Publications by authors named "Chiara Pantaleoni"

80 Publications

Further delineation and long-term evolution of electroclinical phenotype in Mowat Wilson Syndrome. A longitudinal study in 40 individuals.

Epilepsy Behav 2021 Oct 4;124:108315. Epub 2021 Oct 4.

Clinical Neurophysiology Unit, IRCCS E Medea Scientific Institute, Bosisio Parini, Lecco, Italy.

Background: Epilepsy is a main feature of Mowat Wilson Syndrome (MWS), a congenital malformation syndrome caused by ZEB2 variants. The aim of this study was to investigate the long-term evolution of the electroclinical phenotype of MWS in a large population.

Methods: Forty-individuals with a genetically confirmed diagnosis were enrolled. Three age groups were identified (t1 = 0-4; t2 = 5-12; t3 = >13 years); clinical data and EEG records were collected, analyzed, and compared for age group. Video-EEG recorded seizures were reviewed.

Results: Thirty-six of 40 individuals had epilepsy, of whom 35/35 aged >5 years. Almost all (35/36) presented focal seizures at onset (mean age at onset 3.4 ± 2.3 SD) that persisted, reduced in frequency, in 7/22 individuals after the age of 13. Absences occurred in 22/36 (mean age at onset 7.2 ± 0.9 SD); no one had absences before 6 and over 16 years old. Paroxysmal interictal abnormalities in sleep also followed an age-dependent evolution with a significant increase in frequency at school age (p = 0.002) and a reduction during adolescence (p = 0.008). Electrical Status Epilepticus during Sleep occurred in 14/36 (13/14 aged 5-13 years old at onset). Seven focal seizure ictal video-EEGs were collected: all were long-lasting and more visible clinical signs were often preceded by prolonged electrical and/or subtle (erratic head and eye orientation) seizures. Valproic acid was confirmed as the most widely used and effective drug, followed by levetiracetam.

Conclusions: Epilepsy is a major sign of MWS with a characteristic, age-dependent, electroclinical pattern. Improvement with adolescence/adulthood is usually observed. Our data strengthen the hypothesis of a GABAergic transmission imbalance underlying ZEB2-related epilepsy.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.yebeh.2021.108315DOI Listing
October 2021

Neuro-telehealth for fragile patients in a tertiary referral neurological institute during the COVID-19 pandemic in Milan, Lombardy.

Neurol Sci 2021 Jul 30;42(7):2637-2644. Epub 2021 Apr 30.

Fondazione IRCCS Istituto Neurologico Carlo Besta, Milan, Italy.

Background: Lombardy was severely hit by the COVID-19 pandemic since February 2020 and the Health System underwent rapid reorganization. Outpatient clinics were stopped for non-urgent patients: it became a priority to manage hundreds of fragile neurological patients who suddenly had less reference points. In Italy, before the pandemic, Televisits were neither recognized nor priced.

Methods: At the Fondazione IRCCS Istituto Neurologico C. Besta, we reorganized outpatient clinics to deliver Neuro-telemedicine services, including Televisits and Teleneurorehabilitation, since March 2020. A dedicated Working Group prepared the procedure, tested the system, and designed satisfaction questionnaires for adults and children.

Results: After a pilot phase, we prepared a procedure for Telemedicine outpatient clinics which was approved by hospital directions. It included prescription, booking, consenting, privacy and data protection, secure connection with patients (Teams Microsoft 365), electronic report preparation and delivery, reporting, and accountability of the services. During the March-September 2020 period, we delivered 3167 Telemedicine services, including 1618 Televisits, to 1694 patients (972 adults, 722 children) with a wide range of chronic neurological disorders. We successfully administered different clinical assessment and scales. Satisfaction among patients and caregivers was very high.

Conclusions: During the dramatic emergency, we were able to take care of more than 1600 patients by organizing Neuro-telehealth in a few weeks, lessening the impact of the pandemic on fragile patients with chronic neurological disorders; this strategy is now stably embedded in our care pathways. In Italy, Telehealth is at present recognized and priced and is becoming a stable pillar of the health system.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s10072-021-05252-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8086222PMC
July 2021

A Missense De Novo Variant in the CASK-interactor KIRREL3 Gene Leading to Neurodevelopmental Disorder with Mild Cerebellar Hypoplasia.

Neuropediatrics 2021 Apr 14. Epub 2021 Apr 14.

Department of Developmental Neurology, Fondazione IRCCS Istituto Neurologico Carlo Besta, Milan, Italy.

is a gene important for the central nervous system development-in particular for the process of neuronal migration, axonal fasciculation, and synaptogenesis-and colocalizes and cooperates in neurons with gene. Alterations of have been linked to neurodevelopmental disorders, ranging from developmental delay, to autism spectrum disorder, to attention deficit/hyperactivity disorder. The underlying mechanism is not yet fully understood, as it has been hypothesized a fully dominant effect, a risk factor role of partially penetrating variants, and a recessive inheritance pattern. We report a novel and de novo mutation in a child affected by severe neurodevelopmental disorder and with brain magnetic resonance imaging evidence of mega cisterna magna and mild cerebellar hypoplasia. This case strengthens the hypothesis that dominant variants may lead to neurodevelopmental disruption; furthermore, given the strong interaction between and , we discuss as posterior fossa anomalies may also be part of the phenotype of -related syndrome.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1055/s-0041-1725964DOI Listing
April 2021

Electroclinical features of MEF2C haploinsufficiency-related epilepsy: A multicenter European study.

