Mutation update for the SATB2 gene.

SATB2-associated syndrome (SAS) is an autosomal dominant neurodevelopmental disorder caused by alterations in the SATB2 gene. Here we present a review of published pathogenic variants in the SATB2 gene to date and report 38 novel alterations found in 57 additional previously unreported individuals. Overall, we present a compilation of 120 unique variants identified in 155 unrelated families ranging from single nucleotide coding variants to genomic rearrangements distributed throughout the entire coding region of SATB2. Single nucleotide variants predicted to result in the occurrence of a premature stop codon were the most commonly seen (51/120 = 42.5%) followed by missense variants (31/120 = 25.8%). We review the rather limited functional characterization of pathogenic variants and discuss current understanding of the consequences of the different molecular alterations. We present an expansive phenotypic review along with novel genotype-phenotype correlations. Lastly, we discuss current knowledge of animal models and present future prospects. This review should help provide better guidance for the care of individuals diagnosed with SAS.

Education Research: Quality and Validity Evidence for a National In-Training Examination for Epilepsy Fellows.

Background and Objectives: Epilepsy education has been transformed over the past 2 decades, leading to a need for structured formative assessment tools. The American Epilepsy Society developed the Epilepsy Fellowship In-Training Examination (EpiFITE) to provide high-quality formative assessment for fellows, to stimulate program improvement, and to guide future learning and teaching. The aim of this study was to explore validity evidence for the EpiFITE in meeting these goals. Methods: Validity evidence was sought from multiple sources. The content of the examination was linked to the American Board of Psychiatry and Neurology blueprint for initial certification in epilepsy, and items were developed by trained experts. Internal structure was studied using internal consistency and item analysis. Surveys of fellows and fellowship directors focused on the examination experience (response process) and how results influenced fellow assessment, future learning, and program improvement (relationship to other variables and consequences). Results: The EpiFITE was first administered in 2020, with 172 examinees from 67 programs. By 2022 (year 3), the EpiFITE was completed by 195 epilepsy fellows from 77 programs. The overall mean score of the examination was stable from year to year, and the committee predicted the difficulty of individual items with a high degree of accuracy. The examination had high internal consistency (Cronbach α 0.76-0.81). The median item discrimination index ranged from 0.17 in 2020 to 0.21 in 2022. Discrimination indices were lower (mean ≤0.10) for items that were either very easy or very difficult and significantly higher (mean >0.20) for other items. Program directors and epilepsy fellows agreed the examination questions were appropriate and agreed that the EpiFITE helped them identify areas for self-directed learning. Program directors also found the examination helpful in identifying areas of strength and areas for improvement within their programs. Discussion: There are several sources of evidence of the quality and validity of the EpiFITE. By exploring this validity evidence, we have identified several best practices in the development and evaluation of a subspecialty examination, and this experience could be helpful for developers of in-training examinations in other subspecialties.

Birth weight and order as risk factors for childhood central nervous system tumors.

OBJECTIVE: To determine whether birth characteristics related to maternal-fetal health in utero are associated with the development of childhood central nervous system tumors. STUDY DESIGN: We identified, from the California Cancer Registry, 3733 children under age 15 diagnosed with childhood central nervous system tumors between 1988 and 2006 and linked these cases to their California birth certificates. Four controls per case, matched on birth date and sex, were randomly selected from the same birth files. We evaluated associations of multiple childhood CNS tumor subtypes with birth weight and birth order. RESULTS: Low birth weight was associated with a reduced risk of low-grade gliomas (OR=0.67; 95% CI, 0.46 to 0.97) and high birth weight was associated with increased risk of high-grade gliomas (OR=1.57; 95% CI, 1.16 to 2.12). High birth order (fourth or higher) was associated with decreased risk of low-grade gliomas (OR=0.75; 95% CI, 0.56 to 0.99) and increased risk of high-grade gliomas (OR=1.32; 95% CI, 1.01 to 1.72 for second order). CONCLUSIONS: Factors that drive growth in utero may increase the risk of low-grade gliomas. There may be a similar relationship in high-grade gliomas, although other factors, such as early infection, may modify this association. Additional investigation is warranted to validate and further define these findings.

Epilepsy and Electroencephalographic Abnormalities in SATB2-Associated Syndrome.

BACKGROUND: Seizures are an under-reported feature of the SATB2-associated syndrome phenotype. We describe the electroencephalographic findings and seizure semiology and treatment in a population of individuals with SATB2-associated syndrome. METHODS: We performed a retrospective review of 101 individuals with SATB2-associated syndrome who were reported to have had a previous electroencephalographic study to identify those who had at least one reported abnormal result. For completeness, a supplemental survey was distributed to the caregivers and input from the treating neurologist was obtained whenever possible. RESULTS: Forty-one subjects were identified as having at least one prior abnormal electroencephalography. Thirty-eight individuals (93%) had epileptiform discharges, 28 (74%) with central localization. Sleep stages were included as part of the electroencephalographies performed in 31 individuals (76%), and epileptiform activity was recorded during sleep in all instances (100%). Definite clinical seizures were diagnosed in 17 individuals (42%) with a mean age of onset of 3.2 years (four months to six years), and focal seizures were the most common type of seizure observed (42%). Six subjects with definite clinical seizures needed polytherapy (35%). Delayed myelination and/or abnormal white matter hyperintensities were seen on neuroimaging in 19 individuals (61%). CONCLUSIONS: Epileptiform abnormalities are commonly seen in individuals with SATB2-associated syndrome. A baseline electroencephalography that preferably includes sleep stages is recommended during the initial evaluation of all individuals with SATB2-associated syndrome, regardless of clinical suspicion of epilepsy.

