Spinal muscular atrophy (SMA) has traditionally been described as a motor neuron disorder; however, increasing evidence suggests a broader neurodevelopmental involvement, particularly in the era of disease-modifying therapies. As survival and motor outcomes improve, cognitive and behavioral trajectories have become clinically relevant but remain inconsistently characterized. To systematically synthesize current evidence on cognitive and neurodevelopmental outcomes in children and adults with SMA, with particular focus on differences across phenotypes and therapeutic eras. A scoping review was conducted including observational studies, clinical cohorts, and case series reporting cognitive, language, behavioral, or executive outcomes in individuals with SMA. Studies were analyzed qualitatively with attention to disease severity, age, and treatment status. Twenty-three studies were included. Global intellectual functioning was generally preserved, particularly in SMA types II and III. Nevertheless, selective vulnerabilities were frequently reported in processing speed, executive functioning, and language development. Behavioral and socio-emotional challenges were described in pediatric populations. Neurodevelopmental outcomes in early-onset SMA showed substantial heterogeneity, ranging from global developmental delay to relatively preserved cognitive trajectories, especially in pre-symptomatically treated patients. Methodological variability and motor-related testing limitations were common across studies. Cognitive functioning in SMA appears largely preserved in milder phenotypes but domain-specific vulnerabilities in processing speed, working memory, and language are consistently identified across phenotype groups and represent clinically relevant targets for monitoring and intervention. Systematic neurodevelopmental monitoring and standardized assessment protocols are needed to better define long-term outcomes as treatment modifies disease trajectories.

BackgroundTANGO2 deficiency disorder (TDD) is a rare autosomal recessive condition characterized by neurodevelopmental impairment and recurrent metabolic crises. Paroxysmal non-epileptic neurological episodes (“TANGO2 spells”) are increasingly recognized but remain poorly characterized and often misdiagnosed.MethodsWe report a child with TDD presenting with recurrent paroxysmal neurological episodes and performed a scoping review of Scopus and PubMed-indexed literature to summarize clinical features, triggers, diagnostic findings and management of TANGO2 spells.ResultsThe reported patient developed recurrent stereotyped episodes from 23 months of age, characterized by weakness, dystonia with head tilt, vomiting, irritability and reduced responsiveness, lasting several hours and triggered by illness or reduced intake. EEG during spells was without epileptic discharges, metabolic investigations and QTc were normal, and whole-exome sequencing confirmed biallelic pathogenic TANGO2 variants. Following supportive supplementation, no further spells or metabolic crises occurred. Across 7 studies including 93 patients identified by the scoping review, TANGO2 spells typically began in infancy or early childhood, were stress-related, transient, and self-limited, with non-ictal EEG findings when assessed. Cardiac involvement was consistently associated with metabolic crises rather than isolated spells.ConclusionsTANGO2 spells represent a distinctive early neurological manifestation of TDD that may occur independently of metabolic decompensation. Their recognition can facilitate earlier diagnosis and prompt initiation of preventive supportive strategies.

IntroductionPreterm birth remains a major global health concern, with growing evidence linking it to long-term neurodevelopmental and psychiatric sequelae. Children born very or extremely preterm are at increased risk for cognitive, motor, and emotional difficulties that may persist into adolescence.Materials and methodsWe conducted a retrospective and prospective observational study involving 29 adolescents (aged 14–18 years) born very or extremely preterm between 2005 and 2011 at the University Hospital of Parma. Participants underwent in-person neurological examinations, cognitive testing (Raven's Progressive Matrices), and motor assessments (Movement ABC-2 or Brief Motor Scale), alongside retrieval of early developmental scores from the Bayley Scales (administered between 3 and 36 months).ResultsEarly cognitive assessments showed strong predictive associations with later intellectual functioning: MDI scores at 12 and 18 months correlated significantly with Raven QI equivalent scores in adolescence (ρ = 0.705 and ρ = 0.763, respectively, p < .01), while the association at 3 months was weaker and non-significant (ρ = 0.410, p = .052). In contrast, early motor scores showed inconsistent predictive associations, with only the 18-month PDI reaching significance (ρ = 0.583, p = .022). Psychiatric or neurodevelopmental diagnoses were present in 50% of extremely preterm and 33.3% of very preterm adolescents. Visuomotor coordination showed the strongest negative correlation with gestational age among motor domains (r = –0.57).ConclusionsThese findings suggest that the 12–18 month developmental assessment window carries meaningful prognostic value for both cognitive and motor outcomes in preterm survivors, and support the implementation of structured multidisciplinary surveillance extending into adolescence.

