Publications by authors named "Elisa Fazzi"

114 Publications

The Influence of Treatment of Inflammatory Arthritis During Pregnancy on the Long-Term Children's Outcome.

Front Pharmacol 2021 18;12:626258. Epub 2021 Mar 18.

Rheumatology and Clinical Immunology Unit, ASST Spedali Civili and University of Brescia, Brescia, Italy.

The management of reproductive issues in women with inflammatory arthritis has greatly changed over decades. In the 1980-1990s, women with refractory forms of arthritis were either not able to get pregnant or did choose not to get pregnant because of their disabling disease. Hence, the traditional belief that pregnancy can induce a remission of arthritis. The availability of biologic agents has allowed a good control of aggressive forms of arthritis. The main topic of discussion during preconception counselling is the use of drugs during pregnancy and breastfeeding. Physicians are now supported by international recommendations released by the European League Against Rheumatism and the American College of Rheumatology, but still they must face with cultural reluctance in accepting that a pregnant woman can take medications. Patient-physician communication should be centered on the message that active maternal disease during pregnancy is detrimental to fetal health. Keeping maternal disease under control with drugs which are not harmful to the fetus is the best way to ensure the best possible outcome for both the mother and the baby. However, there might be concerns about the influence of the exposure to medications on the newborn's health conditions. Particularly, studies suggesting an increased risk of autism-spectrum-disorders in children born to women with rheumatoid arthritis has raised questions about neuropsychological impairment in the offspring of women with chronic arthritis. As a multidisciplinary group of rheumatologists and child neuropsychiatrists, we conducted a study on 16 women with chronic forms of arthritis whose diagnosis was determined before pregnancy and their 18 school-age children. The children underwent a complete neurological examination and validated tests/questionnaires. Behavioral aspects of somatization and anxiety/depression (internalizing problem) or an "adult profile" were found in nearly one third of children. Children at a high risk of neurodevelopmental problems were born to mothers with a longer history of arthritis and were breastfeed for less than 6 months of age or were not breastfeed at all. No association was found with other maternal characteristics such as autoantibody existence and disease activity during and after the pregnancy.
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http://dx.doi.org/10.3389/fphar.2021.626258DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8013697PMC
March 2021

Being adults with cerebral palsy: results of a multicenter Italian study on quality of life and participation.

Neurol Sci 2021 Feb 23. Epub 2021 Feb 23.

Neurodevelopmental Unit, Fondazione IRCCS Istituto Neurologico C. Besta, Milan, Italy.

Cerebral palsy (CP) is still the most common cause of disability developing in infancy. How such a complex disorder affects adult life raises important questions on the critical issues to consider and the most appropriate care pathway right from early childhood. We conducted a multicenter study on a sample of 109 individuals with CP followed up from infancy and recalled for an assessment at ages ranging between 18 and 50 years (mean age 26 years). Semi-structured interviews and specific questionnaires (SF36, LIFE-H and Hollingshead Index) were conducted to assess general psychological state, quality of life, and socio-economic conditions. Our findings showed a globally positive perception of quality of life, albeit with lower scores for physical than for mental health. Our cases generally showed good scores on participation scales, though those with more severe forms scored lower on parameters such as mobility, autonomy, and self-care. These findings were investigated in more depth in interviews, in which our participants painted a picture showing that gradual improvements have been made in several aspects over the years, in the academic attainment and employment, for instance. On the downside, our sample reported persistent limitations on autonomy in daily life. As for the more profound psychological domain, there was evidence of suffering due to isolation and relational difficulties in most cases that had not emerged from the questionnaires. Our data have possible implications for the management of CP during childhood, suggesting the need to avoid an exclusive focus on motor function goals, and to promote strategies to facilitate communication, participation, autonomy, and social relations.
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http://dx.doi.org/10.1007/s10072-021-05063-yDOI Listing
February 2021

The epileptology of Aicardi-Goutières syndrome: electro-clinical-radiological findings.

Seizure 2021 Mar 1;86:197-209. Epub 2020 Dec 1.

Department of Child Neurology and Psychiatry, IRCCS Mondino Foundation, Pavia, Italy; Department of Brain and Behavioural Sciences, University of Pavia, Pavia, Italy.

Objective: Although epileptic seizures occur in approximately a quarter of patients with Aicardi-Goutières syndrome (AGS), their phenotypic and electrophysiological characterization remains elusive. The aim of our study was to characterize epilepsy phenotypes and electroencephalographic (EEG) patterns in AGS and look for possible correlations with clinical, genetic and neuroradiological features.

Methods: We selected patients with an established AGS diagnosis followed at three Italian reference centers. Medical records, EEGs and MRI/CT findings were reviewed. EEGs were independently and blindly reviewed by three board-certified pediatric epileptologists. Chi square and Fisher's exact tests were used to test associations between epilepsy and EEG feature categories and clinical, radiological and genetic variables.

Results: Twenty-seven patients were enrolled. We reviewed 63 EEGs and at least one brain MRI scan per patient. Epilepsy, mainly in the form of epileptic spasms and focal seizures, was present in 37 % of the cohort; mean age at epilepsy onset was 9.5 months (range 1-36). The presence of epilepsy was associated with calcification severity (p = 0.016) and startle reactions (p = 0.05). Organization of EEG electrical activity appeared to be disrupted or markedly disrupted in 73 % of cases. Severe EEG disorganization correlated with microcephaly (p < 0.001) and highly abnormal MRI T2-weighted signal intensity in white matter (p = 0.022). Physiological organization of the EEG was found to be better preserved during sleep (87 %) than wakefulness (38 %). Focal slow activity was recorded in more than one third of cases. Fast activity, either diffuse or with frontal location, was more frequent in the awake state (78 %) than in sleep (50 %). Interictal epileptiform discharges (IEDs) were present in 33 % of awake and 45 % of sleep recordings. IEDs during sleep were associated with a higher risk of a epileptic seizures (p = 0.008).

Significance: The hallmarks of EEG recordings in AGS were found to be: disruption of electrical organization, the presence of focal slow and fast activity, and the presence of IEDs, both in patients with and in those without epilepsy. The associations between epilepsy and calcification and between EEG pattern and the finding of a highly abnormal white matter T2 signal intensity suggest a common anatomical correlate. However, the complex anatomical-electroclinical basis of AGS-related epilepsy still requires further elucidation.
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http://dx.doi.org/10.1016/j.seizure.2020.11.019DOI Listing
March 2021

Oral melatonin as a new tool for neuroprotection in preterm newborns: study protocol for a randomized controlled trial.

Trials 2021 Jan 22;22(1):82. Epub 2021 Jan 22.

Child Neurology and Psychiatry Unit, Department of Brain and Behavioral Sciences, University of Pavia, 27100, Pavia, Italy.

