Publications by authors named "Alessandra Murgia"

52 Publications

Feasibility and Reliability Assessment of Video-Based Motion Analysis and Surface Electromyography in Children with Fragile X during Gait.

Sensors (Basel) 2021 Jul 12;21(14). Epub 2021 Jul 12.

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

Fragile X Syndrome (FXS), the leading form of inherited intellectual disability and autism, is characterized by specific musculoskeletal conditions. We hypothesized that gait analysis in FXS could be relevant for the evaluation of motor control of gait, and help the understanding of a possible correlation between functional and intellectual abilities. Typical deficits in executive control and hyperactivity have hampered the use of standard gait analysis. The aim of our study was to quantitatively assess musculoskeletal alterations in FXS children in standard ambulatory conditions, in a friendly environment. Ten FXS children and sixteen controls, with typical neurodevelopment, were evaluated through four synchronized video cameras and surface electromyography; lower limb joints rotations, spatiotemporal parameters, duration of muscle contraction, activation timing and envelope peaks were determined. Reliability and repeatability of the video based kinematics analysis was assessed with respect to stereophotogrammetry. The Kruskal-Wallis Test ( < 0.05) or SPM1D were used to compare different groups of subjects. Results show a consistently altered gait pattern associated with abnormal muscle activity in FXS subjects: reduced knee and excessive hip and ankle flexion, and altered duration and activity onset on all the recorded muscles (Rectus/Biceps Femoris, Tibialis Anterior, Gastrocnemius Lateralis). Results of this study could help with planning personalized rehabilitations.
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http://dx.doi.org/10.3390/s21144746DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8309640PMC
July 2021

Impact of the COVID-19 Italian Lockdown on the Physiological and Psychological Well-Being of Children with Fragile X Syndrome and Their Families.

Int J Environ Res Public Health 2021 May 27;18(11). Epub 2021 May 27.

Molecular Genetics of Neurodevelopment, Department of Woman and Child Health, University of Padova, Via Giustiniani 3, 35128 Padova, Italy.

On 10 March 2020, in Italy, a total lockdown was put in place to limit viral transmission of COVID-19 infection as much as possible. Research on the psychological impact of the COVID-19 pandemic highlighted detrimental effects in children and their parents. However, little is known about such effects in children with neurodevelopment disorders and their caregivers. The present study investigated how the lockdown has impacted the physiological and psychological well-being of children with Fragile X-Syndrome (FXS), aged from 2 to 16 years, and their mothers. In an online survey, 48 mothers of FXS children reported their perception of self-efficacy as caregivers and, at the same time, their children's sleep habits, behavioral and emotional difficulties during, and retrospectively, before the lockdown. Results showed a general worsening of sleep quality, and increasing behavioral problems. Although mothers reported a reduction in external support, their perception of self-efficacy as caregivers did not change during the home confinement compared to the period before. Overall, the present study suggested that specific interventions to manage sleep problems, as well as specific therapeutic and social support for increasing children and mother psychological well-being, need to be in place to mitigate the long-term effects of a lockdown.
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http://dx.doi.org/10.3390/ijerph18115752DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8199386PMC
May 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.
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http://dx.doi.org/10.1055/s-0041-1725964DOI Listing
April 2021

Identification of Mutations by Gene Panel Sequencing in Individuals With Intellectual Disability or With "Developmental and Epileptic Encephalopathy".

Front Neurol 2020 16;11:593446. Epub 2020 Dec 16.

Molecular Genetics of Neurodevelopment, Department of Woman and Child Health, University of Padova, Padua, Italy.

mutations are associated with the Schinzel-Giedion syndrome (SGS), characterized by profound neurodevelopmental delay, typical facial features, and multiple congenital malformations (OMIM 269150). Refractory epilepsy is a common feature of SGS. Loss of function mutations have been typically associated with a distinct and milder phenotype characterized by intellectual disability and expressive speech impairment. Here we report three variants of , two novel truncating mutations, identified by NGS analysis of an Intellectual Disability gene panel in 600 subjects with non-specific neurodevelopmental disorders, and one missense identified by a developmental epilepsy gene panel tested in 56 pediatric epileptic cases. The three individuals carrying the identified variants presented mild to severe developmental delay and lacked the cardinal features of classical SGS. One of these subjects, carrying the c.1765C>T (p.Arg589) mutation, had mild Intellectual Disability with speech delay; the second one carrying the c.2199_2203del (p.Glu734Alafs19) mutation had generalized epilepsy, responsive to treatment, and moderate Intellectual Disability; the third patient showed a severe cognitive defects and had a history of drug resistant epilepsy with West syndrome evolved into a Lennox-Gastaut syndrome. This latter subject carries the missense c.2572G>A (p.Glu858Lys) variant, which is absent from the control population, reported as in a subject with ASD, and located close to the hot spot for SGS-associated mutations. Our findings contribute to further characterizing the associated phenotypes and suggest inclusion of in the list of prioritized genes for the genetic diagnosis of overlapping phenotypes ranging from non-specific neurodevelopmental disorders to "developmental and epileptic encephalopathy" (DEE).
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http://dx.doi.org/10.3389/fneur.2020.593446DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7772201PMC
December 2020

Expanding the genetic landscape of Rett syndrome to include lysine acetyltransferase 6A (KAT6A).

