GABRA1-Related Disorders: From Genetic to Functional Pathways.

OBJECTIVE: Variants in GABRA1 have been associated with a broad epilepsy spectrum, ranging from genetic generalized epilepsies to developmental and epileptic encephalopathies. However, our understanding of what determines the phenotype severity and best treatment options remains inadequate. We therefore aimed to analyze the electroclinical features and the functional effects of GABRA1 variants to establish genotype-phenotype correlations. METHODS: Genetic and electroclinical data of 27 individuals (22 unrelated and 2 families) harboring 20 different GABRA1 variants were collected and accompanied by functional analysis of 19 variants. RESULTS: Individuals in this cohort could be assigned into different clinical subgroups based on the functional effect of their variant and its structural position within the GABRA1 subunit. A homogenous phenotype with mild cognitive impairment and infantile onset epilepsy (focal seizures, fever sensitivity, and electroencephalographic posterior epileptiform discharges) was described for variants in the extracellular domain and the small transmembrane loops. These variants displayed loss-of-function (LoF) effects, and the patients generally had a favorable outcome. A more severe phenotype was associated with variants in the pore-forming transmembrane helices. These variants displayed either gain-of-function (GoF) or LoF effects. GoF variants were associated with severe early onset neurodevelopmental disorders, including early infantile developmental and epileptic encephalopathy. INTERPRETATION: Our data expand the genetic and phenotypic spectrum of GABRA1 epilepsies and permit delineation of specific subphenotypes for LoF and GoF variants, through the heterogeneity of phenotypes and variants. Generally, variants in the transmembrane helices cause more severe phenotypes, in particular GoF variants. These findings establish the basis for a better understanding of the pathomechanism and a precision medicine approach in GABRA1-related disorders. Further studies in larger populations are needed to provide a conclusive genotype-phenotype correlation. ANN NEUROL 2023.

Short- vs long-term assessment of heart rate variability: Clinical significance in Dravet Syndrome.

PURPOSE: Heart rate variability (HRV) is a promising prognostic biomarker in Dravet Syndrome (DS), but different studies are not always comparable, limiting its clinical application. In fact, multiple HRV parameters, analyzed over different timescales and in different states are reported. The aim of this study was to assess which HRV parameter is more reproducible and clinically significant, analyzing differences between wake and sleep. METHOD: Patients with DS, with available 24 h-ECG Holter-derived HRV, were screened to evaluate if they had EEG-derived ECG traces available within one month before/after the Holter. A 5-minute period in the awake and sleep state were analyzed and correlated with the 24 h-HRV. Several relevant clinical features such as age, a recent history of status epilepticus (SE), and frequent generalized tonic-clonic seizures (GTCS) were correlated to HRV parameters with multiple linear regression models. RESULTS: Thirty-oneawake recordings and 22 sleep recordings were included. HF was the parameter with the highest correlation in awake (Rho 0.745, p < 0.001) and in sleep (Rho 0.727, p < 0.001). Age was a significant factor in simple models for most of the parameters except RMSSD. A recent history of SE was associated with a significant reduction of HRV, both in simple and multiple regressions for all parameters except for awake LF and for sleep RMSSD and PNN50. Frequent GTCS were associated with a significant decrease in sleep RMSSD, HF, and LF, also when correcting for the effect of age and history of SE. When compared pairwise, a significant increase in sleep was seen for HF (median + 24.45 ms2, IQR -7.51/+172.18 ms2, p = 0.036; increase in 15/22 patients). CONCLUSION: A moderate degree of correlation between long- and short-term HRV was seen both in sleep and in awake, and a strong correlation for awake HF. HF, both in awake and sleep, was significantly associated with high seizure burden, including SE and frequent GTCS.

Infantile epileptic spasms syndrome in children with cardiofaciocutanous syndrome: Clinical presentation and associations with genotype.