Seizure 2021 May 30;88:60-72. Epub 2021 Mar 30.

Maternal and Pediatric Department, Fondazione IRCCS Casa Sollievo della Sofferenza, Poliambulatorio "Giovanni Paolo II", Viale Padre Pio, snc, San Giovanni Rotondo (FG) 71013, Italy.

Purpose: Epilepsy is a main manifestation in the autosomal dominant mental retardation syndrome caused by heterozygous variants in MEF2C. We aimed to delineate the electro-clinical features and refine the genotype-phenotype correlations in patients with MEF2C haploinsufficiency.

Methods: We thoroughly investigated 25 patients with genetically confirmed MEF2C-syndrome across 12 different European Genetics and Epilepsy Centers, focusing on the epileptic phenotype. Clinical features (seizure types, onset, evolution, and response to therapy), EEG recordings during waking/sleep, and neuroimaging findings were analyzed. We also performed a detailed literature review using the terms "MEF2C", "seizures", and "epilepsy".

Results: Epilepsy was diagnosed in 19 out of 25 (~80%) subjects, with age at onset <30 months. Ten individuals (40%) presented with febrile seizures and myoclonic seizures occurred in ~50% of patients. Epileptiform abnormalities were observed in 20/25 patients (80%) and hypoplasia/partial agenesis of the corpus callosum was detected in 12/25 patients (~50%). Nine patients harbored a 5q14.3 deletion encompassing MEF2C and at least one other gene. In 7 out of 10 patients with myoclonic seizures, MIR9-2 and LINC00461 were also deleted, whereas ADGRV1 was involved in 3/4 patients with spasms.

Conclusion: The epileptic phenotype of MEF2C-syndrome is variable. Febrile and myoclonic seizures are the most frequent, usually associated with a slowing of the background activity and irregular diffuse discharges of frontally dominant, symmetric or asymmetric, slow theta waves with interposed spike-and-waves complexes. The haploinsufficiency of ADGRV1, MIR9-2, and LINC00461 likely contributes to myoclonic seizures and spasms in patients with MEF2C syndrome.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.seizure.2021.03.025DOI Listing
May 2021

CGH Findings in Children with Complex and Essential Autistic Spectrum Disorder.

J Autism Dev Disord 2021 Jan 4. Epub 2021 Jan 4.

Developmental Neurology Unit, Fondazione IRCCS Istituto Neurologico Carlo Besta, Via Celoria 11, 20133, Milan, Italy.

Autism spectrum disorder (ASD) is a heterogeneous neurodevelopmental condition with a strong genetic basis. We accurately assessed 209 ASD subjects, categorized in complex (47) and essential (162), and performed array comparative genomic hybridization to identify pathogenic and recurrent Copy Number Variants (CNVs). We found 117 CNVs in 75 patients, 11 classified as pathogenic. The complex ASD subjects have higher frequency of pathogenic CNVs with a diagnostic yield of 12.8%. Familiality, cognitive and verbal abilities, severity of autistic symptoms, neuroimaging and neurophysiological findings are not related to genetic data. This study identifies loci of interest for ASD and highlights the importance of a careful phenotypic characterization, as complex ASD is related to higher rate of pathogenic CNVs.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s10803-020-04833-5DOI Listing
January 2021

Identification of an Identical SCAMP5 Missense Variant in Four Unrelated Patients With Seizures and Severe Neurodevelopmental Delay.

Front Pharmacol 2020 18;11:599191. Epub 2020 Dec 18.

Department of Pediatrics, Peking University First Hospital, Beijing, China.

To establish and broaden the phenotypic spectrum of secretory carrier membrane protein ( associated with epilepsy and neurodevelopmental delay. A Chinese patient was identified at the First Hospital of Peking University, and the three unrelated patients were recruited from two different countries (Italy and United States) through GeneMatcher. pathogenic variants were identified by whole exome sequencing; clinical data of the patients were retrospectively collected and analyzed. The onset age of seizures was ranged from 6 to 15 months. Patients had different types of seizures, including focal seizures, generalized tonic-clonic seizures and tonic seizure. One patient showed typical autism spectrum disorder (ASD) symptoms. Electroencephalogram (EEG) findings presented as focal or multifocal discharges, sometimes spreading to generalization. Brain magnetic resonance imaging (MRI) abnormalities were present in each patient. Severe intellectual disability and language and motor developmental disorders were found in our patients, with all patients having poor language development and were nonverbal at last follow-up. All but one of the patients could walk independently in childhood, but the ability to walk independently in one patient had deteriorated with age. All patients had abnormal neurological exam findings, mostly signs of extrapyramidal system involvement. Dysmorphic features were found in 2/4 patients, mainly in the face and trunk. All four unrelated patients were found to have the same heterozygous pathogenic variant (p. Gly180Trp). Epilepsy, severe developmental delay, abnormal neurological exam findings, with or without ASD or variably dysmorphic features and were common in patients with variant. The onset time and type of seizure varied greatly. The EEG and brain MRI findings were not consistent, but diverse and nonspecific. The motor ability of patients with heterozygous variant might have a regressive course; language development was more severely affected.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3389/fphar.2020.599191DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7775611PMC
December 2020

Milder presentation of TELO2-related syndrome in two sisters homozygous for the p.Arg609His pathogenic variant.