J Genet Genomics 2020 10 4;47(10):650-654. Epub 2020 Nov 4.

Brain and Mitochondrial Research Group, Murdoch Children's Research Institute, Melbourne, Australia; Department of Paediatrics, University of Melbourne, Melbourne, Australia; Victorian Clinical Genetics Services, Murdoch Children's Research Institute, Melbourne, Australia; The University of Sydney, School of Medical Sciences and Discipline of Child and Adolescent Health, Faculty of Medicine and Health, Sydney, Australia. Electronic address:

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http://dx.doi.org/10.1016/j.jgg.2020.09.003DOI Listing
October 2020

Vaccination Attitude and Communication in Early Settings: An Exploratory Study.

Vaccines (Basel) 2020 Nov 20;8(4). Epub 2020 Nov 20.

Department of Medical Science and Public Health, University of Cagliari, University Campus of Monserrato, 09125 Cagliari, Italy.

This study assesses attitudes towards vaccination in mothers of new-born babies and explores its association with different exposures to communication. Data were collected through questionnaires administered by means of interviews. Data highlighted that 20% of mothers showed an orientation towards vaccine hesitancy. As for the reasons behind the attitude to vaccine hesitancy, data showed that concern is a common feature. As for the different exposures to communication, 49% of mothers did not remember having received or looked for any information about vaccination during pregnancy and post-partum; 25% stated they received information from several healthcare and non-healthcare sources; 26% declared having received or looked for information by means of healthcare and non-healthcare sources, as well as having taken part in a specific meeting during antenatal classes or at birth centres. The attitude towards vaccine hesitancy tends to reduce as exposure to different communication increases. This study supports the hypothesis that participation in interactive meetings in small groups focused on vaccination during the prenatal course or at the birth point may act as an enabling factor contributing to a decrease in the tendency to experience vaccine hesitation.
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http://dx.doi.org/10.3390/vaccines8040701DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7712563PMC
November 2020

Clinical and molecular description of 19 patients with GATAD2B-Associated Neurodevelopmental Disorder (GAND).

Eur J Med Genet 2020 Oct 17;63(10):104004. Epub 2020 Jul 17.

Center for Medical Genetics, Ghent University Hospital, Ghent, Belgium.

De novo pathogenic variants in the GATAD2B gene have been associated with a syndromic neurodevelopmental disorder (GAND) characterized by severe intellectual disability (ID), impaired speech, childhood hypotonia, and dysmorphic features. Since its first description in 2013, nine patients have been reported in case reports and a series of 50 patients was recently published, which is consistent with the relative frequency of GATAD2B pathogenic variants in public databases. We report the detailed phenotype of 19 patients from various ethnic backgrounds with confirmed pathogenic GATAD2B variants including intragenic deletions. All individuals presented developmental delay with a median age of 2.5 years for independent walking and of 3 years for first spoken words. GATAD2B variant carriers showed very little subsequent speech progress, two patients over 30 years of age remaining non-verbal. ID was mostly moderate to severe, with one profound and one mild case, which shows a wider spectrum of disease severity than previously reported. We confirm macrocephaly as a major feature in GAND (53%). Most common dysmorphic features included broad forehead, deeply set eyes, hypertelorism, wide nasal base, and pointed chin. Conversely, prenatal abnormalities, non-cerebral malformations, epilepsy, and autistic behavior were uncommon. Other features included feeding difficulties, behavioral abnormalities, and unspecific abnormalities on brain MRI. Improving our knowledge of the clinical phenotype is essential for correct interpretation of the molecular results and accurate patient management.
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http://dx.doi.org/10.1016/j.ejmg.2020.104004DOI Listing
October 2020

Frequency of Usher gene mutations in non-syndromic hearing loss: higher variability of the Usher phenotype.

J Hum Genet 2020 Oct 28;65(10):855-864. Epub 2020 May 28.

Laboratory of Molecular Genetics of Neurodevelopment, Department of Women's and Children's Health, University of Padua, Padua, Italy.

Non-syndromic hearing loss (NSHL) is characterized by a vast genetic heterogeneity; some syndromic forms as Usher syndrome (USH) have onset as isolated deafness and then evolve later in life. We developed an NGS targeted gene-panel containing 59 genes and a customized bioinformatic pipeline for the analysis of DNA samples from clinically highly selected subjects with sensorineural hearing loss, previously resulted negative for GJB2 mutations/GJB6 deletions. Among the 217 tested subjects, 24 (11.1%) were found to carry mutations in genes involved both in NSHL and USH. For 6 out of 24 patients a diagnosis of USH was performed. Eleven subjects out of 24 had hearing loss without vestibular or ocular dysfunction and, due to their young age, it was not possible to establish whether their phenotype could be NSHL or USH. Seven subjects were diagnosed with NSHL, due to their age and phenotype. A total of 41 likely pathogenic/pathogenic mutations were identified, among which 17 novel ones. We report a high frequency of mutations in genes involved both in NSHL and in USH in a cohort of individuals tested for seemingly isolated deafness. Our data also highlight a wider than expected phenotypic variability in the USH phenotype.
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http://dx.doi.org/10.1038/s10038-020-0783-1DOI Listing
October 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.
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http://dx.doi.org/10.3390/genes11030344DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7141116PMC
March 2020

Disruptive mutations in TANC2 define a neurodevelopmental syndrome associated with psychiatric disorders.