Background: Prevention of neurodevelopmental impairment due to preterm birth is a major health challenge. Despite advanced obstetric and neonatal care, to date there are few neuroprotective molecules available. Melatonin has been shown to have anti-oxidant/anti-inflammatory effects and to reduce brain damage, mainly after hypoxic ischemic encephalopathy. The planned study will be the first aiming to evaluate the capacity of melatonin to mitigate brain impairment due to premature birth.

Method: In our planned prospective, multicenter, double-blind, randomized vs placebo study, we will recruit, within 96 h of birth, 60 preterm newborns with a gestational age ≤ 29 weeks + 6 days; these infants will be randomly allocated to oral melatonin, 3 mg/kg/day, or placebo for 15 days. After the administration period, we will measure plasma levels of malondialdehyde, a lipid peroxidation product considered an early biological marker of melatonin treatment efficacy (primary outcome). At term-equivalent age, we will evaluate neurological status (through cerebral ultrasound, cerebral magnetic resonance imaging, vision and hearing evaluations, clinical neurological assessment, and screening for retinopathy of prematurity) as well as the incidence of bronchodysplasia and sepsis. We will also monitor neurodevelopmental outcome during the first 24 months of corrected age (using the modified Fagan Test of Infant Intelligence at 4-6 months and standardized neurological and developmental assessments at 24 months).

Discussion: Preterm birth survivors often present long-term neurodevelopmental sequelae, such as motor, learning, social-behavioral, and communication problems. We aim to assess the role of melatonin as a neuroprotectant during the first weeks of extrauterine life, when preterm infants are unable to produce it spontaneously. This approach is based on the supposition that its anti-oxidant mechanism could be useful in preventing neurodevelopmental impairment. Considering the short- and long-term morbidities related to preterm birth, and the financial and social costs of the care of preterm infants, both at birth and over time, we suggest that melatonin administration could lead to considerable saving of resources. This would be the first study addressing the role of melatonin in very low birth weight preterm newborns, and it could provide a basis for further studies on melatonin as a neuroprotection strategy in this vulnerable population.

Trial Registration: ClinicalTrials.gov NCT04235673 . Prospectively registered on 22 January 2020.
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http://dx.doi.org/10.1186/s13063-021-05034-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7820522PMC
January 2021

Molecular characterization of a complex small supernumerary marker chromosome derived from chromosome 18p: an addition to the literature.

Mol Cytogenet 2021 Jan 20;14(1). Epub 2021 Jan 20.

Division of Biology and Genetics, Department of Molecular and Translational Medicine, University of Brescia, Brescia, Italy.

Background: Small supernumerary marker chromosomes (sSMC) are a heterogeneous group of structurally abnormal chromosomes, with an incidence of 0,044% in newborns that increases up to almost 7 times in developmentally retarded patients. sSMC from all 24 chromosome have been described, most of them originate from the group of the acrocentric, with around half deriving from the chromosome 15. Non-acrocentric sSMC are less common and, in the 30 percent of the cases, are associated with phenotypic effect. Complex sSMC consist of chromosomal material derived from more than one chromosome. Genotype-phenotype correlations in patients with sSMC are difficult to assess. Clinical features depend on factors such as its size, genetic content, the involvement of imprinted genes which may be influenced by uniparental disomy and the level of mosaicism. Trisomy of the short arm of chromosome 18 (18p) is an infrequent finding and does not appear to be associated with a specific syndrome. However, mild intellectual disability with or without other anomalies is reported in almost one-third of the patients.

Case Presentation: Here we present clinical and molecular characterization of a new case of de novo complex sSMC consisting of the entire short arm of chromosome 18p associated with a centromere of either chromosome 13 or 21, evidenced in a 5-year-old boy during diagnostic workup for moderate intellectual disability and dysmorphisms. To date, only seven cases of isolated trisomy 18p due to a sSMC have been reported, three of which have been characterized by array CGH. In two of them the breakpoints and the size of the duplication have been described. In the manuscript we also reviewed cases reported in the DECIPHER database carrying similar duplication and also considered smaller duplications within the region of interest, in order to evaluate the presence of critical regions implicated in the pathological phenotype.

Conclusions: Our case provides additional information about phenotypic effects of pure trisomy 18p, confirms chromosomal microarray analysis as gold standard to characterize complex sSMC, and supplies additional elements for genetic counselling.
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http://dx.doi.org/10.1186/s13039-020-00519-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7818575PMC
January 2021

Neuropsychiatric Outcome of Children Born to Women With Systemic Lupus Erythematosus and Exposed to Azathioprine: A Case-Control Study.

Front Pharmacol 2020 16;11:613239. Epub 2020 Dec 16.

Department of Clinical and Experimental Sciences, University of Brescia, Brescia, Italy.

The long-term outcome of children born to SLE mothers still represents a controversial topic in literature, with some studies reporting a possible increased prevalence of different neurologic and psychiatric diseases (NPD), including neurodevelopmental disorders (ND), and in particular learning disorders (LD). Different risk factors have been advocated, such as the exposure to auto-antibodies and drugs, particularly Azathioprine (AZA). A case-control study was designed to compare pregnancies treated with AZA (cases) with those not treated with AZA (controls). All the pregnancies had been prospectively followed in two Italian centers. The match was based upon renal involvement, antiphospholipid (aPL) status, maternal age at pregnancy (±5 years) and child's age at the time of the study (±2 years). SLE mothers were interviewed by a telephone survey, particularly focused on the presence of a certified NPD in their children ≥6 years of age. Twenty-seven cases and 65 controls were similar in terms of demographic, immunological and clinical features, except for a higher rate of SLE flares during pregnancy in cases (22.2% vs. 10.8%, :0.191). The 92 children had a mean age of 14.0 years at the time of the survey; 11 had at least one NPD (12.0%). The frequency of each single NPD was similar to that of the general pediatric population and no association was found with either the exposure to AZA, or other specific factors (auto-antibodies, disease activity, obstetric complications, prematurity). The long-term neuropsychiatric outcome of the children born to SLE mothers did not show neither an increased frequency of NPD as compared to the general pediatric population nor a specific pattern of NPD. The exposure to AZA was not associated with the development of NPD in this case-control study of prospectively-followed pregnancies. NPD are complex conditions and large prospective studies are needed to capture the wide range of variables that may contribute to their development in the offspring of SLE women.
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http://dx.doi.org/10.3389/fphar.2020.613239DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7772243PMC
December 2020

Measuring the Outcomes of Maternal COVID-19-related Prenatal Exposure (MOM-COPE): study protocol for a multicentric longitudinal project.

BMJ Open 2020 12 31;10(12):e044585. Epub 2020 Dec 31.

Child Neurology and Psychiatry Unit, IRCCS Mondino Foundation, Pavia, Italy.

