Publications by authors named "Alessandro Capuano"

60 Publications

A nationwide study on Sydenham's chorea: Clinical features, treatment and prognostic factors.

Eur J Paediatr Neurol 2021 Nov 6;36:1-6. Epub 2021 Nov 6.

Pediatric Rheumatology, Pediatric University Department, Azienda Ospedaliera Universitaria Pisana, University of Pisa, Pisa, Italy.

Objectives: Sydenham's Chorea (SC) is a neuropsychiatric disorder and a major manifestation of acute rheumatic fever. The erroneous assumption that SC is a benign and self-limiting disease, has led to a lack of high-quality scientific evidence of the therapeutical and prognostic features of SC.

Study Design: We retrospectively analyzed the medical records of patients <18-years old with SC in 17 Italian pediatric centers. Recorded data included clinical, instrumental and laboratory parameters. Prognostic risk factors including treatment regimens were assessed with univariate and multivariate sub-analysis.

Results: We included 171 patients with SC. 66% had generalized chorea, and 34% hemichorea. 81% had carditis (subclinical in 65%). Additional neurological symptoms were reported in 60% of the patients, mainly dysarthria and dysgraphia. 51% had neuropsychiatric symptoms at onset, which persisted after 12 months in 10%. Among psychiatric manifestations, the most common was anxiety disorder/depression (77%). Neurological remission was reached by 93% of the patients at 6 months; 9% relapsed. Patients were treated as follows: 11% penicillin alone, 37% immunomodulatory therapy, 16% symptomatic drugs (i.e. anti-seizure medication, dopamine antagonists) and 37% both symptomatic and immunomodulatory treatment. Neurological outcome did not differ between groups. Patients receiving symptomatic drugs had a higher risk of relapse on multivariate analysis (p = 0.045).

Conclusions: Treatment of SC was largely heterogeneous. Based on our results, immunomodulatory therapy did not show higher efficacy at medium term, although it was associated to a slightly lower risk of relapse compared to symptomatic therapy. Longitudinal studies are needed to assess specific risk factors and best treatment options.
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http://dx.doi.org/10.1016/j.ejpn.2021.11.002DOI Listing
November 2021

Cognitive Assessment in Neurodevelopmental Disorder Using an Eye Tracking System.

J Clin Med 2021 Aug 12;10(16). Epub 2021 Aug 12.

Neurology Unit, Department of Neurosciences, Bambino Gesù Children's Hospital, 00146 Rome, Italy.

gene mutations are associated with a neurodevelopmental disorder characterized by developmental delay, epilepsy, and movement disorder. Eye tracking and eye movement analysis are an intriguing method to assess cognitive and language function and, to the best of our knowledge, it has never been tested in a standardized way in . children are usually wheelchair-bound and with numerous motor constrains, including dystonic movements and postures, heterotropia, and hypotonia, making the cognitive assessment arduous. These contribute to the burden and disability, with a high level of frustration of caregivers and patients. We have herein demonstrated that, through an eye tracking system, six patients evaluated showed variable degrees of communicative intent through intentionally directed gaze. Moreover, three of these were able to complete a cognitive evaluation, and showed normal fluid intelligence and lexical comprehension. In conclusion, in -related disorders, the degree of cognitive development is underestimated; eye tracking technologies may help in overcome these boundaries.
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http://dx.doi.org/10.3390/jcm10163541DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8397136PMC
August 2021

Childhood-onset dystonia-causing KMT2B variants result in a distinctive genomic hypermethylation profile.

Clin Epigenetics 2021 08 11;13(1):157. Epub 2021 Aug 11.

Department of Pathology and Laboratory Medicine, Western University, London, ON, N6A 3K7, Canada.

Background: Dystonia is a clinically and genetically heterogeneous movement disorder characterized by sustained or intermittent muscle contractions causing abnormal, often repetitive, movements and/or postures. Heterozygous variants in lysine methyltransferase 2B (KMT2B), encoding a histone H3 methyltransferase, have been associated with a childhood-onset, progressive and complex form of dystonia (dystonia 28, DYT28). Since 2016, more than one hundred rare KMT2B variants have been reported, including frameshift, nonsense, splice site, missense and other in-frame changes, many having an uncertain clinical impact.

Results: We characterize the genome-wide peripheral blood DNA methylation profiles of a cohort of 18 patients with pathogenic and unclassified KMT2B variants. We resolve the "episignature" associated with KMT2B haploinsufficiency, proving that this approach is robust in diagnosing clinically unsolved cases, properly classifying them with respect to other partially overlapping dystonic phenotypes, other rare neurodevelopmental disorders and healthy controls. Notably, defective KMT2B function in DYT28 causes a non-random DNA hypermethylation across the genome, selectively involving promoters and other regulatory regions positively controlling gene expression.