Nat Commun 2019 10 15;10(1):4679. Epub 2019 Oct 15.

Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, 77030, USA.

Postsynaptic density (PSD) proteins have been implicated in the pathophysiology of neurodevelopmental and psychiatric disorders. Here, we present detailed clinical and genetic data for 20 patients with likely gene-disrupting mutations in TANC2-whose protein product interacts with multiple PSD proteins. Pediatric patients with disruptive mutations present with autism, intellectual disability, and delayed language and motor development. In addition to a variable degree of epilepsy and facial dysmorphism, we observe a pattern of more complex psychiatric dysfunction or behavioral problems in adult probands or carrier parents. Although this observation requires replication to establish statistical significance, it also suggests that mutations in this gene are associated with a variety of neuropsychiatric disorders consistent with its postsynaptic function. We find that TANC2 is expressed broadly in the human developing brain, especially in excitatory neurons and glial cells, but shows a more restricted pattern in Drosophila glial cells where its disruption affects behavioral outcomes.
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http://dx.doi.org/10.1038/s41467-019-12435-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6794285PMC
October 2019

Characterization of intellectual disability and autism comorbidity through gene panel sequencing.

Hum Mutat 2019 09 2;40(9):1346-1363. Epub 2019 Aug 2.

Molecular Genetics of Neurodevelopment, Department of Woman and Child Health, University of Padova, C.so Stati Uniti, 4, Padova, Italy.

Intellectual disability (ID) and autism spectrum disorder (ASD) are clinically and genetically heterogeneous diseases. Recent whole exome sequencing studies indicated that genes associated with different neurological diseases are shared across disorders and converge on common functional pathways. Using the Ion Torrent platform, we developed a low-cost next-generation sequencing gene panel that has been transferred into clinical practice, replacing single disease-gene analyses for the early diagnosis of individuals with ID/ASD. The gene panel was designed using an innovative in silico approach based on disease networks and mining data from public resources to score disease-gene associations. We analyzed 150 unrelated individuals with ID and/or ASD and a confident diagnosis has been reached in 26 cases (17%). Likely pathogenic mutations have been identified in another 15 patients, reaching a total diagnostic yield of 27%. Our data also support the pathogenic role of genes recently proposed to be involved in ASD. Although many of the identified variants need further investigation to be considered disease-causing, our results indicate the efficiency of the targeted gene panel on the identification of novel and rare variants in patients with ID and ASD.
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http://dx.doi.org/10.1002/humu.23822DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7428836PMC
September 2019

Assessment of patient clinical descriptions and pathogenic variants from gene panel sequences in the CAGI-5 intellectual disability challenge.

Hum Mutat 2019 09 3;40(9):1330-1345. Epub 2019 Jul 3.

Department of Woman and Child Health, University of Padua, Padua, Italy.

The Critical Assessment of Genome Interpretation-5 intellectual disability challenge asked to use computational methods to predict patient clinical phenotypes and the causal variant(s) based on an analysis of their gene panel sequence data. Sequence data for 74 genes associated with intellectual disability (ID) and/or autism spectrum disorders (ASD) from a cohort of 150 patients with a range of neurodevelopmental manifestations (i.e. ID, autism, epilepsy, microcephaly, macrocephaly, hypotonia, ataxia) have been made available for this challenge. For each patient, predictors had to report the causative variants and which of the seven phenotypes were present. Since neurodevelopmental disorders are characterized by strong comorbidity, tested individuals often present more than one pathological condition. Considering the overall clinical manifestation of each patient, the correct phenotype has been predicted by at least one group for 93 individuals (62%). ID and ASD were the best predicted among the seven phenotypic traits. Also, causative or potentially pathogenic variants were predicted correctly by at least one group. However, the prediction of the correct causative variant seems to be insufficient to predict the correct phenotype. In some cases, the correct prediction has been supported by rare or common variants in genes different from the causative one.
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http://dx.doi.org/10.1002/humu.23823DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7341177PMC
September 2019

Mavoglurant in Fragile X Syndrome: Results of two open-label, extension trials in adults and adolescents.

Sci Rep 2018 11 19;8(1):16970. Epub 2018 Nov 19.

Neuroscience Development, Novartis Pharma AG, Basel, Switzerland.

