Clinical manifestations and genetic characteristics of PRRT2 mutations
The
PRRT2, which encodes proline-rich transmembrane protein 2, is composed of four exons; this protein consists of 340 amino acids and contains two predicted transmembrane domains [
10]. The
PRRT2 is expressed primarily in the brain, particularly in the cerebral cortex and basal ganglia; this expression pattern may explain why abnormal excitability in the cortex and basal ganglia is detected in a subset of PKD patients [
6]. However, the exact function of the
PRRT2 remains unknown. Reports have indicated that this gene interacts with synaptosomal-associated protein 25 kDa (SNAP25) [
11]. SNAP25 is a presynaptic plasma-membrane-bound protein involved in the synaptic vesicle membrane docking and fusion pathway and plays a key role in calcium-triggered neuronal exocytosis [
12]. Its binding partner PRRT2 may also play a role in this process [
13]. The absence or low expression of PRRT2 due to mutations in the
PRRT2 may result from the loss of a transmembrane domain, which renders PRRT2 unable to anchor to membranes; such changes in PRRT2 may lead to hyperexcitability and trigger dyskinesias [
13]. However, further investigation is needed to elucidate how
PRRT2 mutations cause PKD.
PRRT2 mutations are present in most familial PKD patients; the most common such mutation is c.649dupC [
10]. Among sporadic patients, the rate of
PRRT2 mutations ranges from 20 to 45%, with c.649delC and c.649dupC as commonly observed mutations [
14]. In addition to PKD patients,
PRRT2 mutations have also been identified in patients with infantile convulsions with paroxysmal choreoathetosis, benign familial infantile epilepsy [
15], migraine or episodic ataxia [
16]. This phenomenon could explain why certain PKD patients have comorbidities such as migraine or seizures [
17]. Researchers have determined that among PKD patients, younger age at symptom onset, good response to CBZ and predisposition to non-dyskinetic symptoms are significantly correlated with
PRRT2 mutations [
18,
19].
We enrolled a total of 20 patients.
PRRT2 mutations were detected in 5 patients but not the remaining 15 patients. Four of the 5 patients positive for
PRRT2 mutations had familial PKD. Differences in
PRRT2 mutations between familial PKD patients and sporadic PKD patients were evaluated using unpaired Student’s t-tests or Fisher’s exact test (Table
2). We found a significantly higher positive rate of
PRRT2 mutations among familial PKD patients than among sporadic PKD patients (
p < 0.05); similarly, prior studies revealed that
PRRT2 mutations were related to PKD, especially familial PKD [
10]. PKD patients with
PRRT2 mutations had more comorbidities (
p < 0.05). Gender distribution and the clinical phenotypes of PKD did not differ between PKD patients with
PRRT2 mutations and PKD patients without such mutations. Although many studies have reported that PKD patients with
PRRT2 mutations are younger at disease onset than other PKD patients, in our study, there were no differences between these two patient groups. This finding may be attributable to the small sample sizes in our study or to differences among different populations.
Table 2Comparison of clinical features between the PKD patients with and without PRRT2 mutations
No. of subjects | 5 | 15 | |
Male(%) | 4(80%) | 13(86.7%) | 1.000 |
Age at onset (years) | | | 0.502 |
Mean (SD) | 7.1(3) | 8.4(3.7) | |
Median | 7 | 9 | |
Main phenotype, n | | | 0.338 |
Choreoathetosis | 2 | 2 | |
Dystonia | 1 | 9 | |
Mixed | 2 | 4 | |
Laterality of dyskinesia | | | 0.530 |
Unilateral | 0 | 4 | |
Biateral | 5 | 11 | |
Involved limb | | | 0.805 |
Upper limbs | 0 | 3 | |
Lower limbs | 2 | 6 | |
Both | 3 | 6 | |
Frequency of attack/day, n | | | 0.805 |
< 5 | 2 | 6 | |
5–10 | 3 | 6 | |
> 10 | 0 | 3 | |
Comorbidity | 3 | 1 | 0.032 |
Treatment for PKD
The pathogenesis of PKD has not yet been elucidated; however, recent evidence of abnormal excitability in the cortex and basal ganglia in PKD patients supports the hypothesis that channelopathy is an underlying mechanism of PKD [
20]. Moreover, certain studies report that PKD patients usually exhibit good response to antiepileptic drugs, including lamotrigine, phenytoin, valproic acid, CBZ, and OXC, all of which achieve treatment objectives through the mechanism of modulating ion channels [
21].
