The role of pallidotomy in the precision medicine era Giacomo Garone, Alice Innocenti, Alessandro De Benedictis, Maria Camilla Rossi-Espagnet, Franco Randi, Donatella Lettori, Simone Reali, Flaminia Frascarelli, Alessandra Savioli, Silvia Cossu, Laura Cantonetti, Nazaret Infante, Nicola Specchio, Carlo Efisio Marras Frontiers in Neurology, 2026 Background The use of radiofrequency pallidotomy (RP) for medically refractory dystonia has markedly declined since the introduction of deep brain stimulation (DBS). Conditions such as severe cognitive impairment, poor nutritional status, or acquired dystonia—common in children with severe dystonia—may limit DBS eligibility or benefit. In these cases, RP may represent a valuable alternative. Evidence on RP in this population remains scarce, mostly based on small case-series with limited follow-up. We retrospectively analyzed RP safety, feasibility and long-term outcomes in children with medically refractory dystonia. Methods Records of patients who underwent RP at Bambino Gesù Children’s Hospital were reviewed. Outcomes were retrospectively assessed through the Clinical Global Impression-Improvement scale. For patients with a history of status dystonicus (SD), recurrence was used as outcome measure. Results Eighteen patients underwent 21 procedures. Sixteen received bilateral simultaneous pallidotomy; two unilateral pallidotomy after GPi-DBS removal due to infection. Three patients required repeated surgery for recurrent-SD. Ten had acquired dystonia (cerebral palsy, CP), five genetically confirmed dystonia, three idiopathic dystonia. Three were followed for three months or less; in the others, mean follow-up was 6.62 ± 3.65 years. Three months postoperatively, 12 of 16 patients improved (1 “very much improved,” 2 “much improved,” 9 “minimally improved”), 2 were unchanged and 2 minimally worsened. At last follow-up (15 patients), 1 remained “very much improved,” 2 “minimally improved,” 3 “unchanged,” 6“minimally worsened,” 3 “much worsened.” Among six patients treated for ongoing-SD, crises abated over 50.7 ± 27.8 days. SD recurred in 8 patients (5 CP, 1 genetic, 2 idiopathic) after a mean of 20.3 ± 19.8 months. Conclusion RP emerges as a feasible rescue-therapy for severe medically refractory SD. Most patients show meaningful short-term improvement, but beneficial effects tend to decline over time, with high rate of SD recurrence—particularly in dyskinetic-CP. This may reflect suboptimal lesions’ location and/or size, progressive disease course or re-emergence of dystonia through different networks. In this light, RP should be considered when DBS is contraindicated, the risk of hardware-related complications outweighs the advantages of an adjustable system, or in patients with limited life expectancy, where an irreversible yet effective rescue intervention is clinically justified.
Understanding and targeting repetitive behaviors and restricted interests in autism spectrum disorder via high-definition transcranial direct current stimulation: a study-protocol Giulia Lazzaro, Sara Passarini, Andrea Battisti, Floriana Costanzo, Giacomo Garone, Mattia Mercier, Barbara D’Aiello, Pietro De Rossi, Giovanni Valeri, Silvia Guerrera, Laura Casula, Deny Menghini, Stefano Vicari, Elisa Fucà BMC Psychiatry, 2025 BACKGROUND: Autism spectrum disorder (ASD) is a neurodevelopmental disorder characterized by persistent deficits in social interaction and repetitive behaviors (RBs). Therapies specifically targeting RBs have been underexplored despite advances in understanding their neurobiological basis. This study aims to evaluate whether high-definition transcranial direct current stimulation (HD-tDCS) can reduce dysfunctional RBs in autistic children and investigate whether improvements differ between lower-order and higher-order RBs based on the brain regions stimulated. METHODS: The study entails a multi-session, sham-controlled, site-controlled, double-blind, and between-subjects design. The study will include participants with an ASD diagnosis (aged 8-13 years; IQ ≥ 70), who will undergo the HD-tDCS intervention for 10 sessions. Participants will be randomly assigned to three conditions: (1) Pre-Motor Active Group (active HD-tDCS over pre-SMA cortex); (2) Frontal Active Group (active HD-tDCS over dlPFC); (3) Placebo Control Group. In the active HD-tDCS conditions, the current will be delivered through a 4 × 1 montage; small circular electrodes will be used with the cathode placed centrally with a current intensity of 0.5 mA for a total of 20 min (30 s ramp up/down) per session. Participants during the sham condition will undergo the same procedures as those in the both active conditions actual placement of electrodes, and turning on the HD-tDCS equipment (30 s). The assessment will be completed at baseline (T0), immediately after the end of the intervention (T1) and 3 months after the end of the intervention (T2). The primary outcome measure will be the Total Score of the Repetitive Behavior Scale-Revised. The secondary outcomes measures will comprise ASD symptoms, sensory processing pattern, emotional/behavioral problems, sleep functioning, parental stress, neuropsychological features and High-Density EEG connectivity. We hypothesize that active HD-tDCS will lead to significant reduction in the total score of the primary outcome compared to Sham Group, with site-specific effects on lower-order and higher-order RBs. DISCUSSION: HD-tDCS is an easy-to-deliver, time-efficient, neurobiologically-driven intervention that could be performed as add-on to reduce the time of conventional therapy for ASD. Given the inherent limitations of specific interventions for RBs, tDCS represents an important "third" treatment arm to address the burden of interventions for ASD. TRIAL REGISTRATION DETAILS: The trial has been registered at ClinicalTrials.gov (ID: NCT06645587). Registered 17 October 2024.
