Publications by authors named "Jessica Galli"

37 Publications

Neurodevelopmental Profile in Children Affected by Ocular Albinism.

Neuropediatrics 2021 Jul 29. Epub 2021 Jul 29.

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

Aim:  The aim of this study was to detail the neurodevelopmental profile of subjects affected by ocular albinism (OA) and to collect data on GPR143 gene analysis.

Design:  The design of the study involves a retrospective longitudinal observational case series.

Methods:  We collected data on the neurodevelopmental profile of 13 children affected by OA from clinical annual assessments conducted for a period of 6 years after the first evaluation. We described visual profile, neuromotor development and neurological examination, cognitive profile, communication and language skills and behavioral characteristics. The GPR143 gene analysis was performed as well.

Results:  Children presented a variable combination of ocular and oculomotor disorders unchanged during the follow-up, a deficit in visual acuity and in contrast sensitivity that progressively improved. Abnormalities in pattern visual evoked potential were found. No deficits were detected at neurological examination and neuromotor development except for a mild impairment in hand-eye coordination observed in five cases. A language delay was observed in five cases, two of whom had also a developmental quotient delay at 2 years evolving to a borderline/deficit cognitive level at preschool age, difficulties in adaptive behavior and autistic-like features were found. Mutations in the GPR143 gene were identified in the two patients who presented the most severe clinical phenotype.

Conclusion:  Children with OA may share, in addition to a variable combination of ocular signs and symptoms, a neurodevelopment impairment regarding mostly the cognitive, communicative, and social area, especially those with GPR143 mutation.
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http://dx.doi.org/10.1055/s-0041-1732430DOI Listing
July 2021

Social cognition in individuals born preterm.

Sci Rep 2021 07 14;11(1):14448. Epub 2021 Jul 14.

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

Faces hold a substantial value for effective social interactions and sharing. Covering faces with masks, due to COVID-19 regulations, may lead to difficulties in using social signals, in particular, in individuals with neurodevelopmental conditions. Daily-life social participation of individuals who were born preterm is of immense importance for their quality of life. Here we examined face tuning in individuals (aged 12.79 ± 1.89 years) who were born preterm and exhibited signs of periventricular leukomalacia (PVL), a dominant form of brain injury in preterm birth survivors. For assessing the face sensitivity in this population, we implemented a recently developed experimental tool, a set of Face-n-Food images bordering on the style of Giuseppe Arcimboldo. The key benefit of these images is that single components do not trigger face processing. Although a coarse face schema is thought to be hardwired in the brain, former preterms exhibit substantial shortages in the face tuning not only compared with typically developing controls but also with individuals with autistic spectrum disorders. The lack of correlations between the face sensitivity and other cognitive abilities indicates that these deficits are domain-specific. This underscores impact of preterm birth sequelae for social functioning at large. Comparison of the findings with data in individuals with other neurodevelopmental and neuropsychiatric conditions provides novel insights into the origins of deficient face processing.
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http://dx.doi.org/10.1038/s41598-021-93709-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8280144PMC
July 2021

Promoting Language Skills in Children With Neuromotor and Intellectual Disorders: Telepractice at the Time of SARS-CoV-2.

Am J Speech Lang Pathol 2021 07 7;30(4):1866-1879. Epub 2021 Jul 7.

