Giulia Pisanò

The hypothesis that Group A beta-haemolytic Streptococcus (GAS) triggers an autoimmune cascade targeting basal ganglia dopaminergic circuits—producing obsessive–compulsive disorder (OCD), tic disorders, or chorea depending on the receptor subtype involved—is biologically compelling and supported by emerging molecular evidence. Yet PANDAS has remained a diagnostic conundrum since its original description in 1998, with ongoing uncertainty surrounding diagnostic criteria, the interpretation of streptococcal serology, and the distinction from primary neurodevelopmental disorders. This study aimed to review the diagnostic challenges of PANDAS, with focus on streptococcal serology interpretation, advances in dopamine receptor autoantibody biology, the genetic epidemiology of primary tic disorders, and the differential diagnosis of acute neuropsychiatric presentations in children. A structured narrative review was conducted using PubMed, MEDLINE, EMBASE, and the Cochrane Library for publications from 1998 to early 2025 addressing PANDAS, PANS, streptococcal antibodies, childhood movement disorders, autoimmune encephalitis, and the genetics of tic disorders. No currently available biomarker—including ASO, anti-DNase B, anti-basal-ganglia antibodies, or the Cunningham Panel—has demonstrated adequate individual-level diagnostic accuracy for PANDAS. Emerging molecular evidence identifies anti-D1R autoantibodies, acting via G protein-and beta-arrestin-mediated signalling, as candidate biomarkers for PANDAS/PANS neuropsychiatric phenotypes, and anti-D2R autoantibodies for Sydenham chorea movement phenotypes; independent replication in unselected populations is required. Primary tic disorders carry heritability estimates of 50–80% and first-degree familial risk ratios of approximately 18-fold in large population-based cohorts. Prospective blinded studies have not demonstrated a consistent population-level association between GAS infections and tic or OCD exacerbations: PANDAS and PANS remain diagnoses of exclusion. The high background prevalence of both GAS exposure and primary neurodevelopmental disorders in overlapping paediatric age ranges creates conditions for incidental temporal co-occurrence. In the absence of validated molecular biomarkers, diagnostic imprecision carries direct clinical consequences: children may be exposed to treatments with significant risk profiles—including IVIG, plasma exchange, and prolonged antibiotic prophylaxis—while evidence-based therapies are delayed. A stepwise diagnostic approach incorporating the full differential diagnosis is both an epistemological and a patient safety imperative.

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.

Background/Objectives: Titin (TTN; OMIM 188840) is the largest known human sarcomeric protein, and pathogenic variants in the TTN gene cause a broad spectrum of inherited myopathies and cardiomyopathies. The extent to which TTN variants may also involve the peripheral nervous system remains poorly defined. We aimed to describe two pediatric patients carrying heterozygous truncating TTN variants with neurophysiological evidence of peripheral nerve involvement, and to review the existing literature on this underrecognized association. Pathogenic variants in the TTN gene are associated with a wide spectrum of inherited myopathies and cardiomyopathies. To date, peripheral neur opathy has not been recognized as a defining feature of TTN-related disorders, and neurophysiological investigations in affected individuals typically demonstrate normal or myopathic findings without evidence of a primary neuropathic process. Here, we report two pediatric patients with heterozygous truncating TTN variants and neurophysiological evidence of bilateral axonal involvement of the deep peroneal nerve. Methods: This case report was structured and reported according to the CARE guidelines. Genetic testing was performed using whole-exome sequencing (Blueprint Genetics Whole Exome Family Test). Nerve conduction studies and needle electromyography were performed using the Galileo NT system. Variant classification followed current ACMG guidelines. Results: The first patient, a 10-year-old girl, presented with a symptomatic distal motor phenotype characterized by bilateral pes cavus, anterior compartment muscle atrophy, areflexia, and steppage gait with onset in early childhood. The second patient, an 8-year-old boy, had subclinical bilateral axonal neuropathy identified during neurophysiological evaluation prompted by intermittent lower limb pain; his father, carrying the same variant, showed concordant neurophysiological abnormalities. In both cases, nerve conduction studies demonstrated reduced compound muscle action potential amplitudes with preserved conduction velocities and distal latencies, consistent with axonal neuropathy. Whole-exome sequencing excluded other established genetic causes of inherited neuropathy in both probands. Conclusions: Although a causal relationship cannot be established, these observations raise the possibility that peripheral nerve involvement may represent an underrecognized feature of the titinopathy spectrum. Prospective studies in larger cohorts of TTN variant carriers are needed to clarify the prevalence and pathophysiological basis of neuropathy in this context.

