Search

Objective: The objective of this study is to report the results of the genetic analysis in a large and well-characterized population with pediatric-onset epilepsies and to identify those who could benefit from precision medicine treatments., Methods: In this retrospective observational study, we consecutively recruited patients with pediatric-onset epilepsy observed at a tertiary neurological center over a time span of 7 years, collecting clinical and laboratory findings. Following in-depth diagnostic process to exclude possible structural and metabolic causes of the disease, patients with a suspected genetically determined etiology underwent next-generation sequencing (NGS) screening with panels for the analysis of target genes causative of epilepsy., Results: We detected likely pathogenic or pathogenic variants (classes IV and V) in 24% of the 562 patients who underwent genetic investigations. By the evaluation of patients' data, we observed that some features (onset of epilepsy before one year old, presence of neurological deficits, psychomotor delay/cognitive disability, and malformative aspects at brain MRI) were significantly associated with class IV or V variants. Moreover, statistical analysis showed that the diagnostic yield resulted higher for patients affected by Progressive Myoclonic Epilepsy (PME) and with early onset developmental and epileptic encephalopathies (DEE), compared with focal epilepsies, genetic generalized epilepsies, DEE with onset at/after 1 y.o., and unclassified epileptic syndromes. According to the results of the genetic screening, up to 33% of patients carrying class IV or V variants resulted potentially eligible for precision medicine treatments., Significance: The large-scale application of NGS multigene panels of analysis is a useful tool for the molecular diagnosis of patients with pediatric-onset epilepsies, allowing the identification of those who could benefit from a personalized therapeutic approach., Plain Language Summary: The analysis of patients with pediatric-onset epilepsy using advanced technologies for the screening of all the implicated genes allows the identification of the cause of diseases in an ever-increasing number of cases. Understanding the pathogenic mechanisms could, in some cases, guide the selection and optimization of appropriate treatment approaches for patients., (© 2024 The Author(s). Epilepsia Open published by Wiley Periodicals LLC on behalf of International League Against Epilepsy.)

Objective: YWHAG variant alleles have been associated with a rare disease trait whose clinical synopsis includes an early onset epileptic encephalopathy with predominantly myoclonic seizures, developmental delay/intellectual disability, and facial dysmorphisms. Through description of a large cohort, which doubles the number of reported patients, we further delineate the spectrum of YWHAG-related epilepsy., Methods: We included in this study 24 patients, 21 new and three previously described, with pathogenic/likely pathogenic variants in YWHAG. We extended the analysis of clinical, electroencephalographic, brain magnetic resonance imaging, and molecular genetic information to 24 previously published patients., Results: The phenotypic spectrum of YWHAG-related disorders ranges from mild developmental delay to developmental and epileptic encephalopathy (DEE). Epilepsy onset is in the first 2 years of life. Seizure freedom can be achieved in half of the patients (13/24, 54%). Intellectual disability (23/24, 96%), behavioral disorders (18/24, 75%), neurological signs (13/24, 54%), and dysmorphisms (6/24, 25%) are common. A genotype-phenotype correlation emerged, as DEE is more represented in patients with missense variants located in the ligand-binding domain than in those with truncating or missense variants in other domains (90% vs. 19%, p < .001)., Significance: This study suggests that pathogenic YWHAG variants cause a wide range of clinical presentations with variable severity, ranging from mild developmental delay to DEE. In this allelic series, a genotype-phenotype correlation begins to emerge, potentially providing prognostic information for clinical management and genetic counseling., (© 2024 The Authors. Epilepsia published by Wiley Periodicals LLC on behalf of International League Against Epilepsy.)

Missense variants of hyperpolarization-activated, cyclic nucleotide-gated (HCN) ion channels cause variable phenotypes, ranging from mild generalized epilepsy to developmental and epileptic encephalopathy (DEE). Although variants of HCN1 are an established cause of DEE, those of HCN2 have been reported in generalized epilepsies. Here we describe the first case of DEE caused by the novel de novo heterozygous missense variant c.1379G>A (p.G460D) of HCN2. Functional characterization in transfected HEK293 cells and neonatal rat cortical neurons revealed that HCN2 p.G460D currents were strongly reduced compared to wild-type, consistent with a dominant negative loss-of-function effect. Immunofluorescence staining showed that mutant channels are retained within the cell and do not reach the membrane. Moreover, mutant HCN2 also affect HCN1 channels, by reducing the I h current expressed by the HCN1-HCN2 heteromers. Due to the persistence of frequent seizures despite pharmacological polytherapy, the patient was treated with a ketogenic diet, with a significant and long-lasting reduction of episodes. In vitro experiments conducted in a ketogenic environment demonstrated that the clinical improvement observed with this dietary regimen was not mediated by a direct action on HCN2 activity. These results expand the clinical spectrum related to HCN2 channelopathies, further broadening our understanding of the pathogenesis of DEE., (© 2023 International League Against Epilepsy.)

