Next Generation Sequencing and Electromyography Reveal the Involvement of the P2RX6 Gene in Myopathy.

Ion channelopathies result from impaired ion channel protein function, due to mutations affecting ion transport across cell membranes. Over 40 diseases, including neuropathy, pain, migraine, epilepsy, and ataxia, are associated with ion channelopathies, impacting electrically excitable tissues and significantly affecting skeletal muscle. Gene mutations affecting transmembrane ionic flow are strongly linked to skeletal muscle disorders, particularly myopathies, disrupting muscle excitability and contraction. Electromyography (EMG) analysis performed on a patient who complained of weakness and fatigue revealed the presence of primary muscular damage, suggesting an early-stage myopathy. Whole exome sequencing (WES) did not detect potentially causative variants in known myopathy-associated genes but revealed a novel homozygous deletion of the P2RX6 gene likely disrupting protein function. The P2RX6 gene, predominantly expressed in skeletal muscle, is an ATP-gated ion channel receptor belonging to the purinergic receptors (P2RX) family. In addition, STRING pathways suggested a correlation with more proteins having a plausible role in myopathy. No previous studies have reported the implication of this gene in myopathy. Further studies are needed on patients with a defective ion channel pathway, and the use of in vitro functional assays in suppressing P2RX6 gene expression will be required to validate its functional role.

Drug resistant epilepsies: A multicentre case series of steroid therapy.

PURPOSE: Our study aimed to evaluate the effectiveness of corticosteroids on seizure control in drug-resistant epilepsies (DREs). Our primary goal was to assess the response to steroids for various underlying etiologies, interictal electroencephalographic (EEG) patterns and electroclinical seizure descriptions. Our second goal was to compare steroid responsiveness to different treatment protocols. METHODS: This is a retrospective multicentre cohort study conducted according to the STROBE guidelines (Strengthening the Reporting of Observational Studies in Epidemiology). The following data were collected for each patient: epilepsy etiology, interictal EEG pattern, seizure types and type of steroid treatment protocol administered. RESULTS: Thirty patients with DRE were included in the study. After 6 months of therapy, 62.7 % of patients experienced reduced seizure frequency by 50 %, and 6.6 % of patients experienced complete seizure cessation. Findings associated with favourable response to steroids included structural/lesional etiology of epilepsy, immune/infectious etiology and focal interictal abnormalities on EEG. Comparing four different steroid treatment protocols, the most effective for seizure control was treatment with methylprednisolone at the dose of 30 mg/kg/day administered for 3 days, leading to greater than 50 % seizure reduction at 6 months in 85.7 % of patients. Treatment with dexamethasone 6 mg/day for 5 days decreased seizure frequency in 71.4 % of patients. Hydrocortisone 10 mg/kg administered for 3 months showed a good response to treatment in 71 %. CONCLUSIONS: In our study, two-thirds of patients with DRE experienced a significant seizure reduction following treatment with steroids. We suggest considering steroids as a potential therapeutic option in children with epilepsy not responding to conventional antiseizure medicines (ASM).

Whole Exome Sequencing as a First-Line Molecular Genetic Test in Developmental and Epileptic Encephalopathies.

Developmental and epileptic encephalopathies (DEE) are severe neurodevelopmental disorders characterized by recurrent, usually early-onset, epileptic seizures accompanied by developmental impairment often related to both underlying genetic etiology and abnormal epileptiform activity. Today, next-generation sequencing technologies (NGS) allow us to sequence large portions of DNA quickly and with low costs. The aim of this study is to evaluate the use of whole-exome sequencing (WES) as a first-line molecular genetic test in a sample of subjects with DEEs characterized by early-onset drug-resistant epilepsies, associated with global developmental delay and/or intellectual disability (ID). We performed 82 WESs, identifying 35 pathogenic variants with a detection rate of 43%. The identified variants were highlighted on 29 different genes including, 3 new candidate genes (KCNC2, STXBP6, DHRS9) for DEEs never identified before. In total, 23 out of 35 (66%) de novo variants were identified. The most frequently identified type of inheritance was autosomal dominant de novo (60%) followed by autosomal recessive in homozygosity (17%) and heterozygosity (11%), autosomal dominant inherited from parental mosaicism (6%) and X-linked dominant de novo (6%). The most frequent mutations identified were missense (75%) followed by frameshift deletions (16%), frameshift duplications (5%), and splicing mutations (3%). Considering the results obtained in the present study we support the use of WES as a form of first-line molecular genetic testing in DEEs.