Gene variants that dysregulate signaling through the RAS-MAPK pathway cause cardiofaciocutaneous syndrome (CFCS), a rare multi-system disorder. Infantile epileptic spasms syndrome (IESS) and other forms of epilepsy are among the most serious complications. To investigate clinical presentation, treatment outcomes, and genotype-phenotype associations in CFCS patients with IESS, molecular genetics and clinical neurological history were reviewed across two large clinical research cohorts (n = 180). IESS presented in 18/180 (10%) cases, including 16 patients with BRAF variants and 2 with MAP2K1 variants. Among IESS patients with BRAF variants, 16/16 (100%) had sequence changes affecting the protein kinase domain (exons 11-16), although only 57% of total BRAF variants occurred in this domain. Clinical onset of spasms occurred at a median age of 5.4 months (range: 1-24 months). Among 13/18 patients whose IESS resolved with anti-seizure medications, 10 were treated with ACTH and/or vigabatrin. A substantial majority of CFCS patients with IESS subsequently developed other epilepsy types (16/18; 89%). In terms of neurodevelopmental outcomes, gross motor function and verbal communication were more limited in patients with a history of IESS compared to those without IESS. These findings can inform clinical neurological care guidelines for CFCS and development of relevant pre-clinical models for severe epilepsy phenotypes.

Brain structural changes in patients with cardio-facio-cutaneous syndrome: effects of BRAF gene mutation and epilepsy on brain development. A case-control study by quantitative magnetic resonance imaging.

PURPOSE: To evaluate the brain volumetric changes caused by BRAF gene mutation in non-epileptic CFC patients and the influence of the age of epilepsy onset on brain development in 2 cohorts of epileptic CFC patients. METHODS: We enrolled CFC patients carrying BRAF gene mutations without epilepsy (4 patients) and with epilepsy (16 patients). CFC epileptic patients were divided into two cohorts based on the age of seizure onset: early-age onset (7 children) and late-age onset (9 adolescents). All three cohorts of patients underwent 3D FSPGR T1-weighted imaging to assess supratentorial and infratentorial brain volumes. Moreover, for each compartment, gray matter (GM), white matter (WM), and cerebrospinal fluid (CSF) volumes were measured. All measurements were compared with those of age-matched controls without neuroimaging abnormalities. RESULTS: All CFC patients showed supratentorial and infratentorial WM reduction and supratentorial ventricular enlargement (p < 0.01). However, patients with early age of epilepsy onset, compared with the other two cohorts of CFC patients, showed both GM and a more pronounced WM volume reduction (p < 0.01). CONCLUSION: In non-epileptic CFC children, we demonstrated WM volumetric reduction suggesting a direct effect of BRAF gene mutation on brain development. Nevertheless, in CFC epileptic patients, the age of epilepsy onset may contribute to brain atrophy. Brain atrophy in CFC patients, in part due to the natural history of the disease, may be worsened by epilepsy when it begins in the early ages because of interference with brain growth at that critical age of development.

Temporal lobe epilepsy surgery in children and adults: A multicenter study.

OBJECTIVE: To assess seizure and cognitive outcomes and their predictors in children (<16 years at surgery) and adults undergoing temporal lobe epilepsy (TLE) surgery in eight Italian centers. METHODS: This is a retrospective multicenter study. We performed a descriptive analysis and subsequently carried out multivariable mixed-effect models corrected for multiple comparisons. RESULTS: We analyzed data from 511 patients (114 children) and observed significant differences in several clinical features between adults and children. The possibility of achieving Engel class IA outcome and discontinuing antiepileptic drugs (AEDs) at last follow-up (FU) was significantly higher in children (P = .006 and < .0001). However, percentages of children and adults in Engel class I at last FU (mean ± SD, 45.9 ± 17 months in children; 45.9 ± 20.6 months in adults) did not differ significantly. We identified different predictors of seizure outcome in children vs adults and at short- vs long-term FU. The only variables consistently associated with class I outcome over time were postoperative electroencephalography (EEG) in adults (abnormal, improved,odds ratio [OR] = 0.414, P = .023, Q = 0.046 vs normal, at 2-year FU and abnormal, improved, OR = 0.301, P = .001, Q = 0.002 vs normal, at last FU) and the completeness of resection of temporal magnetic resonance (MR) abnormalities other than hippocampal sclerosis in children (OR = 7.93, P = .001, Q = 0.003, at 2-year FU and OR = 45.03, P < .0001, Q < 0.0001, at last FU). Cognitive outcome was best predicted by preoperative performances in either age group. SIGNIFICANCE: Clinical differences between adult and pediatric patients undergoing TLE surgery are reflected in differences in long-term outcomes and predictors of failures. Children are more likely to achieve sustained seizure freedom and withdraw AEDs after TLE surgery. Earlier referral should be encouraged as it can improve surgical outcome.