Allan-Herndon-Dudley syndrome (AHDS) is caused by mutations in the SLC16A2 gene, encoding for the monocarboxylate transporter 8 (MCT8). Central hypothyroidism and chronic peripheral thyrotoxicosis result in a severe phenotype, mainly characterized by poor growth, intellectual disability, spastic tetraparesis, and movement disorders, including paroxysmal ones (startle reaction and paroxysmal dyskinesias). Seizures are rarely reported. We conducted a retrospective analysis on video electroencephalography (EEG) recordings in four subjects with AHDS, focused on paroxysmal events. Among other manifestations recorded on EEG, we diagnosed repetitive sleep starts (RSS) in all subjects. RSS are a paroxysmal nonepileptic phenomenon occurring during sleep, similar to epileptic spasms in their clinical and electromyography characteristics, but not related to any EEG change. This is the first report on RSS in AHDS. We present video-EEG polygraphic documentation, suggesting that RSS could be underestimated or misdiagnosed. The importance of a correct diagnosis is crucial in a therapeutic perspective., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Inc. All rights reserved.)

The clinical phenotype of Cyclin-Dependent Kinase-Like 5 (CDKL5) deficiency disorder (CDD) has been delineated but neuroimaging features have not been systematically analyzed. We studied brain magnetic resonance imaging (MRI) scans in a cohort of CDD patients and reviewed age at seizure onset, seizure semiology, head circumference. Thirty-five brain MRI from 22 unrelated patients were included. The median age at study entry was 13.4 years. In 14/22 patients (85.7%), MRI in the first year of life was unremarkable in all but two. In 11/22, we performed MRI after 24 months of age (range 2.5-23 years). In 8 out of 11 (72.7%), MRI showed supratentorial atrophy and in six cerebellar atrophy. Quantitative analysis detected volumetric reduction of the whole brain (-17.7%, P-value = 0.014), including both white matter (-25.7%, P-value = 0.005) and cortical gray matter (-9.1%, P-value = 0.098), with a reduction of surface area (-18.0%, P-value = 0.032), mainly involving the temporal regions, correlated with the head circumference (ρ = 0.79, P-value = 0.109). Both the qualitative structural assessment and the quantitative analysis detected brain volume reduction involving the gray and white matter. These neuroimaging findings may be related to either progressive changes due to CDD pathogenesis, or to the extreme severity of epilepsy, or both. Larger prospective studies are needed to clarify the bases for the structural changes we observed., (© The Author(s) 2023. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Variable phenotypes, including developmental encephalopathy with (DEE) or without seizures and myoclonic epilepsy and ataxia due to potassium channel mutation, are caused by pathogenetic variants in KCNC1, encoding for Kv3.1 channel subunits. In vitro, channels carrying most KCNC1 pathogenic variants display loss-of-function features. Here, we describe a child affected by DEE with fever-triggered seizures, caused by a novel de novo heterozygous missense KCNC1 variant (c.1273G>A; V425M). Patch-clamp recordings in transiently transfected CHO cells revealed that, compared to wild-type, Kv3.1 V425M currents (1) were larger, with membrane potentials between -40 and +40 mV; (2) displayed a hyperpolarizing shift in activation gating; (3) failed to inactivate; and (4) had slower activation and deactivation kinetics, consistent with a mixed functional pattern with prevalent gain-of-function effects. Exposure to the antidepressant drug fluoxetine inhibited currents expressed by both wild-type and mutant Kv3.1 channels. Treatment of the proband with fluoxetine led to a rapid and prolonged clinical amelioration, with the disappearance of seizures and an improvement in balance, gross motor skills, and oculomotor coordination. These results suggest that drug repurposing based on the specific genetic defect may provide an effective personalized treatment for KCNC1-related DEEs., (© 2023 International League Against Epilepsy.)

