Misdiagnosis of functional neurological symptom disorders in paediatrics: Narrative review and relevant case report.

Functional neurological symptom disorders (FNSD) pose a common challenge in clinical practice, particularly in pediatric cases where the clinical phenotypes can be intricate and easily confused with structural disturbances. The frequent coexistence of FNSDs with other medical disorders often results in misdiagnosis. In this review, we highlight the distinctions between FNSD and various psychiatric and neurological conditions. Contrary to the misconception that FNSD is a diagnosis of exclusion, we underscore its nature as a diagnosis of inclusion, contingent upon recognizing specific clinical features. However, our focus is on a critical learning point illustrated by the case of a 14-year-old male initially diagnosed with FNSD, but subsequently found to have a rare primary monogenic movement disorder (paroxysmal kinesigenic dyskinesia, PKD). The crucial takeaway from this case is the importance of avoiding an FNSD diagnosis based solely on psychiatric comorbidity and suppressible symptoms. Instead, clinicians should diligently assess for specific features indicative of FNSD, which were absent in this case. This emphasizes the importance of making a diagnosis of inclusion. Extended follow-up and clinical-oriented genetic testing might help identify comorbidities, prevent misdiagnosis, and guide interventions in complex cases, which cannot be simply classified as "functional" solely because other conditions can be excluded.

Understanding and Avoiding Mistakes in Diagnosing Children with Functional Neurological Symptom Disorders: A Review and Case Report: This article discusses Functional Neurological Symptom Disorders (FNSDs), focusing on misdiagnosis, differential diagnosis, and other diagnostic challenges, particularly in pediatric cases. FNSDs involve motor or sensory symptoms that are inconsistent over time and unexplained by neurological disease, often associated with psychosocial factors. The article highlights the complexity of distinguishing FNSDs from other neurological and psychiatric conditions, emphasizing the importance of careful evaluation. The authors review various conditions that can mimic FNSDs, such as epileptic seizures, syncope, and different motor disorders. They emphasize the need to consider psychiatric conditions in the differential diagnosis, including factitious disorders, and malingering. The article presents a case study of a 14-year-old with involuntary movements, initially diagnosed as having a Functional Movement Disorder. After careful evaluation, the patient was diagnosed with a genetic dystonia (PRRT2 mutation). The case shows the importance of not rely solely on psychological problems, bizarre presentations or suppressible symptoms when diagnosing FNSDs.

Proline-rich transmembrane protein 2 knock-in mice present dopamine-dependent motor deficits.

Mutations of proline-rich transmembrane protein 2 (PRRT2) lead to dyskinetic disorders such as paroxysmal kinesigenic dyskinesia (PKD), which is characterized by attacks of involuntary movements precipitated by suddenly initiated motion, and some convulsive disorders. Although previous studies have shown that PKD might be caused by cerebellar dysfunction, PRRT2 has not been sufficiently analyzed in some motor-related regions, including the basal ganglia, where dopaminergic neurons are most abundant in the brain. Here, we generated several types of Prrt2 knock-in (KI) mice harboring mutations, such as c.672dupG, that mimics the human pathological mutation c.649dupC and investigated the contribution of Prrt2 to dopaminergic regulation. Regardless of differences in the frameshift sites, all truncating mutations abolished Prrt2 expression within the striatum and cerebral cortex, consistent with previous reports of similar Prrt2 mutant rodents, confirming the loss-of-function nature of these mutations. Importantly, administration of l-dopa, a precursor of dopamine, exacerbated rotarod performance, especially in Prrt2-KI mice. These findings suggest that dopaminergic dysfunction in the brain by the PRRT2 mutation might be implicated in a part of motor symptoms of PKD and related disorders.

Missense mutations in the membrane domain of PRRT2 affect its interaction with Nav1.2 voltage-gated sodium channels.