An online survey among general pediatricians on melatonin use in children with chronic insomnia.

OBJECTIVES: Although melatonin (MLT) is the molecule most used by pediatricians for sleep problems, scarce evidence exists on its use in healthy pediatric population. The objective of this study was to describe MLT use by Italian pediatricians in healthy children with chronic insomnia. STUDY DESIGN: A cross-sectional open survey was administered to Italian pediatricians, between June and November 2022, collecting information about their use of MLT in healthy children: age range of patients, dosages used, time of administration, duration of treatment, association with other treatments, perceived efficacy, and side effects. Data were reported as frequencies with their respective 95% confidence intervals. Chi-square statistics assessed significant differences between pediatricians who had training in pediatric sleep and those who did not. RESULTS: Among 428 respondents, 97.4% of pediatricians used MLT; 87.3% of them prescribed MLT in children aged 1-2 years, 62.1% in 2-5 years and 42.5% in 10-18 years. 84.9% of them suggested to take MLT 30 min before bedtime. 37.9% indicated to continue treatment for one month, 30.2% for 2-3 months. 74.1% of pediatricians usually prescribed MLT 1 mg/day. The most frequent treatment associated with MLT was sleep hygiene (85.4%). Almost all pediatricians found MLT effective in reducing difficulties falling asleep. Only 3.2% of them reported mild side effects. CONCLUSIONS: MLT is widely prescribed by Italian pediatricians, but no consensus exists about its use in typically developing children. There is a need for clear guidelines to optimize the use of MLT in healthy children.

Eating and Sensory Features of Children With Autism Spectrum Disorder and Their Typically Developing Peers.

IMPORTANCE: Impaired sensory processing is associated with eating problems. There seem to be no previous studies that compare those who have autism spectrum disorder (ASD) with eating problems (ASD-W) and those with ASD without eating problems (ASD-WO) with typically developing (TD) groups. Comparisons are expected to provide further knowledge to guide the intervention programs. OBJECTIVE: To investigate differences among ASD-W, ASD-WO, and TD groups in eating and sensory features; to detect associations between sensory and eating behaviors and any most involved sensory dimensions; and to search for age-related differences in sensory and eating features in ASD. DESIGN: Nonrandomized comparison study. SETTING: Questionnaires administered as parent interviews. PARTICIPANTS: A total of 165 children were recruited: 117 with ASD and 48 TD children. OUTCOMES AND MEASURES: Standardized questionnaires: the Brief Autism Mealtime Behaviors Inventory for eating problems; the Short Sensory Profile and the Sensory Experience Questionnaire for sensory problems. RESULTS: The ASD-W group showed generalized, impaired eating behaviors and turned out to be the most impaired with regard to sensory responsiveness. No differences in feeding behaviors were found between the ASD-WO and TD groups. All children with ASD showed sensory hyper- or hyporesponsiveness. Four main sensory dimensions were found to be associated with eating behaviors in ASD. No age differences were found in the eating and sensory behaviors of children with ASD. CONCLUSIONS AND RELEVANCE: Differing eating and sensory profiles were found between the ASD and TD groups, especially in children with ASD-W. Early eating interventions using sensory stimulations are strongly recommended. What This Article Adds: This study reports novel information derived from the comparisons of children with ASD with eating problems and those with ASD without eating problems with typically developing groups of children.

STXBP6 Gene Mutation: A New Form of SNAREopathy Leads to Developmental Epileptic Encephalopathy.