A novel homozygous variant in JAM3 gene causing hemorrhagic destruction of the brain, subependymal calcification, and congenital cataracts (HDBSCC) with neonatal onset.

BACKGROUND: JAM3 gene, located on human chromosome 11q25, encodes a member of the junctional adhesion molecule (JAM) family. Mutations of this gene are associated with hemorrhagic destruction of the brain, subependymal calcification, and congenital cataracts (HDBSCC). CASE REPORT: Herein, we present a newborn male with a prenatal suspicion of bilateral cataracts but without fetal ultrasound findings of cortical malformations. He was postnatally diagnosed with a clinical picture of HDBSCC and Early-onset Developmental and Epileptic Encephalopathy (DEE), associated to a homozygous variant of JAM3 gene. CONCLUSION: Identification of this variant in affected individuals has implications for perinatal and postnatal management and genetic counseling. To the best of our knowledge, this is the first case reported of a child with a JAM3 variant in Italy, from a different ethnic background than the other reported children until now (Saudi Arabian, Turkish, Afghani, and Moroccan origin). JAM3 screening could be requested in prenatal diagnosis of fetal congenital cataracts and included in Next-Generation DNA Sequencing panels.

Role of high-density EEG (hdEEG) in pre-surgical epilepsy evaluation in children: case report and review of the literature.

INTRODUCTION: Electrical source imaging (ESI) and especially hdEEG represent a noninvasive, low cost and accurate method of localizing epileptic zone (EZ). Such capability can greatly increase seizure freedom rate in surgically treated drug resistant epilepsy cases. Furthermore, ESI might be important in intracranial record planning. CASE REPORT: We report the case of a 15 years old boy suffering from drug resistant epilepsy with a previous history of DNET removal. The patient suffered from heterogeneous seizure semiology characterized by anesthesia and loss of tone in the left arm, twisting of the jaw to the left and dysarthria accompanied by daze; lightheadedness sometimes associated with headache and dizziness and at a relatively short time distance negative myoclonus involving the left hand. Clinical evidence poorly match scalp and video EEG monitoring thus requiring hdEEG recording followed by SEEG to define surgical target. Surgery was also guided by ECoG and obtained seizure freedom. DISCUSSION: ESI offers an excellent estimate of EZ, being hdEEG and intracranial recordings especially important in defining it. We analyzed our results together with the data from the literature showing how in children hdEEG might be even more crucial than in adults due to the heterogeneity in seizures phenomenology. The complexity of each case and the technical difficulties in dealing with children, stress even more the importance of a noninvasive tool for diagnosis. In fact, hdEEG not only guided in the presented case SEEG planning but may also in the future offer the possibility to replace it.

Efficacy and safety of Fenfluramine hydrochloride for the treatment of seizures in Dravet syndrome: A real-world study.

OBJECTIVE: Dravet syndrome (DS) is a drug-resistant, infantile onset epilepsy syndrome with multiple seizure types and developmental delay. In recently published randomized controlled trials, fenfluramine (FFA) proved to be safe and effective in DS. METHODS: DS patients were treated with FFA in the Zogenix Early Access Program at four Italian pediatric epilepsy centers. FFA was administered as add-on, twice daily at an initial dose of 0.2 mg/kg/d up to 0.7 mg/kg/d. Seizures were recorded in a diary. Adverse events and cardiac safety (with Doppler echocardiography) were investigated every 3 to 6 months. RESULTS: Fifty-two patients were enrolled, with a median age of 8.6 years (interquartile range [IQR] = 4.1-13.9). Forty-five (86.5%) patients completed the efficacy analysis. The median follow-up was 9.0 months (IQR = 3.2-9.5). At last follow-up visit, there was a 77.4% median reduction in convulsive seizures. Thirty-two patients (71.1%) had a ≥50% reduction of convulsive seizures, 24 (53.3%) had a ≥75% reduction, and five (11.1%) were seizure-free. The most common adverse event was decreased appetite (n = 7, 13.4%). No echocardiographic signs of cardiac valvulopathy or pulmonary hypertension were observed. There was no correlation between type of genetic variants and response to FFA. SIGNIFICANCE: In this real-world study, FFA provided a clinically meaningful reduction in convulsive seizure frequency in the majority of patients with DS and was well tolerated.