Eur J Med Genet 2021 Jan 8;64(1):104116. Epub 2020 Dec 8.

Developmental Neurology Unit, Fondazione IRCCS Istituto Neurologico Carlo Besta, Milan, Italy.

Biallelic loss of function of TELO2 gene cause a severe syndromic disease mainly characterized by global developmental delay with poor motor and language acquisitions, microcephaly, short stature, minor facial and limbs anomalies, sleep disorder, spasticity, and balance impairment up to ataxia. TELO2-related syndrome, also known as You-Hoover-Fong Syndrome, is extremely rare and since its first description in 2016 only 8 individuals have been reported, all showing a severe disability. The causative gene is member of the big molecular family of genes responsible for cells proliferation and DNA stability. We describe the case of two sisters, carrying the homozygous p. Arg609His variant of the gene, who present a milder phenotype of TELO2-related syndrome. Such variant has been reported once in a more severely affected patient, in compound heterozygous state associated with the p. Pro260Leu variant, suggesting a possible role of the p. Arg609His variant in determining milder phenotypes. Comparing the siblings with all previously reported cases, we offer an overview on the condition and discuss TELO2 genetic interactions, in order to further explore the molecular bases of this recently described disorder.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.ejmg.2020.104116DOI Listing
January 2021

Neurological phenotype of Potocki-Lupski syndrome.

Am J Med Genet A 2020 10 15;182(10):2317-2324. Epub 2020 Aug 15.

Developmental Neurology Unit, Fondazione IRCCS Istituto Neurologico Carlo Besta, Milan, Italy.

Potocki-Lupski syndrome is a condition mainly characterized by infantile hypotonia, developmental delay/intellectual disability (DD/ID), and congenital anomalies, caused by duplications of the 17p11.2 region, encompassing RAI1 gene. Its clinical presentation is extremely variable, especially for what concerns the cognitive level and the behavioral phenotype. Such aspects, as well as the dysmorphic/malformative ones, have been covered by previous studies; otherwise neurological features have never been systematically described. In order to delineate the neurological phenotype of Potocki-Lupski Syndrome, we collect an 8-patients cohort. Developmental milestones are delayed and a mild to moderate cognitive impairment is present in all patients, variably associated with features of autism spectrum disorder, behavioral disturb, and sleep disturb. Hypotonia appears a less frequent finding than what previously reported, while motor clumsiness/coordination impairment is frequent. EGG registration demonstrated a common pattern with excess of diffuse rhythmic activity in sleep phases or while the patient is falling asleep. Brain MRI did not reveal common anomalies, although unspecific white matter changes may be present. We discuss such findings and compare them to literature data, offering an overview on the neurological and cognitive-behavioral presentation of the syndrome.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/ajmg.a.61789DOI Listing
October 2020

Expanding the phenotype of Wiedemann-Steiner syndrome: Craniovertebral junction anomalies.

Am J Med Genet A 2020 12 11;182(12):2877-2886. Epub 2020 Oct 11.

Medical Genetics Unit, Meyer Children's University Hospital, Florence, Italy.

Wiedemann-Steiner syndrome (WDSTS) is a rare autosomal dominant condition caused by heterozygous loss of function variants in the KMT2A (MLL) gene, encoding a lysine N-methyltransferase that mediates a histone methylation pattern specific for epigenetic transcriptional activation. WDSTS is characterized by a distinctive facial phenotype, hypertrichosis, short stature, developmental delay, intellectual disability, congenital malformations, and skeletal anomalies. Recently, a few patients have been reported having abnormal skeletal development of the cervical spine. Here we describe 11 such individuals, all with KMT2A de novo loss-of-function variants: 10 showed craniovertebral junction anomalies, while an 11th patient had a cervical abnormality in C7. By evaluating clinical and diagnostic imaging data we characterized these anomalies, which consist primarily of fused cervical vertebrae, C1 and C2 abnormalities, small foramen magnum and Chiari malformation type I. Craniovertebral anomalies in WDSTS patients have been largely disregarded so far, but the increasing number of reports suggests that they may be an intrinsic feature of this syndrome. Specific investigation strategies should be considered for early identification and prevention of craniovertebral junction complications in WDSTS patients.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/ajmg.a.61859DOI Listing
December 2020

Mirror syndromes regarding AKT3 mutations: Loss of function variant leading to microcephaly.

Am J Med Genet A 2020 11 21;182(11):2800-2802. Epub 2020 Aug 21.

Developmental Neurology Department, Fondazione IRCCS Istituto Neurologico Carlo Besta, Milan, Italy.

