Carmen Fons

Attention deficit hyperactivity disorder (ADHD) is a comorbidity affecting 12%–29% of individuals with epilepsy, significantly impacting learning, psychosocial development, behaviour, and quality of life. Moreover, ADHD and epilepsy share a bidirectional relationship. Although methylphenidate has been proven effective in alleviating ADHD symptoms, its use remains limited in individuals with epilepsy due to outdated concerns—dating back over 20 years—that psychostimulants could increase seizure frequency. This manuscript presents a narrative review of the scientific literature published between January 2000 and May 2026 regarding the use of methylphenidate in patients with epilepsy and ADHD. Based on the available evidence, a panel of paediatric neurologists from five Spanish tertiary hospitals with expertise in epilepsy and neurodevelopmental disorders reached an expert consensus and developed a series of practical recommendations for the assessment and management of these patients. This expert group issued several recommendations, including the proactive screening of ADHD symptoms in all children and adults with epilepsy from the onset of the condition. Current evidence has not consistently demonstrated an increased seizure risk associated with methylphenidate in patients with epilepsy, although available data remain limited for some epilepsy subgroups. Furthermore, undertreatment of ADHD is associated with poorer patient outcomes. Methylphenidate may be considered in children and adults with epilepsy when clinically indicated, following optimization of epilepsy management, associated comorbidities, and behavioural and psychosocial interventions. Treatment decisions should be individualized, particularly in patients with active epilepsy, drug-resistant epilepsy, recent seizure worsening, or developmental and epileptic encephalopathies.

The development of cognitive control during childhood is characterized by progressive improvements in attentional processing and response inhibition. The present study examined neural activity associated with visual attention and inhibitory control in typically developing children aged 6 to 12 years, using quantitative high-density electroencephalography (HD-EEG).A total of 172 typically developing children aged 6 to 12 years participated in the study. Participants completed a computerized Go/NoGo task while EEG activity was recorded. Behavioural performance, event-related potentials (ERPs), and time-frequency EEG features were analysed, including median frequency (MF), spectral entropy (SE), and relative power (RP) in the theta (θ) and beta1 (β1) frequency bands. Differences were observed both between task conditions and across age groups. P300 amplitude and latency decreased linearly with age across conditions. NoGo trials elicited larger P300 amplitudes and longer latencies than Go trials. Time-frequency analyses showed reductions in MF and SE with increasing age. During task performance, RP (θ) increased and RP (β1) decreased relative to the pre-stimulus baseline. These time-frequency changes were observed across all age groups but were more pronounced in older children. All time-frequency measures differentiated Go and NoGo trials, with stronger effect observed during NoGo trials. These patterns suggest that with age, children become progressively more capable of synchronizing their frequency-specific neural activity to meet the functional demands of the task. Together, these findings indicate that HD-EEG biomarkers are useful to study the maturation of large-scale coordination mechanisms and inhibitory control networks across childhood.

Objectives: To expand the clinical features, epilepsy phenotype, and genotype in individuals with AFG2A-related encephalopathy (AFG2A-RE), previously known SPATA5-related encephalopathy, and to explore potential associations between genotype and epilepsy manifestations. Methods: We conducted a systematic literature review focusing on AFG2A-RE publications (45 patients), also included 6 of our patients recently reported as the result of a multicentre, retrospective, observational, and descriptive study. Available clinical descriptions, electroencephalography and MRI data, metabolic screening, genetic findings, and treatment responses were assessed. Results: A total of 51 individuals with AFG2A-RE were included, 29 males; mean age 8.35 years. The most frequently described clinical features included intellectual disability (97.92%), hearing loss (93.62%), microcephaly (85.71%), visual impairment (79.49%), hypotonia (71.74%), spasticity (60.87%), and movement disorders (36.96%). Epilepsy was present in 74.71% of cases, with seizures of generalized onset being the most common (70.83%), and infantile epileptic spasms syndrome (IESS) was the predominant epilepsy syndrome at onset (66.67%). Epilepsy was often drug-resistant (82.35%). Brain MRI abnormalities were frequently observed (68.29%), including hypomyelination (39.02%), brain atrophy (34.15%), and a thin corpus callosum (29.27%). Significance: This review presents the largest cohort of individuals with AFG2A-RE reported to date. AFG2A-RE is an ultra-rare, recessive disorder, sometimes presenting as a developmental and epileptic encephalopathy (DEE), characterised by the triad of epilepsy, congenital microcephaly, and deafness, and typically associated with intellectual disability, spasticity, and movement disorders. The cardinal clinical features of AFG2A-RE may mimic those of a mitochondrial disease. No significant associations between genotype and epilepsy phenotype were observed.

