Mild paroxysmal kinesigenic dyskinesia caused by PRRT2 missense mutation with reduced penetrance

Department of Neurology, MS Center, and Laboratory of Neuroimmunology and the Agnes-Ginges Center for Neurogenetics, Hadassah-Hebrew University Medical Center, Ein-Karem, Jerusalem, Israel.
Neurology (Impact Factor: 8.29). 08/2012; 79(9):946-8. DOI: 10.1212/WNL.0b013e318266fabf
Source: PubMed


Paroxysmal kinesigenic dyskinesia (PKD) is an uncommon disorder characterized by brief episodes of involuntary dystonia or choreoathetosis triggered by sudden voluntary movement.(1) Recently, several groups identified mutations in patients with PKD in the proline-rich transmembrane protein 2 (PRRT2) gene.(2-7) We report a missense c.913G>A (p.Gly305Arg) change in PRRT2 in 4 siblings with PKD, 2 with infrequent symptoms. The association of a milder phenotype and reduced penetrance with this missense mutation suggests partial loss of function.

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Available from: Joseph Gleeson, Oct 10, 2015
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    ABSTRACT: Mutations in PRRT2 genes have been identified as a major cause of benign infantile epilepsy and/or paroxysmal kinesigenic dyskinesia. We explored mutations in PRRT2 in Japanese patients with BIE as well as its related conditions including convulsion with mild gastroenteritis and benign early infantile epilepsy. We explored PRRT2 mutations in Japanese children who had had unprovoked infantile seizures or convulsion with mild gastroenteritis. The probands included 16 children with benign infantile epilepsy, 6 children with convulsions with mild gastroenteritis, and 2 siblings with benign early infantile epilepsy. In addition, we recruited samples from family members when PRRT2 mutation was identified in the proband. Statistical analyses were performed to identify differences in probands with benign infantile epilepsy according to the presence or absence of PRRT2 mutation. Among a total of 24 probands, PRRT2 mutations was identified only in 6 probands with benign infantile epilepsy. A common insertion mutation, c.649_650insC, was found in 5 families and a novel missense mutation, c.981C>G (I327M), in one. The family history of paroxysmal kinesigenic dyskinesia was more common in probands with PRRT2 mutations than in those without mutations. Our study revealed that PRRT2 mutations are common in Japanese patients with benign infantile epilepsy, especially in patients with a family history of paroxysmal kinesigenic dyskinesia.
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    ABSTRACT: Mutations in the gene PRRT2 encoding proline-rich transmembrane protein 2 have recently been identified as the cause of three clinical entities: benign familial infantile epilepsy (BFIE), infantile convulsions with choreoathetosis (ICCA) syndrome, and paroxysmal kinesigenic dyskinesia (PKD). Patients with ICCA have both BFIE and PKD and families with ICCA may contain individuals who exhibit all three phenotypes. These three phenotypes were all mapped by linkage analyses to the pericentromeric region of chromosome 16, and were hypothesised to have the same genetic basis due to the co-occurrence of the disorders in some families. Despite considerable effort, the gene or genes for BFIE, ICCA, and PKD were not identified for many years after the linkage region was identified. Mutations in the gene PRRT2 were identified in several Chinese families with PKD, suggesting that the gene may also be responsible for ICCA and BFIE in families linked to the chromosome 16 locus. This was demonstrated to be the case, with the majority of families with ICCA and BFIE found to have PRRT2 mutations. The vast majority of these mutations are truncating and are predicted to lead to haploinsufficiency. PRRT2 is a largely uncharacterised protein. It is expressed in the brain and has been demonstrated to interact with SNAP-25, a component of the molecular machinery involved in the release of neurotransmitters at the presynaptic membrane. Therefore, the PRRT2 protein may play a role in this process. However, the molecular mechanisms underlying the remarkable pleiotropy associated with PRRT2 mutations have still to be determined.
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    ABSTRACT: In the past year, mutations in the PRRT2 gene have been identified in patients with paroxysmal kinesigenic dyskinesia and other paroxysmal disorders. We conducted a review of the literature on PRRT2 mutation-associated disorders. Our objectives were to describe the wide clinical spectrum associated with PRRT2 mutations, and to present the current hypotheses on the underlying pathophysiology. PRRT2 mutations are associated with a wide range of clinical syndromes: the various paroxysmal dyskinesias, infantile seizures, paroxysmal torticollis, migraine, hemiplegic migraine, episodic ataxia and even intellectual disability in the homozygous state. The PRRT2 protein, through its interaction with SNAP-25, could play a role in synaptic regulation in the cortex and the basal ganglia. The pathogenesis may be caused by PRRT2 loss of function, which may induce synaptic deregulation and neuronal hyperexcitability. However, this does not explain the phenotypic variability, which is likely modulated by environmental factors, modifier genes or age-dependent expression. The clinical spectrum of PRRT2 mutations has expanded among paroxysmal disorders and beyond. Unraveling the molecular pathways linking the genetic defect to its clinical expression will be crucial for the diagnosis and treatment of these disorders.
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