PRRT2 is a neuronal protein that controls neuronal excitability and network stability by modulating voltage-gated Na+ channel (Nav). PRRT2 pathogenic variants cause pleiotropic syndromes including epilepsy, paroxysmal kinesigenic dyskinesia and episodic ataxia attributable to loss-of-function pathogenetic mechanism. Based on the evidence that the transmembrane domain of PRRT2 interacts with Nav1.2/1.6, we focused on eight missense mutations located within the domain that show expression and membrane localization similar to the wild-type protein. Molecular dynamics simulations showed that the mutants do not alter the structural stability of the PRRT2 membrane domain and preserve its conformation. Using affinity assays, we found that the A320V and V286M mutants displayed respectively decreased and increased binding to Nav1.2. Accordingly, surface biotinylation showed an increased Nav1.2 surface exposure induced by the A320V mutant. Electrophysiological analysis confirmed the lack of modulation of Nav1.2 biophysical properties by the A320V mutant with a loss-of-function phenotype, while the V286M mutant displayed a gain-of-function with respect to wild-type PRRT2 with a more pronounced left-shift of the inactivation kinetics and delayed recovery from inactivation. The data confirm the key role played by the PRRT2-Nav interaction in the pathogenesis of the PRRT2-linked disorders and suggest an involvement of the A320 and V286 residues in the interaction site. Given the similar clinical phenotype caused by the two mutations, we speculate that circuit instability and paroxysmal manifestations may arise when PRRT2 function is outside the physiological range.

PRRT2 benign familial infantile seizures (BFIS) with atypical evolution to encephalopathy related to status epilepticus during sleep (ESES).

PURPOSE: Heterozygous variants in PRRT2 are mostly associated with benign phenotypes, being the major genetic cause of benign familial infantile seizures (BFIS), as well as in paroxysmal disorders. We report two children from unrelated families with BFIS that evolved to encephalopathy related to status epilepticus during sleep (ESES). METHODS AND RESULTS: Two probands presented with focal motor seizures at 3 months of age, with a limited course. Both children presented, at around 5 years of age, with centro-temporal interictal epileptiform discharges with a source in the frontal operculum, markedly activated by sleep, and associated with stagnation on neuropsychological development. Whole-exome sequencing and co-segregation analysis revealed a frameshift mutation c.649dupC in the proline-rich transmembrane protein 2 (PRRT2) in both probands and all affected family members. CONCLUSION: The mechanism leading to epilepsy and the phenotypic variability of PRRT2 variants remain poorly understood. However, its wide cortical and subcortical expression, in particular in the thalamus, could partially explain both the focal EEG pattern and the evolution to ESES. No variants in the PRRT2 gene have been previously reported in patients with ESES. Due to the rarity of this phenotype, other possible causative cofactors are likely contributing to the more severe course of BFIS in our probands.

A Push-Pull Mechanism Between PRRT2 and ß4-subunit Differentially Regulates Membrane Exposure and Biophysical Properties of NaV1.2 Sodium Channels.

Proline-rich transmembrane protein 2 (PRRT2) is a neuron-specific protein implicated in the control of neurotransmitter release and neural network stability. Accordingly, PRRT2 loss-of-function mutations associate with pleiotropic paroxysmal neurological disorders, including paroxysmal kinesigenic dyskinesia, episodic ataxia, benign familial infantile seizures, and hemiplegic migraine. PRRT2 is a negative modulator of the membrane exposure and biophysical properties of Na+ channels NaV1.2/NaV1.6 predominantly expressed in brain glutamatergic neurons. NaV channels form complexes with ß-subunits that facilitate the membrane targeting and the activation of the α-subunits. The opposite effects of PRRT2 and ß-subunits on NaV channels raises the question of whether PRRT2 and ß-subunits interact or compete for common binding sites on the α-subunit, generating Na+ channel complexes with distinct functional properties. Using a heterologous expression system, we have observed that ß-subunits and PRRT2 do not interact with each other and act as independent non-competitive modulators of NaV1.2 channel trafficking and biophysical properties. PRRT2 antagonizes the ß4-induced increase in expression and functional activation of the transient and persistent NaV1.2 currents, without affecting resurgent current. The data indicate that ß4-subunit and PRRT2 form a push-pull system that finely tunes the membrane expression and function of NaV channels and the intrinsic neuronal excitability.

Clinical characteristics and genetics of ten Chinese children with PRRT2-associated neurological diseases.

