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

Altered DNA methylation and gene expression predict disease severity in patients with Aicardi-Goutieres syndrome

Aicardi-Goutières Syndrome (AGS) is a rare neuro-inflammatory disease characterized by increased expression of interferon-stimulated genes (ISGs). Disease-causing mutations are present in genes associated with innate antiviral responses. Disease presentation and severity vary, even between patients with identical mutations from the same family. This study investigated DNA methylation signatures in PBMCs to understand phenotypic heterogeneity in AGS patients with mutations in RNASEH2B. AGS patients presented hypomethylation of ISGs and differential methylation patterns (DMPs) in genes involved in "neutrophil and platelet activation". Patients with "mild" phenotypes exhibited DMPs in genes involved in "DNA damage and repair", whereas patients with "severe" phenotypes had DMPs in "cell fate commitment" and "organ development" associated genes. DMPs in two ISGs (IFI44L, RSAD2) associated with increased gene expression in patients with "severe" when compared to "mild" phenotypes. In conclusion, altered DNA methylation and ISG expression as biomarkers and potential future treatment targets in AGS

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

Ketonemia variability through menstrual cycle in patients undergoing classic ketogenic diet

IntroductionKetogenic 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.MethodsThis 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.ResultsWe 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.ConclusionExploring 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 registrationclinicaltrials.gov, identifier NCT05234411

The spectrum of intermediate SCN8A-related epilepsy

Objective: Pathogenic variants in SCN8A have been associated with a wide spectrum of epilepsy phenotypes, ranging from benign familial infantile seizures (BFIS) to epileptic encephalopathies with variable severity. Furthermore, a few patients with intellectual disability (ID) or movement disorders without epilepsy have been reported. The vast majority of the published SCN8A patients suffer from severe developmental and epileptic encephalopathy (DEE). In this study, we aimed to provide further insight on the spectrum of milder SCN8A-related epilepsies. Methods: A cohort of 1095 patients were screened using a next generation sequencing panel. Further patients were ascertained from a network of epilepsy genetics clinics. Patients with severe DEE and BFIS were excluded from the study. Results: We found 36 probands who presented with an SCN8A-related epilepsy and normal intellect (33%) or mild (61%) to moderate ID (6%). All patients presented with epilepsy between age 1.5 months and 7 years (mean = 13.6 months), and 58% of these became seizure-free, two-thirds on monotherapy. Neurological disturbances included ataxia (28%) and hypotonia (19%) as the most prominent features. Interictal electroencephalogram was normal in 41%. Several recurrent variants were observed, including Ile763Val, Val891Met, Gly1475Arg, Gly1483Lys, Phe1588Leu, Arg1617Gln, Ala1650Val/Thr, Arg1872Gln, and Asn1877Ser. Significance: With this study, we explore the electroclinical features of an intermediate SCN8A-related epilepsy with mild cognitive impairment, which is for the majority a treatable epilepsy.Peer reviewe

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

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

Characterization of Mitochondrial Alterations in Aicardi–Goutières Patients Mutated in <i>RNASEH2A</i> and <i>RNASEH2B</i> Genes

Aicardi–Goutières syndrome (AGS) is a rare encephalopathy characterized by neurological and immunological features. Mitochondrial dysfunctions may lead to mitochondrial DNA (mtDNA) release and consequent immune system activation. We investigated the role of mitochondria and mtDNA in AGS pathogenesis by studying patients mutated in RNASEH2B and RNASEH2A genes. Lymphoblastoid cell lines (LCLs) from RNASEH2A- and RNASEH2B-mutated patients and healthy control were used. Transmission Electron Microscopy (TEM) and flow cytometry were used to assess morphological alterations, reactive oxygen species (ROS) production and mitochondrial membrane potential variations. Seahorse Analyzer was used to investigate metabolic alterations, and mtDNA oxidation and VDAC1 oligomerization were assessed by immunofluorescence. Western blot and RT-qPCR were used to quantify mtTFA protein and mtDNA release. Morphological alterations of mitochondria were observed in both mutated LCLs, and loss of physiological membrane potential was mainly identified in RNASEH2A LCLs. ROS production and 8-oxoGuanine levels were increased in RNASEH2B LCLs. Additionally, the VDAC1 signal was increased, suggesting a mitochondrial pore formation possibly determining mtDNA release. Indeed, higher cytoplasmic mtDNA levels were found in RNASEH2B LCLs. Metabolic alterations confirmed mitochondrial damage in both LCLs. Data highlighted mitochondrial alterations in AGS patients’ LCLs suggesting a pivotal role in AGS pathogenesis

Use of Remote Monitoring by E-mail for Long-Term Management of the Classic Ketogenic Diet

The classic ketogenic diet (cKD) requires constant nutritional monitoring over time both to ensure its effectiveness and to reduce the likelihood of short- and long-term adverse effects. We retrospectively described the use of remote monitoring by e-mail during the first year of follow-up on cKD in 34 children (47% males; age range: 2&minus;17 years) diagnosed with drug-resistant epilepsy (DRE; n = 14) or glucose transporter type 1 deficiency syndrome (GLUT1-DS; n = 20). All the e-mails were evaluated analyzing their frequency and content at 3, 6 and 12 months. Three families never sent e-mails. A median of 36.0 (IQR 23.0&ndash;64.0) e-mails per family were sent during the 12 follow-up months by the 31 patients. GLUT1-DS patients sent a greater number of e-mails than the DRE group (median 39.0 (IQR 25.5&ndash;56.5) vs. median 26.0 (IQR 19.0&ndash;65.0)). At the end of the follow-up period, a greater number of e-mails had been exchanged between the nutritional team and the families belonging to the group that increased its linear growth (median 83.5; IQR 48.0&ndash;102.0), compared to the other ones. Constant remote monitoring by e-mail could be a feasible and effective way for a better cKD management

Blindness affects the developmental trajectory of the sleeping brain

Sleep plays a crucial role in brain development, sensory information processing, and consolidation. Sleep spindles are markers of these mechanisms as they mirror the activity of the thalamocortical circuits. Spindles can be subdivided into two groups, slow (10–13 Hz) and fast (13–16 Hz), which are each associated with different functions. Specifically, fast spindles oscillate in the high-sigma band and are associated with sensorimotor processing, which is affected by visual deprivation. However, how blindness influences spindle development has not yet been investigated. We recorded nap video-EEG of 50 blind/severely visually impaired (BSI) and 64 sighted children aged 5 months to 6 years old. We considered aspects of both macro- and micro-structural spindles. The BSI children lacked the evolution of developmental spindles within the central area. Specifically, young BSI children presented low central high-sigma and high-beta (25–30 Hz) event-related spectral perturbation and showed no signs of maturational decrease. High-sigma and high-beta activity in the BSI group correlated with clinical indices predicting perceptual and motor disorders. Our findings suggest that fast spindles are pivotal biomarkers for identifying an early developmental deviation in BSI children. These findings are critical for initial therapeutic intervention