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

Purpose The aim of this pilot study is to gather preliminary results on the effectiveness of intensive, parent-oriented, telepractice-based intervention to improve language skills in preschool children with neuromotor and intellectual disorders. Method Nine preschool children ( = 63 months, = 8.7 months) underwent a telepractice program 4 times a week designed to promote speech, lexical, and syntactic skills. Families were remotely connected from home with the therapists, who controlled the rehabilitation procedures from the hospital. The number of stable phonemes, of understood and repeated words, and of understood and repeated sentences were evaluated as outcome measures 3 months (prebaseline) and 1 week (baseline) before the intervention, immediately after the intervention (T1) and at a 3-month follow-up (T2). Results An increase in the number of stable phonemes was detected after the treatment, even if it was not statistically significant. After the intervention program, there was a significant increase in the number of understood words (ratio T1 vs. baseline: 1.33; 95% CI [1.03, 1.71]) and repeated words (ratio T1 vs. baseline: 1.39; 95% CI [1.00, 1.92]), as well as of understood sentences (ratio T1 vs. baseline: 1.80; 95% CI [1.24, 2.35]) and repeated sentences (ratio T1 vs. baseline: 4.23; 95% CI [1.96, 9.12]). No significant differences were found when comparing all the outcome measures at prebaseline and at baseline. Conclusion An intensive, parent-oriented, telepractice-based intervention has the potential to increase scores of lexical and syntactic tasks in children with neuromotor and intellectual disorders.
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http://dx.doi.org/10.1044/2021_AJSLP-20-00222DOI Listing
July 2021

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 Nov 23;42(11):4543-4550. 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
November 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

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

Pediatr Neurol 2021 02 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

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 REHABILITATIONTele-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

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

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

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

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

Department of Allergy/Immunology, Spectrum Health Helen Devos Children's Hospital, Michigan State University College of Human Medicine, East Lansing, Michigan.

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

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

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

Developmental Outcomes of Aicardi Goutières Syndrome.

J Child Neurol 2020 01 27;35(1):7-16. Epub 2019 Sep 27.

Division of Neurology, Children's Hospital of Philadelphia, Philadelphia, PA, USA.

Aicardi Goutières syndrome is a monogenic interferonopathy caused by abnormalities in the intracellular nucleic acid sensing machinery (, , , , , , or ). Most individuals affected by Aicardi Goutières syndrome exhibit some degree of neurologic impairment, from spastic paraparesis with relatively preserved cognition to tetraparesis and severe intellectual disability. Because of this heterogeneity, it is important to fully characterize the developmental trajectory in Aicardi Goutières syndrome. To characterize the clinical presentation in Aicardi Goutières syndrome, early features were collected from an international cohort of children (n = 100) with genetically confirmed Aicardi Goutières syndrome. There was a heterogeneous age of onset, with overlapping clusters of presenting symptoms: altered mental status, systemic inflammatory symptoms, and acute neurologic disability. Next, we created genotype-specific developmental milestone acquisition curves. Individuals with microcephaly or related Aicardi Goutières syndrome secondary were the most severely affected and less likely to reach milestones, including head control, sitting, and nonspecific mama/dada. Individuals affected by , , and attained the most advanced milestones, with 44% achieving verbal communication and 31% independently ambulating. Retrospective function scales (Gross Motor Function Classification System, Manual Ability Classification System, and Communication Function Classification System) demonstrated that two-thirds of the Aicardi Goutières syndrome population are severely affected. Our results suggest multifactorial influences on developmental trajectory, including a strong contribution from genotype. Further studies are needed to identify the additional factors that influence overall outcomes to better counsel families and to design clinical trials with appropriate clinical endpoints.
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http://dx.doi.org/10.1177/0883073819870944DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7402202PMC
January 2020

Autism in Children With Cerebral and Peripheral Visual Impairment: Fact or Artifact?

Semin Pediatr Neurol 2019 10 11;31:57-67. Epub 2019 May 11.

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

The aim of this study was to evaluate the occurrence and clinical characteristics of autism spectrum disorder in visually impaired children. In total, 273 participants, 214 with cerebral causes of vision impairment and 59 with peripheral causes, were assessed using multiple assessment methods and adapted for individuals with vision loss. We found that autism spectrum disorder was more prevalent in the visually impaired compared to general population, and that the prevalence varied according to the type of visual disorder (2.8% for cerebral and 8.4% for peripheral visual impairment). In subjects with cerebral visual impairment, the presence of autistic symptoms was consistent with the diagnosis of autism spectrum disorder. In children with peripheral visual impairment, certain symptoms related to visual loss overlapped with the clinical features of autism spectrum disorder, thus making clinical diagnosis more challenging. The development of assessment tools that take into account the type and level of visual impairment and validation testing in a larger population sample are needed in order to confirm these initial findings regarding the diagnosis of autism spectrum disorder in visually impaired children.
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http://dx.doi.org/10.1016/j.spen.2019.05.008DOI Listing
October 2019

Molecular Genetics and Interferon Signature in the Italian Aicardi Goutières Syndrome Cohort: Report of 12 New Cases and Literature Review.