Conclusions: We demonstrate a distinctive DNA hypermethylation pattern associated with DYT28, provide an epigenetic signature for this disorder enabling accurate diagnosis and reclassification of ambiguous genetic findings and suggest potential therapeutic approaches.
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http://dx.doi.org/10.1186/s13148-021-01145-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8359374PMC
August 2021

Acute Movement Disorders in Childhood.

J Clin Med 2021 Jun 17;10(12). Epub 2021 Jun 17.

Movement Disorders Clinic, Department of Neurosciences, Bambino Gesù Children's Hospital, IRCCS, viale San Paolo 15, 00146 Rome, Italy.

Acute-onset movement disorders (MDs) are an increasingly recognized neurological emergency in both adults and children. The spectrum of possible causes is wide, and diagnostic work-up is challenging. In their acute presentation, MDs may represent the prominent symptom or an important diagnostic clue in a broader constellation of neurological and extraneurological signs. The diagnostic approach relies on the definition of the overall clinical syndrome and on the recognition of the prominent MD phenomenology. The recognition of the underlying disorder is crucial since many causes are treatable. In this review, we summarize common and uncommon causes of acute-onset movement disorders, focusing on clinical presentation and appropriate diagnostic investigations. Both acquired (immune-mediated, infectious, vascular, toxic, metabolic) and genetic disorders causing acute MDs are reviewed, in order to provide a useful clinician's guide to this expanding field of pediatric neurology.
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http://dx.doi.org/10.3390/jcm10122671DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8234395PMC
June 2021

Working memory, attention and planning abilities in NKX2.1-related chorea.

Parkinsonism Relat Disord 2021 07 27;88:24-27. Epub 2021 May 27.

Movement Disorders Clinic, Neurology Unit, Department of Neurological and Psychiatric Sciences, Bambino Gesù Children's Hospital, Viale San Paolo 15, 00146, Rome, Italy. Electronic address:

Background: Although NKX 2.1 related chorea has been considered benign due to the favourable course of motor phenotype during life, the neurological condition is not limited to chorea, including non-motor symptoms in the developmental, cognitive and psychiatric domain. Aim of our study was to test working memory, attention and planning abilities of a cohort of NKX2.1 choreic patients compared to healthy controls.

Methods: patients and healthy controls were assessed for working memory (Visual Digit Span test), response inhibition and sustained attention (Cued Go/No-Go test), and spatial problem-solving and planning task (Tower of London test). For experimental protocol, we used a computer based tool for neuropsychological experiments, Inquisit 5.0 software (Millisecond Software®). Non-parametric tests were performed for statistical analysis.

Results: six patients and fifteen healthy paediatric controls were recruited. In the Digit Span test, both in forward and backward recall, patients showed statistically significant lower scores than controls. In the Cued Go/No-Go test as well as in the Tower of London, NKX 2.1 patients showed similar scores in the error rate and total score respectively, whereas in both tests they appeared to be slower than controls suggesting a poor performance in the execution of the tests.

Conclusions: our findings demonstrate that patients with NKX2.1-related chorea show a selective impairment in working memory with increased latencies in both planning and attention. A developmental alteration of the cholinergic neurotransmission in the basal forebrain and the disruption of striatal networks could explain, at least in part, this neuropsychological profile.
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http://dx.doi.org/10.1016/j.parkreldis.2021.05.021DOI Listing
July 2021

Novel Variant Underlying Nonprogressive Congenital Ataxia or SCA19/22 Disrupt K4.3 Protein Expression and K+ Currents with Variable Effects on Channel Properties.

Int J Mol Sci 2021 05 7;22(9). Epub 2021 May 7.

Institute of Anatomy and Cell Biology, College of Medicine, National Yang Ming Chiao Tung University, Taipei 112, Taiwan.

encodes the voltage-gated potassium channel K4.3 that is highly expressed in the cerebellum, where it regulates dendritic excitability and calcium influx. Loss-of-function K4.3 mutations have been associated with dominant spinocerebellar ataxia (SCA19/22). By targeted NGS sequencing, we identified two novel missense variants of the K4.3 channel: p.S347W identified in a patient with adult-onset pure cerebellar syndrome and p.W359G detected in a child with congenital nonprogressive ataxia. Neuroimaging showed mild cerebellar atrophy in both patients. We performed a two-electrode voltage-clamp recording of K4.3 currents in Xenopus oocytes: both the p.G345V (previously reported in a SCA19/22 family) and p.S347W mutants exhibited reduced peak currents by 50%, while no K+ current was detectable for the p.W359G mutant. We assessed the effect of the mutations on channel gating by measuring steady-state voltage-dependent activation and inactivation properties: no significant alterations were detected in p.G345V and p.S347W disease-associated variants, compared to controls. K4.3 expression studies in HEK293T cells showed 53% (p.G345V), 45% (p.S347W) and 75% (p.W359G) reductions in mutant protein levels compared with the wildtype. The present study broadens the spectrum of the known phenotypes and identifies additional variants for -related disorders, outlining the importance of SCA gene screening in early-onset and congenital ataxia.
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http://dx.doi.org/10.3390/ijms22094986DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8125845PMC
May 2021

Editorial: Endocrine Modulators of Neurological Processes: Potential Treatment Targets of Pediatric Neurological Diseases.

