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SYNGAP1 haploinsufficiency results in a developmental and epileptic encephalopathy (DEE) causing generalized epilepsies accompanied by a spectrum of neurodevelopmental symptoms. Concerning interictal epileptiform discharges (IEDs) in electroencephalograms (EEG), potential biomarkers have been postulated, including changes in background activity, fixation-off sensitivity (FOS) or eye closure sensitivity (ECS). In this study we clinically evaluate a new cohort of 36 SYNGAP1-DEE individuals. Standardized questionnaires were employed to collect clinical, electroencephalographic and genetic data. We investigated electroencephalographic findings, focusing on the cortical distribution of interictal abnormalities and their changes with age. Among the 36 SYNGAP1-DEE cases 18 presented variants in the SYNGAP1 gene that had never been previously reported. The mean age of diagnosis was 8 years and 8 months, ranging from 2 to 17 years, with 55.9% being male. All subjects had global neurodevelopmental/language delay and behavioral abnormalities; 83.3% had moderate to profound intellectual disability (ID), 91.7% displayed autistic traits, 73% experienced sleep disorders and 86.1% suffered from epileptic seizures, mainly eyelid myoclonia with absences (55.3%). A total of 63 VEEGs were revised, observing a worsening of certain EEG findings with increasing age. A disorganized background was observed in all age ranges, yet this was more common among older cases. The main IEDs were bilateral synchronous and asynchronous posterior discharges, accounting for ≥50% in all age ranges. Generalized alterations with maximum amplitude in the anterior region showed as the second most frequent IED (≥15% in all age ranges) and were also more common with increasing age. Finally, diffuse fast activity was much more prevalent in cases with 6 years or older. To the best of our knowledge, this is the first study to analyze EEG features across different age groups, revealing an increase in interictal abnormalities over infancy and adolescence. Our findings suggest that SYNGAP1 haploinsufficiency has complex effects in human brain development, some of which might unravel at different developmental stages. Furthermore, they highlight the potential of baseline EEG to identify candidate biomarkers and the importance of natural history studies to develop specialized therapies and clinical trials.

BACKGROUND: Seizures are an under-reported feature of the SATB2-associated syndrome phenotype. We describe the electroencephalographic findings and seizure semiology and treatment in a population of individuals with SATB2-associated syndrome. METHODS: We performed a retrospective review of 101 individuals with SATB2-associated syndrome who were reported to have had a previous electroencephalographic study to identify those who had at least one reported abnormal result. For completeness, a supplemental survey was distributed to the caregivers and input from the treating neurologist was obtained whenever possible. RESULTS: Forty-one subjects were identified as having at least one prior abnormal electroencephalography. Thirty-eight individuals (93%) had epileptiform discharges, 28 (74%) with central localization. Sleep stages were included as part of the electroencephalographies performed in 31 individuals (76%), and epileptiform activity was recorded during sleep in all instances (100%). Definite clinical seizures were diagnosed in 17 individuals (42%) with a mean age of onset of 3.2 years (four months to six years), and focal seizures were the most common type of seizure observed (42%). Six subjects with definite clinical seizures needed polytherapy (35%). Delayed myelination and/or abnormal white matter hyperintensities were seen on neuroimaging in 19 individuals (61%). CONCLUSIONS: Epileptiform abnormalities are commonly seen in individuals with SATB2-associated syndrome. A baseline electroencephalography that preferably includes sleep stages is recommended during the initial evaluation of all individuals with SATB2-associated syndrome, regardless of clinical suspicion of epilepsy.

