Clinical and PRRT2 gene variants analysis of three families with benign familial infantile epilepsy / 中华神经科杂志

Objective:To investigate the clinical and gene variant characteristics of benign familial infantile epilepsy in generations of three families.Methods:The clinical data of the three benign familial infantile epilepsy patients with PRRT2 gene variant who were diagnosed and their family members were collected from Children′s Hospital Affiliated to Zhengzhou University between 2018 and 2019. All coding exons from the patients and their parents were screened by targeted next-generation sequencing, and detected variants were verified by Sanger sequencing.Results:In all the patients, a cluster of seizures was observed before one year old,but interictal clinical conditions were normal. The electroencephalograms were all normal in interictal stage. The father of proband 1 presented with convulsion onset at the age of eight months and showed remission before one year old. The grandpa, mother and uncle of proband 2 also presented with convulsion onset in their babyhood of life and showed remission before one year old. The mother of proband 3 presented with convulsion onset in their babyhood of life and showed remission before three years old. Proband 1 carried heterozygous c.937G>C variant in the PRRT2 gene which is inherited from his father. Proband 2 carried c.1075_c.1076insC variant inherited from his mother. A deletion of PRRT2 gene exon 2 was detected in both of proband 3 and her mother. The three variants had not been reported in the Human Gene Mutation Database.Conclusions:Benign familial infantile epilepsy is a kind of inherited epilepsy characterized by early onset of seizure in babyhood with better prognosis, a cluster of focal seizures with or without secondary generalization, and cessation of seizure mostly before two or three years of age. The variants c.937G>C, c.1075_c.1076insC and the deletion of exon 2 in the PRRT2 gene have enriched the gene variant spectrum of benign familial infantile epilepsy.

Penetrance estimation of PRRT2 variants in paroxysmal kinesigenic dyskinesia and infantile convulsions / 医学前沿

Proline-rich transmembrane protein 2 (PRRT2) is the leading cause of paroxysmal kinesigenic dyskinesia (PKD), benign familial infantile epilepsy (BFIE), and infantile convulsions with choreoathetosis (ICCA). Reduced penetrance of PRRT2 has been observed in previous studies, whereas the exact penetrance has not been evaluated well. The objective of this study was to estimate the penetrance of PRRT2 and determine its influencing factors. We screened 222 PKD index patients and their available relatives, identified 39 families with pathogenic or likely pathogenic (P/LP) PRRT2 variants via Sanger sequencing, and obtained 184 PKD/BFIE/ICCA families with P/LP PRRT2 variants from the literature. Penetrance was estimated as the proportion of affected variant carriers. PRRT2 penetrance estimate was 77.6% (95% confidence interval (CI) 74.5%-80.7%) in relatives and 74.5% (95% CI 70.2%-78.8%) in obligate carriers. In addition, we first observed that penetrance was higher in truncated than in non-truncated variants (75.8% versus 50.0%, P = 0.01), higher in Asian than in Caucasian carriers (81.5% versus 68.5%, P = 0.004), and exhibited no difference in gender or parental transmission. Our results are meaningful for genetic counseling, implying that approximately three-quarters of PRRT2 variant carriers will develop PRRT2-related disorders, with patients from Asia or carrying truncated variants at a higher risk.

Identification of two novel PRRT2 gene variants in two children with paroxysmal kinesigenic dyskinesia / 中华医学遗传学杂志

Objective@#To analyze variants of PRRT2 gene in two children with paroxysmal kinesigenic dyskinesia.@*Methods@#Genomic DNA of the two children and their parents was extracted from peripheral venous blood samples. All exons and their flanking regions of the PRRT2 gene were subjected to PCR and Sanger sequencing.@*Results@#The two children were found to respectively harbor a c. 282dupA and a c. 715_716dupCC variant in exon 2 of the PRRT2 gene, which were both inherited from their mothers. Pooling together their frequencies in general population, genetic models, related literature and impact on protein function, the two novel variants were both predicted to be pathogenic.@*Conclusion@#The c. 282dupA and c. 715_716dupCC variants probably underlie the disease in the two children.

A novel frameshift mutation of PRRT2 in a family with infantile convulsions and choreoathetosis syndrome: c.640delinsCC (p.Ala214ProfsTer11)

The infantile convulsions and choreoathetosis (ICCA) syndrome is defined when two overlapping clinical features of benign familial infantile epilepsy (BFIE) and paroxysmal kinesigenic dyskinesia (PKD) are present in an individual or a family. Since the gene encoding proline-rich transmembrane protein 2 (PRRT2) was first identified in Han Chinese families with PKD, mutations of PRRT2 have additionally been reported in patients with BFIE and ICCA. We attempted to identify the genetic etiology in an ICCA family where the proband, her elder sister, and a maternal male cousin had BFIE, and her mother had PKD. Whole-exome sequencing performed in the proband and her sister and mother identified a novel pathogenic mutation of PRRT2 (c.640delinsCC; p.Ala214ProfsTer11), which was verified by Sanger sequencing. This frameshift PRRT2 mutation located near the genetic hot spot of base 649_650 results in the premature termination of the protein, as do most previously reported mutations in BFIE, ICCA, and PKD.