Background: Proline-rich transmembrane protein 2 (PRRT2) plays an important role in the central nervous system and mutations in the gene are implicated in a variety of neurological disorders. This study aimed to summarize the clinical characteristics and gene expression analysis of neurological diseases related to the PRRT2 gene and explore the clinical characteristics, therapeutic effects, and possible pathogenic mechanisms of related diseases. Methods: We enrolled 10 children with PRRT2 mutation-related neurological diseases who visited the Children's Hospital affiliated with the Shanghai Jiaotong University School of Medicine/Shanghai Children's Hospital between May 2017 and February 2022. Video electroencephalography (VEEG), cranial imaging, treatment regimens, gene results, and gene expression were analyzed. Genetic testing involved targeted sequencing or whole-exome genome sequencing (WES). We further analyzed the expression and mutation conservation of PRRT2 and synaptosome-associated protein 25 (SNAP25) in blood samples using quantitative polymerase chain reaction (qPCR) and predicted the protein structure. Summary analysis of the reported gene maps and domains was also performed. Results: Ten children with PRRT2 gene mutations were analyzed, and 4 mutations were identified, consisting of 2 new (c.518A > C, p.Glu173 Ala; c.879 + 112G > A, p.?) and two known (c. 649 dup, p. Arg217Profs * 8; c. 649 del, p. Arg217Glufs * 12) mutations. Among these mutations, one was de novo(P6), and three could not be determined because one parent refused genetic testing. The clinical phenotypes were paroxysmal kinesigenic dyskinesia (PKD), benign familial infantile epilepsy (BFIE), epilepsy, infantile spasms, and intellectual disability. The qPCR results showed that PRRT2 gene expression levels were significantly lower in children and parent carriers than the control group. The SNAP25 gene expression level of affected children was significantly lower (P ≤ 0.001) than that of the control group. The mutation sites reported in this study are highly conserved in different species. Among the various drugs used, oxcarbazepine and sodium valproate were the most effective. All 10 children had a good disease prognosis, and 8 were completely controlled with no recurrence, whereas 2 had less severe and fewer seizures. Conclusion: Mutation of PRRT2 led to a significant decrease in its protein expression level and that of SNAP25, suggesting that the mutant protein may lead to the loss of its function and that of related proteins. This mutation site is highly conserved in most species, and there was no significant correlation between specific PRRT2 genotypes and clinical phenotypes. Asymptomatic carriers also have decreased gene expression levels, suggesting that more factors are involved.

PRRT2 mutation in a Japanese woman: Adult-onset focal epilepsy coexisting with movement disorders and cerebellar atrophy.

Proline-rich transmembrane protein 2 (PRRT2) was confirmed as the causative gene of paroxysmal kinesigenic dyskinesia (PKD) as shown by genome-wide linkage analyses. PRRT2 mutations are also associated with benign familial infantile seizures, infantile convulsions and choreoathetosis, and childhood absence epilepsy, but few reports have investigated adult-onset epilepsy. We describe here a rare presentation of adult-onset focal epilepsy with a PRRT2 mutation in a 31-year-old woman who showed cerebellar atrophy, familial paroxysmal kinesigenic dyskinesia, and paroxysmal non-kinesigenic dystonia. Video-electroencephalography (EEG) demonstrated focal impaired awareness seizures, in which ictal EEG changes showed left temporal onset with rhythmic theta activity over the left temporal region. Magnetic resonance imaging showed mild cerebellar atrophy. The administration of lamotrigine 50 mg/day resulted in freedom from her seizures and lamotrigine 150 mg/day reduced paroxysmal non-kinesigenic dystonia. Furthermore, she had a rare frameshift mutation, c.604_607del, p.Ser202fs of which the pathogenicity has been reported in ClinVar, but it has not been reported in Japan. Mutation of the PRRT2 gene can cause adult-onset epilepsy, paroxysmal non-kinesigenic movement disorder, and cerebellar atrophy, suggesting an expanding clinical phenotypic spectrum associated with PRRT2 mutations.

PRRT2 Mutation and Serum Cytokines in Paroxysmal Kinesigenic Dyskinesia.