Background and Objectives: BRAT1 encephalopathy is an ultra-rare autosomal recessive neonatal encephalopathy. We delineate the neonatal electroclinical phenotype at presentation and provide insights for early diagnosis., Methods: Through a multinational collaborative, we studied a cohort of neonates with encephalopathy associated with biallelic pathogenic variants in BRAT1 for whom detailed clinical, neurophysiologic, and neuroimaging information was available from the onset of symptoms. Neuropathologic changes were also analyzed., Results: We included 19 neonates. Most neonates were born at term (16/19) from nonconsanguineous parents. 15/19 (79%) were admitted soon after birth to a neonatal intensive care unit, exhibiting multifocal myoclonus, both spontaneous and exacerbated by stimulation. 7/19 (37%) had arthrogryposis at birth, and all except 1 progressively developed hypertonia in the first week of life. Multifocal myoclonus, which was present in all but 1 infant, was the most prominent manifestation and did not show any EEG correlate in 16/19 (84%). Video-EEG at onset was unremarkable in 14/19 (74%) infants, and 6 (33%) had initially been misdiagnosed with hyperekplexia. Multifocal seizures were observed at a median age of 14 days (range: 1-29). During the first months of life, all infants developed progressive encephalopathy, acquired microcephaly, prolonged bouts of apnea, and bradycardia, leading to cardiac arrest and death at a median age of 3.5 months (range: 20 days to 30 months). Only 7 infants (37%) received a definite diagnosis before death, at a median age of 34 days (range: 25-126), and almost two-thirds (12/19, 63%) were diagnosed 8 days to 12 years postmortem (median: 6.5 years). Neuropathology examination, performed in 3 patients, revealed severely delayed myelination and diffuse astrogliosis, sparing the upper cortical layers., Discussion: BRAT1 encephalopathy is a neonatal-onset, rapidly progressive neurologic disorder. Neonates are often misdiagnosed as having hyperekplexia, and many die undiagnosed. The key phenotypic features are multifocal myoclonus, an organized EEG, progressive, persistent, and diffuse hypertonia, and an evolution into refractory multifocal seizures, prolonged bouts of apnea, bradycardia, and early death. Early recognition of BRAT1 encephalopathy allows for prompt workup, appropriate management, and genetic counseling., (© 2023 American Academy of Neurology.)

Objective: To report the clinical presentation of the first Italian child affected by hypomyelinating leukodystrophy (HLD) associated with the recurrent variant p.Asp252Asn in the TMEM106B gene., Methods: The methods included clinical case description, neurophysiologic assessment, brain MRI, and whole-exome sequencing (WES)., Results: The child presented soon after birth with nystagmus and hyperkinetic movement disorder. Focal seizures appeared from 2 months of age and recurred at high frequency, despite several antiseizure medications, and focal epileptic status frequently required IV phenytoin. Control of seizures was achieved at the age of 8 months by the association of high doses of sodium blockers. Clinical picture worsened over time and was characterized by axial hypotonia, failure to thrive requiring gastrostomy, pyramidal sings, and severe secondary microcephaly. MRI performed at ages 2, 6, and 20 months showed diffuse supratentorial and subtentorial hypomyelination; multimodal evoked potentials showed increased latency. WES performed at 6 months of age identified the p.Asp252Asn de novo variant in the TMEM106B gene., Discussion: Hyperkinetic movement disorders and seizures may be early symptoms of TMEM106B -HLD. Our observation, supported by video EEG recordings, emphasizes that seizures may be difficult to recognize from movement disorders and that epilepsy may be a severe and prominent symptom of the disease. TMEM106B -HLD should be considered in the genetic screening of infants with early-onset seizures and movement disorders., (Copyright © 2022 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.)

PURA syndrome is a distinct form of developmental encephalopathy, characterized by early-onset hypotonia, severe developmental delay, intellectual disability, epilepsy and respiratory and gastrointestinal disorders. We report a child with PURA syndrome, harbouring a previously described mutation, whose phenotype included two peculiar aspects: (1) hypokinetic-rigid syndrome, which was part of the clinical presentation from an early stage of the disease, and (2) reflex seizures, consisting of a series of spasms. We provide detailed clinical description and video recordings demonstrating both these aspects that are newly described in PURA syndrome. The early clinical features described here may therefore be included in the complex phenotype associated with PURA gene mutations and may help in the early diagnosis of patients. Furthermore, PURA syndrome should be considered in the differential diagnosis of early-onset bradykinetic rigid syndromes.

