Familial Epilepsy Research Articles

Mosaic and non-mosaic protocadherin 19 mutation leads to neuronal hyperexcitability in zebrafish

Epilepsy is one of the most common neurological disorders. The X-linked gene PCDH19 is associated with sporadic and familial epilepsy in humans, typically with early-onset clustering seizures and intellectual disability in females but not in so-called ‘carrier’ males, suggesting that mosaic PCDH19 expression is required to produce epilepsy. To characterize the role of loss of PCDH19 function in epilepsy, we generated zebrafish with truncating pcdh19 variants. Evaluating zebrafish larvae for electrophysiological abnormalities, we observed hyperexcitability phenotypes in both mosaic and non-mosaic pcdh19+/− and pcdh19−/− mutant larvae. Thus, we demonstrate that the key feature of epilepsy—network hyperexcitability—can be modeled effectively in zebrafish, even though overt spontaneous seizure-like swim patterns were not observed. Further, zebrafish with non-mosaic pcdh19 mutation displayed reduced numbers of inhibitory interneurons suggesting a potential cellular basis for the observed hyperexcitability. Our findings in both mosaic and non-mosaic pcdh19 mutant zebrafish challenge the prevailing theory that mosaicism governs all PCDH19-related phenotypes and point to interneuron-mediated mechanisms underlying these phenotypes.

TBC1D24-related familial infantile multifocal myoclonus: Description of a new Chinese pedigree with a 20 year follow up

IntroductionDisorders associated with mutations in the Tre2/Bub2/Cdc16 (TBC)1 domain family member 24 gene (TBC1D24) present a wide range of phenotypes, ranging from mild to fatal seizure diseases, non-syndromic deafness, and complex syndromes such as deafness, onychodystrophy, osteodystrophy, and mental retardation(DOOR syndrome). In this study, we introduce three siblings of a previously unreported Chinese family with familial infantile myoclonic epilepsy caused by a homozygous TBC1D24 mutation. MethodsGenomic DNA was extracted from whole blood of the proband, his parents, and sisters. TBC1D24 exomes were sequenced by whole exome sequencing then analyzed by genetic analysis with Sanger sequencing validation. The patients were followed up for more than 20 years to summarize their clinical features. ResultsGenetic analysis identified a homozygous TBC1D24 mutation (c.241_252del12) in the proband and his sisters. Prediction models suggest that the mutation leads to an alteration in the properties and structure of the TBC1D24 protein, especially in the folding direction of the loop region, which is likely to decrease protein activity. The patients manifested with early-onset myoclonic epilepsy, were prone to status epilepticus, and seizures only occurred during wakefulness. Imaging characteristics included cerebellar atrophy and abnormal cerebellar signals. ConclusionWe report a pedigree case of infantile myoclonic epilepsy caused by a homozygous TBC1D24 mutation. Our long-term clinical follow-up not only enriches the clinical phenotype of the disease, but also provides a clinical experience for the early diagnosis and clinical treatment of the disease.

Genetic Epilepsy Syndromes.

This article reviews the clinical features, typical EEG findings, treatment, prognosis, and underlying molecular etiologies of the more common genetic epilepsy syndromes. Genetic generalized epilepsy, self-limited focal epilepsy of childhood, self-limited neonatal and infantile epilepsy, select developmental and epileptic encephalopathies, progressive myoclonus epilepsies, sleep-related hypermotor epilepsy, photosensitive occipital lobe epilepsy, and focal epilepsy with auditory features are discussed. Also reviewed are two familial epilepsy syndromes: genetic epilepsy with febrile seizures plus and familial focal epilepsy with variable foci. Recent years have seen considerable advances in our understanding of the genetic factors underlying genetic epilepsy syndromes. New therapies are emerging for some of these conditions; in some cases, these precision medicine approaches may dramatically improve the prognosis. Many recognizable genetic epilepsy syndromes exist, the identification of which is a crucial skill for neurologists, particularly those who work with children. Proper diagnosis of the electroclinical syndrome allows for appropriate treatment choices and counseling regarding prognosis and possible comorbidities.

Arrhythmia prevalence and sudden death risk in adults with the m.3243A>G mitochondrial disorder

AimsTo define the prevalence of non-sustained tachyarrhythmias and bradyarrhythmias in patients with the m.3243A>G mitochondrial genotype and a previously defined, profile, associated with ‘high sudden-death risk’.Methods and resultsPatients at high...

