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New Mutation Implicated in Paroxysmal Kinesigenic Dyskinesia

Talan, Jamie

doi: 10.1097/01.NT.0000411146.04489.4e

An international consortium of neurologists and geneticists has identified a gene involved in paroxysmal kinesigenic dyskinesia with infantile convulsions (PKD/IC) that will hopefully lead to a better understanding of the condition. Patients with PKD/IC typically have seizures in infancy and dance-like movements and dyskinesias in adolescence through early adulthood that, for most, virtually disappear by middle age.

The gene is referred to as proline-rich transmembrane protein 2 or PRRT2 and the mutations identified in hundreds of families “represent a crucial entry point to elucidate the pathophysiology of the disorder,” the study authors wrote in the paper published in the Dec. 15 online edition of Cell Reports.

The lead study author Louis J. Ptáček, MD, professor of neurology at the University of California, San Francisco, and a Howard Hughes Medical Institute investigator, and colleagues used whole genome sequencing techniques to narrow their hunt to chromosome 16. Other groups had also mapped the gene to chromosome 16. But there were hundreds of genes in that region to test and scientists decided to band together to find the mutations in families around the world.

The publication represents hundreds of patients and more than a dozen neurologists and scientists from five continents, 10 countries, and 22 institutions. They used whole genome sequencing in six patients, each from a different family with a history of PKD. These families were well characterized and included patients of white, Asian, and African-American descent. In addition to the whole genome sequencing, they looked at copy number variation (CNV) and structural variations in the region of the mutation. They identified mutations on the PRRT2 gene on chromosome 16 and further testing showed that they were truncating (frameshift or nonsense) mutations. There was nothing out of the ordinary in copy number variations or structural variations.



The findings from the first six families were included in this analysis. The investigators went on to test 78 other families but many of these included patients who had not had extensive clinical workups for PKD, said Dr. Ptáček.

The investigators have another paper coming out with a French team that involves other mutations in this gene. “We have so many families now that we did not do them all yet,” he said. An independent group from China reported mutations in the PRRT2 gene in their pedigrees. That paper was also published in December in the journal, Brain.

The investigators are now making mouse models with the mutations to better understand the human form of the disease. If the animals manifest the infantile seizures and the movements in adolescence, they will be able to look at the expression of RNA and see whether changes parallel the timing of the symptoms.

Dr. Ptáček and his colleagues are attempting to determine what the PRRT2 protein does. In neuronal cultures, the protein shares an affinity for axons but does not localize to dendritic processes. In laboratory studies, the mutations led to reduced protein and these dramatically low levels triggered neuronal hyperexcitability. The thought is that this hyperexcitability leads to the phenotype. In culture, they do not see the mutant protein in the neurons, suggesting that it might be around in low supply or not at all.

At first blush, scientists who study PKD thought that it would be another channelopathy. But the new evidence may suggest otherwise. Dr. Ptáˇek said that he has some evidence that PKD/IC might be the result of dysfunction in a protein — synaptosomal-associated protein 25 — involved in synaptic regulation.

“There are many unanswered questions,” he said. How are the seizures in infancy related to the symptoms of chorea years later? Is epilepsy a movement disorder that involves the cortex? What does the protein do in its natural form and in the mutated form?

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“Discovery of genes that cause neurological diseases offer clues to the manner in which the nervous system works,” said John G. Nutt, MD, professor of neurology and physiology & pharmacology at Oregon Health & Science University in Portland. “This discovery is likely to teach us more about the function of the synapse and neurotransmission.”

He added that neurologists must consider that clinically typical PKD is sometimes seen in episodic ataxia type one, which is caused by a mutation in a potassium channel. ”Thus, their finding isn't proof that the disease is not a channelopathy. Or [it is possible that] channelopathies may affect synaptic neurotransmission in a similar way to what PRRT2 does.”



Daniel H. Lowenstein, MD, an endowed professor of neurology and director of the Physician-Scientist Education and Training Programs at the University of California, San Francisco, said that the study is “another important example of progress in identifying genes associated with neuronal hyperexcitability and emphasizing a growing realization that not all epilepsies are channelopathies. It is an elegant study that capitalizes on collaborations among laboratory scientists and clinicians from throughout the world.”

want to hear more about the work on paroxysmal kinesigenic dyskinesia with infantile convulsions? Tune into a podcast interview with Dr. Louis J. Ptáček at

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The lead study author Louis J. Ptáček, MD, professor of neurology at the University of California, San Francisco, and a Howard Hughes Medical Institute investigator, was in medical school in the 1980s when he diagnosed his first case of paroxysmal kinesigenic dyskinesia. Doctors thought the teenager's uncontrolled dance-like movements were part of a psychiatric condition. To Dr. Ptáček, it was a puzzle. The boy seemed so normal in every other way. He asked the boy's father whether there was a family history of any similar phenomenon. Embarrassed, the father confided that he had the same uncontrolled movements as a teenager but that they went away before adulthood.

The student made his way to the library where he found some studies on a rare condition called paroxysmal kinesigenic dyskinesia. The teenager's symptoms were identical. As a neurologist, he dedicated his career to identifying mutations in families with PKD.

The chorea and dyskinesia movements are triggered by motion so when changing velocity or moving from sitting to standing the body can twitch uncontrollably for brief moments — seconds, in fact — before settling into the movement. It was Dr. Ptáček and his colleagues who figured out that the episodic nature of this condition may have its roots in childhood. Careful history taking led him to see that parents recalled benign and unexplained seizures in infancy or early childhood. It was generally years before the chorea movements began, which is why neither doctors nor parents made the connection between the seemingly disparate symptoms when PKD was diagnosed.

PKD is one of many episodic hereditary conditions. Before Dr. Ptáček began combing for disease genes in patients with PKD, he'd identified and cloned a number of muscle genes. By 2004, the neurologist had diagnosed well over 100 patients with the familial condition.

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Lee H-Y, Huang Y, Ptáček LJ, et al. Mutations in the gene PRRT2 cause paroxysmal kinesigenic dyskinesia with infantile convulsions. Cell Reports 2011; E-pub 2011 Dec. 15.
    Wang JL, Cao L, Tang BS, et al. Identification of PRRT2 as the causative gene of paroxysmal kinesigenic dyskinesias. Brain 2011;134(Pt 12):3490-3498.
      ©2012 American Academy of Neurology