Publications by authors named "Aglaia Vignoli"

90 Publications

Sleep and behavior in children and adolescents with tuberous sclerosis complex.

Am J Med Genet A 2021 Mar 1. Epub 2021 Mar 1.

Epilepsy Center-Sleep Medicine Center, Childhood and Adolescence Neuropsychiatry Unit, ASST SS. Paolo e Carlo, San Paolo Hospital, Milan, Italy.

Sleep disorders are frequent in tuberous sclerosis complex (TSC) during the developmental age but are not well characterized. Forty-six TSC patients and 46 healthy age- and sex-matched controls were enrolled. Their parents completed the Sleep Disturbances Scale for Children (SDSC) and the Child Behavior Checklist (CBCL). A total of 17.4% of the TSC patients obtained a total pathologic score at the SDSC versus 4.4% in the control group (p = 0.024). 45.7% of individuals with TSC reported a pathologic score in at least one of the factors. We found a statistically significant difference between the TSC cohort and healthy controls for most of the CBCL scales scores. A significant relationship was found between the Total SDSC score and the Total CBCL score (R-square = 0.387, p < 0.0001), between the Total SDSC score and the Internalizing and Externalizing areas scores (R-square = 0.291, p < 0.0001 and R-square = 0.350, p < 0.0001, respectively) of the CBCL. Sleep disorders are more frequent in TSC than in the general population and correlate with behavior. The use of SDSC and CBCL is proposed as part of the surveillance of TSC patients in the developmental age.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/ajmg.a.62123DOI Listing
March 2021

In vivo magnetic resonance spectroscopy in the brain of Cdkl5 null mice reveals a metabolic profile indicative of mitochondrial dysfunctions.

J Neurochem 2021 Jan 15. Epub 2021 Jan 15.

Department of Medical Biotechnology and Translational Medicine, University of Milan, Segrate (Milan), Italy.

Mutations in the X-linked CDKL5 gene cause CDKL5 deficiency disorder (CDD), a severe neurodevelopmental condition mainly characterized by infantile epileptic encephalopathy, intellectual disability, and autistic features. The molecular mechanisms underlying the clinical symptoms remain largely unknown and the identification of reliable biomarkers in animal models will certainly contribute to increase our comprehension of CDD as well as to assess the efficacy of therapeutic strategies. Here, we used different Magnetic Resonance (MR) methods to disclose structural, functional, or metabolic signatures of Cdkl5 deficiency in the brain of adult mice. We found that loss of Cdkl5 does not cause cerebral atrophy but affects distinct brain areas, particularly the hippocampus. By in vivo proton-MR spectroscopy (MRS), we revealed in the Cdkl5 null brain a metabolic dysregulation indicative of mitochondrial dysfunctions. Accordingly, we unveiled a significant reduction in ATP levels and a decrease in the expression of complex IV of mitochondrial electron transport chain. Conversely, the number of mitochondria appeared preserved. Importantly, we reported a significant defect in the activation of one of the major regulators of cellular energy balance, the adenosine monophosphate-activated protein kinase (AMPK), that might contribute to the observed metabolic impairment and become an interesting therapeutic target for future preclinical trials. In conclusion, MRS revealed in the Cdkl5 null brain the presence of a metabolic dysregulation suggestive of a mitochondrial dysfunction that permitted to foster our comprehension of Cdkl5 deficiency and brought our interest towards targeting mitochondria as therapeutic strategy for CDD.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/jnc.15300DOI Listing
January 2021

Ring Chromosome 20 Syndrome: Genetics, Clinical Characteristics, and Overlapping Phenotypes.

Front Neurol 2020 8;11:613035. Epub 2020 Dec 8.

Child Neuropsychiatry Unit - Epilepsy Center, Department of Health Sciences, ASST Santi Paolo e Carlo, San Paolo Hospital, Università Degli Studi di Milano, Milan, Italy.

Ring chromosome 20 [r(20)] syndrome is a rare condition characterized by a non-supernumerary ring chromosome 20 replacing a normal chromosome 20. It is commonly seen in a mosaic state and is diagnosed by means of karyotyping. r(20) syndrome is characterized by a recognizable epileptic phenotype with typical EEG pattern, intellectual disability manifesting after seizure onset in otherwise normally developing children, and behavioral changes. Despite the distinctive phenotype, many patients still lack a diagnosis-especially in the genomic era-and the pathomechanisms of ring formation are poorly understood. In this review we address the genetic and clinical aspects of r(20) syndrome, and discuss differential diagnoses and overlapping phenotypes, providing the reader with useful tools for clinical and laboratory practice. We also discuss the current issues in understanding the mechanisms through which ring 20 chromosome causes the typical manifestations, and present unpublished data about methylation studies. Ultimately, we explore future perspectives of r(20) research. Our intended audience is clinical and laboratory geneticists, child and adult neurologists, and genetic counselors.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3389/fneur.2020.613035DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7753021PMC
December 2020

Basal Ganglia Dysmorphism in Patients With Aicardi Syndrome.

Neurology 2021 Mar 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.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1212/WNL.0000000000011237DOI Listing
March 2021

Phenotypes in adult patients with Rett syndrome: results of a 13-year experience and insights into healthcare transition.

J Med Genet 2020 Oct 26. Epub 2020 Oct 26.

Department of Health Sciences, Università degli Studi di Milano, Milano, Lombardia, Italy.

Background: Rett syndrome is a complex genetic disorder with age-specific manifestations and over half of the patients surviving into middle age. However, little information about the phenotype of adult individuals with Rett syndrome is available, and mainly relies on questionnaires completed by caregivers. Here, we assess the clinical manifestations and management of adult patients with Rett syndrome and present our experience in transitioning from the paediatric to the adult clinic.

Methods: We analysed the medical records and molecular data of women aged ≥18 years with a diagnosis of classic Rett syndrome and/or pathogenic variants in , and , who were in charge of our clinic.