J Clin Med 2019 05 26;8(5). Epub 2019 May 26.

Molecular medicine, IRCCS Fondazione Stella Maris, 56128 Pisa, Italy.

Aicardi-Goutières syndrome (AGS) is a genetically determined early onset encephalopathy characterized by cerebral calcification, leukodystrophy, and increased expression of interferon-stimulated genes (ISGs). Up to now, seven genes () have been associated with an AGS phenotype. Next Generation Sequencing (NGS) analysis was performed on 51 AGS patients and interferon signature (IS) was investigated in 18 AGS patients and 31 healthy controls. NGS identified mutations in 48 of 51 subjects, with three patients demonstrating a typical AGS phenotype but not carrying mutations in known AGS-related genes. Five mutations, in , and gene, were not previously reported. Eleven patients were positive and seven negatives for the upregulation of interferon signaling (IS > 2.216). This work presents, for the first time, the genetic data of an Italian cohort of AGS patients, with a higher percentage of mutations in and a lower frequency of mutations in than those seen in international series. mutated patients showed a prevalence of negative IS consistent with data reported in the literature. We also identified five novel pathogenic mutations that warrant further functional investigation. Exome/genome sequencing will be performed in future studies in patients without a mutation in AGS-related genes.
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http://dx.doi.org/10.3390/jcm8050750DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6572054PMC
May 2019

Cerebellar involvement in warts Hypogammaglobulinemia immunodeficiency myelokathexis patients: neuroimaging and clinical findings.

Orphanet J Rare Dis 2019 02 28;14(1):61. Epub 2019 Feb 28.

Clinical and Experimental Sciences Department, University of Brescia, c/o ASST Spedali Civili, 25123, Brescia, Italy.

Background: Warts Hypogammaglobulinemia Immunodeficiency Myelokathexis (WHIM) syndrome is a primary immunodeficiency characterized by recurrent bacterial infections, severe chronic neutropenia, with lymphopenia, monocytopenia and myelokathexis which is caused by heterozygous gain of functions mutations of the CXC chemokine receptor 4 (CXCR4). WHIM patients display an increased incidence of non-hematopoietic conditions, such as congenital heart disease suggesting that abnormal CXCR4 may put these patients at increased risk of congenital anomalies. Studies conducted on CXCR4 and SDF-1-deficient mice have demonstrated the role of CXCR4 signaling in neuronal cell migration and brain development. In particular, CXCR4 conditional knockout mice display abnormal cerebellar morphology and poor coordination and balance on motor testing.

Results: In order to evaluate a possible neurological involvement in WHIM syndrome subjects, we performed neurological examination, including International Cooperative Ataxia Rating Scale, cognitive and psychopathological assessment and brain Magnetic Resonance Imaging (MRI) in 6 WHIM patients (age range 8-51 years) with typical gain of functions mutations of CXCR4 (R334X or G336X). In three cases (P3, P5, P6) neurological evaluation revealed fine and global motor coordination disorders, balance disturbances, mild limb ataxia and excessive talkativeness. Brain MRI showed an abnormal orientation of the cerebellar folia involving bilaterally the gracilis and biventer lobules together with the tonsils in four subjects (P3, P4, P5, P6). The neuropsychiatric evaluation showed increased risk of internalizing and/or externalizing problems in four patients (P2, P3, P4, P6).

