Clinical phenotype and genetic characteristics of patients with typical 16p11.2 microdeletion syndrome / 中华神经科杂志

Objective:To analyze the clinical phenotype, copy number variation, treatment and follow-up characteristics of children with typical 16p11.2 deletion syndrome.Methods:The clinical data of 10 children with typical 16p11.2 deletion syndrome who were treated in the Department of Neurology, Children′s Hospital of Fudan University from August 2011 to December 2021 were retrospectively collected, and their clinical phenotype, copy number variation, treatment and follow-up were summarized.Results:Among the 10 children, 4 are female and 6 are male, all with epilepsy. Nine patients had epilepsy in infancy, and the age of onset was 6.0 (4.0, 8.5) months. Four cases had focal seizures (1 with fever), 4 had generalized tonic-clonic seizures, and 2 had focal seizures with generalized tonic-clonic seizures. Eight cases had cluster seizures (more than 2 to 10 seizures within 24 hours), and 1 case had 1 status epilepticus. Nine children did not show obvious developmental delay at the onset of epilepsy, and 1 child had developmental delay at the onset of epilepsy at 14 months of age. One child had parallel toes at left foot, and 1 had macrocephaly and low limb muscle tone. Genetic testing found that 10 children carried typical 16p11.2 heterozygous deletion, the starting position of the deletion fragment was Chr16:29478119-29675016, the ending position was Chr16:30125670-30206112, and the deletion length was 525-712 kb, all of which were considered pathogenic variants. In the antiepileptic drug treatment, 4 children were treated with oxcarbazepine, 2 with sodium valproate, 2 was switched to oxcarbazepine after levetiracetam was ineffective, 1 with levetiracetam combined with sodium valproate, and 1 with levetiracetam in combination with sodium valproate and ketogenic diet, and all 10 children had no seizures. One patient developed episodic exercise-induced dyskinesia at school age, and the seizures decreased after treatment with oxcarbazepine. Follow-up of 10 children found that 9 children had different degrees of developmental delay (language was significantly affected), 3 cases were combined with autism-like manifestations, and 1 case had poor comprehension, learning difficulties, and repeated grades after entering regular primary schools.Conclusion:The typical 16p11.2 microdeletion syndrome has the deletion of gene fragments in the proximal region of 16p11.2, characterized by drug-responsive cluster seizures with onset in infancy, which may be accompanied by language delay, autism spectrum disorder and nonspecific malformations.

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.

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.

Research progress of magnetoencephalography in neurological paroxysmal disease / 上海交通大学学报（医学版）

Neurological paroxysmal disease is a large group of clinical syndrome with a characteristic of sudden, recurrent, self-limiting. Clinically, routine biochemical or imaging examinations are usually with no significant abnormalities in the interictal period. However, magnetoencephalography (MEG), as an important electrophysiological tool in studying brain magnetic signals and monitoring brain electric activity, has highly temporal and spatial resolution for its noninvasive measurement of human brain with superconducting quantum interference. Therefore, it has been gradually used in researching for functional activities and mechanisms of the neuropsychiatric disorders and the advanced brain activity. There mainly reviewed the application and studies of MEG in epilepsy, paroxysmal kinesigenic dyskinesias and migraine.

Application of exercise test in patients with paroxysmal kinesigenic dyskinesia / 中华神经科杂志

Objective To explore the application of the exercise test (ET) in paroxysmal kinesigenic dyskinesia (PKD).Methods We conducted the ET in 33 controls and 45 PKD patients following standardized protocols,and the decrement in the amplitude and in the area of compound muscle action potentials (CMAP) after long ET and other seven parameters were calculated and compared in both groups,and the normal range of parameters was defined as the mean ± two standard deviation of the control values.Results According to the control group,the normal range of the change in the amplitude of CMAP immediately after short ET was-13％-27％ and the normal range of decrement in the amplitude of CMAP after long ET was less than 33％.And the ET was abnormal in 16 of the 45 PKD patients (36％).Comparing the nine parameters between two groups,we found that both the decreases of the amplitude (25.5％ ±13.4％ vs16.2％ ±8.6％,t=-3.72,P=0.00) and the area(31.8％ ±16.3％ vs19.0％ ± 16.8％,t =-2.39,P =0.02) of CMAP after long ET in PKD patients were larger than those in controls.No statistically significant difference was found between 19 non-ion channel disease patients and 14 normal controls.No statistically significant difference was found between the nine parameters in 27 PKD patients before and after medication,though all the patients had obvious clinical improvement.Conclusion We found that abnormal ET may appear in PKD patients,and this finding hinted that abnormal muscle membrane excitability might be an underlying mechanism responsible for PKD.