Fragile X syndrome (FXS) is the most common monogenic cause of inherited intellectual and developmental disabilities. Mavoglurant, a selective metabotropic glutamate receptor subtype-5 antagonist, has shown positive neuronal and behavioral effects in preclinical studies, but failed to demonstrate any behavioral benefits in two 12-week, randomized, placebo-controlled, double-blind, phase IIb studies in adults and adolescents with FXS. Here we report the long-term safety (primary endpoint) and efficacy (secondary endpoint) results of the open-label extensions. Adolescent (n = 119, aged 12-19 years) and adult (n = 148, aged 18-45 years) participants received up to 100 mg bid mavoglurant for up to 34 months. Both extension studies were terminated prematurely due to lack of proven efficacy in the core studies. Mavoglurant was well tolerated with no new safety signal. Five percent of adults and 16.9 percent of adolescents discontinued treatment due to adverse events. Gradual and consistent behavioral improvements as measured by the ABC-C scale were observed, which were numerically superior to those seen in the placebo arm of the core studies. These two extension studies confirm the long-term safety of mavoglurant in FXS, but further investigations are required to determine whether and under which conditions the significant preclinical results obtained with mGluR5 inhibition can translate to humans.
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http://dx.doi.org/10.1038/s41598-018-34978-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6242849PMC
November 2018

Volumetric image-guided conformal radiotherapy for localized prostate cancer: Analysis of dosimetric and clinical factors affecting acute and late toxicity.

Rep Pract Oncol Radiother 2018 Sep-Oct;23(5):315-321. Epub 2018 Aug 13.

Department of Diagnostic Imaging, Molecular Imaging, Interventional Radiology and Radiotherapy, Tor Vergata General Hospital, Rome, Italy.

Aim: To identify factors influencing toxicity in patients affected by localized prostate cancer treated with conformal image-guided radiotherapy.

Background: Image guidance in combination with conformal techniques is the standard of care in localized prostate cancer, but factors affecting toxicity are still under investigation.

Materials And Methods: 294 patients were analyzed. Median age at diagnosis was 71 year. 76 Gy (38 × 2 Gy) were delivered to the target volume. We used the test to analyse associations between toxicity and dosimetric and clinical parameters. Multivariate analysis was performed using binary logistic regression. Kaplan-Meier method was used for survival analysis.

Results: Median follow-up was 62.9 months. Acute grade ≥2 gastro-intestinal toxicity (GI) was 12.1%. Acute genito-urinary (GU) toxicity of grade ≥2 was 33.9%. Actuarial 4 and 5 years late grade ≥2 GI was 3% and 4%, respectively. Four and 5-year late grade ≥2 GU toxicity was 6% and 10%. At multivariate analysis for acute toxicity rectal was correlated with GI toxicity ( = 0.01, HR 2.73 CI 1.19-6.26), and smoking habit with GU toxicity ( < 0.01, HR 2.50 CI 1.51-4.14). For late toxicity, rectal was correlated with gastro-intestinal toxicity ( = 0.04, HR 4.76 CI 1.07-21.13), and pre-radiotherapy urinary symptoms with genito-urinary toxicity ( = 0.01, HR 2.84 CI 1.29-6.22).

Discussion: Conformal image-guided radiotherapy shows low rates of toxicity. Smoking should be avoided during radiotherapy. Besides the evaluation of high doses received by the organs at risk, individual factors, such as co-morbidities and lifestyle choices, have an impact on normal-tissue complication risk.
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http://dx.doi.org/10.1016/j.rpor.2018.07.010DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6097402PMC
August 2018

Brain malformations associated to Aldh7a1 gene mutations: Report of a novel homozygous mutation and literature review.

Eur J Paediatr Neurol 2018 Nov 3;22(6):1042-1053. Epub 2018 Jul 3.

Department of Neurosciences, University Hospital of Padua, Italy. Electronic address:

Background: The ALDH7A1 gene is known to be responsible for autosomal recessive pyridoxine-dependent epilepsy (OMIM 266100). The phenotypic spectrum of ALDH7A1 mutations is very heterogeneous ranging from refractory epilepsy and neurodevelopmental delay, to multisystem neonatal disorder.

Aim: The present study aims at describing the phenotype associated with a novel homozygous ALDH7A1 mutation and the spectrum of brain malformations associated with pyridoxine-dependent epilepsy.

Methods: We conducted a literature review on the Internet database Pubmed (up to November 2017) searching for ALDH7A1 mutations associated with brain malformations and brain MRI findings.

Results: We present the case of two siblings, children of related parents. The proband presented neonatal focal seizures not responding to conventional antiepileptic drugs. Electroencephalography showed a suppression burst pattern and several multifocal ictal patterns, responsive to pyridoxine. Brain MRI was normal. Molecular analysis by targeted next-generation sequencing panel for epileptic encephalopathy disclosed a homozygous missense mutation of ALDH7A1. The same mutation was then found in a stored sample of DNA from peripheral blood of an older sister dead 3 years earlier. This girl presented a complex brain malformation diagnosed with a foetal MRI and had neonatal refractory seizures with suppression burst pattern. She died at 6 months of age.

Literature Review: The brain abnormalities most frequently reported in pyridoxine-dependent epilepsy include: agenesia/hypoplasia of the corpus callosum, not specific white matter abnormalities, large cisterna magna, ventriculomegaly, haemorrhages, cerebellum hypoplasia/dysplasia, and, more rarely, dysplasia of the brainstem and hydrocephalus.

Discussion And Conclusions: ALDH7A1 mutations have been associated to different brain abnormalities, documented by MRI only in few cases. The study cases expand the clinical spectrum of ALDH7A1 associated conditions, suggesting to look for ALDH7A1 mutations not only in classical phenotypes but also in patients with brain malformations, mainly if there is a response to a pyridoxine trial.
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http://dx.doi.org/10.1016/j.ejpn.2018.06.010DOI Listing
November 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.
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http://dx.doi.org/10.1007/s00234-018-2045-xDOI Listing
August 2018

[Accurate compiling of the hospital discharge records according to clinicians' perception: critical issues and perspectives].

