The burden of epilepsy on long-term outcome of genetic developmental and epileptic encephalopathies: A single tertiary center longitudinal retrospective cohort study.

BACKGROUND: This retrospective cohort analysis highlighted neurodevelopmental outcome predictors of genetic developmental and epileptic encephalopathies (DEE). PATIENTS AND METHODS: Patients' demographic, clinical and molecular genetics data were collected. All patients underwent clinical, developmental, and neuropsychological assessments. RESULTS: We recruited 100 participants (53 males, 47 females) with a mean follow-up lasting 10.46 ± 8.37 years. Age at epilepsy-onset was predictive of poor adaptive and cognitive functions (VABS-II score, r = 0.350, p = 0.001; BRIEF control subscale, r = -0.253; p = 0.031). Duration of epilepsy correlated negatively with IQ (r = -0.234, p = 0.019) and VABS-II score (r = -0.367, p = 0.001). Correlations were found between delayed/lacking EEG maturation/organization and IQ (r = 0.587, p = 0.001), VABS-II score (r = 0.658, p = 0.001), BRIEF-MI and BRIEF-GEC scores (r = -0.375, p = 0.001; r = -0.236, p = 0.033), ASEBA anxiety (r = -0.220, p = 0.047) and ADHD (r = -0.233, p = 0.035) scores. The number of antiseizure medications (ASMs) correlated with IQ (r = -0.414, p = 0.001), VABS-II (r = -0.496, p = 0.001), and BRIEF-MI (r = 0.294, p = 0.012) scores; while age at the beginning of therapy with ASEBA anxiety score (r = 0.272, p = 0.013). The occurrence of status epilepticus was associated with worse adaptive performances. The linear regression analysis model showed that delayed/lacking EEG maturation/organization had a significant influence on the IQ (R2 = 0.252, p < 0.001) and the BRIEF-GEC variability (R2 = 0.042, p = 0.036). The delayed/lacking EEG maturation/organization and the duration of epilepsy also had a significant influence on the VABS-II score (R2 = 0.455, p = 0.005). CONCLUSIONS: Age at seizure-onset, EEG maturation/organization, duration of epilepsy, occurrence of status epilepticus, age at the introduction and number of ASMs used are reliable predictors of long-term outcomes in patients with genetic DEE.

L-serine treatment in patients with GRIN-related encephalopathy: a phase 2A, non-randomized study.

GRIN-related disorders are rare developmental encephalopathies with variable manifestations and limited therapeutic options. Here, we present the first non-randomized, open-label, single-arm trial (NCT04646447) designed to evaluate the tolerability and efficacy of L-serine in children with GRIN genetic variants leading to loss-of-function. In this phase 2A trial, patients aged 2-18 years with GRIN loss-of-function pathogenic variants received L-serine for 52 weeks. Primary end points included safety and efficacy by measuring changes in the Vineland Adaptive Behavior Scales, Bayley Scales, age-appropriate Wechsler Scales, Gross Motor Function-88, Sleep Disturbance Scale for Children, Pediatric Quality of Life Inventory, Child Behavior Checklist and the Caregiver-Teacher Report Form following 12 months of treatment. Secondary outcomes included seizure frequency and intensity reduction and EEG improvement. Assessments were performed 3 months and 1 day before starting treatment and 1, 3, 6 and 12 months after beginning the supplement. Twenty-four participants were enrolled (13 males/11 females, mean age 9.8 years, SD 4.8), 23 of whom completed the study. Patients had GRIN2B, GRIN1 and GRIN2A variants (12, 6 and 5 cases, respectively). Their clinical phenotypes showed 91% had intellectual disability (61% severe), 83% had behavioural problems, 78% had movement disorders and 58% had epilepsy. Based on the Vineland Adaptive Behavior Composite standard scores, nine children were classified as mildly impaired (cut-off score > 55), whereas 14 were assigned to the clinically severe group. An improvement was detected in the Daily Living Skills domain (P = 0035) from the Vineland Scales within the mild group. Expressive (P = 0.005), Personal (P = 0.003), Community (P = 0.009), Interpersonal (P = 0.005) and Fine Motor (P = 0.031) subdomains improved for the whole cohort, although improvement was mostly found in the mild group. The Growth Scale Values in the Cognitive subdomain of the Bayley-III Scale showed a significant improvement in the severe group (P = 0.016), with a mean increase of 21.6 points. L-serine treatment was associated with significant improvement in the median Gross Motor Function-88 total score (P = 0.002) and the mean Pediatric Quality of Life total score (P = 0.00068), regardless of severity. L-serine normalized the EEG pattern in five children and the frequency of seizures in one clinically affected child. One patient discontinued treatment due to irritability and insomnia. The trial provides evidence that L-serine is a safe treatment for children with GRIN loss-of-function variants, having the potential to improve adaptive behaviour, motor function and quality of life, with a better response to the treatment in mild phenotypes.