Programs for Undiagnosed Rare Diseases (URD) with anonymized data sharing are contributing to the earlier genetic diagnosis of patients and to the identification and characterization of novel genetic disorders. Recently, de novo pathogenic variants in two non-coding spliceosomal small nuclear RNAs (snRNAs), RNU4-2 and RNU2-2 , key regulators of gene expression during neurodevelopment, have been linked to neurodevelopmental disorders (NDD). With the aim to identify individuals with causal genetic variants in known and novel snRNA genes, we analyzed WGS and clinical data of 1,708 probands with undiagnosed NDD enrolled in the Spanish URD Programs. Selected individuals underwent in-depth re-phenotyping including facial mask analyses (Face2Gene), and blood-DNA methylation profiling was obtained (Infinium methylation Epicv2 microarrays). We identified 38 patients (2.22%) with de novo pathogenic variants in snRNA genes, 28 in RNU4-2 (1.64%), 6 in RNU2-2 (0.35%), and 4 in RNU5B-1 (0,23%). A clinically recognizable NDD (ReNU syndrome) is caused by RNU4-2 variants, with dysmorphic features making a disease-associated facial mask, RNU2-2 associates an early onset epileptic encephalopathy, and RNU5-B1 a less defined NDD with overlapping features. A DNA methylomic episignature was also identified for RNU4-2 , which does not overlap with the other conditions. We have also defined autosomal recessive inheritance in 8 additional patients (0.47%) with NDD and biallelic variants in three snRNA genes (3 in RNU4-2 , 3 in RNU2-2 , and 2 in RNU4-1 ). Our study has facilitated the quick diagnosis, management, and genetic counselling of 2.69% previously undiagnosed patients with NDD, further reinforcing the value and utility of the URD Programs. GRAPHICAL

Rare variants in GRIA3, the gene encoding the GluA3 subunit of amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA)-type glutamate receptors (AMPARs), are associated with defects in early brain development. Disease-causing variants are generally categorised as either loss of function (LoF) or gain of function (GoF) that appear to be linked to different symptoms. Here, we reported a de novo variant (N651D) that has mixed LoF and GoF in a female patient with a devastating developmental and epileptic encephalopathy, parkinsonism and cortical malformation. N651D is located in the M3 segment, which forms the filter pore of AMPAR tetramers. Interestingly, functional assays revealed that glutamate induced no currents in GluA3_N651D homomeric receptors, likely indicating an LoF effect. However, when co-expressed with the GluA2 subunit, the GluA2/A3_N651D heteromeric receptors showed slower deactivation and desensitisation curves, along with elevated non-desensitising steady-state currents, features typically observed in GoF variants. We speculate that variants with mixed LoF and GoF effects may lead to a more devastating phenotype compared with variants with GoF effects only.

Creatine transporter deficiency (CRTR‐D) is a rare X‐linked inherited disease belonging to the group of cerebral creatine deficiency disorders. Major clinical features include developmental delay and epilepsy. To date, fewer than 200 individuals with CRTR‐D have been reported. As a result, there is little evidence for effective treatment. Available therapies are creatine precursors, with a mild effect on disease progression. Concerning epilepsy, standard management is recommended and no specific anti‐seizure medication (ASM) has been shown to be effective in refractory cases. We report the case of a 28‐year‐old male patient with CRTR‐D and childhood‐onset refractory epilepsy. He had an average of 10–20 focal motor seizures with impaired consciousness per month. He had tried several ASMs without significant improvement. Treatment with cannabidiol (CBD) and clobazam (CLB) in combination was added. The patient became seizure‐free from the first week, and up to 1 year of follow‐up. Behavioral improvement was also noted by his caregivers. No adverse effects were reported. Very few cases of CRTR‐D with refractory epilepsy have been reported. This calls for more extensive research and suggests a possible role for CBD in cerebral creatine metabolism and transport and valuable option for future studies.Plain Language Summary: Creatine transporter deficiency (CRTR‐D) is a rare genetic disorder causing mental, behavioral, and movement problems. More than half of patients also have seizures, but because there are fewer than 200 known cases, it is difficult to know the best treatment options. We present a 28‐year‐old man with CRTR‐D who had severe developmental delays and frequent seizures since childhood, despite trying many medications. After starting cannabidiol and clobazam, he has been seizure‐free for a year. Sharing this success might help other people with CRTR‐D benefit from similar treatments.