Paroxysmal Dyskinesia in Children: from Genes to the Clinic

BACKGROUND AND PURPOSE: Paroxysmal dyskinesia is a genetically and clinically heterogeneous movement disorder. Recent studies have shown that it exhibits both phenotype and genotype overlap with other paroxysmal disorders as well as clinical heterogeneity. We investigated the clinical and genetic characteristics of paroxysmal dyskinesia in children. METHODS: Fifty-five patients (16 from 14 families and 39 sporadic cases) were enrolled. We classified them into three phenotypes: paroxysmal kinesigenic dyskinesia (PKD), paroxysmal nonkinesigenic dyskinesia (PNKD), and paroxysmal exercise-induced dyskinesia (PED). We sequenced PRRT2, SLC2A1, and MR-1 in these patients and reviewed their medical records. RESULTS: Forty patients were categorized as PKD, 14 as PNKD, and 1 as PED. Thirty-eight (69.1%) patients were male, and their age at onset was 8.80±4.53 years (mean±SD). Dystonia was the most common symptom (38 patients, 69.1%). Pathogenic variants were identified in 20 patients (36.4%): 18 with PRRT2 and 2 with SLC2A1. All of the patients with PRRT2 mutations presented with PKD alone. The 2 patients carrying SLC2A1 mutations presented as PNKD and PED, and one of them was treated effectively with a ketogenic diet. Six mutations in PRRT2 (including 2 novel variants) were identified in 9 of the 13 tested families (69.2%) and in 8 patients of the 25 tested sporadic cases (32.0%). There were no significant differences in clinical features or drug response between the PRRT2-positive and PRRT2-negative PKD groups. CONCLUSIONS: This study has summarized the clinical and genetic heterogeneity of paroxysmal dyskinesia in children. We suggest that pediatric paroxysmal dyskinesia should not be diagnosed using clinical features alone, but by combining them with broader genetic testing.

Clinical characteristics and genetic features of benign infantile epilepsy with PRRT2 mutation / 中华儿科杂志

Objective@#To summarize the detailed clinical characteristics and genetic features of benign infantile epilepsy with PRRT2 mutation, in order to improve the understanding of the disease.@*Methods@#The clinical data and genetic results of 40 benign infantile epilepsy patients with PRRT2 mutation who were diagnosed and treated in the neurology department of National Center for Children's Health (Beijing) , Beijing Children's Hospital affiliated to Capital Medical University from January 2002 to October 2017 and their affected family members were analyzed.@*Results@#Forty benign infantile epilepsy patients were recruited for this study, with 18 males and 22 females. The age at onset ranged from 3 to 15 months (median: 4.6 months). All patients presented focal seizures with or without secondary generalization. Decreased responsiveness, eyes stare and cyanosis were commonly observed. A cluster of seizures was observed in 20 patients at the beginning of the disease, but interictal clinical conditions were normal. Interictal electroencephalograms were normal in 32 cases but 8 cases showed small amount scattered spike and spike wave. Two patients developed paroxysmal kinesigenic dyskinesia in 30 months and 12 years respectively after the cessation of the seizure. Thirty-four affected pedigree members had a history of paroxysmal episodes in 24 families, including 19 individuals of infantile afebrile convulsion, 6 individuals of paroxysmal kinesigenic dyskinesia during childhood or adulthood, 8 individuals of infantile convulsion and paroxysmal kinesigenic dyskinesia during adulthood, one individual of infantile febrile convulsion. The follow-up time ranged from 6 months to 15 years. Thirty-six patients were treated with antiepileptic drugs and their seizures were easy to control. Four patients stayed seizure free without medication (all <2 years). Seizure stopped in 24 patients within 1 year of age, in 10 patients stopped during 12-24 months and in 2 patients stopped during 24-36 months. All cases had PRRT2 mutations, 7 cases of a complete PRRT2 deletion, 33 cases of PRRT2 heterozygous mutations consisted of 28 frameshift mutations and 5 missense mutations. Of these heterozygous mutations, 30 cases were hereditary mutations while 3 were de novo mutations. Nine family members harbored the same PRRT2 mutations without any symptom.@*Conclusions@#Benign infantile epilepsy with PRRT2 mutation is characterized by early onset of seizure mostly before 6 months, focal seizures with or without secondary generalization, a high incidence of a cluster of seizures, rapid resolution of seizure by antiepileptic drugs and cessation of seizure mostly before 2 years of age. Partial patients may develop paroxysmal kinesigenic dyskinesia increasing with age. Most PRRT2 gene mutations are heterozygous mutations, and a few are the overall deletion of PRRT2 gene.