PHACE syndrome is a rare neurocutaneous disorder defined by the association of large segmental infantile hemangiomas of the head and neck with malformations of the posterior fossa, cerebral and cervical arteries, heart, eyes, and ventral midline structures. Although facial hemangiomas are often the presenting feature, the cerebrovascular, neurodevelopmental, and airway manifestations are responsible for the greatest long-term morbidity. A systematic literature review was conducted following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines, searching PubMed, Web of Science, EMBASE, and PsycINFO. After removal of duplicates and screening of 308 records, five studies meeting the inclusion criteria were retained for qualitative synthesis. We additionally present the case of a now 12-year-old girl with PHACE syndrome characterized by a left V1-distribution facial hemangioma, ocular abnormalities, multiple cerebrovascular venous and arterial malformations, neonatal intraventricular hemorrhage with hydrocephalus, and a subsequently diagnosed dural arteriovenous fistula requiring repeated embolization. The five included studies collectively describe epidemiology and early supportive care needs, long-term health outcomes and quality of life into adulthood, airway hemangioma prevalence and management, and the clinical spectrum of infantile hemangiomas with minimal or arrested growth (IH-MAG) as a cutaneous marker of PHACE syndrome. Across studies, cerebrovascular arteriopathy (72–91

TANGO2-deficiency disorder (TDD) is a rare autosomal recessive condition characterised by neurodevelopmental delay, TANGO2 spells, life-threatening metabolic crises, and cardiac arrhythmias. Genotype-phenotype correlations remain poorly defined and the neurobehavioural profile of affected individuals is largely unexplored. We conducted a retrospective multicentre study of five Italian patients with genetically confirmed TDD, identified between June 2023 and May 2025. Clinical, neurophysiological, neuroimaging, genetic, and neurodevelopmental data were collected. Adaptive functioning, cognitive ability, and behavioural profiles were assessed using standardised instruments. All five patients carried biallelic TANGO2 mutations, including two previously unreported variants. Clinical severity ranged from an asymptomatic individual under preventive therapy to a fatal early-onset metabolic crisis. Marked intrafamilial variability was observed in two siblings sharing the same genotype. Systematic neurodevelopmental assessment revealed a spectrum of cognitive and adaptive outcomes, with attentional difficulties identified as a recurrent feature. No metabolic crises or TANGO2 spells were documented following initiation of B-vitamin and cofactor supplementation in surviving patients. This cohort expands the mutational and phenotypic spectrum of TDD and highlights the diagnostic value of TANGO2 testing in patients with neurodevelopmental delay or paroxysmal neurological episodes, even in the absence of metabolic crises. Early supplementation therapy may contribute to clinical stability, though prospective controlled studies are needed.

IntroductionThe gold standard for diagnosing central precocious puberty(CPP) is the gonadotropin-releasing hormone stimulation test, along with magnetic resonance imaging(MRI) of the brain and hypothalamus-pituitary region to rule out central organic causes. Recent advancements have led to a new medical imaging approach called radiomics. Our recent study showed that pituitary gland radiomics is a promising tool for diagnosing CPP. However, the role of the pineal gland in the onset of puberty has long been debated. Therefore, we investigated radiomic features of the pineal gland associated with puberty onset to identify changes that could assist physicians in the diagnostic workup of CPP.Methods45 girls with a confirmed diagnosis of CPP and 47 pre-pubertal, age-and sex-matched subjects(controls) were retrospectively enrolled. Two readers(R1, R2) with different levels of expertise in pediatric neuroradiology blindly segmented the pineal gland on MRI studies for radiomic features(RFs) calculation and manually evaluated the number and diameter of pineal cysts. Cross-validated linear discriminant analysis was used to develop, for each reader, both a radiomic model and a reference model based on pineal cyst features. Radiomics was evaluated in terms of predictive performances(ROC-AUC) and reliability of predictors between readers (intraclass correlation coefficient). Finally, the correlation between cysts' features and basal/peak gonadotropin and estradiol levels was also investigated.ResultsTwo radiomic features were identified as the most predictive of CPP for both readers. However, these features were not the same for R1 and R2 readers and their values showed poor inter-reader reliability. Unpromising performance in the validation set was observed for pineal gland radiomics (ROC-AUC of 0.64 for R1 and 0.59 for R2). Similarly, the reference model based on pineal cyst features demonstrated a poor performance (ROC-AUC = 0.52, both readers). No significant correlations between cyst features and basal/peak gonadotropin levels were observed.ConclusionRadiomic features of the pineal gland in girls did not show consistent and relevant changes with the onset of puberty and do not hold promise for the CPP diagnosis at variance with previous findings in the pituitary gland. Similarly, the number and size of cysts were not found to be specific for the onset of puberty.