Narcolepsy type 1 (NT1) and narcolepsy type 2 (NT2) are rare, chronic neurologic disorders of hypersomnolence. Narcolepsy type 1 results from the selective loss of orexin-producing neurons, leading to markedly reduced levels of orexin neuropeptides in the brain and CSF. NT2 shares some symptoms with the former but has no orexin deficiency. Both disorders manifest as a spectrum of debilitating symptoms, including excessive daytime sleepiness (EDS), cataplexy (NT1 only), fragmented nocturnal sleep, sleep paralysis, and hallucinations. Diagnosis is particularly challenging, especially in pediatric patients. We describe 7 pediatric patients presenting with complex narcolepsy phenotype of EDS or cataplexy with a diverse array of comorbid genetic, neurologic, and neuropsychiatric conditions. These cases illustrate the diagnostic challenges in differentiating "primary narcolepsy" from "narcolepsy because of a medical disorder" (e.g., Prader-Willi Syndrome) or "narcolepsy associated with autism spectrum disorder or very early-onset schizophrenia." The patients underwent a comprehensive diagnostic workup, including polysomnography, multiple sleep latency testing (performed after wash-out of concomitant medications), brain magnetic resonance imaging, CSF hypocretin-1 assay, and, in case of consistent clues, autoimmune, and genetic testing. Ensuring accurate and prompt narcolepsy diagnosis allows effective and patient-centered management.

Background: Violent TV series and streaming content are increasingly accessible to children, raising concerns about behavioral imitation and psychological effects. This study examined copycat behaviors and associated emotional and somatic symptoms among children who reported watching the age-restricted series Squid Game. Methods: In this observational study of 228 Italian primary school children (aged 8–11), 128 who had watched Squid Game formed the analytic sample. They were categorized into a Copycat Behavior (CB) group or a Non-Copycat Behavior (NCB) group based on self-reported imitation of scenes or games from the series. Parents completed the Child Behavior Checklist (CBCL). Group differences were assessed using Mann–Whitney U tests, and gender distribution was compared with Chi-square tests (α = 0.05). Results: Among viewers, 42 children (32%) engaged in imitation behaviors, typically reenacting game-based violent scenes with friends (52%), siblings (28%), or classmates (20%). Age and gender distributions did not differ between groups. The CB group scored slightly higher on the CBCL Somatic Complaints scale compared with the NCB group (M = 54.12 vs. 52.92; U = 1414.5, p = 0.033), although this difference was small. No significant differences emerged on other CBCL syndrome or broadband scales. Conclusions: Among children engaging in copycat behaviors exhibited a small, subclinical increase in somatic complaints. While causality cannot be inferred, the findings highlight the need to protect vulnerable children—particularly those prone to somatic distress—from unsupervised access to violent, age-inappropriate content. Media literacy for parents and educators, and longitudinal studies including non-viewers are recommended.

