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Rapid-onset dystonia-parkinsonism

ORPHA71517
Synonym(s) DYT12
Dystonia 12
Prevalence <1 / 1 000 000
Inheritance Autosomal dominant
or Not applicable
Age of onset Adolescent
Adult
Childhood
ICD-10
  • G24.1
OMIM
UMLS -
MeSH -
MedDRA -

Summary

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.

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

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.

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.

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.

Differential diagnosis includes other forms of dystonia-parkinsonism, such as young adult-onset parkinsonism, dopa-responive dystonia (DRD), dystonia 16 (DYT16) and X-linked dystonia parkinsonism (DYT3; see these terms). Unlike DYT3 and other forms of young-onset parkinsonism, RDP is not a neurodegenerative disorder.

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

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

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.

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

Expert reviewer(s)

  • Dr Christoph KAMM

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Detailed information

Review article
  • EN (2011)Patient Inform
Clinical practice guidelines
  • EN (2011)Patient Inform
Clinical genetics review
  • EN (2014)
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