Reciprocal chromosome translocation t(3;4)(q27;q31.2) with deletion of 3q27 and reduced FBXW7 expression in a patient with developmental delay, hypotonia, and seizures.

Reciprocal chromosomal translocation is one of genomic variations. When cytogenetically de novo reciprocal translocations are identified in patients with some clinical manifestations, the genes in the breakpoints are considered to be related to the clinical features. In this study, we encountered a patient with severe developmental delay, intractable epilepsy, growth failure, distinctive features, and skeletal manifestations.

A severe case of cardiospondylocarpofacial syndrome with a novel MAP3K7 variant.

Cardiospondylocarpofacial syndrome (CSCFS) is a congenital malformation characterized by growth retardation, facial features, short toes with carpal and tarsal fusion, extensive posterior neck vertebral fusion, congenital heart disease, and deafness. Here, we report a severe case of CSCFS with a novel variant, p.Thr187Ile, in MAP3K7.

Stretch-activated ion channel TMEM63B associates with developmental and epileptic encephalopathies and progressive neurodegeneration.

By converting physical forces into electrical signals or triggering intracellular cascades, stretch-activated ion channels allow the cell to respond to osmotic and mechanical stress. Knowledge of the pathophysiological mechanisms underlying associations of stretch-activated ion channels with human disease is limited. Here, we describe 17 unrelated individuals with severe early-onset developmental and epileptic encephalopathy (DEE), intellectual disability, and severe motor and cortical visual impairment associated with progressive neurodegenerative brain changes carrying ten distinct heterozygous variants of TMEM63B, encoding for a highly conserved stretch-activated ion channel.

The HCN1 p.Ser399Pro variant causes epileptic encephalopathy with super-refractory status epilepticus.

HCN1 is one of four genes encoding hyperpolarization-activated cyclic nucleotide-gated channels. The phenotypic spectrum associated with HCN1 variants ranges from neonatal developmental and epileptic encephalopathy to idiopathic generalized epilepsy. We report a Japanese patient with repetitive focal seizures and super-refractory status epilepticus since early infancy caused by a de novo HCN1 variant, NM_021072.

Two-year efficacy of lacosamide as adjunctive therapy for generalized tonic-clonic seizures in patients with juvenile myoclonic epilepsy.

Objective: To report the long-term efficacy of adjunctive lacosamide therapy in patients with juvenile myoclonic epilepsy whose generalized tonic-clonic seizures were significantly reduced by treatment.

Methods: A retrospective study was conducted in patients who visited the Department of Child Neurology, National Hospital Organization Nishiniigata Chuo Hospital and the Department of Pediatrics, National Hospital Organization Nagasaki Medical Center. Among patients who had been diagnosed with juvenile myoclonic epilepsy, those who received lacosamide as adjunctive therapy for refractory generalized tonic-clonic seizures for at least 2 years from January 2017 to December 2022, and who achieved seizure freedom or >50% seizure reduction in tonic-clonic seizures were included.

Molecular diagnosis of 405 individuals with autism spectrum disorder.

Autism spectrum disorder (ASD) is caused by combined genetic and environmental factors. Genetic heritability in ASD is estimated as 60-90%, and genetic investigations have revealed many monogenic factors. We analyzed 405 patients with ASD using family-based exome sequencing to detect disease-causing single-nucleotide variants (SNVs), small insertions and deletions (indels), and copy number variations (CNVs) for molecular diagnoses.

Clinical and electroencephalographic findings prior to the onset of juvenile myoclonic epilepsy: A case series.

The purpose of this study was to investigate the timing of generalized electroencephalographic abnormalities in patients with juvenile myoclonic epilepsy who were followed up long term before the onset of juvenile myoclonic epilepsy. We enrolled juvenile myoclonic epilepsy patients whose course of epilepsy had been observed for >5 years before the onset of juvenile myoclonic epilepsy, those who had undergone electroencephalogram recording more than twice before the onset of juvenile myoclonic epilepsy, and those who had terminated antiseizure medications for at least 2 years before the onset of juvenile myoclonic epilepsy. Patients who had transitioned from childhood absence epilepsy to juvenile myoclonic epilepsy were excluded.

An integrated genetic analysis of epileptogenic brain malformed lesions.

Focal cortical dysplasia is the most common malformation during cortical development, sometimes excised by epilepsy surgery and often caused by somatic variants of the mTOR pathway genes. In this study, we performed a genetic analysis of epileptogenic brain malformed lesions from 64 patients with focal cortical dysplasia, hemimegalencephy, brain tumors, or hippocampal sclerosis. Targeted sequencing, whole-exome sequencing, and single nucleotide polymorphism microarray detected four germline and 35 somatic variants, comprising three copy number variants and 36 single nucleotide variants and indels in 37 patients.

Genetic and clinical landscape of childhood cerebellar hypoplasia and atrophy.

Purpose: Cerebellar hypoplasia and atrophy (CBHA) in children is an extremely heterogeneous group of disorders, but few comprehensive genetic studies have been reported. Comprehensive genetic analysis of CBHA patients may help differentiating atrophy and hypoplasia and potentially improve their prognostic aspects.

Methods: Patients with CBHA in 176 families were genetically examined using exome sequencing.

Recurrence rates and risk factors for seizure recurrence following antiseizure medication withdrawal in adolescent patients with genetic generalized epilepsy.