Epidemiol Prev 2018 Jan-Feb;42(1):34-39

Azienda ospedaliero-universitaria, Cagliari.

Objectives: to explore clinicians vision on hospital discharge records in order to identify useful elements to foster a more accurate compiling.

Design: qualitative research with phenomenological approach.

Setting And Participants: participants were selected through purposive sampling among clinicians of two hospitals located in Sardinia; the sample included 76 people (32 medical directors and 44 doctors in training).

Main Outcome Measures: identified codes for themes under investigation: vision of accurate compiling, difficulties, and proposals.

Results: collected data highlighted two prevailing visions, respectively focused on the importance of an accurate compiling and on the burden of such activity. The accurate compiling is hindered by the lack of motivation and training, by the limits of the registration system and the information technology, by the distortions induced by the prominent role of the hospital discharge records in the evaluation processes. Training, timely updating of the information system accompanied by a proper cross-cultural validation process, improvement of the computer system, and activation of support services could promote more accurate compiling.

Conclusions: the implementation of services, unconnected with evaluation and control processes, dedicated to training and support in the compiling of the hospital discharge records and in the conduction of related epidemiological studies would facilitate the compliance to the compilation. Such services will make tangible the benefits obtainable from this registration system, increasing skills, motivation, ownership, and facilitating greater accuracy in compiling.
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http://dx.doi.org/10.19191/EP18.1.P034.013DOI Listing
March 2019

A novel mutation of the EYA4 gene associated with post-lingual hearing loss in a proband is co-segregating with a novel PAX3 mutation in two congenitally deaf family members.

Int J Pediatr Otorhinolaryngol 2018 Jan 31;104:88-93. Epub 2017 Oct 31.

Laboratory of Molecular Genetics of Neurodevelopment, Department of Women's and Children's Health, University of Padova, Italy; Neuroscience Department, University of Padova, Italy. Electronic address:

Objectives: This work was aimed at establishing the molecular etiology of hearing loss in a 9-year old girl with post-lingual non-syndromic mild sensorineural hearing loss with a complex family history of clinically heterogeneous deafness.

Methods: The proband's DNA was subjected to NGS analysis of a 59-targeted gene panel, with the use of the Ion Torrent PGM platform. Conventional Sanger sequencing was used for segregation analysis in all the affected relatives. The proband and all the other hearing impaired members of the family underwent a thorough clinical and audiological evaluation.

Results: A new likely pathogenic mutation in the EYA4 gene (c.1154C > T; p.Ser385Leu) was identified in the proband and in her 42-year-old father with post-lingual non-syndromic profound sensorineural hearing loss. The EYA4 mutation was also found in the proband's grandfather and uncle, both showing clinical features of Waardenburg syndrome type 1. A novel pathogenic splice-site mutation (c.321+1G > A) of the PAX3 gene was found to co-segregate with the EYA4 mutation in these two subjects.

Conclusion: The identified novel EYA4 mutation can be considered responsible of the hearing loss observed in the proband and her father, while a dual molecular diagnosis was reached in the relatives co-segregating the EYA4 and the PAX3 mutations. In these two subjects the DFNA10 phenotype was masked by Waardenburg syndrome. The use of NGS targeted gene-panel, in combination with an extensive clinical and audiological examination led us to identify the genetic cause of the hearing loss in members of a family in which different forms of autosomal dominant deafness segregate. These results provide precise and especially important prognostic and follow-up information for the future audiologic management in the youngest affected member.
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http://dx.doi.org/10.1016/j.ijporl.2017.10.042DOI Listing
January 2018

CNTNAP2 mutations and autosomal dominant epilepsy with auditory features.

Epilepsy Res 2018 01 21;139:51-53. Epub 2017 Nov 21.

CNR-Neuroscience Institute, Section of Padua, Padova, Italy; Department of Biomedical Sciences, University of Padua, Padova, Italy. Electronic address:

Autosomal dominant epilepsy with auditory features (ADEAF) is clinically characterized by focal seizures with prominent auditory or aphasic auras and absence of structural brain abnormalities. Mutations in LGI1 and RELN genes account for the disorder in about 50% of ADEAF families. In a recent paper, a heterozygous intragenic deletion in the CNTNAP2 gene has been associated to ADEAF in a single family. We screened 28 ADEAF families for mutations in CNTNAP2 by next generation sequencing and copy number variation analyses and found no likely pathogenic mutations segregating with the disease. CNTNAP2 should be screened in genetically unsolved ADEAF families, but causative mutations are expected to be infrequent in this gene.
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http://dx.doi.org/10.1016/j.eplepsyres.2017.11.006DOI Listing
January 2018

Pyridoxine-dependent epilepsies: an observational study on clinical, diagnostic, therapeutic and prognostic features in a pediatric cohort.

Metab Brain Dis 2018 02 25;33(1):261-269. Epub 2017 Nov 25.