BackgroundIn recent decades, advances in neonatal care have led to a substantial reduction in mortality associated with prematurity. However, preterm birth remains the leading contributor to long-term neurodevelopmental impairment across the lifespan. The present study aimed to longitudinally assess neurodevelopmental outcomes in individuals born very preterm (VPT) or extremely preterm (EPT) and to retrospectively investigate associations between early neurodevelopmental trajectories and psychopathological and functional profiles in adolescence.MethodsThe study included 52 adolescents aged 14–18 years, drawn from an original cohort of 118 individuals born before 31 weeks of gestation between 2005 and 2011. Neonatal clinical and anamnestic data were collected, and early neurodevelopment within the first two years of life was assessed using the Bayley Scales of Infant and Toddler Development, Second Edition. Fifteen years later, participants underwent a multidimensional follow-up assessment via self-administered questionnaires delivered through a secure web-based platform. Both participants and one parent completed a comprehensive psychopathological evaluation, including the Child Behavior Checklist (CBCL), Autism Spectrum Quotient (AQ), Obsessive–Compulsive Inventory (OCI), Prodromal Questionnaire–16 (PQ-16), and Inventory of Psychotic-Like Anomalous Self-Experiences (IPASE).ResultsThe mean gestational age was 28 weeks (SD = 1.8; range: 23–31), and the mean birth weight was 1,120.8 g (SD = 322.4). VPT individuals showed higher AQ scores, suggesting increased vulnerability to autistic traits, whereas EPT individuals exhibited higher CBCL Attention Problems scores, consistent with ADHD-related features. Latent Profile Analysis identified a two-profile solution: Profile 1 (“High autism traits”) was characterized by elevated AQ scores and relatively low OCI, PQ-16, and IPASE scores, whereas Profile 2 (“High psychotic and OCD traits”) showed markedly elevated PQ-16, IPASE and OCI scores. Hierarchical multiple regression analyses revealed that the Psychomotor Development Index slope was the only significant predictor of later social functioning (B = −5.782, β = −.289, p = .040), with more favorable early motor trajectories associated with fewer social difficulties in adolescence.ConclusionsVery and extremely preterm birth are associated with long-term neurodevelopmental and psychopathological vulnerability. Early motor development appears to be a key predictor of later social functioning, potentially shaping distinct developmental trajectories toward autism-related features or psychosis vulnerability.

Objective Pediatric pseudotumor cerebri syndrome (PTCS) differs from adult disease in epidemiology, risk factors and clinical presentation. Female predominance and obesity are typically reported after puberty, while secondary forms are more frequent in younger children. Due to limited data on prepubertal patients, this study aimed to analyze clinical features, management and outcomes of pediatric PTCS, focusing on metabolic factors and disease course. Methods We retrospectively analyzed 14 children and adolescents diagnosed with PTCS in a pediatric center between 2015 and 2025, according to Friedman criteria. Data included demographics, pubertal status, body mass index, presenting symptoms, secondary causes, treatments and outcomes over 12 months. Additional post-study follow-up was performed when available. Results Female predominance was observed regardless of pubertal status. All patients were overweight or obese at diagnosis. Headache was the most frequent presenting symptom (85.7%), often accompanied by visual symptoms. Papilledema was present in all patients. Secondary PTCS occurred in three patients. Treatment included weight loss and acetazolamide in all patients. At 12 months, complete clinical and ophthalmologic remission was achieved in 64.3%. Recurrences occurred in three patients, both early and late: two required surgical interventions. Conclusion PTCS should be suspected in overweight or obese children and adolescents presenting with persistent headache or visual symptoms, regardless of pubertal status. Early diagnosis, weight control and regular ophthalmologic monitoring are essential to reduce the risk of permanent visual impairment. Long-term follow-up is necessary, as relapses may occur beyond the first year after diagnosis. Prospective studies are warranted to confirm these findings.