Front Endocrinol (Lausanne) 2021 18;12:655290. Epub 2021 Feb 18.

Movement Disorders Clinic, Neurology Unit, Department of Neuroscience, Bambino Gesù Children's Hospital (IRCCS), Rome, Italy.

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http://dx.doi.org/10.3389/fendo.2021.655290DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7930474PMC
February 2021

Biallelic variants in cause a severe neurodevelopmental disorder with microcephaly, bilateral cataract, epilepsy and simplified gyration.

J Med Genet 2021 Jan 4. Epub 2021 Jan 4.

Medical Genetics Laboratory, Bambino Gesù Children's Hospital, IRCCS, Rome, Italy.

Background: Next-generation sequencing, combined with international pooling of cases, has impressively enhanced the discovery of genes responsible for Mendelian neurodevelopmental disorders, particularly in individuals affected by clinically undiagnosed diseases. To date, biallelic missense variants in gene, encoding a Krüppel-type zinc-finger protein, have been reported in three families with non-syndromic intellectual disability.

Methods: Here, we describe five individuals from four unrelated families with an undiagnosed neurodevelopmental disorder in which we performed exome sequencing, on a combination of trio-based (4 subjects) or single probands (1 subject).

Results: We identified five patients from four unrelated families with homozygous variants by whole exome sequencing. Four had variants resulting in truncation of ZNF526; they were affected by severe prenatal and postnatal microcephaly (ranging from -4 SD to -8 SD), profound psychomotor delay, hypertonic-dystonic movements, epilepsy and simplified gyral pattern on MRI. All of them also displayed bilateral progressive cataracts. A fifth patient had a homozygous missense variant and a slightly less severe disorder, with postnatal microcephaly (-2 SD), progressive bilateral cataracts, severe intellectual disability and unremarkable brain MRI.Mutant zebrafish larvae had notable malformations of the eye and central nervous system, resembling findings seen in the human holoprosencephaly spectrum.

Conclusion: Our findings support the role of biallelic variants in a complex neurodevelopmental disorder, primarily affecting brain and eyes, resulting in severe microcephaly, simplified gyral pattern, epileptic encephalopathy and bilateral cataracts.
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http://dx.doi.org/10.1136/jmedgenet-2020-107430DOI Listing
January 2021

Impaired Motor Timing in Tourette Syndrome: Results From a Case-Control Study in Children.

Front Neurol 2020 29;11:552701. Epub 2020 Oct 29.

Movement Disorders Clinic, Department of Neurosciences, Bambino Gesù Children's Hospital, Rome, Italy.

Tourette syndrome (TS) is a neurodevelopmental disorder characterized by motor and vocal tics. Co-occurrence of attention-deficit/hyperactivity disorder (ADHD) or obsessive-compulsive disorder (OCD) is very frequent in the pediatric population as well as the presence of an impairment of the executive functions. The aim of our study was to investigate motor timing, that is, the temporal organization of motor behavior, in a pediatric population of Tourette patients. Thirty-seven Tourette patients (divided in 22 "pure" Tourette patients and 15 with ADHD) were compared with 22 healthy age- and gender-matched subjects. All subjects underwent a neuropsychiatric screening and were tested for their planning and decision-making abilities by using a standardized test, such as Tower of London (ToL). Two experimental paradigms were adopted: finger-tapping test (FTT), a free motor tapping task, and synchronization-continuation task. An accuracy index was calculated as measure of ability of synchronization. We found that "pure" TS as well as TS+ADHD showed lower scores in the FTT for the dominant and non-dominant hands than controls. Moreover, in the synchronization and continuation test, we observed an overall lack of accuracy in both TS groups in the continuation phase for 2,000 ms (supra-second interval), interestingly, with opposite direction of accuracy index. Thus, "pure" TS patients were classified as "behind the beat," whereas, TS+ADHD as "ahead of the beat." The performance in the finger tapping was inversely correlated to ToL total scores and execution time, whereas we did not find any correlation with the accuracy index of the synchronization and continuation test. In conclusion, here, we explored motor timing ability in a childhood cohort of Tourette patients, confirming that patients exhibit an impaired temporal control of motor behavior and these findings may be explained by the common underlying neurobiology of TS and motor timing.
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http://dx.doi.org/10.3389/fneur.2020.552701DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7658319PMC
October 2020

Clinical course of paroxysmal dyskinesias throughout pregnancy.

