PRRT2 mutation in Japanese children with benign infantile epilepsy

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.     

PRRT2-related disorders: further PKD and ICCA cases and review of the literature

Recent studies reported mutations in the gene encoding the proline-rich transmembrane protein 2 (PRRT2) to be causative for paroxysmal kinesigenic dyskinesia (PKD), PKD combined with infantile seizures (ICCA), and benign familial infantile seizures (BFIS). PRRT2 is a presynaptic protein which seems to play an important role in exocytosis and neurotransmitter release. PKD is the most common form of paroxysmal movement disorder characterized by recurrent brief involuntary hyperkinesias triggered by sudden movements. Here, we sequenced PRRT2 in 14 sporadic and 8 familial PKD and ICCA cases of Caucasian origin and identified three novel mutations (c.919C>T/p.Gln307*, c.388delG/p.Ala130Profs*46, c.884G>A/p.Arg295Gln) predicting two truncated proteins and one probably damaging point mutation. A review of all published cases is also included. PRRT2 mutations occur more frequently in familial forms of PRRT2-related syndromes (80–100 %) than in sporadic cases (33-46 %) suggesting further heterogeneity in the latter. PRRT2 mutations were rarely described in other forms of paroxysmal dyskinesias deviating from classical PKD, as we report here in one ICCA family without kinesigenic triggers. Mutations are exclusively found in two exons of the PRRT2 gene at a high rate across all syndromes and with one major mutation (c.649dupC) in a mutational hotspot of nine cytosines, which is responsible for 57 % of all cases in all phenotypes. We therefore propose that genetic analysis rapidly performed in early stages of the disease is highly cost-effective and can help to avoid further unnecessary diagnostic and therapeutic interventions.     

PRRT2 mutations in a cohort of Chinese families with paroxysmal kinesigenic dyskinesia and genotype–phenotype correlation reanalysis in literatures

Purpose of the study: Though rare, children are susceptible to paroxysmal dyskinesias such as paroxysmal kinesigenic dyskinesia, and infantile convulsions and choreoathetosis. Recent studies showed that the cause of paroxysmal kinesigenic dyskinesia or infantile convulsions and choreoathetosis could be proline-rich transmembrane protein 2 (PRRT2) gene mutations.

Material and methods: This study analysed PRRT2 gene mutations in 51 families with paroxysmal kinesigenic dyskinesia or infantile convulsions and choreoathetosis by direct sequencing. In particular, we characterize the genotype–phenotype correlation between age at onset and the types of PRRT2 mutations in all published cases.

Results: Direct sequencing showed that 12 out of the 51 families had three different pathogenic mutations (c.649dupC, c.776dupG, c.649C>T) in the PRRT2 gene. No significant difference of age at onset between the patients with and without PRRT2 mutations was found in this cohort of patients. A total of 97 different PRRT2 mutations have been reported in 87 studies till now. The PRRT2 mutation classes are wide, and most mutations are frameshift mutations but the most common mutation remains c.649dupC. Comparisons of the age at onset in paroxysmal kinesigenic dyskinesia or infantile convulsions patients with different types of mutations showed no significant difference.

Conclusions: This study expands the clinical and genetic spectrums of Chinese patients with paroxysmal kinesigenic dyskinesia and infantile convulsions and choreoathetosis. No clear genotype–phenotype correlation between the age at onset and the types of mutations has been determined.     

Phenotypic overlap among paroxysmal dyskinesia subtypes: Lesson from a family with PRRT2 gene mutation

Paroxysmal dyskinesia (PD) is a group of rare neurological conditions which was divided into paroxysmal kinesigenic dyskinesia (PKD), paroxysmal non-kinesigenic dyskinesia (PNKD) and paroxysmal exercise-induced dyskinesia (PED) according to their clinical features. PRRT2 gene was initially identified as the major gene responsible for PKD followed by presence of various PRRT2 mutations discovered in families with benign familial infantile convulsions (BFIC) and infantile convulsions and choreoathetosis (ICCA). We describe a family with characteristic PD showing overlaps in clinical pictures among the three PD subgroups, and a nonsense PRRT2 mutation c.649C > T (p.Arg217X) was also detected. This broadens the phenotypic spectrum in PRRT2-related disorders. In addition, an unusual exercise trigger observed in the proband, likely representing an underestimated occurrence, together with the current clinical PD classification is also elucidated.     