Conclusions: Taken together, these observations suggest CXCR4 gain of function mutations can be associated with cerebellar malformation, mild neuromotor and psychopathological dysfunction in WHIM patients.
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http://dx.doi.org/10.1186/s13023-019-1030-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6396443PMC
February 2019

Social Cognition in Down Syndrome: Face Tuning in Face-Like Non-Face Images.

Front Psychol 2018 18;9:2583. Epub 2018 Dec 18.

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

Individuals with Down syndrome (DS) are widely believed to possess considerable socialization strengths. However, the findings on social cognition capabilities are controversial. In the present study, we investigated whether individuals with DS exhibit shortage in face tuning, one of the indispensable components of social cognition. For this purpose, we implemented a recently developed Face-n-Food paradigm with food-plate images composed of food ingredients such as fruits and vegetables. The key benefit of such face-like non-face images is that single elements do not facilitate face processing. In a spontaneous recognition task, 25 children with DS aged 9 to 18 years were presented with a set of Face-n-Food images bordering on the Giuseppe Arcimboldo style. The set of images was administered in a predetermined order from the least to most resembling a face. In DS individuals, thresholds for recognition of the Face-n-Food images as a face were drastically higher as compared not only with typically developing controls, but also with individuals with autistic spectrum disorders and Williams-Beuren syndrome. This outcome represents a significant step toward better conceptualization of the visual social world in DS and neurodevelopmental disorders in general.
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http://dx.doi.org/10.3389/fpsyg.2018.02583DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6305370PMC
December 2018

Sine causa tetraparesis: A pilot study on its possible relationship with interferon signature analysis and Aicardi Goutières syndrome related genes analysis.

Medicine (Baltimore) 2018 Dec;97(52):e13893

Department of Clinical and Experimental Sciences, University of Brescia.

Tetraparesis is usually due to cerebral palsy (CP), inborn errors of metabolism, neurogenetic disorders and spinal cord lesions. However, literature data reported that about 10% of children with tetraparesis show a negative/non-specific neuroradiological findings without a specific etiological cause. Aicardi Goutières Syndrome (AGS) is a genetic encephalopathy that may cause tetraparesis. Interferon signature is a reliable biomarker for AGS and could be performed in sine-causa tetraparesis. The aim of the study was to examine the type I interferon signature and AGS related-genes in children with sine causa tetraparesis, to look for misdiagnosed AGS. A secondary aim was to determine which aspects of the patient history, clinical picture and brain imaging best characterize tetraparesis due to an interferonopathy.Seven out of 78 patients affected by tetraparesis, characterized by unremarkable pre-peri-postnatal history and normal/non-specific brain magnetic resonance imaging (MRI) were selected and underwent anamnestic data collection, clinical examination, brain imaging review, peripheral blood interferon signature and AGS-related genes analysis.At our evaluation time (mean age of 11.9 years), all the 7 patients showed spastic-dystonic tetraparesis. At clinical onset brain MRI was normal in 4 and with non-specific abnormalities in 3; at follow-up 3 patients presented with new white-matter lesions, associated with brain calcification in 1 case. Interferon signature was elevated in one subject who presented also a mutation of the IFIH1 gene.AGS should be considered in sine-causa tetraparesis. Core features of interferonopathy-related tetraparesis are: onset during first year of life, psychomotor regression with tetraparesis evolution, brain white-matter lesions with late calcifications. A positive interferon signature may be a helpful marker to select patients with spastic tetraparesis who should undergo genetic analysis for AGS.
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http://dx.doi.org/10.1097/MD.0000000000013893DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6314769PMC
December 2018

Action Observation Treatment Improves Upper Limb Motor Functions in Children with Cerebral Palsy: A Combined Clinical and Brain Imaging Study.

Neural Plast 2018 4;2018:4843985. Epub 2018 Jul 4.