Spinal Muscular Atrophy (SMA) is a genetic disorder characterized by the progressive loss of motor neurons and consequent muscle atrophy. Although SMN-targeted therapies have significantly improved survival and motor outcomes, residual muscle weakness remains a major clinical challenge, particularly in patients treated later in the disease course. Myostatin, a potent negative regulator of skeletal muscle mass, has emerged as a promising therapeutic target to address this gap. This review summarizes the preclinical and clinical evidence supporting the modulation of the myostatin pathway in SMA. Preclinical studies have demonstrated that inhibiting myostatin, especially when combined with SMN-enhancing agents, can increase muscle mass, improve motor function, and enhance neuromuscular connectivity in SMA mouse models. These findings provide a strong rationale for translating myostatin inhibition into clinical practice as an adjunctive strategy. Early clinical trials investigating myostatin inhibitors have shown favorable safety profiles and preliminary signs of target engagement. However, large-scale trials have yet to demonstrate widespread, robust efficacy across diverse patient populations. Despite this, myostatin pathway inhibition remains a compelling approach, particularly when integrated into broader treatment paradigms aimed at enhancing motor unit stability and function in individuals with SMA. Further clinical research is essential to validate efficacy, determine optimal timing, and define the patient subgroups most likely to benefit from myostatin-targeted therapies.

Spinal muscular atrophy (SMA) frequently causes scoliosis (up to 90% of cases), due to weakened axial muscles impacting motor and respiratory function. While new SMA treatments improve motor function, their effect on scoliosis progression is unclear. This scoping review (2016-October 2024) analyzed literature from Pubmed, MEDLINE, EMBASE, and Scopus, focusing on studies of SMA, scoliosis, and treatment approaches. The aim of this work was to describe the clinical features and the possible therapeutic approaches of scoliosis in the "new population" of pharmacologically treated SMA patients. We included all types of SMA as well as all the approved disease modifying therapies (DMTs). The review found significant variability in scoliosis presentation and surgical intervention among different types of treated SMA patients. Early pharmacological treatment may slow scoliosis progression, particularly in Type II SMA. Interestingly, Type I SMA patients, who typically don't develop scoliosis due to severe hypotonia, showed an increased scoliosis onset. Larger studies are needed to fully evaluate the impact of different treatments on scoliosis progression in SMA, especially in Type I SMA patients, to establish updated standards of care.

Aim To investigate the prevalence, severity, and clinical correlates of obsessive-compulsive symptoms (OCS) in pediatric patients with primary headache disorders. Methods In this monocentric, observational, and retrospective study, we assessed 100 children and adolescents (mean age = 12.0 years; 63% female) diagnosed with migraine, tension-type headache (TTH) or coexisting migraine and TTH at a tertiary child neuropsychiatry outpatient clinic. OCS were evaluated using the Obsessive-Compulsive Inventory–Child Version (OCI-CV), with clinically significant symptoms defined as a total score ≥21. A multivariable logistic regression model examined associations with sex, age, and neurovegetative features. A post-hoc power analysis was also conducted. Results Clinically significant OCS were present in 17% of participants. Female sex (OR = 5.18, 95% CI = 1.24–36.32, p = .046) and the presence of neurovegetative symptoms (OR = 1.51, 95% CI = 1.11–2.08, p = .009) were significant predictors, whereas age showed no significant effect. The most elevated OCI-CV subscales were “Obsessing,” “Hoarding,” and “Ordering.” Conclusion OCS are relatively common in pediatric patients with primary headache, especially among females and those reporting autonomic symptoms. Routine psychopathological screening in this population may support early identification and targeted clinical management.

