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INTRODUCTION: CTNNB1 gene loss-of-function variants cause Neurodevelopmental disorder with spastic diplegia and visual defects (NEDSDV, OMIM 615075). Although motor impairment represents a core feature of this condition, the motor phenotype remains poorly described. We systematically assessed a cohort of 14 patients with disease-causing CTNNB1 variants to better characterize the movement disorder phenotype. METHODS: patients were enrolled at Bambino Gesù Children's Hospital in Rome, Italy, between January 2019 and February 2024. 14 participants were included and underwent extensive genetic and neurologic examination. Clinical features, neuroimaging and neurophysiological investigations were retrospectively analyzed from medical charts and video recordings. RESULTS: 13 out of 14 patients showed motor disorders (one only showing mild coordination difficulties). 12 presented abnormal gait (11 patients with broad-based gait, one with narrow-based in-toeing gait, one with broad-based gait with unilateral intoeing). One did not achieve walking ability. 13 patients presented progressive lower limbs hypertonia without overt pyramidal signs. Five patients reported exaggerated startle, three developed upper body (prominently cervical) dystonia in the second decade, with or without bradykinesia (2/13). Treatment efficacy was variable: botulinum toxin was (at least partially) effective in 5/6, levodopa in 1 of 4 treated patients. CONCLUSIONS: CTNNB1-syndrome is associated with a peculiar, but recognizable movement disorder phenotype, encompassing complex gait disorders with progressive lower limb hypertonia, exaggerated startle, and possible occurrence in the second decade of life of upper body dystonia with or without bradykinesia.
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We aimed to conduct a state-of-the-art review of the current literature and offer further insights into the methodological aspects concerning induced sputum. The increasing popularity of sputum induction as a non-invasive and cost-effective method for obtaining lower airway secretions from patients who cannot produce sputum naturally has led to extensive research and applications in respiratory conditions like asthma and COPD. This technique allows for analysis of the cellular and biochemical components of the sputum to take place, providing insights into airway inflammation, immune cells, and help in predicting treatment response. Furthermore, induced sputum enables various analyses, including microRNA and gene expression studies and immunophenotyping. The procedure is generally safe and well tolerated, even in patients with airflow limitations; however, monitoring lung function is essential, especially in those with airway hyperresponsiveness. Optimal saline solution concentration and inhalation duration have been investigated, recommending a 15-20 min induction with hypertonic saline. Expectoration involves coughing at the end of each inhalation time. Careful handling during sputum processing is necessary for obtaining accurate results in cell cytology, immunocytochemistry, and in situ hybridization. Overall, induced sputum offers significant advantages as a preferred alternative for large-scale and repeated airway sampling, despite some technical demands and limitations.
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Asma , Esputo , Humanos , Asma/metabolismo , Solución Salina Hipertónica/uso terapéutico , Solución Salina Hipertónica/metabolismo , Pulmón , Administración por InhalaciónRESUMEN
BACKGROUND: The NKX2-1-related disorders (NKX2-1-RD) is a rare disorder characterized by choreiform movements along with respiratory and endocrine abnormalities. The European Reference Network of Rare Neurological Disorders funded by the European Commission conducted a systematic review to assess drug treatment of chorea in NKX2-1-RD, aiming to provide clinical recommendations for its management. METHODS: A systematic pairwise review using various databases, including MEDLINE, Embase, Cochrane, CINAHL, and PsycInfo, was conducted. The review included patients diagnosed with chorea and NKX2-1-RD genetic diagnosis, drug therapy as intervention, no comparator, and outcomes of chorea improvement and adverse events. The methodological quality of the studies was assessed, and the study protocol was registered in PROSPERO. RESULTS: Of the 1417 studies examined, 28 studies met the selection criteria, consisting of 68 patients. The studies reported 22 different treatments for chorea, including carbidopa/levodopa, tetrabenazine, clonazepam, methylphenidate, carbamazepine, topiramate, trihexyphenidyl, haloperidol, propranolol, risperidone, and valproate. No clinical improvements were observed with carbidopa/levodopa, tetrabenazine, or clonazepam, and various adverse effects were reported. However, most patients treated with methylphenidate experienced improvements in chorea and reported only a few negative effects. The quality of evidence was determined to be low. CONCLUSIONS: The management of chorea in individuals with NKX2-1-RD presents significant heterogeneity and lack of clarity. While the available evidence suggests that methylphenidate may be effective in improving chorea symptoms, the findings should be interpreted with caution due to the limitations of the studies reviewed. Nonetheless, more rigorous and comprehensive studies are necessary to provide sufficient evidence for clinical recommendations.
