 7. 3 percent; four times that of the general population. ^[44][45] Suicide, in general, is likely to be underestimated; reports, which have accounted for this, estimate up to 27 percent of possibly affected individuals attempt suicide. ^[1]

Social impact

Whether or not to have the test for HD Genetic counseling may provide perspective for those at risk of the disease. Genetic counseling 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 Some choose not to undergo HD testing due to numerous concerns (for example, insurability). The term health insurance is generally used to describe a form of Insurance that pays for medical expenses Testing of a descendant of a person, who is 'at-risk', has serious ethical implications as a positive result automatically diagnoses one of the parents.

Parents and grandparents have to decide when and how to tell their children and grandchildren. The issue of disclosure also comes up when siblings are diagnosed with the disease, and especially in the case of identical twins. Twins are Offspring resulting from the same Pregnancy, either of the same or opposite Sex.

For those at risk, or known to have the disease, consideration is necessary prior to having children due to the genetically dominant nature of the disease. In vitro and embryonic genetic screening now make it possible (with 99 percent certainty) to have an HD-free child; however, the cost of this process can easily reach tens of thousands of dollars. An embryo (from Greek:, plural, lit "that which grows" from en- "in" + bryein "to swell be full" is a multicellular Genetic testing allows the genetic Diagnosis of vulnerabilities to inherited Diseases, and can also be used to determine a person's Ancestry.

Huntington's disease was one of the targets of the eugenics movement, for example the American scientist Charles Davenport proposed in 1910 that compulsory sterilization and immigration control be used for people with certain disease, including HD. Eugenics is a social Philosophy which advocates the improvement of Human Hereditary traits through various forms of intervention The United States of America —commonly referred to as the Charles Benedict Davenport ( June 1, 1866 &ndash February 18, 1944) was a prominent American biologist and eugenicist Immigration refers to the movement of people among countries While the movement of people has existed throughout human history at various levels modern immigration implies long-term ^[46]

Financial institutions are also faced with the question of whether to use genetic testing results when assessing an individual, e. g. for life insurance. Some countries' organisations have already agreed not to use this information.

Epidemiology

As HD is autosomnal dominant, and doesn't usually affect reproduction, areas of increased prevalence occur according to historical migration of carriers, some of which can be traced back thousands of years using the genes haplotypes. The term haplotype is a contraction of the term " haploid Genotype. ^[47] New mutations are less than 10 percent of HD carriers, but account for the less localised occurrences, and origins, of the disorder. ^[48]

Since the discovery of a genetic test that can also be used pre-symptomatically, estimates of the incidence of the disorder are likely to increase. This is because, without the genetic test, only individuals displaying physical symptoms and a few neurologically examined cases were diagnosed, which excluded anyone who died of other causes before diagnosis. These cases can now be included in statistics as the test becomes more widely available.

The prevalence is, on average, between 3 to 7 per 100,000 people of Western European descent, down to 1 per 1,000,000 of Asian and African descent, but this varies greatly according to geographical location, both by ethnicity and local migration. ^[49] The highest occurrence is in peoples of Western Europe descent, and relatively lower in the rest of the world. For example the isolated populations of the Lake Maracaibo region of Venezuela ( where the marker for the gene was discovered ), have an extremely high prevalence of up to 700 per 100,000^[50], leading to the conclusion that one of their initial founders must have been a carrier of the gene. This is known as the local founder effect. In Population genetics, the founder effect refers to the loss of genetic variation when a new colony is established by a very small number of individuals from a larger ^[51]

About 7 percent of HD cases occur in people under the age of 20 years. This is referred to as Juvenile HD, "akinetic-rigid", or "Westphal variant" HD. Huntington's disease, also called Huntington's chorea, chorea major, or HD, is a genetic neurological disorder characterized after ^[52]

History

In the first part of the twentieth century and earlier, many people with HD were misdiagnosed as suffering from alcoholism or manic depression. Previously mortality due to starvation or dehydration was a major risk.