Case report: Childhood epilepsy and borderline intellectual functioning hiding an AADC deficiency disorder associated with compound heterozygous DDC gene pathogenic variants.

Aromatic L-amino acid decarboxylase (AADC) deficiency is a rare autosomal recessive neurometabolic disorder leading to severe combined serotonin, dopamine, norepinephrine, and epinephrine deficiency. We report on a female patient with borderline functioning and sporadic clear-cut focal to bilateral seizures from age 10 years. A neuropsychological assessment highlighted a mild impairment in executive functions, affecting attention span and visual-spatial abilities. Following the diagnosis of epilepsy with a presumed genetic etiology, we applied a diagnostic approach inclusive of a next-generation sequencing (NGS) gene panel, which uncovered two variants in trans in the DOPA decarboxylase (DDC) gene underlying an AADC deficiency. This compound heterozygous genotype was associated with a mild reduction of homovanillic acid, a low level of the norepinephrine catabolite, and a significant reduction of 5-hydroxyindoleacetic acid in cerebrospinal fluid. Remarkably, 3-O-methyldopa (3-OMD) and 5-hydroxytryptophan were instead increased. During the genetically guided re-evaluation process, some mild signs of dysautonomic dysfunction (nasal congestion, abnormal sweating, hypotension and fainting, excessive sleepiness, small hands and feet, and increased levels of prolactin, tiredness, and fatigue), more typical of AADC deficiency, were evaluated with new insight. Of the two AADC variants, the R347Q has already been characterized as a loss-of-function with severe catalytic impairments, while the novel L391P variant has been predicted to have a less severe impact. Bioinformatic analyses suggest that the amino acid substitution may affect affinity for the PLP coenzyme. Thus, the genotype corresponds to a phenotype with mild and late-onset symptoms, of which seizures were the clinical sign, leading to medical attention. This case report expands the spectrum of AADC deficiency phenotypes to encompass a less-disabling clinical condition including borderline cognitive functioning, drug-responsive epilepsy, and mild autonomic dysfunction.

Natural Course of IQSEC2-Related Encephalopathy: An Italian National Structured Survey.

Pathogenic loss-of-function variants in the IQ motif and SEC7 domain containing protein 2 (IQSEC2) gene cause intellectual disability with Rett syndrome (RTT)-like features. The aim of this study was to obtain systematic information on the natural history and extra-central nervous system (CNS) manifestations for the Italian IQSEC2 population (>90%) by using structured family interviews and semi-quantitative questionnaires. IQSEC2 encephalopathy prevalence estimate was 7.0 to 7.9 × 10-7. Criteria for typical RTT were met in 42.1% of the cases, although psychomotor regression was occasionally evidenced. Genetic diagnosis was occasionally achieved in infancy despite a clinical onset before the first 24 months of life. High severity in both the CNS and extra-CNS manifestations for the IQSEC2 patients was documented and related to a consistently adverse quality of life. Neurodevelopmental delay was diagnosed before the onset of epilepsy by 1.8 to 2.4 years. An earlier age at menarche in IQSEC2 female patients was reported. Sleep disturbance was highly prevalent (60 to 77.8%), with mandatory co-sleeping behavior (50% of the female patients) being related to de novo variant origin, younger age, taller height with underweight, better social interaction, and lower life quality impact for the family and friends area. In conclusion, the IQSEC2 encephalopathy is a rare and likely underdiagnosed developmental encephalopathy leading to an adverse life quality impact.