Parkinsonism Relat Disord 2020 11 9;80:19-20. Epub 2020 Sep 9.

Department of System Medicine, University of Rome "Tor Vergata", Rome, Italy; IRCCS Fondazione Santa Lucia, European Centre for Brain Research, Rome, Italy.

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http://dx.doi.org/10.1016/j.parkreldis.2020.09.017DOI Listing
November 2020

Movement disorders in ADAR1 disease: Insights from a comprehensive cohort.

Parkinsonism Relat Disord 2020 10 30;79:100-104. Epub 2020 Aug 30.

Department of Systems Medicine, University of Roma Tor Vergata, Rome, Italy; Department of Neurosciences, IRCCS Bambino Gesù Children's Hospital, Rome, Italy. Electronic address:

ADAR1 variants are associated to rare and heterogenous neurological conditions, including Aicardi-Goutières syndrome type 6, bilateral striatal necrosis, and dyschromatosis symmetrica hereditaria. Movement disorders (MDs) commonly occur in ADAR1-related diseases although a complete overview on the phenomenology has not been provided yet. Here, a cohort of 57 patients with ADAR1-related diseases, including 3 unpublished patients and 54 previously reported cases, was reviewed. Data on demographics, clinical features of MDs, genetics and biomarkers were collected and descriptive statistics, group analysis for genotype and logistic regression were run. Manifestations of MD characterized the onset of ADAR1-related disease in 60% of patients. Specifically, dystonia occurred in 39% of cases, even as severe status dystonicus, while prevalence of other MDs was lower. Patients often presented brain lesions (>90%) and progressive disease course (43%), fatal in some cases. Clinical presentation and outcome differed among patients with distinct genotype. This review shows that phenomenology of MDs in ADAR1-related diseases is wide and heterogeneous, although a severe motor syndrome (often characterized by dystonia) secondary to brain lesions represents the most common manifestation. Waiting for future development of disease-modifying treatments, an appropriate symptomatic intervention is crucial for ADAR1 patients. Accordingly, a deeper knowledge of phenomenology is fundamental.
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http://dx.doi.org/10.1016/j.parkreldis.2020.08.039DOI Listing
October 2020

Impact of Italian lockdown on Tourette's syndrome patients at the time of the COVID-19 pandemic.

Psychiatry Clin Neurosci 2020 11 2;74(11):610-612. Epub 2020 Sep 2.

Department of Neuroscience and Neurorehabilitation, Movement Disorders Clinic, Bambino Gesù Children's Hospital, Rome, Italy.

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http://dx.doi.org/10.1111/pcn.13131DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7436875PMC
November 2020

Clinical and Genetic Overview of Paroxysmal Movement Disorders and Episodic Ataxias.

Int J Mol Sci 2020 May 20;21(10). Epub 2020 May 20.

Unit of Neuromuscular and Neurodegenerative Diseases, Department of Neuroscience and Neurorehabilitation, IRCCS Bambino Gesù Children's Hospital, 00146 Rome, Italy.

Paroxysmal movement disorders (PMDs) are rare neurological diseases typically manifesting with intermittent attacks of abnormal involuntary movements. Two main categories of PMDs are recognized based on the phenomenology: Paroxysmal dyskinesias (PxDs) are characterized by transient episodes hyperkinetic movement disorders, while attacks of cerebellar dysfunction are the hallmark of episodic ataxias (EAs). From an etiological point of view, both primary (genetic) and secondary (acquired) causes of PMDs are known. Recognition and diagnosis of PMDs is based on personal and familial medical history, physical examination, detailed reconstruction of ictal phenomenology, neuroimaging, and genetic analysis. Neurophysiological or laboratory tests are reserved for selected cases. Genetic knowledge of PMDs has been largely incremented by the advent of next generation sequencing (NGS) methodologies. The wide number of genes involved in the pathogenesis of PMDs reflects a high complexity of molecular bases of neurotransmission in cerebellar and basal ganglia circuits. In consideration of the broad genetic and phenotypic heterogeneity, a NGS approach by targeted panel for movement disorders, clinical or whole exome sequencing should be preferred, whenever possible, to a single gene approach, in order to increase diagnostic rate. This review is focused on clinical and genetic features of PMDs with the aim to (1) help clinicians to recognize, diagnose and treat patients with PMDs as well as to (2) provide an overview of genes and molecular mechanisms underlying these intriguing neurogenetic disorders.
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http://dx.doi.org/10.3390/ijms21103603DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7279391PMC
May 2020

Alternating Hemiplegia of Childhood: Understanding the Genotype-Phenotype Relationship of ATP1A3 Variations.