• c. 300: Along with other conditions with abnormal movements, it may have been referred to as St Vitus' dance. St Vitus is the patron saint of epileptics who was martyred in 303. "Saint Guy" redirects here For the Belgian saint see Guy of Anderlecht. The patron saint of a particular group of people is a Saint who would protect and 'love' the group and its members Epilepsy is a common chronic Neurological disorder that is characterized by recurrent unprovoked seizures. The term martyr ( Greek μάρτυς martys "witness" is most commonly used today to describe an individual who sacrifices their life (or personal freedom
• Middle Ages: People with the condition were probably persecuted as being witches or as being possessed by spirits, and were shunned, exiled or worse. "Witch trial" redirects here For the song by Rush, see Fear series. Shunning is the act of deliberately avoiding association with and habitually keeping away from an individual or group Exile means to be away from one's home (ie city state or country while either being explicitly refused permission to return and/or being threatened by prison or death upon return Some speculate that the "witches" in the Salem Witch Trials in 1692 had HD. The Salem witch trials were a series of hearings before local magistrates followed by county court Trials to prosecute people accused of Witchcraft in Essex ^[53]
• 1860: One of the early medical descriptions of HD was made in 1860 by a Norwegian district physician, Johan Christian Lund. Norway ( Norwegian: Norge ( Bokmål) or Noreg ( Nynorsk) officially the Kingdom of Norway, is a Constitutional He noted that in Setesdalen, a remote and rather secluded area, there was a high prevalence of dementia associated with a pattern of jerking movement disorders that tended to run in families. Setesdal (older name Sætersdal) is a Valley and a traditional district in Aust-Agder County ( fylke) in Southern Dementia (from Latin de- "apart away" + Mens ( genitive mentis) "mind" is the progressive decline This is the reason for the disease being commonly referred to as Setesdalsrykkja (Setesdalen=the location, rykkja=jerking movements) in Norwegian. Norwegian ( norsk) is a North Germanic Language spoken primarily in Norway, where it is an official language
• 1872: George Huntington was the third generation of a family medical practice in Long Island. George Huntington ( April 9, 1850 &ndash March 3, 1916) was an American Physician. Long Island is an island located in southeastern New York, USA, its western shores directly across from Manhattan, from which the island stretches With their combined experience of several generations of a family with the same symptoms, he realised their conditions were linked and set about describing it. A year after leaving medical school, in 1872, he presented his accurate definition of the disease to a medical society in Middleport, Ohio. Middleport is a village in Meigs County, Ohio, United States, along the Ohio River. Ohio ( is a Midwestern state of the United States. As part of the Great Lakes region, Ohio has long been a cultural and geographical crossroads
• c. 1923: Smith Ely Jelliffe (1866–1945) and Frederick Tilney (1875–1938) began analyzing the history of HD sufferers in New England. Smith Ely Jelliffe (1866-1945 American Neurologist, Psychiatrist, and Psychoanalyst who lived and practiced in New York City nearly his entire History See also History of New England New England's earliest inhabitants were Algonquian -speaking Native Americans including the
• 1932: P. R. Vessie expanded Jelliffe and Tilney's work, tracing about a thousand people with HD back to two brothers and their families who left Bures in Essex for Suffolk bound for Boston in 1630. Essex is a county in the East of England. The County town is Chelmsford, and the highest point of the county is Chrishall Common Suffolk (ˈsʌfək is a non-metropolitan county of historic origin in East Anglia, England.
• 1979: The U. S-Venezuela Huntington's Disease Collaborative Research Project began an extensive study which gave the basis for the gene to be discovered. Venezuela (ˌvɛnəˈzweɪlə) officially the Bolivarian Republic of Venezuela (Spanish República Bolivariana de Venezuela) is a country on the This was conducted in the small and isolated Venezuelan fishing villages of Barranquitas and Lagunetas. Families there have a high presence of the disease.
• 1983: James Gusella, David Housman, P. Michael Conneally, Nancy Wexler, and their colleagues find the general location of the gene, using DNA marking methods for the first time — an important first step toward the Human Genome Project. The Human Genome Project (HGP was an international Scientific research project with a primary goal to determine the sequence of chemical base pairs which make up DNA
• 1992: Anita Harding, et al. Anita Harding ( September 17, 1952 - September 11, 1995) was a British Neurologist. , find that trinucleotide repeats affect disease severity^[54]
• 1993: The Huntington's Disease Collaborative Research Group isolates the precise gene at 4p16. 3.
• 1996: A transgenic mouse (the R6 line) was created that could be made to exhibit HD, greatly advancing how much experimentation can be achieved. This article is about organisms which have been genetically modified
• 1997: DiFiglia M, Sapp E, Chase KO, et al. , discover that mHtt aggregates (misfolds) to form nuclear inclusions. Protein folding is the physical process by which a Polypeptide folds into its characteristic and functional three-dimensional structure. Inclusion bodies are nuclear or Cytoplasmic aggregates of stainable substances usually proteins ^[24]
• The full record of research is extensive. ^[55][56][57]