The impact of a newly established specialized pediatric epilepsy center in Tanzania: An observational study.

PURPOSE: This study evaluated the impact of a newly established clinic for the diagnosis of pediatric epilepsy in a resource-limited center (Ifakara, Tanzania). METHODS: Patients aged 0-18 years referred to the Pediatric Epilepsy Unit of Saint Francis Referral Hospital were recruited. Demographic and clinical data were collected through Kobo Toolbox and analyzed through a descriptive analysis.. RESULTS: 143 patients were evaluated, and for 48 of them an EEG was recorded (abnormalities were detected in 80.85% of the cases). The diagnosis of epilepsy was confirmed in 87 patients. Focal epilepsy was diagnosed in 57 patients, generalized epilepsy in 24 patients, and forms of unknown onset in 6 patients. Epilepsy was excluded for 9 children. Etiologies included hypoxic-ischemic encephalopathy (39%), central nervous system infections (3.4%), and genetic diseases (3.4%). A specific epilepsy syndrome was diagnosed in 16 patients. 74 patients were under treatment; the most used antiseizure medication (ASM) was phenobarbital (43.36%), followed by carbamazepine (16.08%), sodium valproate (11.19%), phenytoin (2.8%), and lamotrigine (0.7%). Therapeutic changes were proposed to 95 patients, more frequently consisting of withdrawing phenobarbital (39.16%), switching to sodium valproate (27.97%), switching to or adjusting carbamazepine dosage (27.27%), and starting prednisone (2.8%). 76% of the patients with confirmed epilepsy achieved complete seizure freedom at the fourth follow-up consultation. CONCLUSIONS: Our data depicted the epilepsy spectrum and highlighted the prognostic implications of improving the availability of ASMs such as sodium valproate and second- and third-generation ones in resource-limited countries.

Clinical profiles of acute arterial ischemic neonatal stroke.

INTRODUCTION: Perinatal stroke includes a heterogeneous group of early focal neurological injuries affecting subsequent brain development, often resulting in motor sequelae, symptomatic epilepsies, and cognitive, language and behavioral impairment. The incidence of perinatal stroke is about 1/3500 live birth. EVIDENCE ACQUISITION: A PubMed and SCOPUS search strategy included the entries "neonatal ischemic stroke" OR "perinatal ischemic stroke" and the age of the filter under 18 years and January 2000-August 2022. EVIDENCE SYNTHESIS: The cumulative literature analysis highlighted 3880 published patients (from 98 articles) with stroke, mainly presenting with clinical or electro-graphical seizures (2083 patients). The mean age at presentation was 2,5±2,4 days (data available for 1182 patients). Stroke occurred in the first week of life in 1164 newborns. The mainly involved ischemic areas were within the territories of the middle cerebral artery (1403 patients). Predisposing risk factors included fetal/newborn factors (1908 patients), dystocial birth (759 patients), maternal (678 patients), and placental factors (63 patients). No thrombolysis and/or endovascular treatments were performed, while data about other pharmacological treatments were restricted to a single article. The death occurred in 29 newborns. Motor, neurocognitive and language impairment were cumulatively reported in 875 patients. Epileptic seizures during the follow-up were reported in 238 cases. CONCLUSIONS: The literature analysis highlighted that every term newborn presenting with acute neurological signs and symptoms during the first week of life should always be considered for the identification of an ischemic stroke.

Epilepsy Phenotypes of Vitamin B6-Dependent Diseases: An Updated Systematic Review.