BackgroundThe X-chromosome gene USP9X encodes a deubiquitylating enzyme that has been associated with neurodevelopmental disorders primarily in female subjects. USP9X escapes X inactivation, and in female subjects de novo heterozygous copy number loss or truncating mutations cause haploinsufficiency culminating in a recognizable syndrome with intellectual disability and signature brain and congenital abnormalities. In contrast, the involvement of USP9X in male neurodevelopmental disorders remains tentative.MethodsWe used clinically recommended guidelines to collect and interrogate the pathogenicity of 44 USP9X variants associated with neurodevelopmental disorders in males. Functional studies in patient-derived cell lines and mice were used to determine mechanisms of pathology.ResultsTwelve missense variants showed strong evidence of pathogenicity. We define a characteristic phenotype of the central nervous system (white matter disturbances, thin corpus callosum, and widened ventricles); global delay with significant alteration of speech, language, and behavior; hypotonia; joint hypermobility; visual system defects; and other common congenital and dysmorphic features. Comparison of in silico and phenotypical features align additional variants of unknown significance with likely pathogenicity. In support of partial loss-of-function mechanisms, using patient-derived cell lines, we show loss of only specific USP9X substrates that regulate neurodevelopmental signaling pathways and a united defect in transforming growth factor β signaling. In addition, we find correlates of the male phenotype in Usp9x brain-specific knockout mice, and further resolve loss of hippocampal-dependent learning and memory.ConclusionsOur data demonstrate the involvement of USP9X variants in a distinctive neurodevelopmental and behavioral syndrome in male subjects and identify plausible mechanisms of pathogenesis centered on disrupted transforming growth factor β signaling and hippocampal function.

The protein SLITRK2 plays an important role in synaptic communication. This study identifies X-linked SLITRK2 variants that underlie neurodevelopmental disorders by impairing excitatory synapses.

Hyaline cartilage’s inability to self-repair can lead to osteoarthritis and joint replacement. Various treatments, including cell therapy, have been developed for cartilage damage. Autologous chondrocyte implantation (ACI) is considered the best option for focal chondral lesions. In this article, we aimed to create a narrative review that highlights the evolution and enhancement of our chondrocyte implantation technique: High-Density-ACI (HD-ACI) Membrane-assisted Autologous Chondrocyte Implantation (MACI) improved ACI using a collagen membrane as a carrier. However, low cell density in MACI resulted in softer regenerated tissue. HD-ACI was developed to improve MACI, implanting 5 million chondrocytes per cm2, providing higher cell density. In animal models, HD-ACI formed hyaline-like cartilage, while other treatments led to fibrocartilage. HD-ACI was further evaluated in patients with knee or ankle defects and expanded to treat hip lesions and bilateral defects. HD-ACI offers a potential solution for cartilage defects, improving outcomes in regenerative medicine and cell therapy. HD-ACI, with its higher cell density, shows promise for treating chondral defects and advancing cartilage repair in regenerative medicine and cell therapy.

BK K+ channels are critical regulators of neuron and muscle excitability, comprised of a tetramer of pore-forming αsubunits from the KCNMA1 gene and cell- and tissue-selective β subunits (KCNMB1-4). Mutations in KCNMA1 are associated with neurological disorders, including autism. However, little is known about the role of neuronal BK channel β subunits in human neuropathology. The β2 subunit is expressed in central neurons and imparts inactivation to BK channels, as well as altering activation and deactivation gating. In this study, we report the functional effect of G124R, a novel KCNMB2 mutation obtained from whole-exome sequencing of a patient diagnosed with autism spectrum disorder. Residue G124, located in the extracellular loop between TM1 and TM2, is conserved across species, and the G124R missense mutation is predicted deleterious with computational tools. To investigate the pathogenicity potential, BK channels were co-expressed with β2WT and β2G124R subunits in HEK293T cells. BK/β2 currents were assessed from inside-out patches under physiological K+ conditions (140/6 mM K+ and 10 μM Ca2+) during activation and inactivation (voltage-dependence and kinetics). Using β2 subunits lacking inactivation (β2IR) revealed that currents from BK/β2IRG124R channels activated 2-fold faster and deactivated 2-fold slower compared with currents from BK/β2IRWT channels, with no change in the voltage-dependence of activation (V1/2). Despite the changes in the BK channel opening and closing, BK/β2G124R inactivation rates (τinact and τrecovery), and the V1/2 of inactivation, were unaltered compared with BK/β2WT channels under standard steady-state voltage protocols. Action potential-evoked current was also unchanged. Thus, the mutant phenotype suggests the β2G124R TM1-TM2 extracellular loop could regulate BK channel activation and deactivation kinetics. However, additional evidence is needed to validate pathogenicity for this patient-associated variant in KCNMB2.