发作性运动诱发性运动障碍36例临床及影像学研究

目的观察发作性运动诱发性运动障碍(PKD)的临床特征及影像学改变,探讨其发病机制。方法详细观察36例PKD的临床特征,影像学和脑电图改变,并综合文献,简述其发病机制及遗传规律。结果36例均由运动诱发,呈发作性运动诱发性肌张力障碍30例,发作性运动诱发性舞蹈手足徐动症6例,发作时意识清楚,影像学有异常者4例,脑电图1例放电。抗癫痫药疗效好。结论发作性运动障碍是一种少见的运动障碍疾病,临床表现类似癫痫,可能是一种离子通道病,与基底节区功能障碍关系密切,大部分抗癫痫药物治疗有效。     

Paroxysmal dyskinesias in childhood

We report on clinical features of a large series of patients with paroxysmal dyskinesias. Fourteen patients had paroxysmal kinesigenic dyskinesia, with a mean age at onset of 7.1 years. In thirteen children the condition was idiopathic and nine of them had a positive family history; the remaining one had a Chiari malformation. Response to antiepileptic drugs was good in 60% of the treated patients. Six children had paroxysmal non-kinesigenic dyskinesia, with a mean age at onset of 8.1 years. Five children were symptomatic because of cerebral palsy (two patients), basal ganglia stroke (one patient), and acute inflammatory encephalopathy (one patient); the remaining patient's condition was familial with autosomal-dominant mode of inheritance. Response to medical treatment was unsuccessful contrasting with paroxysmal kinesigenic dyskinesia. Six children had paroxysmal exercise-induced dyskinesia, with a mean age at onset of 5 years. Their condition was idiopathic, with a positive family history in four. Two of these patients had also rolandic epilepsy and writer's cramp, and the syndrome had been previously mapped to chromosome 16. Although there have been great advances in the genetics of paroxysmal dyskinesias in which an ion channel dysfunction has been hypothesized, the diagnosis is still based on clinical grounds. The precise classification of the patients with paroxysmal dyskinesias is important for therapeutic decisions.     

A new case of concurrent existence of PRRT2-associated paroxysmal movement disorders with c.649dup variant and 16p11.2 microdeletion syndrome

BackgroundThe PRRT2 gene located at 16p11.2 encodes proline-rich transmembrane protein 2. In recent reviews, clinical spectrum caused by pathogenic PRRT2 variants is designated as PRRT2-associated paroxysmal movement disorders, which include paroxysmal kinesigenic dyskinesia, benign familial infantile epilepsy, and infantile convulsions with choreoathetosis, and hemiplegic migraine. The recurrent 16p11.2 microdeletion encompassing PRRT2 has also been reported to cause neurodevelopmental syndrome, associated with autism spectrum disorder. Although PRRT2 variants and 16p11.2 microdeletion cause each disease with the autosomal dominant manner, rare cases with bi-allelic PRRT2 variants or concurrent existence of PRRT2 variants and 16p11.2 microdeletion have been reported to show more severe phenotypes.Case reportA 22-year-old man presents with episodic ataxia, paroxysmal kinesigenic dyskinesia, seizure, intellectual disability and autism spectrum disorder. He also has obesity, hypertension, hyperuricemia, and mild liver dysfunction. Exome sequencing revealed a c.649dup variant in PRRT2 in one allele and a de novo 16p11.2 microdeletion in another allele.ConclusionsOur case showed combined clinical features of PRRT2-associated paroxysmal movement disorders and 16p11.2 microdeletion syndrome. We reviewed previous literatures and discussed phenotypic features of patients who completely lack the PRRT2 protein.     

