Dentatorubral-pallidoluysian atrophy (DRPLA) is a progressive brain disorder that causes involuntary movements, mental and emotional problems, and a decline in thinking ability. The average age of onset for DRPLA is around 30 years, but this condition can appear any time between infancy and mid-adulthood.

The signs and symptoms of DRPLA differ somewhat between affected children and adults. When DRPLA appears before age 20, it most often involves episodes of involuntary muscle jerking or twitching (myoclonus), seizures, behavioral changes, intellectual disabilities, and problems with balance and coordination (ataxia). When DRPLA begins after age 20, the most frequent signs and symptoms are ataxia, uncontrollable movements of the limbs (choreoathetosis), psychiatric symptoms such as delusions, and deterioration of intellectual function (dementia).

DRPLA is caused by a variant (also called mutation) in the ATN1 gene. This gene provides instructions for making a protein called atrophin 1. Although the exact function of atrophin 1 is unknown, it appears to play an important role in nerve cells (neurons) in many areas of the brain.

The ATN1 gene variant that underlies DRPLA 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, this segment is repeated 6 to 35 times within the ATN1 gene. In people with DRPLA, the CAG segment is repeated at least 48 times, and the repeat region may be two or three times its usual length. The abnormally long CAG trinucleotide repeat changes the structure of the atrophin 1 protein. This altered protein accumulates in neurons and interferes with normal cell functions. The dysfunction and eventual death of these neurons lead to uncontrolled movements, intellectual decline, and the other characteristic features of DRPLA.

Normal Function

The ATN1 gene provides instructions for making a protein called atrophin 1. Although the exact function of this protein is unknown, it appears to play an important role in nerve cells (neurons) in many areas of the brain. Researchers speculate that atrophin 1 may act as a transcriptional co-repressor. A transcriptional co-repressor is a protein that interacts with other DNA-binding proteins to suppress the activity of certain genes, although it cannot attach (bind) to DNA by itself.

One region of the ATN1 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. In most people, the number of CAG repeats in the ATN1 gene ranges from 6 to 35.

Health Conditions Related to Genetic Changes

Dentatorubral-pallidoluysian atrophy

Dentatorubral-pallidoluysian atrophy (DRPLA) is a progressive brain disorder that causes involuntary movements, mental and emotional problems, and a decline in thinking ability. DRPLA results from an increased number of copies (expansion) of the CAG trinucleotide repeat in the ATN1 gene. Specifically, the CAG segment is repeated at least 48 times, and the repeat region may be two or three times its usual length. The extended CAG region changes the structure of atrophin 1 and how the protein interacts with other proteins to control gene function. This altered protein accumulates in neurons and interferes with normal cell functions. The dysfunction and eventual death of these neurons lead to involuntary movements, intellectual decline, and the other characteristic features of DRPLA.

Other disorders

Variants (also called mutations) in the ATN1 gene can cause a very rare condition called congenital hypotonia, epilepsy, developmental delay, and digital anomalies (CHEDDA) syndrome. Individuals with this condition have severe intellectual and developmental delays. They also have a very limited or no ability to talk and cannot walk. People with CHEDDA can have weak muscle tone (hypotonia), recurring seizures (epilepsy), vision and hearing problems, distinctive facial features, and skeletal abnormalities. Many affected individuals have brain malformations.

The ATN1 gene variants that cause CHEDDA syndrome occur in one of the two copies of the gene in each cell and lead to a change in single protein building blocks (amino acids) in atrophin 1. As a result, the protein is altered and cannot function normally, though it is unclear how these changes lead to the specific features of CHEDDA syndrome.

Other Names for This Gene

• ATN1_HUMAN
• atrophin-1
• B37
• D12S755E
• dentatorubral-pallidoluysian atrophy protein
• DRPLA
• NOD

Genomic Location

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. In most cases, an affected person has one parent with the condition.

As the altered ATN1 gene is passed from one generation to the next, the CAG trinucleotide repeat may increase in size. A minor increase in length may lead to mild symptoms or even no symptoms at all. Larger increases are usually associated with an earlier onset of the disorder and more severe signs and symptoms. This phenomenon is called anticipation. Anticipation tends to be more prominent when the altered ATN1 gene is inherited from a person's father (paternal inheritance) than when it is inherited from a person's mother (maternal inheritance).

The signs and symptoms of DRPLA may differ depending on whether they begin in childhood or adulthood.

When DRPLA begins before 20 years of age, it typically involves:

• Involuntary muscle jerking or twitching (myoclonus)
• Seizures
• Behavioral changes
• Intellectual disability
• Problems with balance and coordination (ataxia)

Epileptic seizures occur in all people with onset before 20 years of age.When DRPLA begins after 20 years of age, the most frequent signs and symptoms include:

• Ataxia
• Uncontrollable movements of the limbs (choreoathetosis)
• Psychiatric symptoms (such as delusions)
• Dementia

Seizures are less frequent in people with onset between the ages of 20 and 40 and rarely occur in those with onset after age 40.People who have inherited the condition from an affected parent typically have symptoms 26 to 29 years earlier than affected fathers, and 14 to 15 years earlier than affected mothers.

There is no cure for DRPLA; however there may be ways in which the signs and symptoms can be managed including:

• Treatment of seizures with anti-epileptic drugs
• Treatment of psychiatric problems with appropriate psychotropic medications
• Adaptation of environment and care to the level of dementia
• Adaptation of educational programs for affected children

A medication typically used to slow the progress of amyotrophic lateral sclerosis (ALS or Lou Gehrig's disease) called riluzole may also be useful in managing ataxia in people with DRPLA.

DRPLA is most common in the Japanese population, where it is estimated to affect 2 to 7 per million people. However, this condition has also been seen in families around world.

Although DRPLA is rare in the United States, it has been studied in a large African American family from the Haw River area of North Carolina. When the family was first identified, researchers named the disorder Haw River syndrome. Later, researchers determined that Haw River syndrome and DRPLA are the same condition.