Publications by authors named "Alessandro Orsini"

39 Publications

The brain-heart interaction in epilepsy: implications for diagnosis, therapy, and SUDEP prevention.

Ann Clin Transl Neurol 2021 Jul 28;8(7):1557-1568. Epub 2021 May 28.

IRCCS Istituto Giannina Gaslini, Genova, Italy.

The influence of the central nervous system and autonomic system on cardiac activity is being intensively studied, as it contributes to the high rate of cardiologic comorbidities observed in people with epilepsy. Indeed, neuroanatomic connections between the brain and the heart provide links that allow cardiac arrhythmias to occur in response to brain activation, have been shown to produce arrhythmia both experimentally and clinically. Moreover, seizures may induce a variety of transient cardiac effects, which include changes in heart rate, heart rate variability, arrhythmias, asystole, and other ECG abnormalities, and can trigger the development of Takotsubo syndrome. People with epilepsy are at a higher risk of death than the general population, and sudden unexpected death in epilepsy (SUDEP) is the most important direct epilepsy-related cause of death. Although the cause of SUDEP is still unknown, cardiac abnormalities during and between seizures could play a significant role in its pathogenesis, as highlighted by studies on animal models of SUDEP and registration of SUDEP events. Recently, genetic mutations in genes co-expressed in the heart and brain, which may result in epilepsy and cardiac comorbidity/increased risk for SUDEP, have been described. Recognition and a better understanding of brain-heart interactions, together with new advances in sequencing techniques, may provide new insights into future novel therapies and help in the prevention of cardiac dysfunction and sudden death in epileptic individuals.
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http://dx.doi.org/10.1002/acn3.51382DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8283165PMC
July 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.
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http://dx.doi.org/10.1016/j.seizure.2021.03.025DOI Listing
May 2021

Italian cohort of Lafora disease: Clinical features, disease evolution, and genotype-phenotype correlations.

J Neurol Sci 2021 May 20;424:117409. Epub 2021 Mar 20.

Unit of Medical Genetics, IRCCS Istituto Giannina Gaslini, Genova, Italy; Department of Neurosciences, Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health, Università degli Studi di Genova, Genova, Italy.

Background: Lafora disease (LD) is characterized by progressive myoclonus, refractory epilepsy, and cognitive deterioration. This complex neurodegenerative condition is caused by pathogenic variants in EPM2A/EPM2B genes, encoding two essential glycogen metabolism enzymes known as laforin and malin. Long-term follow-up data are lacking. We describe the clinical features and genetic findings of a cohort of 26 Italian patients with a long clinical follow-up.

Methods: Patients with EPM2A/EPM2B pathogenic variants were identified by direct gene sequencing or gene panels with targeted re-sequencing. Disease progression, motor functions, and mental performance were assessed by a simplified disability scale. Spontaneous/action myoclonus severity was scored by the Magaudda Scale.

Results: Age range was 12.2-46.2 years (mean:25.53 ± 9.14). Age at disease onset ranged from 10 to 22 years (mean:14.04 ± 2.62). The mean follow-up period was 11.48 ± 7.8 years. Twelve out of the 26 (46%) patients preserved walking ability and 13 (50%) maintained speech. A slower disease progression with preserved ambulation and speech after ≥4 years of follow-up was observed in 1 (11%) out of the 9 (35%) EPM2A patients and in 6 (35%) out of the 17 (65%) EPM2B patients. Follow-up was >10 years in 7 (41.2%) EPM2B individuals, including two harbouring the homozygous p.(D146N) pathogenic variant.

Conclusions: This study supports an overall worse disease outcome with severe deterioration of ambulation and speech in patients carrying EPM2A mutations. However, the delayed onset of disabling symptoms observed in the EPM2B subjects harbouring the p.(D146N) pathogenic variant suggests that the underlying causative variant may still influence LD severity.
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http://dx.doi.org/10.1016/j.jns.2021.117409DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8166462PMC
May 2021

The role of inflammatory mediators in epilepsy: Focus on developmental and epileptic encephalopathies and therapeutic implications.

Epilepsy Res 2021 May 18;172:106588. Epub 2021 Feb 18.

Pediatric Clinic, IRCCS Policlinico San Matteo Foundation, University of Pavia, Viale Golgi 19, 27100 Pavia, Italy.

In recent years, there has been an increasing interest in the potential involvement of neuroinflammation in the pathogenesis of epilepsy. Specifically, the role of innate immunity (that includes cytokines and chemokines) has been extensively investigated either in animal models of epilepsy and in clinical settings. Developmental and epileptic encephalopathies (DEE) are a heterogeneous group of epileptic disorders, in which uncontrolled epileptic activity results in cognitive, motor and behavioral impairment. By definition, epilepsy in DEE is poorly controlled by common antiepileptic drugs but may respond to alternative treatments, including steroids and immunomodulatory drugs. In this review, we will focus on how cytokines and chemokines play a role in the pathogenesis of DEE and why expanding our knowledge about the role of neuroinflammation in DEE may be crucial to develop new and effective targeted therapeutic strategies to prevent seizure recurrence and developmental regression.
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http://dx.doi.org/10.1016/j.eplepsyres.2021.106588DOI Listing
May 2021

PTSD in parents of children with severe diseases: a systematic review to face Covid-19 impact.