ADCY5-Mosaic Variants: A Diagnosis Not to Be Missed Alice Innocenti, Emmanuel Roze, Florence Riant, Marie‐Céline François‐Heude, Bérénice Lecardonnel, Giacomo Garone, Maxime Colmard, Eline Chauvet‐Piat, Anne‐Cécile Chaux, Marie‐Aude Spitz, Beatrice Desnous, Catherine Sarret, Philippe Damier, Thomas Wirth, Mathieu Anheim, Emilie Retailleau, Estelle Conabady, Caroline Dubacq, Oriane Trouillard, Aurélie Méneret, Agathe Roubertie Movement Disorders Clinical Practice, 2025 BackgroundAn increasing number of ADCY5‐mosaic patients, seemingly with a milder phenotype, are being identified. However, an in‐depth assessment of their clinical characteristics is lacking.CasesWe collected and analyzed data from 12 consecutive ADCY5‐mosaic patients diagnosed at our center and 7 cases from the literature; 63% of the patients presented with a baseline hyperkinetic motor disorder with paroxysmal motor exacerbations; 30% had isolated paroxysmal dyskinesias (PxD). Caffeine treatment was highly effective. Developmental delay was observed in 5 patients and especially in those with persistent motor symptoms. PxD were the initial motor symptom in 70% of cases.ConclusionsADCY5‐mosaic carriers may have the same phenotypic spectrum as non‐mosaic carriers but with a milder clinical presentation. Isolated PxD with onset in infancy are a red flag for ADCY5‐mosaic variants. Particular attention should be paid when genetic analysis of patients with this phenotype is conducted as mosaicism can be easily missed.
ATP1A3 Variants, Variably Penetrant Short QT Intervals, and Lethal Ventricular Arrhythmias Mary E. Moya-Mendez, Minu-Tshyeto Bidzimou, Padmapriya Muralidharan, Zhushan Zhang, Jordan E. Ezekian, Robin M. Perelli, Lauren E. Parker, Lyndsey Prange, April Boggs, Jeffrey J. Kim, Taylor S. Howard, Tarah A. Word, Xander H. T. Wehrens, Gabriela Reyes Valenzuela, Roberto Caraballo, Giacomo Garone, Federico Vigevano, Sarah Weckhuysen, Charissa Millevert, Monica Troncoso, Mario Matamala, Simona Balestrini, Sanjay M. Sisodiya, Josephine Poole, Claudio Zucca, Eleni Panagiotakaki, Maria T. Papadopoulou, Sébile Tchaicha, Marta Zawadzka, Maria Mazurkiewicz-Bełdzińska, Carmen Fons, Jennifer Anticona, Elisa De Grandis, Ramona Cordani, Livia Pisciotta, Sergiu Groppa, Sandra Paryjas, Francesca Ragona, Elena Mangia, Tiziana Granata, Andrey Megvinov, Mirjana Pavlicek, Kevin Ess, Christine Q. Simmons, Alfred L. George, Rosaria Vavassori, Mohamad A. Mikati, Andrew P. Landstrom JAMA Pediatrics, 2025 ImportanceAlternating hemiplegia of childhood (AHC) is a disorder that can result from pathogenic variants in ATP1A3-encoded sodium-potassium adenosine triphosphatase alpha 3 (ATP1A3). While AHC is primarily a neurologic disease, some individuals experience sudden unexplained death (SUD) potentially associated with cardiac arrhythmias.ObjectiveTo determine the impact of ATP1A3 variants on cardiac electrophysiology and whether lethal ventricular arrhythmias are associated with SUD in patients with AHC.Design, Setting, and ParticipantsIn this international, multicenter case-control study from 12 centers across 10 countries, patients with AHC were grouped by ATP1A3 variant status (positive vs negative) and into subgroups with the most common AHC variants (D801N, E815K, G947R, and other). A healthy control cohort was established for comparison. Blinded, manual measurements of QT intervals and corrected QT interval (QTc) were performed independently by 2 pediatric cardiac electrophysiologists. Induced pluripotent stem cell cardiomyocytes were derived from patients with AHC who were positive for the D801N variant of ATP1A3 (iPSC-CMD801N cells). Data analysis was performed from April to June 2022.ExposurePresence of ATP1A3 variant.Main Outcomes and MeasuresThe primary outcome was QTc. Outcomes, including survival, were abstracted and variants were mapped on cryogenic electron microscopy structure