Cannabidiol in patients with treatment-resistant epilepsy: an open-label interventional trial.

BACKGROUND: Almost a third of patients with epilepsy have a treatment-resistant form, which is associated with severe morbidity and increased mortality. Cannabis-based treatments for epilepsy have generated much interest, but scientific data are scarce. We aimed to establish whether addition of cannabidiol to existing anti-epileptic regimens would be safe, tolerated, and efficacious in children and young adults with treatment-resistant epilepsy. METHODS: In this open-label trial, patients (aged 1-30 years) with severe, intractable, childhood-onset, treatment-resistant epilepsy, who were receiving stable doses of antiepileptic drugs before study entry, were enrolled in an expanded-access programme at 11 epilepsy centres across the USA. Patients were given oral cannabidiol at 2-5 mg/kg per day, up-titrated until intolerance or to a maximum dose of 25 mg/kg or 50 mg/kg per day (dependent on study site). The primary objective was to establish the safety and tolerability of cannabidiol and the primary efficacy endpoint was median percentage change in the mean monthly frequency of motor seizures at 12 weeks. The efficacy analysis was by modified intention to treat. Comparisons of the percentage change in frequency of motor seizures were done with a Mann-Whitney U test. RESULTS: Between Jan 15, 2014, and Jan 15, 2015, 214 patients were enrolled; 162 (76%) patients who had at least 12 weeks of follow-up after the first dose of cannabidiol were included in the safety and tolerability analysis, and 137 (64%) patients were included in the efficacy analysis. In the safety group, 33 (20%) patients had Dravet syndrome and 31 (19%) patients had Lennox-Gastaut syndrome. The remaining patients had intractable epilepsies of different causes and type. Adverse events were reported in 128 (79%) of the 162 patients within the safety group. Adverse events reported in more than 10% of patients were somnolence (n=41 [25%]), decreased appetite (n=31 [19%]), diarrhoea (n=31 [19%]), fatigue (n=21 [13%]), and convulsion (n=18 [11%]). Five (3%) patients discontinued treatment because of an adverse event. Serious adverse events were reported in 48 (30%) patients, including one death-a sudden unexpected death in epilepsy regarded as unrelated to study drug. 20 (12%) patients had severe adverse events possibly related to cannabidiol use, the most common of which was status epilepticus (n=9 [6%]). The median monthly frequency of motor seizures was 30.0 (IQR 11.0-96.0) at baseline and 15.8 (5.6-57.6) over the 12 week treatment period. The median reduction in monthly motor seizures was 36.5% (IQR 0-64.7). INTERPRETATION: Our findings suggest that cannabidiol might reduce seizure frequency and might have an adequate safety profile in children and young adults with highly treatment-resistant epilepsy. Randomised controlled trials are warranted to characterise the safety profile and true efficacy of this compound. FUNDING: GW Pharmaceuticals, Epilepsy Therapy Project of the Epilepsy Foundation, Finding A Cure for Epilepsy and Seizures.

Birth anomalies and obstetric history as risks for childhood tumors of the central nervous system.

OBJECTIVE: The causes of childhood central nervous system (CNS) tumors are largely unknown. Birth characteristics have been examined as possible risk factors for childhood CNS tumors, although the studies have been underpowered and inconclusive. We hypothesized that birth anomalies and a mother's history of previous pregnancy losses, as a proxy for genetic defects, increase the risk for CNS tumors. METHODS: From the California Cancer Registry, we identified 3733 patients aged 0 to 14 years with CNS tumors, diagnosed from 1988 through 2006 and linked to a California birth certificate. Four controls were matched to each patient. We calculated odds ratios (ORs) for the reported presence of a birth defect and for history of pregnancy losses by using logistic regression, adjusted for race, Hispanic ethnicity, maternal age, birth weight, and birth order. RESULTS: Offspring from mothers who had ≥ 2 fetal losses after 20 weeks' gestation had a threefold risk for CNS tumors (OR: 3.13 [95% confidence interval (CI): 1.32-7.41]) and a 14-fold risk for high-grade glioma (OR: 14.28 [95% CI: 1.56-130.65]). Birth defects increased risk for the CNS cancers medulloblastoma (OR: 1.70 [95% CI: 1.12-2.57]), primitive neuroectodermal tumor (OR: 3.64 [95% CI: 1.54-8.56]), and germ cell tumors (OR: 6.40 [95% CI: 2.09-19.56]). CONCLUSIONS: Multiple pregnancy losses after 20 weeks' gestation and birth defects increase the risk of a childhood CNS tumor. Previous pregnancy losses and birth defects may be surrogate markers for gene defects in developmental pathways that lead to CNS tumorigenesis.