ILAE Genetic Literacy Series: familial focal epilepsy syndromes.

There are a number of familial focal epilepsy syndromes, each with distinct clinical characteristics. Here, we review the epilepsy phenotypes and the genetic architecture of these syndromes. Using an illustrative clinical case, we describe the important steps in making a diagnosis and ordering appropriate genetic tests. Our discussion on the genetics of the familial focal epilepsies will provide a framework for interpreting the results of genetic testing, and allow us to apply this information to patient management.

SCN2A-Related Epilepsy: The Phenotypic Spectrum, Treatment and Prognosis.

ObjectiveThe aim of this study was to analyze the phenotypic spectrum, treatment, and prognosis of 72 Chinese children with SCN2A variants.MethodsThe SCN2A variants were detected by next-generation sequencing. All patients were followed up at a pediatric neurology clinic in our hospital or by telephone.ResultsIn 72 patients with SCN2A variants, the seizure onset age ranged from the first day of life to 2 years and 6 months. The epilepsy phenotypes included febrile seizures (plus) (n = 2), benign (familial) infantile epilepsy (n = 9), benign familial neonatal-infantile epilepsy (n = 3), benign neonatal epilepsy (n = 1), West syndrome (n = 16), Ohtahara syndrome (n = 15), epilepsy of infancy with migrating focal seizures (n = 2), Dravet syndrome (n = 1), early infantile epileptic encephalopathy (n = 15), and unclassifiable developmental and epileptic encephalopathy (n = 8). Approximately 79.2% (57/72) patients had varying degrees of developmental delay. All patients had abnormal MRI findings with developmental delay. 91.7% (55/60) patients with de novo SCN2A variants had development delay, while only 16.7% (2/12) patients with inherited SCN2A variants had abnormal development. 83.9% (26/31) SCN2A variants that were located in transmembrane regions of the protein were detected in patients with development delay. Approximately 69.2% (9/13) SCN2A variants detected in patients with normal development were located in the non-transmembrane regions. Approximately 54.2% (39/72) patients were seizure-free at a median age of 8 months. Oxcarbazepine has been used by 38 patients, and seizure-free was observed in 11 of them (11/38, 28.9%), while 6 patients had seizure worsening by oxcarbazepine. All 3 patients used oxcarbazepine and with seizure onset age > 1 year presented seizure exacerbation after taking oxcarbazepine. Valproate has been used by 53 patients, seizure-free was observed in 22.6% (12/53) of them.ConclusionThe phenotypic spectrum of SCN2A-related epilepsy was broad, ranging from benign epilepsy in neonate and infancy to severe epileptic encephalopathy. Oxcarbazepine and valproate were the most effective drugs in epilepsy patients with SCN2A variants. Sodium channel blockers often worsen seizures in patients with seizure onset beyond 1 year of age. Abnormal brain MRI findings and de novo variations were often related to poor prognosis. Most SCN2A variants located in transmembrane regions were related to patients with developmental delay.

Characteristics of infantile convulsions and choreoathetosis syndrome caused by PRRT2 mutation.

ABSTRACTImportanceInfantile convulsions and choreoathetosis (ICCA) is a rare neurological disorder. Many affected patients are either misdiagnosed or prescribed multiple antiepileptic drugs.ObjectiveTo explore therapeutic drug treatments and dosages for ICCA in children.MethodsDetailed clinical features (e.g., past medical history and family history), genetic features, and treatment outcomes were collected from the records of six patients with ICCA.ResultsMean age at paroxysmal kinesigenic dyskinesia (PKD) onset was 8 years 8 months (range, 3–12 years); the clinical presentation was characterized by daily short paroxysmal episodes of dystonia/dyskinesia. All patients had infantile convulsions at less than 1 year of age, and the mean onset age was 5.5 months (range, 4–7 months). Two patients had a family history of ICCA, PKD, or benign familial infantile epilepsy. Whole exome sequencing identified the c.649–650insC mutation in PRRT2 in six patients; three mutations were inherited and three were de novo. All patients were prescribed low‐dose carbamazepine and showed dramatic improvement with the complete disappearance of dyskinetic episodes after 3 days. They attended follow‐up for 5–17 months and were attack‐free until the final follow‐up.Interpretation PRRT2 mutations are the primary cause of ICCA. Low‐dose carbamazepine monotherapy is effective and well‐tolerated in children.