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

The aim of the present study was to assess the role of action observation treatment (AOT) in the rehabilitation of upper limb motor functions in children with cerebral palsy. We carried out a two-group, parallel randomized controlled trial. Eighteen children (aged 5-11 yr) entered the study: 11 were treated children, and 7 served as controls. Outcome measures were scores on two functional scales: Melbourne Assessment of Unilateral Upper Limb Function Scale (MUUL) and the Assisting Hand Assessment (AHA). We collected functional scores before treatment (T1), at the end of treatment (T2), and at two months of follow-up (T3). As compared to controls, treated children improved significantly in both scales at T2 and this improvement persisted at T3. AOT has therefore the potential to become a routine rehabilitation practice in children with CP. Twelve out of 18 enrolled children also underwent a functional magnetic resonance study at T1 and T2. As compared to controls, at T2, treated children showed stronger activation in a parieto-premotor circuit for hand-object interactions. These findings support the notion that AOT contributes to reorganize brain circuits subserving the impaired function rather than activating supplementary or vicariating ones.
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http://dx.doi.org/10.1155/2018/4843985DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6079352PMC
November 2018

Music reduces pain perception in healthy newborns: A comparison between different music tracks and recoded heartbeat.

Early Hum Dev 2018 09 2;124:7-10. Epub 2018 Aug 2.

Child and Adolescent Neurology and Psychiatry Unit, Children Hospital, ASST Spedali Civili of Brescia, Brescia, Italy; Department of Clinical and Experimental Sciences, University of Brescia, Brescia, Italy.

Objectives: To assess the effect of 3 musical interventions, as compared to no music, on the physiological response of healthy newborns undergoing painful medical procedures (Guthrie test and/or intramuscular antibiotic injections).

Methods: Prospective study of 80 full-term newborns, aged 1 to 3 days, randomly allocated to exposure to Mozart's Sonata for two pianos K.448, Beethoven's Moonlight Sonata, heartbeat sound recordings (70 bpm) or no music. Pain perception (evaluated using the Neonatal Infant Pain Scale), heart rate and oxygen saturation were measured 10 min before (T0), during (T1), 10 (T2) and 20 (T3) minutes after the interventions.

Results: Infants who were exposed to the three music interventions displayed a significant reduction in heart rate and in pain perception and an increase in oxygen saturation, as compared to the control group, which showed less modifications on stress measurements after painful medical procedures (F = 6.40, p = .001, partial η = 0.20).

Conclusions: Exposure to music and heartbeat sound recordings changes short-term physiological parameters in healthy newborns undergoing potentially painful procedures. The similar effect shown by the 3 interventions might be explained by the common characteristics of the sound shared by the various tracks. Further research is needed to investigate the impact of different types of music used in intervention, in order to develop guidelines and include music as a part of evidence-based strategies to promote the outcome for neonates.
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http://dx.doi.org/10.1016/j.earlhumdev.2018.07.006DOI Listing
September 2018

Childhood Absence Epilepsy evolving to Eyelid Myoclonia with Absence Epilepsy.

Seizure 2018 Oct 18;61:1-3. Epub 2018 Jul 18.

Child Neurology and Psychiatry Unit, ASST Civil Hospital -Brescia, Italy. Electronic address:

Purpose: Children with Childhood Absence Epilepsy (CAE) may develop generalized tonic-clonic seizure or juvenile myoclonic epilepsy. A possible evolution to Eyelid Myoclonia with Absence Epilepsy (EMA) hasn't been documented yet. We report the electroclinical features of a case series of children with CAE that evolved to EMA after therapy withdrawal.

Method: Of 108 patients with CAE referred at our Epilepsy Center in the last ten years, 5 satisfied the inclusion criteria: CAE diagnosis, a minimum of 3 years follow-up, a progression to EMA after therapy withdrawal.

Results: All the six subjects were females. CAE was characterized by typical absences induced by hyperventilation; intermittent photic stimulation (IPS) was negative. All subjects were treated successfully with valproate. After drug withdrawal, all the six girls presented EMA. EMA was characterized by eyelid myoclonia with or without brief absences related to generalized spike/polyspike-waves discharges induced by IPS and less frequently by eye-closure.