Background/Objectives: Pediatric acquired demyelinating syndromes (ADSs) encompass a heterogeneous group of disorders, including multiple sclerosis (MS), MOG antibody-associated disease (MOGAD), and neuromyelitis optica spectrum disorder (NMOSD), with distinct clinical trajectories and prognoses. While analyzed collectively at baseline to reflect real-world diagnostic uncertainty, outcome predictors were also examined according to final diagnosis. Identifying early predictors is crucial for optimizing long-term outcomes. Methods: We retrospectively analyzed 30 pediatric patients (mean onset age: 11.3 years) with ADSs. Clinical, radiological, CSF, antibody, and neurophysiological data were collected and analyzed alongside treatment strategies. Outcomes—EDSS scores, neuroradiological changes, and clinical status—were evaluated over a 3-year period. Results: Final diagnoses included MOGAD (36.6%), MS (33.3%), NMOSD (6.6%), ADEM (10%), and other ADSs (13.3%). At onset, ≥3 brain lesions were present in 76.7% of patients. Disease-modifying therapies (DMTs) were used in 37% and acute immunotherapy in 90%. EDSS progression was significantly associated with DMT use at multiple timepoints, with additional predictors including MRI lesion type, CSF findings, antibody status, and evoked potentials. At 3 years, neurocognitive function predicted clinical outcome. Conclusions: Early immunotherapy and baseline instrumental findings are key predictors of outcome in pediatric ADSs. MOGAD showed a more favorable course, while MS and NMOSD were associated with greater long-term disability. A comprehensive, early diagnostic approach is essential for improving prognosis.

BackgroundThe aim of the study was to explore a radiomic model that could assist physicians in the diagnosis of central precocious puberty (CPP). A predictive model based on radiomic features (RFs), extracted form magnetic resonance imaging (MRI) of the pituitary gland, was thus developed to distinguish between CPP and control subjects.Methods45 girls with confirmed diagnosis of CPP (CA:8.4 ± 0.9 yr) according to the current criteria and 47 age-matched pre-pubertal control subjects (CA:8.7 ± 1.2 yr) were retrospectively enrolled. Two readers (R1, R2) blindly segmented the pituitary gland on MRI studies for RFs and performed a manual estimation of the pituitary volume. Radiomics was compared against pituitary volume in terms of predictive performances (metrics: ROC-AUC, accuracy, sensitivity and specificity) and reliability (metric: intraclass correlation coefficient, ICC). Pearson correlation between RFs and auxological, biochemical, and ultrasound data was also computed.ResultsTwo different radiomic parameters, Shape Surface Volume Ratio and Glrlm Gray Level Non-Uniformity, predicted CPP with a high diagnostic accuracy (ROC-AUC 0.81 ± 0.08) through the application of our ML algorithm. Anthropometric variables were not confounding factors of these RFs suggesting that premature thelarche and/or pubarche would not be potentially misclassified. The selected RFs correlated with baseline and peak LH (p < 0.05) after GnRH stimulation. The diagnostic sensitivity was improved compared to pituitary volume only (0.76 versus 0.68, p<0.001) and demonstrated higher inter-reader reliability (ICC>0.57 versus ICC=0.46).DiscussionRadiomics is a promising tool to diagnose CPP as it reflects also functional aspects. Further studies are warranted to validate these preliminary data.

Myelin oligodendrocyte glycoprotein (MOG)-IgG-associated disease (MOGAD) is a relatively uncommon autoantibody demyelinating disorder of the central nervous system (CNS) with heterogeneous clinical manifestations and magnetic resonance imaging (MRI) findings. In recent years, a rare MOGAD subtype characterized by distinct clinical and MRI findings has been described. Seizures and cortical hyperintensities best seen on MRI T2-weighted fluid-attenuated inversion recovery (FLAIR) sequences, associated with headache and cerebral spine fluid (CSF) pleocytosis, are the most important characteristics of this MOGAD entity that is named FLAMES (FLAIR hyperintense cortical lesions in MOG-associated encephalitis with seizures). Because of its rarity and the peculiarities of the brain damage and clinical manifestations, it can be under-recognized and confused with focal viral encephalitis, meningitis, subarachnoid hemorrhage, CNS vasculitis, or mitochondrial cytopathy. We described the case of a 4-year-old previously healthy girl who was admitted for focal-onset, tonic-clonic seizures, fever, and headache, combined with optic neuritis. MRI was characterized by FLAIR imaging showing hyperintense cortical lesions, and a mild leukocytosis in the CSF was detected. Efficacy and rapid response to steroid therapy was observed, and no recurrences of neurological problems or further seizures were reported in the following 12 months. This case report can help in understanding FLAMES characteristics in pediatrics in order to favor early diagnosis and prompt therapy.