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/ajmg.a.61821DOI Listing
November 2020

Vascular Remodeling in Moyamoya Angiopathy: From Peripheral Blood Mononuclear Cells to Endothelial Cells.

Int J Mol Sci 2020 Aug 11;21(16). Epub 2020 Aug 11.

Laboratory of Cellular Neurobiology, Neurology IX Unit, UCV, Fondazione IRCCS Istituto Neurologico Carlo Besta, 20133 Milan, Italy.

The pathophysiological mechanisms of Moyamoya angiopathy (MA), which is a rare cerebrovascular condition characterized by recurrent ischemic/hemorrhagic strokes, are still largely unknown. An imbalance of vasculogenic/angiogenic mechanisms has been proposed as one possible disease aspect. Circulating endothelial progenitor cells (cEPCs) have been hypothesized to contribute to vascular remodeling of MA, but it remains unclear whether they might be considered a disease effect or have a role in disease pathogenesis. The aim of the present study was to provide a morphological, phenotypical, and functional characterization of the cEPCs from MA patients to uncover their role in the disease pathophysiology. cEPCs were identified from whole blood as CD45CD34CD133 mononuclear cells. Morphological, biochemical, and functional assays were performed to characterize cEPCs. A significant reduced level of cEPCs was found in blood samples collected from a homogeneous group of adult (mean age 46.86 ± 11.7; 86.36% females), Caucasian, non-operated MA patients with respect to healthy donors (HD; = 0.032). Since no difference in cEPC characteristics and functionality was observed between MA patients and HD, a defective recruitment mechanism could be involved in the disease pathophysiology. Collectively, our results suggest that cEPC level more than endothelial progenitor cell (EPC) functionality seems to be a potential marker of MA. The validation of our results on a larger population and the correlation with clinical data as well as the use of more complex cellular model could help our understanding of EPC role in MA pathophysiology.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3390/ijms21165763DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7460840PMC
August 2020

Teaching NeuroImages: Symmetrical abnormalities of the globi pallidi in succinic semialdehyde dehydrogenase deficiency.

Neurology 2020 10 17;95(16):e2316-e2317. Epub 2020 Jul 17.

From the Developmental Neurology Unit (S.E., E.G., C.P.), Neuroradiology Department (M.M., L.F.), Unit of Medical Genetics and Neurogenetics (C.C., C.G.), and Unit of Child Neurology (A.A.), Fondazione IRCCS Istituto Neurologico Carlo Besta, Milan; and Neuroimaging Laboratory (L.F.), IRCCS Fondazione Santa Lucia, Rome, Italy.

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1212/WNL.0000000000010367DOI Listing
October 2020

Mowat-Wilson syndrome: growth charts.

Orphanet J Rare Dis 2020 06 15;15(1):151. Epub 2020 Jun 15.

ATS Bergamo, Brembana Valley district, Bergamo, Italy.

Background: Mowat-Wilson syndrome (MWS; OMIM #235730) is a genetic condition caused by heterozygous mutations or deletions of the ZEB2 gene. It is characterized by moderate-severe intellectual disability, epilepsy, Hirschsprung disease and multiple organ malformations of which congenital heart defects and urogenital anomalies are the most frequent ones. To date, a clear description of the physical development of MWS patients does not exist. The aim of this study is to provide up-to-date growth charts specific for infants and children with MWS. Charts for males and females aged from 0 to 16 years were generated using a total of 2865 measurements from 99 MWS patients of different ancestries. All data were collected through extensive collaborations with the Italian MWS association (AIMW) and the MWS Foundation. The GAMLSS package for the R statistical computing software was used to model the growth charts. Height, weight, body mass index (BMI) and head circumference were compared to those from standard international growth charts for healthy children.

Results: In newborns, weight and length were distributed as in the general population, while head circumference was slightly smaller, with an average below the 30th centile. Up to the age of 7 years, weight and height distribution was shifted to slightly lower values than in the general population; after that, the difference increased further, with 50% of the affected children below the 5th centile of the general population. BMI distribution was similar to that of non-affected children until the age of 7 years, at which point values in MWS children increased with a less steep slope, particularly in males. Microcephaly was sometimes present at birth, but in most cases it developed gradually during infancy; many children had a small head circumference, between the 3rd and the 10th centile, rather than being truly microcephalic (at least 2 SD below the mean). Most patients were of slender build.

Conclusions: These charts contribute to the understanding of the natural history of MWS and should assist pediatricians and other caregivers in providing optimal care to MWS individuals who show problems related to physical growth. This is the first study on growth in patients with MWS.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1186/s13023-020-01418-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7294656PMC
June 2020

Severe Phenotype in a Patient With Homozygous 15q21.2 Microdeletion Involving , , and Genes, Resembling Infantile Developmental Disorder With Cardiac Arrhythmias (IDDCA).

Front Genet 2020 13;11:399. Epub 2020 May 13.

Developmental Neurology Unit, Fondazione IRCCS Istituto Neurologico Carlo Besta, Milan, Italy.