The Clinical and prognosis of PRRT2 gene-related paroxysmal disorders (Report of 1 case) / 临床神经病学杂志

Objective To investigate the clinical features and prognosis of PRRT2-related paroxysmal disorders. Methods Retrospected clinical data of one cases of benign infantile epilepsy diagnosed by gene diagnosis. Results The clinical manifestations of this Children were recurrent convulsions,cluster seizures,and no obvious abnormalities in physical examination. Genetic examination showed mutation of PRRT2 frameshift. Her mother had a history of paroxysmal motor-induced dyskinesia,and her uncle and cousin had a history of convulsions when they were young. The patient did not convulse after oral oxcarbazepine. Conclusions PRRT2 gene-related paroxysmal diseases are characterized by self-limited infantile epilepsy and paroxysmal motor-induced dyskinesia. Genetic diagnosis is needed for definitive diagnosis.The main treatment of this disease is to control epilepsy,and the prognosis is good.

Study of Pathogenic gene spectrum in benign familial infantile epilepsy / 中华实用儿科临床杂志

Objective To investigate the gene mutations in benign familial infantile epilepsy(BFIE)in Chi-na. Methods Data of all BFIE probands and their family members were collected from Peking University First Hospital and other three hospitals between October 2006 and June 2017. Clinical phenotypes of affected members were analyzed. Genomic DNA was extracted from peripheral blood samples with standard protocol. Mutations in PRRT2 were screened using Sanger sequencing. For families that PRRT2 mutations were not detected by Sanger sequencing,candidate gene mutations were further screened by next - generation sequencing. Results A total of 71 families including 227 affected members were collected. Genetic testing led to the identification of gene mutations in 52 families (52 / 71,73. 2％). Forty - three families had PRRT2 mutations (43 / 71,60. 6％),including 40 families with frameshift mutations(hotspot mutations c. 649_650insC and c. 649delC were detected in 29 families and 6 families,respectively),one family with nonsense mutation,one family with a loss of a stop codon,and one family with a microdeletion of the gene. C. 560_561insT and c. 679C > T were novel PRRT2 mutations. Five families had SCN2A mutations. All SCN2A mutations were missense mutations(c. 668G > A,c. 752T > C,c. 1307T > C,c. 4835C > G,c. 1737C > G). Mutation c. 752T > C, c. 1307T > C,c. 4835C > G,and c. 1737C > G were novel mutations. Three families had KCNQ2 mutations. All KCNQ2 mutations were missense mutations(c. 775G > A,c. 237T > G,c. 1510C > T). Mutation c. 237T > G and c. 1510C > T were novel mutations. One family had a novel GABRA6 mutation c. 523G > T. In 71 BFIE families,16 families had mem-bers who showed paroxysmal kinesigenic dyskinesias(PKD)and subclassified as infantile convulsions with paroxysmal choreoathetosis syndrome(ICCA). Fifteen ICCA families were found having PRRT2 mutations (15 / 16,93. 8％). The remaining ICCA family was not detected with any pathogenic mutation. Conclusion There is high frequency of gene mutations in BFIE families. Mutations in KCNQ2,SCN2A,and PRRT2 are genetic causes of BFIE. PRRT2 is the main gene responsible for BFIE. GABRA6 mutation might be a new cause of BFIE.

Clinical Manifestation and PRRT2 Analysis of Korean Patients with Paroxysmal Kinesigenic Dyskinesia