12例发作性运动诱发性肌张力障碍的临床、脑电图特点及文献复习

目的观察发作性运动诱发性肌张力障碍(PKD)的临床表现、脑电图特征,提高对本病的认识及选择有效的治疗药物。方法回顾性分析12例PKD患者的临床资料、脑电及影像学改变,并结合文献进行总结分析。结果临床症状表现为发作性运动诱发性手足扭转、肢体僵直、舞蹈手足徐动征等,有明确的运动诱发因素,同步脑电记录无异常,正确选择抗癫痫药物可有效控制其发作。结论 PKD是一种少见的运动障碍疾病,应与癫痫、假性发作、TIA、部分性发作等相鉴别。对抗癫痫药物敏感,早期诊断早期治疗预后较好。     

发作性运动障碍(附33例临床分析和文献复习)

目的　了解发作性运动障碍的临床特点以及治疗方法。方法　分析 33例发作性运动障碍病例的临床表现和实验室检查。结果　 (1)发作性运动诱发性运动障碍 (PKD) 32例 (96 .97% ) ;(2 )发作性非运动诱发性运动障碍 (PNKD) 3例 (9.0 9% ) ;(3)发作性过度运动导致的运动障碍 (PED) 6例 (18.18% ) ;(4)发作性睡眠诱发性运动障碍 (PHD) 3例 (9.0 9% )。除 2 4例为单纯 PKD外 ,其余病例均与其它类型互相重叠。 EEG大多正常 (32 /33) ,32例 CT/MRI正常。部分可合并癫痫 (5 /33) ,抗癫痫治疗多数 (2 9/33)有效。结论　发作性运动障碍是一种少见的运动障碍疾病 ,和癫痫有一定关系 ,各型可互相重叠 ,EEG大多正常 ,大部分抗癫痫药物治疗有效。     

Homozygous c.649dupC mutation in PRRT2 worsens the BFIS/PKD phenotype with mental retardation,episodic ataxia,and absences

Heterozygous mutations of PRRT2, which encodes proline‐rich transmembrane protein 2, are associated with heterogeneous phenotypes including benign familial infantile seizures (BFIS), or familial paroxysmal kinesigenic dystonia (PKD). We report a consanguineous Italian family with BFIS/PKD phenotype that contained 14 living members with 6 affected individuals (four men, ranging in age from 6–44 years). We identified the reported c.649dupC (p.Arg217ProfsX8) mutation of PRRT2 gene that cosegregated with the disease and was not observed in 100 controls of matched ancestry. Four patients with BFIS phenotype were heterozygous for this mutation, including the consanguineous parents of the two affected brothers with more severe phenotypes of BFIS/PKD—mental retardation, episodic ataxia, and absences—who were the only individuals to carry a homozygous c.649dupC mutation. This family provides strong evidence that homozygous PRRT2 mutations give rise to more severe clinical disease of mental retardation, episodic ataxia, and absences, and, thus, enlarges the clinical spectrum related to PRRT2 mutations. Moreover, it suggests an additive effect of double dose of the genetic mutation and underscores the complexity of the phenotypic consequences of mutations in this gene.     

Channelopathy: hypothesis of a common pathophysiologic mechanism in different forms of paroxysmal dyskinesia

Paroxysmal dyskinesias are a rare heterogeneous group of neurologic disorders, characterized by transient sudden choreoathetoid or dystonic attacks without loss of consciousness. This study reports a family with six affected members in three generations, and two sporadic cases of paroxysmal dyskinesia. Familial cases of paroxysmal dyskinesia are affected by idiopathic long-lasting paroxysmal exertion-induced dyskinesia and the sporadic cases by idiopathic short-lasting paroxysmal kinesigenic dyskinesia. Familial cases also suffer from epilepsy, mainly of generalized type, with benign outcome; one sporadic case is affected by migraine. Results presented in this neurophysiologic study include electromyography, somatosensory evoked potentials by median nerve stimulation, somatosensory evoked potentials by posterior tibial nerve stimulation, motor evoked potentials by magnetic transcranial cortical stimulation, visual evoked potentials, brainstem auditory evoked potentials, blink reflex, reflex H, and electroencephalography. The clinical and neurophysiologic findings presented here suggest a condition of hyperexcitability at the muscular and brain level, perhaps as a result of an ion channel disorder, which is in agreement with reports in the literature.     

Dystonic attacks related to sleep and exercise.