General Pediatrics and Pediatric Acute and Emergency Unit, Policlinico-Vittorio-Emanuele University Hospital, University of Catania, Catania, Italy.

The aim of our study was to describe the clinical, electroencephalogram, molecular findings and the diagnostic and therapeutic flow-chart of children with pyridoxine-dependent epilepsies (PDEs). We performed a retrospective observational study on children with PDEs, diagnosed and followed-up in Italian Pediatric Departments. In each centre, the authors collected data from a cohort of children admitted for intractable seizures, responsive to pyridoxine administration and resistant to other anticonvulsant therapies. Data were retrospectively analysed from January 2016 to January 2017. Sixteen patients (13 males, and 3 females) were included. We found that 93.75% of patients underwent conventional anticonvulsant therapy before starting pyridoxine administration and 62.5% had ex-juvantibus diagnosis, as specific serum diagnostic tests had been performed in only 37.5% of patients by alpha-AASA and pipecolic acid blood and urine dosage. The most common type of seizure was generalized tonic-clonic in 7 patients and the most common EEG pattern was characterized by a "burst suppression" pattern. Before pyridoxine administration, other anticonvulsant drugs were used in 93.75% of patients, with consequent onset of drug-resistance. Phenobarbital was the most frequently used drug as first-line treatment. The importance of our study relies on the need of a deeper knowledge of PDEs in terms of early diagnosis, avoiding incorrect treatment and related adverse events, clinical and EEG pathognomonic features, and genetic aspects of the disease.
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http://dx.doi.org/10.1007/s11011-017-0150-xDOI Listing
February 2018

Oligometastatic cancer: stereotactic ablative radiotherapy for patients affected by isolated body metastasis.

Acta Oncol 2017 Nov 18;56(11):1621-1625. Epub 2017 Aug 18.

a Department of Diagnostic Imaging, Molecular Imaging, Interventional Radiology and Radiotherapy , Tor Vergata General Hospital , Rome , Italy.

Background: To evaluate the outcome of patients affected by a single isolated body metastasis treated with stereotactic body radiotherapy (SBRT).

Material And Methods: Seven-eight patients were treated with SBRT for isolated body metastasis. The most frequent primary tumor was prostate cancer (28.2%), followed by colorectal cancer (23.1%) and lung cancer (20.5%). Median age at diagnosis of oligometastatic disease was 70 years (range 47-88). Median Karnofsky Performance Status (KPS) was 90 (range 70-100). The most common SBRT fractionation scheme was 5 × 7 Gy (total dose 35 Gy). Response to radiotherapy was determined according to RECIST criteria v1.1. Toxicity was registered according to Common Terminology Criteria for Adverse Events (CTCAE) v4.0. The survival analysis was performed with the Kaplan-Meier method. The correlation between time actuarial incidence and clinical parameters was studied, and the Kaplan-Meier method of log-rank test was applied.

Results: With a median follow-up of 22.68 months, local control was achieved in 89.7% of the cases. The two-year overall survival (OS) and progression-free survival (PFS) were 68% and 42%, respectively. On univariate analysis, KPS ≥80 is predictive for improved OS (p = .001) and PFS (p = .001). Acute toxicity of grade ≥2 occurred in eight (10.2%) patients and late grade ≥2 toxicity in five (6.4%) patients.

Conclusions: Ablative radiotherapy in 'early oligometastatic state' is a safe, effective and minimally invasive treatment modality. A good performance status (KPS ≥80) seems to influence the clinical outcome.
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http://dx.doi.org/10.1080/0284186X.2017.1346383DOI Listing
November 2017

Dynamic scaffolds for neuronal signaling: in silico analysis of the TANC protein family.

Sci Rep 2017 07 28;7(1):6829. Epub 2017 Jul 28.

Molecular Genetics of Neurodevelopmental disorders, Department of Woman and Child Health, University of Padua, Padua, Italy.

The emergence of genes implicated across multiple comorbid neurologic disorders allows to identify shared underlying molecular pathways. Recently, investigation of patients with diverse neurologic disorders found TANC1 and TANC2 as possible candidate disease genes. While the TANC proteins have been reported as postsynaptic scaffolds influencing synaptic spines and excitatory synapse strength, their molecular functions remain unknown. Here, we conducted a comprehensive in silico analysis of the TANC protein family to characterize their molecular role and understand possible neurobiological consequences of their disruption. The known Ankyrin and tetratricopeptide repeat (TPR) domains have been modeled. The newly predicted N-terminal ATPase domain may function as a regulated molecular switch for downstream signaling. Several putative conserved protein binding motifs allowed to extend the TANC interaction network. Interestingly, we highlighted connections with different signaling pathways converging to modulate neuronal activity. Beyond a known role for TANC family members in the glutamate receptor pathway, they seem linked to planar cell polarity signaling, Hippo pathway, and cilium assembly. This suggests an important role in neuron projection, extension and differentiation.
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http://dx.doi.org/10.1038/s41598-017-05748-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5533708PMC
July 2017

Volumetric image-guided highly conformal radiotherapy of the prostate bed: Toxicity analysis.

Rep Pract Oncol Radiother 2017 Jan-Feb;22(1):64-70. Epub 2016 Nov 24.

