X-Linked Epilepsies: A Narrative Review.

X-linked epilepsies are a heterogeneous group of epileptic conditions, which often overlap with X-linked intellectual disability. To date, various X-linked genes responsible for epilepsy syndromes and/or developmental and epileptic encephalopathies have been recognized. The electro-clinical phenotype is well described for some genes in which epilepsy represents the core symptom, while less phenotypic details have been reported for other recently identified genes. In this review, we comprehensively describe the main features of both X-linked epileptic syndromes thoroughly characterized to date (PCDH19-related DEE, CDKL5-related DEE, MECP2-related disorders), forms of epilepsy related to X-linked neuronal migration disorders (e.g., ARX, DCX, FLNA) and DEEs associated with recently recognized genes (e.g., SLC9A6, SLC35A2, SYN1, ARHGEF9, ATP6AP2, IQSEC2, NEXMIF, PIGA, ALG13, FGF13, GRIA3, SMC1A). It is often difficult to suspect an X-linked mode of transmission in an epilepsy syndrome. Indeed, different models of X-linked inheritance and modifying factors, including epigenetic regulation and X-chromosome inactivation in females, may further complicate genotype-phenotype correlations. The purpose of this work is to provide an extensive and updated narrative review of X-linked epilepsies. This review could support clinicians in the genetic diagnosis and treatment of patients with epilepsy featuring X-linked inheritance.

Mystery(n) Phenotypic Presentation in Europeans: Report of Three Further Novel Missense RNF213 Variants Leading to Severe Syndromic Forms of Moyamoya Angiopathy and Literature Review.

Moyamoya angiopathy (MMA) is a rare cerebral vasculopathy in some cases occurring in children. Incidence is higher in East Asia, where the heterozygous p.Arg4810Lys variant in RNF213 (Mysterin) represents the major susceptibility factor. Rare variants in RNF213 have also been found in European MMA patients with incomplete penetrance and are today a recognized susceptibility factor for other cardiovascular disorders, from extracerebral artery stenosis to hypertension. By whole exome sequencing, we identified three rare and previously unreported missense variants of RNF213 in three children with early onset of bilateral MMA, and subsequently extended clinical and radiological investigations to their carrier relatives. Substitutions all involved highly conserved residues clustered in the C-terminal region of RNF213, mainly in the E3 ligase domain. Probands showed a de novo occurring variant, p.Phe4120Leu (family A), a maternally inherited heterozygous variant, p.Ser4118Cys (family B), and a novel heterozygous variant, p.Glu4867Lys, inherited from the mother, in whom it occurred de novo (family C). Patients from families A and C experienced transient hypertransaminasemia and stenosis of extracerebral arteries. Bilateral MMA was present in the proband's carrier grandfather from family B. The proband from family C and her carrier mother both exhibited annular figurate erythema. Our data confirm that rare heterozygous variants in RNF213 cause MMA in Europeans as well as in East Asian populations, suggesting that substitutions close to positions 4118-4122 and 4867 of RNF213 could lead to a syndromic form of MMA showing elevated aminotransferases and extracerebral vascular involvement, with the possible association of peculiar skin manifestations.

Neurophysiological Signatures of Motor Impairment in Patients with Rett Syndrome.