Two unrelated children displayed attacks of paroxysmal jerky 'puppet-like' movements lasting 2-3 min. The attacks were not kinesigenic and occurred during wakefulness precipitated by physical exercise and during NREM sleep, spontaneous or upon arousal and awakenings. Paroxysmal dystonic choreoathetosis was excluded by the absent family history, and paroxysmal kinesigenic dystonia by the absence of triggering effects by sudden movements and efficacy of anticonvulsants. Pattern and duration of involuntary movements were not those typical of nocturnal paroxysmal dystonia. Our cases emphasize that overlap exists among the different clinical categories of paroxysmal dyskinesia.     

The PRRT2 mutation c.649dupC is the so far most frequent cause of benign familial infantile convulsions

PurposeMutations in the PRRT2 gene have been recently described as a cause of paroxysmal kinesigenic dyskinesia, infantile convulsions with choreoathetosis syndrome and, less often, infantile convulsions. We have analysed the frequency of PRRT2 mutations in families with benign familial infantile convulsions without paroxysmal kinesigenic dyskinesia.Methods and resultsDirect sequencing of the coding region identified the PRRT2 mutation c.649dupC in 5/5 families with infantile convulsions. The mutation was present in 23 family members, of which 18 were clinically affected and 2 were obligate carriers. The affected carriers of this mutation presented with different types of epileptic seizures during early childhood but did not develop additional neurological symptoms later in life.ConclusionOur data demonstrate that the PRRT2 mutation c.649dupC is a frequent cause of benign familial infantile convulsions.     

Biallelic XPR1 mutation associated with primary familial brain calcification presenting as paroxysmal kinesigenic dyskinesia with infantile convulsions

BackgroundMutations in the XPR1 gene are associated with primary familial brain calcifications (PFBC). All reported mutations are missense and inherited as an autosomal dominant trait. PFBC patients exhibited movement disorders, neuropsychiatric symptoms, and other associated symptoms with diverse severity, even within the same family.Materials and methodsWe identified and enrolled a patient with PFBC. Clinical data were comprehensively collected, including the age of onset, seizure types and frequency, trigger factors of paroxysmal dyskinesia, response to drugs, and general and neurological examination results. Whole-exome sequencing (WES) was performed to detect pathogenic variants. We further systematically reviewed the phenotypic and genetic features of patients with XPR1 mutations.ResultsThe patient showed bilateral calcification involving basal ganglia and cerebellar dentate. Clinically, he presented as paroxysmal kinesigenic dyskinesia with infantile convulsions (PKD/IC) with favorable outcome. We identified a compound heterozygous XPR1 mutation (c.786_789delTAGA/p.D262Efs*6, c.1342C>T/p.R448W), which were inherited from unaffected parents respectively. Further literature review shows a wide range of clinical manifestations of patients with XPR1 mutations, with movement disorders being the most common.ConclusionsThis is the first report of biallelic mutations in XPR1. The findings suggest for the first time a possible link between PKD/IC and XPR1 mutations.     

Paroxysmal dyskinesia with interictal myoclonus and dystonia: a report of two cases

Idiopathic paroxysmal dyskinesias (PxD) are characterized by attacks of hyperkinetic movement, with no inter-ictal symptoms. We report two cases, one with paroxysmal kinesigenic dyskinesia and another with paroxysmal exercise-induced dystonia, both of whom had myoclonus and dystonia between attacks. This previously unreported association highlights the heterogeneity of paroxysmal movement disorders.     

41例发作性运动诱发性运动障碍临床与神经电生理分析

目的　观察发作性运动诱发性运动障碍 (PKMD)的临床特征及与癫的关系。方法　详细观察 4 1例PKMD的临床特征 ,影像学和脑电图改变。结果　 4 1例均由运动诱发 ,呈发作性运动诱发性舞蹈手足徐动症 30例 ,发作性运动诱发性肌张力障碍 11例 ,发作时意识清楚 ,影像学有异常者 6例 ,脑电图有样放电者 12例 ,其中 2例发作时有样放电 ,脑体感诱发电位半数以上病例有定位侧半球改变。对抗药有良效。结论　本症障碍的部位可能在感觉刺激的传入通路与发作症状的传出通路之间的反射中枢。具有某些癫性质 ,推测与癫发作可能有某些共同的生物学基础     

Effective treatments for FGF12-related early-onset epileptic encephalopathies patients