Syntaxin-binding protein 6 (STXBP6), also known as amysin, is an essential component of the SNAP receptor (SNARE) complex and plays a crucial role in neuronal vesicle trafficking. Mutations in genes encoding SNARE proteins are often associated with a broad spectrum of neurological conditions defined as "SNAREopathies", including epilepsy, intellectual disability, and neurodevelopmental disorders such as autism spectrum disorders. The present whole exome sequencing (WES) study describes, for the first time, the occurrence of developmental epileptic encephalopathy and autism spectrum disorders as a result of a de novo deletion within the STXBP6 gene. The truncated protein in the STXBP6 gene leading to a premature stop codon could negatively modulate the synaptic vesicles' exocytosis. Our research aimed to elucidate a plausible, robust correlation between STXBP6 gene deletion and the manifestation of developmental epileptic encephalopathy.

Treatment of seizures in the neonate: Guidelines and consensus-based recommendations-Special report from the ILAE Task Force on Neonatal Seizures.

Seizures are common in neonates, but there is substantial management variability. The Neonatal Task Force of the International League Against Epilepsy (ILAE) developed evidence-based recommendations about antiseizure medication (ASM) management in neonates in accordance with ILAE standards. Six priority questions were formulated, a systematic literature review and meta-analysis were performed, and results were reported following the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) 2020 standards. Bias was evaluated using the Cochrane tool and risk of Bias in non-randomised studies - of interventions (ROBINS-I), and quality of evidence was evaluated using grading of recommendations, assessment, development and evaluation (GRADE). If insufficient evidence was available, then expert opinion was sought using Delphi consensus methodology. The strength of recommendations was defined according to the ILAE Clinical Practice Guidelines development tool. There were six main recommendations. First, phenobarbital should be the first-line ASM (evidence-based recommendation) regardless of etiology (expert agreement), unless channelopathy is likely the cause for seizures (e.g., due to family history), in which case phenytoin or carbamazepine should be used. Second, among neonates with seizures not responding to first-line ASM, phenytoin, levetiracetam, midazolam, or lidocaine may be used as a second-line ASM (expert agreement). In neonates with cardiac disorders, levetiracetam may be the preferred second-line ASM (expert agreement). Third, following cessation of acute provoked seizures without evidence for neonatal-onset epilepsy, ASMs should be discontinued before discharge home, regardless of magnetic resonance imaging or electroencephalographic findings (expert agreement). Fourth, therapeutic hypothermia may reduce seizure burden in neonates with hypoxic-ischemic encephalopathy (evidence-based recommendation). Fifth, treating neonatal seizures (including electrographic-only seizures) to achieve a lower seizure burden may be associated with improved outcome (expert agreement). Sixth, a trial of pyridoxine may be attempted in neonates presenting with clinical features of vitamin B6-dependent epilepsy and seizures unresponsive to second-line ASM (expert agreement). Additional considerations include a standardized pathway for the management of neonatal seizures in each neonatal unit and informing parents/guardians about the diagnosis of seizures and initial treatment options.

The Role of Supplements and Over-the-Counter Products to Improve Sleep in Children: A Systematic Review.

The sleep-wake cycle is a complex multifactorial process involving several neurotransmitters, including acetylcholine, norepinephrine, serotonin, histamine, dopamine, orexin and GABA, that can be, in turn, regulated by different nutrients involved in their metabolic pathways. Although good sleep quality in children has been proven to be a key factor for optimal cognitive, physical and psychological development, a significant and ever-increasing percentage of the pediatric population suffers from sleep disorders. In children, behavioral interventions along with supplements are recommended as the first line treatment. This systematic review was conducted, according to the PRISMA guidelines, with the purpose of assessing the principal nutrients involved in the pathways of sleep-regulating neurotransmitters in children and adolescents. Our focus was the utilization of over the counter (OTC) products, specifically iron, hydroxytryptophan, theanine and antihistamines in the management of different pediatric sleep disorders with the intention of providing a practical guide for the clinician.

The Italian registry for patients with Prader-Willi syndrome.