BACKGROUND: Vitamin B6-dependent epilepsies include treatable diseases responding to pyridoxine or pyridoxal-5Iphosphate (ALDH7A1 deficiency, PNPO deficiency, PLP binding protein deficiency, hyperprolinemia type II and hypophosphatasia and glycosylphosphatidylinositol anchor synthesis defects). PATIENTS AND METHODS: We conducted a systematic review of published pediatric cases with a confirmed molecular genetic diagnosis of vitamin B6-dependent epilepsy according to PRISMA guidelines. Data on demographic features, seizure semiology, EEG patterns, neuroimaging, treatment, and developmental outcomes were collected. RESULTS: 497 published patients fulfilled the inclusion criteria. Seizure onset manifested at 59.8 ± 291.6 days (67.8% of cases in the first month of life). Clonic, tonic-clonic, and myoclonic seizures accounted for two-thirds of the cases, while epileptic spasms were observed in 7.6%. Burst-suppression/suppression-burst represented the most frequently reported specific EEG pattern (14.4%), mainly in PLPB, ALDH7A1, and PNPO deficiency. Pyridoxine was administered to 312 patients (18.5% intravenously, 76.9% orally, 4.6% not specified), and 180 also received antiseizure medications. Pyridoxine dosage ranged between 1 and 55 mg/kg/die. Complete seizure freedom was achieved in 160 patients, while a significant seizure reduction occurred in 38. PLP, lysine-restricted diet, and arginine supplementation were used in a small proportion of patients with variable efficacy. Global developmental delay was established in 30.5% of a few patients in whom neurocognitive tests were performed. CONCLUSIONS: Despite the wide variability, the most frequent hallmarks of the epilepsy phenotype in patients with vitamin B6-dependent seizures include generalized or focal motor seizure semiology and a burst suppression/suppression burst pattern in EEG.

Extended Glasgow Outcome Scale to Evaluate the Functional Impairment of Patients With Subcortical Band Heterotopia: A Multicentric Cross-sectional Study.

BACKGROUND: Subcortical band heterotopia (SBH) is a rare malformation of the cortical development characterized by a heterotopic band of gray matter between cortex and ventricles. The clinical presentation typically includes intellectual disability and epilepsy. PURPOSE: To evaluate if the Extended Glasgow Outcome Scale-pediatric version (EGOS-ped) is a feasible tool for evaluating the functional disability of patients with (SBH). METHOD: Cross-sectional multicenter study of a cohort of 49 patients with SBH (female n = 30, 61%), recruited from 23 Italian centers. RESULTS: Thirty-nine of 49 (80%) cases showed high functional disability at EGOS-ped assessment. In the poor result subgroup (EGOS-ped >3) motor deficit, language impairment, and lower intelligence quotient were more frequent (P < 0.001, P = 0.02, and P = 0.01, respectively); the age at epilepsy onset was remarkably lower (P < 0.001); and the prevalence of epileptic encephalopathy (West syndrome or Lennox-Gastaut-like encephalopathy) was higher (P = 0.04). The thickness and the extension of the heterotopic band were associated with EGOS-ped score (P < 0.01 and P = 0.02). Pachygyria was found exclusively among patients with poor outcome (P < 0.01). CONCLUSIONS: The EGOS-ped proved to be a reliable tool for stratifying the functional disability of patients with SBH. According to this score, patients could be dichotomized: group 1 (80%) is characterized by a poor overall functionality with early epilepsy onset, thick heterotopic band, and pachygyria, whereas group 2 (20%) is characterized by a good overall functionality with later epilepsy onset and thinner heterotopic band.

Phenotypes and Genotypes of Inherited Disorders of Biogenic Amine Neurotransmitter Metabolism.

Inherited disorders of biogenic amine metabolism are genetically determined conditions resulting in dysfunctions or lack of enzymes involved in the synthesis, degradation, or transport of dopamine, serotonin, adrenaline/noradrenaline, and their metabolites or defects of their cofactor or chaperone biosynthesis. They represent a group of treatable diseases presenting with complex patterns of movement disorders (dystonia, oculogyric crises, severe/hypokinetic syndrome, myoclonic jerks, and tremors) associated with a delay in the emergence of postural reactions, global development delay, and autonomic dysregulation. The earlier the disease manifests, the more severe and widespread the impaired motor functions. Diagnosis mainly depends on measuring neurotransmitter metabolites in cerebrospinal fluid that may address the genetic confirmation. Correlations between the severity of phenotypes and genotypes may vary remarkably among the different diseases. Traditional pharmacological strategies are not disease-modifying in most cases. Gene therapy has provided promising results in patients with DYT-DDC and in vitro models of DYT/PARK-SLC6A3. The rarity of these diseases, combined with limited knowledge of their clinical, biochemical, and molecular genetic features, frequently leads to misdiagnosis or significant diagnostic delays. This review provides updates on these aspects with a final outlook on future perspectives.