Introduction: In this work we describe the use of high-density autologous chondrocyte implantation (HD-ACI) to treat 2 patients with chondral defects in the hip. Case Presentation: Two male, 35- and 37-year-old, with chondral lesions and femoroacetabular impingement (FAI) were included. Chondrocytes were isolated expanded in vitro and then implanted at a density of 5 million cells per cm2 onto a type I/III porcine collagen membrane. None of the patients had surgery-derived complications. Pain disappeared in both cases at 6 months after surgery and was maintained until follow-up end (36 months). International Hip Outcome Tool (iHOT) score increased at 6 and 12 months and then leveled off until month 36.Three-year arthro-MRI showed the cartilage defects had been filled with a material similar to the surrounding healthy cartilage. Conclusion: HD-ACI is a safe and effective technique for focal cartilage lesion treatment in patients affected by evolved FAI.

Anoctamin 3 (ANO3) belongs to a family of transmembrane proteins that form phospholipid scramblases and ion channels. A large number of ANO3 variants were identified as the cause of craniocervical dystonia, but the underlying pathogenic mechanisms remain obscure. It was suggested that ANO3 variants may dysregulate intracellular Ca2+ signalling, as variants in other Ca2+ regulating proteins like hippocalcin were also identified as a cause of dystonia. In this study, we conducted a comprehensive evaluation of the clinical, radiological and molecular characteristics of four individuals from four families who carried heterozygous variants in ANO3. The median age at follow-up was 6.6 years (ranging from 3.8 to 8.7 years). Three individuals presented with hypotonia and motor developmental delay. Two patients exhibited generalized progressive dystonia, while one patient presented with paroxysmal dystonia. Additionally, another patient exhibited early dyskinetic encephalopathy. One patient underwent bipallidal deep brain stimulation (DBS) and showed a mild but noteworthy response, while another patient is currently being considered for DBS treatment. Neuroimaging analysis of brain MRI studies did not reveal any specific abnormalities. The molecular spectrum included two novel ANO3 variants (V561L and S116L) and two previously reported ANO3 variants (A599D and S651N). As anoctamins are suggested to affect intracellular Ca2+ signals, we compared Ca2+ signalling and activation of ion channels in cells expressing wild-type ANO3 and cells expressing anoctamin variants. Novel V561L and S116L variants were compared with previously reported A599D and S651N variants and with wild-type ANO3 expressed in fibroblasts isolated from patients or when overexpressed in HEK293 cells. We identified ANO3 as a Ca2+-activated phospholipid scramblase that also conducts ions. Impaired Ca2+ signalling and compromised activation of Ca2+-dependent K+ channels were detected in cells expressing ANO3 variants. In the brain striatal cells of affected patients, impaired activation of KCa3.1 channels due to compromised Ca2+ signals may lead to depolarized membrane voltage and neuronal hyperexcitability and may also lead to reduced cellular viability, as shown in the present study. In conclusion, our study reveals the association between ANO3 variants and paroxysmal dystonia, representing the first reported link between these variants and this specific dystonic phenotype. We demonstrate that ANO3 functions as a Ca2+-activated phospholipid scramblase and ion channel; cells expressing ANO3 variants exhibit impaired Ca2+ signalling and compromised activation of Ca2+-dependent K+ channels. These findings provide a mechanism for the observed clinical manifestations and highlight the importance of ANO3 for neuronal excitability and cellular viability. [ABSTRACT FROM AUTHOR]

El propósito de este artículo es presentar una caracterización sintáctica y semántica de los verbos llamarse y apellidarse efectuada desde los presupuestos de la lingüística cognitivo-funcional. Nuestro objetivo es poner de manifiesto cómo funcionan estos verbos en español, cuáles son sus peculiaridades conceptuales (peculiaridades muy notables en el contexto de las lenguas europeas) y cuáles son las posibles razones -históricas y lingüísticas- por las que estas formas verbales pronominales y no otras se utilizan en español para expresar el nombre propio y el apellido. El trabajo ofrece reflexiones originales acerca de estos verbos e hipótesis novedosas sobre la relación entre los verbos de habla, la reflexividad, la representación de uno mismo y la fuerza ilocutiva del lenguaje.