Trends in pediatric epilepsy surgery in Europe between 2008 and 2015: Country-, center-, and age-specific variation.

OBJECTIVE: To profile European trends in pediatric epilepsy surgery (<16 years of age) between 2008 and 2015. METHODS: We collected information on volumes and types of surgery, pathology, and seizure outcome from 20 recognized epilepsy surgery reference centers in 10 European countries. RESULTS: We analyzed retrospective aggregate data on 1859 operations. The proportion of surgeries significantly increased over time (P < .0001). Engel class I outcome was achieved in 69.3% of children, with no significant improvement between 2008 and 2015. The proportion of histopathological findings consistent with glial scars significantly increased between the ages of 7 and 16 years (P for trend = .0033), whereas that of the remaining pathologies did not vary across ages. A significant increase in unilobar extratemporal surgeries (P for trend = .0047) and a significant decrease in unilobar temporal surgeries (P for trend = .0030) were observed between 2008 and 2015. Conversely, the proportion of multilobar surgeries and unrevealing magnetic resonance imaging cases remained unchanged. Invasive investigations significantly increased, especially stereo-electroencephalography. We found different trends comparing centers starting their activity in the 1990s to those whose programs were developed in the past decade. Multivariate analysis revealed a significant variability of the proportion of the different pathologies and surgical approaches across countries, centers, and age groups between 2008 and 2015. SIGNIFICANCE: Between 2008 and 2015, we observed a significant increase in the volume of pediatric epilepsy surgeries, stability in the proportion of Engel class I outcomes, and a modest increment in complexity of the procedures.

Early neurodevelopmental characterization in children with cobalamin C/defect.

Cobalamin C (cblC) defect is the most common inherited disorder of cobalamin metabolism. Developmental delay, behavioral problems, and maculopathy are common, but they have not been systematically investigated. The aim of this study was to define early neurodevelopment in cblC patients and the possible contribution of different factors, such as mode of diagnosis, age at diagnosis, presence of brain lesions and epilepsy. Children up to the age of 4 years with a visual acuity ≥1/10 were evaluated using the Griffiths' Mental Development Scales. Eighteen children were enrolled (age range 12-48 months). Four were diagnosed by newborn screening (NBS); in the others mean age at diagnosis was 3.5 months (range 0.3-18 months). Eight had seizures: three in the first year, and five after the second year of life. Fourteen had brain lesions on magnetic resonance imaging (MRI). Neurovisual assessment evidenced low visual acuity (<3/10) in 4/18. NBS diagnosed patients had higher general and subquotients neurodevelopmental scores, normal brain MRI, and no epilepsy. The others showed a progressive reduction of the developmental quotient with age and language impairment, which was evident after 24 months of age. Our findings showed a progressive neurodevelopmental deterioration and a specific fall in language development after 24 months in cblC defect. The presence of brain lesions and epilepsy was associated with a worst neurodevelopmental outcome. NBS, avoiding major disease-related events and allowing an earlier treatment initiation, appeared to have a protective effect on the development of brain lesions and to promote a more favorable neurodevelopment.

Multimodal assessment of motor pathways and intracortical connections in functional hemispherectomy.