OBJECTIVE: Rett syndrome (RTT) is an X-linked dominant neurodevelopmental disorder due to pathogenic mutations in the MECP2 gene. Motor impairment constitutes the core diagnostic feature of RTT. Preclinical studies have consistently demonstrated alteration of excitation/inhibition (E/I) balance and aberrant synaptic plasticity at the cortical level. We aimed to understand neurobiological mechanisms underlying motor deficit by assessing in vivo synaptic plasticity and E/I balance in the primary motor cortex (M1). METHODS: In 14 patients with typical RTT, 9 epilepsy control patients, and 11 healthy controls, we applied paired-pulse transcranial magnetic stimulation (TMS) protocols to evaluate the excitation index, a biomarker reflecting the contribution of inhibitory and facilitatory circuits in M1. Intermittent TMS-theta burst stimulation was used to probe long-term potentiation (LTP)-like plasticity in M1. Motor impairment, assessed by ad hoc clinical scales, was correlated with neurophysiological metrics. RESULTS: RTT patients displayed a significant increase of the excitation index (p = 0.003), as demonstrated by the reduction of short-interval intracortical inhibition and increase of intracortical facilitation, suggesting a shift toward cortical excitation likely due to GABAergic dysfunction. Impairment of inhibitory circuits was also confirmed by the reduction of long-interval intracortical inhibition (p = 0.002). LTP-like plasticity in M1 was abolished (p = 0.008) and scaled with motor disability (all p = 0.003). INTERPRETATION: TMS is a method that can be used to assess cortical motor function in RTT patients. Our findings support the introduction of TMS measures in clinical and research settings to monitor the progression of motor deficit and response to treatment. ANN NEUROL 2020;87:763-773.

Temporal lobe malformations, focal epilepsy, and FGFR3 mutations: a non-causal association?

Temporal lobe abnormalities and focal epilepsy have been documented in FGFR3-related clinical condition, including hypochondroplasia and Muenke syndrome. FGFR3 is expressed in the brain during development and could play a role in nervous system development and hippocampal formation. These observations suggest a non-casual association between temporal malformation, epilepsy, and FGFR3 mutations. Herein, we report clinical, electroclinical, and neuroimaging findings of three additional cases of focal epilepsy and temporal lobe malformations occurring in children with FGFR3 gene mutations.

A novel RAB39B mutation and concurrent de novo NF1 mutation in a boy with neurofibromatosis type 1, intellectual disability, and autism: a case report.

BACKGROUND: Mutations in RAB39B at Xq28 causes a rare form of X-linked intellectual disability (ID) and Parkinson's disease. Neurofibromatosis type 1 (NF1) is caused by heterozygous mutations in NF1 occurring de novo in about 50% of cases, usually due to paternal gonadal mutations. This case report describes clinical and genetic findings in a boy with the occurrence of two distinct causative mutations in NF1 and RAB39B explaining the observed phenotype. CASE PRESENTATION: Here we report a 7-year-old boy with multiple café-au-lait macules (CALMs) and freckling, severe macrocephaly, peculiar facial gestalt, severe ID with absent speech, epilepsy, autistic traits, self-harming, and aggressiveness. Proband is an only child born to a father aged 47. Parents did not present signs of NF1, while a maternal uncle showed severe ID, epilepsy, and tremors.By RNA analysis of NF1, we identified a de novo splicing variant (NM_000267.3:c.6579+2T>C) in proband, which explained NF1 clinical features but not the severe ID, behavioral problems, and aggressiveness. Family history suggested an X-linked condition and massively parallel sequencing of X-exome identified a novel RAB39B mutation (NM_171998.2:c.436_447del) in proband, his mother, and affected maternal uncle, subsequently validated by Sanger sequencing in these and other family members. CONCLUSIONS: The case presented here highlights how concurrent genetic defects should be considered in NF1 patients when NF1 mutations cannot reasonably explain all the observed clinical features.

Epilepsy in NF1: a systematic review of the literature.

Epilepsy is one of the possible neurological manifestations of the neurofibromatosis type 1 (NF1) that represents the most common neurocutaneous disorder. We performed a systematic review of the literature on epilepsy associated with NF1 since 1995 in order to better define prevalence and describe type and causes of seizures. Data on type, nature of studies, number of patients, gender, and inheritance of NF1 were recorded as well as data on causes, type, EEGs, brain imaging, intellectual disability (ID), surgical treatment, and outcome of epilepsy. We identified a total of 141 references through the literature search of Pubmed and Embase. After screening, 42 records were identified, including 11617 individuals with NF1 (53% of males). Overall prevalence was estimated at 5.4% lifelong with values that seemed to be slightly lower in children, 3.7% (p 0.0016). Neither gender differences nor correlation with NF1 inheritance was found. Focal with or without bilateral tonic-clonic seizures were the most common seizure type encountered (60.9%). Structural causes were identified in half of cases (114/226). Low-grade gliomas were the most frequent associated lesions followed by mesial temporal sclerosis, malformation of cortical development, dysembryoplastic neuroepithelial tumor, and cerebrovascular lesions. In these cases, the surgical approach improved the epileptic outcome. Prevalence of epilepsy is higher in subjects with NF1 respect of the general population, with values apparently significantly lower in pediatric age. Brain tumors and cytoarchitectural abnormalities are the most frequent causes of epilepsy in this population, although many other brain complications should be taken in account.