BackgroundFGF12 (FHF1) gene encodes voltage-gated sodium channel (Nav)-binding protein fibroblast growth factor homologous factor 1, which could cause seizures by regulating voltage dependence of Nav fast inactivation and neuron excitability. The most common pathogenic variant FGF12 c.341G > A related early-onset epileptic encephalopathies (EOEE) was characterized by intractable seizures and developmental disabilities.ResultsUsing whole exome sequencing, a de novo hotspot variant c.341G > A (NM_021032.4) of FGF12 was identified in three unrelated EOEE probands. All probands were seizure free after a combination treatment of valproic acid (VPA) and topiramate (TPM). The motor and cognitive skills in two probands were improved due to the early and effective treatment. In order to compare the effectiveness of different treatment strategies for the disease, a review of treatments for FGF12-related epilepsy was made.ConclusionWe reported three FGF12 c.341G > A related EOEE patients responded well to a combination antiepileptic therapy of VPA and TPM. The current study is the first to describe the combination therapy of VPA and TPM in FGF12 c.341G > A related EOEE patients. This study may contribute to future medication consultation for intractable epilepsy with FGF12 hotspot variants.     

Missense mutations of the proline-rich transmembrane protein 2 gene cosegregate with mild paroxysmal kinesigenic dyskinesia and infantile convulsions in a Chinese pedigree

Paroxysmal kinesigenic dyskinesia is an autosomal dominant dystonia induced by sudden voluntary movements. Recently, proline-rich transmembrane protein 2 (PRRT2) gene mutations, especially frameshift mutations, were described for PKD. In our study, we have collected a three-generation paroxysmal kinesigenic dyskinesia-infantile convulsions pedigree in Tianjin, North China. The symptoms of six patients varied; age of onset decreased in each generation. Mutations in the PRRT2 gene in nine PKD family members were screened by PCR sequencing of genomic DNA samples. Missense mutations of the PRRT2 gene were found in all four PKD patients and two children with infantile convulsions. All six individuals carried heterozygous codon 138 (Pro/Ala) and codon 306 (Ala/Asp) mutations. Missense mutations of the PRRT2 gene other than truncate and frameshift mutations were account for PKD and/or infantile convulsions. Age of onset and symptoms were not necessarily associated with PRRT2 mutations.     

Re-evaluation of PRRT2 mutations in paroxysmal disorders

Mutations in PRRT2 have recently been identified as the major cause of autosomal dominant benign familial infantile epilepsy (BFIE), infantile convulsions with choreoathetosis syndrome (ICCA), and paroxysmal kinesigenic dyskinesia (PKD). Other paroxysmal disorders like febrile seizures, migraine, paroxysmal exercise-induced dyskinesia, and paroxysmal non-kinesigenic dyskinesia have also been shown to be associated with this gene. We re-evaluated PRRT2 mutations and genetic–clinical correlations in additional cases with PKD/ICCA and other paroxysmal disorders. Two novel mutations in PRRT2 were revealed in PKD/ICCA cases, while no mutations were detected in other diseases, which suggests BFIE and PKD are still core phenotypes of PRRT2-related spectrum disorders.     

Genetics of paroxysmal dyskinesias

Paroxysmal dyskinesias (PDs) are a heterogeneous group of disorders characterized by sudden attacks of involuntary movements that are mostly a combination of dystonia, chorea, athetosis, and ballism. They can sometimes be symptomatic, but usually an underlying cerebral lesion is not present. Most PDs have a genetic background and are divided into kinesigenic, nonkinesigenic, and exercise-induced forms. Recently, the first genes have been identified for paroxysmal nonkinesigenic dyskinesia (MR1) and paroxysmal exercise-induced dyskinesia (PED) (SLC2A1). Whereas the function of the MR-1 protein and the pathophysiology are still poorly understood, mutations in SLC2A1 and their functional characterization predict a reduced transport of glucose across the blood-brain barrier as the underlying mechanism of PED. A locus on chromosome 16 has been described for the kinesigenic forms, but the underlying genetic alterations are unknown. This review summarizes clinical symptoms of the PDs, imaging findings, therapeutic options, and the pathophysiologic background.