PURPOSE: Paroxysmal kinesigenic dyskinesia (PKD) is a rare paroxysmal movement disorder characterized by recurrent and brief dyskinesia attacks triggered by sudden voluntary movement. The diagnosis of PKD is based on clinical findings, and mutations in the proline-rich transmembrane protein 2 (PRRT2) gene have been identified as the cause of PKD. Two Korean cohorts have been reported on PRRT2 mutation analysis in PKD patients. The purpose of this study was to determine the mutation spectrum of the PRRT2 gene and to examine the clinical characteristics associated with PRRT2 mutations. METHODS: We studied 23 members of four families with familial PKD and two families with sporadic PKD which included 9 patients and 2 patients, respectively. Mutation analysis of the PRRT2 gene was performed using Sanger sequencing. Clinical features of PKD were compared between patients with a PRRT2 mutation and those with no detectable PRRT2 mutation. RESULTS: PRRT2 mutations were detected in three of four PKD families (75%), and in none of the two sporadic cases (0%). All detected PRRT2 mutations were c.649dupC (p.Arg217Profs*8). Subjects with detected PRRT2 mutations had earlier age at onset and longer duration of attacks. CONCLUSION: As previously reported in Korean PKD patients, our results confirmed that PRRT2 is a major causative gene for familial PKD, and the c.649dupC is the most frequent mutation. PRRT2 mutation analysis is required for the molecular diagnosis of familial PKD and for evaluating the clinical manifestations of PKD.

A case report of paroxysmal kinesigenic dyskinesia and literature review / 临床儿科杂志

Objective To investigate the clinical features of paroxysmal kinesigenic dyskinesia (PKD) and the mutation features of its pathogenic gene proline-rich transmenbrane protein 2 (PRRT2). Method The clinical manifestations and genetic tests of one case of PKD were retrospectively analyzed, and the related literatures were reviewed. Results A 10 year and 9 month male patient was recruited. The age of dyskinesias onset was 7 year and 6 month. The descriptions of the attacks were abnormal involuntary movements which were induced by sudden voluntary movements and presented with dystonia. The frequency of the attacks was three to ifve times per day with the duration lasting ten to twenty seconds, and there is no loss of consciousness. Treatment with oxcarbazepine is effective. A heterozygous mutation in PRRT2 gene, c.649_650insC (p. 217fs224X), was found by genetic testing, and the mutation was inherited from the patient’s mother who showed no symptom of PKD. Conclusion The onset age of PKD could be in the childhood and adolescence. The attack is provoked by sudden movements and the duration time is short. Treatment with antiepileptic drug is effective. The test of PRRT2 gene may help diagnosis. Mutation c.649_650insC is the hotspot mutation of the gene.

Clinical Manifestations in Paroxysmal Kinesigenic Dyskinesia Patients with Proline-Rich Transmembrane Protein 2 Gene Mutation

BACKGROUND AND PURPOSE: Given the diverse phenotypes including combined non-dyskinetic symptoms in patients harboring mutations of the gene encoding proline-rich transmembrane protein 2 (PRRT2), the clinical significance of these mutations in paroxysmal kinesigenic dyskinesia (PKD) is questionable. In this study, we investigated the clinical characteristics of PKD patients with PRRT2 mutations. METHODS: Familial and sporadic PKD patients were enrolled and PRRT2 gene sequencing was performed. Demographic and clinical data were compared between PKD patients with and without a PRRT2 mutation. RESULTS: Among the enrolled PKD patients (8 patients from 5 PKD families and 19 sporadic patients), PRRT2 mutations were detected in 3 PKD families (60%) and 2 sporadic cases (10.5%). All familial patients with a PRRT2 gene mutation had the c.649dupC mutation, which is the most commonly reported mutation. Two uncommon mutations (c.649delC and c.629dupC) were detected only in the sporadic cases. PKD patients with PRRT2 mutation were younger at symptom onset and had more non-dyskinetic symptoms than those without PRRT2 mutation. However, the characteristics of dyskinetic movement did not differ between the two groups. CONCLUSIONS: This is the first study of PRRT2 mutations in Korea. The presence of a PRRT2 mutation was more strongly related to familial PKD, and was clinically related with earlier age of onset and common non-dyskinetic symptoms in PKD patients.

Recent advances of paroxysmal kinesigenic dyskinesia / 中华实用儿科临床杂志

Paroxysmal kinesigenic dyskinesia (PKD) is the most frequently described subtype of paroxysmal dyskinesias.The precipitating factor is usually sudden movement or startle.Clinically,PKD cases suffer involuntary movements including unilateral or bilateral chorea,athetosis,dystonia or ballismus,with preserved consciousness.Family history is commonly noted in idiopathic PKD,but sporadic cases are also reported.Familial PKD is inherited in an autosomal dominant fashion with incomplete penetrance.To date,2 loci 16p11-q12 and 16q13-q22 have been mapped to PKD,although a 3rd locus is also suspected.PRRT2,which was located in 16p12.1,was recently identified as causative gene of PKD.However,culprit genes in the other 2 loci remain to be investigated.The potential mechanism of PKD remains largely unclear and the role of mutant PRRT2 in the pathogenesis of PKD is still unknown.In this review,the recent advances of PKD were summarized and hypothesis regarding the mechanisms of PKD was put up,which may make significant contributions to the diagnosis and treatment of PKD.