Results: Of the 50 women with classic Rett syndrome, 94% had epilepsy (26% drug-resistant), 20% showed extrapyramidal signs, 40% sleep problems and 36% behavioural disorders. Eighty-six % patients exhibited gastrointestinal problems; 70% had scoliosis and 90% low bone density. Breathing irregularities were diagnosed in 60%. None of the patients had cardiac issues. CDKL5 patients experienced fewer breathing abnormalities than women with classic Rett syndrome.

Conclusion: The delineation of an adult phenotype in Rett syndrome demonstrates the importance of a transitional programme and the need of a dedicated multidisciplinary team to optimise the clinical management of these patients.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1136/jmedgenet-2020-107333DOI Listing
October 2020

De novo ARHGEF9 missense variants associated with neurodevelopmental disorder in females: expanding the genotypic and phenotypic spectrum of ARHGEF9 disease in females.

Neurogenetics 2020 Sep 17. Epub 2020 Sep 17.

Pediatric Neurology and Muscular Diseases Unit, IRCCS Istituto Giannina Gaslini, Genoa, Italy.

Individuals harboring pathogenic variants in ARHGEF9, encoding an essential submembrane protein for gamma-aminobutyric acid (GABA)-ergic synapses named collybistin, show intellectual disability (ID), facial dysmorphism, behavioral disorders, and epilepsy. Only few affected females carrying large chromosomal rearrangements involving ARHGEF9 have been reported so far. Through next-generation sequencing (NGS)-based panels, we identified two single nucleotide variants (SNVs) in ARHGEF9 in two females with neurodevelopmental features. Sanger sequencing revealed that these variants were de novo. The X-inactivation pattern in peripheral blood cells was random. We report the first affected females harboring de novo SNVs in ARHGEF9, expanding the genotypic and phenotypic spectrum of ARHGEF9-related neurodevelopmental disorder in females.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s10048-020-00622-5DOI Listing
September 2020

The TAND checklist: a useful screening tool in children with tuberous sclerosis and neurofibromatosis type 1.

Orphanet J Rare Dis 2020 09 7;15(1):237. Epub 2020 Sep 7.

Epilepsy Center- Child Neuropsychiatry Unit, ASST Santi Paolo Carlo, Department of Health Sciences, University of Milan, Via di Rudinì 8, 20142, Milan, Italy.

Background: Tuberous Sclerosis Complex (TSC) and Neurofibromatosis type 1 (NF1) are neurocutaneous disorders commonly characterized by neuropsychiatric comorbidities. The TAND (Tuberous Sclerosis Associated Neuropsychiatric Disorders) Checklist is currently used to quickly screen for behavioural, psychiatric, intellectual, academic, neuropsychological and psychosocial manifestations in patients with TSC. We administered the authorized Italian version of the TAND Checklist to the parents of 42 TSC patients and 42 age- and sex-matched NF1 patients, for a total of 84 individuals, aged 4-20 years. Aims of this study: - to test the overall usability of the TAND Checklist in NF1, -to compare the results between children and adolescents with TSC and NF1, and -to examine the association between neuropsychiatric manifestations and severity of the phenotype in terms of epilepsy severity in the TSC cohort and disease severity according to the modified version of the Riccardi severity scale in the NF1 cohort.

Results: TSC cohort: 35.6% had Intellectual Disability (ID), 11.9% Specific Learning Disorders (SLD), 50.0% Attention Deficit Hyperactivity Disorder (ADHD) and 16.6% anxious/mood disorder. 33.3% had a formal diagnosis of Autism Spectrum Disorder (ASD). Paying attention and concentrating (61.9%), impulsivity (54.8%), temper tantrums (54.8%), anxiety (45.2%), overactivity/hyperactivity (40.5%), aggressive outburst (40.5%), absent or delayed onset of language (40.5%), repetitive behaviors (35.7%), academic difficulties (> 40%), deficits in attention (61.9%) and executive skills (50.0%) were the most commonly reported problems. NF1 cohort: 9.5% had ID, 21.4% SLD, 46.6% ADHD, and 33.3% anxious/mood disorder. No one had a diagnosis of ASD. Commonly reported issues were paying attention and concentrating (59.5%), impulsivity (52.4%), anxiety (50.0%), overactivity/hyperactivity (38.1%), temper tantrums (38.1%), academic difficulties (> 40%), deficits in attention (59.5%), and executive skills (38.1%). Neuropsychiatric features in TSC vs NF1: Aggressive outburst and ASD features were reported significantly more frequently in TSC than in NF1. Neuropsychiatric manifestations and phenotype severity: Depressed mood, absent or delayed onset of language, repetitive language, difficulties in relationship with peers, repetitive behaviors, spelling, mathematics, dual-tasking, visuo-spatial tasks, executive skills, and getting disoriented were significantly different among TSC patients with different epilepsy severity. No statistically significant differences in the NF1 subgroups were noted for any of the items in the checklist.

Conclusion: The TAND Checklist used for TSC is acceptable and feasible to complete in a clinical setting, and is able to detect the complexity of neuropsychiatric involvement in NF1 as well. NF1 is mainly characterized by an ADHD profile, anxiety problems and SLD, while ASD features are strongly associated with TSC. In conclusion, the TAND Checklist is a useful and feasible screening tool, in both TSC and NF1.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1186/s13023-020-01488-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7487732PMC
September 2020

Tuberous sclerosis complex (TSC), lymphangioleiomyomatosis, and COVID-19: The experience of a TSC clinic in Italy.

Am J Med Genet A 2020 11 17;182(11):2479-2485. Epub 2020 Aug 17.

Child Neuropsychiatry Unit - Epilepsy Center, ASST Santi Paolo e Carlo, San Paolo Hospital, Department of Health Sciences, Università degli Studi di Milano, Milan, Italy.