Appl Clin Genet 2020 30;13:71-81. Epub 2020 Mar 30.

Movement Disorders Clinic, Department of Neuroscience and Neurorehabilitation, IRCCS Bambino Gesù Children's Hospital, Rome, Italy.

Alternating hemiplegia of childhood (AHC) is a rare neurological disorder affecting children with an onset before 18 months. Diagnostic clues include transient episodes of hemiplegia alternating in the laterality or quadriparesis, nystagmus and other paroxysmal attacks as tonic and dystonic spells. Epilepsy is also a common feature. In the past, a great effort has been done to understand the genetic basis of the disease leading to the discovery of mutations in the ATP1A3 gene encoding for the alpha3 subunit of Na/KATPase, a protein already related to another disease named Rapid Onset Dystonia Parkinsonism (RDP). ATP1A3 mutations account for more than 70% of cases of AHC. In particular, three hotspot mutations account for about 60% of all cases, and these data have been confirmed in large population studies. Specifically, the p.Asp801Asn variant has been found to cause 30-43% of all cases, p.Glu815Lys is responsible for 16-35% of cases and p.Gly947Arg accounts for 8-15%. These three mutations are associated with different clinical phenotype in terms of symptoms, severity and prognosis. In vitro and in vivo models reveal that a crucial role of Na/KATPase pump activity emerges in maintaining a correct membrane potential, survival and homeostasis of neurons. Herein, we attempt to summarize all clinical, genetic and molecular aspects of AHC considering ATP1A3 as its primary disease-causing determinant.
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http://dx.doi.org/10.2147/TACG.S210325DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7125306PMC
March 2020

Prestatus and status dystonicus in children and adolescents.

Dev Med Child Neurol 2020 06 13;62(6):742-749. Epub 2019 Dec 13.

Movement Disorders Clinic, Division of Neurology, Department of Neuroscience and Neurorehabilitation, IRCCS Bambino Gesù Children's Hospital, Rome, Italy.

Aim: To critically analyse the management of status dystonicus and prestatus dystonicus in children and adolescents, in order to examine clinical features, acute management, and risk of relapse in a paediatric cohort.

Method: Clinical, demographic, and therapeutic features were analysed according to disease severity. Risk of subsequent relapse was estimated through Kaplan-Meier curves.

Results: Thirty-four patients (eight females, 26 males) experiencing 63 episodes of acute dystonia exacerbations at a tertiary referral Italian hospital were identified. Mean age at status dystonicus presentation was 9 years 11 months (11y at inclusion in the study). Onset of dystonia dated back to infancy in most cases. Fourteen patients experienced two or more episodes. Infections were the most common trigger (48%). Benzodiazepines were the most commonly used drugs for acute management. Stereotactic pallidotomy was performed in six cases during status dystonicus, and in two additional patients it was electively performed after medical management. The probability of survival free from status dystonicus relapses was 78% after 4 months and 61% after 27 months.

Interpretation: Dystonia exacerbations are potentially life-threating emergencies, with a considerable risk of relapse. Nevertheless, no obvious factors for relapse risk stratification exist. Pallidotomy is a feasible option in medical refractory status dystonicus for patients with limited deep brain stimulation applicability, but the risk of recurrence is elevated.

What This Paper Adds: Acute exacerbations may affect up to 10% of children with dystonia. Infections are the most common precipitant factor. In about 30% of the cases, intensive care unit admission is needed. Subsequent relapses are common, reaching 25% risk at 1 year. Pallidotomy can be considered in medical-refractory cases with no deep brain stimulation applicability.
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http://dx.doi.org/10.1111/dmcn.14425DOI Listing
June 2020

Infantile-Onset Syndromic Cerebellar Ataxia and CACNA1G Mutations.

Pediatr Neurol 2020 03 19;104:40-45. Epub 2019 Oct 19.

Genetics and Rare Diseases Research Division, Ospedale Pediatrico Bambino Gesù, IRCCS, Rome, Italy.

Background: Congenital ataxias associated with cerebellar atrophy are clinically heterogeneous conditions with a variable age of onset and a diverse molecular basis. The hypothesis-free approach of genomic sequencing has led to the discovery of new genes implicated in these disorders and the identification of unexpected genotype-phenotype correlations. Although a recurrent heterozygous mutation (p.Arg1715His) in CACNA1G is known to cause adult-onset spinocerebellar ataxia 42 (SCA42*616795), gain-of-function mutations in this gene have recently been identified by whole exome sequencing (WES) in four children with cerebellar atrophy and ataxia, psychomotor delay, and other variable features.