Introduction: COVID-19 is a highly infectious respiratory disease that rapidly emerged as an unprecedented epidemic in Europe, with a primary hotspot in Northern Italy during the first months of 2020. Its high infection rate and rapid spread contribute to set the risk for relevant psychological stress in citizens. In this context, mother-infant health is at risk not only because of potential direct exposure to the virus but also due to high levels of stress experienced by mothers from conception to delivery. Prenatal stress exposure associates with less-than-optimal child developmental outcomes, and specific epigenetic mechanisms (eg, DNA methylation) may play a critical role in mediating this programming association.

Methods And Analysis: We present the methodological protocol for a longitudinal, multicentric study on the behavioural and epigenetic effects of COVID-19-related prenatal stress in a cohort of mother-infant dyads in Northern Italy. The dyads will be enrolled at 10 facilities in Northern Italy. Saliva samples will be collected at birth to assess the methylation status of specific genes linked with stress regulation in mothers and newborns. Mothers will provide retrospective data on COVID-19-related stress during pregnancy. At 3, 6 and 12 months, mothers will provide data on child behavioural and socioemotional outcomes, their own psychological status (stress, depressive and anxious symptoms) and coping strategies. At 12 months, infants and mothers will be videotaped during semistructured interaction to assess maternal sensitivity and infant's relational functioning.

Ethics And Dissemination: This study was approved by the Ethics Committee (Pavia). Results will be published in peer-reviewed journals and presented at national and international scientific conferences.

Trial Registration Number: NCT04540029; Pre-results.
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http://dx.doi.org/10.1136/bmjopen-2020-044585DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7780424PMC
December 2020

Late-Onset Aicardi-Goutières Syndrome: A Characterization of Presenting Clinical Features.

Pediatr Neurol 2021 Feb 2;115:1-6. Epub 2020 Nov 2.

Children's Hospital of Philadelphia, Philadelphia, Pennsylvania. Electronic address:

Background: Aicardi-Goutières syndrome (AGS) is a genetic interferonopathy characterized by early onset of severe neurological injury with intracranial calcifications, leukoencephalopathy, and systemic inflammation. Increasingly, a spectrum of neurological dysfunction and presentation beyond the infantile period is being recognized in AGS. The aim of this study was to characterize late-infantile and juvenile-onset AGS.

Methods: We conducted a multi-institution review of individuals with AGS who were older than one year at the time of presentation, including medical history, imaging characteristics, and suspected diagnoses at presentation.

Results: Thirty-four individuals were identified, all with pathogenic variants in RNASEH2B, SAMHD1, ADAR1, or IFIH1. Most individuals had a history of developmental delay and/or systemic symptoms, such as sterile pyrexias and chilblains, followed by a prodromal period associated with increasing symptoms. This was followed by an abrupt onset of neurological decline (fulminant phase), with a median onset at 1.33 years (range 1.00 to 17.68 years). Most individuals presented with a change in gross motor skills (97.0%), typically with increased tone (78.8%). Leukodystrophy was the most common magnetic resonance imaging finding (40.0%). Calcifications were less common (12.9%).

Conclusions: This is the first study to characterize the presentation of late-infantile and juvenile onset AGS and its phenotypic spectrum. Late-onset AGS can present insidiously and lacks classical clinical and neuroimaging findings. Signs of early systemic dysfunction before fulminant disease onset and loss of motor symptoms were common. We strongly recommend genetic testing when there is concern for sustained inflammation of unknown origins or changes in motor skills in children older than one year.
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http://dx.doi.org/10.1016/j.pediatrneurol.2020.10.012DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7856674PMC
February 2021

Basal Ganglia Dysmorphism in Patients With Aicardi Syndrome.

Neurology 2021 03 4;96(9):e1319-e1333. Epub 2020 Dec 4.