PURPOSE: For selected children with medically intractable epilepsy, hemispherectomy can be an excellent treatment option and its efficacy in achieving seizure freedom or reduction in seizure frequency has been shown in several studies, but patients' selection could not be straightforward and often it is taken on subjective basis. We described a multimodal approach to assess patient eligible for hemispherectomy and possibly predicting post-surgical outcomes. METHODS: We describe pre- and post-surgical clinical features along with neuroradiological results by magnetic resonance imaging (MRI), functional magnetic resonance imaging (fMRI), MR-tractography (MRT), and neurophysiological study by single and paired pulses transcranial magnetic stimulation (TMS) in a child with cerebral palsy with epileptic encephalopathy, eligible for epilepsy surgery. RESULTS: Presurgical TMS evaluation showed a lateralization of motor function on the left motor cortex for both arms, and results were confirmed by MRI studies. Interestingly, after surgery, both epilepsy and motor performances improved and TMS showed enhancement of intracortical inhibition and facilitation activity. CONCLUSION: Functional hemispherectomy is an effective treatment for drug-resistant epilepsy, and multimodal presurgical assessment may be a useful approach to guide surgeons in selecting patients. Moreover, pre- and post-surgical evaluation of these patients may enhance our understanding of brain plasticity phenomena.

Sturge-Weber syndrome: an update on the relevant issues for neurosurgeons.

PURPOSE: Sturge-Weber syndrome (SWS) is a neurocutaneous facomatosis characterized by facial and leptomeningeal angioma, glaucoma, seizures, and neurological disability. Therefore, a challenging multidisciplinary interaction is required for its management. The goal of this paper is to review the main aspects of SWS and to present an illustrative pediatric series. METHODS: The pertinent literature has been analyzed, focused mainly on etiopathogenesis, pathology, clinical features, diagnostic tools, management, and outcome of the disease. Moreover, a series of 11 children operated on for refractory epilepsy between 2005 and 2015 (minimum follow-up 5 years, mean follow-up 9.6 years) is reported. The series consists of six boys and five girls with 6.5-month and 16.2-month mean age at seizure onset and at surgery, respectively. Seizures affected all children, followed by hemiparesis and psychomotor delay (81%), glaucoma (54%), and other neurological deficits (45%). RESULTS: All children underwent hemispherectomy (anatomical in three cases, functional in two cases, hemispherotomy in six cases); one patient needed a redo hemispherotomy. Mortality was nil; disseminated intravascular coagulation and interstitial pneumonia occurred in one patient each; three children had subdural fluid collection. Eight patients (72%) are in the ILAE Class 1 (completely seizure and aura free), two in Class 2 (only auras, no seizure), and one in Class 3 (1-3 seizure days per year). AEDs discontinuation was possible in 73% of cases. The most important news from the literature concerned the pathogenesis (role of the mutation of the GNAQ gene in the abnormal SWS vasculogenesis), the clinical findings (the features and pathogenesis of the stroke-like episodes are being understood), the diagnostic tools (quantitative MRI and EEG), and both the medical (migraine, seizures) and surgical management (epilepsy). The epileptic outcome of SWS patients is very good (80% are seizure-free), if compared with other hemispheric syndromes. The quality of life is affected by the neurological and cognitive deficits. CONCLUSIONS: SWS still is an etiological and clinical challenge. However, the improvements over the time are consistent. In particular, the neurosurgical treatment of refractory epilepsy provides very good results as long as the indication to treatment is correct.

Clinical-genetic features and peculiar muscle histopathology in infantile DNM1L-related mitochondrial epileptic encephalopathy.

Mitochondria are highly dynamic organelles, undergoing continuous fission and fusion. The DNM1L (dynamin-1 like) gene encodes for the DRP1 protein, an evolutionary conserved member of the dynamin family, responsible for fission of mitochondria, and having a role in the division of peroxisomes, as well. DRP1 impairment is implicated in several neurological disorders and associated with either de novo dominant or compound heterozygous mutations. In five patients presenting with severe epileptic encephalopathy, we identified five de novo dominant DNM1L variants, the pathogenicity of which was validated in a yeast model. Fluorescence microscopy revealed abnormally elongated mitochondria and aberrant peroxisomes in mutant fibroblasts, indicating impaired fission of these organelles. Moreover, a very peculiar finding in our cohort of patients was the presence, in muscle biopsy, of core like areas with oxidative enzyme alterations, suggesting an abnormal distribution of mitochondria in the muscle tissue.

Clinical features and genetic analysis of two siblings with startle disease in an Italian family: a case report.