BACKGROUND: Prader-Willi syndrome (PWS) is a rare and complex genetic disease, with numerous implications on metabolic, endocrine, neuropsychomotor systems, and with behavioural and intellectual disorders. Rare disease patient registries are important scientific tools (1) to collect clinical and epidemiologic data, (2) to assess the clinical management including the diagnostic delay, (3) to improve patients' care and (4) to foster research to identify new therapeutic solutions. The European Union has recommended the implementation and use of registries and databases. The main aims of this paper are to describe the process of setting up the Italian PWS register, and to illustrate our preliminary results. MATERIALS AND METHODS: The Italian PWS registry was established in 2019 with the aims (1) to describe the natural history of the disease, (2) to determine clinical effectiveness of health care services, (3) to measure and monitor quality of care of patients. Information from six different variables are included and collected into this registry: demographics, diagnosis and genetics, patient status, therapy, quality of life and mortality. RESULTS: A total of 165 patients (50.3% female vs 49.7% male) were included into Italian PWS registry in 2019-2020 period. Average age at genetic diagnosis was 4.6 years; 45.4% of patients was less than 17 years old aged, while the 54.6% was in adult age (> 18 years old). Sixty-one percent of subjects had interstitial deletion of the proximal long arm of paternal chromosome 15, while 36.4% had uniparental maternal disomy for chromosome 15. Three patients presented an imprinting centre defect and one had a de novo translocation involving chromosome 15. A positive methylation test was demonstrated in the remaining 11 individuals but the underlying genetic defect was not identified. Compulsive food-seeking and hyperphagia was present in 63.6% of patients (prevalently in adults); 54.5% of patients developed morbid obesity. Altered glucose metabolism was present in 33.3% of patients. Central hypothyroidism was reported in 20% of patients; 94.7% of children and adolescents and 13.3% of adult patients is undergoing GH treatment. CONCLUSIONS: The analyses of these six variables allowed to highlight important clinical aspects and natural history of PWS useful to inform future actions to be taken by national health care services and health professionals.

Epilepsy: A Multifaced Spectrum Disorder.

Epilepsy is one of the most widespread chronic conditions, affecting about 50 million people worldwide [...].

Poor School Academic Performance and Benign Epilepsy with Centro-Temporal Spikes.

BACKGROUND: Poor academic performance of students with epilepsy seems to be a multifactorial problem related to difficulties in reading, writing, math, and logic skills. Poor school and academic performances refer to learning problems in a specific academic area due to learning disorders and learning difficulties not excluding the ability to learn in a different manner during school and academic life. Sometimes, school, academic difficulties, and Rolandic epilepsy can coexist together, and there may be comorbidities. Consequently, the risk of impaired academic performance in people with epilepsy is high. METHODS: This review analyzed the relationship between Benign Epilepsy with Centro-Temporal Spikes (BECTS) and poor school and academic performance (PSAP) in children and adolescents (aged 6 to 19), and in adults (aged 20 to no age limit). The PRISMA guideline was used to guide our review strategy. RESULTS: This research shows that Benign Epilepsy with Centro-Temporal Spikes (BECTS) and poor school and academic performances are strongly correlated. An early onset age, as well as a long persistence of seizures, correlate more closely with PSAP. On the other hand, it appears that good pharmacological control of seizures and remission from the acute phase of the pathology support better school performance. CONCLUSIONS: This review highlights how neuropsychological aspects are also involved in patients with BECTS and PSAP, both in the greater predisposition to the establishment of other neuropsychiatric conditions and in the possibility that stigma conditions and poor academic results may have repercussions on the adaptation and functioning of these subjects. Global management of the subject with BECTS and PSAP is essential, which also pays attention to the aspects of social and scholastic inclusion, both to achieve age-appropriate educational and behavioral objectives, to give the necessary tools for the growth of the individual, and to allow a serene transition to adulthood, favoring autonomous learning and better outcomes.

Phenotypic Spectrum of NFIA Haploinsufficiency: Two Additional Cases and Review of the Literature.