Ital J Pediatr 2021 Jan 14;47(1). Epub 2021 Jan 14.

Department of Clinical and Experimental Medicine, Psychiatric Clinic, Azienda Ospedaliero-Universitaria Pisana, University of Pisa, Pisa, Italy.

Context: The literature agrees on the impact of post-traumatic stress symptoms in parents of seriously ill children but there is less clarity about the real extent and gender differences of this psychopathological risk. The recent Covid-19 outbreak highlighted new burdens for researchers on Post Traumatic Stress Disorder (PTSD) and clear evidence-based knowledge on this issue is timely needed.

Objective: In this review, we present a synthesis of the updated evidence on PTSD rates in parents of children with severe diseases. We also aim to try to understand if research in this field has been refined over time with the long-term intent to better face the new challenges of Covid-19 in the paediatric field.

Data Sources: The PubMed database was searched.

Study Selection: Studies were included if they assessed PTSD in parents of children diagnosed with physical illnesses.

Data Extraction: Of 240 studies, 4 were included.

Results: Analysis of the 4 studies revealed 2 studies with PTSD rates around 20% and in line with previous best-evidence. All 4 studies tried to provide more data on fathers, however, all the studies present the lack of a control group.

Limitations: The limited number of studies, which also differ widely in the methodology used.

Conclusions: Methodological errors evidenced in all the 4 studies limit their reliability, making the understanding of the paediatric caregiver's concern regarding PTSD still difficult. More sound research is needed.
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http://dx.doi.org/10.1186/s13052-021-00957-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7807213PMC
January 2021

Trait impulsivity in Juvenile Myoclonic Epilepsy.

Ann Clin Transl Neurol 2021 01 2;8(1):138-152. Epub 2020 Dec 2.

Department of Basic & Clinical Neurosciences, Institute of Psychiatry, Psychology & Neuroscience, King's College London, UK.

Objective: Impulsivity is a multidimensional construct that can predispose to psychopathology. Meta-analysis demonstrates an association between response impulsivity and Juvenile Myoclonic Epilepsy (JME), a common genetic generalized epilepsy. Here, we test the hypotheses that trait impulsivity is (i) elevated in JME compared to controls; (ii) moderated by specific seizure characteristics; and (iii) associated with psychiatric adverse effects of antiepileptic drugs (AEDs).

Methods: 322 participants with JME and 126 age and gender-matched controls completed the Barratt's Impulsiveness Scale (BIS-brief) alongside information on seizure history and AED use. We compared group BIS-brief scores and assessed associations of JME BIS-brief scores with seizure characteristics and AED adverse effects.

Results: The mean BIS-brief score in JME was 18.1 ± 4.4 compared with 16.2 ± 4.1 in controls (P = 0.0007). Elevated impulsivity was associated with male gender (P = 0.027), frequent absence seizures (P = 0.0004) and lack of morning predominance of myoclonus (P = 0.008). High impulsivity significantly increased the odds of a psychiatric adverse event on levetiracetam (P = 0.036), but not any other psychiatric or somatic adverse effects.

Interpretation: Trait impulsivity is elevated in JME and comparable to scores in personality and neurotic disorders. Increased seizure frequency and absence of circadian seizure pattern moderate BIS score, suggesting disruption of both cortico-striatal and thalamocortical networks as a shared mechanism between seizures and impulsivity in JME. These findings warrant consideration of impulsivity as a distinct target of intervention, and as a stratifying factor for AED treatment in JME, and perhaps other types of epilepsy. The role of impulsivity in treatment adherence and psychosocial outcome requires further investigation.
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http://dx.doi.org/10.1002/acn3.51255DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7818143PMC
January 2021

Unilateral Lisch nodules in a pediatric patient: a sign for genetic mosaicism?

Minerva Pediatr 2020 Nov 17. Epub 2020 Nov 17.

Department of Neurosciences, Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health, G. Gaslini Institute, University of Genoa, Genoa, Italy.

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http://dx.doi.org/10.23736/S0026-4946.20.06134-4DOI Listing
November 2020

Posterior Reversible Encephalopathy Syndrome in infants and young children.

Eur J Paediatr Neurol 2021 Jan 28;30:128-133. Epub 2020 Oct 28.

Unit of Pediatric Oncology and Haematology "Lalla Seràgnoli", Department of Pediatrics, Sant'Orsola Hospital, University of Bologna, Bologna, Italy. Electronic address:

Aim: The aim of this study was to describe the characteristics of Posterior Reversible Encephalopathy Syndrome (PRES) in infants and young children (<6 years) and to compare them with the older pediatric population affected by PRES.