Individuals with comorbidities are at higher risk of coronavirus disease 2019 (COVID-19) and worse outcome, but little information has been available about patients with genetic diseases and COVID-19. This study aims at evaluating the presence and outcome of COVID-19 in a cohort of Italian patients with tuberous sclerosis complex (TSC) and/or lymphangioleiomyomatosis (LAM), and at reviewing the possible effects of mTOR inhibitors on SARS-CoV-2 infection. We included 102 unselected individuals with a diagnosis of TSC and/or LAM assessed between January 1, 2020 and April 24, 2020 (29% children, 71% adults). Twenty-six patients were on mTOR inhibitors. Demographic data, TSC manifestations, presence, and outcomes in individuals with confirmed or suspected SARS-CoV-2 infection were evaluated. Health status and outcomes of all patients on mTOR inhibitors were assessed. One patient with severe TSC had polymerase chain reaction (PCR)-confirmed SARS-CoV-2 infection, was admitted to ICU, and died. Nine additional patients either met the definition of suspect case or presented with at least two of the most common symptoms of SARS-CoV-2 infection. All recovered fully. None of the patients treated with mTOR inhibitors for their underlying comorbidities was diagnosed with COVID-19, and those who showed suspicious respiratory symptoms recovered fully. This cohort study provides preliminary information on COVID-19 in people with TSC in Italy and suggests feasibility to systematically evaluate the role of mTOR inhibitors in SARS-CoV-2 infection.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/ajmg.a.61810DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7461282PMC
November 2020

Clinical spectrum and genotype-phenotype correlations in PRRT2 Italian patients.

Eur J Paediatr Neurol 2020 Sep 23;28:193-197. Epub 2020 Jun 23.

Pediatric Neurology and Muscular Diseases Unit, IRCCS "G. Gaslini" Institute, Genova, Italy; Department of Neurosciences, Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health, University of Genoa, Italy.

Prrt2 is a neuron-specific protein expressed at axonal and pre-synaptic domains, involved in synaptic neurotransmitter release and modulation of intrinsic excitability. Mutations in PRRT2 cause a spectrum of autosomal dominant paroxysmal neurological disorders including epilepsy, movement disorders, and hemiplegic migraine and show incomplete penetrance and variable expressivity. We assessed the diagnostic rate of PRRT2 in a cohort of Italian patients with epilepsy and/or paroxysmal kinesigenic dyskinesia (PKD) and evaluated genotype-phenotype correlations. Clinical data were collected using a structured questionnaire. Twenty-seven out of 55 (49.1%) probands carried PRRT2 heterozygous pathogenic variants, including six previously known genotypes and one novel missense mutation. A family history of epilepsy starting in the first year of life and/or PKD was strongly suggestive of a PRRT2 pathogenic variant. Epilepsy patients harbouring PRRT2 pathogenic variants showed earlier seizure onset and more frequent clusters compared with PRRT2-negative individuals with epilepsy. Moreover, we did also identify individuals with PRRT2 pathogenic variants with atypical age at onset, i.e. childhood-onset epilepsy and infantile-onset PKD. However, the lack of a clear correlation between specific PRRT2 genotypes and clinical manifestations and the high incidence of asymptomatic carriers suggest the involvement of additional factors in modulating expressivity of PRRT2-related disorders. Finally, our study supports the pleiotropic and multifaceted physiological role of PRRT2 gene which is emerging from experimental neuroscience.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.ejpn.2020.06.005DOI Listing
September 2020

Effects of Combined Transcranial Direct Current Stimulation with Cognitive Training in Girls with Rett Syndrome.

Brain Sci 2020 May 2;10(5). Epub 2020 May 2.

Department of Clinical and Experimental Medicine, University of Messina, Via Bivona, 98100 Messina, Italy.

Background: Transcranial Direct Current Stimulation (tDCS) combined with traditional rehabilitative techniques has not been widely applied to Rett Syndrome (RTT). The aim of this study was to examine the effects of combined cognitive traditional training with tDCS applied to attention and language measures in subjects with RTT.

Methods: 31 subjects with RTT were randomly allocated into two groups: non-sham tDCS ( = 18) and sham tDCS ( = 13). The former received the integrated intervention non-sham tDCS plus cognitive empowerment during the treatment phase. The latter received sham stimulation plus cognitive empowerment. All participants underwent neurological and cognitive assessment to evaluate attention and language measures: before integrated treatment (pre-test phase), at the conclusion of the treatment (post-test phase), and at 1 month after the conclusion of the treatment (follow-up phase).

Results: the results indicated longer attention time in the non-sham tDCS group compared to the sham tDCS group with a stable trend also in the follow-up phase; an increase of the number of vowel/phoneme sounds in the non-sham tDCS group; and an improvement in the neurophysiological parameters in the non-sham tDCS group.

Conclusions: This study supports the use of tDCS as a promising and alternative approach in the RTT rehabilitation field.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3390/brainsci10050276DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7287589PMC
May 2020

Sleep disturbances in Italian children and adolescents with epilepsy: A questionnaire study.

Epilepsy Behav 2020 05 28;106:107014. Epub 2020 Mar 28.

Epilepsy Center - Sleep Medicine Center, Childhood and Adolescence Neuropsychiatry Unit, ASST SS. Paolo e Carlo, San Paolo Hospital, Milan, Italy; Department of Health Sciences, University of Milan, Italy.