Homozygous and compound heterozygous mutations in gene have been associated with a wide spectrum of clinical presentations, ranging from neurodevelopmental issues with or without cardiac arrhythmia (LADCI) to severe developmental delay with epileptic encephalopathy, retinal dystrophy, and heart rhythm abnormalities (IDDCA). While missense or missense/non-sense mutations usually lead to milder form, the biallelic loss of function of 5 gene causes the severe multisystemic IDDCA phenotype. So far, only 27 patients have been described with -associated disease. We report the first case of a patient carrying a homozygous 15q21.2 microdeletion, encompassing and the two contiguous genes and . The clinical features of the child are consistent with the severe IDDCA phenotype, thus confirming the loss-of-function mechanism in determining such presentation of the disease.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3389/fgene.2020.00399DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7237723PMC
May 2020

So far so close: an insight into smart working and telehealth reorganization of a Language and Learning Disorders Service in Milan during COVID-19 pandemic.

Neurol Sci 2020 07 29;41(7):1659-1662. Epub 2020 May 29.

Developmental Neurology Unit - Language and Learning Disorders Service, Fondazione IRCCS Istituto Neurologico Carlo Besta, Milan, Italy.

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s10072-020-04481-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7257356PMC
July 2020

Chromosomal Microarray Analysis Has a Poor Diagnostic Yield in Children with Developmental Delay/Intellectual Disability When Concurrent Cerebellar Anomalies Are Present.

Cerebellum 2020 Oct;19(5):629-635

Developmental Neurology Department, Fondazione IRCCS Istituto Neurologico Carlo Besta, Via Celoria, 11, 20133, Milan, Italy.

Chromosomal microarray analysis is commonly used as screening test for children with neurodevelopmental issues, also in case of complex neurological phenotypes. Developmental delay/intellectual disability is a common presentation sign in pediatric ataxias, diseases with high clinical and genetic heterogeneity. In order to determine the diagnostic yield of Array-CGH in such conditions, all the tests performed in the last 10-year activity of a single referral center in children who present, besides the neurodevelopmental impairment, cerebellar abnormalities have been systematically gathered. The study demonstrates that, except for Dandy-Walker malformation or poly-malformative phenotypes, chromosomal microarray analysis should be discouraged as first-line diagnostic test in pediatric ataxias with neurodevelopmental disability.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s12311-020-01145-3DOI Listing
October 2020

Abnormal cerebellar foliation in mutation.

Neurology 2020 05 4;94(21):933-935. Epub 2020 May 4.

From the Developmental Neurology Unit (S.D., C.C., C.P.) and Neuroradiology Department (M.M., L.C.), Fondazione IRCCS Istituto Neurologico Carlo Besta, Milan; and Telethon Institute of Genetics and Medicine (R.C.), Pozzuoli, Naples, Italy.

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1212/WNL.0000000000009486DOI Listing
May 2020

A Novel WAC Loss of Function Mutation in an Individual Presenting with Encephalopathy Related to Status Epilepticus during Sleep (ESES).

Genes (Basel) 2020 03 24;11(3). Epub 2020 Mar 24.

Molecular Genetics of Neurodevelopment, Department of Women's and Children's Health, University of Padova, 35128 Padova, Italy.

WAC (WW Domain Containing Adaptor With Coiled-Coil) mutations have been reported in only 20 individuals presenting a neurodevelopmental disorder characterized by intellectual disability, neonatal hypotonia, behavioral problems, and mildly dysmorphic features. Using targeted deep sequencing, we screened a cohort of 630 individuals with variable degrees of intellectual disability and identified five rare variants: two variants were inherited from healthy parents; two previously reported de novo mutations, c.1661_1664del (p.Ser554*) and c.374C>A (p.Ser125*); and a novel c.381+2T>C variant causing the skipping of exon 4 of the gene, inherited from a reportedly asymptomatic father with somatic mosaicism. A phenotypic evaluation of this individual evidenced areas of cognitive and behavioral deficits. The patient carrying the novel splicing mutation had a clinical history of encephalopathy related to status epilepticus during slow sleep (ESES), recently reported in another individual. This first report of a somatic mosaic remarks the contribution of mosaicism in the etiology of neurodevelopmental and neuropsychiatric disorders. We summarized the clinical data of reported individuals with pathogenic mutations, which together with our findings, allowed for the expansion of the phenotypic spectrum of WAC-related disorders.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3390/genes11030344DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7141116PMC
March 2020

Circulating MyomiRs as Potential Biomarkers to Monitor Response to Nusinersen in Pediatric SMA Patients.

Biomedicines 2020 Jan 26;8(2). Epub 2020 Jan 26.

Neurology IV-Neuroimmunology and Neuromuscular Diseases Unit, Fondazione IRCCS Istituto Neurologico Carlo Besta, Via Celoria 11, 20133 Milan, Italy.