BACKGROUND: Hyperekplexia also known as Startle disease is a rare neuromotor hereditary disorder characterized by exaggerated startle responses to unexpected auditory, tactile, and visual stimuli and generalized muscle stiffness, which both gradually subside during the first months of life. Although the diagnosis of Hyperekplexia is based on clinical findings, pathogenic variants in five genes have been reported to cause Hyperekplexia, of which GLRA1 accounts for about 80% of cases. Dominant and recessive mutations have been identified in GLRA1 gene as pathogenic variants in many individuals with the familial form of Hyperekplexia and occasionally in simplex cases. CASE PRESENTATION: In the present study, we describe clinical and genetic features of two Italian siblings, one with the major and one with the minor form of the disease. DNA samples from the probands and their parents were performed by NGS approach and validated by Sanger sequencing. The analysis of the GLRA1 gene revealed, in both probands, compound heterozygous mutations: c.895C > T or p.R299X inherited from the mother and c.587C > A or p.D98E inherited from the father. CONCLUSIONS: Until now, these two identified mutations in GLRA1 have not been reported before as compound mutations. What clearly emerges within our study is the clinical heterogeneity in the same family. In fact, even though in the same pedigree, the affected mother showed only mild startle responses to unexpected noise stimuli, which might be explained by variable expressivity, while the father, showed no clear signs of symptomatology, which might be explained by non-penetrance. Finally, the two brothers have different form of the disease, even if the compound heterozygous mutations in GLRA1 are the same, showing that the same mutation in GLRA1 could have different phenotypic expressions and suggesting an underling mechanism of variable expressivity.

Dravet syndrome: Early electroclinical findings and long-term outcome in adolescents and adults.

To describe the outcome of Dravet syndrome (DS) in adolescents and adults we conducted a longitudinal retrospective study of two independent cohorts of 34 adolescents (group 1) and 50 adults (group 2). In both cohorts, we collected information about genetic mutation, and semiology of seizures at onset and during disease course. At the last evaluation, we considered the following features: epilepsy (distinguishing myoclonic/complete and nonmyoclonic/incomplete phenotype), neurologic signs, intellectual disability (ID), and behavioral disorders. Moreover, in both cohorts, we performed a correlation analysis between early characteristics of the disease and the outcome of DS with regard to seizure persistence, ID, behavioral disorder, and neurologic impairment at last evaluation. Group 1 includes 22 adolescents with complete form of DS and 12 with incomplete form; group 2 includes 35 adults with complete form and 15 with incomplete form. The seizures persisted in 73.6% of adolescents and in 80% of adults, but epilepsy severity progressively decreased through age. Seizure persistence correlated with the complete phenotype and with the occurrence of reflex seizures. At last evaluation, ID was moderate or severe in 70.5% of adolescents and in 80% of adults. The most severe cognitive and motor impairment was observed in patients with persisting seizures. The severity of cognition, language, and neurologic impairment at last evaluation correlated statistically with the complete phenotype. The study confirms that the global outcome of DS is poor in most cases, albeit epilepsy severity decreases throughout adulthood. The improvement of epilepsy throughout ages is not associated with improvement in intellectual abilities and motor skills; this confirms that the unfavorable outcome is not a pure consequence of epilepsy.

Defining the electroclinical phenotype and outcome of PCDH19-related epilepsy: A multicenter study.

OBJECTIVE: PCDH19-related epilepsy is an epileptic syndrome with infantile onset, characterized by clustered and fever-induced seizures, often associated with intellectual disability (ID) and autistic features. The aim of this study was to analyze a large cohort of patients with PCDH19-related epilepsy and better define the epileptic phenotype, genotype-phenotype correlations, and related outcome-predicting factors. METHODS: We retrospectively collected genetic, clinical, and electroencephalogram (EEG) data of 61 patients with PCDH19-related epilepsy followed at 15 epilepsy centers. All consecutively performed EEGs were analyzed, totaling 551. We considered as outcome measures the development of ID, autistic spectrum disorder (ASD), and seizure persistence. The analyzed variables were the following: gender, age at onset, age at study, genetic variant, fever sensitivity, seizure type, cluster occurrence, status epilepticus, EEG abnormalities, and cognitive and behavioral disorders. Receiver operating characteristic curve analysis was performed to evaluate the age at which seizures might decrease in frequency. RESULTS: At last follow-up (median = 12 years, range = 1.9-42.1 years), 48 patients (78.7%) had annual seizures/clusters, 13 patients (21.3%) had monthly to weekly seizures, and 12 patients (19.7%) were seizure-free for ≥2 years. Receiver operating characteristic analysis showed a significant decrease of seizure frequency after the age of 10.5 years (sensitivity = 81.0%, specificity = 70.0%). Thirty-six patients (59.0%) had ID and behavioral disturbances. ASD was present in 31 patients. An earlier age at epilepsy onset emerged as the only predictive factor for ID (P = 0.047) and ASD (P = 0.014). Conversely, age at onset was not a predictive factor for seizure outcome (P = 0.124). SIGNIFICANCE: We found that earlier age at epilepsy onset is related to a significant risk for ID and ASD. Furthermore, long-term follow-up showed that after the age of 10 years, seizures decrease in frequency and cognitive and behavioral disturbances remain the primary clinical problems.