Objective: This study aimed to identify the recurrence rate of genetic generalized epilepsy (GGE) and risk factors for recurrence after antiseizure medication (ASM) withdrawal in adolescent patients.

Methods: We retrospectively reviewed medical records of patients with GGE who were included in the registry at the Department of Child Neurology, National Hospital Organization Nishiniigata Chuo Hospital from 2000 through 2020. The eligibility criteria were as follows: onset of epileptic seizures at <15 years of age, treatment with an ASM, and attempted treatment withdrawal at 10-19 years of age.

Sirolimus for epileptic seizures associated with focal cortical dysplasia type II.

Objective: To determine whether sirolimus, a mechanistic target of rapamycin (mTOR) inhibitor, reduces epileptic seizures associated with focal cortical dysplasia (FCD) type II.

Methods: Sixteen patients (aged 6-57 years) with FCD type II received sirolimus at an initial dose of 1 or 2 mg/day based on body weight (FCDS-01). In 15 patients, the dose was adjusted to achieve target trough ranges of 5-15 ng/mL, followed by a 12-week maintenance therapy period.

Amelioration of a neurodevelopmental disorder by carbamazepine in a case having a gain-of-function GRIA3 variant.

GRIA3 at Xq25 encodes glutamate ionotropic receptor AMPA type 3 (GluA3), a subunit of postsynaptic glutamate-gated ion channels mediating neurotransmission. Hemizygous loss-of-function (LOF) variants in GRIA3 cause a neurodevelopmental disorder (NDD) in male individuals. Here, we report a gain-of-function (GOF) variant at GRIA3 in a male patient.

Different pharmacoresistance of focal epileptic spasms, generalized epileptic spasms, and generalized epileptic spasms combined with focal seizures.

Objective: Among standard treatments for infantile spasms, adrenocorticotropic hormone (ACTH) is reported as the best treatment, but ACTH is ineffective in one-half of the patients. To establish precision medicine, we examined pharmacoresistance of focal epileptic spasms (ES), generalized ES, and generalized ES combined with focal seizures, diagnosed based on the revised seizure classification of ILAE in 2017.

Methods: We conducted a retrospective nationwide study in Japan on the long-term seizure outcome of ES.

Thymic stromal lymphopoietin induces adipose loss through sebum hypersecretion.

Emerging studies indicate that the immune system can regulate systemic metabolism. Here, we show that thymic stromal lymphopoietin (TSLP) stimulates T cells to induce selective white adipose loss, which protects against obesity, improves glucose metabolism, and mitigates nonalcoholic steatohepatitis. Unexpectedly, adipose loss was not caused by alterations in food intake, absorption, or energy expenditure.

A Single-Arm Open-Label Clinical Trial on the Efficacy and Safety of Sirolimus for Epileptic Seizures Associated with Focal Cortical Dysplasia Type II: A Study Protocol.

Epileptic seizures are core symptoms in focal cortical dysplasia (FCD), a disease that often develops in infancy. Such seizures are refractory to conventional antiepileptic drugs (AED) and temporarily disappear in response to AED in only 17% of patients. Currently, surgical resection is an important option for the treatment of epileptic seizures in FCD.

Positive and negative effects of perampanel treatment on psychiatric and behavioral symptoms in adult patients with epilepsy.

Purposes: The purpose of the study was to investigate the positive and negative effects of perampanel (PER) treatment on the psychiatric and behavioral symptoms in patients with epilepsy and to evaluate factors associated with the psychiatric and behavioral changes caused by PER.

Methods: We retrospectively examined medical records of patients with epilepsy treated with PER in the Department of Psychiatry, Epilepsy Center, Nishiniigata Chuo National Hospital. Multiple regression analyses were performed with the psychiatric and behavioral prognoses as dependent variables and clinical characteristics of the patients as independent variables.

Differences in levetiracetam and perampanel treatment-related irritability in patients with epilepsy.

Purpose: The present study evaluated whether patients with epilepsy who received both levetiracetam (LEV) and perampanel (PER) therapy showed side effects of irritability. The study also examined the relationship between patient characteristics and irritability when it occurred as a side effect.

Methods: We retrospectively examined medical records of 98 patients with epilepsy who were treated with both LEV and PER at the Department of Psychiatry in the Epilepsy Center of Nishiniigata Chuo National Hospital in Japan.

Clinical manifestations and epilepsy treatment in Japanese patients with pathogenic CDKL5 variants.

Objective: Patients with pathogenic cyclin-dependent kinase-like-5 gene (CDKL5) variants are designated CDKL5 deficiency disorder (CDD). This study aimed to delineate the clinical characteristics of Japanese patients with CDD and elucidate possible appropriate treatments.

Methods: We recruited patients with pathogenic or likely pathogenic CDKL5 variants from a cohort of approximately 1,100 Japanese patients with developmental and epileptic encephalopathies, who underwent genetic analysis.

Polymicrogyria with calcification in Pallister-Killian syndrome detected by microarray analysis.

Background: Pallister-Killian syndrome (PKS) is a rare disorder caused by the mosaic tetrasomy of chromosome 12p, and is characterized by facial dysmorphism, developmental delay, hypotonia and seizures.

Results: We report a patient with PKS showing unique polymicrogyria with calcification. He had delayed development and dysmorphic facial features including frontal bossing, hypertelorism, and high arched palate at 6 months of age.