OBJECTIVE: Paroxysmal kinesigenic dyskinesia (PKD) is a rare movement disorder PRRT2 gene mutations have been reported to cause PKD. However, the pathophysiological mechanism of PKD remains unclear, and it is unknown whether an inflammatory response is involved in the occurrence of this disease. We aimed to investigate the symptomatology, genotype, and serum cytokines of patients with PKD. METHODS: We recruited 21 patients with PKD, including 7 with familial PKD and 14 with sporadic PKD. Their clinical features were investigated, and blood samples were collected, and PRRT2 mutations and cytokine levels were detected. RESULTS: The mean age at PKD onset was 12.3±2.2 years old. Dystonia was the most common manifestation of dyskinesia, and the limbs were the most commonly affected parts. All attacks were induced by identifiable kinesigenic triggers, and the attack durations were brief (<1 min). Four different mutations from 9 probands were identified in 7 familial cases (71.4%) and 14 sporadic cases (28.6%). Two of these mutations (c.649dupC, c.620_621delAA) had already been reported, while other 2 (c.1018_1019delAA, c.1012+1G>A) were previously undocumented. The tumor necrosis factor (TNF)-α level in the PKD group was significantly higher than that in the age- and sex-matched control group (P=0.025). There were no significant differences in the interleukin (IL)-1ß, IL-2R, IL-6, IL-8, or IL-10 levels between the two groups. CONCLUSION: In this study, we summarized the clinical and genetic characteristics of PKD. We found that the serum TNF-α levels were elevated in patients clinically diagnosed with PKD, suggesting that an inflammatory response is involved in the pathogenesis of PKD.

Exercise test for patients with new-onset paroxysmal kinesigenic dyskinesia.

The pathogenesis of primary paroxysmal kinesigenic dyskinesia (PKD) remains unclear, and channelopathy is a possibility. In a pilot study, we found that PKD patients had abnormal exercise test (ET) results. To investigate the ET performances in patients affected by PKD, and the role of the channelopathies in the pathogenesis of PKD, we compared the ET results of PKD patients, control subjects, and hypokalemic periodic paralysis (HoPP) patients, and we analyzed ET changes in 32 PKD patients before and after treatment. Forty-four PKD patients underwent genetic testing for the PRRT2, SCN4A, and CLCN1 genes. Sixteen of 59 (27%) patients had abnormal ET results in the PKD group, while 28 of 35 (80%) patients had abnormal ET results in the HoPP group. Compared with the control group, the PKD group showed a significant decrease in the compound muscle action potential (CMAP) amplitude and area after the long ET (LET), while the HoPP group showed not only greater decreases in the CMAP amplitude and area after the LET but also greater increases in the CMAP amplitude and area immediately after the LET. The ET parameters before and after treatment were not significantly different. Nine of 44 PKD patients carried PRRT2 mutations, but the gene abnormalities were unrelated to any ET parameter. The PKD group demonstrated an abnormal LET result by electromyography (EMG), and this abnormality did not seem to correlate with the PRRT2 variant or sodium channel blocker therapy.

A Child Who Suddenly Freezes While Trying to Cross Crosswalks-Unique Clinical Manifestation of Paroxysmal Kinesigenic Dyskinesia: A Case Report.

(1) Background: We report the case of a patient with a unique clinical presentation of inability to cross crosswalks due to paroxysmal kinesigenic dyskinesia (PKD). (2) Case presentation: A 14-year-old boy presented with the inability to move his right leg at gait initiation from the standing position. This episode lasted for approximately 20-30 s and manifested 1-3 times a day. The difficulty in gait initiation usually occurred when the patient tried to cross crosswalks when the traffic light turned from red to blue. His right arm stiffened occasionally while trying to write with a pencil and eat food with a spoon or chopsticks. Other neurological manifestations and pain were absent during these episodes. No neurological symptoms were observed between the attacks. Brain magnetic resonance imaging did not reveal any abnormalities. A next-generation sequencing study revealed a pathological variant in the proline-rich transmembrane protein 2 (PRRT2) gene. The patient was diagnosed with PKD. His symptoms disappeared completely after treatment with carbamazepine (100 mg/day). (3) Conclusions: The symptoms of PKD can be successfully controlled using antiepileptic medications. Therefore, clinicians should be aware of the clinical manifestations of PKD to provide appropriate treatment.