Pediatric Autoimmune Neuropsychiatric Disorder Associated with Streptococcal Infections (PANDAS) and Pediatric Acute-onset Neuropsychiatric Syndrome (PANS) are broad diagnoses that encompass a range of sudden-onset neuropsychiatric symptoms in children, which can include obsessive-compulsive disorder (OCD), tics, anxiety, emotional instability, and cognitive difficulties. Unlike PANDAS, PANS is not strictly linked to group A streptococcal infections but can be triggered by various infectious or environmental factors. Lights and shadows remain upon the management of children with PANS and PANDAS and there is no clear consensus regarding definition, diagnostic criteria, treatment, and follow-up. The aim of the present study was to evaluate the level of agreement on PANS and PANDAS definition, diagnostic criteria, treatment and follow-up and to assess on the basis of recent studies whether there is a need to modify the current recommendations used by primary care pediatricians and hospital pediatricians in clinical practice in order to improve outcomes. Using the Delphi method, this consensus provides shared indications on PANS and PANDAS management in pediatric age, based on the most updated literature. This work represents, in our opinion, the most complete and up-to-date information on the diagnosis of PANS and PANDAS, as well as consensus statements about several aspects of clinical care. Undoubtedly, more randomized and controlled trials are needed in the pediatric population to better define the best management, also in terms of adequate follow-up examinations and period of observation.

In this case report, we present the case of a 20-month-old girl who manifested paroxysmal “bidet-induced” episodes characterized by impaired awareness, pallor, and hypotonia, with a duration of less than a minute. Initial neurological examination yielded unremarkable results, prompting further investigation. A video-electroencephalogram recording documented the epileptic nature of these episodes, revealing an ictal discharge originating from the right central-temporal region. A brain magnetic resonance imaging exhibited a sulcal/gyral asymmetry within the central sulci, along with the presence of the “power button sign” within the right central sulcus. These findings were indicative of a focal cortical dysplasia type-2. Subsequent genetic analysis through a gene panel identified the presence of an NPRL2 variant. Mutations affecting this particular gene are known to disrupt the normal functioning of the GATOR1 complex, potentially causing focal cortical dysplasia and various forms of epilepsy, including familial focal epilepsy with variable foci. On the diagnosis, the patient received levetiracetam, and the ictal episodes promptly ceased. At the most recent follow-up (at 4 years old), the patient remained free of seizures without the need for any treatment, and her neurodevelopment so far had exhibited no abnormalities. Considering the landscape of epilepsy-related GATOR1 variants, it is conceivable that this gene family may play a significant role in the pathogenesis of benign forms of focal reflex seizures, including bathing epilepsy.

Aromatic L-amino acid decarboxylase deficiency (AADCd) is a rare recessive metabolic disorder caused by pathogenic homozygous or compound heterozygous variants in the dopa decarboxylase (DDC) gene. Adeno-associated viral vector-mediated gene transfer of the human DDC gene injected into the putamen is available. The typical presentation is characterized by early-onset hypotonia, severe developmental delay, movement disorders, and dysautonomia. Recently, mild and even atypical phenotypes have been reported, increasing the diagnostic challenge. The aim of this multicentric study is to identify the prevalence of AADCd in a population of patients with phenotypic clusters characterized by neurodevelopmental disorders (developmental delay/intellectual disability, and/or autism) by 3-O-methyldopa (3-OMD) detection in dried blood spots (DBS). It is essential to identify AADCd promptly, especially within non-typical phenotypic clusters, because better results are obtained when therapy is quickly started in mild-moderate phenotypes. Between 2021 and 2023, 390 patients with non-specific phenotypes possibly associated with AADCd were tested; none resulted in a positive result. This result highlights that the population to be investigated for AADCd should have more defined clinical characteristics: association with common signs (hypotonia) and/or pathognomonic symptoms (oculogyric crisis and dysautonomia). It is necessary to continue to screen selected clusters for reaching diagnosis and improving long-term outcomes through treatment initiation. This underscores the role of newborn screening in identifying AADCd.