Sleep and epilepsy interact with each other in a complex bidirectional way. The main objective of this study was to characterize and determine the prevalence of sleep and behavioral disorders among Italian children and adolescents with epilepsy. We asked 84 consecutive parents/caregivers of patients with epilepsy aged between 6 and 17 years old to fill out the Sleep Disturbances Scale for Children (SDSC) and Child Behavior Checklist (CBCL). An abnormal total sleep score was found in 20 subjects with epilepsy (23.8%), compared with 4 (4.4%) of control group (P < .001). Forty-eight patients (57.1%) had an abnormal score in at least one SDSC factor: disorders in initiating and maintaining sleep (DIMS; 13.1%), sleep breathing disorders (SBD; 13.1%), disorders of arousal (DA; 5.9%), sleep-wake transition disorders (SWTD; 15.5%), disorders of excessive somnolence (DOES; 20.2%), and sleep hyperhidrosis (SHY; 5.9%). Patients with epilepsy showed higher prevalence of behavioral/emotional disturbances in all CBCL domains but one compared with patients without epilepsy. The SDSC and CBCL total scores showed a significant correlation (R-square = 0.256; P < .001). Sleep and behavioral/emotional disorders are common in epilepsy during childhood and adolescence. The SDSC could be a valid tool to screen sleep disturbances in this group of patients.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.yebeh.2020.107014DOI Listing
May 2020

PIGW-related glycosylphosphatidylinositol deficiency: Description of a new patient and review of the literature.

Am J Med Genet A 2020 06 21;182(6):1477-1482. Epub 2020 Mar 21.

Child Neuropsychiatry Unit-Epilepsy Center, ASST Santi Paolo e Carlo, San Paolo Hospital, Department of Health Sciences, Università degli Studi di Milano, Milan, Italy.

Inherited glycosylphosphatidylinositol (GPI) deficiencies are a group of clinically and genetically heterogeneous conditions belonging to the congenital disorders of glycosylation. PIGW is involved in GPI biosynthesis and modification, and biallelic pathogenic variants in this gene cause autosomal recessive GPI biosynthesis defect 11. Only five patients and two fetuses have been reported in the literature thus far. Here we describe a new patient with a novel homozygous missense variant in PIGW, who presented with hypotonia, severe intellectual disability, early-onset epileptic seizures, brain abnormalities, nystagmus, hand stereotypies, recurrent respiratory infections, distinctive facial features, and hyperphosphatasia. Our report expands the phenotype of GPI biosynthesis defect 11 to include stereotypies and recurrent respiratory infections. A detailed and long-term analysis of the electroclinical characteristics and review of the literature suggest that early-onset epileptic seizures are a key manifestation of GPI biosynthesis defect 11. West syndrome and focal-onset epileptic seizures are the most common seizure types, and the fronto-temporal regions may be the most frequently involved areas in these patients.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/ajmg.a.61555DOI Listing
June 2020

Missense variants in the Arg206 residue of HNRNPH2: Further evidence of causality and expansion of the phenotype.

Am J Med Genet A 2020 04 14;182(4):823-828. Epub 2020 Jan 14.

Child Neuropsychiatry Unit - Epilepsy Center, San Paolo Hospital, Milan, Italy.

Missense variants in HNRNPH2 cause Bain type syndromic X-linked intellectual disability (XLID). To date, only six affected females and three affected males have been reported in the literature, and the phenotype has yet to be delineated in detail. Here, we report on a 35-year-old female with a novel de novo variant in HNRNPH2, providing further evidence that missense changes in the nuclear localization sequence cause Bain type XLID and that aminoacid 206 likely represents a mutational hotspot. We expand the phenotype of Bain type XLID to include breathing, sleep and movement disorders, cerebellar vermis hypoplasia, stereotypies, and hypersensitivity to noise. Our data indicate that the phenotype may be broader and more variable than initially reported, and suggest Rett syndrome as a possible differential diagnosis.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/ajmg.a.61486DOI Listing
April 2020

Mapping the Effect of Interictal Epileptic Activity Density During Wakefulness on Brain Functioning in Focal Childhood Epilepsies With Centrotemporal Spikes.

Front Neurol 2019 19;10:1316. Epub 2019 Dec 19.

Neurology Unit, OCB Hospital, AOU Modena, Modena, Italy.

Childhood epilepsy with centrotemporal spikes (CECTS) is the most common type of "self-limited focal epilepsies." In its typical presentation, CECTS is a condition reflecting non-lesional cortical hyperexcitability of rolandic regions. The benign evolution of this disorder is challenged by the frequent observation of associated neuropsychological deficits and behavioral impairment. The abundance (or frequency) of interictal centrotemporal spikes (CTS) in CECTS is considered a risk factor for deficits in cognition. Herein, we captured the hemodynamic changes triggered by the CTS density measure (i.e., the number of CTS for time bin) obtained in a cohort of CECTS, studied by means of video electroencephalophy/functional MRI during quite wakefulness. We aim to demonstrate a direct influence of the diurnal CTS frequency on epileptogenic and cognitive networks of children with CECTS. A total number of 8,950 CTS (range between 27 and 801) were recorded in 23 CECTS (21 male), with a mean number of 255 CTS/patient and a mean density of CTS/30 s equal to 10,866 ± 11.46. Two independent general linear model models were created for each patient based on the effect of interest: "individual CTS" in model 1 and "CTS density" in model 2. Hemodynamic correlates of CTS density revealed the involvement of a widespread cortical-subcortical network encompassing the sensory-motor cortex, the Broca's area, the premotor cortex, the thalamus, the putamen, and red nucleus, while in the CTS event-related model, changes were limited to blood-oxygen-level-dependent (BOLD) signal increases in the sensory-motor cortices. A linear relationship was observed between the CTS density hemodynamic changes and both disease duration (positive correlation) and age (negative correlation) within the language network and the bilateral insular cortices. Our results strongly support the critical role of the CTS frequency, even during wakefulness, to interfere with the normal functioning of language brain networks.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3389/fneur.2019.01316DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6930928PMC
December 2019

Effects of postpartum depression on the behaviour of children born to mothers with epilepsy.

Seizure 2019 Dec 31;73:31-38. Epub 2019 Oct 31.

