Huntington disease

• Huntington chorea
• Huntington Chronic Progressive Hereditary Chorea
• Huntington's Disease
• Progressive Chorea, Chronic Hereditary (Huntington)

Huntington disease (HD) is inherited as an autosomal dominant disease that gives rise to
progressive, selective (localized) neural cell death associated with choreic movements
and dementia. The disease is associated with increases in the length of a CAG triplet
repeat present in a gene called 'huntingtin' located on chromosome 4p16.3.
Huntington disease is a progressive brain disorder that causes uncontrolled movements,
emotional problems, and loss of thinking ability (cognition).
Adult-onset Huntington disease, the most common form of this disorder, usually appears
in a person's thirties or forties. Early signs and symptoms can include irritability,
depression, small involuntary movements, poor coordination, and trouble learning new
information or making decisions. Many people with Huntington disease develop
involuntary jerking or twitching movements known as chorea. As the disease progresses,
these movements become more pronounced. Affected individuals may have trouble
walking, speaking, and swallowing. People with this disorder also experience changes in
personality and a decline in thinking and reasoning abilities. Individuals with the adult-
onset form of Huntington disease usually live about 15 to 20 years after signs and
symptoms begin.
A less common, early-onset form of Huntington disease begins in childhood or
adolescence. It also involves movement problems and mental and emotional changes.
Additional signs of the early-onset form include slow movements, clumsiness, frequent
falling, rigidity, slurred speech, and drooling. School performance often declines as
thinking and reasoning abilities become impaired. Seizures occur in 30 percent to 50
percent of children with this condition. Early-onset Huntington disease tends to progress
more quickly than the adult-onset form; affected individuals usually live 10 to 15 years
after signs and symptoms appear.

Prevalence

Huntington disease affects an estimated 3 to 7 per 100,000 people of European ancestry.

The disorder appears to be less common in some other populations, including people of
Japanese, Chinese, and African descent.

What genes are related to Huntington disease?

Mutations in the HTT gene cause Huntington disease. The HTT gene provides
instructions for making a protein called huntingtin. Although the function of this protein
is unknown, it appears to play an important role in nerve cells (neurons) in the brain.
The HTT mutation that causes Huntington disease involves a DNA segment known as a
CAG trinucleotide repeat. This segment is made up of a series of three DNA building
blocks (cytosine, adenine, and guanine) that appear multiple times in a row. Normally,
the CAG segment is repeated 10 to 35 times within the gene. In people with Huntington
disease, the CAG segment is repeated 36 to more than 120 times. People with 36 to 40
CAG repeats may or may not develop the signs and symptoms of Huntington disease,
while people with more than 40 repeats almost always develop the disorder.
An increase in the size of the CAG segment leads to the production of an abnormally
long version of the huntingtin protein. The elongated protein is cut into smaller, toxic
fragments that bind together and accumulate in neurons, disrupting the normal functions
of these cells. The dysfunction and eventual death of neurons in certain areas of the brain
underlie the signs and symptoms of Huntington disease.

How do people inherit Huntington disease?

This condition is inherited in an autosomal dominant pattern, which means one copy of
the altered gene in each cell is sufficient to cause the disorder. An affected person usually
inherits the altered gene from one affected parent. In rare cases, an individual with
Huntington disease does not have a parent with the disorder.
As the altered HTT gene is passed from one generation to the next, the size of the CAG
trinucleotide repeat often increases in size. A larger number of repeats is usually
associated with an earlier onset of signs and symptoms. This phenomenon is called
anticipation. People with the adult-onset form of Huntington disease typically have 40 to
50 CAG repeats in the HTT gene, while people with the early-onset form of the disorder
tend to have more than 60 CAG repeats.
Individuals who have 27 to 35 CAG repeats in the HTT gene do not develop Huntington
disease, but they are at risk of having children who will develop the disorder. As the gene
is passed from parent to child, the size of the CAG trinucleotide repeat may lengthen into
the range associated with Huntington disease (36 repeats or more).

HTT GENE ----The official name of this gene is “huntingtin.”

Cytogenetic Location: 4p16.3
Molecular Location on chromosome 4: base pairs 3,046,205 to 3,215,484
• HD
• HD_HUMAN
• HTT
• huntingtin (Huntington disease)
• Huntington's disease protein
• IT15

What is the normal function of the HTT gene?