Generation of an induced pluripotent stem cell line CSSi015-A (9553), carrying a point mutation c.2915C > T in the human calcium sensing receptor (CasR) gene.

Familial Hypocalciuric Hypercalcemia (FHH1) is a rare autosomal dominant disease with low penetrance, caused by inactivating mutations of the calcium-sensing receptor (CaSR) gene, characterized by significant hypercalcemia, inappropriately normal serum PTH levels and a low urinary calcium level. Human induced pluripotent stem cells (hiPSCs) from a patient carrying a previously identified heterozygous mutation, a p.T972M amino acid substitution in cytoplasmic tail of CasR, were produced using a virus, xeno-free and non-integrative protocol.

Biallelic variants in HECT E3 paralogs, HECTD4 and UBE3C, encoding ubiquitin ligases cause neurodevelopmental disorders that overlap with Angelman syndrome.

PURPOSE: Pathogenic variants in genes encoding ubiquitin E3 ligases are known to cause neurodevelopmental syndromes. Additional neurodevelopmental disorders associated with the other genes encoding E3 ligases are yet to be identified. METHODS: Chromosomal analysis and exome sequencing were used to identify the genetic causes in 10 patients from 7 unrelated families with syndromic neurodevelopmental, seizure, and movement disorders and neurobehavioral phenotypes. RESULTS: In total, 4 patients were found to have 3 different homozygous loss-of-function (LoF) variants, and 3 patients had 4 compound heterozygous missense variants in the candidate E3 ligase gene, HECTD4, that were rare, absent from controls as homozygous, and predicted to be deleterious in silico. In 3 patients from 2 families with Angelman-like syndrome, paralog-directed candidate gene approach detected 2 LoF variants in the other candidate E3 ligase gene, UBE3C, a paralog of the Angelman syndrome E3 ligase gene, UBE3A. The RNA studies in 4 patients with LoF variants in HECTD4 and UBE3C provided evidence for the LoF effect. CONCLUSION: HECTD4 and UBE3C are novel biallelic rare disease genes, expand the association of the other HECT E3 ligase group with neurodevelopmental syndromes, and could explain some of the missing heritability in patients with a suggestive clinical diagnosis of Angelman syndrome.

Long-term neurological and psychiatric outcomes in patients with aromatic l-amino acid decarboxylase deficiency.

INTRODUCTION: l-amino acid decarboxylase deficiency (AADCD) is an ultrarare autosomal recessive defect of biogenic amine synthesis that presents with early-onset encephalopathy progressing to severe neurological impairment and intellectual disability. We aimed to explore neurocognitive and behavioral profiles associated with AADCD and possible factors predicting outcome in more detail. METHODS: Nine AADCD patients (23.2 ± 10.3 years; range 8-40) underwent systematic clinical and neuropsychological assessment. Diagnostic levels of CSF 5-hydroxyindolacetic acid (5-HIAA) and homovanillic acid (HVA), and DDC genotype (as ascertained by American College of Medical Genetics and Genomics grading) were included in the data analysis. RESULTS: All AADCD patients were affected by intellectual disability and psychiatric disorders. Movement disorders included parkinsonism-dystonia, dysarthria, and oculogyric crises. CSF 5-HIAA and HVA levels at diagnosis had a significant influence on adaptive behavior and executive function performance. Patients homozygous for DDC pathogenetic variants showed lower CSF 5-HIAA and HVA levels and higher Unified Parkinson's Disease Rating Scale scores. The disease showed a self-limiting clinical course with partial improvement under pharmacological treatment (B6 and dopamine mimetic drugs). CONCLUSIONS: Patients with AADCD suffer from neuropsychological and psychopathological impairment, which may be improved but not reversed under the present therapeutic approach. However, cognitive functioning should be specifically examined in order to avoid its underestimation on the basis of movement disorder severity. Genotype and biogenic amine level at diagnosis have an important prognostic value.

Paediatric sudden unexpected death in epilepsy: From pathophysiology to prevention.