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Corea , Metilfenidato , Humanos , Corea/tratamiento farmacológico , Corea/genética , Tetrabenazina/uso terapéutico , Levodopa , Carbidopa , ClonazepamRESUMEN
BACKGROUND: Status Dystonicus (SD) represents the most severe end of the spectrum of dystonia. We aimed to explore whether reported features of cases of SD have changed over time. METHODS: A systematic review of cases of SD reported from 2017 to 2023 and comparison of features to data extracted from 2 previous literature reviews (epochs 2012-2017 and pre-2012). RESULTS: From 53 papers, a total 206 SD episodes in 168 patients were identified from 2017 to 2023. Combining data from all 3 epochs, a total of 339 SD episodes were reported from 277 patients. SD episodes occurred mostly in children, with a trigger identified in 63.4% of episodes, most commonly infection/inflammation. Most reported underlying aetiologies were genetic (e.g. 49.5% between 2017 and 2023), including new associated aetiologies in each epoch. Deep Brain Stimulation (DBS)-related SD increased over time. Neurosurgical interventions were more frequently reported in later epochs. Across the epochs, return to or improvement post SD episode, compared to baseline was reported above 70%. Reported mortality was 4.9% most recently, compared to 11.4% and 7.9%, previously. CONCLUSIONS: SD episodes reported have more than doubled in the last 5 years. Reports of medication change-induced SD have become less frequent, whilst episodes of DBS-related SD have become more frequent. More dystonia aetiologies, including novel aetiologies have been reported in recent cohorts, reflecting advances in genetic diagnosis. Neurosurgical interventions are increasingly reported in the management of SD episodes, including novel use of intraventricular baclofen. Overall outcomes from SD remain largely unchanged over time. No prospective epidemiological studies of SD were identified.
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Estimulación Encefálica Profunda , Distonía , Trastornos Distónicos , Niño , Humanos , Distonía/etiología , Distonía/terapia , Trastornos Distónicos/terapia , Trastornos Distónicos/complicaciones , Procedimientos Neuroquirúrgicos/efectos adversos , Estudios Prospectivos , Estimulación Encefálica Profunda/efectos adversos , Globo PálidoRESUMEN
AIM: To evaluate clinical phenotype and molecular findings of 157 cases with GNAO1 pathogenic or likely pathogenic variants delineating the clinical spectrum, course, and response to treatments. METHOD: Clinical phenotype, genetic data, and pharmacological and surgical treatment history of 11 novel cases and 146 previously published patients were analyzed. RESULTS: Complex hyperkinetic movement disorder (MD) characterizes 88% of GNAO1 patients. Severe hypotonia and prominent disturbance of postural control seem to be hallmarks in the early stages preceding the hyperkinetic MD. In a subgroup of patients, paroxysmal exacerbations became so severe as to require admission to intensive care units (ICU). Almost all patients had a good response to deep brain stimulation (DBS). Milder phenotypes with late-onset focal/segmental dystonia, mild to moderate intellectual disability, and other minor neurological signs (i.e., parkinsonism and myoclonus) are emerging. MRI, previously considered noncontributory to a diagnosis, can show recurrent findings (i.e., cerebral atrophy, myelination and/or basal ganglia abnormalities). Fifty-eight GNAO1 pathogenic variants, including missense changes and a few recurrent splice site defects, have been reported. Substitutions at residues Gly203, Arg209 and Glu246, together with the intronic c.724-8G > A change, account for more than 50% of cases. INTERPRETATION: Infantile or childhood-onset complex hyperkinetic MD (chorea and/or dystonia) with or without paroxysmal exacerbations, associated hypotonia, and developmental disorders should prompt research for GNAO1 mutations. DBS effectively controls and prevents severe exacerbations and should be considered early in patients with specific GNAO1 variants and refractory MD. Prospective and natural history studies are necessary to define genotype-phenotype correlations further and clarify neurological outcomes.