The HTT gene provides instructions for making a protein called huntingtin. Although the
exact function of this protein is unknown, it appears to play an important role in nerve
cells (neurons) in the brain and is essential for normal development before birth.
Huntingtin is found in many of the body's tissues, with the highest levels of activity in the
brain. Within cells, this protein may be involved in chemical signaling, transporting
materials, attaching (binding) to proteins and other structures, and protecting the cell
from self-destruction (apoptosis).
One region of the HTT gene contains a particular DNA segment known as a CAG
trinucleotide repeat. This segment is made up of a series of three DNA building blocks
(cytosine, adenine, and guanine) that appear multiple times in a row. Normally, the CAG
segment is repeated 10 to 35 times within the gene.

How are changes in the HTT gene related to health conditions?

Huntingtons Disease- caused by mutations in the HTT gene The inherited mutation that
causes Huntington disease is known as a CAG trinucleotide repeat expansion. This
mutation increases the size of the CAG segment in the HTT gene. People with
Huntington disease have 36 to more than 120 CAG repeats. People with 36 to 40 CAG
repeats may or may not develop the signs and symptoms of Huntington disease, while
people with more than 40 repeats almost always develop the disorder.
The expanded CAG segment leads to the production of an abnormally long version of the
huntingtin protein. The elongated protein is cut into smaller, toxic fragments that bind
together and accumulate in neurons, disrupting the normal functions of these cells. This
process particularly affects regions of the brain that help coordinate movement and
control thinking and emotions (the striatum and cerebral cortex). The dysfunction and
eventual death of neurons in these areas of the brain underlie the signs and symptoms of
Huntington disease.
As the altered HTT gene is passed from one generation to the next, the size of the CAG
trinucleotide repeat often increases in size. A larger number of repeats is usually
associated with an earlier onset of signs and symptoms. This phenomenon is called
anticipation. People with the adult-onset form of Huntington disease (which appears in
mid-adulthood) typically have 40 to 50 CAG repeats in the HTT gene, while people with
the less common, early-onset form of the disorder (which appears in childhood or
adolescence) tend to have more than 60 CAG repeats.
Individuals who have 27 to 35 CAG repeats in the HTT gene do not develop Huntington
disease, but they are at risk of having children who will develop the disorder. As the gene
is passed from parent to child, the size of the CAG trinucleotide repeat may lengthen into
the range associated with Huntington disease (36 repeats or more).
Huntington Disease

Huntington disease (MIM 143100) is a slowly progressive autosomal dominant

neurodegenerative disease. Onset is usually in adult life, with a mean of around 40
years. However, onset before age 20 or after age 60 is well described. The disease
progresses inexorably, with death occurring approximately 18 years from the time of
onset. Prevalence is between 3 and 7 per 100,000 in populations of western
European descent, but Huntington disease (HD) has been described in populations of
many different ancestries.

The neuropathologic hallmark of the disease is neuronal loss and gliosis in the
caudate nucleus and the putamen (the striatum), with resulting atrophy. Medium-
sized striatal neurons that contain gamma-aminobutyric acid and enkephalin or
gamma-aminobutyric acid and substance P as their neurotransmitters are selectively
depleted. Other, neurochemically distinct striatal neuronal populations are spared,
such as large aspiny acetylcholinesterase-containing neurons or NADPH-diaphorase
neurons with somatostatin and neuropeptide Y. Apart from the striatum, the whole
brain undergoes generalized atrophy. No specific pathologic changes have been
found outside the central nervous system.

Clinical manifestations consist of gradually evolving involuntary movements,

progressive dementia, and psychiatric disturbances, especially mood disorder and
personality changes. Chorea is the most prominent abnormality, but parkinsonism,
dystonia, and involuntary motor impairment all may be present. Minor motor
abnormalities, including clumsiness, hyperreflexia, and eye movement disturbances,
often appear as early manifestations of HD. Patients with onset before age 20
frequently have prominent bradykinesia, rigidity, epilepsy, severe dementia, and a
shorter duration of illness. In contrast, cognitive decline is often less severe in
patients with onset aftetr age 60.

In 1993, a novel gene containing a CAG trinucleotide repeat that is expanded on HD

chromosomes was identified. This highly polymorphic CAG repeat located in the 5′
end of the gene has been shown to range between 10 and 29 copies on normal
chromosomes, whereas it is expanded to a range of 36 to 121 on HD chromosomes.
The vast majority of patients with the clinical diagnosis of HD have expansion of the
CAG repeat. Age of onset shows a highly significant association with the length of the
CAG repeat.

The biochemical defect underlying HD is unknown. Recent data suggest that cells die
via apoptotic pathways. Cleavage of huntingtin, the polypeptide product of the HD
gene, into a smaller fragment containing the expanded polyglutamine tract appears
to be an important step in pathogenesis of the illness. There is no known treatment
to retard disease progression. Neuroleptic medication is able to alleviate choreic
movements to some extent, but side effects may be severe. Antidepressant therapy
may be helpful in the early stages to alleviate the mood disorder.