Department of Diagnostic Imaging, Molecular Imaging, Interventional Radiology and Radiotherapy, Tor Vergata General Hospital, Rome, Italy.

Aim: To evaluate toxicity of high conformal image-guided radiotherapy of the prostate bed.

Background: Radiotherapy of the prostate bed has a pivotal role in the post-operative and salvage settings, but few clinical data are available on the use of daily image guidance in combination with highly conformal techniques, and data on long-term results are lacking.

Materials And Methods: We analyzed 118 patients irradiated on the prostate bed using conformal plans processed with a micro-multileaf collimator, and daily checking treatment set-up with a cone-beam CT system. Correlation between toxicity and clinical-dosimetric parameters was assessed by the Cox regression model and log-rank test. Survival analyses were performed with the Kaplan-Meier method.

Results: Median follow-up was 54.08 months. Late grade ≥2 gastro-intestinal (GI) and genito-urinary (GU) toxicity were 3.4% and 4.2%, respectively. Actuarial 4-year late grade ≥2 GI and GU toxicities were 4% and 6%, respectively. Four-year relapse-free survival was 87%. At log-rank test, acute grade ≥2 GI toxicity is associated with the use of antihypertensives ( = 0.03), and there is a trend toward significance between the use of anticoagulants and late grade ≥2 GI toxicity ( = 0.07). At Cox analysis, acute grade ≥2 GU toxicity is correlated with the percentage of bladder volume receiving more than 65 Gy ( = 0.02, HR 1.87 CI 1.25-2.8), and the maximal dose to the rectum is correlated to the development of late grade ≥2 GI toxicity ( = 0.03, HR 2.75 CI 1.10-6.9).

Conclusions: Conformal volumetric image-guided radiotherapy of the prostate bed leads to low toxicity rates.
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http://dx.doi.org/10.1016/j.rpor.2016.10.006DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5126144PMC
November 2016

Technical solutions to reduce mediastinal irradiation in young patients undergoing treatment for lymphomas: Preliminary experience.

Med Dosim 2016 Winter;41(4):281-284. Epub 2016 Aug 21.

Radiation Therapy Unit, Department of Diagnostic Imaging, Molecular Imaging, Interventional Radiology and Radiotherapy, University of Tor Vergata, Rome, Italy.

This study aims at optimizing treatment planning in young patients affected by lymphoma (Stage II to III) by using an inclined board (IB) that allows reducing doses to the organs at risk. We evaluated 19 young patients affected by stage I to III lymphomas, referred to our Department for consolidation radiotherapy (RT) treatment on the mediastinum. Patients underwent 2 planning computed tomography (CT) scans performed in different positions: flat standard position and inclined position. A direct comparison between the different treatment plans was carried out analyzing dosimetric parameters obtained from dose-volume histograms generated for each plan. Comparison was performed to evaluate the sparing obtained on breast and heart. Dosimetric evaluation was performed for the following organs at risk (OARs): mammary glands, lungs, and heart. A statistically significant advantage was reported for V, V, and V for the breast when using the inclined board. A similar result was obtained for V and V on the heart. No advantage was observed in lung doses. The use of a simple device, such as an inclined board, allows the optimization of treatment plan, especially in young female patients, by ensuring a significant reduction of the dose delivered to breast and heart.
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http://dx.doi.org/10.1016/j.meddos.2016.06.004DOI Listing
August 2017

Von Hippel-Lindau disease: an evaluation of natural history and functional disability.

Neuro Oncol 2016 07 12;18(7):1011-20. Epub 2016 Jan 12.

Department of Neurosciences, Neurosurgery Unit, NOCSAE Modena Hospital, Modena, Italy (A.F., G.P.); Department of Medicine-DIMED, Section of Radiology, University of Padova, Italy (M.A.); Department of Statistical Sciences, University of Padova, Italy (B.S.); Familial Cancer Clinic and Oncoendocrinology, Veneto Institute of Oncology, IRCCS, Padova, Italy (F.S., F.B., S.Z., E.T., G.O.); Department of Urology, Ospedale Sant'Antonio, Padova, Italy (M.G.); Department of Neurosciences, Otosurgery Unit, University of Padova, Italy (E.Z.); Department of Neurosciences, Ophthalmology Unit, University of Padova, Italy (S.P.); Department of Women's and Children's Health, Pediatric Neurology Unit, University of Padova, Italy (A.M.); Department of Medicine-DIMED, University of Padova, Italy (G.O.).

Background: Although many studies have been published about specific lesions characterizing von Hippel-Lindau(VHL) disease, none have dealt with the natural history of the whole disease and the consequent disabilities. We aim to define the comprehensive natural history of VHL disease and to describe the functional disabilities and their impact upon patients' quality of life, thereby tailoring the follow-up schedule accordingly.

Methods: We performed a prospective analysis on 128 VHL-affected patients beginning in 1996. For each affected organ, we defined intervals between the first and subsequent VHL-related manifestations and compared them with current VHL surveillance protocols. We looked for any association of the number of involved organs with age, sex, type of VHL gene mutation, and functional domain mutation. Ultimately, we assessed the organ-specific disabilities caused by VHL disease.