From the Department of Brain and Behavioural Neurosciences (S.M., A.P., M. Formica, S.O.) and Department of Public Health Experimental and Forensic Medicine, Biostatistic and Clinical Epidemiology Unit (P. Borrelli), University of Pavia; Pediatric Neurology Unit (S.M., M. Mastrangelo, P.V.), V. Buzzi Children's Hospital, Milan; Department of Neuroradiology (A.P.), Child Neurology and Psychiatry Unit (R.B., V.D.G., S.O.), and Department of Internal Medicine and Therapeutics, Member of the ERN EpiCARE, University of Pavia and Clinical Trial Center (E.P.), IRCCS Mondino Foundation Pavia; Neuroimaging Lab (F.A.) and Neuropsychiatry and Neurorehabilitation Unit (R.R.), Scientific Institute, IRCCS Eugenio Medea, Bosisio Parini, Lecco; Child Neuropsychiatric Unit (P.A., L.G.), Civilian Hospital, Brescia; Scientific Institute (P. Bonanni, A.D., E.O.), IRCCS E. Medea, Epilepsy and Clinical Neurophysiology Unit, Conegliano, Treviso; UOC Child Neuropsychiatry (B.D.B., F.D.), Department of Surgical Sciences, Dentistry, Gynecology and Pediatrics, University of Verona, Italy; Département de Neurologie Pédiatrique (N.D.), Hôpital Universitaire des Enfants Reine Fabiola, Université Libre de Bruxelles, Belgium; AdPueriVitam (O.D.), Antony; Service d'Explorations Fonctionnelles (S.G.), Centre de Médecine du Sommeil, l'Hôpital Àntoine Béclère, AP-HP, Clamart; Pediatrics Departement (S.G.), André-Grégoire Hospital, Centre Hospitalier Inter Communal, Montreuil, France; Pediatric Neurology, Neurogenetics and Neurobiology Unit and Laboratories, Neuroscience Department (R.G., M. Montomoli, M.C.) and Radiology (M. Mortilla), A. Meyer Children's Hospital, Member of the ERN EpiCARE, University of Florence; IRCCS Stella Maris Foundation (R.G.), Pisa; Child Neuropsychiatry Unit, Epilepsy Center (F.L.B., A.V.), San Paolo Hospital, Department of Health Sciences, Università degli Studi di Milano, Milan; Child Neurology, NESMOS Department (P.P.), Faculty of Medicine & Psychology, Sant'Andrea Hospital, Sapienza University, Rome; Department of Neuroradiology (L.P.), Pediatric Neuroradiology Section, ASST Spedali Civili, Brescia; Pediatric Neuroradiology Unit (M.S.), IRCCS Istituto Giannina Gaslini, Genova; Neurology Unit, Department of Neuroscience, Member of the ERN EpiCARE (F.V.), Oncological Neuroradiology Unit, Department of Imaging, IRCCS (G.C.), and Department of Neuroscience and Neurorehabilitation (A.F.), Bambino Gesù Children's Hospital, Rome, Italy; Institut Imagine (N.B.-B.), Université Paris Descartes-Sorbonne Paris Cités; Pediatric Neurology (N.B.-B., I.D.), Necker Enfants Malades Hospital, Member of the ERN EpiCARE, Assistance Publique-Hôpitaux de Paris; INSERM UMR-1163 (N.B.-B., A. Arzimanoglou), Embryology and Genetics of Congenital Malformations, France; UOC Neurochirurgia (A. Accogli, V.C.), Pediatric Neurology and Muscular Diseases Unit, Department of Neurosciences, Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health, University of Genoa (F.Z.), and Laboratory of Neurogenetics and Neuroscience, IRCCS (F.Z.), Istituto Giannina Gaslini, Genoa, Italy; Neurochirurgie Pédiatrique (M.B.), Hôpital NEM, Paris, France; Centre Médico-Chirurgical des Eaux-Vives (V.C.-V.), Swiss Medical Network, Genève, Switzerland; Neuroradiology Unit (L.C.) and Developmental Neurology Unit (S.D.), Foundation IRCCS C. Besta Neurological Institute, Milan; Service de Génétique (M.D.-F.), AMH2, CHU Reims, UFR de Médecine, Reims, France; Epilepsy Centre-Clinic of Nervous System Diseases (G.d.), Riuniti Hospital, Foggia, Italy; MediClubGeorgia Co Ltd (N.E.), Tbilisi, Georgia; Epilepsy Center (N.E.), Medical Center, Faculty of Medicine, University of Freiburg, Germany; Child and Adolescence Neurology and Psychiatry Unit (E. Fazzi), ASST Civil Hospital, Department of Clinical and Experimental Sciences, University of Brescia; Child Neurology Department (E. Fiorini), Verona, Italy; Service de Genetique Clinique (M. Fradin, P.L., C.Q.), CLAD-Ouest, Hospital Sud, Rennes, France; Child Neurology Unit, Pediatric Department (C.F., C.S.), Azienda USL-IRCCS di Reggio Emilia; Department of Pediatric Neuroscience (T.G., R.S.), Fondazione IRCCS Istituto Neurologico Carlo Besta, Member of the ERN EpiCARE, Milan, Italy; Department of Epilepsy Genetics and Personalized Treatment (K.M.J., R.S.M.), The Danish Epilepsy Centre, Dianalund; Institute for Regional Health Services (K.M.J., R.S.M.), University of Southern Denmark, Odense; Unit of Pediatric Neurology and Pediatric Neurorehabilitation (S.L.), Woman-Mother-Child Department, Lausanne University Hospital CHUV, Switzerland; Unit of Neuroradiology (D.M.), Fondazione CNR/Regione Toscana G. Monasterio, Pisa; Pediatric Neurology Unit and Epilepsy Center (E.R., A.R.), Fatebenefratelli Hospital, Milan, Italy; KJF Klinik Josefinum GmbH (C.U.), Klinik für Kinder und Jugendliche, Neuropädiatrie, Augsburg, Germany; Department of Paediatric Clinical Epileptology, Sleep Disorders and Functional Neurology (A. Arzimanoglou), University Hospitals of Lyon, Coordinator of the ERN EpiCARE, France; and Pediatric Epilepsy Unit, Child Neurology Department (P.V.), Hospital San Juan de Dios, Member of the ERN EpiCARE and Universitat de Barcelona, Spain.

Objective: Aiming to detect associations between neuroradiologic and EEG evaluations and long-term clinical outcome in order to detect possible prognostic factors, a detailed clinical and neuroimaging characterization of 67 cases of Aicardi syndrome (AIC), collected through a multicenter collaboration, was performed.

Methods: Only patients who satisfied Sutton diagnostic criteria were included. Clinical outcome was assessed using gross motor function, manual ability, and eating and drinking ability classification systems. Brain imaging studies and statistical analysis were reviewed.

Results: Patients presented early-onset epilepsy, which evolved into drug-resistant seizures. AIC has a variable clinical course, leading to permanent disability in most cases; nevertheless, some cases presented residual motor abilities. Chorioretinal lacunae were present in 86.56% of our patients. Statistical analysis revealed correlations between MRI, EEG at onset, and clinical outcome. On brain imaging, 100% of the patients displayed corpus callosum malformations, 98% cortical dysplasia and nodular heterotopias, and 96.36% intracranial cysts (with similar rates of 2b and 2d). As well as demonstrating that posterior fossa abnormalities (found in 63.63% of cases) should also be considered a common feature in AIC, our study highlighted the presence (in 76.36%) of basal ganglia dysmorphisms (never previously reported).

Conclusion: The AIC neuroradiologic phenotype consists of a complex brain malformation whose presence should be considered central to the diagnosis. Basal ganglia dysmorphisms are frequently associated. Our work underlines the importance of MRI and EEG, both for correct diagnosis and as a factor for predicting long-term outcome.

Classification Of Evidence: This study provides Class II evidence that for patients with AIC, specific MRI abnormalities and EEG at onset are associated with clinical outcomes.
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http://dx.doi.org/10.1212/WNL.0000000000011237DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8055324PMC
March 2021

Imitation in Angelman syndrome: the role of social engagement.

Sci Rep 2020 10 2;10(1):16398. Epub 2020 Oct 2.

Unit of Child Neurology and Psychiatry, ASST Spedali Civili of Brescia, Brescia, Italy.

Individuals with Angelman syndrome (AS) are characterized by severe cognitive impairments alongside an enhanced drive for social engagement. As knowledge on imitation skills in this population is limited, we conducted the first controlled study of imitation in AS. We examined how 23 individuals with AS and 21 typically developing young children with similar mental age imitated novel actions in response to socially or non-socially engaging models, and in response to video-recorded versus live demonstrations of novel actions. Individuals with AS imitated as frequently and as accurately as typical young children in response to live demonstrations; but they imitated less frequently and less accurately in response to video-recorded demonstrations. Further, imitation was modulated by whether the demonstrator was socially engaging or emotionally neutral in the AS group, while this modulation was not present in the comparison group. Individuals with higher mental age imitated more frequently and more accurately across groups. Imitation performance in AS appears to be more modulated by the social context compared to typical infants and young children with similar mental age, possibly reflecting an enhanced drive for social engagement. A socially engaging instructional style might facilitate imitative learning in this population.
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http://dx.doi.org/10.1038/s41598-020-72079-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7532435PMC
October 2020

Commentary on "Catatonia in a Patient with Aicardi-Goutières Syndrome Efficiently Treated with Immunoadsorption".

Schizophr Res 2020 10 12;224:188-189. Epub 2020 Sep 12.

Department of Child Neurology and Psychiatry, IRCCS Mondino Foundation, Pavia, Italy; Department of Brain and Behavioral Sciences, University of Pavia, Pavia, Italy.