Society and culture

See also: List of Huntington's disease media depictions

As public awareness has increased, HD has been depicted increasingly in numerous books, films and TV series. Huntington's Disease has been shown in numerous formats more so as awareness of the condition has increased Early works were Arlo Guthrie's 1969 film Alice's Restaurant and Jacqueline Susann's 1966 American novel Valley of the Dolls , with more recent references in ER, Private Practice, Everwood, All Saints, and House. Arlo Davy Guthrie (born July 10 1947 is an American folk singer Alice's Restaurant is a 1969 movie adapted from a song by Arlo Guthrie. Jacqueline Susann ( August 20, 1918, Philadelphia, Pennsylvania &ndash September 21, 1974, New York City Valley of the Dolls is the title of a best selling Novel by Jacqueline Susann, published in 1966 ER is an Emmy Award -winning American Medical drama series created by Novelist Michael Crichton and airing on Private Practice is a Spin-off of the popular television show Grey's Anatomy. Everwood was a Prime time television Drama that aired in the United States on The WB. All Saints is a Logie Award -winning Australian Medical drama which airs on the Seven Network, and various international networks House, also known as House MD, is an American Medical drama, which debuted on the FOX network on November 16 2004

Organizations

• 1967: Woody Guthrie's wife, Marjorie, helped found the Committee to Combat Huntington's Disease, after his death from HD complications. Woodrow Wilson "Woody" Guthrie (July 14 1912–October 3 1967 was an American Singer-songwriter and Folk musician Guthrie's musical legacy Marjorie Mazia Guthrie ( October 6, 1917 &ndash March 13, 1983) was for a time the wife of folk musician Woody Guthrie, and was the This eventually became the Huntington's Disease Society of America. Huntington's Disease Society of America is a national non-profit organization committed to finding a cure for Huntington's disease. ^[58] Since then, lay organizations have been formed in many countries around the world.
• 1968: After experiencing HD in his wife's family Dr. Milton Wexler was inspired to start the Hereditary Disease Foundation (HDF). Professor Nancy S. Wexler, Dr. Wexler's daughter, was in the research team in Venezuela and is now president of the HDF. Venezuela (ˌvɛnəˈzweɪlə) officially the Bolivarian Republic of Venezuela (Spanish República Bolivariana de Venezuela) is a country on the
• 1974: The first international meeting took place when the founders of the Canadian HD Society (Ralph Walker) and of the British HD Society (Mauveen Jones) attended the annual meeting of the American HD Society.
• 1977: second meeting organized by the Dutch Huntington Society the "Vereniging van Huntington", representatives of six countries were present. The Netherlands ( Dutch:, ˈnedərlɑnt is the European part of the Kingdom of the Netherlands, which consists of the Netherlands the Netherlands
• 1979: International Huntington Association (IHA) formed during international meeting in Oxford, England organized by HDA of England. Oxford is currently bidding for the 2010 Wikimania Conference Oxford () is a city, and the County town of Oxfordshire, England is a Country which is part of the United Kingdom. Its inhabitants account for more than 83% of the total UK population whilst its mainland
• 1981–2001: Biennial meetings held by IHA which became the World Congress on HD.
• 2003: The first World Congress on Huntington's Disease was held in Toronto. Toronto (təˈrɒntoʊ colloquially pronounced or) is the largest city in Canada and is the provincial capital of Ontario ^[59] This is a biennial meeting for associations and researchers to share ideas and research, which is held on odd-number years. The Euro-HD Network^[60] was started as part of the Huntington Project,^[61] funded by the High-Q Foundation. ^[62]

