Huntington's disease (HD), also known as Huntington's chorea, is an inherited disorder that results in the death of brain cells.[5] The earliest symptoms are often subtle problems with mood or mental abilities.[2] A general lack of coordination and an unsteady gait often follow.[3] As the disease advances, uncoordinated, jerky body movements become more apparent.[2] Physical abilities gradually worsen until coordinated movement becomes difficult and the person is unable to talk.[2][3] Mental abilities generally decline into dementia.[4] The specific symptoms vary somewhat between people.[2] Symptoms usually begin between 30 and 50 years of age, but can start at any age.[5][4] The disease may develop earlier in life in each successive generation.[2] About eight percent of cases start before the age of 20 years and typically present with symptoms more similar to Parkinson's disease.[4] People with HD often underestimate the degree of their problems.[2]
HD is typically inherited, although up to 10% of cases are due to a new mutation.[2] The disease is caused by an autosomal dominant mutation in either of an individual's two copies of a gene called Huntingtin.[5] This means a child of an affected person typically has a 50% chance of inheriting the disease.[5] The Huntingtin gene provides the genetic information for a protein that is also called "huntingtin".[2] Expansion of CAG (cytosine-adenine-guanine) triplet repeats in the gene coding for the Huntingtin protein results in an abnormal protein, which gradually damages cells in the brain, through mechanisms that are not fully understood.[5] Diagnosis is by genetic testing, which can be carried out at any time, regardless of whether or not symptoms are present.[6] This fact raises several ethical debates: the age at which an individual is considered mature enough to choose testing; whether parents have the right to have their children tested; and managing confidentiality and disclosure of test results.[3]
There is no cure for HD.[5] Full-time care is required in the later stages of the disease.[3] Treatments can relieve some symptoms and in some improve quality of life.[4] The best evidence for treatment of the movement problems is with tetrabenazine.[4] HD affects about 4 to 15 in 100,000 people of European descent.[2][4] It is rare among Japanese, while the occurrence rate in Africa is unknown.[4] The disease affects men and women equally.[4] Complications such as pneumonia, heart disease, and physical injury from falls reduce life expectancy.[4] Suicide is the cause of death in about 9% of cases.[4] Death typically occurs fifteen to twenty years from when the disease was first detected.[5]
The first likely description of the disease was in 1841 by Charles Oscar Waters.[8] The condition was described in further detail in 1872 by the physician George Huntington.[8] The genetic basis was discovered in 1993 by an international collaborative effort led by the Hereditary Disease Foundation.[9][10] Research and support organizations began forming in the late 1960s to increase public awareness, to provide support for individuals and their families, and to promote research.[10][11] Current research directions include determining the exact mechanism of the disease, improving animal models to aid with research, testing of medications to treat symptoms or slow the progression of the disease, and studying procedures such as stem cell therapy with the goal of repairing damage caused by the disease.
Genetics
All humans have two copies of the Huntingtin gene (HTT), which codes for the protein Huntingtin (HTT). The gene is also called HD and IT15, which stands for 'interesting transcript 15'. Part of this gene is a repeated section called a trinucleotide repeat, which varies in length between individuals and may change length between generations. If the repeat is present in a healthy gene, a dynamic mutation may increase the repeat count and result in a defective gene. 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 penetrant: mutation of either of a person's HTT alleles 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.[13]
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.[13] The HTT gene is located on the short arm of chromosome 4[13] 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.[13] CAG is the 3-letter genetic code (codon) for the amino acid glutamine, so a series of them results in the production of a chain of glutamine known as a polyglutamine tract (or polyQ tract), and the repeated part of the gene, the PolyQ region
Generally, people have fewer than 36 repeated glutamines in the polyQ region which results in production of the cytoplasmic protein Huntingtin.[13] However, a sequence of 36 or more glutamines results in the production of a protein which has different characteristics.[13] This altered form, called mutant huntingtin (mHTT), increases the decay rate of certain types of neurons. Regions of the brain have differing amounts and reliance on these types of neurons, and are affected accordingly.[13] 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.[13] 36–39 repeats result in a reduced-penetrance 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.[13] 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.[25]
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 allele) from an affected parent.[13] 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.[26]
Trinucleotide CAG repeats over 28 are unstable during replication, and this instability increases with the number of repeats present.[13] This usually leads to new expansions as generations pass (dynamic mutations) instead of reproducing an exact copy of the trinucleotide repeat.[13] 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.[13] Such increases in the number of repeats (and hence earlier age of onset and severity of disease) in successive generations is known as genetic anticipation.[13] Instability is greater in spermatogenesis than oogenesis;[13] maternally inherited alleles are usually of a similar repeat length, whereas paternally inherited ones have a higher chance of increasing in length.[13][27] It is rare for Huntington's disease to be caused by a new mutation, where neither parent has over 36 CAG repeats.[28]
In the rare situations where both parents have an expanded HD gene, the risk increases to 75%, and when either parent has two expanded copies, the risk is 100% (all children will be affected). Individuals with both genes affected are rare. 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,[29] but it has since been found that it can affect the phenotype and the rate of progression.