Methods: We describe four children from unrelated families with cerebellar anomalies on magnetic resonance imaging (atrophy or hypoplasia of the cerebellar vermis), hypertonia, psychomotor and speech delay, severe intellectual disability, ophthalmologic features and peculiar dysmorphic traits. All patients underwent a trio-based WES analysis. Clinical records were used to characterize the clinical profile of this newly recognized disorder.

Results: Two previously reported de novo disease-causing mutations in CACNA1G (c.2881G>A, p.Ala961Thr and c.4591A>G, p.Met1531Val) were identified in these patients, providing further evidence of the specific impact of these variants. All four patients exhibit distinctive dysmorphic and ectodermal features which overlap those of the previously reported patients, allowing us to define the major features characterizing this homogeneous neurodevelopmental syndromic disorder associated with upregulated CACNA1G function.

Conclusion: Our findings confirm the specific association between a narrow spectrum of missense mutations in CACNA1G and a novel syndrome with infantile-onset cerebellar ataxiaand provide a dysmorphologic delineation of this novel neurodevelopmental trait.
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http://dx.doi.org/10.1016/j.pediatrneurol.2019.09.005DOI Listing
March 2020

Diagnostic Yield of a Targeted Next-Generation Sequencing Gene Panel for Pediatric-Onset Movement Disorders: A 3-Year Cohort Study.

Front Genet 2019 29;10:1026. Epub 2019 Oct 29.

Movement Disorders Clinic, Department of Neurosciences, Bambino Gesù Children's Hospital, Rome, Italy.

In recent years, genetic techniques of diagnosis have shown rapid development, resulting in a modified clinical approach to many diseases, including neurological disorders. Movement disorders, in particular those arising in childhood, pose a diagnostic challenge. First, from a purely phenomenological point of view, the correct clinical classification of signs and symptoms may be difficult and require expert evaluation. This is because the clinical picture is often a mixture of hyperkinetic and hypokinetic disorders, and within hyperkinetic movement disorders, combined phenotypes are not unusual. Second, although several genes that cause movement disorders in children are now well-known, many of them have only been described in adult populations or discovered in patients after many years of disease. Furthermore, diseases that alter their mechanisms from childhood to adulthood are still little known, and many phenotypes in children are the result of a disruption of normal neurodevelopment. High-throughput gene screening addresses these difficulties and has modified the approach to genetic diagnosis. In the exome-sequencing era, customized genetic panels now offer the ability to perform fast and low-cost screening of the genes commonly involved in the pathogenesis of the disease. Here, we describe a 3-year study using a customized gene panel for pediatric-onset movement disorders in a selected cohort of children and adolescents. We report a satisfying diagnostic yield, further confirming the usefulness of gene panel analysis.
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http://dx.doi.org/10.3389/fgene.2019.01026DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6828958PMC
October 2019

Heterozygous missense variants of SPTBN2 are a frequent cause of congenital cerebellar ataxia.

Clin Genet 2019 08 5;96(2):169-175. Epub 2019 Jun 5.

Unit of Muscular and Neurodegenerative Diseases, Department of Neurosciences, Bambino Gesù Children's Hospital, Rome, Italy.

Heterozygous missense variants in the SPTBN2 gene, encoding the non-erythrocytic beta spectrin 2 subunit (beta-III spectrin), have been identified in autosomal dominant spinocerebellar ataxia type 5 (SCA5), a rare adult-onset neurodegenerative disorder characterized by progressive cerebellar ataxia, whereas homozygous loss of function variants in SPTBN2 have been associated with early onset cerebellar ataxia and global developmental delay (SCAR14). Recently, heterozygous SPTBN2 missense variants have been identified in a few patients with an early-onset ataxic phenotype. We report five patients with non-progressive congenital ataxia and psychomotor delay, 4/5 harboring novel heterozygous missense variants in SPTBN2 and one patient with compound heterozygous SPTBN2 variants. With an overall prevalence of 5% in our cohort of unrelated patients screened by targeted next-generation sequencing (NGS) for congenital or early-onset cerebellar ataxia, this study indicates that both dominant and recessive mutations of SPTBN2 together with CACNA1A and ITPR1, are a frequent cause of early-onset/congenital non-progressive ataxia and that their screening should be implemented in this subgroup of disorders.
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http://dx.doi.org/10.1111/cge.13562DOI Listing
August 2019

Vertical Gaze Palsy in Kernicterus.

Neuropediatrics 2019 08 7;50(4):262-263. Epub 2019 May 7.

Movement Disorders Clinic, Neurology Unit, Department of Neurosciences, Bambino Gesù Children's Hospital, Rome, Italy.

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http://dx.doi.org/10.1055/s-0039-1685527DOI Listing
August 2019

An unusual case of late-infantile onset Krabbe disease with selective bilateral corticospinal tract involvement, peripheral demyelinating neuropathy, and mild phenotype.