The Mediating Roles of Family Resilience and Social Support in the Relationship Between Illness Severity and Depressive Symptoms Among Primary Caregivers of Children With Epilepsy in China.

PurposeThis study was designed to assess the effects of epilepsy severity, family resilience, and social support on depression in primary caregivers of children with epilepsy (CWE), and to test the mediating roles of family resilience and social support in this relationship.MethodTwo hundred fifty-two caregivers of children with epilepsy were recruited from October 2020 to May 2021. The questionnaire contained sociodemographic characteristics, Epilepsy Severity, Chinese-Family Resilience Assessment Scale (C-FRAS), Social Support Rating Scale (SSRS), Beck Depression Inventory (BDI). Structural equation models were used to evaluate whether family resilience and social support as mediators between epilepsy severity and depression.ResultsIn this study, the prevalence of depressive symptoms among primary caregivers of CWE in China was 69.84%. Epilepsy severity was positively associated with depression. Family resilience and social support were negatively correlated with depressive symptoms (both p < 0.01). Furthermore, the fitness indices of structural models were satisfactory. The direct effect of epilepsy severity on depression was 0.266 (95% CI 0.064–0.458), this pathway explained 62.88% variance of depression. The indirect effect of family resilience and then social support was 0.069 (95% CI 0.025–0.176), indicating that the serial multiple mediation was significant. The serial mediation pathway explained 16.31% variance of depression.ConclusionsThe high incidence of depression among primary carers of CWE deserves more attention. They should be screened routinely, especially those parents of children with severe epilepsy. Family resilience and social support could be protective factors for caregivers' mental adjustment. Therefore, future psychosocial interventions for enhancing family resilience and social support should be implemented, in order to reduce their depression.

NPRL2 Inhibition of mTORC1 Controls Sodium Channel Expression and Brain Amino Acid Homeostasis.

Genetic mutations in nitrogen permease regulator-like 2 (NPRL2) are associated with a wide spectrum of familial focal epilepsies, autism, and sudden unexpected death of epileptics (SUDEP), but the mechanisms by which NPRL2 contributes to these effects are not well known. NPRL2 is a requisite subunit of the GAP activity toward Rags 1 (GATOR1) complex, which functions as a negative regulator of mammalian target of rapamycin complex 1 (mTORC1) kinase when intracellular amino acids are low. Here, we show that loss of NPRL2 expression in mouse excitatory glutamatergic neurons causes seizures before death, consistent with SUDEP in humans with epilepsy. Additionally, the absence of NPRL2 expression increases mTORC1-dependent signal transduction and significantly alters amino acid homeostasis in the brain. Loss of NPRL2 reduces dendritic branching and increases the strength of electrically stimulated action potentials (APs) in neurons. The increased AP strength is consistent with elevated expression of epilepsy-linked, voltage-gated sodium channels in the NPRL2-deficient brain. Targeted deletion of NPRL2 in primary neurons increases the expression of sodium channel Scn1A, whereas treatment with the pharmacological mTORC1 inhibitor called rapamycin prevents Scn1A upregulation. These studies demonstrate a novel role of NPRL2 and mTORC1 signaling in the regulation of sodium channels, which can contribute to seizures and early lethality.

Cannabidiol differentially modulates Kv7 channelopathy-related phenotypes

Mutations in members of voltage-gated potassium channel family 7 (Kv7) modify electrophysiological properties and cause distinct clinical presentations. Mutations of the M-channel (Kv7.2/3 heterotetramer) underlying the neuronal M-current cause benign familial neonatal epilepsy (BFNE). Mutations in the Kv7.1 or KCNE1 subunit of the Kv7.1/KCNE1 heteromultimer underlying the ventricular repolarization current IKS cause Long-(L)QT-syndrome. The phytocannabinoid cannabidiol (CBD) is an FDA-approved anticonvulsant.

