Cerebellar heterotopia in an 11-year-old child with KDM6B-related neurodevelopmental disorder: A case report and review of the literature.

Heterozygous pathogenic variants in KDM6B have recently been associated to a rare neurodevelopmental disorder referred to as "Neurodevelopmental disorder with coarse facies and mild distal skeletal abnormalities" and characterized by non-pathognomonic facial and body dysmorphisms, a wide range of neurodevelopmental and behavioral disorders and nonspecific neuroradiological findings. KDM6B encodes a histone demethylase, expressed in different tissues during development, which regulates gene expression through the modulation of chromatin accessibility by RNA polymerase. We herein describe a 11-year-old male patient carrying a novel de novo pathogenic variant in KDM6B exhibiting facial dysmorphisms, dysgraphia, behavioral traits relatable to oppositional defiant, autism spectrum, and attention deficit hyperactivity disorders, a single seizure episode, and a neuroimaging finding of a single cerebellar heterotopic nodule, never described to date in this genetic condition. These findings expand the phenotypic spectrum of this syndrome, highlighting the potential role for KDM6B in cerebellar development and providing valuable insights for genetic counseling.

The effect of executive function on health related quality of life in children with self-limited epilepsy with centrotemporal spikes.

AIM: The current study aims to investigate the effect of Executive Functions (EFs) on Health Related Quality of Life (HRQoL) in a cohort of children with self-limited epilepsy with centrotemporal spikes (SeLECTS) and to identify possible factors that impact HRQoL specifically related to epilepsy-related variables and EFs skills. MATERIAL AND METHOD: The Pediatric Quality of Life Inventory 4.0 Generic Core Scales (PedsQL) and The Behavior Rating Inventory of Executive Function (BRIEF-2 and BRIEF-P) were completed by the parents of 129 patients with SeLECTS. Demographic variables and epilepsy-related variables were collected. RESULTS: Our sample performed in the average range across all the subscales and summary scores of the PedsQL and performed in the normal range of the BRIEF questionnaire. We observed that a lower functioning in EFs was associated with lower overall HRQoL scores. We explored the relationship between epilepsy characteristics and scores on the PedsQL. We found that the use of antiseizure medications (ASMs), longer duration of the treatment, and a higher seizure frequency were associated with a lower HRQoL. Moreover, we observed that executive dysfunction was a significant predictor of reduced HRQoL. CONCLUSION: Our results suggest the importance of the identification of patients with SeLECTS with a high level of risk for a poor HRQoL. We may now add executive dysfunction to the list of known risk factors for poor HRQoL in children with SeLECTS, along with such factors as seizure frequency, recent seizures, use of ASMs and longer duration of therapy. The early identification of children with SeLECTS at risk of a poor HRQoL could allow the activation of adequate interventions.

The effects of ketogenic dietary therapies on sleep: A scoping review.

Sleep problems are common in neurological conditions for which ketogenic dietary therapies (KDTs) are recognised as an effective intervention (drug-resistant epilepsy, autism spectrum disorder, and migraine). Given the composite framework of action of ketogenic dietary therapies, the prevalence of sleep disturbance, and the importance of sleep regulation, the present scoping review aimed at identifying and mapping available evidence of the effects of ketogenic dietary therapies on sleep. A comprehensive web-based literature search was performed retrieving publications published to June 2023 using PubMed and Scopus, yielding to 277 records. Twenty papers were finally selected and included in the review. Data were abstracted by independent coders. High variability was identified in study design and sleep outcome evaluation among the selected studies. Several changes in sleep quality and sleep structure under ketogenic dietary therapies were found, namely an improvement of overall sleep quality, improvement in the difficulty falling asleep and nighttime awakenings, improvement in daytime sleepiness and an increase of REM sleep. The relevance and possible physiological explanations of these changes, clinical recommendations, and future directions in the field are discussed.

Impact of COVID-19 pandemic in pediatric patients with epilepsy with neuropsychiatric comorbidities: A telemedicine evaluation.