Novel mutation of the PRRT2 gene in two cases of paroxysmal kinesigenic dyskinesia: Two case reports.

Paroxysmal kinesigenic dyskinesia (PKD) is a rare condition characterized by recurrent brief episodes of dystonia, chorea, athetosis or any combination of these, without alterations of consciousness. The proline-rich transmembrane protein 2 (PRRT2) gene has been widely investigated as a causative gene of PKD. To date, a cluster of pathogenic variants associated with PKD have been identified in the PRRT2 gene. In the present case report, two Chinese patients with sporadic PKD are discussed. Genetic analysis revealed a de novo heterozygous missense mutation, c.955G>T (p.Val319Leu) in exon 3 of the PRRT2 gene. Compared with the commonly reported clinical manifestation of PRRT2-associated PKD, the patients in this report showed several primary distinctive features. The mutations identified in the present analysis expand upon the mutation spectrum of the PRRT2 gene, and this newly found variant further reinforces the importance of the PRR2 gene in PKD.

Proteomics-based screening of the target proteins associated with antidepressant-like effect and mechanism of Saikosaponin A.

Depression is a commonly occurring neuropsychiatric disease with an increasing incidence rate. Saikosaponin A (SA), a major bioactive component extracted from Radix Bupleuri, possesses anti-malignant cell proliferation, anti-inflammation, anti-oxidation and liver protective effects. However, few studies have investigated SA's antidepressant effects and pharmacological mechanisms of action. Our study aimed to explore the anti-depression effect of SA and screen the target proteins regulated by SA in a rat model of chronic unpredictable mild stress (CUMS)-induced depression. Results showed that 8-week CUMS combined with separation could successfully produce depressive-like behaviours and cause a decrease of dopamine (DA) in rat hippocampus, and 4-week administration of SA could relieve CUMS rats' depressive symptoms and up-regulated DA content. There were 15 kinds of significant differentially expressed proteins that were detected not only between the control and CUMS groups, but also between the CUMS and SA treatment groups. Proline-rich transmembrane protein 2 (PRRT2) was down-regulated by CUMS while up-regulated by SA. These findings reveal that SA may exert antidepressant effects by up-regulating the expression level of PRRT2 and increasing DA content in hippocampus. The identification of these 15 differentially expressed proteins, including PRRT2, provides further insight into the treatment mechanism of SA for depression.

[An adult female with proline-rich transmembrane protein 2 related paroxysmal disorders manifesting paroxysmal kinesigenic choreoathetosis and epileptic seizures].

A 21-year-old woman presented with a chief complaint of generalized tonic-clonic seizures occurring once a month at night since the age of 14. The patient was treated with clonazepam plus levetiracetam, but seizure frequency was not reduced. After the detailed re-examination of her history of illness, it was revealed that she has been suffering from transient and recurrent choreoathetoid attacks triggered by sudden voluntary movements since she was a junior high school student, and it recently increased in frequency. Neither she nor her family recognize that it was significant to describe to the doctors. She was diagnosed as a complex of paroxysmal kinesigenic choreoathetosis (PKC) and its related conditions. Direct sequencing of proline-rich transmembrane protein 2 (PRRT2) revealed the most frequently described gene mutation, (NM_145239.2:c.649dupC), among PRRT2-related paroxysmal disorders. PKC and seizures were readily controlled with small dose of carbamazepine. Given the broad spectrum of PRRT2-related paroxysmal disorders, assessment of potential clinical complication of paroxysmal disorders including PKC might therefore be critical.

The study of exercise tests in paroxysmal kinesigenic dyskinesia.