Sudden unexpected death in epilepsy (SUDEP) is a fatal event, occurring in patients with epilepsy, in which seizures may or may not precede the exitus, and no other potential causes of death are identifiable. The proposed pathophysiological mechanisms for SUDEP include cardio-respiratory dysfunctions, brainstem arousal system impairment, and dysregulation in the neurotransmitter/neuromodulator systems. This narrative review provides an overview of primary research on SUDEP in paediatric populations. Some studies report an incidence of paediatric SUDEP which is about five times lower than in adults (between 0.02 and 0,34 per 1,000 person-years) even if more recent studies suggested similar incidence rates than in adulthood (between 1.20 / 1,000 and 1.45 / 1,000 person per years). Risk factors for SUDEP in children include genetic predisposition, neurological comorbidities, epilepsy phenotype, adequacy/adherence to treatment, adequate supervision by caregivers and access to adequate health care support. The early identification of risk factors, the definition of reliable biomarkers and the building of efficacious preventive strategies, including parental/caregiver counselling, novel technological devices, and pharmacological treatments, may reduce the risk of paediatric SUDEP.

Presenting Patterns of Genetically Determined Developmental Encephalopathies With Epilepsy and Movement Disorders: A Single Tertiary Center Retrospective Cohort Study.

Background: This paper aimed to evaluate the frequency of observation of genetically determined developmental encephalopathies with epilepsy and movement disorders in a specialistic center, the distribution of etiologies and presenting clinical hallmarks, and the mean times for the achievement of molecular genetic diagnosis. Patients and Methods: Retrospective data about clinical phenotypes, etiology, and diagnostic pathways were collected in all the genetically confirmed patients with developmental encephalopathies with epilepsy and movement disorders referred to our institution between 2010 and 2020. The cohort was divided into two groups according to the predominant movement disorder type: 1) Group A: patients with hyperkinetic movement disorders; 2) Group B: patients with hypokinetic movement disorders. Both groups were analyzed in terms of developmental, epileptic, and movement disorder phenotypes. Results: The cohort included 69 patients (Group A = 53; Group B = 16). The etiological spectrum was heterogeneous with a predominance of Rett and Angelman syndrome in Group A and neurodegenerative disorders in Group B. A moderate/severe intellectual disability was assessed in 58/69 patients (mean age at the first signs of developmental impairment = 1,87 ± 1,72 years). Group A included patients with an earlier onset of epileptic seizures (2,63 ± 3,15 vs. 4,45 ± 5,55 years of group B) and a predominant generalized motor semiology of seizures at the onset. Focal seizures were the main initial epileptic manifestations in Group B. Seizures were noticed earlier than movement disorders in Group A while the opposite occurred in Group B. A higher increase in molecular genetic diagnosis was obtained in the last five years. Mean diagnostic delay was longer in Group B than in Group A (12,26 ± 13,32 vs. 5.66 ± 6.41 years). Chorea as an initial movement disorder was associated with a significantly longer diagnostic delay and a higher age at etiological diagnosis. Conclusions: This study suggested: (a) a higher frequency of genetic defects involving neurotransmission, neuronal excitability, or neural development in patients with hyperkinetic movement disorders; (b) a higher frequency of neurodegenerative courses and a longer diagnostic delay in patients with hypokinetic movement disorders.

Loss of Continuity of Care in Pediatric Neurology Services during COVID-19 Lockdown: An Additional Stressor for Parents.

Background. This study aimed to investigate the consequence of the COVID 19-related lockdown on the well-being of children with neurological and neurodevelopmental disorders and the repercussion on parental stress during the period 9 March 2020-3 May 2020. Methods. A web-based survey was shared via mail with the parents of children affected by chronic neurologic disorders and neurodevelopmental disorders in the continuity of care in two Italian tertiary centers, independently by the severity of the diseases and the required frequency of controls. For each patient, they were asked to identify a single main caregiver, among the two parents, to fill in the questionnaire. Parental stress was measured via the Perceived Stress Scale (PSS). Statistical analysis was performed with IBM SPSS Statistics version 25. The differences between the clinical groups were performed with one way ANOVA. The dimensional effect of the clinical variables on outcome was evaluated by multiple linear regression analysis. Results. The survey was completed by 250 parents (response rate = 48.9 %). Sars-Cov2 infection was reported in two patients only. A total of 44.2% of the patients had completely interrupted school activities while 70% of parents underwent changes in their job modalities. Health care services were disrupted in 77% of patients. Higher PSS scores were detected in the parents of children with neurodevelopmental disorders (p = 0.035). Conclusions. The loss of continuity of care during the lockdown must be considered as a risk factor for parents caring for children with chronic neurologic diseases and neurodevelopmental disorders in further phases of the current pandemic.