Results: Hemangioblastomas show different patterns of progression depending on their location, whereas both renal cysts and carcinomas have similar progression rates. Surgery for pheochromocytoma and CNS hemangioblastoma is performed earlier than for pancreatic or renal cancer. The number of involved organs is associated with age but not with sex, type of VHL gene mutation, or functional domain mutation. A thorough analysis of functional disabilities showed that age is related to the first-appearing functional impairment, but it is not predictive of the final number of disabilities.

Conclusions: Our study defines the disease progression and provides a comprehensive view of the syndrome over time. We analyzed for the first time the functional disability of VHL patients, assessing the progression for each function.
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http://dx.doi.org/10.1093/neuonc/nov313DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4896541PMC
July 2016

Functional characterization of CDK5 and CDK5R1 mutations identified in patients with non-syndromic intellectual disability.

J Hum Genet 2016 Apr 10;61(4):283-93. Epub 2015 Dec 10.

Dipartimento di Biotecnologie Mediche e Medicina Traslazionale, Università degli Studi di Milano, Milan, Italy.

Cyclin-dependent kinase 5 (CDK5) and cyclin-dependent kinase 5, regulatory subunit 1 (CDK5R1), encoding CDK5 activator p35, have a fundamental role in central nervous system (CNS) development and function, and are involved in the pathogenesis of several neurodegenerative disorders, thus constituting strong candidate genes for the onset of intellectual disability (ID). We carried out a mutation screening of CDK5 and CDK5R1 coding regions and CDK5R1 3'-UTR on a cohort of 360 patients with non-syndromic ID (NS-ID) using denaturing high performance liquid chromatography (DHPLC) and direct sequencing. We found one novel silent mutation in CDK5 and one novel silent mutation in CDK5R1 coding regions, three novel intronic variations in CDK5, not causing any splicing defect, and four novel heterozygous variations in CDK5R1 3'-UTR. None of these variations was present in 450 healthy controls and single-nucleotide polymorphism (SNP) databases. The functional study of CDK5R1 p.A108V mutation evidenced an impaired p35 cleavage by the calcium-dependent protease calpain. Moreover, luciferase constructs containing the CDK5R1 3'-UTR mutations showed altered gene expression levels. Eight known polymorphisms were also identified displaying different frequencies in NS-ID patients compared with the controls. In particular, the minor allele of CDK5R1 3'-UTR rs735555 polymorphism was associated with increased risk for NS-ID. In conclusion, our data suggest that mutations and polymorphisms in CDK5 and CDK5R1 genes may contribute to the onset of the NS-ID phenotype.
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http://dx.doi.org/10.1038/jhg.2015.144DOI Listing
April 2016

Distribution of AGG interruption patterns within nine world populations.

Intractable Rare Dis Res 2014 Nov;3(4):153-61

Department of Biochemistry and Molecular Medicine, University of California Davis, School of Medicine, Davis, CA, USA; ; M.I.N.D. Institute, University of California Davis Medical Center, Davis, CA, USA.

The CGG trinucleotide repeat within the FMR1 gene is associated with multiple clinical disorders, including fragile X-associated tremor/ataxia syndrome, fragile X-associated primary ovarian insufficiency, and fragile X syndrome. Differences in the distribution and prevalence of CGG repeat length and of AGG interruption patterns have been reported among different populations and ethnicities. In this study we characterized the AGG interruption patterns within 3,065 normal CGG repeat alleles from nine world populations including Australia, Chile, United Arab Emirates, Guatemala, Indonesia, Italy, Mexico, Spain, and United States. Additionally, we compared these populations with those previously reported, and summarized the similarities and differences. We observed significant differences in AGG interruption patterns. Frequencies of longer alleles, longer uninterrupted CGG repeat segments and alleles with greater than 2 AGG interruptions varied between cohorts. The prevalence of fragile X syndrome and FMR1 associated disorders in various populations is thought to be affected by the total length of the CGG repeat and may also be influenced by the AGG distribution pattern. Thus, the results of this study may be important in considering the risk of fragile X-related conditions in various populations.
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http://dx.doi.org/10.5582/irdr.2014.01028DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4298645PMC
November 2014

Acute and late toxicity after three-dimensional conformal image-guided radiotherapy for localized prostate cancer.

Cancer Invest 2014 Dec 27;32(10):526-32. Epub 2014 Oct 27.

Department of Diagnostic Imaging, Molecular Imaging, Interventional Radiology and Radiotherapy, Tor Vergata University General Hospital, 00133 Rome, Italy1.

We evaluated the clinical impact of a high definition micro-multileaf collimator and a linac-integrated cone-beam computed tomography in 142 patients treated with conformal radiotherapy for localized prostate cancer to a total dose of 76 Gy. Details on treatment toxicity and tumour control were collected. The 3 years biochemical relapse-free survival was 90%. Acute and late gastrointestinal toxicities were low (3-year actuarial late toxicity of 11.2%). Acute genitourinary toxicity was relatively high, the 3-year actuarial genitourinary late toxicity was 12%. Conformal image-guided radiotherapy for localized prostate cancer leads to low rates of late toxicity with a high rate of tumor control.
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http://dx.doi.org/10.3109/07357907.2014.970193DOI Listing
December 2014
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