Spinal muscular atrophy (SMA) is an autosomal recessive disorder caused by mutations in survival motor neuron (SMN) 1 gene, resulting in a truncated SMN protein responsible for degeneration of brain stem and spinal motor neurons. The paralogous SMN2 gene partially compensates full-length SMN protein production, mitigating the phenotype. Antisense oligonucleotide nusinersen (Spinraza) enhances SMN2 gene expression. SMN is involved in RNA metabolism and biogenesis of microRNA (miRNA), key gene expression modulators, whose dysregulation contributes to neuromuscular diseases. They are stable in body fluids and may reflect distinct pathophysiological states, thus acting as promising biomarkers. Muscle-specific miRNAs (myomiRs) as biomarkers for clinical use in SMA have not been investigated yet. Here, we analyzed the expression of miR-133a, -133b, -206 and -1, in serum of 21 infantile SMA patients at baseline and after 6 months of nusinersen treatment, and correlated molecular data with response to therapy evaluated by the Hammersmith Functional Motor Scale Expanded (HFMSE). Our results demonstrate that myomiR serological levels decrease over disease course upon nusinersen treatment. Notably, miR-133a reduction predicted patients' response to therapy. Our findings identify myomiRs as potential biomarkers to monitor disease progression and therapeutic response in SMA patients.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3390/biomedicines8020021DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7168147PMC
January 2020

Infantile-Onset Syndromic Cerebellar Ataxia and CACNA1G Mutations.

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

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

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

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

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

Conclusion: Our findings confirm the specific association between a narrow spectrum of missense mutations in CACNA1G and a novel syndrome with infantile-onset cerebellar ataxiaand provide a dysmorphologic delineation of this novel neurodevelopmental trait.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.pediatrneurol.2019.09.005DOI Listing
March 2020

A Case of Severe Early-Onset Neuropathy Caused by a Compound Heterozygous Deletion of the PMP22 Gene: Clinical and Neurographic Aspects.

Neuropediatrics 2020 06 29;51(3):173-177. Epub 2019 Nov 29.

Department of Diagnostics and Applied Technology, Neurophysiopathology and Epilepsy Centre, Fondazione IRCCS, Istituto Neurologico "C. Besta," Milan, Italy.

Heterozygous deletions of the gene are associated to hereditary neuropathy with liability to pressure palsies (HNPP), a demyelinating neuromuscular disease causing variable transitory focal muscles weakness. Deletions involving both copies of cause more severe phenotypes, with early-onset neuropathy and impairment in motor development. We report a patient with a severe early-onset demyelinating neuropathy, caused by two different inherited deletions of , whose parents had an HNPP. The patient showed neurological signs and delay in motor development but normal intellective abilities. A motor and sensitive conduction study showed severe signs of demyelination, suggestive for Dejerine Sottas Syndrome (DSS). The patient's father had a typical HNPP caused by a heterozygous 17p11.2 deletion, encompassing . The patient's mother reported no neuropathic symptoms, but in a nerve conduction studies, parents and several relatives showed signs of sensory-motor deficit with focal slowing of conduction at common sites of entrapment. Quantitative analysis of , performed in our patient by multiplex ligation-dependent probe amplification, revealed a compound heterozygous status with the same deletion of the father and a deletion of exon 5, after proved to be inherited from the mother. Therefore, when we face an early-onset, severe form of neuropathy, we have to consider rare forms of hereditary neuropathy caused by homozygous or compound heterozygous mutations in , even if parents are asymptomatic; an exhaustive family history and an electrodiagnostic study are essential to guide genetic tests and to make a diagnosis.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1055/s-0039-3400985DOI Listing
June 2020

Risk of Optic Pathway Glioma in Neurofibromatosis Type 1: No Evidence of Genotype-Phenotype Correlations in A Large Independent Cohort.

Cancers (Basel) 2019 11 21;11(12). Epub 2019 Nov 21.

Developmental Neurology Unit, Fondazione IRCCS Istituto Neurologico Carlo Besta, via Celoria 11, 20121 Milan, Italy.

The occurrence of optic pathway gliomas (OPGs) in children with neurofibromatosis type 1 (NF1) still raises many questions regarding screening and surveillance because of the lack of robust prognostic factors. Recent studies of an overall cohort of 381 patients have suggested that the genotype may be the main determinant of the development of OPG, with the risk being higher in patients harbouring mutations in the 5' tertile and the cysteine/serine-rich domain. In an attempt to confirm this hypothesis, we used strict criteria to select a large independent cohort of 309 NF1 patients with defined constitutional NF1 mutations and appropriate brain images (255 directly enrolled and 54 as a result of a literature search). One hundred and thirty-two patients had OPG and 177 did not. The association of the position (tertiles and functional domains) and type of mutation with the development of OPG was analysed using the χ2 test and Fisher's exact probability test; odds ratios (ORs) with 95% confidence intervals were calculated, and Bonferroni's correction for multiple comparisons was applied; multiple logistic regression was also used to study genotype-phenotype associations further. Our findings show no significant correlation between the site/type of NF1 mutation and the risk of OPG, and thus do not support the hypothesis that certain constitutional mutations provide prognostic information in this regard. In addition, we combined our cohort with a previously described cohort of 381 patients for a total of 690 patients and statistically re-analysed the results. The re-analysis confirmed that there were no correlations between the site (tertile and domain) and the risk of OPG, thus further strengthening our conclusions.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3390/cancers11121838DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6966666PMC
November 2019

Connectivity measures suggest a sub-cortical generator of myoclonus in Angelman syndrome.