OBJECTIVE: The objective of this study was to evaluate care needs, emotional and behavioral changes, and parental stress indices in a cohort of pediatric patients with epilepsy with neurocognitive and emotional comorbidities at the time of the coronavirus disease 2019 (COVID-19) pandemic. METHODS: This is a prospective observational study involving pediatric patients with epilepsy with neurocognitive and emotional comorbidities. Included patients were admitted to our hospital between August 2019 and February 2020 for epilepsy and neuropsychiatric assessment, and Child Behavior Checklist (CBCL) questionnaires were filled in by parents. Those patients and their families accepted to participate in a phone follow-up visit in April-May 2020 and to refill CBCL and Parenting Stress Index-Short Form (PSI-SF) questionnaires. Descriptive statistics for demographic and clinical data, CBCL questionnaire scores before and during the COVID-19 pandemic, and PSI-SF scores have been computed. Moreover, results of a short phone survey on the psychological burden during COVID lockdown have been reported. RESULTS: This study provides the parental-proxy report of emotional and behavioral profile changes of 23 pediatric patients with epilepsy and neurocognitive and emotional comorbidities during the COVID-19 pandemic. Concerns for therapy monitoring at the time of lockdown emerged in 43% of families, and 30% of patients showed worries for an altered contact with the referring medical team. Patients with neurocognitive comorbidities were more likely to exhibit behavioral problems, especially externalizing problems compared with patients with a diagnosis of anxiety/depression. CONCLUSION: Our data suggest the importance to monitor disease trajectory and behavior and affective symptoms with telehealth strategies to provide effective care to patients and their families.

Systematic review of executive functions in children with self-limited epilepsy with centrotemporal spikes.

Self-limited Epilepsy with Centrotemporal Spikes (ECTS) is a self-limiting childhood epilepsy with an overall good prognosis. The neurocognitive profile of ECTS shows various degrees of neuropsychological impairment, with speech impairment and executive dysfunction being the most prominent. This review aimed to clarify the executive function (EF) profile of children with ECTS and the clinical variables' impact on these abilities. We conducted a systematic review of the relevant literature for articles published up to January 2021. Demographic and clinical characteristics were abstracted from the original records. EF tasks used in the studies were classified according to Diamond's model, which identified four components: working memory, inhibitory control, cognitive flexibility, and higher order EFs. Twenty-three studies were included. Among the included records, 14 studies examined working memory, 15 inhibitory control, 15 flexibility, 4 higher order EFs, and 2 general EFs. Results confirmed the presence of a specific impairment in two abilities: inhibitory control and cognitive flexibility. This review confirms the need to assess each EF both in verbal and visual-spatial tasks. The early detection of children with ECTS at risk of developing neuropsychological impairment could activate interventions and prevent worse school achievement, social functioning, and a poor quality of life. Systematic review registration: PROSPERO: CRD42021245959.

Alazami syndrome: Phenotypic expansion and clinical resemblance to Smith-Lemli-Opitz syndrome.

Biallelic mutations in the LARP7 gene have been recently shown to cause Alazami syndrome, a rare condition characterized by short stature, intellectual disability, and peculiar facial dysmorphisms. To date, only 24 cases have been reported. Here, we describe two brothers initially suspected to have Smith-Lemli-Opitz syndrome, in whom clinical exome sequencing detected a novel homozygous truncating variant in LARP7. These cases expand the phenotypic spectrum of Alazami syndrome to include toes syndactyly and adaptive behavior, and confirm the power of "genotype first" approach in patients with syndromic presentations overlapping distinct rare conditions.

Pathways to quality of life in adolescents with genetic generalized epilepsy: The role of seizure features and affective symptoms.

Both clinical features of seizures and affective problems (i.e., depressive and/or anxious symptoms) affect quality of life perception in patients with epilepsy. Although genetic generalized epilepsies (GGEs) represent one-third of all epilepsies, very few studies focused on the association among seizures, affective problems, and perceived quality of life in pediatric patients with GGE. Here, we assessed the relative contributions of seizure characteristics and affective symptoms on quality of life in patients with adolescence-onset GGE. Forty pediatric outpatients completed self-report questionnaires on affective symptoms and quality of life. Sociodemographic and clinical variables were obtained from medical charts. Affective symptoms were present in 40% of patients. Higher scores emerged in patients who were seizure-free at the time of the survey for both the physical and mental components of quality of life. Higher seizure frequency was significantly associated with lower quality of life scores in the mental component, whereas the presence of depressive and/or anxious symptoms was significantly associated with lower scores in the physical component. These associations were confirmed after controlling for sociodemographic confounders. These findings suggest that adolescents with GGE are at increased risk for affective symptoms. Moreover, both GGE-related clinical features (i.e., seizure frequency) and the presence of affective symptoms (i.e., depression, anxiety) are relevant and independent contributors to quality of life. The investigation of affective problems is warranted to be included in routine assessments of GGE in pediatric populations.

Adherence to ketogenic dietary therapies in epilepsy: A systematic review of literature.