The NFIA (nuclear factor I/A) gene encodes for a transcription factor belonging to the nuclear factor I family and has key roles in various embryonic differentiation pathways. In humans, NFIA is the major contributor to the phenotypic traits of "Chromosome 1p32p31 deletion syndrome". We report on two new cases with deletions involving NFIA without any other pathogenic protein-coding gene alterations. A cohort of 24 patients with NFIA haploinsufficiency as the sole anomaly was selected by reviewing the literature and public databases in order to analyze all clinical features reported and their relative frequencies. This process was useful because it provided an overall picture of the phenotypic outcome of NFIA haploinsufficiency and helped to define a cluster of phenotypic traits that can facilitate clinicians in identifying affected patients. NFIA haploinsufficiency can be suspected by a careful observation of the dysmorphisms (macrocephaly, craniofacial, and first-finger anomalies), and this potential diagnosis is strengthened by the presence of intellectual and developmental disabilities or other neurodevelopmental disorders. Further clues of NFIA haploinsufficiency can be provided by instrumental tests such as MRI and kidney urinary tract ultrasound and confirmed by genetic testing.

An Italian consensus on the management of Lennox-Gastaut syndrome.

PURPOSE: Although international guidelines exist, the clinical heterogeneity of Lennox-Gastaut syndrome (LGS) and the increasing availability of new and repurposed drugs (e.g., fenfluramine and cannabidiol) requires a practical guide to patient management in the clinical context. We report the results of a consensus survey among 42 Italian experts in the diagnosis and treatment of LGS. METHODS: The consensus procedure followed a modified Delphi approach. Statements were formulated, based on the most recent published evidence and the clinicians' personal experience, then discussed, and agreed upon by the experts through a two-round voting procedure. Approval of a statement was reached with an average score ≥7. RESULTS: Thirteen statements dealing with three main topics (i.e., clinical diagnosis and prognosis, impact on the Quality of Life (QoL), and treatment strategies) were generated. Six statements achieved a level of agreement sufficient for approval on the first voting round. Following the discussion and a few consequent amendments, most of the statements increased their level of agreement and all 13 were approved. CONCLUSIONS: Overall, the statements draw a slightly more benign picture of this rare and severe disease, highlighting the possibility of remission - albeit modest -, an apparent trend towards lower mortality, and the availability of several effective drugs, to which greater accessibility would be hoped for. Valproate remains a major therapeutic option in LGS patients although lamotrigine, rufinamide, topiramate, cannabidiol, and clobazam are popular therapeutic options in Italy, allowing for a tailor-made antiseizure therapy.

Therapeutic approach to neurological manifestations of Angelman syndrome.

INTRODUCTION: Angelman syndrome (AS) is a neurogenetic disorder due to deficient expression of the maternal copy of the UBE3A gene, which encodes ubiquitin ligase E3A protein. Severe developmental delay, seizures and other neurological disorders characterize AS. AREAS COVERED: In this review, we focus on a comprehensive therapeutic approach to the most disabling neurological manifestations of AS: epilepsy, sleep disturbances, behavioral and movement disorders. Articles were identified through PubMed and Google Scholar up to October 2021. EXPERT OPINION: Evidence for the treatment of neurological manifestations in AS mainly derives from poor quality studies (case reports, small case series, expert opinions). Seizures can be polymorphic and includes atypical absences, myoclonic, generalized tonic-clonic, unilateral clonic, or atonic attacks. Sodium valproate, levetiracetam, and benzodiazepines are the most commonly used anti-seizure medications. Melatonin or mirtazapine seem to improve sleep quality. Antipsychotics, antidepressants, and anxiolytics have been proposed for the treatment of behavioral manifestations, but no evidence-based studies are available. Non-pharmacological approach may also be useful. Mild dystonia is common but usually does not significantly impact patients' motor performances. Well-conducted clinical trials aimed to evaluate treatment of neurological complications of AS are warranted. Gene and molecular precision therapies represent a fascinating area of research in the future.

Electroencephalographic findings in ATRX syndrome: A new case series and review of literature.