Prior studies have suggested that a low dosage of CBZ (75–300 mg/d) can significantly improve paroxysmal dyskinesia for certain PKD patients during the first week of treatment; however, attacks will recur once the medication is withdrawn or missed [
22]. Although CBZ benefits certain PKD patients, the adverse effects, which include serious idiosyncratic adverse effects, cannot be ignored. Toxic epidermal necrolysis and Stevens-Johnson syndrome are serious dermatological reactions to CBZ. The incidence of these reactions is 1 in 60,000 among Caucasians, but the risk is tenfold higher in certain Asian countries due to HLA-B1502 [
23]. As a result, the use of CBZ is limited in various Asian countries, including China. As a structural derivative of CBZ, OXC mainly blocks voltage-sensitive sodium currents [
24]. Unlike CBZ, OXC is not metabolized by the hepatic cytochrome-P450 enzyme system, and OXC has a lower plasma protein binding rate than CBZ; thus, OXC has fewer side effects and drug interactions [
25]. OXC is rapidly and extensively reduced by cytosolic hepatic enzymes to its monohydroxylated derivative (MHD), which represents the antiepileptic agent and the active metabolite of OXC [
26]. Half-lives in a healthy person are 1–5 h for OXC and 7–20 h for MHD [
24]. A retrospective study addressing the use of CBZ or OXC monotherapy for PKD from 2005 to 2011 found that both CBZ and OXC had similar efficacies and tolerability. Patients experienced significant improvement with low doses of OXC (75–300 mg/d) or CBZ (50–300 mg/d), but 3 patients exhibited better tolerance after conversion from CBZ to OXC [
8].
Because attacks of dystonia and choreoathetosis are triggered by sudden movements and patients may engage in more movements during the day, attacks are more likely to occur during the day than at night. Given this characteristic of PKD and the half-lives of OXC and MHD, OXC taken as a morning draught may have good efficacy and improve quality of life. This study observed the efficacy of low doses of OXC taken as a draught in the treatment of paediatric PKD patients. Prior reports have already showed that low doses of OXC are effective for PKD patients. Moreover, because attacks associated with PKD were mainly triggered by movement during the day, to decrease the frequency of drug administration and improve therapy compliance, all 20 enrolled patients took OXC as morning draughts. All but 1 of the 20 patients exhibited considerable improvement in dystonia or choreoathetosis with low doses of OXC (5–20 mg/kg·d).
Differential diagnosis and misdiagnosis of PKD patients
PKD should be distinguished from the other paroxysmal dyskineias such as paroxysmal non-kinesigenic dyskinesia (PNKD) (OMIM 118800) and paroxysmal exertion-induced dyskinesia (PED) (OMIM 612126) as the similar movement disorder could present in all of them [
1]. PED need physical exercise for more long time than PKD to trigger and last time varies from 5 to 30 min [
7].Unlike PKD and PED, the cause of PNKD has nothing to do with voluntary movement or exercise, attack could be triggered by caffeine, alcohol, excitement and fatigue, the symptom duration minutes to 4 h.
As a paroxysmal disease, PKD can also be misdiagnosed as epilepsy, especially partial epilepsy, given that PKD patients are conscious during dyskinesia attacks. After treatment with antiepileptic drugs, certain PKD patients may not experience attacks, which may lead doctors to mistakenly believe that epilepsy is a reliable diagnosis for these patients. Moreover, PKD patients may have seizures as a comorbidity, contributing to misdiagnoses of PKD.
Two-thirds of the patients in our group had been misdiagnosed with epilepsy; therefore, it is necessary for doctors to distinguish between PKD and epilepsy to improve diagnostic accuracy. Attacks of dyskinesia in PKD patients are triggered by sudden movements, which may help distinguish PKD from epilepsy. Video-Electroencephalogram (VEEG), which can reveal whether epileptic discharge is present during an attack, could be a major approach for the diagnosis and differential diagnosis of PKD. It is also important to identify a syndrome when PKD patients experience seizure attacks, such as infantile convulsions with paroxysmal choreoathetosis (ICCA) (OMIM 602066) or benign familial infantile epilepsy (OMIM 605751).