Delineating SPTAN1 associated phenotypes: from isolated epilepsy to encephalopathy with progressive brain atrophy.

De novo in-frame deletions and duplications in the SPTAN1 gene, encoding the non-erythrocyte αII spectrin, have been associated with severe West syndrome with hypomyelination and pontocerebellar atrophy. We aimed at comprehensively delineating the phenotypic spectrum associated with SPTAN1 mutations. Using different molecular genetic techniques, we identified 20 patients with a pathogenic or likely pathogenic SPTAN1 variant and reviewed their clinical, genetic and imaging data. SPTAN1 de novo alterations included seven unique missense variants and nine in-frame deletions/duplications of which 12 were novel. The recurrent three-amino acid duplication p.(Asp2303_Leu2305dup) occurred in five patients. Our patient cohort exhibited a broad spectrum of neurodevelopmental phenotypes, comprising six patients with mild to moderate intellectual disability, with or without epilepsy and behavioural disorders, and 14 patients with infantile epileptic encephalopathy, of which 13 had severe neurodevelopmental impairment and four died in early childhood. Imaging studies suggested that the severity of neurological impairment and epilepsy correlates with that of structural abnormalities as well as the mutation type and location. Out of seven patients harbouring mutations outside the α/ß spectrin heterodimerization domain, four had normal brain imaging and three exhibited moderately progressive brain and/or cerebellar atrophy. Twelve of 13 patients with mutations located within the spectrin heterodimer contact site exhibited severe and progressive brain, brainstem and cerebellar atrophy, with hypomyelination in most. We used fibroblasts from five patients to study spectrin aggregate formation by Triton-X extraction and immunocytochemistry followed by fluorescence microscopy. αII/ßII aggregates and αII spectrin in the insoluble protein fraction were observed in fibroblasts derived from patients with the mutations p.(Glu2207del), p.(Asp2303_Leu2305dup) and p.(Arg2308_Met2309dup), all falling in the nucleation site of the α/ß spectrin heterodimer region. Molecular modelling of the seven SPTAN1 amino acid changes provided preliminary evidence for structural alterations of the A-, B- and/or C-helices within each of the mutated spectrin repeats. We conclude that SPTAN1-related disorders comprise a wide spectrum of neurodevelopmental phenotypes ranging from mild to severe and progressive. Spectrin aggregate formation in fibroblasts with mutations in the α/ß heterodimerization domain seems to be associated with a severe neurodegenerative course and suggests that the amino acid stretch from Asp2303 to Met2309 in the α20 repeat is important for α/ß spectrin heterodimer formation and/or αII spectrin function.

Increasing volume and complexity of pediatric epilepsy surgery with stable seizure outcome between 2008 and 2014: A nationwide multicenter study.