Epilepsy Center-Child Neuropsychiatry Unit, ASST Santi Paolo Carlo, San Paolo Hospital, Milan, Italy; Department of Health Sciences, University of Milan, Italy.

Purpose: Postpartum depression (PPD) is a non-psychotic depressive disorder that begins within 4 weeks of childbirth. This study aimed to evaluate the prevalence of PPD by screening mothers with the Edinburgh Postnatal Depression Scale (EPDS), to assess the behavioural outcome of children born to mothers with and without epilepsy and to investigate the relationship between PPD and children's behavioural problems.

Method: We enrolled 80 pregnancies of women with epilepsy, who filled in EPDS after birth, and afterward we asked them to complete the Child Behavior Checklist (CBCL).

Results: 23.8% of patients presented PPD. Children, when the CBCL were completed, had a mean age of 6.05 ± 3.07 years. The CBCL results indicate the occurrence of at least one behavioural issue in 25.0% (20/80) of children. CBCL scores revealed a higher prevalence of behavioural disturbances with regards to the CBCL Total (P = 0.016), internalizing (P = 0.014) and somatic problems (P = 0.048) in patients with PPD vs. patients without PPD. We found an association between mothers' EPDS total score and children's CBCL global score (P = 0.034), internalizing score (P = 0.021), anxiety problems (P = 0.05), affective problems (P = 0.027) and withdrawn/depressed (P = 0.05). We recorded a statistically higher malformation rate in patients with PPD (P = 0.005) compared to the general population.

Conclusions: Children born from mothers with epilepsy have an increased risk for emotional disorders. These findings highlight the importance of screening for emotional distress and providing adequate interventions to children born to women with epilepsy.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.seizure.2019.10.018DOI Listing
December 2019

Rett Syndrome and Other Neurodevelopmental Disorders Share Common Changes in Gut Microbial Community: A Descriptive Review.

Int J Mol Sci 2019 Aug 26;20(17). Epub 2019 Aug 26.

Department of Health Sciences, Università degli Studi di Milano, 20142 Milan, Italy.

In this narrative review, we summarize recent pieces of evidence of the role of microbiota alterations in Rett syndrome (RTT). Neurological problems are prominent features of the syndrome, but the pathogenic mechanisms modulating its severity are still poorly understood. Gut microbiota was recently demonstrated to be altered both in animal models and humans with different neurodevelopmental disorders and/or epilepsy. By investigating gut microbiota in RTT cohorts, a less rich microbial community was identified which was associated with alterations of fecal microbial short-chain fatty acids. These changes were positively correlated with severe clinical outcomes. Indeed, microbial metabolites can play a crucial role both locally and systemically, having dynamic effects on host metabolism and gene expression in many organs. Similar alterations were found in patients with autism and down syndrome as well, suggesting a potential common pathway of gut microbiota involvement in neurodevelopmental disorders.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3390/ijms20174160DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6747313PMC
August 2019

Pathogenic Variants in and in Genes for GABAa Receptor Subunities Cause Atypical Rett/Rett-like Phenotypes.

Int J Mol Sci 2019 Jul 24;20(15). Epub 2019 Jul 24.

Istituto Auxologico Italiano, IRCCS, Cytogenetics and Molecular Genetics Laboratory, 20145 Milan, Italy.

Rett syndrome (RTT) is a neurodevelopmental disorder, affecting 1 in 10,000 girls. Intellectual disability, loss of speech and hand skills with stereotypies, seizures and ataxia are recurrent features. Stringent diagnostic criteria distinguish classical Rett, caused by a pathogenic variant in 95% of cases, from atypical girls, 40-73% carrying variants, and rarely and alterations. A large fraction of atypical and RTT-like patients remain without genetic cause. Next Generation Sequencing (NGS) targeted to multigene panels/Whole Exome Sequencing (WES) in 137 girls suspected for RTT led to the identification of a de novo variant in gene in four atypical RTT and two RTT-like girls. De novo pathogenic variants-one in and, for first time, one in -were disclosed in classic and atypical RTT patients. Interestingly, the variant occurred at low rate percentage in blood and buccal swabs, reinforcing the relevance of mosaicism in neurological disorders. We confirm the role of in atypical RTT/RTT-like patients if early psychomotor delay and epilepsy before 2 years of age are observed, indicating its inclusion in the RTT diagnostic panel. Lastly, we report pathogenic variants in Gamma-aminobutyric acid-A (GABAa) receptors as a cause of atypical/classic RTT phenotype, in accordance with the deregulation of GABAergic pathway observed in defective and models.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3390/ijms20153621DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6696386PMC
July 2019

Cerebellar lesions as potential predictors of neurobehavioural phenotype in tuberous sclerosis complex.

Dev Med Child Neurol 2019 10 16;61(10):1221-1228. Epub 2019 Jul 16.

Neuroradiology Unit, University of Salerno, Salerno, Italy.

Aim: To improve the genetic, clinical, and neuroradiological characterization of cerebellar involvement in tuberous sclerosis complex (TSC) and determine whether cerebellar lesions could be a reliable biomarker of neurological impairment.

Method: This retrospective cohort study, held at two tertiary paediatric university centres, was conducted on patients with a confirmed diagnosis of TSC who underwent brain magnetic resonance imaging between October 2009 and May 2016. The study population consisted of 112 patients with TSC (median age 10y; range 5mo-38y; 61 females, 51 males).

Results: The results from multivariable statistical analysis indicated that cerebellar involvement (34 out of 112 patients, none carrying a TSC1 mutation) was the most powerful predictor of supratentorial cortical tuber load; however, cerebellar involvement was not the best predictor of clinical phenotype when supratentorial tuber load and TSC2 mutations were taken into consideration. The association between cerebellar lesions and a more severe clinical and neuroradiological phenotype was statistically significant and may be due to its strong association with TSC2 mutations and higher cortical tuber load.