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http://dx.doi.org/10.1016/j.schres.2020.08.023DOI Listing
October 2020

Cognitive improvement after cochlear implantation in deaf children with associated disabilities.

Dev Med Child Neurol 2020 12 11;62(12):1429-1436. Epub 2020 Sep 11.

Department of Medical and Surgical Specialties, Radiological Sciences and Public Health, Section of Head and Neck Surgery, University of Brescia, Brescia, Italy.

Aim: To monitor functional auditory and non-verbal cognitive skills in children with cochlear implants who had associated disabilities over a 24-month period and define how cochlear implantation may impact on non-verbal cognition by restoring functional auditory skills.

Method: Sixty-four children with cochlear implants (36 females, 28 males; mean age 4y 3mo, SD 3y 5mo, 9mo-14y 5mo) were recruited and divided into three groups: children with typical development group (TDG); children with associated disabilities not linked to non-verbal cognitive disorders group (ADG1); and children with associated disabilities linked to non-verbal cognitive disorders group (ADG2). Tests of functional auditory, communicative, and non-verbal cognitive skills were performed before cochlear implantation and at 12 and 24 months after cochlear implantation.

Results: Functional auditory and communicative skills improved similarly in the three groups at 12 and 24 months after implantation. An increase in non-verbal cognitive scores was present in children in the ADG2 from baseline to 12 and 24 months (p<0.01), whereas scores remained stable in children in the TDG and ADG1. The increased functional auditory skills scores after cochlear implantation corresponded to an increase in non-verbal cognitive scores (p=0.032) in children in the ADG2.

Interpretation: Children with associated disabilities, especially if linked to non-verbal cognitive disorders, benefitted from cochlear implantation. They improved their comprehension of acoustic information inferred from the environment, improving not only functional auditory skills but also non-verbal cognition.
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http://dx.doi.org/10.1111/dmcn.14671DOI Listing
December 2020

Action Observation Treatment in a tele-rehabilitation setting: a pilot study in children with cerebral palsy.

Disabil Rehabil 2020 Aug 17:1-6. Epub 2020 Aug 17.

Division of Neuroscience, IRCCS San Raffaele and University San Raffaele, Milan, Italy.

Objective: Action Observation Treatment is a novel rehabilitation approach exploiting a neurophysiological mechanism that allows one to recruit the neural structures sub-serving action execution during the mere observation of those same actions. Action Observation Treatment is effective in the rehabilitation of several neurological diseases. In this pilot study, we used Action Observation Treatment in a telerehabilitation setting in children with Cerebral Palsy.

Materials And Methods: Ten children with Cerebral Palsy, aged 5-12 years, entered the study. They followed the Action Observation Treatment rehabilitation program at home with remote supervision by a child neurologist located at the hospital. Outcome measures were the scores at the Melbourne Assessment of Unilateral Upper Limb Function Scale and the Assisting Hand Assessment.

Results: Scores obtained after treatment and at a two months' follow-up significantly differed from baseline and overlapped those obtained in randomized controlled studies carried out in a conventional setting.

Conclusions: Action Observation Treatment is therefore a promising approach that can be used on a large scale in a telerehabilitation setting. IMPLICATIONS FOR REHABILITATION Tele-rehabilitation has the potential to enhance early intervention service provision for children with Cerebral Palsy. Action Observation Treatment has the potential to become a routine approach in a telerehabilitation setting.
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http://dx.doi.org/10.1080/09638288.2020.1793009DOI Listing
August 2020

"APS pregnancy - The offspring".

Lupus 2020 Oct 4;29(11):1336-1345. Epub 2020 Aug 4.

Department of Obstetrics and Gynecology, I.M. Sechenov First Moscow State Medical University, Ministry of Health of the Russian Federation (Sechenov University), Moscow, Russia.

Background: Antiphospholipid antibody syndrome (APS) is an autoimmune disease that affects women in childbearing age. In recent years, great improvements were achieved in the management of pregnancies in these women. Prematurity could be an issue in these pregnancies, mainly due to the direct pathogenic effect of antiphospholipid antibodies (aPL) on the placental surface. Maternal IgG aPL can cross the placenta and theoretically interact with the growing fetus; it could reach the fetal brain because of the incompleteness of the fetal blood-brain barrier: whether this can have an effect on brain development is still debated. Neonatal thrombosis episodes have been described in children positive for aPL, not always associated with maternal antibody positivity, suggesting the hypothesis of a possible aPL de novo synthesis in fetus and neonates.

Methods: A keyword-based literature search was conducted. We also described a case of neonatal catastrophic antiphospholipid syndrome (CAPS).

Results: Offspring of patients with APS are generally healthy but the occurrence of neonatal thrombosis or minor neurological disorders were reported.

Conclusions: The limited number of the available data on this sensitive issue supports the need for further studies. Clinical follow-up of children of mothers with APS seems to be important to exclude, in the neonatal period, the occurrence of aPL associated pathological events such as thrombosis, and in the long-term, impairment in learning skills or behavioral problems.
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http://dx.doi.org/10.1177/0961203320947154DOI Listing
October 2020

Autistic-Like Features in Visually Impaired Children: A Review of Literature and Directions for Future Research.

Brain Sci 2020 Aug 1;10(8). Epub 2020 Aug 1.

Unit of Child Neurology and Psychiatry, ASST Spedali Civili of Brescia, 25121 Brescia, Italy.

There remains great interest in understanding the relationship between visual impairment (VI) and autism spectrum disorder (ASD) due to the extraordinarily high prevalence of ASD in blind and visually impaired children. The broad variability across individuals and assessment methodologies have made it difficult to understand whether autistic-like symptoms shown by some children with VI might reflect the influence of the visual deficit, or represent a primary neurodevelopmental condition that occurs independently of the VI itself. In the absence of a valid methodology adapted for the visually impaired population, diagnosis of ASD in children with VI is often based on non-objective clinical impression, with inconclusive prevalence data. In this review, we discuss the current state of knowledge and suggest directions for future research.
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http://dx.doi.org/10.3390/brainsci10080507DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7465914PMC
August 2020

Early Parenting Intervention - Biobehavioral Outcomes in infants with Neurodevelopmental Disabilities (EPI-BOND): study protocol for an Italian multicentre randomised controlled trial.

BMJ Open 2020 07 21;10(7):e035249. Epub 2020 Jul 21.

Child Neurology and Psychiatry Unit, IRCCS Mondino Foundation, Pavia, Italy.

Introduction: Neurodevelopmental disability (ND) represents an adverse condition for infants' socio-emotional and behavioural development as well as for caregiving (eg, parental sensitivity) and mother-infant interaction. Adverse exposures are associated with altered neuroendocrine hormones concentrations (eg, oxytocin and cortisol) and epigenetic regulation (eg, methylation of stress-related genes), which in turn may contribute to less-than-optimal mother-infant interaction. Parental sensitivity is a protective factor for childrens' development and early parental interventions (eg, video-feedback intervention) can promote parental caregiving and better developmental outcomes in children. The present multi-centric and longitudinal randomised controlled trial aims to assess if and to which extent early VFI could benefit both infants and mothers in terms of behavioural outcomes as well as neuroendocrine and epigenetic regulation.