maps. iPSC-CMD801N cells were used to validate ventricular repolarization and arrhythmic susceptibility in vitro.ResultsAmong the 222 individuals included (148 with AHC and 74 control), the mean (SD) age at diagnostic electrocardiography was 11.0 (9.4) years and 119 (54%) were female. The cohort with AHC consisted of 148 largely unrelated probands (mean [SD] age at diagnostic electrocardiography, 11.5 [10.5] years). Of these, 123 individuals were ATP1A3 genotype positive, including 35 (28%) with the D801N variant, 21 (17%) with the E815K variant, 8 (7%) with the G947R variant, and 8 (7%) with a loss-of-function variant. Probands with the D801N variant had shorter mean (SD) QTcs (381.8 [36.6] milliseconds; 24 [69%] with QTc <370 milliseconds) compared with those who had the E815K variant (393.6 [43.1] milliseconds; P = .001; 4 [19%] with QTC <370 milliseconds), the G947R variant (388.4 [26.5] milliseconds; P = .02; 1 [13%] with QTc <370 milliseconds), a loss-of-function variant (403.0 [33.5] milliseconds; P < .001; 1 [13%] with QTc <370 milliseconds), all other variants (387.8 [37.1] milliseconds; P < .001; 44 [86%] with QTc <370 milliseconds), and healthy controls (415.4 [21.0] milliseconds; P < .001; 0 with QTc <370 milliseconds). Three D801N-positive individuals had a major cardiac event, compared with 0 major cardiac events in all other individuals (P = .02). The D801N variant and 4 rare variants (D805N, P323S, S772R, and C333F) found in individuals with the shortest QTcs localized to the potassium-binding domain of ATP1A3. IPSC-CMD801N lines demonstrated shortened action potential duration, higher mean diastolic potential, and delayed afterdepolarizations compared with controls.Conclusions and RelevanceNearly 70% of individuals with D801N variants of ATP1A3 had short QTcs (<370 milliseconds), with an association between ventricular arrhythmias and cardiac arrest. This may underlie the SUD etiology in AHC.
Congenital Ataxia with Progressive Cerebellar Atrophy, Camptodactyly, and Hypertrichosis: A Novel Recognizable Phenotype for NALCN Heterozygous Variants Jacopo Sartorelli, Lorena Travaglini, Giacomo Garone, Maria L. Dentici, Lorenzo Sinibaldi, Maria C. Digilio, Antonio Novelli, Emanuele Agolini, Adele D'Amico, Enrico Bertini, Francesco Nicita Neuropediatrics, 2025 Background Non-selective sodium leak channel (NALCN) protein encoded by the NALCN gene is of key importance for neuronal cell excitability. Previous reports showed that biallelic NALCN pathogenic variants cause infantile hypotonia with psychomotor retardation and characteristic facies 1 (IHPRF1) while monoallelic variants lead to congenital contractures of the limbs and face, hypotonia, and developmental delay (CLIFAHDD). In our work, we aimed to expand the heterozygous NALCN-related clinical spectrum, presenting two affected individuals and a literature review. Methods We describe two new unrelated subjects harboring monoallelic NALCN pathogenic variants identified through clinical exome sequencing and review the current literature of other heterozygous NALCN patients. Results The c.3542G > A (p.Arg1181Gln) and the novel c.3423C > A (p.Phe1141Leu) heterozygous missense variants were disclosed in two subjects manifesting a similar phenotype characterized by congenital ataxia with progressive cerebellar atrophy, camptodactyly, and hypertrichosis of the arms (CAPCACH). Other NALCN subjects with overlapping features have already been reported. A combination of these clinical and neuroimaging findings suggests the definition of the new CAPCACH phenotype. Conclusion We expand the heterozygous NALCN-related clinical spectrum from the more severe CLIFFAHDD to the milder CAPCACH phenotype. These conditions should be considered in the differential diagnosis of syndromic congenital ataxias, and the presence of camptodactyly and/or hypertrichosis may represent peculiar diagnostic clues.