Interpretation: Cerebellar involvement is not the best predictor of neurobehavioural outcome, including TSC-related autism, after adjusting for TSC2 and the number of cortical tubers. Its role in the TSC clinical phenotype needs to be investigated further.

What This Paper Adds: Cerebellar involvement is a powerful predictor of supratentorial cortical involvement and a potential biomarker of disease severity. Cerebellar lesions significantly correlate with a more severe clinical and neuroradiological phenotype. Cerebellar involvement is not the best predictor of neurobehavioural outcome.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/dmcn.14313DOI Listing
October 2019

Perinatal distress in 1p36 deletion syndrome can mimic hypoxic ischemic encephalopathy.

Am J Med Genet A 2019 08 17;179(8):1543-1546. Epub 2019 Jun 17.

Stanford University, Stanford, California.

1p36 deletion syndrome is a well-described condition with a recognizable phenotype, including cognitive impairment, seizures, and structural brain anomalies such as periventricular leukomalacia (PVL). In a large series of these individuals by Battaglia et al., "birth history was notable in 50% of the cases for varying degrees of perinatal distress." Given the potential for perinatal distress, seizures and PVL, we questioned if this disorder has clinical overlap with hypoxic ischemic encephalopathy (HIE). We reviewed the medical records of 69 individuals with 1p36 deletion to clarify the perinatal phenotype of this disorder and determine if there is evidence of perinatal distress and/or hypoxic injury. Our data provides evidence that these babies have signs of perinatal distress. The majority (59% term; 75% preterm) needed resuscitation and approximately 18% had cardiac arrest. Most had abnormal brain imaging (84% term; 73% preterm) with abnormal white matter findings in over half of patients. PVL or suggestion of "hypoxic insult" was present in 18% of term and 45% of preterm patients. In conclusion, individuals with 1p36 deletion have evidence of perinatal distress, white matter changes, and seizures, which can mimic HIE but are likely related to their underlying chromosome disorder.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/ajmg.a.61266DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7254578PMC
August 2019

Myoclonic epilepsy with photosensitivity in infants with Pallister-Killian Syndrome.

Eur J Paediatr Neurol 2019 Jul 25;23(4):653-656. Epub 2019 May 25.

Child Neurology and Psychiatry Unit, Department of Medical and Surgical Sciences (DIMEC), S. Orsola Hospital, University of Bologna, Bologna, Italy. Electronic address:

Introduction: Pallister-Killian Syndrome (PKS) (OMIM #601803) is a rare genetic disorder caused by a mosaic tetrasomy of the short arm of chromosome 12. Epilepsy is a frequent concern in PKS patients.

Methods: we report 3 PKS patients, with early-onset myoclonic epilepsy and photosensitivity. In these children, we analysed epileptic history and the EEG phenotype.

Results: Epilepsy onset was in the first 2 years of life in all patients and in 2 of them myoclonic seizures were the only seizure type. In all children photosensitivity was observed and myoclonic seizures were mainly related to low-frequency (1-6 Hz) intermittent photic stimulation. Levetiracetam was effective and well tolerated in the 2 treated patients.

Conclusions: early-onset myoclonic epilepsy is a possible clinical manifestation of PKS. Low-frequency photosensitivity is a peculiar bioelectrical marker in these children.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.ejpn.2019.05.012DOI Listing
July 2019

Analysis of the Phenotypes in the Rett Networked Database.

Int J Genomics 2019 27;2019:6956934. Epub 2019 Mar 27.

Medical Genetics, University of Siena, Italy.

Rett spectrum disorder is a progressive neurological disease and the most common genetic cause of intellectual disability in females. is the major causative gene. In addition, and mutations have been reported in Rett patients, especially with the atypical presentation. Each gene and different mutations within each gene contribute to variability in clinical presentation, and several groups worldwide performed genotype-phenotype correlation studies using cohorts of patients with classic and atypical forms of Rett spectrum disorder. The Rett Networked Database is a unified registry of clinical and molecular data of Rett patients, and it is currently one of the largest Rett registries worldwide with several hundred records provided by Rett expert clinicians from 13 countries. Collected data revealed that the majority of -mutated patients present with the classic form, the majority of -mutated patients with the early-onset seizure variant, and the majority of -mutated patients with the congenital form. A computation of severity scores further revealed significant differences between groups of patients and correlation with mutation types. The highly detailed phenotypic information contained in the Rett Networked Database allows the grouping of patients presenting specific clinical and genetic characteristics for studies by the Rett community and beyond. These data will also serve for the development of clinical trials involving homogeneous groups of patients.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1155/2019/6956934DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6458890PMC
March 2019

Perinatal outcome and healthcare resource utilization in the first year of life after antiepileptic exposure during pregnancy.

Epilepsy Behav 2019 03 29;92:14-17. Epub 2018 Dec 29.

Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Milan, Italy.

Healthcare administrative databases of Italy's Lombardy Region were analyzed with the aim to assess perinatal outcomes and healthcare resource utilization during the first year of life in infants exposed to antiepileptic drugs (AEDs) during pregnancy. Drug prescriptions dispensed in the 12 months before delivery to women, who delivered between 2005 and 2011, were analyzed. Neonates were classified as cases if exposed to AEDs, and each case was randomly matched to seven controls. No significant differences were observed in the risk of congenital malformations between 526 cases and 3682 controls except for valproic acid (odds ratio (OR): 2.29; 95% confidence interval (CI): 1.24-4.22) where cases were more likely to be small for gestational age (χ = 7.66; p = 0.006). Cases also had a higher probability than controls of needing at least one specialist visit in a child neuropsychiatry outpatient service (OR: 1.74; 95% CI: 1.22-2.49).
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.yebeh.2018.09.033DOI Listing
March 2019

Hot water epilepsy and SYN1 variants.