Purpose: To study clinical outcome of patients with bilateral ankle chondral defects treated with High-Density Autologous Chondrocyte Implantation (HD-ACI) in the same surgical act. Cases presentation: Two men (27 and 48 years-old) with chondral defects in both ankles evidenced by MRI. Chondral lesions were treated with HD-ACI in the same surgical act and anesthesia, consecutively. Patients were evaluated 2, 6 and 12 months after surgery to check for treatment safety and efficacy. Pain, evaluated by the Visual Analogic Scale (VAS), decreased from very high values (8.5 – 9) to normal or almost normal scores one year after surgery (0 – 1). Ankle functionality measured by the American Orthopedic Foot & Ankle Society score (AOFAS) and quality of life evaluated by the EuroQol five-dimensional five-level questionnaire (EQ-5D-5L) behaved similarly to pain. Thus, both parameters increased and/or slightly decreased at 2 months (AOFAS score: 53 and 51; EQ-5D-5L score: 0.42 and 0.33) and reached their maximum value at 12 months (AOFAS score: 90 and 89; EQ-5D-5L score: 0.89 and 0.91). MRI from both ankles revealed that chondral defects were filled with a material of similar aspect to the surrounding cartilage. Conclusion: Treatment of both ankles with HD-ACI in the same surgical act in patients with bilateral chondral lesions is a safe procedure, providing positive results from the clinical and patients’ quality of life points of view.

ABSTRACT: Introduction: Bilateral knee chondral defects can be treated in one or two surgical acts. Objectives: To study clinical outcome of patients with bilateral knee chondral defects treated with High-Density Autologous Chondrocyte Implantation (HD-ACI) during the same surgery. Methods: Study on eight patients (4 women and 4 men) with chondral defects in both knees treated with HD-ACI during the same surgical act. Patients were evaluated 2, 6, 12 and 24 months post-op for treatment safety and efficacy: visual analogic scale (VAS) for pain, International Knee Documentation Committee (IKDC) for subjective patient's perception of both knees and EuroQol five-dimensional five-level questionnaire (EQ-5D-5 L) for quality of life. Integrity of neoformed tissue at 12 and 24-month follow-up was assessed by the magnetic resonance observation of cartilage repair tissue (MOCART) score. Results: VAS decreased from baseline to 24 months from a median of 8 (6 – 9) to a median of 0 (0 – 5) (P < .001). IKDC increased from a median value of 39.0 (17.2 – 48.3) in the basal visit to a median of 83.7 (24.0 – 98.0) in the 24-month visit (P < .001). EQ-5D-5 L decreased at 2 months post-op and increased throughout the follow-up visits thereafter, needing 24 months after surgery to reach a value higher than the basal one. Median MOCART at 12 months was 80.3 (58.0 – 89.7) and 81.3 (54.0 – 89.9) at 24 months. Conclusions: Treatment of both knees with HD-ACI during the same surgical act in patients with bilateral chondral lesions is a safe procedure, providing good clinical results.

Resumen: Introducción: El trastorno por déficit de atención con hiperactividad (TDAH) y su comorbilidad repercuten en la ansiedad social de niños y adolescentes, no obstante, apenas hay estudios que aborden este tema en la adolescencia. El objetivo era evaluar el grado de ansiedad social y analizar la presencia de comorbilidades psiquiátricas (CPS). Metodología: Estudio observacional transversal en el que se incluyeron pacientes de 12-18 años con diagnóstico confirmado de TDAH (DSM-5). Se recogió información sobre la presencia y tipo de CPS y se evaluó la ansiedad social mediante la escala Social Anxiety Scale for Adolescents (SAS-A). Resultados: Participaron 46 especialistas de psiquiatría del niño y del adolescente o neuropediatría, que incluyeron a 234 pacientes. El 68,8% (159) eran varones y el 31,2% (72) mujeres, con edad media de 14,9 años (IC 95%: 14,6-15,1). El 51,7% (121) tenía TDAH de tipo combinado (TC), el 37,2% (87) con predominio del déficit de atención (TDA) y el 9% (21) con predominio hiperactivo-impulsivo (TH). El 97,9% (229 pacientes) recibía tratamiento farmacológico: metilfenidato en el 78,6% (184), lisdexanfetamina en el 15% (35) y atomoxetina en el 4,3% (10).El 50,4% (118) presentaba alguna CPS, con predominio de los trastornos del aprendizaje y de la comunicación (47, 20,1%) y los trastornos de ansiedad (45, 19,2%). Se observó un grado de ansiedad social significativamente mayor en comparación con los valores normales de la escala en la población sana. Los adolescentes con TDA presentaron peores puntuaciones en la escala SAS-A en comparación con adolescentes con TH (p = 0,015). La presencia de trastornos de ansiedad comórbidos se relacionó con peores puntuaciones en la escala SAS-A, reflejando una mayor ansiedad social en estos pacientes (p