OBJECTIVE: To unravel if there was muscular ion channel dysfunction in paroxysmal kinesigenic dyskinesia (PKD) patients using the exercises tests (ET). METHODS: Sixty PKD patients including 28 PRRT2 mutations carriers were enrolled in this study, as well as 19 hypokalaemic periodic paralysis (HypoPP) patients as the positive controls and 45 healthy subjects as the negative controls. ET including long exercise test (LET) and short exercise test (SET) was performed in the corresponding subjects. RESULTS: In the LET, both the overall PKD patients and HypoPP patients had greater CMAP amplitude and area increments during exercise than healthy controls. At most 25% of PKD patients were identified from the normality with greater amplitude increment than the area. On the contrary, 50% of HypoPP patients were differentiated with greater area increment than the amplitude. More percentage of PRRT2- patients than PRRT2+ patients had abnormal average amplitude increment. Unexpectedly, five PKD patients had abnormal maximum CMAP amplitude decrements after exercise in the LET, and one had abnormal maximum immediate amplitude decrement in the SET. CONCLUSIONS: Distinct ET manifestations were found in PKD patients compared to normal controls and HypoPP patients. SIGNIFICANCE: Abnormal muscle membrane excitability might be involved in the mechanisms responsible for PKD.

A case of paroxysmal kinesigenic dyskinesia which exhibited the phenotype of anxiety disorder.

BACKGROUND: Paroxysmal kinesigenic dyskinesia (PKD) is a rare heritable neurologic disorder characterized by attacks of involuntary movement induced by sudden voluntary movements. No previous reports have described cases showing comorbidity with psychiatric disease or symptoms. In this case, we showed a patient with PKD who exhibited several manifestations of anxiety disorder. CASE: A 35-year-old Japanese man with PKD had been maintained on carbamazepine since he was 16 years of age without any attacks. However, 10 years before this referral, he became aware of a feeling of breakdown in his overall physical functions. He had then avoided becoming familiar with people out of concern that his physical dysfunctions might be perceived in a negative light. One day he was referred by the neurologic department at our hospital to the Department of Psychiatry because of severe anxiety and hyperventilation triggered by carbamazepine. We treated with escitalopram, aripiprazole, and ethyl loflazepate. Both his subjective physical condition and objective expressions subsequently showed gradual improvement. At last, the feelings of chest compression and anxiety entirely disappeared. Accordingly, increases in plasma monoamine metabolite levels were observed, and the c.649dupC mutation, which has been found in most Japanese PKD families, was detected in his proline-rich transmembrane protein 2 gene. CONCLUSION: This is the first report to describe psychiatric comorbidities or symptoms in a PKD case. The efficacy of psychotropic medication used in this case, the resulting changes in plasma monoamine metabolite levels, and the recent advances in the molecular understanding of PKD suggested slight, but widespread alterations to the neurotransmitter systems in the brain.

A Novel Truncation Mutation of the PRRT2 Gene Resulting in a 16-Amino-Acid Protein Causes Self-inducible Paroxysmal Kinesigenic Dyskinesia.

Paroxysmal kinesigenic dyskinesia (PKD) is a sporadic or autosomal-dominant, hereditary disorder characterized by brief, recurrent attacks of involuntary movements triggered by sudden, voluntary movement that generally develops during childhood and adolescence and is typically treated with carbamazepine. The proline-rich transmembrane protein 2 (PRRT2) gene contains 4 exons that encode 340 amino acids as the major isoform, and recent research has identified PRRT2 as the primary causative gene in PKD, benign familial infantile epilepsy (BFIE), and infantile convulsions with PKD (PKD/IC). Here, the authors report the phenotype of a family with a novel p.E16X (c.46G>T) nonsense mutation of the PRRT2 gene that lacked almost a full allele. In this family, none of the individuals in the pedigree exhibited evidence of cognitive impairment: the elder brother had PKD/IC with migraine; the younger brother had PKD with ataxia; the father had PKD; both siblings experienced a sensory aura; and all 3 had a history of febrile seizures. This is the first report of a short nonsense mutation in PRRT2 and indicates that the manifestations of the disease, including other mutations to date, can be explained by haploinsufficiency and that 1 intact PRRT2 allele can allow normal cognitive development.

The PRRT2 knockout mouse recapitulates the neurological diseases associated with PRRT2 mutations.