Epilepsia 2018 11;59(11):2162-2163

Child Neuropsychiatric Unit, Epilepsy Center, San Paolo Hospital, Department of Health Sciences, University of Milan, Milan, Italy.

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/epi.14572DOI Listing
November 2018

Current concepts on epilepsy management in tuberous sclerosis complex.

Am J Med Genet C Semin Med Genet 2018 09 26;178(3):299-308. Epub 2018 Sep 26.

Department of Neurology and Epileptology, The Children's Memorial Health Institute, Warsaw, Poland.

Tuberous sclerosis complex (TSC) is an autosomal dominant neurocutaneous disease affecting approximately 1 in 6,000 people, and represents one of the most common genetic causes of epilepsy. Epilepsy affects 90% of the patients and appears in the first 2 years of life in the majority of them. Early onset of epilepsy in the first 12 months of life is associated with high risk of cognitive decline and neuropsychiatric problems including autism. Prenatal or early infantile diagnosis of TSC, before the onset of epilepsy, provides a unique opportunity to monitor EEG before the onset of clinical seizures, thus enabling early intervention in the process of epileptogenesis. In this review, we discuss the current status of knowledge on epileptogenesis in TSC, and present recommendations of American and European experts in the field of epilepsy.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/ajmg.c.31652DOI Listing
September 2018

Healthcare transition from childhood to adulthood in Tuberous Sclerosis Complex.

Am J Med Genet C Semin Med Genet 2018 09 25;178(3):355-364. Epub 2018 Sep 25.

Department of Health Sciences, Child Neuropsychiatry Unit - Epilepsy Center, San Paolo Hospital, Università degli Studi di Milano, Milan, Italy.

Healthcare transition from childhood to adulthood is required to ensure continuity of care of an increasing number of individuals with chronic conditions surviving into adulthood. The transition for patients with tuberous sclerosis complex (TSC) is complicated by the multisystemic nature of this condition, age-dependent manifestations, and high clinical variability and by the presence of intellectual disability in at least half of the individuals. In this article, we address the medical needs regarding each TSC-related manifestation in adulthood, and the services and support required. We review existing models of transition in different chronic conditions, discuss our experience in transitioning from the pediatric to the adult TSC Clinic at our Institution, and propose general rules to follow when establishing a transition program for TSC. Although a generalizable transition model for TSC is likely not feasible for all Institutions, a multidisciplinary TSC clinic is probably the best model, developed in accordance with the resources available and country-specific healthcare systems. Coordination of care and education of the adult team should be always sought regardless of the transition model.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/ajmg.c.31653DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6635672PMC
September 2018

Rhinencephalon changes in tuberous sclerosis complex.

Neuroradiology 2018 Aug 17;60(8):813-820. Epub 2018 Jun 17.

Pediatric Neurology and Neurophysiology Unit, Department of Woman and Child Health, University Hospital of Padova, Padova, PD, Italy.

Purpose: Despite complex olfactory bulb embryogenesis, its development abnormalities in tuberous sclerosis complex (TSC) have been poorly investigated.

Methods: Brain MRIs of 110 TSC patients (mean age 11.5 years; age range 0.5-38 years; 52 female; 26 TSC1, 68 TSC2, 8 without mutation identified in TSC1 or TSC2, 8 not tested) were retrospectively evaluated. Signal and morphological abnormalities consistent with olfactory bulb hypo/aplasia or with olfactory bulb hamartomas were recorded. Cortical tuber number was visually assessed and a neurological severity score was obtained. Patients with and without rhinencephalon abnormalities were compared using appropriate parametric and non-parametric tests.

Results: Eight of110 (7.2%) TSC patients presented rhinencephalon MRI changes encompassing olfactory bulb bilateral aplasia (2/110), bilateral hypoplasia (2/110), unilateral hypoplasia (1/110), unilateral hamartoma (2/110), and bilateral hamartomas (1/110); olfactory bulb hypo/aplasia always displayed ipsilateral olfactory sulcus hypoplasia, while no TSC patient harboring rhinencephalon hamartomas had concomitant forebrain sulcation abnormalities. None of the patients showed overt olfactory deficits or hypogonadism, though young age and poor compliance hampered a proper evaluation in most cases. TSC patients with rhinencephalon changes had more cortical tubers (47 ± 29.1 vs 26.2 ± 19.6; p = 0.006) but did not differ for clinical severity (p = 0.45) compared to the other patients of the sample.

Conclusions: Olfactory bulb and/or forebrain changes are not rare among TSC subjects. Future studies investigating clinical consequences in older subjects (anosmia, gonadic development etc.) will define whether rhinencephalon changes are simply an imaging feature among the constellation of TSC-related brain changes or a feature to be searched for possible implications in the management of TSC subjects.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s00234-018-2045-xDOI Listing
August 2018

Ictal signs in tuberous sclerosis complex: Clinical and video-EEG features in a large series of recorded seizures.

Epilepsy Behav 2018 08 12;85:14-20. Epub 2018 Jun 12.

Epilepsy Center-Child Neuropsychiatric Unit, ASST Santi Paolo e Carlo, Milan, Italy; Department of Health Sciences, University of Milan, Italy.