Conclusions: Our study documented another possible evolution of CAE into EMA. These results support the hypothesis that these two epileptic conditions are dynamic processes evolving into one another. CAE and EMA could be considered "system epilepsy" characterized by a high susceptibility to changes in the brain networks during specific life periods such as childhood and puberty.
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http://dx.doi.org/10.1016/j.seizure.2018.07.009DOI Listing
October 2018

White matter changes associated with cognitive visual dysfunctions in children with cerebral palsy: A diffusion tensor imaging study.

J Neurosci Res 2018 11 12;96(11):1766-1774. Epub 2018 Jun 12.

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

Children with cerebral palsy often present with cognitive-visual dysfunctions characterized by visuo-perceptual and/or visuo-spatial deficits associated with a malfunctioning of visual-associative areas. The neurofunctional model of this condition remains poorly understood due to the lack of a clear correlation between cognitive-visual deficit and morphological brain anomalies. The aim of our study was to quantify the pattern of white matter abnormalities within the whole brain in children with cerebral palsy, and to identify white matter tracts sub-serving cognitive-visual functions, in order to better understand the basis of cognitive-visual processing. Nine subjects (three males, mean age 8 years 9 months) with cerebral palsy underwent a visual and cognitive-visual evaluation. Conventional brain MRI and diffusion tensor imaging were performed. The fractional anisotropy maps were calculated for every child and compared with data from 13 (four males, mean age 10 years 7 months) healthy children. Children with cerebral palsy showed decreased fractional anisotropy (a marker of white matter integrity) in corticospinal tract bilaterally, left superior longitudinal fasciculus and bilateral hippocampus. Focusing on the superior longitudinal fasciculus, the mean fractional anisotropy values were significantly lower in children affected by cerebral palsy with cognitive-visual deficits than in those without cognitive-visual deficits. Our findings reveal an association between cognitive-visual profile and the superior longitudinal fasciculus integrity in children with cerebral palsy, supporting the hypothesis that visuo-associative deficits are related to changes in fibers connecting the occipital cortex with the parietal-frontal cortices. Decreased fractional anisotropy within the superior longitudinal fasciculus could be considered a biomarker for cognitive-visual dysfunctions.
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http://dx.doi.org/10.1002/jnr.24307DOI Listing
November 2018

Neurovisual Assessment in Children with Ataxia Telangiectasia.

Neuropediatrics 2018 02 9;49(1):26-34. Epub 2017 Oct 9.

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

Aim: Visual impairment is present in almost all patients with ataxia telangiectasia (AT) and, due to their early onset, constitute an important disabling aspect of the syndrome: the quality of vision is limited by dyspraxia and oculomotor abnormal movements. The purpose of this observational study was to describe visual disorders, notably oculomotor impairment, in a sample of children with AT.

Methods: Fifteen AT patients (mean age 12 years and 4 months) underwent a neurovisual evaluation, particularly focused on oculomotor functions (fixation, smooth pursuit, saccades, and abnormal ocular movements). We compared the visual profile obtained with that described using the International Cooperative Ataxia Rating Scale (ICARS) subscale of oculomotor dysfunction.

Results: Refractive errors were seen in eight patients and strabismus in three. Major oculomotor findings were fixation abnormalities (6/15), saccadic impairment (15/15), and abnormal smooth pursuit (14/15). Abnormal ocular movements were seen in 13/15 (saccadic intrusion in 8 and nystagmus in 5). Using ICARS scale, 13/15 children presented gaze-evoked nystagmus, 4/15 a clearly saccadic pursuit, and 11/15 dysmetria of saccades.

Discussion: We propose a clinical neurovisual evaluation, which could be integrated with ICARS scores in the study of oculomotor involvement in AT pediatric patients. We strongly recommend the empowerment of visual functions to slow down progressive global disability of these patients.
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http://dx.doi.org/10.1055/s-0037-1607216DOI Listing
February 2018
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