Research directions

Appropriate animal models are critical for understanding the fundamental mechanisms causing the disease and for supporting the early steps of drug development before moving on to human clinical trials. Neurochemically induced mice or monkeys were first available^{[63] [64]}, but they could not mimick the progressive features of the disease. After the HD gene was discovered, transgenic animals exhibiting HD were generated by inserting a CAG repeat expansion into the genome of mice (strain R6/2^{[65] [66]}), Drosophila fruit flies^[67], or more recently in monkeys^[68]. Drosophila melanogaster (from the Greek for black-bellied dew-lover) is a two-winged insect that belongs to the Diptera, the order Expression without insertion of a CAG repeat in nematode worms^[69] also produced a valuable model. The nematodes or roundworms ( Phylum Nematoda from Greek (nema "thread" + -ode "like" are one of the most common

As for humans, there are trials of various compounds that are in development, recruiting volunteers^[70], in progress or completed. Some of these trials are at the point of testing on larger numbers of people, known as phase III of the clinical trials. In health care clinical trials are conducted to allow safety and Efficacy data to be collected for new drugs or devices

Intrabody therapy

Genetically engineered antibody fragments called intrabodies have shown therapeutic results against mHtt aggregates in drosophila models. Antibodies (also known as immunoglobulins, abbreviated Ig) are Gamma globulin Proteins that are found in Blood or other Bodily This was achieved using an intrabody called C4 sFv, a single chain variable fragment which binds to the end of mHtt within a cell. Single Chain Variable Fragment ( scFv) is a fusion of the variable regions of the heavy and light chains of Immunoglobulins, linked together with a short (usually Not to be confused with Intercellular, meaning "between cells" C4 sFv has been shown to reduce mHtt aggregate formation and accumulation in cultures of tissue taken from the model. ^[71][72] The intrabody increased larval and pupal survival from 23% to 100% and delayed neurodegeneration in the adult, significantly increasing their lifespan. A larva ( Latin; plural larvae) is a juvenile form of Animal with indirect development, undergoing Metamorphosis (for example A pupa ( Latin pupa for doll pl pupae or pupas) is the life stage of some Insects undergoing transformation ^[73] Intrabody therapy shows promise as a tool for drug discovery, and as a potential therapy for neurodegenerative disorders caused by protein mis-folding or abnormal protein interactions. ^[74]

Gene silencing

Since HD has been conclusively linked to a single gene, gene silencing could be simpler than with multiple-gene disorders. Gene silencing is a general term describing Epigenetic processes of Gene regulation. Researchers have investigated using gene knockdown of mHtt as a potential treatment. For knockdowns in Combat sports see Knockout. Gene knockdown refers to techniques by which the expression of one or Using a mouse model, siRNA therapy achieved a 60 percent reduction in expression of the mHtt and progression of the disease was stalled. Small interfering RNA ( siRNA) sometimes known as short interfering RNA or silencing RNA, is a class of 20-25 Nucleotide -long double-stranded ^[75] In another study, mouse models in late stages of the disease recovered motor function after expression of mHtt was shut down. ^[76]

Stem cell implants

Main article: Stem cell treatments

Treatment using stem cell implants is based on the replacement of damaged neurons by injecting stem cells, which can form themselves into specialized cells, into the damaged area. Many Medical researchers believe that stem cell treatments have the potential to change the face of human disease and alleviate suffering Stem cells are cells found in most if not all multi-cellular Organisms. The stem cell then transforms itself into a replacement neuron. If enough damaged neurons are replaced, symptoms should be alleviated. This treatment would not prevent further neuronal damage, so would be an ongoing treatment. The treatment has yielded some positive results in animal models. ^[77]