Paroxysmal Kinesigenic Dyskinesia as the Presenting and Only Manifestation of Multiple Sclerosis after Eighteen Months of Follow-Up

Other than tremor, movement disorders are uncommon in multiple sclerosis. Among these uncommon clinical manifestations, paroxysmal kinesigenic dyskinesia is the most frequently reported. It is characterized by episodic attacks of involuntary movements that are induced by repetitive or sudden movements, startling noise or hyperventilation. The diagnosis is essentially clinical and based on a good observation of the attacks. It is very easy to misdiagnose it. We describe the case of a young female patient who presented paroxysmal kinesigenic dyskinesia as the first and only clinical manifestation of multiple sclerosis, with no recurrence of attacks nor any other neurologic symptom after eighteen months of follow-up.

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

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.

Analysis of clinical and genetic features of one family with paroxysmal kinesigenic dyskinesia / 中国神经精神疾病杂志

Objective To study the clinical and genetic features of familial paroxysmal kinesigenic dyskinesia (PKD). Methods The clinical information of 14 family members in one pedigree, including 2 patients (one treated in hos?pital, the other not treated) were analyzed and the response to treatment and prediction were followed up. DNA was ex?tracted from peripheral blood samples, and then screened for PRRT2 mutations. Results There were two male patients in the pure PKD pedigree, Prevalence rate was 14.3%,One of the PKD patients showed good response to carbamazepine as well as lamotrigine whereas other patients recovered without treatment. We detected a nonsense mutation c.797G>A (p.266R>Q) in PRRT2 gene in three family members. One affected member harboring PRRT2 mutation resulted from the incomplete penetrance of the disease,PKD and polycystic kidney disease coexist in the pedigree which showed autoso?mal dominant inheritance with incomplete penetrance and anticipation. Conclusions The curative effect of antiepileptic drugs to purely familial PKD is related to mutations and clinical features;Treatments should be decided based upon clini?cal features and mutations.

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.

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

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.

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.

The Clinical Analysis of Paroxysmal Kinesigenic Dyskinesia / 대한소아신경학회지

PURPOSE: Paroxysmal kinesigenic dyskinesia (PKD) is one of the movement disorders in which dyskinesia occurs in a part of the body by a sudden movement after a rest under a tension or a stress. This study was aimed to evaluate the clinical features of children and adolescents with PKD in Korea via analysing the patients who have treated in Department of Pediatrics, Kyungpook National University Hospital. METHODS: A total of seven children with PKD was involved in the study and their medial records were retrospectively evaluated. RESULTS: The mean age of the 7 subjects was 15.7 years (10.0-21.4 years old). The male to female ratio was 6:1. They presented with dystonia with the average duration of 10.5 seconds (3.5-17.5 seconds), which triggered by various sudden movements. No accompanying cormorbidities were noted. Their laboratory findings were unremarkable. Six of the patients, except one who refused treatment with medicine, responded well to medication and remained symptom free. The average time response to medication was 3.4 weeks (0.95-7.81 weeks). They were of treated with either oxcarbazepine (n=4, 14.9+/-5.8 mg/kg/day) or lamotrigine (n=2, 1.5+/-0.9 mg/kg/day). There was no significant difference between two groups in terms of age, response, adverse events, and so on. CONCLUSION: This study showed that clinical features of Korean children with PKD are quite similar to those of other countries. They responded well to the medication. In addition, lamotrigine can be an alternative choice for the treatment.

Clinical Characteristics of Paroxysmal Kinesigenic Choreoathetosis:Diagnosis,Treatment and Prognosis / 华中科技大学学报（医学）（英德文版）

The clinical characters,diagnosis and differential diagnosis of paroxysmal kinesigenic choreoathetosis (PKC),and efficacy of the anti-epileptic drugs (AEDs) were investigated.Thirty-one patients with PKC were collected,and the clinical characters and change of EEG were analyzed.The average age of the first attack was 16.8 years old and the pinnacle was 10 to 20 years old.There were definite causes for every attack and the sudden movement was the most common one (92%).Time for the whole attack was always less than 1 rain.The attack presented with muscle tension disturbance (83.9%),movement like dancing (16.1%),abnormal movement of mouth and face and other symp-toms (16.2%).The attack tended to be very frequent and 71% patients were beyond once per day.The EEG examination and image scan of primary PKC were normal in most patients.Low dosage of AEDs could control the attack of 50%-77.3% patients.It was concluded that PKC was a common disease of movement disorder.The therapy by AEDs was very effective.PKC should be differentiated from epilepsy and the relationship between PKC and epilepsy needs further research.

A familial case report of paroxysmal kinesigenic dyskinesia in three brothers / 소아과

Paroxysmal kinesigenic dyskinesia (PKD), previously referred to as movement-provoked seizures, is a rare neurological condition that is characterized by short duration dystonic or choreoathetotic movements precipitated by sudden movement, a change in position or hyperventilation. It can be difficult to distinguish this syndrome from seizures. We reported on three brothers in one family all of whom developed abnormal involuntary dystonic or choreoathetotic movement with a tingling or stiffness sensory aura. Evaluations of the patients included general physical examinations, endoclinologic, metabolic studies, chromosomal analysis, video electroencephalograms and brain MRI imaging. All of these studies were normal except for an arachnoid cyst found in one patient. All symptoms showed excellent response to oxcarbamazepine (Trileptal(R)) or carbamazepine. Use of the video electroencephalogram can help differentiate familial PKD from seizures.