Treatment adherence, defined as the degree to which the patient actively follows the plan of care, is very difficult for subjects undergoing ketogenic dietary therapies (KDTs). This is a relevant issue because adherence to dietary therapies is considered 1 of the primary determinants of the treatment's success. This paper aimed to review the literature evidence about KDT adherence according to age and diagnosis of patients. Performed based on the Preferred Reporting Items for Systematic Reviews and Meta-Analyses method, this systematic review included clinical trials and observational studies. The risk of bias was assessed by the RoB 2.0 Cochrane tool and the quality of evidence according to the Mixed Methods Appraisal Tool system. Twenty-two articles were included, with more than half (n = 12) having average quality (2-3 stars). The studies' heterogeneity in measuring adherence and diagnosis made it difficult to compare results. Mean adherence rates were 71.5%, 66%, and 63.9% for children, adolescents, and adults, respectively. Adherence and compliance rates varied according to the follow-up period (79.7%, 66.7%, and 37.7% at 6, 24, and 36 months, respectively). The most frequent reasons for low adherence were linked to inefficacy in seizure control, adverse effects, food refusal, difficulty in preparing KDT meals or diet restrictiveness, lack of motivation, poor parental compliance, or cost of the diet. To conclude, there is a lack of standardized tools to measure adherence. Several studies highlighted the families' challenges in adhering to KDTs. These factors should be considered when creating strategies and resources on family education.

GLUT1DS focus on dysarthria.

RESEARCH PURPOSE: GLUT1 deficiency syndrome (GLUT1DS) is a rare genetic disorder caused by a mutation in the SLC2A1 gene that limits the transport of glucose across the blood-brain barrier. Speech disorders and dysarthria are typical findings in patients with GLUT1DS, but have never been deeply phenotyped. The aim of the present study was to characterize speech abilities in a sample of patients with GLUT1DS. RESULTS: 30 patients with GLUT1DS were recruited. We reported impairments in different speech and oromotor domains: the speech was characterized by dysarthria, inaccurate articulation of consonants, abnormal nasal resonance, errors in intonation and prosody and low intelligibility. We observed difficulties in motor planning and programming. Moreover, we observed a significant difference between the dysarthric level of impairment with genotype groups. CONCLUSIONS: The presence of a speech disorder in patients with GLUT1DS represents a core feature of the syndrome. Our findings suggest that patients with GLUT1DS would benefit from a comprehensive neurocognitive assessment to detect strengths and weaknesses of the speech profile. Understanding the speech and language phenotype in GLUT1DS is critical for planning early intervention to positively influence the global development of patients with GLUT1DS.

Case report: KETOLAND the psychoeducation program for ketogenic diet.

Glucose transporter type 1 deficiency syndrome (GLUT1DS) is a rare neurological disorder characterized by a wide spectrum of symptoms: epilepsy, movement disorders and neurocognitive impairment. The gold standard treatment for GLUT1DS are ketogenic dietary therapies (KDTs), specifically classical ketogenic diet (CKD). Despite the benefits, CKD often represents a challenge for patients and their families since meal preparation is extremely demanding and deviates a lot from normal diet. To assure an optimal compliance to CKD a psychological support for parents and patients with GLUT1DS is highly recommended. Specifically, a psychoeducational intervention that ameliorates the knowledge about the illness and its therapy improves treatment' s adherence and efficacy. The aim of this case report is to investigate the effectiveness of a psychoeducational program, partially implemented through telepsychology, based on the theoretical model of Cognitive Behavioral Play Therapy (CBPT) to support KDT knowledge and adherence in a patient with GLUT1DS who presented a worsening of her clinical picture due to a sparse knowledge of KDTs principles which determined a low adherence. Thus, with this case report we propose a model of intervention with psychoeducation in a patient with a complex chronic disease.

Electroclinical Improvement in a Patient with Ring Chromosome 20 Syndrome Treated with Zonisamide: A Case Report.

Ring chromosome 20 or r(20) syndrome is a rare chromosomal disorder, mainly characterized by childhood-onset drug-resistant epilepsy with typical electroencephalographic findings, followed by mild to severe cognitive-behavioral decline. Recent studies support a possible role of the dopaminergic system in the epileptogenesis of this syndrome. We report the case of a 13-year-old female with mosaic r(20) who showed typical disease onset and evolution and a remarkable electroclinical improvement with zonisamide. Epilepsy related to r(20) is often medically intractable. When valproate and lamotrigine are not effective, zonisamide could be further investigated as a therapeutic option, since it acts as antifocal and it has a potential role in the prevention of dopamine depletion.

Validation of an Italian Questionnaire of Adherence to the Ketogenic Dietary Therapies: iKetoCheck.