Clin Neurophysiol 2019 12 24;130(12):2231-2237. Epub 2019 Oct 24.

Department of Medical and Surgical Sciences, Magna Graecia University, Catanzaro, Italy; Regional Epilepsy Centre, Great Metropolitan Hospital "Bianchi-Melacrino-Morelli", Reggio Calabria, Italy.

Objective: The clinical and neurophysiological characteristics of myoclonus in Angelman syndrome (AS) have been evaluated in single case or small cohorts, with contrasting results. We evaluated the features of myoclonus in a wide cohort of AS patients.

Methods: We performed polygraphic EEG-EMG recording in 24 patients with genetically confirmed AS and myoclonus. Neurophysiological investigations included jerk-locked back-averaging (JLBA), cortico-muscular coherence (CMC) and generalised partial directed coherence (GPDC). CMC and GPDC analyses were compared to those obtained from 10 healthy controls (HC).

Results: Twenty-four patients (aged 3-35 years, median 20) were evaluated. Sequences of quasi-continuous rhythmic jerks mostly occurred at alpha frequency or just below (mean 8.4 ± 1.4 Hz), without EEG correlate. JLBA did not show any clear transient preceding the jerks. CMC showed bilateral over-threshold CMC in alpha band that was prominent on the contralateral hemisphere in the patient group as compared to HC group. GPDC showed a significantly higher alpha outflow from both hemispheres toward activated muscles in the patient group, and a significantly higher beta outflow from contralateral hemisphere in the HC group.

Conclusions: These neurophysiological findings suggest a subcortical generator of myoclonus in AS.

Significance: Myoclonus in AS has not a cortical origin as previously hypothesised.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.clinph.2019.08.031DOI Listing
December 2019

From congenital microcephaly to adult onset cerebellar ataxia: Distinct and overlapping phenotypes in patients with PNKP gene mutations.

Am J Med Genet A 2019 11 22;179(11):2277-2283. Epub 2019 Aug 22.

Unit of Medical Genetics and Neurogenetics, Fondazione IRCCS Istituto Neurologico Carlo Besta, Milan, Italy.

Pathogenic variants in polynucleotide kinase 3'-phosphatase (PNKP) gene have been associated with two distinct clinical presentations: autosomal recessive microcephaly, seizures, and developmental delay (MCSZ; MIM 613402) and ataxia with oculomotor apraxia type 4 (AOA4; MIM 616267). More than 40 patients have been reported so far, and their clinical presentations revealed a continuum phenotypic spectrum ranging from congenital microcephaly and early-onset intractable seizures, to adult onset slowly progressive sensory-motor neuropathy and cerebellar ataxia. We describe three unrelated Italian patients with different phenotypes and novel or recurrent pathogenic variants in PNKP gene. Patient 1, homozygous for the recurrent frameshift variant (p.Thr424Glyfs*49), had an early-onset MCSZ phenotype. Late in the disease progression, cerebellar ataxia and peripheral neuropathy were recognized. Patient 2, homozygous for a frameshift variant (p.Ala429Thrfs*42), presented a phenotype partially consistent with MCSZ including microcephaly and developmental delay, but without seizures. Patient 3 is one of the oldest patients described to date and presented polyneuropathy, and cerebellar signs. Biochemical tests showed abnormalities of cholesterol, albumin, or alpha-fetoprotein plasma levels. The clinical presentation of our patients encompassed early-to-adult-onset manifestations. For these cases, the long clinical follow-up allowed an in-depth phenotypic characterization and a better delineation of the natural history of patients carrying PNKP pathogenic variants.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/ajmg.a.61339DOI Listing
November 2019

Consolidating the Role of TDP2 Mutations in Recessive Spinocerebellar Ataxia Associated with Pediatric Onset Drug Resistant Epilepsy and Intellectual Disability (SCAR23).

Cerebellum 2019 Oct;18(5):972-975

Developmental Neurology Unit, Fondazione IRCCS Istituto Neurologico Carlo Besta, Via Celoria, 11, 20133, Milan, Italy.

Spinocerebellar Ataxia 23 (SCAR23) is a newly described condition caused by mutations in TDP2 gene. To date, only four patients from two families have been reported, all carrying the same homozygous mutation. We describe a fifth patient, carrying a novel mutation in the same gene, thus confirming the role of TDP2 mutations in determining the disease and defining the main features SCAR23: pediatric onset ataxia and drug-resistant epilepsy and intellectual disability. We further show the clinical presentation which is associated with the neuroradiological evidence of progressive cerebellar atrophy, giving the evidence that SCAR23 can be classified as a degenerative condition.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s12311-019-01069-7DOI Listing
October 2019

Chiari I malformation in defined genetic syndromes in children: are there common pathways?

Childs Nerv Syst 2019 10 30;35(10):1727-1739. Epub 2019 Jul 30.

Department of Neurosurgery, Fondazione IRCCS Istituto Neurologico Carlo Besta, Milan, Italy.

Purpose: Chiari malformation type I (CMI) is a common pediatric neurologic anomaly that can be associated with a variety of genetic disorders; however, it is not always clear whether the observed associations are real or random. The knowledge of the real associations could provide useful guidance to clinicians. Furthermore, it could be of help to better understand the still unknown genetic etiology of CMI.