Neurodevelopmental Impairment As the Main Phenotypic Hallmark Associated with the Translocation t(7;10)(7p22.3;q26.11).

Reported here is a novel patient carrying an unbalanced t (10q26.11-q26.3; 7p22.3) and presenting with a severe intellectual disability with autistic features, abnormalities of muscle tone, and a drug-responsive epilepsy. The prominence of neurological and neurodevelopmental abnormalities in the clinical phenotype highlights a possible pathogenic role for different genes in the involved regions. Hypothetical mechanisms may include a possible gene dosage effect for DOCK1 and/or haploinsufficiency of PRKAR1B SUN1, ADAP1 , and GPER1 .

Stroke and stroke-like episodes in inborn errors of metabolism: Pathophysiological and clinical implications.

Inborn errors of metabolism causing stroke (ischemic or haemorrhagic) or stroke-like episodes (e.g., that are also called "metabolic strokes" and include acute brain lesions not related with alterations of blood flow) cover a wide range of diseases in which acute metabolic decompensations after trigger events (e.g., fever, dehydration, sepsis etc.) may have a variable frequency. The early diagnosis of these conditions is essential because, despite their rarity, effective symptomatic treatments may be available for acute settings (e.g., arginine for Mitochondrial myopathy, Encephalopathy, Lactic Acidosis, and Stroke-like episodes- MELAS) while in other cases disease modifying therapies may be useful to prevent stroke occurrence, recurrence, or relapse (e.g., Fabry disease). The detection of a non-vascular distribution of lesions and the diffuse use of 1HMRS are often diriment in the differential of ischemic and metabolic strokes. This review summarized the main clinical features and the pathophysiological mechanisms of stroke and stroke-like episodes in inborn errors of metabolism presenting with stroke as part of natural history of the disease. These conditions belong to different etiological groups, such as organic acidurias, mitochondrial encephalopathies, homocystinuria and remethylation disorders, urea cycle disorders, lysosomal diseases (e.g. Fabry disease, glycogen storage disease), congenital disorders of glycosylation, neurotransmitter disorders, adenosine deaminase 2 deficiency and few other neurometabolic disorders.

Expanding the genetic and phenotypic spectrum of CHD2-related disease: From early neurodevelopmental disorders to adult-onset epilepsy.

CHD2 encodes the chromodomain helicase DNA-binding protein 2, an ATP-dependent enzyme that acts as a chromatin remodeler. CHD2 pathogenic variants have been associated with various early onset phenotypes including developmental and epileptic encephalopathy, self-limiting or pharmacoresponsive epilepsies and neurodevelopmental disorders without epilepsy. We reviewed 84 previously reported patients carrying 76 different CHD2 pathogenic or likely pathogenic variants and describe 18 unreported patients carrying 12 novel pathogenic or likely pathogenic variants, two recurrent likely pathogenic variants (in two patients each), three previously reported pathogenic variants, one gross deletion. We also describe a novel phenotype of adult-onset pharmacoresistant epilepsy, associated with a novel CHD2 missense likely pathogenic variant, located in an interdomain region. A combined review of previously published and our own observations indicates that although most patients (72.5%) carry truncating CHD2 pathogenic variants, CHD2-related phenotypes encompass a wide spectrum of conditions with developmental delay/intellectual disability (ID), including prominent language impairment, attention deficit hyperactivity disorder and autistic spectrum disorder. Epilepsy is present in 92% of patients with a median age at seizure onset of 2 years and 6 months. Generalized epilepsy types are prevalent and account for 75.5% of all epilepsies, with photosensitivity being a common feature and adult-onset nonsyndromic epilepsy a rare presentation. No clear genotype-phenotype correlation has emerged.