Pathogenic variants in the SCN8A gene have been associated with a broad phenotypic spectrum, ranging from benign familial infantile seizures to severe, early-onset developmental and epileptic encephalopathy. This spectrum also includes an "intermediate phenotype" characterized by different degrees of cognitive disability, mild neurological impairment, and therapeutically manageable epilepsy. We report on a child harbouring a de novo, novel SCN8A deletion, whose clinical picture is consistent with an SCN8A-related "intermediate phenotype". This patient's peculiar feature is the occurrence of paroxysmal tonic upgaze (PTU), a non-epileptic disorder consisting of sustained conjugate upward deviation of the eyes, with neck flexion, and downbeat saccades. PTU has been described in otherwise healthy children, as well as in a few genetic syndromes, but has never been observed in SCN8A-related phenotypes. This report, therefore, adds a new symptom to the spectrum of movement disorders associated with SCN8A-related developmental and epileptic encephalopathy. In this short communication, we provide video-EEG documentation of PTU and seizures, and discuss the challenging differential diagnosis between the two symptoms.

The X-linked Cyclin-Dependent Kinase-Like 5 (CDKL5) gene encodes a serine-threonine kinase highly expressed in the developing brain. Loss of function of CDKL5 is pointed out to underlie the CDKL5 Deficiency Disorder (CDD), an X-linked dominant disease characterized by early-onset epileptic encephalopathy and developmental delay, usually affecting females more than males. To the best to our knowledge, only 45 males with CDD have been reported so far. Type and position of CDKL5 variants with different impact on the protein are reported to influence the clinical presentation. X-chromosome inactivation occurring in females and post-zygotic mosaicism in males are also believed to contribute to this variability. Based on these issues, genotype-phenotype correlations are still challenging. Here, we describe clinical features of five additional affected males with unreported CDKL5 variants, expanding the molecular spectrum of the disorder. We also reviewed the clinical profile of the previously reported 45 males with molecularly confirmed CDD. Severe developmental delay, cortical visual impairment, and early-onset refractory epilepsy characterize the CDD picture in males. By assessing the molecular spectrum, we confirm that germ-line truncating CDKL5 variants, equally distributed across the coding sequence, are the most recurrent mutations in CDD, and cause the worsen phenotype. While recurrence and relevance of missense substitutions within C-terminal remain still debated, disease-causing missense changes affecting the N-terminal catalytic domain correlate to a severe clinical phenotype. Finally, our data provide evidence that post-zygotic CDKL5 mosaicism may result in milder phenotypes and, at least in a subset of subjects, in variable response to antiepileptic treatments., (Copyright © 2021 European Paediatric Neurology Society. Published by Elsevier Ltd. All rights reserved.)

Objective: To further delineate the electroclinical features of individuals with SYNGAP1 pathogenic variants., Methods: Participants with pathogenic SYNGAP1 variants and available video-electroencephalogram (EEG) recordings were recruited within five European epilepsy reference centers. We obtained molecular and clinical data, analyzed EEG recordings and archived video-EEGs of seizures and detailed characteristics of interictal and ictal EEG patterns for every patient., Results: We recruited 15 previously unreported patients and analyzed 72 EEGs. Two distinct EEG patterns emerged, both triggered by eye closure. Pattern 1 (14/15 individuals) consisted of rhythmic posterior/diffuse delta waves appearing with eye-closure and persisting until eye opening (strongly suggestive of fixation-off sensitivity). Pattern 2 (9/15 individuals) consisted of diffuse polyspike-and-wave discharges triggered by eye closure (eye-closure sensitivity). Both patterns presented in 8/15. Including archived video-EEG clips of seizures from 9/15 patients, we analyzed 254 seizures. Of 224 seizures experienced while awake, 161 (72%) occurred at or following eye closure. In 119/161, pattern 1 preceded an atypical absence, myoclonic seizure or myoclonic absence; in 42/161, pattern 2 was associated with eyelid myoclonia, absences and myoclonic or atonic seizures., Conclusions: Fixation-off and eye closure were the main triggers for seizures in this SYNGAP1 cohort., Significance: Combining these clinical and electroencephalographic features could help guide genetic diagnosis., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2021 International Federation of Clinical Neurophysiology. Published by Elsevier B.V. All rights reserved.)