Methods: we retrospectively reviewed records of 111 children (0-17 years) diagnosed with PRES from 2000 to 2018 in 6 referral pediatric hospitals in Italy. The clinical, radiological and EEG features, as well as intensive care unit (ICU) admission rate and outcome of children aged <6 years were compared to those of older children (6-17 years). Factors associated with ICU admission in the whole pediatric cohort with PRES were also evaluated.

Results: Twenty-nine patients younger than 6 years (26%) were enrolled with a median age at onset of PRES of 4 years (range: 6 months-5 years). Epileptic seizures were the most frequent presentation at the disease onset (27/29 patients). Status epilepticus (SE) was observed in 21/29 patients: in detail, 11 developed convulsive SE and 10 presented nonconvulsive SE (NCSE). SE was more frequent in children <6 years compared with older children (72% vs 45%) as well as NCSE (35% vs 10%). Seventeen children aged <6 years required ICU admission. Prevalence of ICU admissions was higher within younger population compared to older (59% vs 37%). In the whole study population SE was significantly associated with ICU admission (p = 0.001).

Conclusions: PRES in children < 6 years differs from older children in clinical presentation suggesting a more severe presentation at younger age.
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http://dx.doi.org/10.1016/j.ejpn.2020.10.009DOI Listing
January 2021

Challenges and management of neurological and psychiatric manifestations in SARS-CoV-2 (COVID-19) patients.

Neurol Sci 2020 Sep 6;41(9):2353-2366. Epub 2020 Aug 6.

Pediatric Neurology Unit, IRCCS Istituto Giannina Gaslini, Genoa, Italy.

COVID-19 is a pandemic caused by human coronavirus (HCoV) SARS-CoV-2, which originated in Wuhan, China, at the end of 2019 and spread globally during 2020. Due to the difficulty of clinical decision-making during this period, our study group reviewed current literature focusing on the neurological and psychiatric aspects of COVID-19. Despite the knowledge on this newly discovered virus which is constantly evolving, different pieces of evidence reported an association between COVID-19 and neurological symptoms like headache, dizziness, taste and smell disorders and complications involving the nervous system eventually triggered by the pathologic processes elicited by SARS-CoV-2. It seems that younger patients are less prone to develop severe forms of COVID-19. However, neurological signs have been reported in paediatric patients as well, and in some cases, the infection presented neurological sequelae. Furthermore, children with particular neurological diseases or treated with specific drugs (e.g. immune-suppressant therapies) must be carefully monitored during this pandemic. Neurologists should be aware of the main drug-drug interactions and the neurological side effects of COVID-19 treatments. Notably, adverse mental health impact has been reported in patients with SARS-CoV-2, which could be related either to the social strain or to the eventual neurotropic effects of the virus, which in other infections have been proven to promote the onset of psychiatric symptoms. Further, psychiatric population may be more vulnerable to the infection and at higher risk for adverse outcomes.
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http://dx.doi.org/10.1007/s10072-020-04544-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7410516PMC
September 2020

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

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

Istituto di Ricovero e Cura a Carattere Scientifico, Ospedale Policlinico San Martino, Genoa, Italy; Center for Synaptic Neuroscience and Technology, Istituto Italiano di Tecnologia, Genoa, Italy.

Prrt2 is a neuron-specific protein expressed at axonal and pre-synaptic domains, involved in synaptic neurotransmitter release and modulation of intrinsic excitability. Mutations in PRRT2 cause a spectrum of autosomal dominant paroxysmal neurological disorders including epilepsy, movement disorders, and hemiplegic migraine and show incomplete penetrance and variable expressivity. We assessed the diagnostic rate of PRRT2 in a cohort of Italian patients with epilepsy and/or paroxysmal kinesigenic dyskinesia (PKD) and evaluated genotype-phenotype correlations. Clinical data were collected using a structured questionnaire. Twenty-seven out of 55 (49.1%) probands carried PRRT2 heterozygous pathogenic variants, including six previously known genotypes and one novel missense mutation. A family history of epilepsy starting in the first year of life and/or PKD was strongly suggestive of a PRRT2 pathogenic variant. Epilepsy patients harbouring PRRT2 pathogenic variants showed earlier seizure onset and more frequent clusters compared with PRRT2-negative individuals with epilepsy. Moreover, we did also identify individuals with PRRT2 pathogenic variants with atypical age at onset, i.e. childhood-onset epilepsy and infantile-onset PKD. However, the lack of a clear correlation between specific PRRT2 genotypes and clinical manifestations and the high incidence of asymptomatic carriers suggest the involvement of additional factors in modulating expressivity of PRRT2-related disorders. Finally, our study supports the pleiotropic and multifaceted physiological role of PRRT2 gene which is emerging from experimental neuroscience.
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http://dx.doi.org/10.1016/j.ejpn.2020.06.005DOI Listing
September 2020

Targeted re-sequencing for early diagnosis of genetic causes of childhood epilepsy: the Italian experience from the 'beyond epilepsy' project.

Ital J Pediatr 2020 Jul 6;46(1):92. Epub 2020 Jul 6.