Acta Neurol Belg 2019 Dec 7;119(4):619-620. Epub 2019 Feb 7.

Department of Neurosciences, Movement Disorders Clinic, Bambino Gesù Research Hospital, Rome, Italy.

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http://dx.doi.org/10.1007/s13760-019-01087-6DOI Listing
December 2019

Phenomenology and clinical course of movement disorder in GNAO1 variants: Results from an analytical review.

Parkinsonism Relat Disord 2019 04 16;61:19-25. Epub 2018 Nov 16.

Department of Pediatrics and Child Neurology and Psychiatry, Sapienza University of Rome, Rome, Italy.

GNAO1 variants were recently discovered as causes of epileptic encephalopathies and heterogeneous syndromes presenting with movement disorders (MDs), whose phenomenology and clinical course are yet undefined. We herein focused on GNAO1-related MD, providing an analytical review of existing data to outline the main MD phenomenology and management, clinical evolution and genotype-phenotype correlations. Reviewing 41 previously published patients and assessing 5 novel cases, a comprehensive cohort of 46 patients was analyzed, reassuming knowledge about genotypes, phenotypes, disease course and treatment of this condition. GNAO1-related MD consisted of a severe early-onset hyperkinetic syndrome, with prominent chorea, dystonia and orofacial dyskinesia. Symptoms are poorly responsive to medical therapy and fluctuate, with critical and life-threatening exacerbations, such as status dystonicus. The presence of a choreiform MD appears to be predictive of a higher risk of movement disorder emergency. Surgical treatments are sometimes effective, although severe disabilities persist. Differently from the early infantile epileptic encephalopathy phenotype (associated with loss of function variants), no clear correlation between genotype and MD phenotype emerged, although some variants recurred more frequently, mainly affecting exons 6 and 7.
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http://dx.doi.org/10.1016/j.parkreldis.2018.11.019DOI Listing
April 2019

A novel KCTD17 mutation is associated with childhood early-onset hyperkinetic movement disorder.

Parkinsonism Relat Disord 2019 04 7;61:4-6. Epub 2018 Dec 7.

Department of Neuroscience, Movement Disorders Clinic, Bambino Gesù Children's Hospital, Viale San Paolo 15, 00146, Rome, Italy. Electronic address:

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http://dx.doi.org/10.1016/j.parkreldis.2018.12.001DOI Listing
April 2019

Acute hyperkinetic movement disorders in Italian paediatric emergency departments.

Arch Dis Child 2018 08 8;103(8):790-794. Epub 2018 Mar 8.

Pediatric Emergency Department, Bambino Gesù Children's Hospital, IRCCS, Rome, Italy.

Introduction: Limited data exist on epidemiology, clinical presentation and management of acute hyperkinetic movement disorders (AHMD) in paediatric emergency departments (pED).

Methods: We retrospectively analysed a case series of 256 children (aged 2 months to 17 years) presenting with AHMD to the pEDs of six Italian tertiary care hospitals over a 2-year period (January 2012 to December 2013).

Results: The most common type of AHMD was tics (44.5%), followed by tremors (21.1%), chorea (13.7%), dystonia (10.2%), myoclonus (6.3%) and stereotypies (4.3%). Neuropsychiatric disorders (including tic disorders, psychogenic movement disorders and idiopathic stereotypies) were the most represented cause (51.2%). Inflammatory conditions (infectious and immune-mediated neurological disorders) accounted for 17.6% of the cases whereas non-inflammatory disorders (including drug-induced AHMDs, genetic/metabolic diseases, paroxysmal non-epileptic movements and idiopathic AHMDs) accounted for 31.2%. Neuropsychiatric disorders prevailed among preschoolers and schoolers (51.9% and 25.2%, respectively), non-inflammatory disorders were more frequent in infants and toddlers (63.8%), whereas inflammatory conditions were more often encountered among schoolers (73.3%). In 5 out of 36 Sydenham's chorea (SC) cases, tics were the presentation symptom on admission to emergency department (ED), highlighting the difficulties in early diagnosis of SC. Inflammatory disorders were associated with a longer hospital stay and a greater need of neuroimaging test compared with other disorders.

Conclusions: This study provides the first large sample of paediatric patients presenting to the ED for AHMDs, helping to elucidate the epidemiology, aetiology and clinical presentation of these disorders.
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http://dx.doi.org/10.1136/archdischild-2017-314464DOI Listing
August 2018

Childhood Rapid-Onset Ataxia: Expanding the Phenotypic Spectrum of ATP1A3 Mutations.