Heterozygous and rare homozygous mutations in PRoline-Rich Transmembrane protein 2 (PRRT2) underlie a group of paroxysmal disorders including epilepsy, kinesigenic dyskinesia episodic ataxia and migraine. Most of the mutations lead to impaired PRRT2 expression and/or function. Recently, an important role for PRTT2 in the neurotransmitter release machinery, brain development and synapse formation has been uncovered. In this work, we have characterized the phenotype of a mouse in which the PRRT2 gene has been constitutively inactivated (PRRT2 KO). ß-galactosidase staining allowed to map the regional expression of PRRT2 that was more intense in the cerebellum, hindbrain and spinal cord, while it was localized to restricted areas in the forebrain. PRRT2 KO mice are normal at birth, but display paroxysmal movements at the onset of locomotion that persist in the adulthood. In addition, adult PRRT2 KO mice present abnormal motor behaviors characterized by wild running and jumping in response to audiogenic stimuli that are ineffective in wild type mice and an increased sensitivity to the convulsive effects of pentylentetrazol. Patch-clamp electrophysiology in hippocampal and cerebellar slices revealed specific effects in the cerebellum, where PRRT2 is highly expressed, consisting in a higher excitatory strength at parallel fiber-Purkinje cell synapses during high frequency stimulation. The results show that the PRRT2 KO mouse reproduces the motor paroxysms present in the human PRRT2-linked pathology and can be proposed as an experimental model for the study of the pathogenesis of the disease as well as for testing personalized therapeutic approaches.

Paroxysmal kinesigenic dyskinesia in a patient with a PRRT2 mutation and centrotemporal spike discharges on electroencephalogram: case report of a 10-year-old girl.

Coexistence of paroxysmal kinesigenic dyskinesia (PKD) with benign infantile convulsion (BIC) and centrotemporal spikes (CTS) is very rare. A 10-year-old girl presented with a 3-year history of frequent attacks of staggering while laughing and of suddenly collapsing while walking. Interictal electroencephalogram (EEG) revealed bilateral CTS, but no changes in EEG were observed during movement. The patient's medical history showed afebrile seizures 6 months after birth, while the family history showed that the patient's mother and relatives on the mother's side had similar dyskinesia. Genetic testing demonstrated that the patient had a heterozygous mutation, c.649_650insC, in the PRRT2 gene. To our knowledge, this constitutes only the second report of a patient with PKD, BIC, CTS, and a PRRT2 mutation.

Aberrant transcriptional networks in step-wise neurogenesis of paroxysmal kinesigenic dyskinesia-induced pluripotent stem cells.

Paroxysmal kinesigenic dyskinesia (PKD) is an episodic movement disorder with autosomal-dominant inheritance and marked variability in clinical manifestations.Proline-rich transmembrane protein 2 (PRRT2) has been identified as a causative gene of PKD, but the molecular mechanism underlying the pathogenesis of PKD still remains a mystery. The phenotypes and transcriptional patterns of the PKD disease need further clarification. Here, we report the generation and neural differentiation of iPSC lines from two familial PKD patients with c.487C>T (p. Gln163X) and c.573dupT (p. Gly192Trpfs*8) PRRT2 mutations, respectively. Notably, an extremely lower efficiency in neural conversion from PKD-iPSCs than control-iPSCs is observed by a step-wise neural differentiation method of dual inhibition of SMAD signaling. Moreover, we show the high expression level of PRRT2 throughout the human brain and the expression pattern of PRRT2 in other human tissues for the first time. To gain molecular insight into the development of the disease, we conduct global gene expression profiling of PKD cells at four different stages of neural induction and identify altered gene expression patterns, which peculiarly reflect dysregulated neural transcriptome signatures and a differentiation tendency to mesodermal development, in comparison to control-iPSCs. Additionally, functional and signaling pathway analyses indicate significantly different cell fate determination between PKD-iPSCs and control-iPSCs. Together, the establishment of PKD-specific in vitro models and the illustration of transcriptome features in PKD cells would certainly help us with better understanding of the defects in neural conversion as well as further investigations in the pathogenesis of the PKD disease.