Pediatric Neurology and Muscular Diseases Unit, IRCCS 'G. Gaslini' Institute, 16147, Genoa, Italy.

Background: Childhood epilepsies are a heterogeneous group of conditions differing in diagnostic criteria, management, and outcome. Late-infantile neuronal ceroid lipofuscinosis type 2 (CLN2) is a neurodegenerative condition caused by biallelic TPP1 variants. This disorder presents with subtle and relatively non-specific symptoms, mimicking those observed in more common paediatric epilepsies and followed by rapid psychomotor deterioration and drug-resistant epilepsy. A prompt diagnosis is essential to adopt appropriate treatment and disease management strategies.

Methods: This is a prospective, multicentre study on the efficiency of targeted re-sequencing in the early identification of the genetic causes of childhood epilepsy, with particular regard to CLN2. After phenotypic characterization, a 283-gene Next Generation Sequencing panel was performed in 21 Italian children with neurodevelopmental abnormalities, aged between 24 and 60 months, experiencing first unprovoked seizure after 2 years of age.

Results: The average age at enrolment was 39.9 months, with a mean age at seizure onset of 30.9 months and a mean time interval between seizure onset and targeted resequencing of 9 months. Genetic confirmation was achieved in 4 out of 21 patients, with a diagnostic yield of 19%. In one case, the homozygous splice acceptor variant c.509-1G > C in TPP1 was identified, leading to a CLN2 diagnosis. Three pathogenic variants in MECP2 were also detected in three patients, including the frameshift variant c.1157_1186delinsA (p.Leu386Hisfs*9) in a girl with negative single gene sequencing. Variants of unknown significance (VUS) were found in 11 out of 21 (52.4%) individuals, whereas no clinically significant variants were observed in the remaining 6 subjects.

Conclusions: Our findings support the efficacy of target re-sequencing in the identification of the genetic causes of childhood epilepsy and suggest that this technique might prove successful in the early detection of CLN2 as well as other neurodevelopmental conditions.
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http://dx.doi.org/10.1186/s13052-020-00860-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7339579PMC
July 2020

Advanced pharmacological therapies for neurofibromatosis type 1-related tumors.

Acta Biomed 2020 06 30;91(7-S):101-114. Epub 2020 Jun 30.

Pediatric Clinic, Department of Pediatrics, Fondazione IRCCS Policlinico San Matteo, University of Pavia, Pavia, Italy.

Neurofibromatosis Type 1 (NF1) is an autosomal dominant tumor-predisposition disorder that is caused by a heterozygous loss of function variant in the NF1 gene, which encodes a protein called neurofibromin. The absence of neurofibromin causes increased activity in the Rat sarcoma protein (RAS) signalling pathway, which results in an increased growth and cell proliferation. As a result, both oncological and non-oncological comorbidities contribute to a high morbidity and mortality in these patients. Optic pathways gliomas, plexiform neurofibromas and malignant peripheral nerve sheath tumor (MPNST) are the most frequent NF1-associated tumors. The treatment of these complications is often challenging, since surgery may not be feasible due to the location, size, and infiltrative nature of these tumors, and standard chemotherapy or radiotherapy are burdened by significant toxicity and risk for secondary malignancies. For these reasons, following the novel discoveries of the pathophysiological mechanisms that lead to cell proliferation and tumorigenesis in NF1 patients, emerging drugs targeting specific signalling pathways (i.e. the MEK/ERK cascade), have been developed with promising results.
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http://dx.doi.org/10.23750/abm.v91i7-S.9961DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7975824PMC
June 2020

Enhancing the Separation Performance of Glassy PPO with the Addition of a Molecular Sieve (ZIF-8): Gas Transport at Various Temperatures.

Membranes (Basel) 2020 Mar 27;10(4). Epub 2020 Mar 27.

Sotacarbo S.p.A., Grande Miniera di Serbariu, 09013 Carbonia (CA), Italy.

In this study, we prepared and characterized composite films formed by amorphous poly(2,6-dimethyl-1,4-phenylene oxide) (PPO) and particles of the size-selective Zeolitic Imidazolate Framework 8 (ZIF-8). The aim was to increase the permselectivity properties of pure PPO using readily available materials to enable the possibility to scale-up the technology developed in this work. The preparation protocol established allowed robust membranes with filler loadings as high as 45 wt% to be obtained. The thermal, morphological, and structural properties of the membranes were analyzed via DSC, SEM, TGA, and densitometry. The gas permeability and diffusivity of He, CO, CH, and N were measured at 35, 50, and 65 °C. The inclusion of ZIF-8 led to a remarkable increase of the gas permeability for all gases, and to a significant decrease of the activation energy of diffusion and permeation. The permeability increased up to +800% at 45 wt% of filler, reaching values of 621 Barrer for He and 449 for CO at 35 °C. The ideal size selectivity of the PPO membrane also increased, albeit to a lower extent, and the maximum was reached at a filler loading of 35 wt% (1.5 for He/CO, 18 for CO/N, 17 for CO/CH, 27 for He/N, and 24 for He/CH). The density of the composite materials followed an additive behavior based on the pure values of PPO and ZIF-8, which indicates good adhesion between the two phases. The permeability and He/CO selectivity increased with temperature, which indicates that applications at higher temperatures than those inspected should be encouraged.
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http://dx.doi.org/10.3390/membranes10040056DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7231394PMC
March 2020

Long-term dentoskeletal changes of class II growing patients' treatment with the propulseur universal light appliance. A prospective controlled study.