Objective: Aiming to detect associations between neuroradiologic and EEG evaluations and long-term clinical outcome in order to detect possible prognostic factors, a detailed clinical and neuroimaging characterization of 67 cases of Aicardi syndrome (AIC), collected through a multicenter collaboration, was performed., Methods: Only patients who satisfied Sutton diagnostic criteria were included. Clinical outcome was assessed using gross motor function, manual ability, and eating and drinking ability classification systems. Brain imaging studies and statistical analysis were reviewed., Results: Patients presented early-onset epilepsy, which evolved into drug-resistant seizures. AIC has a variable clinical course, leading to permanent disability in most cases; nevertheless, some cases presented residual motor abilities. Chorioretinal lacunae were present in 86.56% of our patients. Statistical analysis revealed correlations between MRI, EEG at onset, and clinical outcome. On brain imaging, 100% of the patients displayed corpus callosum malformations, 98% cortical dysplasia and nodular heterotopias, and 96.36% intracranial cysts (with similar rates of 2b and 2d). As well as demonstrating that posterior fossa abnormalities (found in 63.63% of cases) should also be considered a common feature in AIC, our study highlighted the presence (in 76.36%) of basal ganglia dysmorphisms (never previously reported)., Conclusion: The AIC neuroradiologic phenotype consists of a complex brain malformation whose presence should be considered central to the diagnosis. Basal ganglia dysmorphisms are frequently associated. Our work underlines the importance of MRI and EEG, both for correct diagnosis and as a factor for predicting long-term outcome., Classification of Evidence: This study provides Class II evidence that for patients with AIC, specific MRI abnormalities and EEG at onset are associated with clinical outcomes., (© 2020 American Academy of Neurology.)

De novo variants in KCNQ2 encoding for Kv7.2 voltage-dependent neuronal potassium (K + ) channel subunits are associated with developmental epileptic encephalopathy (DEE). We herein describe the clinical and electroencephalographic (EEG) features of a child with early-onset DEE caused by the novel KCNQ2 p.G310S variant. In vitro experiments demonstrated that the mutation induces loss-of-function effects on the currents produced by channels incorporating mutant subunits; these effects were counteracted by the selective Kv7 opener retigabine and by gabapentin, a recently described Kv7 activator. Given these data, the patient started treatment with gabapentin, showing a rapid and sustained clinical and EEG improvement over the following months. Overall, these results suggest that gabapentin can be regarded as a precision therapy for DEEs due to KCNQ2 loss-of-function mutations., (Copyright © 2020 The Authors. Published by Elsevier Ltd.. All rights reserved.)

We report the atypical presentation of Lafora disease in a Senegalese girl carrying the homozygous variant, c.560A>C, in the NHLRC1 gene. At 13 years, the patient developed myoclonic and visual seizures, progressive psychomotor slowing, and cognitive decline. At 14 years, a neurological examination showed severe hypomimia, bradykinesia, rigidity and low-amplitude myoclonic jerks. Flash-visual and somatosensory evoked potentials showed an increased amplitude of the cortical components, while an electroretinogram showed attenuated responses. An EEG showed diffuse polyspikes associated with positive-negative jerks as well as posterior slow waves and irregular spikes. The electroclinical picture suggested the diagnosis of Lafora disease regarding the association of visual seizures, cognitive deterioration, and action myoclonus, together with the EEG and evoked potential findings. Two uncommon findings were the prominence of extrapyramidal signs in the early stage of disease (which are rarely reported) and attenuation of electroretinal responses. We consider that Lafora disease should be included in the diagnostic work-up for juvenile Parkinsonism, when associated with epilepsy.

An increasing number of developmental and epileptic encephalopathies have been correlated with variants of ion channel genes, and in particular of potassium channels genes, such as KCNA1, KCNA2, KCNB1, KCNQ2, KCTD7 and KCNT1. Here we report a child with an early severe developmental and epileptic encephalopathy, spastic tetraplegia, opisthotonos attacks. The whole exome sequencing showed the de novo heterozygous variant c.1411G > C (p.Val471Leu) in the KCNC2 gene. Although this is, to our knowledge, the first case of encephalopathy associated with a KCNC2 gene variant, and further confirmatory studies are needed, previous preclinical and clinical evidence seems to suggest that KCNC2 is a new candidate epilepsy gene., Competing Interests: Declaration of competing interest There is no conflict of interest among authors., (Copyright © 2020 Elsevier Masson SAS. All rights reserved.)