Mechanism
The huntingtin protein interacts with over 100 other proteins, and appears to have multiple biological functions.[31] The behavior of this mutated protein is not completely understood, but it is toxic to certain cell types, particularly in the brain. Early damage is most evident in the striatum, but as the disease progresses, other areas of the brain are also more conspicuously affected. Early symptoms are attributable to functions of the striatum and its cortical connections—namely control over movement, mood and higher cognitive function.[13] DNA methylation also appears to be changed in HD
HD is typically inherited, although up to 10% of cases are due to a new mutation.[2] The disease is caused by an autosomal dominant mutation in either of an individual's two copies of a gene called Huntingtin.[5] This means a child of an affected person typically has a 50% chance of inheriting the disease.[5] The Huntingtin gene provides the genetic information for a protein that is also called "huntingtin".[2] Expansion of CAG (cytosine-adenine-guanine) triplet repeats in the gene coding for the Huntingtin protein results in an abnormal protein, which gradually damages cells in the brain, through mechanisms that are not fully understood.[5] Diagnosis is by genetic testing, which can be carried out at any time, regardless of whether or not symptoms are present.[6] This fact raises several ethical debates: the age at which an individual is considered mature enough to choose testing; whether parents have the right to have their children tested; and managing confidentiality and disclosure of test results.[3]
There is no cure for HD.[5] Full-time care is required in the later stages of the disease.[3] Treatments can relieve some symptoms and in some improve quality of life.[4] The best evidence for treatment of the movement problems is with tetrabenazine.[4] HD affects about 4 to 15 in 100,000 people of European descent.[2][4] It is rare among Japanese, while the occurrence rate in Africa is unknown.[4] The disease affects men and women equally.[4] Complications such as pneumonia, heart disease, and physical injury from falls reduce life expectancy.[4] Suicide is the cause of death in about 9% of cases.[4] Death typically occurs fifteen to twenty years from when the disease was first detected.[5]
The first likely description of the disease was in 1841 by Charles Oscar Waters.[8] The condition was described in further detail in 1872 by the physician George Huntington.[8] The genetic basis was discovered in 1993 by an international collaborative effort led by the Hereditary Disease Foundation.[9][10] Research and support organizations began forming in the late 1960s to increase public awareness, to provide support for individuals and their families, and to promote research.[10][11] Current research directions include determining the exact mechanism of the disease, improving animal models to aid with research, testing of medications to treat symptoms or slow the progression of the disease, and studying procedures such as stem cell therapy with the goal of repairing damage caused by the disease.
Genetics
All humans have two copies of the Huntingtin gene (HTT), which codes for the protein Huntingtin (HTT). The gene is also called HD and IT15, which stands for 'interesting transcript 15'. Part of this gene is a repeated section called a trinucleotide repeat, which varies in length between individuals and may change length between generations. If the repeat is present in a healthy gene, a dynamic mutation may increase the repeat count and result in a defective gene. 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 penetrant: mutation of either of a person's HTT alleles 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.[13]
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.[13] The HTT gene is located on the short arm of chromosome 4[13] 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.[13] CAG is the 3-letter genetic code (codon) for the amino acid glutamine, so a series of them results in the production of a chain of glutamine known as a polyglutamine tract (or polyQ tract), and the repeated part of the gene, the PolyQ region
Generally, people have fewer than 36 repeated glutamines in the polyQ region which results in production of the cytoplasmic protein Huntingtin.[13] However, a sequence of 36 or more glutamines results in the production of a protein which has different characteristics.[13] This altered form, called mutant huntingtin (mHTT), increases the decay rate of certain types of neurons. Regions of the brain have differing amounts and reliance on these types of neurons, and are affected accordingly.[13] 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.[13] 36–39 repeats result in a reduced-penetrance 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.[13] 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.[25]
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 allele) from an affected parent.[13] 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.[26]
Trinucleotide CAG repeats over 28 are unstable during replication, and this instability increases with the number of repeats present.[13] This usually leads to new expansions as generations pass (dynamic mutations) instead of reproducing an exact copy of the trinucleotide repeat.[13] 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.[13] Such increases in the number of repeats (and hence earlier age of onset and severity of disease) in successive generations is known as genetic anticipation.[13] Instability is greater in spermatogenesis than oogenesis;[13] maternally inherited alleles are usually of a similar repeat length, whereas paternally inherited ones have a higher chance of increasing in length.[13][27] It is rare for Huntington's disease to be caused by a new mutation, where neither parent has over 36 CAG repeats.[28]
In the rare situations where both parents have an expanded HD gene, the risk increases to 75%, and when either parent has two expanded copies, the risk is 100% (all children will be affected). Individuals with both genes affected are rare. 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,[29] but it has since been found that it can affect the phenotype and the rate of progression.
Mechanism
The huntingtin protein interacts with over 100 other proteins, and appears to have multiple biological functions.[31] The behavior of this mutated protein is not completely understood, but it is toxic to certain cell types, particularly in the brain. Early damage is most evident in the striatum, but as the disease progresses, other areas of the brain are also more conspicuously affected. Early symptoms are attributable to functions of the striatum and its cortical connections—namely control over movement, mood and higher cognitive function.[13] DNA methylation also appears to be changed in HD
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