Biophysical and molecular studies of an epilepsy related single-point mutant in the S4-S5 linker of the kv7.3 subunit of M-channel

Benign familial neonatal epilepsy (BFNE) is a form of childhood epilepsy, occurring along the first days of life, and can be prolonged for months and in some cases even for years. Many forms of BFNE are associated to mutations in a type of slowly opening and closing voltage-dependent potassium channel called the “M-channel”. The M-channel is a hetero-tetramer containing two different members of the Kv7 family: Kv7.2/Kv7.3 or Kv7.3/Kv7.5. It plays an important role in setting the membrane resting potential in sympathetic neurons, but it is also expressed widely in the brain.

Collagenase and the Treatment of Dupuytren Contracture: Efficacy of Treatment and Patient Satisfaction.

Background: Collagenase clostridium histolyticum has become a widely used treatment in the management of Dupuytren disease. The aims of this study are to assess the immediate success of treatment of Dupuytren contracture with collagenase injection, to measure long-term patient-rated outcomes, to determine whether the risk factors for the disease impacted outcomes and to report complications of collagenase treatment. Methods: A prospective study was performed in a tertiary referral centre. Measurements were recorded pre-treatment, day 1 and day 90. Patient-rated outcome scores were measured using Disability of the Arm, Shoulder and Hand questionnaire (DASH) and the Michigan Hand Questionnaire (MHQ) at minimum 36 months post-injection. Results: The study included 45 patients with 53 hands with a mean age of 65.7 years. The treatment was successful in 62% of patients with the greatest improvement in the metacarpal-phalangeal joint of the little finger. Diabetes, epilepsy, gender, alcohol intake and positive family history had no statistically significant predictive value on successful outcomes. Patient satisfaction at 41 months was high with mean MHQ score of 97.3. Conclusions: Collagenase is effective in the treatment of Dupuytren contracture, with disease involving the little finger showing the greatest benefit. Risk factors for development of Dupuytren disease had no effect on successful outcome and long-term satisfaction rates are high. Level of Evidence: Level III (Therapeutic).

Familial adult myoclonic epilepsy (FAME): clinical features, molecular characteristics, pathophysiological aspects and diagnostic work-up.

Familial adult myoclonic epilepsy (FAME) is a rare autosomal dominant disorder characterized by myoclonus and seizures. The genetic variant underlying FAME is an intronic repeat expansion composed of two different pentamers: an expanded TTTTA, which is the motif originally present at the locus, and an insertion of TTTCA repeats, which is usually located at the 3' end and likely corresponds to the pathogenic part of the expansion. This repeat expansion has been identified so far in six genes located on different chromosomes, which remarkably encode proteins with distinct cellular localizations and functions. Although the exact pathophysiological mechanisms remain to be clarified, it is likely that FAME repeat expansions lead to disease independently of the gene where they occur. We herein review the clinical and molecular characteristics of this singular genetic disorder, which interestingly shares clinical features with other more common neurological disorders whose etiology remains mainly unsolved.

Abnormal sensorimotor cortex and thalamo-cortical networks in familial adult myoclonic epilepsy type 2: pathophysiology and diagnostic implications.

