PGAP2-Related Hyperphosphatasia-Mental Retardation Syndrome: Report of a Novel Patient, Toward a Broadening of Phenotypic Spectrum and Therapeutic Perspectives.

PGAP2 gene has been known to be the cause of "hyperphosphatasia, mental retardation syndrome-3" (HPMRS3). To date, 14 pathogenic variants in PGAP2 have been identified as the cause of this syndrome in 24 patients described in single-case reports or small clinical series with pan-ethnic distribution. We aim to present a pediatric PGAP2-mutated case, intending to further expand the clinical phenotype of the syndrome and to report our experience on a therapeutic approach to drug-resistant epilepsy.We present the clinical, neuroradiological, and genetic characterization of a Caucasian pediatric subject with biallelic pathogenic variants in the PGAP2 gene revealed by next generation sequencing analysis.We identified a subject who presented with global developmental delay and visual impairment. Brain magnetic resonance imaging showed mild hypoplasia of the inferior cerebellar vermis and corpus callosum and mild white matter reduction. Laboratory investigations detected an increase in alkaline phosphatase. At the age of 13 months, he began to present epileptic focal seizures with impaired awareness, which did not respond to various antiseizure medications. Electroencephalogram (EEG) showed progressive background activity disorganization and multifocal epileptic abnormalities. Treatment with high-dose pyridoxine showed partial benefit, but the persistence of seizures and the lack of EEG amelioration prompted us to introduce ketogenic diet treatment.Our case provides a further phenotypical expansion of HPMRS3 to include developmental and epileptic encephalopathy. Due to the limited number of patients reported so far, the full delineation of the clinical spectrum of HPMRS3 and indications for precision medicine would benefit from the description of new cases and their follow-up evaluations.

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.

Behavioral Phenotype, Electroclinical Features, and Treatment Options in Twins with Lrp2 Candidate Variants (Donnay-Barrow/Foar Syndrome).

The LRP2 gene encodes megalin (LRP-2/GP330), a large single-spanning transmembrane glycoprotein that serves as a multiligand endocytotic receptor and mediates the reabsorption of albumin in the proximal renal tubule. LRP2 is implicated in an autosomal recessive disorder characterized by dimorphisms, ocular anomalies, sensorineural deafness, proteinuria, epilepsy, and intellectual disability: a clinical condition called Donnai-Barrow syndrome (DBS) or facio-oculo-acoustico-renal (FOAR) syndrome. Pathogenic variants in LRP2 have been reported in fewer than 60 patients, but a detailed description of seizures, electroencephalographic patterns, imaging findings, behavioral phenotype, and long-term follow-up is still needed. We provide a clinical report of two mono-chorionic twins with LRP2-related disease manifesting developmental delay, autistic features, seizures, proteinuria, and sleep disorders. By sequencing clinical exome, LRP2 candidate rare variants, c.6815G > A, p. (Arg2272His), inherited from the mother and c.12725A > G, p. (Asp4242Gly), inherited from the father, were identified. During follow-up, at the age of 7, the main clinical features of the patients included insomnia, autistic features, severe psychomotor delay, and absent speech. The patients were under treatment with risperidone, antiseizure medications (ASMs), and supplementation of alpha-lactalbumin for self-injury and sleep disturbance. Our study confirmed the wide spectrum of behavioral and neurological and psychiatric features of this rare condition, suggesting new treatment options.

Ketonemia variability through menstrual cycle in patients undergoing classic ketogenic diet.

Introduction: Ketogenic dietary therapies (KDT) are well-established, safe, non-pharmacologic treatments used for children and adults with drug-resistant epilepsy and other neurological disorders. Ketone bodies (KBs) levels are recognized as helpful to check compliance to the KDT and to attempt titration of the diet according to the individualized needs. KBs might undergo inter-individual and intra-individual variability and can be affected by several factors. Possible variations in glycemia and ketone bodies blood levels according to the menstrual cycle have not been systematically assessed yet, but this time window deserves special attention because of hormonal and metabolic related changes. Methods: This study aims at searching for subtle changes in KBs blood level during menstrual cycle in female patients undergoing a stable ketogenic diet, by analyzing 3-months daily measurement of ketone bodies blood levels and glucose blood levels throughout the menstrual cycle. Results: We report the preliminary results on six female patients affected by GLUT1DS or drug resistant epilepsy, undergoing a stable classic ketogenic diet. A significant increase in glucose blood levels during menstruation was found in the entire cohort. As far as the ketone bodies blood levels, an inversely proportional trend compared to glycemia was noted. Conclusion: Exploring whether ketonemia variations might occur according to the menstrual cycle is relevant to determine the feasibility of transient preventive diet adjustments to assure a continuative treatment efficacy and to enhance dietary behavior support. Clinical trial registration: clinicaltrials.gov, identifier NCT05234411.

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.

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.

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.

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.

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.