Alpha-thalassemia X-linked intellectual disability syndrome (ATRX) is a rare genetic condition caused by mutations in the ATRX gene characterized by distinctive dysmorphic features, alpha thalassemia, mild-to-profound intellectual disability, and epilepsy, reported in nearly 30% of the patients. To date, different types of seizures are reported in patients with ATRX syndrome including either clonic, tonic, myoclonic seizures or myoclonic absences. However, an accurate analysis of electroencephalographic features is lacking in literature. We report on the epileptic and electroencephalographic phenotype of seven unpublished patients with ATRX syndrome, highlighting the presence of a peculiar EEG pattern characterized by diffuse background slowing with superimposed low voltage fast activity. Likewise, we also review the available literature on this topic.

Phosphatase and tensin homolog (PTEN) variants and epilepsy: A multicenter case series.

PURPOSE: EEG anomalies and epilepsy are a not so rare clinical manifestation in patients with Phosphatase and tensin homolog (PTEN) variants. The main aim of this study is to analyze the characteristics of EEG traces, neuroimaging findings and epilepsy to better define the neurological aspects in a set of patients with PTEN variants collected in four Italian Centres. As a secondary aim, we describe the neurodevelopmental profile and the psychiatric comorbidities of this cohort. METHODS: Patients with PTEN variants, identified by Sanger sequencing or target resequencing, were enrolled. For each subjects, clinical data were retrospectively extracted from medical charts, with a focus on epilepsy and neuroimaging data. RESULTS: 54 patients with PTEN variants were enrolled, with a mean age of 18.8 years. 72.2% have at least one psychiatric diagnosis, being Autism Spectrum Disorder and Intellectual Disability the most frequent diagnosis (29 and 25 cases, respectively). 22 subjects show an abnormal EEG and 8 received a diagnosis of epilepsy, mainly focal epilepsy (7/8), with a mean age at seizure onset of 3.8 years. 3/8 subjects have a drug resistant epilepsy, independently from the underlying neuroimaging pattern. The finding of a Focal cortical dysplasia is significantly associated with both an abnormal EEG (p = 0.02) and the occurrence of seizures (p = 0.002). CONCLUSION: EEG should be taken into consideration in the first-line diagnostic flowchart of subjects with PTEN variants. The onset of a focal epilepsy, independently from its response to antiepileptic drugs, highly recommends to carry out a neuroimaging exam.

Exome sequencing in a child with neurodevelopmental disorder and epilepsy: Variant analysis of the AHNAK2 gene.

BACKGROUND: The AHNAK2 gene encodes a large nucleoprotein expressed in several tissues, including brain, squamous epithelia, smooth muscle, and neuropil. Its role in calcium signaling has been suggested and to date, clear evidence about its involvement in the pathogenesis of clinical disorders is still lacking. METHODS: Here, we report a female 24-year-old patient diagnosed with a cardio-facio-cutaneous-like phenotype (CFC-like), characterized by epilepsy, psychomotor development delay, atopic dermatitis, congenital heart disease, hypotonia, and facial dysmorphism, who is compound heterozygote for two missense mutations in the AHNAK2 gene detected by exome sequencing. RESULTS: This patient had no detectable variant in any of the genes known to be associated with the cardio-facio-cutaneous syndrome. Moreover, the mode of inheritance does not appear to be autosomal dominant, as it is in typical CFC syndrome. We have performed in silico assessment of mutation severity separately for each missense mutation, but this analysis excludes a severe effect on protein function. Protein structure predictions indicate the mutations are located in flexible regions possibly involved in molecular interactions. CONCLUSION: We discuss an alternative interpretation on the potential involvement of the two missense mutations in the AHNAK2 gene on the expression of CFC-like phenotype in this patient based on inter-allelic complementation.

Epilepsy, electroclinical features, and long-term outcomes in Pitt-Hopkins syndrome due to pathogenic variants in the TCF4 gene.