Paroxysmal kinesigenic Dyskinesia:Analysis of 33 cases / 中国实用内科杂志

Objective To investigate the clinical characteristics of the patients with paroxysmal kinesigenic dyskinesia(PKD)and it's diagnosis.Methods 33 patients with PKD were analyzed and followed up.Results Patients with PKD were liable to attacks provoked by sudden movement,startle,stress and hyperventilation and its clinical characteristics were dystonic postures,chorea,athetosis or ballism which lasted usually 3 to 10 seconds each time but never more than five minutes and recured ranging from several dozen times per day to several times per week.Moreover,patients never lost their consciousness during the attack and restored to normality during the interval.The age of onset of the disease was 4-18 years old.Eight patients had positive EEG findings,the rest of the patients' electrophysiology and neuroimaging examination showed no abnormality.All cases responded favorably to anti-epileptic drugs,especially carbamazepine.Conclusion PKD was characterized by movement induced,transient,local or generalized involuntary movement,and belonged to channelopathy.Antiepileptic drugs,particularly carbamazepine,were effective to PKD.The precise classification of the patients with paroxysmal dyskinesias is important for therapeutic decisions.

Clinical Analysis of Paroxysmal Kinesigenic Dyskinesia

BACKGROUND: To define the pathophysiology of paroxysmal kinesigenic dyskinesia(PKD), we analyzed detailed clin-ical features. METHODS: We studied characteristics of the attack, family history, response to the treatment and clinical courses of 30 patients with PKD. RESULTS: Twenty-six of the 30 patients were men and four were women. Thirteen patients had a family history of PKD. There were no patients who had symptomatic PKD. In three-fourths of our patients, the attacks ameliorated within 10 seconds and two-thirds experienced one to ten attacks per day. They showed dystonia much more frequently than chorea. In all patients,sudden movements of the legs while standing precipitated the attacks. The attack occurred very rarely during driving or swimming. Sudden movements of the arm did not precipi-tate the attacks. CONCLUSIONS: We suggest that neuronal system maintaining standing posture and strong afferent inputs delivering sudden high velocity movements of the legs to the spinal cord are involved in the genesis of PKD.

Clinical features and pathogenesis of paroxysmal dyskinesias / 临床神经病学杂志

Objective To investigate the clinical characteristics and pathogenesis of paroxysmal dyskinesias.Methods Retrospective analysis was performed in 5 patients suffering from paroxysmal kinesigenic choreoathetosis(PKC) and 2 patients with paroxysmal persistent exercise-induced dystonia(PED).Results The episodes of all cases of PKC were induced by sudden movements.3 cases showed rigidty and hypertonia.3 cases presented with twist of limbs and dystonia.2 PED cases were induced by persistent movement,manifested involuntary movements of limbs,and the duration of the attack usually last seconds to minutes.5 patients showed epileptic discharges in EEG or AEEG.2 patients had abnormal findings of brain CT or MRI.4 PKC cases responded well to carbamazepine and 1 PED patients to large dose of valproate sodium.Conclusions Paroxysmal dyskinesias are usually induced by sudden movement and present paroxysmal extrapyramidal symptoms.Most of the patients show epileptic discharges in EEG and responded well to antiepileptic drugs.This implies the underlying relationship of pathogenesis between paroxysmal dyskinesia and epilepsy.

A study of Paroxysmal Kinesigenic Choreoathetosis / 대한소아신경학회지

The paroxysmal kinesigenic chereoathetosis is characterized by choreoathetotic, dystonic movements induced by sudden movements without loss of consciousness, urinary incontinence and clonic movement. These attacks begin in childhood. The effect of anticonvulsants is usually excellent. We report one case of paroxysmal kinesigenic choreoathetosis.

Paroxysmal kinesigenic choreoathetosis

Paroxysmal kinesigenic choreoathetosis (PKC) is characterized by short paroxysms of focal or generalized involuntary movement induced by sudden movements, and is a well-known disease in the neurologic literature, but only 4 cases have been reported in Korea. The purpose of the presentation is to clarify the clinical features of PKC in Korea. We clinically analyzed 20 patients with PKC between 1986 and 1994 at Yongdong Severance Hospital, Yonsei Medical Center, with a minimum of a 1 to 2 year follow-up period. There were 14 men and 6 women. The age at onset of the condition ranged from 8 to 17 years (mean, 13.1 years). Six patients (30%) had a family history of the condition and the mode of inheritance was suggestive of an autosomal recessive pattern. The involuntary movements seemed to be dystonic rather than choreoathetonic upon a mild attack, and the paroxysms were precipitated by sudden movements. The attacks occurred on one or both sides, and were often associated with dysarthria, upward gaze and sensory aura. Consciousness was never lost. Their duration were usually 10 to 30 seconds, and never more than two minutes. All laboratory tests including electroencephalographic and neuroimaging studies showed no abnormality. All patients responded well to diphenylhydantoin. PKC is not rare in Korea and has a benign course.