High-functioning autism spectrum disorder with fluent speech and late-onset epilepsy: an unusual presentation of Inv-Dup (15) syndrome.

Many neuropsychiatric phenotypes have been reported in association with rearrangements in the 15q11-q13 region. Clinical presentations can include hypotonia, developmental delay, severe/moderate intellectual disabilities, poor expressive language, difficult to treat epilepsy, and autism spectrum disorders. Here we report an additional case of a girl with inversion duplication on chromosome 15 (Inv-Dup 15) showing a peculiar and milder clinical phenotype, including atypical high-functioning autism disorder, late onset and drug-responsive epilepsy, and a relatively good language development . This report suggests that a diagnosis of Inv-Dup (15) can be suspected during more benign atypical condition with a better outcome than usually reported.

Cognitive Profile, Emotional-Behavioral Features, and Parental Stress in Boys With 47,XYY Syndrome.

OBJECTIVE: To describe (a) the observed cognitive, emotional, and behavioral phenotype in a cohort of male children with 47,XYY syndrome and (b) stress levels in their parents. METHODS: We conducted a cross-sectional observational study of 11 boys diagnosed with 47,XYY syndrome and compared them with 11 age-matched boys with normal karyotype (46,XY). The participants performed standardized assessments of cognitive function, emotional state, and behavioral features; the parents completed a questionnaire evaluating parental stress. All data were analyzed using parametric and nonparametric statistical methods. RESULTS: All of the boys exhibited a normal cognitive profile. However, emotional-behavioral profiling revealed that internalizing and externalizing problems were more prevalent in the 47,XYY group. In addition, the stress levels of the parents of the 47,XYY group were reportedly higher than those of the parents of the 46,XY group. We also found that the time of the diagnosis had an effect on the mothers' stress levels; that is, postnatal fetal 47,XYY diagnosis was associated with higher maternal stress, whereas prenatal fetal 47,XYY diagnosis was not. CONCLUSIONS: Generally, 47,XYY syndrome is associated with certain cognitive, emotional, and behavioral features. High stress levels have been reported by the mothers of 47,XYY boys who had been diagnosed postnatally because of unexpected developmental delay and/or learning difficulties. The present study highlights the need to better define the neuropsychiatric phenotype of 47,XYY children; namely, the effect of the chromosomal abnormality on their cognitive function and emotional-behavioral (internalizing and externalizing) features. This study could improve prenatal counseling and pediatric surveillance.

UBE2A deficiency in two siblings: A novel splicing variant inherited from a maternal germline mosaicism.

UBE2A deficiency is a syndromic condition of X-linked intellectual disability (ID) characterized by typical dysmorphic features that include synophrys, prominent supraorbital ridges, almond-shaped, and deep-set eyes, large ears, wide mouth, myxedematous appearance, hirsutism, micropenis, and onychodystrophy. To date, only seven familial UBE2A intragenic mutations and nine larger microdeletions encompassing UBE2A have been reported. Here, we describe two siblings with X-linked ID and typical clinical features of UBE2A deficiency caused by a novel hemizygous variant, identified by massively parallel sequencing of X-exome. The synonymous c.330G>A substitution in UBE2A modifies the last nucleotide of exon 5, causing the exon skipping and resulting in an out-of-frame transcript, likely encoding for a truncated form of the ubiquitin-conjugating enzyme E2 A. As confirmed by deep sequencing, the c.330G>A substitution in UBE2A was undetectable in genomic DNA from maternal blood cells, suggesting that the recurrent UBE2A deficiency observed in males of this family is caused by a maternal germline mosaicism.