Cerebellum 2018 Aug;17(4):489-493

Department of Neurosciences, Bambino Gesù Children's Hospital, IRCCS, Piazza Sant'Onofrio 4, 00165, Rome, Italy.

ATP1A3 mutations are related to a wide spectrum of clinical conditions, including several defined syndromes as rapid-onset dystonia-parkinsonism (RDP), alternating hemiplegia of childhood (AHC), and cerebellar ataxia, areflexia, pes cavus, optic atrophy, and sensorineural hearing loss (CAPOS), together with many other intermediate phenotypes. Ataxia is always more increasingly reported, either as accessory or prominent sign, in ATP1A3-related conditions, being thus considered as a peculiar feature of this spectrum. Here, we report three cases of childhood rapid-onset ataxia due to two different ATP1A3 variants. Interestingly, two patients (mother and son) showed a variant c.2266C>T (p.R756C), while the third carried the c.2452G>A (p.E818K) variant, commonly described in association with CAPOS syndrome. Our report contributes to extent the phenotypic spectrum of ATP1A3 mutations, remarking childhood rapid-onset ataxia as an additional clinical presentation of ATP1A3-related conditions. Finally, we discussed this phenomenology in the light of translational evidence from a RDP animal model.
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http://dx.doi.org/10.1007/s12311-018-0920-yDOI Listing
August 2018

ATP1A3-related epileptic encephalopathy responding to ketogenic diet.

Brain Dev 2018 May 1;40(5):433-438. Epub 2018 Feb 1.

Dept. of Neuroscience, Bambino Gesù Children's Hospital, IRCCS, Rome, Italy. Electronic address:

Background: Alternating Hemiplegia of Childhood (AHC) is a rare neurological disease caused by mutations in ATP1A3 gene codifying for alpha3 subunit of Na-K ATPase pump. Repeated and transient attacks of hemiplegia, usually affecting one side of the body or the other, or both sides of the body at once, are the core features of AHC. Monocular nystagmus, other abnormalities in ocular movements, dystonic posturing and epilepsy are commonly associated to AHC. However, the spectrum of ATP1A3 related diseases is still expanding and new phenotypes have been reported.

Case Report: Here, we described a patient who developed a severe early onset drug-resistant epileptic encephalopathy and months later, he presented episodes of hemiplegic attacks and monocular nystagmus. Thus, AHC was hypothesized and a novel mutation in ATP1A3 gene was found. Interestingly, ketogenic diet (KD) was started and both epileptic seizures and classical AHC paroxysmal episodes stopped. Long-term follow-up shows a global improvement of neurological development.

Conclusions: Our case reinforces the role of KD as a novel therapeutic option for ATP1A3-related conditions. However, proper dedicated confirmatory trials on KD are necessary.
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http://dx.doi.org/10.1016/j.braindev.2018.01.002DOI Listing
May 2018

Features of aura in paediatric migraine diagnosed using the ICHD 3 beta criteria.

Cephalalgia 2018 10 14;38(11):1742-1747. Epub 2017 Dec 14.

1 Headache Centre, Bambino Gesù Children Hospital, IRCCS, Rome, Italy.

Background In children and adolescents, the prevalence rate of migraine with aura is 1.6%. Few studies concerning migraine with aura features in paediatric population have been reported. Aim The aim of our study was to investigate clinical features of aura in a retrospective cohort of children with migraine with aura. Furthermore, we studied whether the International Classification of Headache Disorder (ICHD) 3 beta version criteria could efficiently detect migraine with aura in a paediatric population. Results We included 164 patients who experienced aura associated with headache (mean age 9.92 ± 2.64 years). When the ICHD-II criteria were used, a final diagnosis of migraine with typical aura was obtained in 15.3% of patients, probable migraine with typical aura in 13.4%, and typical aura with headache in 61.8%, while in in 9.5% of patients the diagnosis was undetermined. According to ICHD-3 beta, we diagnosed migraine with typical aura in 77.7% of patients, probable migraine with typical aura in 13.4%, and an undetermined diagnosis in 9.5% (less than two attacks). Conclusion Aura features did not depend on age and were similar to those of adults. However, the headache could be difficult to classify if headache duration was considered. In this view, the ICHD-3 beta offers the advantage of not considering headache features, including pain duration, for the diagnosis of migraine with typical aura, thus making this diagnosis easier in children and adolescents.
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http://dx.doi.org/10.1177/0333102417748571DOI Listing
October 2018

O019. Headache as an emergency in children and adolescents.

J Headache Pain 2015 Dec;16(Suppl 1):A142

Headache Centre, Division of Neurology, Ospedale Pediatrico Bambino Gesú, Istituto di ricovero e cura a carattere scientifico, Rome, Italy.

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http://dx.doi.org/10.1186/1129-2377-16-S1-A142DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4715049PMC
December 2015
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