Dentatorubral–pallidoluysian atrophy

Congenital neurodegenerative disorder

Dentatorubral–pallidoluysian atrophy
Synonyms	Haw River syndrome, Naito–Oyanagi disease
Pronounce	N/A
Field	Neurology, Genetics
Symptoms	Ataxia, choreoathetosis, myoclonus, seizures, dementia
Complications	Progressive neurodegeneration, epilepsy, loss of mobility
Onset	Childhood or adulthood (varies by CAG repeat length)
Duration	Lifelong
Types	Juvenile-onset, early adult-onset, late adult-onset
Causes	Mutation in the ATN1 gene
Risks	Family history of DRPLA
Diagnosis	Genetic testing, neuroimaging, clinical evaluation
Differential diagnosis	Huntington's disease, spinocerebellar ataxia, Lafora disease, sialidosis
Prevention	None
Treatment	Symptomatic management
Medication	Anticonvulsants, psychotropic medications
Prognosis	Progressive and variable
Frequency	Rare, more common in Japan
Deaths	Progressive neurodegeneration may lead to early death

Dentatorubral–pallidoluysian atrophy (DRPLA) is a rare neurodegenerative disorder inherited in an autosomal dominant pattern. It is caused by a CAG repeat expansion in the ATN1 gene, which encodes the protein atrophin-1. The condition leads to progressive spinocerebellar degeneration and affects various parts of the central nervous system, including the dentate nucleus, red nucleus, globus pallidus, and subthalamic nucleus.

DRPLA is also known as Haw River syndrome or Naito–Oyanagi disease. It is most commonly found in individuals of Japanese descent but has been reported in other populations.

Clinical presentation

DRPLA has variable onset, categorized into three types:

• Juvenile-onset (before age 20): Presents with myoclonus, epilepsy, ataxia, and cognitive decline resembling progressive myoclonus epilepsy.
• Early adult-onset (age 20–40): Characterized by ataxia, seizures, and dementia.
• Late adult-onset (after age 40): Symptoms include choreoathetosis, ataxia, and cognitive impairment.

Additional features may include dystonia, sleep apnea, autism spectrum disorders, and corneal degeneration.

Genetics

The disorder is caused by a pathogenic expansion of the CAG trinucleotide repeat in the ATN1 gene on chromosome 12. Normal individuals have fewer than 35 repeats; those with DRPLA typically have more than 49. The expansion leads to an abnormally long polyglutamine tract in the atrophin-1 protein.

DRPLA shows genetic anticipation, where symptoms appear earlier and more severely in subsequent generations, particularly with paternal transmission.

Pathophysiology

The mutant atrophin-1 protein accumulates in neuronal nuclei and forms neuronal intranuclear inclusions (NIIs), which are associated with neurotoxicity. The inclusions are found throughout the brain, especially in the basal ganglia, cerebellum, and brainstem. The disease is marked by progressive brain atrophy and loss of neuronal function.

Diagnosis

Diagnosis is based on:

• Family history and clinical symptoms
• Genetic testing to confirm CAG repeat expansion in ATN1
• MRI to detect cerebral atrophy
• EEG to assess seizure activity
• Neuropsychological testing for cognitive decline

Differential diagnosis

Conditions that may mimic DRPLA include:

• Huntington's disease
• Spinocerebellar ataxias
• Lafora disease
• Neuronal ceroid lipofuscinosis
• Sialidosis
• Unverricht–Lundborg disease

Management

There is no cure for DRPLA. Management includes:

• Anticonvulsants for seizure control
• Psychotropic drugs for mood or psychotic symptoms
• Physical therapy and occupational therapy
• Supportive care for mobility and activities of daily living

Prognosis

DRPLA is progressive and leads to increasing neurological impairment. The rate of progression varies by age of onset and size of the CAG repeat expansion. Juvenile-onset cases generally have a more rapid and severe course.

Epidemiology

DRPLA is rare worldwide but more prevalent in Japan, with an estimated frequency of 2–7 per million people. The disorder is much less common in Western populations.

Related topics

• Trinucleotide repeat disorder
• Huntington's disease
• Spinocerebellar ataxia
• Neurodegeneration
• Ataxia
• Epilepsy