Methods And Analysis: Dyads will be randomly assigned to the video-feedback Intervention Group or Control Group ('dummy' intervention: telephone calls). Infants with ND aged 3 to 18 months will be recruited from three major child neuropsychiatric units in northern Italy. A multi-layer approach to intervention effects will include videotapes of mother-infant interaction, maternal reports as well as saliva samples for hormones concentrations and target-gene methylation analysis (eg, , , ) that will be obtained at each of the four assessment sessions: T, baseline; T, post-intervention; T, short-term follow-up (3 month); T, long-term follow-up (6 month). Primary effectiveness measures will be infant socio-emotional behaviour and maternal sensitivity. Neuroendocrine hormones concentrations and DNA methylation status of target genes will be secondary outcomes. Feasibility, moderation and confounding variables will be measured and controlled between the two groups.

Ethics And Dissemination: Ethics approval has been obtained in all three participating units. Results of the main trial and each of the secondary endpoints will be submitted for publication in peer-reviewed journals and international conferences.

Trial Registration Number: NCT03853564; Pre-results.
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http://dx.doi.org/10.1136/bmjopen-2019-035249DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7375429PMC
July 2020

Aicardi Syndrome: Key Fetal MRI Features and Prenatal Differential Diagnosis.

Neuropediatrics 2020 08 3;51(4):276-285. Epub 2020 Jul 3.

Department of Pediatric Radiology and Neuroradiology, Children's Hospital V. Buzzi, Milan, Italy.

Objective: This study was aimed to investigate the prenatal findings in Aicardi syndrome (AIC) by intrauterine magnetic resonance imaging (iuMRI) suggesting possible diagnostic criteria and differential diagnosis.

Methods: The iuMRI features of nine AIC confirmed cases were described and then compared with those of postnatal MRI. Furthermore, all iuMRI cases with both corpus callosum (CC) agenesis-dysgenesis and cortical malformation (AIC mimickers) were retrospectively reviewed and compared with iuMRI AIC cases, in order to identify possible neuroradiological predictors of AIC syndrome. For this purpose, Chi-square statistic and binary logistic regression analysis were performed.

Results: In all AIC cases, iuMRI was able to detect CC agenesis-dysgenesis and cortical development anomalies. Postnatal MRI revealed some additional findings mainly including further cystic lesions and in two cases small coloboma. A statistically significant difference between AIC and AIC mimicker were found regarding sex, nodular heterotopias, posterior fossa abnormalities, coloboma, and cortical gyration abnormalities. The most predictive variables in the logistic regression model were cortical gyration abnormalities, coloboma, and sex.

Conclusion: The iuMRI findings may suggest prenatal diagnosis of AIC syndrome with significant impact on parental counseling. Among possible differential diagnoses, tubulinopathies emerged.
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http://dx.doi.org/10.1055/s-0040-1710528DOI Listing
August 2020

Morpho-functional survey in children suspected of inherited retinal dystrophies via video recording, electrophysiology and genetic analysis.

Int Ophthalmol 2020 Oct 7;40(10):2523-2534. Epub 2020 Jun 7.

Ophthalmic Clinic IRCCS San Matteo Hospital, P.zzale Golgi 19, 27100, Pavia, Italy.

Purpose: To present a detailed study matching functional response and video imaging with genetic analysis in children suspected of inherited retinal dystrophy (IRD).

Methods: Sixteen children underwent fundus examination via video recording (Heine Omega 500 indirect ophthalmoscope with DV1 camera) and electroretinogram (ERG) under general anesthesia to investigate the cause of suspected low vision. The patients [median age 12 (interquartile range 8-57.5) months] had associated genetic analysis performed with next-generation sequencing or array-comparative genomic hybridization.

Results: Four children had potential pathogenic variants in genes involved in Leber congenital amaurosis and Joubert syndrome (NMNAT1, CEP290, KCNJ13, IMPDH1); 1 child had a 16p11.2 microdeletion and 1 in 2q22.1. The ERG was altered in 6 patients, fundus imaging showed serious abnormality matching an IRD in 7 children, and less severe fundus alterations were found in 2 subjects.

Conclusion: Fundus imaging associated with ERG may be significant in IRD diagnosis and visual impairment prognosis, alongside genetic analysis and therapy in selected cases.
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http://dx.doi.org/10.1007/s10792-020-01432-2DOI Listing
October 2020

New clinical needs and strategies for care in children with neurodisability during COVID-19.

Dev Med Child Neurol 2020 07 2;62(7):879-880. Epub 2020 May 2.

Child and Adolescence Neurology and Psychiatry Unit, Department of Clinical and Experimental Sciences, ASST Spedali Civili di Brescia, University of Brescia, Brescia, Italy.

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http://dx.doi.org/10.1111/dmcn.14557DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7267576PMC
July 2020

Development of a neurologic severity scale for Aicardi Goutières Syndrome.

Mol Genet Metab 2020 06 2;130(2):153-160. Epub 2020 Apr 2.

Division of Neurology, Children's Hospital of Philadelphia, United States.

Background And Purpose: Aicardi Goutières Syndrome (AGS) is a severe, autoinflammatory leukodystrophy characterized by global neurologic dysfunction. Our goal was to create an easy-to-apply scale relevant to the unique developmental challenges associated with AGS.

Methods: All individuals were recruited through our natural history study. Individuals were classified by AGS severity as mild, moderate, or severe, and clinical encounters were assigned a composite score for neurologic function calculated from the sum of three functional classification scales. Through expert consensus, we identified 11 key items to reflect the severity of AGS across gross motor, fine motor, and cognitive skills to create the AGS Scale. There was strong interrater reliability. The AGS scale was applied across available medical records to evaluate neurologic function over time. The AGS scale was compared to performance on a standard measure of gross motor function (Gross Motor Function Measure-88, GMFM-88) and a putative diagnostic biomarker of disease, the interferon signaling gene expression score (ISG).

Results: The AGS scale score correlated with severity classifications and the composite neurologic function scores. When retrospectively applied across our natural history study, the majority of individuals demonstrated an initial decline in function followed by stable scores. Within the first 6 months of disease, the AGS score was the most dynamic. The AGS scale correlated with performance by the GMFM-88, but did not correlate with ISG levels.

