Clinical Description
The core phenotypes of PRRT2-associated paroxysmal movement disorders (PRRT2-PxMD) include paroxysmal kinesigenic dyskinesia (PKD), benign familial infantile epilepsy (BFIE), paroxysmal kinesigenic dyskinesia with infantile convulsions (PKD/IC), and hemiplegic migraine (HM). In addition, PRRT2 pathogenic variants have been identified in other childhood-onset movement disorders and different types of seizures, including a small number of individuals who meet clinical criteria for paroxysmal nonkinesigenic dyskinesia (PNKD) [Liu et al 2012, Becker et al 2013, Liu et al 2013, Wang et al 2013, Delcourt et al 2015], paroxysmal exertion-induced dyskinesia [Liu et al 2012], and episodic ataxia [Gardiner et al 2012, Labate et al 2012, Delcourt et al 2015]. Thus, it is likely that the understanding of the spectrum of associated phenotypes is still evolving [Ebrahimi-Fakhari et al 2015].
Paroxysmal Kinesigenic Dyskinesia (PKD)
To date, the primary paroxysmal movement disorder of PRRT2-PxMD is PKD (see Suggestive Findings, PKD). Paroxysmal attacks are often characterized by dystonia, followed by choreoathetosis, and rarely ballism. Attacks often occur bilaterally. The arms are the most commonly involved, followed in decreasing order by involvement of the legs, trunk, face, and neck.
Onset of PRRT2-PKD is in childhood or adolescence (mean age: 10.3±4.9 [SD] years; range: 1-20 years) [Ebrahimi-Fakhari et al 2015].
The most common triggers are sudden voluntary movements, stress, being startled, intent to perform a voluntary movement, and sleep deprivation. While caffeine and alcohol are precipitating factors in a few affected individuals and attacks at rest are reported in approximately 2% of affected individuals, both of these triggers are more typical of paroxysmal nonkinesigenic dyskinesia (PNKD) than PKD.
A nonspecific aura precedes PKD attacks in about 10% of individuals. Reported aura symptoms include a crawling sensation in the affected limb, paresthesias, or nonspecific epigastric discomfort.
Attacks are usually brief – in the range of a few seconds – but in some individuals last five minutes or more.
The frequency of attacks is highly variable, ranging from 100 per day to one per week [Ebrahimi-Fakhari et al 2015].
Attacks tend to become less frequent with age and often respond well to anticonvulsants such as carbamazepine.
Benign Familial Infantile Epilepsy (BFIE)
The seizures are complex partial seizures or localization-related epilepsy (see Suggestive Findings, BFIE). Ictal patterns have been described as focal; onset has been reported in temporal, central, parietal, and occipital areas, with or without secondary generalization [Caraballo et al 2002].
Seizures may occur in clusters with multiple complex partial seizures per day. Less common are motor arrest, decreased responsiveness, and automatisms [Watanabe et al 1987]. Seizures rarely progress into status epilepticus. While respiratory depression can occur either during seizures or from medications including benzodiazepines, sudden unexpected death in epilepsy and long-term sequelae have not been reported.
In the vast majority of individuals the interictal EEG is unremarkable. In rare instances interictal focal epileptiform discharges may be seen, including bilateral centrotemporal spikes [Seo & You 2016], bilateral parietotemporal spikes [Torisu et al 2014], and unilateral frontocentral spikes [El Achkar et al 2017].
Epilepsy-related brain MRI abnormalities are not reported.
Paroxysmal Kinesigenic Dyskinesia with Infantile Convulsions (PKD/IC)
A seizure disorder in the form of BFIE is present in about 30% of PRRT2-PKD, leading to the diagnosis of PKD/IC. It is currently unknown how frequently BFIE evolves into PKD/IC.
Hemiplegic Migraine (HM)
HM falls within the classification of migraines with aura, characterized by an aura that localizes to the cerebral cortex. These auras comprise the following (in order of frequency):
Visual symptoms or disturbance (e.g., scotoma, photopsia, or diplopia)
Sensory loss (e.g., numbness or paresthesias)
Dysphasia
HM additionally presents with motor symptoms in the form of some degree of hemiparesis.
Attack frequency often declines over time. Many affected individuals even report a complete remission during adulthood. Improvement during pregnancy has also been observed [Bruno et al 2004].
Genotype-Phenotype Correlations
No clear evidence for genotype-phenotype correlations exists for PKD, BFIE, PKD/IC, and HM, the four core PRRT2-PxMD phenotypes [Ebrahimi-Fakhari et al 2015]. Considerable variation in phenotype is seen both within and between families with the same pathogenic PRRT2 variant.
Individuals with a 16p11.2 deletion who have PRRT2-PKD tend to have additional clinical features including developmental delay, intellectual disability, and/or autism spectrum disorder [Dale et al 2012, Silveira-Moriyama et al 2013, Weber et al 2013, Termsarasab et al 2014].
Individuals with biallelic PRRT2 pathogenic variants tend to have a more severe phenotype that often includes intellectual disability, episodic ataxia, and different seizure types [Labate et al 2012, Delcourt et al 2015].
Nomenclature
Paroxysmal kinesigenic dyskinesia (PKD) was formerly known as paroxysmal kinesigenic choreoathetosis (PKC).
Benign familial infantile epilepsy (BFIE) is also known as benign familial infantile seizures (BFIS).
Paroxysmal kinesigenic dyskinesia with infantile convulsions (PKD/IC) was formerly known as infantile convulsions and choreoathetosis (ICCA).
Current recommendations are use of the designation PRRT2-PxMD for paroxysmal movement disorders associated with PRRT2 [Marras et al 2016].
Prevalence
The PRRT2-associated paroxysmal movement disorders (PRRT2-PxMD) are rare.
Prevalence for PKD, the most common of the paroxysmal movement disorders (including both PRRT2-PxMD and PKD of unknown or secondary cause), has been estimated at 1:150,000 individuals [Ebrahimi-Fakhari et al 2015].
To date approximately 600 individuals with PRRT2-BFIE, 560 with PRRT2-PKD, and 210 with PRRT2-PKD/IC have been reported [Ebrahimi-Fakhari et al 2015].
The majority of these individuals are of Asian ethnicity from China and Japan, followed by individuals from North America and Europe.
PRRT2-PKD appears to be more common in males with about 1.5-fold more males reported than females.