Low-grade epilepsy-associated tumors: Epilepsy outcome and antiseizure medication discontinuation after lesionectomies as first-line surgical approach in pediatric population.

OBJECTIVE: This study aimed to evaluate epilepsy outcome and antiseizure medication (ASM) discontinuation after lesionectomies as first surgical approach in pediatric population diagnosed with low-grade epilepsy-associated neuroepithelial tumors (LEATs). METHODS: We conducted a retrospective study. Thirty-six consecutive patients with histological diagnoses of LEATs who underwent surgery between 2018 and 2021 at our institution were included. The clinical and surgical data were retrospectively analyzed. RESULTS: Thirty (83.3%) of 36 patients are free of disabling seizures (Engel class I) and 19 (63,4%) of them are classified as Engel Ia. In 17 (47.2%) patients, ASM could be discontinued. The mean age at surgery was 8.6 years (±4.04) and the mean age at onset of epilepsy was 7.2 years (±3.8), whereas the mean duration of epilepsy in months at the time of surgery was 21.3 months (±23.7). The epileptogenic tumor was in the temporal lobe in 20 (55.5%) patients. Because of seizure persistence, a second or a third surgery was necessary for six patients (16.7%) and four of them had residual lesions (three in temporal and one in extratemporal site). No perioperative complications were recorded, including acute seizures, with a median hospitalization time of 7 days. Shorter epilepsy duration at time of surgery as long as a single ASM was significantly correlated with an Engel class I outcome (p-value = .01 and p-value = .016, respectively). Focal seizure semeiology was associated with an increased probability of antiseizure medication discontinuation (p-value = .042). SIGNIFICANCE: Our findings confirm that shorter epilepsy disease duration, monotherapy before surgery, and seizure semeiology are determinant factors for a positive seizure outcome and medication discontinuation, also with less invasive surgical approaches such as lesionectomies. However, considering the intrinsic multifactorial epileptogenic nature of LEATs, a tailored surgical approach should be considered to optimize clinical and seizure outcome, especially for lesions located in the temporal lobe.

Structural brain abnormalities in Pallister-Killian syndrome: a neuroimaging study of 31 children.

BACKGROUND: Pallister-Killian syndrome (PKS) is a rare genetic disorder caused by mosaic tetrasomy of 12p with wide neurological involvement. Intellectual disability, developmental delay, behavioral problems, epilepsy, sleep disturbances, and brain malformations have been described in most individuals, with a broad phenotypic spectrum. This observational study, conducted through brain MRI scan analysis on a cohort of patients with genetically confirmed PKS, aims to systematically investigate the neuroradiological features of this syndrome and identify the possible existence of a typical pattern. Moreover, a literature review differentiating the different types of neuroimaging data was conducted for comparison with our population. RESULTS: Thirty-one individuals were enrolled (17 females/14 males; age range 0.1-17.5 years old at first MRI). An experienced pediatric neuroradiologist reviewed brain MRIs, blindly to clinical data. Brain abnormalities were observed in all but one individual (compared to the 34% frequency found in the literature review). Corpus callosum abnormalities were found in 20/30 (67%) patients: 6 had callosal hypoplasia; 8 had global hypoplasia with hypoplastic splenium; 4 had only hypoplastic splenium; and 2 had a thin corpus callosum. Cerebral hypoplasia/atrophy was found in 23/31 (74%) and ventriculomegaly in 20/31 (65%). Other frequent features were the enlargement of the cisterna magna in 15/30 (50%) and polymicrogyria in 14/29 (48%). Conversely, the frequency of the latter was found to be 4% from the literature review. Notably, in our population, polymicrogyria was in the perisylvian area in all 14 cases, and it was bilateral in 10/14. CONCLUSIONS: Brain abnormalities are very common in PKS and occur much more frequently than previously reported. Bilateral perisylvian polymicrogyria was a main aspect of our population. Our findings provide an additional tool for early diagnosis.Further studies to investigate the possible correlations with both genotype and phenotype may help to define the etiopathogenesis of the neurologic phenotype of this syndrome.