Minerva Stomatol 2020 Apr 16;69(2):79-86. Epub 2020 Mar 16.

Department of Orthodontics, School of Dentistry, University of Genoa, Genoa, Italy.

Background: Class II is one of the most common malocclusions. The prevailing aspect in Class II patients is a mandibular deficiency. Various removable and fixed functional therapies are used in order to enhance the mandibular growth or position. The aim of this prospectively controlled study was to evaluate long-term dentoskeletal changes obtained by a functional appliance for Class II.

Methods: Prospective controlled study, based on a sample size calculation. 26 Class II Division 1 patients (11.8±1.5 years) were consecutively treated with the propulseur universal light (PUL) appliance and a multi bracket appliance (PG), they were compared to a sample of 26 Class II untreated patients (11.5±0.8 years) (CG). Lateral cephalograms were taken before and after the PUL therapy, and after multibracket treatment. Interaction analysis was carried out to test whether the PUL parameters in treatment groups were different according to the acquisition times, using the Linear Mixed-Effects Model.

Results: Significant ANB, Overjet and WITS differences existed in treatment groups according to the time. In particular, comparing to T1 vs. T0, the relative difference (RD) means in the control group were -0.34, -0.31 and 0.17 for ANB, Overjet and WITS, respectively. The corresponding RD means in the treated group PG were -1.58, -4.27 and -2.38. Comparing to T2 vs. T0, the RD means in the control group were -0.36, -0.51 and 0.63 for ANB, Overjet and WITS, respectively. While the corresponding RD means in the treated group were -2.08, -5.12 and -2.50.

Conclusions: The PUL appliance successfully corrected class II malocclusion. The long term correction was mainly due to dentoalveolar effects: therapy success was 91% for overjet correction and 76% for ANB correction. During the post functional appliance period, overjet was stable in 77% of the treated subjects, and ANB in 74% of the treated subjects.
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http://dx.doi.org/10.23736/S0026-4970.19.04283-3DOI Listing
April 2020

Distal motor neuropathy associated with novel EMILIN1 mutation.

Neurobiol Dis 2020 04 21;137:104757. Epub 2020 Jan 21.

Department of Neurosciences, Rehabilitation, Ophthalmology, Genetics, Maternal and Child Health (DINOGMI), University of Genoa, Genoa, Italy; Paediatric Neurology and Neuromuscular Disorders Unit, IRCCS Istituto Giannina Gaslini, Genoa, Italy. Electronic address:

Elastin microfibril interface-located proteins (EMILINs) are extracellular matrix glycoproteins implicated in elastogenesis and cell proliferation. Recently, a missense mutation in the EMILIN1 gene has been associated with autosomal dominant connective tissue disorder and motor-sensory neuropathy in a single family. We identified by whole exome sequencing a novel heterozygous EMILIN1 mutation c.748C>T [p.R250C] located in the coiled coil forming region of the protein, in four affected members of an autosomal dominant family presenting a distal motor neuropathy phenotype. In affected patient a sensory nerve biopsy showed slight and unspecific changes in the number and morphology of myelinated fibers. Immunofluorescence study of a motor nerve within a muscle biopsy documented the presence of EMILIN-1 in nerve structures. Skin section and skin derived fibroblasts displayed a reduced extracellular deposition of EMILIN-1 protein with a disorganized network of poorly ramified fibers in comparison with controls. Downregulation of emilin1a in zebrafish displayed developmental delay, locomotion defects, and abnormal axonal arborization from spinal cord motor neurons. The phenotype was complemented by wild-type zebrafish emilin1a, and partially the human wild-type EMILIN1 cRNA, but not by the cRNA harboring the novel c.748C>T [p.R250C]. These data suggest a role of EMILIN-1 in the pathogenesis of diseases affecting the peripheral nervous system.
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http://dx.doi.org/10.1016/j.nbd.2020.104757DOI Listing
April 2020

A pathway to precision therapy even for mitochondrial myoclonic epilepsy.

Seizure 2020 05 15;78:170-171. Epub 2019 Nov 15.

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

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http://dx.doi.org/10.1016/j.seizure.2019.11.001DOI Listing
May 2020

Gelastic seizures not associated with hypothalamic hamartoma: A long-term follow-up study.

Epilepsy Behav 2020 02 1;103(Pt A):106578. Epub 2019 Nov 1.