Methods: With the aim of implementing such insights, we retrospectively reviewed clinical, neuroradiological, and genetic data of patients harboring CMI evaluated at the Child Neurology Unit of our institution between January 2008 and December 2018.

Results: The cohort consists of 205 patients (111 males and 94 females), with a mean age at diagnosis of 6.3 years (range 0-18 years). 188 patients completed an average follow-up period of 5.2 years (range one month-18 years). Mean age at last assessment was 11.4 years (range nine months-23 years). 127 (62%) children have been classified as syndromic due to the presence of neurodevelopmental disorders, phenotypic anomalies, or malformations. Among syndromic CMI children, a molecular diagnosis was identified in 35/127 (27.6%) (20 males and 15 females). The most common diagnoses were syndromic craniosynostosis in 8/35 children (22.9%), among which sevenare FGFR-related and one ERF-related craniosynostosis; disorders of the RAS/MAPK pathway, termed RASopathies or RAS/MAPK syndromes in 9/35 (25.7%); disorders of the PTEN-PI3K/AKT signal transduction cascade, termed PTENopathies in 3/35 children (8.6%); and chromosomal rearrangements in 6/35 patients (17.1%), two of whom with del16p11.2.

Conclusions: We polarized our attention on the defined genetic diagnoses focusing not only on the phenotypic hallmarks but also on the phenotypic overlapping features. In addition, we discussed the pathophysiological mechanisms leading to progressive cerebellar ectopia and the involved molecular pathways. Along with the recent literature evidence, we suppose that interactions between FGFR and RAS/MAPK pathway and between RAS/MAPK and PTEN-PI3K/AKT pathways could explain some phenotypic overlapping features and could have a significant role in the pathogenesis of CMI.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s00381-019-04319-5DOI Listing
October 2019

Flunarizine and Aspirin for Transient Hemiparesis in Sturge-Weber Syndrome.

Neuropediatrics 2019 12 4;50(6):406-407. Epub 2019 Jul 4.

Neurophysiopathology Department, Fondazione IRCCS Istituto Neurologico "C. Besta," Milan, Italy.

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1055/s-0039-1685528DOI Listing
December 2019

Pott's Disease: An Emerging Source of Potentially Inappropriate Treatment.

Neuropediatrics 2019 10 29;50(5):334-335. Epub 2019 May 29.

Neuropathology Unit, Fondazione IRCCS Istituto Neurologico Carlo Besta, Via Celoria 11, Milan, Italy.

Spinal Tuberculosis in children is uncommon, even more so in cases of involvement of posterior vertebral elements, and its diagnosis is often delayed. Here we report the case of a young female presenting neuroradiological features and clinical symptoms suspicious for malignant tumor. Histological examination of biopsy specimen evidenced a Pott's disease. We highlight the importance of suspecting this disorder in children with both aspecific systemic and neurological symptoms, in order to reach a timely diagnosis for appropriate and targeted intervention, avoiding the risk of overtreatment and malpractice claims.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1055/s-0039-1691833DOI Listing
October 2019

Levetiracetam Pregnancy Registry: Final results and a review of the impact of registry methodology and definitions on the prevalence of major congenital malformations.

Birth Defects Res 2019 08 23;111(13):872-887. Epub 2019 May 23.

UCB Pharma, Raleigh, North Carolina.

Background: To evaluate pregnancy outcomes among women participating in the antiepileptic drug (AED) Levetiracetam Registry (LEV-Registry), and to review the impact of using two other registries' outcome definitions on the number of major congenital malformations (MCMs).

Methods: This US-based prospective study (ClinicalTrials.gov NCT00345475) was overseen by an independent Expert Panel. Women exposed to levetiracetam at any time during pregnancy enrolled, directly, or via their healthcare provider. The primary outcome was prevalence of MCMs, defined according to a modified version of the Metropolitan Atlanta Congenital Defects Program criteria.

Results: Of 491 women enrolled, 465 (94.7%) had a documented outcome. Most (92.3%) received levetiracetam for epilepsy; 323 (69.4%) as monotherapy and 142 (30.5%) as polytherapy. With three twin pregnancies, there were 468 outcomes-444 livebirths, 3 stillbirths, 19 miscarriages, and 2 terminations. Based on the MCM definition used by LEV-Registry, 46 infants among 444 livebirths had MCMs resulting in 10.4% (95% CI 7.7, 13.6) for overall prevalence, 9.4% (95% CI 6.4, 13.2) with monotherapy, and 12.6% (95% CI 7.5, 19.4) with polytherapy. When MCM reports were reviewed independently by staff at EURAP (International Registry of AEDs) and North American AED Pregnancy Registry according to their respective criteria, only 22 and 7 infants of the 46, respectively, were classified as having MCMs.

Conclusion: The LEV-Registry Expert Panel did not find evidence suggestive of teratogenic association with prenatal exposure to levetiracetam. The substantial differences in which physical findings were considered MCMs highlight the major impact of pregnancy registry methodology on MCM prevalence estimates.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/bdr2.1526DOI Listing
August 2019
-->