Conclusions: This study demonstrates the utility of the AGS scale as a multimodal tool for the assessment of neurologic function in AGS. The AGS scale correlates with clinical severity and with a more labor-intensive tool, GMFM-88. This study underscores the limitations of the ISG score as a marker of disease severity. With the AGS scale, we found that AGS neurologic severity is the most dynamic early in disease. This novel AGS scale is a promising tool to longitudinally follow neurologic function in this unique population.
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http://dx.doi.org/10.1016/j.ymgme.2020.03.008DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7366613PMC
June 2020

Biomarkers and Precision Therapy for Primary Immunodeficiencies: An In Vitro Study Based on Induced Pluripotent Stem Cells From Patients.

Clin Pharmacol Ther 2020 Aug 9;108(2):358-367. Epub 2020 May 9.

Department of Life Sciences, University of Trieste, Trieste, Italy.

Ataxia telangiectasia (AT) and Aicardi-Goutières syndrome (AGS) are inherited disorders of immunity with prevalent neurological phenotype. Available treatments are only partially effective, and the prognosis is poor. Induced pluripotent stem cells (iPSCs) are obtained by reprogramming patient somatic cells, preserving the donor individual genetic heritage and creating patient-specific disease models, useful to investigate pathogenesis and drug effects and to develop precision therapies. The aim is to investigate the cytotoxicity of a panel of immunomodulators using iPSCs of patients with AT or different forms of AGS (AGS1, AGS2, and AGS7). iPSCs were obtained by reprogramming AT and AGS patients' cells and, as a control, the BJ normal human fibroblast line, using Sendai virus. Cytotoxic effects of two drugs proposed to treat respectively AT and AGS (dexamethasone and mepacrine) were tested by the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay after 72 hours' exposure. Data were obtained also for other immunomodulatory drugs (thioguanine, mercaptopurine, thalidomide, and lenalidomide). Relative expression of genes involved in the tested drug pathways was analyzed. AGS7-derived iPSCs displayed altered viability when treated with a low dose of mepacrine and higher expression of cyclic guanosine monophosphate-adenosine monophosphate synthase, which is the main target for mepacrine action. AGS7-derived iPSCs were also more sensitive to thioguanine, while AGS2 and AT iPSCs were less sensitive to this medication than the BJ-iPSC. All iPSCs were equally sensitive to mercaptopurine and resistant to dexamethasone, thalidomide, and lenalidomide. This work establishes an innovative in vitro model that is useful to investigate the mechanisms of drugs potentially effective in AT and AGS.
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http://dx.doi.org/10.1002/cpt.1837DOI Listing
August 2020

Questionnaires as screening tools for children with cerebral visual impairment.

Dev Med Child Neurol 2020 08 21;62(8):891. Epub 2020 Feb 21.

Unit of Child Neurology and Psychiatry, ASST Spedali Civili of Brescia, Brescia, Italy.

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http://dx.doi.org/10.1111/dmcn.14497DOI Listing
August 2020

Genetic and phenotypic spectrum associated with IFIH1 gain-of-function.

Hum Mutat 2020 04 14;41(4):837-849. Epub 2020 Jan 14.

Laboratory of Neurogenetics and Neuroinflammation, Institut Imagine, Paris, France.

IFIH1 gain-of-function has been reported as a cause of a type I interferonopathy encompassing a spectrum of autoinflammatory phenotypes including Aicardi-Goutières syndrome and Singleton Merten syndrome. Ascertaining patients through a European and North American collaboration, we set out to describe the molecular, clinical and interferon status of a cohort of individuals with pathogenic heterozygous mutations in IFIH1. We identified 74 individuals from 51 families segregating a total of 27 likely pathogenic mutations in IFIH1. Ten adult individuals, 13.5% of all mutation carriers, were clinically asymptomatic (with seven of these aged over 50 years). All mutations were associated with enhanced type I interferon signaling, including six variants (22%) which were predicted as benign according to multiple in silico pathogenicity programs. The identified mutations cluster close to the ATP binding region of the protein. These data confirm variable expression and nonpenetrance as important characteristics of the IFIH1 genotype, a consistent association with enhanced type I interferon signaling, and a common mutational mechanism involving increased RNA binding affinity or decreased efficiency of ATP hydrolysis and filament disassembly rate.
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http://dx.doi.org/10.1002/humu.23975DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7457149PMC
April 2020

Novel and emerging treatments for Aicardi-Goutières syndrome.

Expert Rev Clin Immunol 2020 02 6;16(2):189-198. Epub 2020 Jan 6.

Department of Brain and Behavioural Sciences, University of Pavia, Pavia, Italy.

: Aicardi-Goutières syndrome (AGS) is the prototype of the type I interferonopathies, a new heterogeneous group of autoinflammatory disorders in which type I interferon plays a pivotal role. The disease usually manifests itself during infancy, primarily affecting the brain and the skin, and is characterized by cerebrospinal fluid chronic lymphocytosis and raised levels of interferon-alpha and by cardinal neuroradiological features: cerebral calcification, leukoencephalopathy and cerebral atrophy. Recently many aspects of the pathogenesis of AGS have been clarified, making it possible to hypothesize new therapeutic strategies.: We here review recent data concerning pathogenesis and novel therapeutic strategies in AGS, including the use of Janus kinase inhibitors, reverse transcriptase inhibitors, anti-IFN-α antibodies, anti-interleukin antibodies, antimalarial drugs and other cGAS inhibitors.: Thanks to the identification of the molecular basis of AGS, many aspects of its pathogenesis have been clarified, making it possible to propose new therapeutic strategies for AGS and type I interferonopathies. A number of therapeutic options are now becoming possible, even though their efficacy is still to be proven. However, in spite of research advances coming from clinical trials and case series, there are still a number of open questions, which urgently need to be addressed.
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http://dx.doi.org/10.1080/1744666X.2019.1707663DOI Listing
February 2020

Long-term outcome of children born from mothers with autoimmune diseases.

Best Pract Res Clin Obstet Gynaecol 2020 Apr 13;64:107-116. Epub 2019 Nov 13.

Rheumatology and Immunology Unit, Department of Clinical and Experimental Sciences, University of Brescia and ASST Spedali Civili of Brescia, Piazzale Spedali Civili 1, 25123, Brescia, Italy.

Autoimmune diseases often affect young women and this may represent a problem in family planning. Pregnancies in these patients may carry several complications but nowadays the continued amelioration in treatment and management has greatly improved the pregnancy outcome. The main concern of these women obviously is the short- and long-term outcome of their children. A child born from a woman with autoimmune disease is potentially exposed in utero to maternal autoantibodies, cytokines, and drugs, and each item could impair his or her development. In addition, the maternal genetic heritage can favor autoimmunity. All these items could have a role, for example, in the development of autoimmune diseases (the same as the mother or different ones) or neurological disorders. Data in literature are controversial. This review will gather the available data possibly providing a useful tool for counseling future mothers.
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http://dx.doi.org/10.1016/j.bpobgyn.2019.11.003DOI Listing
April 2020

Visuospatial Attention and Saccadic Inhibitory Control in Children With Cerebral Palsy.