Epilepsy is the most common neurological symptom in tuberous sclerosis complex (TSC), occurring in 72-85% of affected individuals. Despite the large number of patients reported, their electroclinical phenotype has been rarely described. We analyzed seizure semiology through ictal video-electroencephalography (V-EEG) recordings in a large series of patients. In this multicenter study, we reviewed V-EEGs of 51 patients: ictal recordings were analyzed in correlation with their clinical variables. The median age of epilepsy onset was six months (one day-16 years), with onset in the first year of life in 71% patients (36/51), in 10 of them during the neonatal period. Sixty-five percent of patients (33/51) experienced epileptic spasms in their life, with late-onset (>two years) in five; 42% of the epileptic spasms persisted after age two years, despite the onset in the first year of life. We identified four different electroclinical subsets: focal epilepsy (35%, 18/51), Lennox-Gastaut Syndrome evolution (27%, 14/51), focal seizures with persisting spasms (33%, 17/51), and spasms only (4%, 2/51). We reviewed 45 focal seizures, 13 clusters of epileptic spasms, and seven generalized seizures. In 12 patients, we recorded different seizure types. In 71% of the focal seizures (32/45), the ictal pattern was focal without diffusion. In 38% of the patients (5/13) epileptic spasms were related to typical diffuse slow wave pattern associated with superimposed fast activity, with focal predominance. Focal seizures and focal spasms resulted as the most frequent seizure types in TSC. Seizure onset was variable but showing a predominant involvement of the frontocentral regions (40%). Discrete clinical signs characterized the seizures, and behavioral arrest was the predominant first clinical objective sign. Epileptic spasms were a typical presentation at all ages, frequently asymmetrical and associated with lateralizing features, especially in older patients.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.yebeh.2018.05.027DOI Listing
August 2018

Genetic and imaging features of cerebellar abnormalities in tuberous sclerosis complex: more insights into their pathogenesis.

Dev Med Child Neurol 2018 07;60(7):724-725

Department of Woman and Child Health, Pediatric Neurology and Neurophysiology Unit, University Hospital of Padova, Padova, Italy.

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/dmcn.13769DOI Listing
July 2018

Deep phenotyping of patients with Tuberous Sclerosis Complex and no mutation identified in TSC1 and TSC2.

Eur J Med Genet 2018 Jul 9;61(7):403-410. Epub 2018 Feb 9.

Child Neuropsychiatry Unit - Epilepsy Center, San Paolo Hospital, Milan, Italy; Department of Health Sciences, Università degli Studi di Milano, Milan, Italy.

Tuberous Sclerosis Complex (TSC) is a multisystemic condition caused by mutations in TSC1 or TSC2, but a pathogenic variant is not identified in up to 10% of the patients. The aim of this study was to delineate the phenotype of pediatric and adult patients with a definite clinical diagnosis of TSC and no mutation identified in TSC1 or TSC2. We collected molecular and clinical data of 240 patients with TSC, assessing over 50 variables. We compared the phenotype of the homogeneous group of individuals with No Mutation Identified (NMI) with that of TSC patients with a TSC1 and TSC2 pathogenic variant. 9.17% of individuals were classified as NMI. They were diagnosed at an older age (p = 0.001), had more frequent normal cognition (p < 0.001) and less frequent epilepsy (p = 0.010), subependymal nodules (p = 0.022) and giant cell astrocytomas (p = 0.008) than patients with TSC2 pathogenic variants. NMI individuals showed more frequent bilateral and larger renal angiomyolipomas (p = 0.001; p = 0.003) and pulmonary involvement (trend) than patients with TSC1 pathogenic variants. Only one NMI individual had intellectual disability. None presented with a subependymal giant cell astrocytoma. Other medical problems not typical of TSC were found in 42.86%, without a recurrent pattern of abnormalities. Other TSC-associated neuropsychiatric disorders and drug-resistance in epilepsy were equally frequent in the three groups. This study provides a systematic clinical characterization of patients with TSC and facilitates the delineation of a distinctive phenotype indicative of NMI patients, with important implications for surveillance.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.ejmg.2018.02.005DOI Listing
July 2018

Early diagnosis of tuberous sclerosis complex: a race against time. How to make the diagnosis before seizures?

Orphanet J Rare Dis 2018 01 29;13(1):25. Epub 2018 Jan 29.

Department of Neurology and Epileptology, The Children's Memorial Health Institute, Al. Dzieci Polskich 20, 04-730, Warszawa, Poland.

Background: Tuberous sclerosis complex (TSC) is a genetic disorder with an incidence of 1:6000 live births and associated with the development of benign tumors in several organs. It is also characterized by high rates of neurological and neuropsychiatric abnormalities, including epilepsy affecting 70-90% of patients and being one of the major risk factors of intellectual disability. The first seizures in TSC patients appear usually between the 4th and the 6th months of life. Recent studies have shown the beneficial role of preventative antiepileptic treatment in TSC patients, with the possibility for improvement of cognitive outcome. Moreover, European recommendations suggest early introduction of Vigabatrin if ictal discharges occur on EEG recordings, with or without clinical manifestation. The aim of this study was to define the most useful approach to make the diagnosis of TSC before seizure onset (before age 4th months), in order to start early EEG monitoring with possible preventative treatment intervention.

Methods: We performed a retrospective review of children who were suspected of having TSC due to single or multiple cardiac tumors as the first sign of the disease. We analyzed the medical records in terms of conducted clinical tests and TSC signs, which were observed until the end of the 4th month of age. Subsequently, we described the different clinical scenarios and recommendations for early diagnosis.

Results: 82/100 children were diagnosed with TSC within the first 4 months of life. Apart from cardiac tumors, the most frequently observed early TSC signs were subependymal nodules (71/100, 71%), cortical dysplasia (66/100, 66%), and hypomelanotic macules (35/100, 35%). The most useful clinical studies for early TSC diagnosis were brain magnetic resonance imaging (MRI), skin examination and echocardiography. Genetic testing was performed in 49/100 of the patients, but the results were obtained within the first 4 months of life in only 3 children.

Conclusions: Early diagnosis of TSC, before seizure onset, is feasible and it is becoming pivotal for epilepsy management and improvement of cognitive outcome. Early TSC diagnosis is mostly based on clinical signs. Brain MRI, echocardiography, skin examination and genetic testing should be performed early in every patient suspected of having TSC.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1186/s13023-018-0764-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5789613PMC
January 2018