Background. PMP22-related neuropathies comprise a spectrum of predominantly demyelinating disorders, most commonly Charcot–Marie–Tooth type 1A (CMT1A; 17p12 duplication) and hereditary neuropathy with liability to pressure palsies (HNPP; 17p12 deletion), with rarer phenotypes due to PMP22 sequence variants (CMT1E, Dejerine–Sottas syndrome [DSS]). Methods. We conducted a PRISMA-compliant systematic review (PROSPERO ID: 1139921) of PubMed and Scopus (January 2015–August 2025). Eligible studies reported genetically confirmed PMP22-related neuropathies with clinical and/or neurophysiological data. Owing to heterogeneous reporting, we synthesized pooled counts and proportions without meta-analysis, explicitly tracking missing denominators. Results. One hundred twenty-seven studies (n = 4493 patients) were included. Sex was available for 995 patients (males 53.8% [535/995]; females 46.2% [460/995]); mean age at onset was 23.7 years in males and 16.4 years in females. Phenotypic classification was reported for 4431/4493 (75.4% CMT1A, 20.9% HNPP, 2.6% CMT1E, 1.2% DSS). Across phenotypes, weakness/foot drop was the leading presenting symptom when considering only cohorts that explicitly reported it (e.g., 65.3% in CMT1A; 76.0% in HNPP); sensory complaints (numbness, paresthesia/dysesthesia) were variably documented. Neurophysiology consistently showed demyelinating patterns, with median and ulnar nerves most frequently abnormal among assessed nerves; in HNPP, deep peroneal and sural involvement were also common in evaluated subsets. Comorbidities clustered by phenotype: orthopedic/neuromuscular features (pes cavus/hammer toes, scoliosis/kyphosis, tremor) in CMT1A and DSS; broader metabolic/autoimmune and neurodevelopmental associations in HNPP; and higher syndromic/ocular/hearing involvement in CMT1E. Genetically, 75.6% (3241/4291) had 17p12 duplication, 19.6% (835/4291) 17p12 deletion, and 4.8% (215/4291) PMP22 sequence variants with marked allelic heterogeneity. Among 2571 cases with available methods, MLPA was most used (41.9%), followed by NGS (20.4%) and Sanger sequencing (17.8%). Main limitations include heterogeneous and incomplete reporting across studies (especially symptoms and nerve-specific data) and the absence of a formal risk-of-bias appraisal, which preclude meta-analysis and may skew phenotype proportions toward more frequently reported entities (e.g., CMT1A). Conclusions. Recent literature confirms that PMP22 copy-number variants account for the vast majority of cases, while sequence-level variants underpin a minority with distinct phenotypes (notably CMT1E/DSS). Routine MLPA, complemented by targeted/NGS, optimizes diagnostic yield. Standardized reporting of nerve-conduction parameters and symptom denominators is urgently needed to enable robust cross-study comparisons in both pediatric and adult populations.

Background: Paroxysmal dyskinesias (PDs) are rare, episodic movement disorders characterized by sudden and involuntary hyperkinetic motor events. In paediatric populations, their diagnosis is often complicated by clinical overlap with epilepsy and other neurological conditions. Genetic underpinnings have increasingly been recognized as key to understanding phenotypic heterogeneity and guiding treatment. Objectives: This systematic review aims to provide a comprehensive overview of paediatric PD, with a focus on genetic aetiologies, clinical features, subtype classification, and therapeutic approaches, including genotype–treatment correlations. Methods: We systematically reviewed the literature from 2014 to 2025 using PubMed. Inclusion criteria targeted paediatric patients (aged 0–18 years) with documented paroxysmal hyperkinetic movements and genetically confirmed or clinically suggestive PD. Data were extracted regarding demographics, dyskinesia subtypes, age at onset, genetic findings, and treatment efficacy. Gene categories were classified as PD-specific or pleiotropic based on functional and clinical features. Results: We included 112 studies encompassing 605 paediatric patients. The most common subtype was Paroxistic Kinesigenic Dyskinesia (PKD). Male sex was more frequently reported. The mean onset age was 5.99 years. A genetic diagnosis was confirmed in 505 patients (83.5%), involving 38 different genes. Among these, PRRT2 was the most frequently implicated gene, followed by SLC2A1 and ADCY5. Chromosomal abnormalities affecting the 16p11.2 region were identified in ten patients, including deletions and duplications. Among the 504 patients with confirmed monogenic variants, 390 (77.4%) had mutations in PD-specific genes, while 122 (24.2%) carried pleiotropic variants. Antiseizure drugs—particularly sodium channel blockers such as carbamazepine and oxcarbazepine—were the most frequently reported treatment, with complete efficacy documented in 59.7% of the studies describing their use. Conclusions: Paediatric PDs exhibit significant clinical and genetic heterogeneity. While PRRT2 remains the most common genetic aetiology, emerging pleiotropic genes highlight the need for comprehensive diagnostic strategies. Sodium channel blockers are effective in a subset of genetically defined PD, particularly PRRT2-positive cases. Patients with pathogenic variants in other genes, such as ADCY5 and SLC2A1, may benefit from specific therapies that can potentially change their clinical course and prognosis. These findings support genotype-driven management approaches and underscore the importance of genetic testing in paediatric movement disorders.