OBJECTIVE: The objective of the study was to assess common practice in pediatric epilepsy surgery in Italy between 2008 and 2014. METHODS: A survey was conducted among nine Italian epilepsy surgery centers to collect information on presurgical and postsurgical evaluation protocols, volumes and types of surgical interventions, and etiologies and seizure outcomes in pediatric epilepsy surgery between 2008 and 2014. RESULTS: Retrospective data on 527 surgical procedures were collected. The most frequent surgical approaches were temporal lobe resections and disconnections (133, 25.2%) and extratemporal lesionectomies (128, 24.3%); the most frequent etiologies were FCD II (107, 20.3%) and glioneuronal tumors (105, 19.9%). Volumes of surgeries increased over time independently from the age at surgery and the epilepsy surgery center. Engel class I was achieved in 73.6% of patients (range: 54.8 to 91.7%), with no significant changes between 2008 and 2014. Univariate analyses showed a decrease in the proportion of temporal resections and tumors and an increase in the proportion of FCDII, while multivariate analyses revealed an increase in the proportion of extratemporal surgeries over time. A higher proportion of temporal surgeries and tumors and a lower proportion of extratemporal and multilobar surgeries and of FCD were observed in low (<50surgeries/year) versus high-volume centers. There was a high variability across centers concerning pre- and postsurgical evaluation protocols, depending on local expertise and facilities. SIGNIFICANCE: This survey reveals an increase in volume and complexity of pediatric epilepsy surgery in Italy between 2008 and 2014, associated with a stable seizure outcome.

Congenital immunodeficiency in an individual with Wiedemann-Steiner syndrome due to a novel missense mutation in KMT2A.

Wiedemann-Steiner Syndrome (WSS) is an autosomal dominant disorder characterized by hypertrichosis, short stature, intellectual disability, developmental delay, and facial dysmorphism. Since the original reports by Wiedemann and co-workers, and Steiner and Marques, only a few cases have been described. Recently, the clinical variability of the disorder has more precisely been characterized by Jones and co-workers, who also identified heterozygous KMT2A mutations as the molecular defect underlying this condition. Here, we report on a boy with a complex phenotype overlapping WSS but exhibiting epilepsy, feeding difficulties, microcephaly, and congenital immunodeficiency with low levels of immunoglobulins as additional features. Whole exome sequencing allowed identifying a previously unreported de novo KMT2A missense mutation affecting the DNA binding domain of the methyltransferase. This finding expands the clinical phenotype associated with KMT2A mutations to include immunodeficiency and epilepsy as clinically relevant features for this disorder. © 2016 Wiley Periodicals, Inc.

Symptomatic and presumed symptomatic focal epilepsies in childhood: An observational, prospective multicentre study.

OBJECTIVE: To describe the clinical, neuropsychological, and psychopathologic features of a cohort of children with a new diagnosis of symptomatic or presumed symptomatic focal epilepsy at time of recruitment and through the first month. The selected population will be followed for 2-5 years after enrollment to investigate the epilepsy course and identify early predictors of drug resistance. METHODS: In this observational, multicenter, nationwide study, children (age 1 month-12.9 years) with a new diagnosis of symptomatic or presumed symptomatic focal epilepsy were consecutively enrolled in 15 Italian tertiary childhood epilepsy centers. Inclusion criteria were as follows: (1) diagnosis of symptomatic focal epilepsy due to acquired and developmental etiologies, and presumed symptomatic focal epilepsy; (2) age at diagnosis older than 1 month and <13 years; and (3) written informed consent. Children were subdivided into three groups: ≤3 years, >3 to 6 years, and >6 years. Clinical, electroencephalography (EEG), neuroimaging, and neuropsychological variables were identified for statistical analyses. RESULTS: Two hundred fifty-nine children were enrolled (116 female and 143 male). Median age: 4.4 years (range 1 month-12.9 years); 46.0% (n = 119) of children were younger than 3 years, 24% (61) from 3 to 6 years of age, and 30% (79) older than 6 years. Neurologic examination findings were normal in 71.8%. Brain magnetic resonance imaging (MRI) was abnormal in 59.9%. Children age ≤3 years experienced the highest seizure frequency in the first month after recruitment (p < 0.0001). Monotherapy in the first month was used in 67.2%. Cognitive tests at baseline revealed abnormal scores in 30%; behavioral problems were present in 21%. At multivariate analysis, higher chances to exhibit more than five seizures in the first month after epilepsy onset was confirmed for younger children and those with temporal lobe epilepsy. SIGNIFICANCE: In this prospective cohort study, an extensive characterization of epilepsy onset in children with symptomatic or presumed symptomatic focal epilepsies is reported in relation to the age group and the localization of the epileptogenic zone.