Description, Causes and Risk Factors:
Dentatorubral-pallidoluysian atrophy (DRPLA) is an autosomal dominant Neurodegenerative disorder characterized clinically by myoclonus, epileptic seizures, cerebellar ataxia, choreoathetotic movements, personality change and dementia. The cardinal clinical features depend on the age of onset. The dentate nucleus of the cerebellum is the most severely affected site followed by the pallidum.
Dentatorubral-pallidoluysian atrophy is caused by a mutation in the ATN1 gene. This gene provides instructions for making a protein called atrophin-1. Although the function of atrophin-1 is unclear, it likely plays an important role in nerve cells (neurons) in many areas of the brain.
The ATN1 mutation 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 Dentatorubral-pallidoluysian atrophy, 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 atrophin-1. 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 Dentatorubral-pallidoluysian atrophy.
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 size of the CAG trinucleotide repeat often increases in size. Larger repeat expansions 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 ATN1 gene is inherited from a person's father (paternal inheritance) than when it is inherited from a person's mother (maternal inheritance).
DRPLA has been reported to occur most often in the Japanese population, although it has been described in other ethnic groups including those in Europe and North America. The prevalence of Dentatorubral-pallidoluysian atrophyin the Japanese population is estimated to be 2-7 in 1,000,000, which is similar to the prevalence of Huntington disease in this population. A CAG repeat size of 17 or higher (usually 20-35) is more common in healthy Japanese individuals than Caucasians, which may explain why DRPLA is more common in the Japanese. In other words, a larger repeat size in a parent increases the possibility that the DNA will become unstable and expand when transmitted to the next generation. Even though DRPLA is rare in the United States, a large African-American family in North Carolina has Dentatorubral-pallidoluysian atrophy.
The cardinal features of Dentatorubral-pallidoluysian atrophy are involuntary movements (usually in the face, neck, tongue and hands) and dementia (inability to clearly think; confusion; poor judgment; failure to recognize people, places, and things; personality changes) regardless of the age of onset. A history of ataxia
, epilepsy, and mental retardation in children, combined with a positive family history, are often the presenting signs of this condition in an individual under 20 years of age. Seizures are always present in patients under 20, but are not as common in patients age 20-40, and rarely seen in patients with onset after 40. Adult onset DRPLA (after 20) presents with ataxia, choreoathetosis, dementia, and psychiatric disturbances.
Clinical diagnoses of Dentatorubral-pallidoluysian atrophy patients are sometimesdifficult due to the diversity of the clinical features.However, it is not impossible to reach the correct diagnosis, if (i) the clear relationship between the age of onsetand the clinical types, (ii) autosomal dominant inheritance with clear anticipation, and (iii) MRI imagingshowing small-sized cerebellum and brainstem, and adiffuse high-intensity lesion in T2-weighted condition inadult patients, are taken into consideration. After theidentification of the responsible gene for Dentatorubral-pallidoluysian atrophy, theabove concept is strongly supported by the clear correlation between the length of the CAG repeat and the age ofonset. As one of the members of the CAG repeat diseases,neurons in the nervous system of DRPLA patientscontain inclusion bodies, which provide the most plausiblemarker of neuronal cell death at present.
For pregnancies at 50% risk, prenatal diagnosis is available via either CVS (chorionic villus sampling) or amniocentesis. CVS is a biopsy of the placenta performed in the first trimester of pregnancy under ultrasound guidance. The genetic makeup of the placenta is identical to the fetus (developing baby) and therefore the DRPLA gene can be studied from this tissue. There is approximately a 1 in 100 chance for miscarriage with CVS. Amniocentesis is a procedure done under ultrasound guidance where a long thin needle is inserted into the mother's abdomen, into the uterus, to withdraw a couple of tablespoons of amniotic fluid (fluid surrounding the developing baby) to study. The Dentatorubral-pallidoluysian atrophy gene can be studied using cells from the amniotic fluid. Other genetic tests, such as a chromosome analysis, may also be performed on either a CVS or amniocentesis. A small risk of miscarriage (1 in 300) is associated with amniocentesis.
There is currently no known cure for Dentatorubral-pallidoluysian atrophy; treatment is supportive. Epilepsy is treated with anti-seizure medication and psychiatric disturbances with psychotropic medications. Physiotherapy may be helpful to help improve and maintain mobility. Speech & Language assessment and therapy may also be required. Occupational therapists can help determine any adaptations that need to be made in the home.
NOTE: The above information is educational purpose. The information provided herein should not be used during any medical emergency or for the diagnosis or treatment of any medical condition.
DISCLAIMER: This information should not substitute for seeking responsible, professional medical care.