Basilicata‐Akhtar syndrome (BAS) is an ultra‐rare X‐linked neurodevelopmental disorder caused by pathogenic variants in the MSL3 gene, critical for histone H4 acetylation and chromatin regulation. To date, only 42 cases have been documented, affecting both males and females, with most variants being de novo and loss‐of‐function. We present a case of a 30‐year‐old male with BAS, exhibiting developmental delay, intellectual disability, hypotonia, motor disturbances, and dysmorphic features. Genetic testing revealed a novel de novo hemizygous variant in the MSL3 gene (NM_078629:c.1293G > A, NP_523353.2:p.(Trp431*)), leading to loss of function. Neuroimaging showed multifocal leukoencephalopathy, and the individual is receiving treatment with carbidopa‐levodopa with improvement in bradykinesia and camptocormia. This case expands our understanding of BAS and highlights the importance of genetic testing, especially Exome Sequencing (ES), in diagnosing rare conditions. Early diagnosis and multidisciplinary care are crucial for managing BAS and improving outcomes.

Background and Objectives: Toe walking (TW) is frequently observed in children with Autism Spectrum Disorder (ASD), yet its clinical significance and association with comorbid conditions remain poorly understood. This study aimed to examine the prevalence of TW in a large Italian cohort of children with ASD and to explore its association with ASD severity, sleep disturbances, feeding behaviors, and gastrointestinal symptoms. Materials and Methods: A total of 289 children with ASD and 289 typically developing controls (TDC), matched for age and sex, were evaluated in a multicentric observational study. TW was assessed during neurodevelopmental evaluations. Sleep quality was assessed using the Sleep Disturbance Scale for Children (SDSC), feeding behaviors via the Brief Autism Mealtime Behavior Inventory (BAMBI), and gastrointestinal symptoms through clinical reporting. Statistical analyses included Chi-square tests, Mann–Whitney U tests, Spearman correlations, and logistic regressions. Results: TW was significantly more prevalent in the ASD group (27.3%) than in TDC (5.5%, p < 0.0001). Within the ASD group, TW occurred in 50.5% of children with Level 3 severity but was absent in Levels 1 and 2 (p < 0.0001). Males exhibited TW more frequently than females. Children with TW had higher SDSC scores (ρ = 0.33, p < 0.0001), though no subscale independently predicted TW. Constipation was reported in 100% of children with Level 3 ASD and was strongly correlated with SDSC total scores (ρ = 0.58, p < 0.0001). The Disorders of Arousal (DA) subscale emerged as an independent predictor of constipation (β = 0.184, p = 0.019). Conclusions: TW in ASD appears to be a marker of greater neurodevelopmental severity and is associated with sleep disturbances and gastrointestinal dysfunction. These findings support the hypothesis that TW may reflect broader dysfunctions involving the gut–brain axis, sensory processing, and motor control. The routine clinical assessment of TW should include the evaluation of sleep and somatic symptoms to better understand the multisystemic nature of ASD phenotypes.