Three Cases of Spinocerebellar Ataxia Type 2 (SCA2) and Pediatric Literature Review: Do Not Forget Trinucleotide Repeat Disorders in Childhood-Onset Progressive Ataxia Jacopo Sartorelli, Maria Grazia Pomponi, Giacomo Garone, Gessica Vasco, Francesca Cumbo, Vito Luigi Colona, Adele D’Amico, Enrico Bertini, Francesco Nicita Brain Sciences, 2025 Background: Childhood-onset progressive ataxias are rare neurodegenerative disorders characterized by cerebellar signs, sometimes associated with other neurological or extra-neurological features. The autosomal dominant forms, known as spinocerebellar ataxias (SCAs), linked to trinucleotide (i.e., CAG) repeat disorders, are ultra-rare in children. We describe three patients from two unrelated families affected by spinocerebellar ataxia type 2 (SCA2) and present a literature review of pediatric cases. Methods: The patients’ clinical and genetic data were collected retrospectively. Results: The first case was a 9.5-year-old boy, affected by ataxia with oculomotor apraxia and cerebellar atrophy, subcortical myoclonus, and peripheral axonal sensitive polyneuropathy caused by a pathologic expansion in ATXN2, inherited from his asymptomatic father. Two brothers with familial SCA2 presented neurodegeneration leading to early death in one case and progressive ataxia, parkinsonism, and epilepsy with preserved ambulation at age 18 years in the second. To date, 19 pediatric patients affected by SCA2 have been reported, 3 of whom had a phenotype consistent with progressive ataxia with shorter CAG repeats, while 16 had more severe early-onset encephalopathy, with longer alleles. Conclusions: Although they are ultra-rare, trinucleotide repeat disorders must be considered in differential diagnosis of hereditary progressive ataxias in children, especially considering that they require targeted genetic testing and can manifest even before a parental carrier becomes symptomatic. Thus, they must also be taken into account with negative family history and when Next-Generation Sequencing (NGS) results are inconclusive. Notably, the association between cerebellar ataxia and other movement disorders should raise suspicion of SCA2 among differential diagnoses.
Pediatric torticollis: clinical report and predictors of urgency of 1409 cases Umberto Raucci, Marco Roversi, Alessandro Ferretti, Valerio Faccia, Giacomo Garone, Fabio Panetta, Carlo Mariani, Eloisa Rizzotto, Antonio Torelli, Giovanna Stefania Colafati, Angelo Gabriele Aulisa, Pasquale Parisi, Alberto Villani Italian Journal of Pediatrics, 2024
Movement disorder phenotype in CTNNB1-syndrome: A complex but recognizable phenomenology Giacomo Garone, Alice Innocenti, Melissa Grasso, Alessandra Mandarino, Alessandro Capuano, Gessica Della Bella, Flaminia Frascarelli, Daria Diodato, Roberta Onesimo, Giuseppe Zampino, Antonio Novelli, Maria Cristina Digilio, Andrea Bartuli, Maria Lisa Dentici, Pasquale Parisi, Serena Galosi, Davide Tonduti, Enrico Bertini, Lorenzo Sinibaldi, Nicola Specchio Parkinsonism and Related Disorders, 2024
Dyskinetic crisis in GNAO1-related disorders: clinical perspectives and management strategies Jana Domínguez Carral, Carola Reinhard, Darius Ebrahimi-Fakhari, Nathalie Dorison, Serena Galosi, Giacomo Garone, Masa Malenica, Claudia Ravelli, Esra Serdaroglu, Laura A. van de Pol, Anne Koy, Vincenzo Leuzzi, Agathe Roubertie, Jean-Pierre Lin, Diane Doummar, Laura Cif, Juan Darío Ortigoza-Escobar Frontiers in Neurology, 2024
Characteristics of acute nystagmus in the pediatric emergency department Giacomo Garone, Agnese Suppiej, Nicola Vanacore, Francesco La Penna, Pasquale Parisi, Lucia Calistri, Antonella Palmieri, Alberto Verrotti, Elisa Poletto, Annalisa Rossetti, Duccio Maria Cordelli, Mario Velardita, Renato d’Alonzo, Paola De Liso, Daniela Gioè, Marta Marin, Luca Zagaroli, Salvatore Grosso, Rocco Bonfatti, Elisabetta Mencaroni, Stefano Masi, Elena Bellelli, Liviana Da Dalt, Umberto Raucci Pediatrics, 2020
Prestatus and status dystonicus in children and adolescents Giacomo Garone, Federica Graziola, Francesco Nicita, Flaminia Frascarelli, Franco Randi, Marco Zazza, Laura Cantonetti, Silvia Cossu, Carlo Efisio Marras, Alessandro Capuano Developmental Medicine and Child Neurology, 2020