Department of Pediatrics, University of L'Aquila, Via Vetoio, 1. Coppito, L'Aquila, Italy. Electronic address:

Objective: The objective of the study was to describe the electroclinical features, seizure semiology, and the long-term evolution of gelastic seizures (GS) not associated with hypothalamic hamartoma (HH).

Methods: We reviewed video-electroencephalogram (video-EEG) recordings from pediatric patients with GS without HH admitted to 14 Italian epilepsy centers from 1994 to 2013. We collected information about age at onset, seizures semiology, EEG and magnetic resonance imaging (MRI) findings, treatment, and clinical outcome in terms of seizure control after a long-term follow-up.

Results: A total of 30 pediatric patients were stratified into two groups according to neuroimaging findings: group 1 including 19 children (63.3%) with unremarkable neuroimaging and group 2 including 11 children with structural brain abnormalities (36.7%). At the follow-up, patients of group 1 showed better clinical outcome both in terms of seizure control and use of AED polytherapy. Our patients showed remarkable clinical heterogeneity, including seizure semiology and epilepsy severity. Electroencephalogram recordings showed abnormalities mainly in the frontal, temporal, and frontotemporal regions without relevant differences between the two groups. Overall, carbamazepine showed good efficacy to control GS.

Conclusions: Patients with nonlesional GS have a more favorable outcome with better drug response, less need of polytherapy, and good long-term prognosis, both in terms of seizure control and EEG findings.
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http://dx.doi.org/10.1016/j.yebeh.2019.106578DOI Listing
February 2020

A prenatal case with multiple supernumerary markers identified as derivatives of chromosomes 13, 15, and 20: molecular cytogenetic characterization and review of the literature.

J Matern Fetal Neonatal Med 2021 Sep 1;34(17):2918-2922. Epub 2019 Oct 1.

Cytogenetics Unit, Department of Laboratory Medicine, Azienda Ospedaliero Universitaria Pisana, Pisa, Italy.

Multiple small supernumerary marker chromosomes (sSMCs) are among the rarest cytogenetic abnormalities as they represent roughly 1.4% of cases with sSMCs. We report on a prenatal case presenting de novo multiple sSMCs; these sSMCs were characterized by array CGH and FISH and resulted deriving from three different chromosomes: a der(13), a der(15) and a der(20). The co-presence of der(13), der(20), and der(15) have not been reported yet. The clinical consequences of this marker combination cannot be precisely predicted. However, according to the publicly available databases, the partial trisomies of chromosome 13 and 20 have probably a pathogenic effect. It is worth noting that a cooperative effect, due to interactions among genes harbored on the three derivatives, cannot be excluded, making the genetic counseling challenging.
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http://dx.doi.org/10.1080/14767058.2019.1670808DOI Listing
September 2021

The best evidence for progressive myoclonic epilepsy: A pathway to precision therapy.

Seizure 2019 Oct 23;71:247-257. Epub 2019 Aug 23.

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

Progressive Myoclonus Epilepsies (PMEs) are a group of uncommon clinically and genetically heterogeneous disorders characterised by myoclonus, generalized epilepsy, and neurological deterioration, including dementia and ataxia. PMEs may have infancy, childhood, juvenile or adult onset, but usually present in late childhood or adolescence, at variance from epileptic encephalopathies, which start with polymorphic seizures in early infancy. Neurophysiologic recordings are suited to describe faithfully the time course of the shock-like muscle contractions which characterize myoclonus. A combination of positive and negative myoclonus is typical of PMEs. The gene defects for most PMEs (Unverricht-Lundborg disease, Lafora disease, several forms of neuronal ceroid lipofuscinoses, myoclonus epilepsy with ragged-red fibers [MERRF], and type 1 and 2 sialidoses) have been identified. PMEs are uncommon disorders, difficult to diagnose in the absence of extensive experience. Thus, aetiology is undetermined in many patients, despite the advance in molecular medicine. Treatment of PMEs remains essentially symptomaticof seizures and myoclonus, together with palliative, supportive, and rehabilitative measures. The response to therapy may initially be relatively favourable, afterwards however, seizures may become more frequent, and progressive neurologic decline occurs. The prognosis of a PME depends on the specific disease. The history of PMEs revealed that the international collaboration and sharing experience is the right way to proceed. This emerging picture and biological insights will allow us to find ways to provide the patients with meaningful treatment.
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http://dx.doi.org/10.1016/j.seizure.2019.08.012DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7288863PMC
October 2019

The spectrum of intermediate SCN8A-related epilepsy.

Epilepsia 2019 05 10;60(5):830-844. Epub 2019 Apr 10.

Neuroscience Department, Children's Hospital Anna Meyer, University of Florence, Florence, Italy.

Objective: Pathogenic variants in SCN8A have been associated with a wide spectrum of epilepsy phenotypes, ranging from benign familial infantile seizures (BFIS) to epileptic encephalopathies with variable severity. Furthermore, a few patients with intellectual disability (ID) or movement disorders without epilepsy have been reported. The vast majority of the published SCN8A patients suffer from severe developmental and epileptic encephalopathy (DEE). In this study, we aimed to provide further insight on the spectrum of milder SCN8A-related epilepsies.