Expanding the Mutational Landscape and Clinical Phenotype of CHD2-Related Encephalopathy.

Objectives: To present a case series of novel CHD2 variants in patients presenting with genetic epileptic and developmental encephalopathy. Background: CHD2 gene encodes an ATP-dependent enzyme, chromodomain helicase DNA-binding protein 2, involved in chromatin remodeling. Pathogenic variants in CHD2 are linked to early-onset conditions such as developmental and epileptic encephalopathy, drug-resistant epilepsies, and neurodevelopmental disorders. Approximately 225 diagnosed patients from 28 countries exhibit various allelic variants in CHD2, including small intragenic deletions/insertions and missense, nonsense, and splice site variants. Results: We present the molecular and clinical characteristics of 17 unreported individuals from 17 families with novel pathogenic or likely pathogenic variants in CHD2. All individuals presented with severe global developmental delay, childhood-onset myoclonic epilepsy, and additional neuropsychiatric features, such as behavioral including autism, ADHD, and hyperactivity. Additional findings include abnormal reflexes, hypotonia and hypertonia, motor impairment, gastrointestinal problems, and kyphoscoliosis. Neuroimaging features included hippocampal signal alterations (4/10), with additional volume loss in 2 cases, inferior vermis hypoplasia (7/10), mild cerebellar atrophy (4/10), and cerebral atrophy (1/10). Discussion: Our study broadens the geographic scope of CHD2-related phenotypes, providing valuable insights into the prevalence and clinical characteristics of this genetic disorder in previously underrepresented populations.

Immediate and progressive neurological damage after electrical injury: A pediatric case report.

BACKGROUND: An electrical injury can cause multiple consequences, especially to the nervous system, both peripheral and central. Such consequences may present immediately as well as later on. AIMS OF THE STUDY: To report on a case of a 5-year-old boy with focal refractory status epilepticus after an electrical injury. METHODS: Clinical history, electroencephalography, neuroimaging, and laboratory data of a patient admitted to our emergency department. RESULTS: A 5-year-old male received an electrical shock by contact with an alternating current source after coming out of the pool. When reaching our emergency department, focal seizures was observed in the same site affected by the electrical insult, with progressive structural changes in the related brain area. In the days after, his neurological conditions dramatically evolved leading to brain death. CONCLUSIONS: Based on our knowledge, this is the first report on refractory status epilepticus in a child after electrical injury. The possible underlying pathogenetic mechanisms are not yet clear.

Neuroendoscopic treatment of symptomatic cyst of the septum pellucidum in children: A case series.

BACKGROUND: Symptomatic cysts of the septum pellucidum (CSP) are extremely rare in children and surgical indications are not well defined. A very careful clinical and neuroradiologic evaluation is necessary to consider a patient for surgical indication. METHODS: We present a surgical series of 7 pediatric patients. Clinical and radiological features of the patients, including clinical presentation, previous treatment, pre, and post-operative MRI, immediate postoperative, neuropsychiatric assessment, and outcomes were reviewed. RESULTS: There were 5 males and 2 females (mean age 8 yrs). Five patients presented a history of severe intermittent headaches, two of them were admitted with acute symptoms of raised intracranial pressure. One patient presented Epilepsy and ADHD and one patient had severe psychosis. Overall, psychiatric disorders were diagnosed in six patients, three patients had Intellectual Disability (ID). In all cases, the cyst presented a ballooning feature, with a mean volume of 18,36 cm3 (range 10,62-28,5) and significant lateral bulging of both layers. All were operated on endoscopically without complications. After surgery, a very significant decrease in cyst volume was observed (mean volume 5,68 cm3; range 3,18-10,1) with complete disappearance of the ballooning aspect. Headaches resolved in all patients. In two patients operated in emergency papilloedema and vision improved in the first week after surgery. No recurrence of the cysts was noted during follow-up in all patients. CONCLUSIONS: CSP may be associated with behavioral or psychiatric problems also in children. Neuroendoscopic surgery is a safe and effective therapeutic modality to treat CSP presenting with symptoms and signs of intracranial hypertension with good clinical results.