Familial adult myoclonic epilepsy type 2 is a hereditary condition characterized by cortical tremor, myoclonus and epilepsy. It belongs to the spectrum of cortical myoclonus and the sensorimotor cortex hyperexcitability represents an important pathogenic mechanism underlying this condition. Besides pericentral cortical structures, the impairment of subcortical networks seems also to play a pathogenetic role, mainly via the thalamo-cortical pathway. However, the mechanisms underlying cortical–subcortical circuits dysfunction, as well as their impact on clinical manifestations, are still unknown. Therefore, the main aims of our study were to systematically study with an extensive electrophysiological battery, the cortical sensorimotor, as well as thalamo-cortical networks in genetically confirmed familial adult myoclonic epilepsy patients and to establish reliable neurophysiological biomarkers for the diagnosis.In 26 familial myoclonic epilepsy subjects, harbouring the intronic ATTTC repeat expansion in the StAR-related lipid transfer domain-containing 7 gene, 17 juvenile myoclonic epilepsy patients and 22 healthy controls, we evaluated the facilitatory and inhibitory circuits within the primary motor cortex using single and paired-pulse transcranial magnetic stimulation paradigms. We also probed the excitability of the somatosensory, as well as the thalamo-somatosensory cortex connection by using ad hoc somatosensory evoked potential protocols. The sensitivity and specificity of transcranial magnetic stimulation and somatosensory evoked potential metrics were derived from receiver operating curve analysis. Familial adult myoclonic epilepsy patients displayed increased facilitation and decreased inhibition within the sensorimotor cortex compared with juvenile myoclonic epilepsy patients (all P < 0.05) and healthy controls (all P < 0.05). Somatosensory evoked potential protocols also displayed a significant reduction of early high-frequency oscillations and less inhibition at paired-pulse protocol, suggesting a concomitant failure of thalamo-somatosensory cortex circuits. Disease onset and duration and myoclonus severity did not correlate either with sensorimotor hyperexcitability or thalamo-cortical measures (all P > 0.05). Patients with a longer disease duration had more severe myoclonus (r = 0.467, P = 0.02) associated with a lower frequency (r = −0.607, P = 0.001) and higher power of tremor (r = 0.479, P = 0.02). Finally, familial adult myoclonic epilepsy was reliably diagnosed using transcranial magnetic stimulation, demonstrating its superiority as a diagnostic factor compared to somatosensory evoked potential measures. In conclusion, deficits of sensorimotor cortical and thalamo-cortical circuits are involved in the pathophysiology of familial adult myoclonic epilepsy even if these alterations are not associated with clinical severity. Transcranial magnetic stimulation-based measurements display an overall higher accuracy than somatosensory evoked potential parameters to reliably distinguish familial adult myoclonic epilepsy from juvenile myoclonic epilepsy and healthy controls.

Generation of a human iPSC line CIPi001-A from a benign familial infantile epilepsy patient related 16p11.2 deletion

The features of 16p11.2 deletion phenotype is developmental delay, intellectual disability, and autism spectrum disorder. Seizures are observed in approximately 20% of individuals with the microdeletion. Induced pluripotent stem cells (iPSCs) were generated from erythroblasts obtained from a child diagnosed with benign familial infantile epilepsy, caused by 16p11.2 deletion. These iPSCs exhibited stable amplification, expressed pluripotent markers, and differentiated spontaneously into three germ layers in vitro.

The L1624Q Variant in SCN1A Causes Familial Epilepsy Through a Mixed Gain and Loss of Channel Function.

Variants of the SCN1A gene encoding the neuronal voltage-gated sodium channel NaV1.1 cause over 85% of all cases of Dravet syndrome, a severe and often pharmacoresistent epileptic encephalopathy with mostly infantile onset. But with the increased availability of genetic testing for patients with epilepsy, variants in SCN1A have now also been described in a range of other epilepsy phenotypes. The vast majority of these epilepsy-associated variants are de novo, and most are either nonsense variants that truncate the channel or missense variants that are presumed to cause loss of channel function. However, biophysical analysis has revealed a significant subset of missense mutations that result in increased excitability, further complicating approaches to precision pharmacotherapy for patients with SCN1A variants and epilepsy. We describe clinical and biophysical data of a familial SCN1A variant encoding the NaV1.1 L1624Q mutant. This substitution is located on the extracellular linker between S3 and S4 of Domain IV of NaV1.1 and is a rare case of a familial SCN1A variant causing an autosomal dominant frontal lobe epilepsy. We expressed wild-type (WT) and L1642Q channels in CHO cells. Using patch-clamp to characterize channel properties at several temperatures, we show that the L1624Q variant increases persistent current, accelerates fast inactivation onset and decreases current density. While SCN1A-associated epilepsy is typically considered a loss-of-function disease, our results put L1624Q into a growing set of mixed gain and loss-of-function variants in SCN1A responsible for epilepsy.

Penetrance estimation of PRRT2 variants in paroxysmal kinesigenic dyskinesia and infantile convulsions.

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.

Activation of SGK1.1 Upregulates the M-current in the Presence of Epilepsy Mutations.