Methods: A cohort of 1095 patients were screened using a next generation sequencing panel. Further patients were ascertained from a network of epilepsy genetics clinics. Patients with severe DEE and BFIS were excluded from the study.

Results: We found 36 probands who presented with an SCN8A-related epilepsy and normal intellect (33%) or mild (61%) to moderate ID (6%). All patients presented with epilepsy between age 1.5 months and 7 years (mean = 13.6 months), and 58% of these became seizure-free, two-thirds on monotherapy. Neurological disturbances included ataxia (28%) and hypotonia (19%) as the most prominent features. Interictal electroencephalogram was normal in 41%. Several recurrent variants were observed, including Ile763Val, Val891Met, Gly1475Arg, Gly1483Lys, Phe1588Leu, Arg1617Gln, Ala1650Val/Thr, Arg1872Gln, and Asn1877Ser.

Significance: With this study, we explore the electroclinical features of an intermediate SCN8A-related epilepsy with mild cognitive impairment, which is for the majority a treatable epilepsy.
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http://dx.doi.org/10.1111/epi.14705DOI Listing
May 2019

Advantages of Array Comparative Genomic Hybridization Using Buccal Swab DNA for Detecting Pallister-Killian Syndrome.

Ann Lab Med 2019 Mar;39(2):232-234

Department of Medicine of Laboratory, Section of Cytogenetics, Azienda Ospedaliero Universitaria Pisana, Pisa, Italy.

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http://dx.doi.org/10.3343/alm.2019.39.2.232DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6240520PMC
March 2019

Should children over 12 years have an EEG after a single unprovoked epileptic seizure?

Minerva Pediatr 2018 08;70(4):409-411

Department of Paediatric Neurology, Oxford Children's Hospital, Oxford, UK.

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http://dx.doi.org/10.23736/S0026-4946.17.04986-6DOI Listing
August 2018

Mothers and fathers of children with epilepsy: gender differences in post-traumatic stress symptoms and correlations with mood spectrum symptoms.

Neuropsychiatr Dis Treat 2018 25;14:1371-1379. Epub 2018 May 25.

Psychiatric Clinic.

Background: Post-traumatic stress disorder (PTSD) and post-traumatic stress spectrum have been recently applied to understand the impact of life-threatening disease or injury in one's child; nevertheless, scant data are available on a particular chronic illness such as epilepsy whose phenotypic expression is seizures, which are acute, sudden, and unpredictable manifestations. Subjects with bipolar disorders or with mood spectrum symptoms demonstrated to be more vulnerable to develop PTSD in the aftermath of a trauma.

Objectives: The main aim of this study was to evaluate post-traumatic symptoms among 134 parents of children with a diagnosis of epilepsy, followed at the outpatient neurologic unit of Department of Pediatrics in Santa Chiara Hospital in Pisa, as well as gender differences. The second aim of this study was to estimate the impact of lifetime mood spectrum on post-traumatic stress symptoms in the same study sample after fulfillment of the Trauma and Loss Spectrum-Self Report (TALS-SR) and the Mood Spectrum-Self Report (MOODS-SR) lifetime version.

Results: Results showed 10.4% and 37.3% of PTSD full and partial, respectively. Demographic characteristics and clinical features of the study sample did not show any impact on stress symptomatology. Mothers presented higher rates at all (DSM)-5 PTSD symptoms' clusters except avoidance. Nevertheless, noteworthy correlations between post-traumatic symptomatology and mood spectrum symptoms detected with the self-report tools, emerged only in the subgroup of the fathers.

Conclusion: These findings corroborate the need to provide assistance to caregivers of pediatric patients and confirm the hypothesis that lifetime mood spectrum may have an impact on reaction to traumas.
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http://dx.doi.org/10.2147/NDT.S158249DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5973431PMC
May 2018

Medical management for neurosurgical related seizures.

Expert Opin Pharmacother 2017 Oct 1;18(14):1491-1498. Epub 2017 Sep 1.

b Paediatric Neurology and Muscular Diseases Unit, Department of Neurosciences , "G.Gaslini" Institute, University of Genova , Genova , Italy.

Introduction: Seizures or chronic epilepsy are a relatively common occurrence in a neurosurgical setting. However, seizure treatment after neurosurgery has received less attention compared with other causes and only few data are availaible in the literature on management in neurosurgical patients. Areas covered: This paper reviews the availaible data on the risk of seizures in patients undergoing neurosurgery and discusses the role of antiseizure therapy in the management of the postoperative period. Finally, some controversial issues on this topic are addressed. Expert opinion: Despite the studies so far published on this topic, there are still no guidelines for the clinical practice. International recommendations do not generally support the use of antiseizure drugs in postsurgical patients. Nevertheless, their use still remains wide in the routine practice. Initiation of a treatment should be considered when the risk for prolonged seizures or chronic epilepsy is high and the risk of toxicity is acceptable. First generation antiseizures drugs seem to be quite effective although new drugs are associated with lower adverse effects risk and better tolerability.
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http://dx.doi.org/10.1080/14656566.2017.1373092DOI Listing
October 2017

Novel mutation in pontocerebellar hypoplasia, dysmorphisms, and teeth abnormalities.