Introduction: Attention-deficit/hyperactivity disorder (ADHD) and its comorbidities have an impact on the social anxiety of children and adolescents, but there are practically no studies addressing this topic in adolescence. Our objective was to assess the degree of social anxiety and to analyse the presence of psychiatric comorbidities (PSCs) in adolescents with ADHD. Methodology: We conducted a cross-sectional observational study in patients aged 12–18 years with a confirmed diagnosis of ADHD (DSM-5). We collected data on the presence and type of PSCs and assessed social anxiety by means of the Social Anxiety Scale for Adolescents (SAS-A). Results: Forty-six child and adolescent psychiatrists and paediatric neurologists participated in the study and recruited 234 patients. Of the total patients, 68.8% (159) were male and 31.2% (72) female, with a mean age in the sample of 14.9 years (95% CI, 14.6–15.1). The type of ADHD was combined type (C) in 51.7% (121), predominantly inattentive (PI) in 37.2% (87), and predominantly hyperactive-impulsive (PH) in 9% (21). Of all patients, 97.9% (229) received pharmacological therapy: 78.6% (184) methylphenidate, 15% (35) lisdexamfetamine and 4.3% (10) atomoxetine.We found PSCs in 50.4% of the patients (118), of which the most frequent were learning and communication disorders (20.1%, n = 47) and anxiety disorders (19.2%, n = 45). The patients scored significantly higher in the SAS-A compared to reference values in the healthy population. The scores in the SAS-A were less favourable in adolescents with the PI type compared to those with the PH type (P = .015). The presence of a comorbid anxiety disorder was associated with worst scores in SAS-A (P

Abstract Background Attention-deficit/hyperactivity disorder (ADHD) is a common neurodevelopmental condition in childhood (5.3% to 7.1% worldwide prevalence), with substantial overall financial burden to children/adolescents, their families, and society. The aims of this study were to describe the clinical characteristics of children and adolescents with ADHD in Spain, estimate the associated direct/indirect costs of the disorder, and assess whether the characteristics and financial costs differed between children/adolescents adequately responding to currently available pharmacotherapies compared with children/adolescents for whom pharmacotherapies failed. Methods This was a multicenter, cross-sectional, descriptive analysis conducted in 15 health units representative of the overall Spanish population. Data on demographic characteristics, socio-occupational status, social relationships, clinical variables of the disease, and pharmacological and non-pharmacological treatments received were collected in 321 children and adolescents with ADHD. Direct and indirect costs were estimated over one year from both a health care system and a societal perspective. Results The estimated average cost of ADHD per year per child/adolescent was €5733 in 2012 prices; direct costs accounted for 60.2% of the total costs (€3450). Support from a psychologist/educational psychologist represented 45.2% of direct costs and 27.2% of total costs. Pharmacotherapy accounted for 25.8% of direct costs and 15.5% of total costs. Among indirect costs (€2283), 65.2% was due to caregiver expenses. The total annual costs were significantly higher for children/adolescents who responded poorly to pharmacological treatment (€7654 versus €5517; P = 0.024), the difference being mainly due to significantly higher direct costs, particularly with larger expenses for non-pharmacological treatment (P = 0.012). Conclusions ADHD has a significant personal, familial, and financial impact on the Spanish health system and society. Successful pharmacological intervention was associated with lower overall expenses in the management of the disorder.

Tatton‐Brown–Rahman syndrome (TBRS) or DNMT3A‐overgrowth syndrome is characterized by overgrowth and intellectual disability associated with minor dysmorphic features, obesity, and behavioral problems. It is caused by variants of the DNMT3A gene. We report four patients with this syndrome due to de novo DNMT3A pathogenic variants, contributing to a deeper understanding of the genetic basis and pathophysiology of this autosomal dominant syndrome. Clinical and magnetic resonance imaging assessments were also performed. All patients showed corpus callosum anomalies, small posterior fossa, and a deep left Sylvian fissure; as well as asymmetry of the uncinate and arcuate fascicles and marked increased cortical thickness. These results suggest that structural neuroimaging anomalies have been previously overlooked, where corpus callosum and brain tract alterations might be unrecognized neuroimaging traits of TBRS syndrome caused by DNMT3A variants. [ABSTRACT FROM AUTHOR]

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