BACKGROUND AND PURPOSE: Pitt-Hopkins syndrome (PTHS) is a rare neurodevelopmental disorder caused by deletions/variants in the TCF4 gene. Seizures may be present in up to half of the patients, leading to a more severe disease burden. This study aims to analyse the electroclinical phenotype, treatment options, and long-term outcomes of epilepsy in PTHS. METHODS: A multicentre observational cohort study was performed, and the electroclinical data of PTHS individuals affected by epileptic seizures were retrospectively reviewed and analysed. RESULTS: The series includes 21 patients (11 female) with a median age at seizure onset of 2 years (range = 0.5-8). The median time of follow-up was 7.9 years (range = 2-27). Both generalized and focal epilepsies were present at the same prevalence (42.8%), whereas a minority of patients presented developmental and epileptic encephalopathies (14.4%). At the long-term follow-up, 42.8% achieved seizure freedom, whereas 42.8% developed drug-resistant epilepsy (DRE). The age at seizure onset was found to be an independent predictor for seizure outcome; in this regard, patients having seizure onset after the age of 2 years were more prone to achieve seizure freedom (odds ratio = 0.04, 95% confidence interval = 0.003-0.53; p = 0.01). During evolution, seizures tended to settle down, and even in patients with DRE, seizures tended to persist at a lower frequency and appeared to be more easily manageable over time. CONCLUSIONS: This study provides new insight into the natural history of epilepsy in PTHS. Better characterization of epileptic phenotype and prompt tailored treatment improve overall management and quality of life.

Heterozygous Deletion of Long Noncoding RNA AK127244 Is a Susceptibility Factor for Neurodevelopmental Delay.

Neurodevelopmental syndromes due to copy number variation are well-known clinical entities. While the numerical variation of gene-harboring regions has been widely investigated at both molecular and clinical levels, much less is understood about unbalanced expression of long noncoding RNAs. Few studies have been performed on the clinical consequences of such unbalanced expression. Heterozygous deletions of NRXN1 have been well described to cause neuropsychological features. Heterozygous deletion of adjacent long noncoding RNA AK127244, either isolated or combined with partial NRXN1 deletion, was recently reported in association with neurodevelopmental delay. In our retrospective study, we analyze a bicentric cohort of 4 individuals, comprising 2 siblings, which bear an isolated heterozygous deletion in long noncoding RNA AK127244 and present with nonsyndromic neurodevelopmental delay.

Epilepsy in "Sunflower syndrome": electroclinical features, therapeutic response, and long-term follow-up.

BACKGROUND: Sunflower syndrome (SFS) is a rare childhood-onset generalized epilepsy characterized by photosensitivity, heliotropism, and drug-resistant stereotyped seizures maybe self-induced by hand-waving maneuvers. Data on the long-term prognosis are scantly and evidence over best treatment strategies is lacking. METHODS: We retrospectively describe the electroclinical features, and therapeutic response in a group of 21 patients with SFS, without intellectual disability. RESULTS: 16 patients were female (67%), with a median age at onset of 7 years. In all patients, ictal episodes began with sun-staring, and hand-waving in front of the sunlight, accompanied by brief typical absence seizures. 17 patients (81%) showed interictal EEG abnormalities, mainly characterized by spike and polyspike-and-wave discharges. Ictal epileptiform activity occurred approximately less than one second after the start of hand-waving. At the last follow-up (median length 8.2 years), 12 patients (57%) were drug-resistant. Nine of them (75%) achieved seizure control with the use of tainted lenses, either alone or compared with anti-seizure medications (ASM). Disappearance of seizures was associated with EEG improvement/normalization when tinted glasses were used during EEG recordings. CONCLUSION: While the clinical and EEG characteristics of SFS are well defined, the best therapeutic approaches are still under debate. Our data confirms a high rate of drug-resistance and frequent need of polytherapy. Of note, in drug-resistant patients, lenses (but not ASM) were able to suppress PPR in our patients while wearing lenses. Regarding the role of lenses, we do not only rely on the PPR reduction but also clinically by the reduction of seizures. Although additional data are needed, lenses seem to have a powerful potential role for the management of SFS.