Ketogenic dietary therapies (KDTs) are an effective and safe non-pharmacological treatment for drug-resistant epilepsy, but adherence can be challenging for both patients and caregivers. In Europe, there are no adequate tools to measure it other than monitoring ketosis. This study aimed to adapt and validate the Brazilian adherence questionnaire, Keto-check, into the Italian version: iKetoCheck. Using the Delphi technique, 12 judges validated the contents through agreement rates and the Content Validity Index (CVI). The iKetocheck was self-completed electronically by 61 drug-resistant epilepsy or GLUT1 deficiency patients within an interval of 15 days to measure its reproducibility. The test-retest reliability was evaluated using Pearson's correlation and relative significance test. Exploratory and confirmatory factorial analyses were made using Factor software version 12.03.02. The final tool, iKetoCheck, consists of 10 questions with 5-point Likert scale answers. It evaluates various aspects such as informing caregivers about the diet, organization of meals, measurement of ketosis, weighing food consumed, diet negligence, use of carbohydrate-free medications, attending follow-up visits, reading food labels, consulting an expert for dietary concerns, and cooking at home. The factorial analysis resulted in three factors: "attention," "organization," and "precision," with satisfactory results for indices in exploratory and confirmatory analyses. Although higher mean values of ketonemia measurement were observed in patients with a higher adherence score, these values were not statistically significant (p = 0.284). In conclusion, despite the small sample size, iKetoCheck is a valid tool for evaluating KDTs' adherence in Italian drug-resistant epilepsy or GLUT1 deficiency patients. It can provide valuable information to improve patient management and optimize the effectiveness of KDTs.

WISC-IV intellectual profiles in Italian children with self-limited epilepsy with centrotemporal spikes.

OBJECTIVE: This study aimed to describe the intellectual profile based on the Wechsler Intelligence Scale for Children 4th edition (WISC-IV) in children with self-limited epilepsy with centrotemporal spikes (SeLECTS), with an attempt to define possible predictive epilepsy-related variables of cognitive performance. METHODS: The WISC-IV was assessed in 161 children with SeLECTS and their cognitive profiles were compared to a matched sample of healthy control children. RESULTS: Children with SeLECTS performed within normal range across all indices, demonstrating particular strength based on the Perceptual Reasoning Index. Compared to healthy control children, we observed a significant difference in performance based on the Full Scale Intelligence Quotient, Verbal Comprehension Index and Processing Speed Index. Regarding epilepsy-related variables, earlier onset of epilepsy, use of anti-seizure medications, the presence of neurodevelopmental disorders, a higher frequency of seizures, and a longer treatment duration were associated with an overall lower level of performance. SIGNIFICANCE: Children with SeLECTS performed within the average range for cognitive assessment based on the WISC-IV, demonstrating that children had normal levels of global intelligence. However, compared to healthy control children, children with SeLECTS showed a slightly lower level of performance. Reasoning skills represented the relative strengths in children with SeLECTS. Predictors of intellectual performance in patients with SeLECTS include epilepsy-related variables and neurodevelopmental comorbidities.

Ketogenic dietary therapies in epilepsy: recommendations of the Italian League against Epilepsy Dietary Therapy Study Group.

A stepwise increase in the utilization of ketogenic dietary therapies for drug-resistant epilepsy has been observed in Italy in the last decade, although it is still considered often underused in many centers when compared to other countries. The Dietary Therapy Study Group of the Italian League against Epilepsy proposes practical recommendations to improve shared knowledge and facilitate the application of ketogenic dietary therapies, optimizing its efficacy and tolerability. The experts involved (11 child neuropsychiatrists, two adult neurologists, one psychologist, one pharmacologist, one pediatric endocrinologist, one representative of patients' associations, and three dietitians and clinical nutritionists) responded to a survey on current clinical practice issues and were asked to discuss controversial topics related to supplementation, long-term maintenance, transition, and a multidisciplinary approach to ketogenic dietary therapies. Practical indications for patient selection, diet initiation, management, side effects prevention, and follow-up are provided.

Characterization of Speech and Language Phenotype in GLUT1DS.

BACKGROUND: To analyze the oral motor, speech and language phenotype in a sample of pediatric patients with GLUT 1 transporter deficiency syndrome (GLUT1DS). METHODS: eight Italian-speaking children with GLUT1DS (aged 4.6-15.4 years) in stable treatment with ketogenic diet from a variable time underwent a specific and standardized speech and language assessment battery. RESULTS: All patients showed deficits with different degrees of impairment in multiple speech and language areas. In particular, orofacial praxis, parallel and total movements were the most impaired in the oromotor domain; in the speech domain patients obtained a poor performance in the diadochokinesis rate and in the repetition of words that resulted as severely deficient in seven out of eight patients; in the language domain the most affected abilities were semantic/phonological fluency and receptive grammar. CONCLUSIONS: GLUT1DS is associated to different levels of speech and language impairment, which should guide diagnostic and therapeutic intervention. Larger population data are needed to identify more precisely a speech and language profile in GLUT1DS patients.

