Rapid-onset dystonia-parkinsonism

Alternate names

DYT12; RDP; DYT-ATP1A3; Dystonia 12

Definition

Rapid-onset dystonia-parkinsonism (RDP) is a very rare movement disorder, characterized by the abrupt onset of parkinsonism and dystonia, often triggered by physical or psychological stress.

Epidemiology

The prevalence is unknown. Fewer than 100 patients have been described worldwide to date.

Cause

• RDP is caused by several missense mutations in the ATP1A3 gene (19q13.2) 'encoding the sodium/potassium-transporting ATPase subunit alpha-3 protein', which is important for maintaining the electrochemical gradients of potassium and sodium across the plasma membrane.
• These mutations are thought to lead to neuronal dysfunction.
• Other genes, which have not yet been identified, may also be involved.

Inheritance

Autosomal dominant pattern, a 50/50 chance.

RDP is inherited in an autosomal dominant manner with reduced penetrance, and genetic counseling is possible and recommended. De novo mutations are also observed.

Signs and symptoms

• RDP typically presents in childhood or early adulthood (but age of onset can range from 4-55 years) with the abrupt onset of dystonia along with parkinsonism (bradykinesia and postural instability) with a rostrocaudal gradient and prominent bulbar symptoms (dysarthria and dysphagia) that do not respond to dopaminergic medication.
• Symptoms may develop over several minutes to 30 days, after which time they stabilize.
• Often onset is triggered by physical exertion, fever, extreme heat, childbirth, excessive alcohol consumption or emotional stress.
• Some patients experience mild upper limb dystonia (mainly in the hands) and cramping before disease onset occurs.
• In most cases the disease stabilizes, but a few cases have been reported where a second episode of worsening of symptoms occurred 1-9 years after initial onset.
• In rare cases seizures, anxiety and depression have been reported.
• Recently, a variant phenotype in infants (<4 years of age) has been reported with initially episodic hypotonia, gait ataxia, motor delay, and speech and swallowing difficulties.

Clinical presentation

For most diseases, symptoms will vary from person to person. People with the same disease may not have all the symptoms listed.

30%-79% of people have these symptoms

• Bradykinesia(Slow movements)
• Drooling(Dribbling)
• Dysarthria(Difficulty articulating speech)
• Dysphagia(Poor swallowing
• Gait ataxia(Inability to coordinate movements when walking)
• Hypomimic face(Dull facial expression)
• Limb dystonia
• Motor delay
• Mutism(Inability to speak)
• Parkinsonism
• Postural instability(Balance impairment)
• Torticollis(Wry neck)
• Young adult onset

5%-29% of people have these symptoms

• Anxiety(Excessive, persistent worry and fear)
• Cerebellar atrophy(Degeneration of cerebellum)
• Depressivity(Depression)
• Emotional lability(Emotional instability)
• Resting tremor(Tremor at rest)
• Seizure

1%-4% of people have these symptoms

• Generalized hypotonia(Decreased muscle tone)

Diagnosis

• Diagnosis is based on the sudden onset of clinical manifestations (parkinsonism and dystonia), the finding of low homovanillic acid concentrations in cerebrospinal fluid (CSF), normal brain imaging studies and the lack of response to levodopa (L-dopa) therapy.
• Positron emission tomography (PET) and single-photon emission computed tomography (SPECT) studies show normal dopamine reuptake in dopamine transporters.
• A mutation in the ATP1A3 gene may confirm diagnosis.

Antenatal diagnosis Prenatal diagnosis is possible in families where a disease causing mutation is known.

Treatment

• There is no effective treatment for RDP at present. L-dopa is ineffective.
• Pallidal deep brain stimulation (DBS) has shown limited or no therapeutic effects.
• If present, seizures, anxiety and depression can be treated with standard therapy.
• High-dose benzodiazepines and possibly other muscle relaxants may offer some symptomatic relief.
• All known triggers of RDP should be avoided.
• Physical therapy is recommended.

Prognosis

There is no effect on life expectancy, but quality of life is severely affected.

NIH genetic and rare disease info

• NIH info on Rapid-onset dystonia-parkinsonism

Rapid-onset dystonia-parkinsonism is a rare disease.

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