The Hyperpolarization-activated Cyclic Nucleotide-gated (HCN) channels are highly expressed in the Central Nervous Systems, where they are responsible for the I h current. Together with specific accessory proteins, these channels finely regulate neuronal excitability and discharge activity. In the last few years, a substantial body of evidence has been gathered showing that modifications of I h can play an important role in the pathogenesis of epilepsy. However, the extent to which HCN dysfunction is spread among the epileptic population is still unknown. The aim of this work is to evaluate the impact of genetic mutations potentially affecting the HCN channels' activity, using a NGS approach. We screened a large cohort of patients with epilepsy of unknown etiology for mutations in HCN1, HCN2 and HCN4 and in genes coding for accessory proteins (MiRP1, Filamin A, Caveolin-3, TRIP8b, Tamalin, S-SCAM and Mint2). We confirmed the presence of specific mutations of HCN genes affecting channel function and predisposing to the development of the disease. We also found several previously unreported additional genetic variants, whose contribution to the phenotype remains to be clarified. According to these results and data from literature, alteration of HCN1 channel function seems to play a major role in epilepsy, but also dysfunctional HCN2 and HCN4 channels can predispose to the development of the disease. Our findings suggest that inclusion of the genetic screening of HCN channels in diagnostic procedures of epileptic patients should be recommended. This would help pave the way for a better understanding of the role played by I h dysfunction in the pathogenesis of epilepsy., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Glucose transporter type 1 deficiency syndrome (Glut1 DS) is a rare neurological disorder caused by impaired glucose delivery to the brain. The clinical spectrum of Glut1 DS mainly includes epilepsy, paroxysmal dyskinesia (PD), developmental delay and microcephaly. Glut1 DS diagnosis is based on the identification of hypoglycorrhachia and pathogenic mutations of the SLC2A1 gene. Here, we report the molecular screening of SLC2A1 in 354 patients clinically suspected for Glut1 DS. From this cohort, we selected 245 patients for whom comprehensive clinical and laboratory data were available. Among them, we identified 19 patients carrying nucleotide variants of pathological significance, 5 of which were novel. The symptoms of onset, which varied from neonatal to adult age, included epilepsy, PD or non-epileptic paroxysmal manifestations. The comparison of the clinical features between the 19 SLC2A1 mutated and the 226 non-mutated patients revealed that the onset of epilepsy within the first year of life (when associated with developmental delay or other neurological manifestations), the association of epilepsy with PD and acquired microcephaly are more common in mutated subjects. Taken together, these data confirm the variability of expression of the phenotypes associated with mutation of SLC2A1 and provide useful clinical tools for the early identification of subjects highly suspected for the disease.

Mutations in the CDKL5 (cyclin-dependent kinase-like-5) gene are known to determine early-onset drug resistant epilepsies and severe cognitive impairment with absent language, hand stereotypies, and deceleration of head growth. Reflex seizures are epileptic events triggered by specific stimuli and diaper changing is a very rare triggering event, previously described in individual cases of both focal and unclassified epilepsy, as well as in Dravet syndrome. Our aim was to describe diaper changing-induced reflex seizures as one of the presenting features in a case of CDKL5-related epilepsy, providing video-EEG documentation and focusing discussion on hyperexcitability determined by the disease. [Published with video sequence on www.epilepticdisorders.com].

Background: Paroxysmal Kinesigenic Dyskinesia (PKD, OMIM 128200) is the most common type of autosomal dominant Paroxysmal Dyskinesias characterized by attacks of dystonia and choreoathetosis triggered by sudden movements. Recently PRRT2, encoding proline-rich transmembrane protein 2, has been described as the most frequent causative gene for PKD., Methods: We studied the incidence of PRRT2 mutations in a cohort of 16 PKD patients and their relatives for a total of 39 individuals., Results: We identify mutations in 10/16 patients and 23 relatives. In 27/33 the mutation was the c.insC649 p.Arg217Profs*8. In 6 individuals from 3 families we found three new mutations: c.insT27 p.Ser9*, c.G967A p.Gly323Arg and c.delCA215&#95;216 p.Thr72Argfs*62. Family history was positive in 9 patients. The mean age of onset was 10 years. Attacks lasted from a few seconds to 1 min and ranged from several per day to some per week, and were generalised in all patients. The main distinctive features of mutation-negative patients were the sporadic occurrence, the absence of association with epilepsy or EEG abnormalities and the poor response to Carbamazepine or other antiepileptic agents., Conclusions: We report the first cohort of Italian patients mutated in PRRT2 and we confirm that this is the most frequent gene involved in PKD., (Copyright © 2015 European Paediatric Neurology Society. Published by Elsevier Ltd. All rights reserved.)