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Trastornos del Movimiento , Humanos , Masculino , Femenino , Niño , Trastornos del Movimiento/tratamiento farmacológico , Trastornos del Movimiento/patología , Trastornos del Movimiento/fisiopatología , Trastornos del Movimiento/cirugía , Hipotonía Muscular , Discapacidades del Desarrollo , Informes de Casos como AsuntoRESUMEN
BACKGROUND: Most reported patients carrying GNAO1 mutations showed a severe phenotype characterized by early-onset epileptic encephalopathy and/or chorea. OBJECTIVE: The aim was to characterize the clinical and genetic features of patients with mild GNAO1-related phenotype with prominent movement disorders. METHODS: We included patients diagnosed with GNAO1-related movement disorders of delayed onset (>2 years). Patients experiencing either severe or profound intellectual disability or early-onset epileptic encephalopathy were excluded. RESULTS: Twenty-four patients and 1 asymptomatic subject were included. All patients showed dystonia as prominent movement disorder. Dystonia was focal in 1, segmental in 6, multifocal in 4, and generalized in 13. Six patients showed adolescence or adulthood-onset dystonia. Seven patients presented with parkinsonism and 3 with myoclonus. Dysarthria was observed in 19 patients. Mild and moderate ID were present in 10 and 2 patients, respectively. CONCLUSION: We highlighted a mild GNAO1-related phenotype, including adolescent-onset dystonia, broadening the clinical spectrum of this condition. © 2022 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.
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Distonía , Trastornos Distónicos , Subunidades alfa de la Proteína de Unión al GTP Gi-Go , Trastornos del Movimiento , Trastornos Parkinsonianos , Distonía/genética , Trastornos Distónicos/genética , Subunidades alfa de la Proteína de Unión al GTP Gi-Go/genética , Humanos , Trastornos del Movimiento/genética , Trastornos Parkinsonianos/genética , FenotipoRESUMEN
Subacute sclerosing panencephalitis (SSPE) is a late complication of measles virus infection that occurs in previously healthy children. This disease has no specific cure and is associated with a high degree of disability and mortality. In recent years, there has been an increase in its incidence in relation to a reduction in vaccination adherence, accentuated by the COVID-19 pandemic. In this article, we take stock of the current evidence on SSPE and report our personal clinical experience. We emphasise that, to date, the only effective protection strategy against this disease is vaccination against the measles virus.
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COVID-19 , Sarampión , Panencefalitis Esclerosante Subaguda , COVID-19/prevención & control , Niño , Humanos , Sarampión/epidemiología , Sarampión/prevención & control , Virus del Sarampión , Pandemias , Panencefalitis Esclerosante Subaguda/epidemiología , Panencefalitis Esclerosante Subaguda/etiología , Panencefalitis Esclerosante Subaguda/prevención & control , Vacunación/efectos adversosRESUMEN
The "Spazio Huntington-A Place for Children" program was launched in 2019. The aim was to contact at risk kids within Huntington disease (HD) families, to provide counseling to their parents and to start a prospective follow-up of kids suspicious to manifest pediatric HD (PHD). We met 25 at risk kids in two years, four of whom with PHD and highly expanded (HE) mutations beyond 80 CAG repeats. We rated motor, neuropsychological and behavioral changes in all PHD kids by the Unified HD Rating Scale (UHDRS)-total motor score (TMS) and additional measures of (1) cognitive level (Leiter International Performance Scale), (2) adaptive functioning (Adaptive Behavior Assessment Systems), (3) receptive language (Peabody Picture Vocabulary Test) and (4) behavioral abnormalities (Child Behavior Check List and Children's Yale-Brown Obsessive Compulsive Scale). All PHD kids showed a severe progression of neurological and psychiatric manifestations including motor, cognitive and behavioral changes. The magnetic resonance imaging contributed to confirm the suspicious clinical observation by highlighting very initial striatum abnormalities in PHD. Spazio Huntington is a program to prospectively study PHD, the most atypical face of HD, and may represent the basis to recruit PHD patients in future clinical trials.
