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Defining and refining the phenotype of PRRT2 mutations

Paroxysmal dyskinesias constitute a group of episode movement disorders that have been historically classified based on precipitant, duration, and family history. Careful description of phenotypes has shown that classification based on precipitant is the most powerful for predicting features and clinical course. The three major groups are: (1) kinesigenic – triggered by sudden movement; (2) exertional – triggered by sustained exertion; (3) non-kinesigenic – no discrete trigger but with attacks often following ingestion of ethanol or caffeine, or after sleep deprivation. All three forms can exist as primary disorders or may be secondary to specific brain lesions. The primary forms typically begin in childhood and are not associated with neurologic abnormalities between episodes. Several causative genes have been described, but the major gene responsible for paroxysmal kinesigenic dyskinesia (PKD) has been elusive until recently. Silveira-Moriyama et al. describe the clinical features of children with PKD and PRRT2 gene mutations. Since discovery of the association between PRRT2 mutations and PKD, there has been substantial progress in further defining the phenotypic spectrum of these mutations. Mutations in the PRRT2 gene may cause PKD, infantile convulsions, or familial hemiplegic migraine. PRRT2 mutations may also cause episodic ataxia or febrile seizures. In addition to contributions toward better understanding of the disorder and its prognosis, the findings of SilvieraMoriyama et al. raise important conceptual questions about the pathophysiology of paroxysmal disorders. Early reports of paroxysmal dyskinesias raised the question of whether they might be a form of epilepsy, yet surface electroencephalography is normal during attacks. By convention, seizures are viewed as cortical phenomena due to the paroxysmal discharge of neurons. However, it is reasonable to hypothesize that paroxysmal dyskinesias are due to paroxysmal discharge of subcortical neurons. Supporting this notion is the exquisite clinical response of PKD to low doses of anticonvulsant medications such as carbamazepine or phenytoin. Can some forms of hemiplegic migraine also result from paroxysmal neuronal discharge? Or can PRRT2 mutations lead to paroxysmal of neuronal depression? Further study of neuronal function in the setting of PRRT2 mutations is likely to shed light on the pathophysiology of many paroxysmal disorders including seizures, migraine, paroxysmal movement disorders, and paroxysmal ataxia.