Others

Other agents and measures that have shown promise in initial experiments include dopamine receptor blockers, select dopamine antagonists, such as tetrabenazine, creatine, CoQ10, the antibiotic Minocycline, exercise, antioxidant-containing foods and nutrients, and antidepressants (notably, but not exclusively, selective serotonin reuptake inhibitors SSRIs, such as sertraline, fluoxetine, and paroxetine). Dopamine is a Hormone and Neurotransmitter occurring in a wide variety of animals including both vertebrates and invertebrates A dopamine antagonist is a drug which blocks Dopamine receptors by Receptor antagonism. Tetrabenazine is a drug for the symptomatical treatment of hyperkinetic Movement disorder and is marketed under the trade names Nitoman in Canada and Creatine is Nitrogenous Organic acid that occurs naturally in Vertebrates and helps to supply energy to Muscle and nerve cells Coenzyme Q10 (also known as ubiquinone ubidecarenone coenzyme Q and abbreviated at times to CoQ10 CoQ Q10 or Q is a Benzoquinone, where Q Minocycline hydrochloride, also known as minocycline, is a member of the broad spectrum Tetracycline antibiotics, and has a broader spectrum than the other members Selective serotonin reuptake inhibitors ( SSRIs) are a class of Antidepressants used in the treatment of depression, Anxiety disorders

References

Sources

• Conomy, John P. , M. D. , J. D. Dr. George Sumner Huntington and the Disease Bearing His Name.
• Huntington, G. (1872-04-13). "On Chorea". Medical and Surgical Reporter of Philadelphia 26 (15): 317-321.  
• Online Mendelian Inheritance in Man, Article 143100 - Huntington Disease, Johns Hopkins University
• Online Mendelian Inheritance in Man, Article 606438 - Huntingtons Disease-Like 2, Johns Hopkins University
• Stevenson, Charles S. The Mendelian Inheritance in Man project is a Database that catalogues all the known Diseases with a genetic component, and—when possible—links them The Mendelian Inheritance in Man project is a Database that catalogues all the known Diseases with a genetic component, and—when possible—links them (April 1934). "A Biography of George Huntington, M.D." (Microsoft Word). Bulletin of the Institute of the History of Medicine II (2). Johns Hopkins University.  
• Vessie, P. R. (1932). "On the transmission of Huntington's chorea for 300 years—the Bures family group". Journal of Nervous and Mental Disease, Baltimore 76: 553–573.  

Bibliography

• Gillian Bates, Peter Harper, and Lesley Jones (2002). Huntington's Disease - Third Edition. Oxford: Oxford University Press. ISBN 0-19-851060-8.  

External links

Professional and research

• Huntington Project - worldwide umbrella organization for the clinical research efforts for HD.
• Huntington Study Group
• Huntington's Disease Research - Research abstracts on HD.
• Huntington's Outreach Project for Education, at Stanford (HOPES) - A layperson's guide to HD
• Worldwide Education and Awareness for Movement Disorders - HD section
• University College London Huntington's Disease Research
• TRACK-HD, an international observational study of HD

Support and advocacy

• The International Huntington Association - Coordinates support organizations in 39 countries, and individual contacts in others.
• Hereditary Disease Foundation - Spearheaded Venezuela Collaborative Huntington's Disease Project.
• Huntington's Disease Lighthouse - Reports on the latest research and studies.
• Huntington's Disease Advocacy Center - Provides community support through shared stories and forums.
• Huntington's Disease Support Club
• European HD Network European research network
• Huntington's Disease Associations of New Zealand
• Australian Huntington's Disease Association (NSW) Inc.
• Huntington's Disease Society of America
• Huntington Society of Canada - Resource materials, latest in Canadian and International HD research and description of comprehensive services portfolio to help families struggling with HD
• Scottish Huntingtons Association - Provides expert care and information for people affected by Huntingtons Disease. Just as importantly, support is offered by families for families via a network of local family support groups.
• Huntington's Disease Association UK United Kingdom support group

Other

• Huntington's Disease Drug Works - Website covering results and progress of clinical trials and alternative treatments for HD.
• WeAreHD.org - Online Community for those living with Huntington's Disease.

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