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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 ZNF526 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 ZNF526 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 znf526 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 ZNF526 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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Catarata , Epilepsia , Discapacidad Intelectual , Microcefalia , Malformaciones del Sistema Nervioso , Trastornos del Neurodesarrollo , Animales , Humanos , Catarata/genética , Epilepsia/genética , Discapacidad Intelectual/genética , Microcefalia/genética , Trastornos del Neurodesarrollo/genética , Linaje , Pez Cebra/genéticaRESUMEN
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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Corea , Trastornos Mentales , Fiebre Reumática , Adolescente , Niño , Corea/diagnóstico , Corea/tratamiento farmacológico , Corea/epidemiología , Humanos , Pronóstico , Estudios RetrospectivosRESUMEN
GNAO1 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 GNAO1. GNAO1 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 GNAO1 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 GNAO1-related disorders, the degree of cognitive development is underestimated; eye tracking technologies may help in overcome these boundaries.
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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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Metilación de ADN/genética , Trastornos Distónicos/complicaciones , Trastornos Distónicos/genética , Trastornos Distónicos/fisiopatología , N-Metiltransferasa de Histona-Lisina/genética , N-Metiltransferasa de Histona-Lisina/metabolismo , Adolescente , Adulto , Factores de Edad , Niño , Preescolar , Estudios de Cohortes , Epigénesis Genética , Femenino , Variación Genética , Humanos , Lactante , Recién Nacido , Masculino , Persona de Mediana Edad , Mutación , FenotipoRESUMEN
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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KCND3 encodes the voltage-gated potassium channel KV4.3 that is highly expressed in the cerebellum, where it regulates dendritic excitability and calcium influx. Loss-of-function KV4.3 mutations have been associated with dominant spinocerebellar ataxia (SCA19/22). By targeted NGS sequencing, we identified two novel KCND3 missense variants of the KV4.3 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 KV4.3 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. KV4.3 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 KCND3-related disorders, outlining the importance of SCA gene screening in early-onset and congenital ataxia.
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Activación del Canal Iónico , Mutación/genética , Canales de Potasio Shal/genética , Ataxias Espinocerebelosas/genética , Ataxias Espinocerebelosas/fisiopatología , Secuencia de Aminoácidos , Animales , Niño , Femenino , Células HEK293 , Humanos , Imagen por Resonancia Magnética , Masculino , Persona de Mediana Edad , Proteostasis , Ataxias Espinocerebelosas/diagnóstico por imagen , Xenopus laevisRESUMEN
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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Atención/fisiología , Corea/genética , Corea/fisiopatología , Disfunción Cognitiva/fisiopatología , Función Ejecutiva/fisiología , Memoria a Corto Plazo/fisiología , Factor Nuclear Tiroideo 1/genética , Niño , Corea/complicaciones , Disfunción Cognitiva/etiología , HumanosAsunto(s)
Enfermedades del Sistema Endocrino/complicaciones , Sistema Endocrino/efectos de los fármacos , Enfermedades del Sistema Nervioso/prevención & control , Fármacos Neuroprotectores/uso terapéutico , Niño , Humanos , Enfermedades del Sistema Nervioso/etiología , Enfermedades del Sistema Nervioso/metabolismo , Enfermedades del Sistema Nervioso/patología , PronósticoRESUMEN
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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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.