In the central nervous system, the M-current plays a critical role in regulating subthreshold electrical excitability of neurons, determining their firing properties and responsiveness to synaptic input. The M-channel is mainly formed by subunits Kv7.2 and Kv7.3 that co-assemble to form a heterotetrametric channel. Mutations in Kv7.2 and Kv7.3 are associated with hyperexcitability phenotypes including benign familial neonatal epilepsy (BFNE) and neonatal epileptic encephalopathy (NEE). SGK1.1, the neuronal isoform of the serum and glucocorticoids-regulated kinase 1 (SGK1), increases M-current density in neurons, leading to reduced excitability and protection against seizures. Herein, using two-electrode voltage clamp on Xenopus laevis oocytes, we demonstrate that SGK1.1 selectively activates heteromeric Kv7 subunit combinations underlying the M-current. Importantly, activated SGK1.1 increases M-channel activity in the presence of two different epilepsy mutations found in Kv7.2, R207W and A306T. In addition, proximity ligation assays in the N2a cell line allowed us to address the effect of these mutations on Kv7-SGK1.1-Nedd4 molecular associations, a proposed pathway underlying augmentation of M-channel activity by SGK1.1

A Novel Loss-of-Function Mutation in the NPRL3 Gene Identified in Chinese Familial Focal Epilepsy with Variable Foci.

Familial focal epilepsy with variable foci is an autosomal dominant disorder characterized by partial epilepsy with variable foci. In this study, we report a six-generation with segregation of the mutation present in four generations Chinese family presenting with focal epilepsy with variable foci. Whole exome sequencing confirms a novel pathogenic mutation in the NPRL3 gene (c316C>T; p. Q106*). PCR, Western blotting, and immunohistochemistry were conducted to analyze the gene transcription, protein expression, and subcellular localization of NPRL3 and related signaling molecules in peripheral blood cells from family members. As compared with healthy family members, both mRNA level and protein expression of NPRL3 are decreased in peripheral blood cells of the mutation carrier. In addition, the expression of downstream molecular Phospho-p70 S6 kinase (P-s6k) are increased consequently. Our findings expand the genotypic and phenotypic spectrum of the NPRL3-associated epilepsy and reveal the mechanisms of mTOR pathway signaling and GATOR1 pathogenesis in focal epilepsies, providing exciting potential for future diagnostic and therapeutic interventions. However, further in vitro and animal experiments are still needed to evaluate the role of NPRL3 loss-of-function mutation in epileptogensis.

Bilateral Representation of Sensorimotor Responses in Benign Adult Familial Myoclonus Epilepsy: An MEG Study.

Patients with cortical reflex myoclonus manifest typical neurophysiologic characteristics due to primary sensorimotor cortex (S1/M1) hyperexcitability, namely, contralateral giant somatosensory-evoked potentials/fields and a C-reflex (CR) in the stimulated arm. Some patients show a CR in both arms in response to unilateral stimulation, with about 10-ms delay in the non-stimulated compared with the stimulated arm. This bilateral C-reflex (BCR) may reflect strong involvement of bilateral S1/M1. However, the significance and exact pathophysiology of BCR within 50 ms are yet to be established because it is difficult to identify a true ipsilateral response in the presence of the giant component in the contralateral hemisphere. We hypothesized that in patients with BCR, bilateral S1/M1 activity will be detected using MEG source localization and interhemispheric connectivity will be stronger than in healthy controls (HCs) between S1/M1 cortices. We recruited five patients with cortical reflex myoclonus with BCR and 15 HCs. All patients had benign adult familial myoclonus epilepsy. The median nerve was electrically stimulated unilaterally. Ipsilateral activity was investigated in functional regions of interest that were determined by the N20m response to contralateral stimulation. Functional connectivity was investigated using weighted phase-lag index (wPLI) in the time-frequency window of 30–50 ms and 30–100 Hz. Among seven of the 10 arms of the patients who showed BCR, the average onset-to-onset delay between the stimulated and the non-stimulated arm was 8.4 ms. Ipsilateral S1/M1 activity was prominent in patients. The average time difference between bilateral cortical activities was 9.4 ms. The average wPLI was significantly higher in the patients compared with HCs in specific cortico-cortical connections. These connections included precentral-precentral, postcentral-precentral, inferior parietal (IP)-precentral, and IP-postcentral cortices interhemispherically (contralateral region-ipsilateral region), and precentral-IP and postcentral-IP intrahemispherically (contralateral region-contralateral region). The ipsilateral response in patients with BCR may be a pathologically enhanced motor response homologous to the giant component, which was too weak to be reliably detected in HCs. Bilateral representation of sensorimotor responses is associated with disinhibition of the transcallosal inhibitory pathway within homologous motor cortices, which is mediated by the IP. IP may play a role in suppressing the inappropriate movements seen in cortical myoclonus.