Front Hum Neurosci 2019 8;13:392. Epub 2019 Nov 8.

Department of Clinical and Experimental Sciences, University of Brescia, Brescia, Italy.

Cerebral palsy (CP) is a non-progressive syndrome due to a pre-, peri- or post-natal brain injury, which frequently involves an impairment of non-motor abilities. The aim of this article was to examine visuospatial attention and inhibitory control of prepotent motor responses in children with CP showing a normal IQ or mild cognitive impairment, measuring their performance in oculomotor tasks. Ten children (9-16-year-old) with spastic CP and 13 age-matched, typically developing children (TDC) participated in the study. Subjects performed a simple visually-guided saccade task and a task, in which they performed a saccade towards a peripheral target, after a non-informative visual cue was flashed 150 ms before the imperative target, either at the same () or at a different () spatial position. Children with CP showed severe executive deficits in maintaining sustained attention and complying with task instructions. Furthermore, saccadic inhibitory control appeared to be significantly impaired in the presence of both stimulus-driven and goal-directed captures of attention. In fact, patients showed great difficulties in suppressing saccades not only to the cue stimuli but also to the always-present target placeholders, which represented powerful attentional attractors that had to be covertly attended throughout the task execution. Moreover, impairment did not affect in equal manner the whole visual field but showed a marked spatial selectivity in each individual subject. Saccade latencies in the task were faster in the than in the condition in both child groups, indicating the preservation of low-level visuospatial attentive capabilities. Finally, this study provides evidence that these impairments of executive skills and in inhibitory control, following early brain injuries, manifest in childhood but recover to virtually normal level during adolescence.
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http://dx.doi.org/10.3389/fnhum.2019.00392DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6856641PMC
November 2019

Generation of three isogenic induced Pluripotent Stem Cell lines (iPSCs) from fibroblasts of a patient with Aicardi Goutières Syndrome carrying a c.2471G>A dominant mutation in IFIH1 gene.

Stem Cell Res 2019 12 22;41:101623. Epub 2019 Oct 22.

Department of Molecular and Translational Medicine, University of Brescia, Brescia, Italy; "Angelo Nocivelli" Institute for Molecular Medicine, ASST Spedali Civili, Brescia, Italy.

Aicardi-Goutières syndrome (AGS) is an early-onset monogenic encephalopathy characterized by intracranial calcification, leukodystrophy and cerebrospinal fluid lymphocytosis. To date, seven genes have been related to AGS. Among these, IFIH1 encodes for MDA5, a cytosolic double-stranded RNA receptor, and is responsible for AGS type 7. We generated three isogenic iPSC clones, using a Sendai virus-based vector, starting from fibroblasts of a patient carrying a dominant mutation in IFIH1. All lines were characterized for genomic integrity, genetic uniqueness, pluripotency, and differentiation capability. Our clones might offer a good model to investigate AGS7 pathophysiological mechanism and to discover new biomarkers for this condition treatment.
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http://dx.doi.org/10.1016/j.scr.2019.101623DOI Listing
December 2019

Incontinentia Pigmenti Associated with Aplasia Cutis Congenita in a Newborn Male with Klinefelter Syndrome: Is the Severity of Neurological Involvement Linked to Skin Manifestations?

Dermatol Ther (Heidelb) 2020 Feb 6;10(1):213-220. Epub 2019 Nov 6.

Dermatologic Clinic, Department of Medicine and Aging Science, Università degli Studi "G. d'Annunzio" Chieti-Pescara, Chieti, Italy.

We report a rare case of a newborn male affected by incontinentia pigmenti, Klinefelter syndrome, and aplasia cutis congenita, who developed severe cutaneous, neurological, and ophthalmological manifestations. Genetic analysis showed the presence of the common mutation of NEMO (exon 4-10 deletion), Klinefelter syndrome karyotype (47 XXY), and random X inactivation. This is in accordance with the severity of involvement of the affected tissues (skin, central nervous system, and retina). Indeed, the patient developed typical skin lesions all over the body, except the head. Equally, multiple lesions diffusely involving both the cortical grey matter and subcortical white matter of the cerebellum and cerebral hemispheres were observed. Discussing current knowledge about the etiopathogenesis of skin and brain lesions in incontinentia pigmenti, our case seems to support the proapoptotic origin of central nervous system involvement. Possibly, incontinentia pigmenti patients suffer an impaired protection against apoptosis at the level of cerebral endothelial cells of small vessels, leading to vascular damage and subsequent ischemic brain lesions.
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http://dx.doi.org/10.1007/s13555-019-00336-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6994639PMC
February 2020

Establishment of three iPSC lines from fibroblasts of a patient with Aicardi Goutières syndrome mutated in RNaseH2B.

Stem Cell Res 2019 12 22;41:101620. Epub 2019 Oct 22.

Department of Molecular and Translational Medicine, University of Brescia, Brescia, Italy; Angelo Nocivelli Institute for Molecular Medicine, ASST Spedali Civili, Brescia, Italy.

We report the generation of three isogenic iPSC clones (UNIBSi007-A, UNIBSi007-B, and UNIBSi007-C) obtained from fibroblasts of a patient with Aicardi Goutières Syndrome (AGS) carrying a homozygous mutation in RNaseH2B. Cells were transduced using a Sendai virus based system, delivering the human OCT4, SOX2, c-MYC and KLF4 transcription factors. The resulting transgene-free iPSC lines retained the disease-causing DNA mutation, showed normal karyotype, expressed pluripotent markers and could differentiate in vitro toward cells of the three embryonic germ layers.
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http://dx.doi.org/10.1016/j.scr.2019.101620DOI Listing
December 2019

Generation of three iPSC lines from fibroblasts of a patient with Aicardi Goutières Syndrome mutated in TREX1.

Stem Cell Res 2019 12 14;41:101580. Epub 2019 Sep 14.

"Angelo Nocivelli" Institute for Molecular Medicine, Department of Molecular and Translational Medicine, University of Brescia, Italy, ASST Spedali Civili, Brescia, Italy.

Fibroblasts from a patient with Aicardi Goutières Syndrome (AGS) carrying a compound heterozygous mutation in TREX1, were reprogrammed into induced pluripotent stem cells (iPSCs) to establish isogenic clonal stem cell lines: UNIBSi006-A, UNIBSi006-B, and UNIBSi006-C. Cells were transduced using the episomal Sendai viral vectors, containing human OCT4, SOX2, c-MYC and KLF4 transcription factors. The transgene-free iPSC lines showed normal karyotype, expressed pluripotent markers and displayed in vitro differentiation potential toward cells of the three embryonic germ layers.
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http://dx.doi.org/10.1016/j.scr.2019.101580DOI Listing
December 2019