Ketogenic Dietary Therapies in Patients with Autism Spectrum Disorder: Facts or Fads? A Scoping Review and a Proposal for a Shared Protocol.

Autism spectrum disorder (ASD) is a neurodevelopmental disorder with increasing incidence. An expanding body of literature is examining connections between ASD and dietary interventions. Existing reports suggest a beneficial effect of ketogenic dietary therapies (KDTs) in improving behavioral symptoms in ASD. In this context, the purpose of this scoping review was to identify and map available evidence in the literature about the feasibility and potential efficacy of KDTs in pediatric patients with ASD and to inform clinical practice in the field. Moreover, based on the resulting data from the literature review, we aimed to provide a shared protocol to develop a personalized KDT intervention in patients with ASD. A comprehensive and structured web-based literature search was performed using PubMed and Scopus and it yielded 203 records. Seven papers were finally selected and included in the review. Data were abstracted by independent coders. High variability was identified in study designs and dietary aspects emerged among selected studies. Results supported the effectiveness of KDTs in promoting behavioral improvements. Clinical recommendations on which patients may benefit most from KDTs implementation and difficulties in dietary adherence were discussed.

Childhood Epilepsy with Centrotemporal Spikes: Clinical and Neuropsychological Outcomes 5 Years after Remission.

Although specific neuropsychological deficits have been recognized during the active phase of epilepsy with centrotemporal spikes (ECTS), the natural cognitive and neuropsychological history after remission has not been elucidated so far. We evaluated the natural cognitive and neuropsychological outcomes five years after disease remission and investigated possible predictors of long-term outcome among socio-demographic and electro-clinical variables. We performed an observational cross-sectional study. Electro-clinical characteristics during the active phase of epilepsy, as well as antiepileptic treatment and premorbid neurodevelopmental concerns were reviewed for 70 patients. At least five years after epilepsy remission, all patients were contacted, and 46 completed a structured questionnaire about patients' current education and academic skills, general health, and parents' socio-economic status. Among them, 23 patients underwent an ad hoc cognitive and neuropsychological protocol and emotional-behavioral assessment. Chi-square tests and t-tests were carried out to define the role of putative predictors of neuropsychological outcomes. Mean cognitive and neuropsychological performances appeared to be overall adequate, except for the dictation. Positive family history for epilepsy (p = 0.01769) and familial socioeconomic status (mother's schooling (p = 0.04169), father's schooling (p = 0.01939), mother's income (p = 0.0262), father's income (p = 0.01331)) were identified as predictors of outcomes. Our data suggest that ECTS with typical electro-clinical features depicts an overall preserved cognitive and neuropsychological long-term outcome. We suggest particular attention should be paid to patients with socio-economic disadvantage and familial history of epilepsy, as they may experience worse neurocognitive post-morbid performances.

Quality of Life in Chronic Ketogenic Diet Treatment: The GLUT1DS Population Perspective.

BACKGROUND: Glucose transporter type 1 deficiency syndrome (GLUT1DS) is a rare, genetically determined neurological disorder, for which Ketogenic Diet (KD) represents the gold standard life-long treatment. The aim of this study is to investigate health related quality of life in a well characterized cohort of patients affected by GLUT1DS treated with KD, evaluating factors that can influence patients' and parents' quality of life perception. METHODS: This is a double center exploratory research study. A postal survey with auto-administrable questionnaires was conducted among 17 subjects (aged 3-22 years) with diagnosis of GLUT1DS, receiving a stable KD treatment for more than 1 year. The Pediatric Quality of Life Inventory (PedsQL) 4.0 Generic Core Scales was adopted. Clinical variables analyzed in relation to quality of life were frequency of epileptic seizures and movement disorder since KD introduction, presence of intellectual disability (ID), and KD ratio. RESULTS: Quality of life global scores were impaired both in parents' and children's perspectives, with a significant concordance. Taking into consideration subscales, the average was 64.17 (range 10-100) for physical functioning, 74.23 (range 30-100) for emotional functioning, 62.64 (range 10-100) for social functioning, and 56 (range 15-92) for school functioning. CONCLUSIONS: In patients with GLUT1DS the quality of life perception is comparable to that of other patients with chronic disease. In our sample, the presence of movement disorder seems to be a crucial element in quality of life perception.