Dentatorubral-Pallidoluysian Atrophy (DRPLA)

What happens in DRPLA

The name lists the brain regions affected: the dentate nucleus of the cerebellum, the red nucleus (rubral), the globus pallidus and the subthalamic nucleus of Luys. These structures coordinate movement. Damage to them and to brain white matter causes problems with balance, involuntary movements and cognition.

DRPLA is a polyglutamine disorder, like Huntington's disease and several spinocerebellar ataxias. The ATN1 gene normally has a short stretch of repeated CAG building blocks. In DRPLA, the stretch is expanded (typically 48 repeats or more), producing an abnormal protein that accumulates in nerve cells.

Inheritance

• Autosomal dominant: each child of an affected parent has a 50% chance of inheriting the expansion.
• Anticipation: the repeat can grow when passed on, especially from fathers, so children may develop symptoms earlier and more severely than their parent.
• Longer repeats are associated with younger onset.

DRPLA is most frequent in Japan, where its prevalence is estimated at a few people per million. It occurs worldwide, including a family in North Carolina described as Haw River syndrome.

Symptoms

Juvenile onset (before about age 20)

• progressive myoclonus epilepsy: sudden muscle jerks plus seizures of several types
• intellectual decline and learning difficulties
• behavior changes
• ataxia (unsteadiness)

Adult onset (after about age 40)

• ataxia: unsteady walking and clumsy movements
• choreoathetosis (chorea with writhing): involuntary, irregular jerking and writhing movements
• dementia: memory and thinking decline
• psychiatric symptoms: personality change, irritability, delusions and hallucinations

Early adult onset (20 to 40)

A mix of both patterns, including seizures, ataxia and involuntary movements.

DRPLA vs Huntington's disease

Spinocerebellar ataxias and other progressive myoclonus epilepsies can also look similar.

Diagnosis

• Neurological examination and family history
• MRI of the brain: shrinkage of the cerebellum and brainstem, and white matter changes in adults
• EEG: for seizures and myoclonus
• Genetic testing: counting the CAG repeats in ATN1 confirms the diagnosis

Testing people without symptoms (predictive testing) is offered with genetic counseling, because there is no treatment that prevents the disease and results have major personal implications. Prenatal and preimplantation genetic testing are available.

Treatment and management

There is no cure or treatment to slow DRPLA. Care is aimed at symptoms and quality of life:

• anti-seizure medicines for epilepsy and myoclonus, chosen by a neurologist
• medicines for involuntary movements and psychiatric symptoms
• physical therapy for balance and mobility, and walking aids
• occupational and speech therapy, including swallowing assessment
• educational support for children
• nutrition support if swallowing becomes difficult
• palliative care and caregiver support as the disease advances

Outlook

DRPLA progresses over years to decades. Juvenile-onset disease tends to progress more quickly. Over time, people lose independence with mobility, communication and self-care. Complications such as pneumonia from swallowing problems are common causes of death. Research into gene-silencing therapies for polyglutamine diseases is ongoing.

Frequently asked questions

What is DRPLA?

DRPLA is a rare inherited brain disease caused by an expanded CAG repeat in the ATN1 gene. It damages brain areas controlling movement and thinking, causing combinations of seizures, muscle jerks, unsteadiness, involuntary movements, dementia and psychiatric symptoms.

How is DRPLA inherited?

It is autosomal dominant, so each child of an affected parent has a 50% chance of inheriting it. The repeat can lengthen across generations, especially when passed from the father, causing earlier and more severe symptoms in children. This is called anticipation.

What are the symptoms of DRPLA?

When it starts before age 20, the main symptoms are muscle jerks, epilepsy and intellectual decline. When it starts after 40, the main symptoms are unsteadiness, involuntary writhing movements, dementia and psychiatric changes. Many people have a mixture.

Is DRPLA the same as Huntington's disease?

No, but they are similar. Both are caused by CAG repeat expansions and cause involuntary movements, dementia and psychiatric symptoms. DRPLA involves a different gene, ATN1, and juvenile forms more often cause myoclonus and epilepsy. Genetic testing distinguishes them.

Is there a cure for DRPLA?

No. Treatment manages symptoms with anti-seizure medicines, medicines for movement and psychiatric problems, and therapies for mobility, speech and swallowing. Research into treatments that lower the abnormal protein is underway for this and related diseases.