Neurol Genet 2017 Oct 9;3(5):e179. Epub 2017 Aug 9.

Istituto G. Gaslini (A.A., M.I., F.P., A.O., M.S.V., C.M., M.S., P.S., V.C., F.Z.), Genova; Università degli Studi di Genova (A.A., M.I., C.M., P.S.); Ospedale San Paolo (R.S.), Milano, Italy; Dipartimento di Biochimica Biofisica e Patologia Generale (A.T., V.N.), Seconda Università di Napoli; and Telethon Institute of Genetics and Medicine (A.T., V.N.).

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http://dx.doi.org/10.1212/NXG.0000000000000179DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5550382PMC
October 2017

Recent advances in epilepsy genetics.

Neurosci Lett 2018 02 10;667:4-9. Epub 2017 May 10.

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

In last few years there has been rapid increase in the knowledge of epilepsy genetics. Nowadays, it is estimated that genetic epilepsies include over than 30% of all epilepsy syndromes. Several genetic tests are now available for diagnostic purposes in clinical practice. In particular, next-generation sequencing has proven to be effective in revealing gene mutations causing epilepsies in up to a third of the patients. This has lead also to functional studies that have given insight into disease pathophysiology and consequently to the identification of potential therapeutic targets opening the way of precision medicine for epilepsy patients. This minireview is focused on the most recent advances in genetics of epilepsies. We will also overview the modern genomic technologies and illustrate the diagnostic pathways in patients with genetic epilepsies. Finally, the potential implications for a personalized treatment (precision medicine) are also discussed.
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http://dx.doi.org/10.1016/j.neulet.2017.05.014DOI Listing
February 2018

DSM-5 criteria for PTSD in parents of pediatric patients with epilepsy: What are the changes with respect to DSM-IV-TR?

Epilepsy Behav 2017 05 13;70(Pt A):97-103. Epub 2017 Apr 13.

Psychiatric Clinic, Department of Clinical and Experimental Medicine, University of Pisa, Via Roma 67, 56100 Pisa, Italy. Electronic address:

Increasing literature suggests the need to explore for post-traumatic stress disorder (PTSD) and post-traumatic stress symptoms in parents and caregivers of children with acute and chronic illnesses but scant data are available on epilepsy. The aim of the present study was to estimate full and partial PTSD rates among parents of children with epilepsy comparing DSM-5 and DSM-IV-TR criteria. Further, the aim of the present study was to examine possible gender differences between mothers and fathers. Results showed 9.1% and 12.1% PTSD rates in the total sample, according to DSM-5 or DSM-IV-TR criteria, respectively, with an overall consistency of 92.9% (Kohen's K=0.628, p=.453). Significant gender differences emerged for Avoidance/Numbing and Hyperarousal symptoms diagnosed by means of DSM-IV-TR criteria, as well as for Negative alterations in cognitions/mood and Hyperarousal symptoms, when adopting DSM-5 criteria. This study underscores the relevance of detecting PTSD in parents of children with a chronic illness such as epilepsy.
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http://dx.doi.org/10.1016/j.yebeh.2017.02.025DOI Listing
May 2017

A Case of 22q11 Deletion Syndrome (22q11DS) with a Panayiotopoulos Epileptic Pattern: Are Additional Copy-Number Variations a Possible Second Hit in Modulating the 22q11DS Phenotype?

Front Pediatr 2017 21;5:48. Epub 2017 Mar 21.

Section of Pediatric Neurology, Azienda Ospedaliero-Universitaria Pisana , Pisa , Italy.

"22q11 deletion syndrome" (22q11DS) is a rare genetic syndrome, in which most patients share the same deletion, but their clinical features may vary a great deal. The genetic mechanisms underlying the variable expressivity and reduced penetrance of 22q11DS still have to be fully elucidated. Epilepsy has been reported in about 15.2% of the patients; however, few studies have focused on this topic, and in most cases, a detailed epileptic profile is missing. Since only a minority of patients experience epileptic seizures, 22q11deletion can be considered a predisposing factor, which is not sufficient "" to cause epilepsy; to date, no candidate gene for epilepsy has been identified in the deleted region. We report on a 6-year-old girl with 22q11DS presenting a form of epilepsy that can be classified as "Panayiotopoulos syndrome." Array CGH revealed an additional microduplication of 172 kb in 2q37, harboring three genes. One of these, (diacylglycerol kinase delta), is interrupted by the distal breakpoint of the duplication. encodes a cytoplasmic enzyme that phosphorylates diacylglycerol to produce phosphatidic acid. This is an important second messenger in a pathway of lipid signaling that has been implicated in epilepsy and other neurological diseases. Disruption of by a t(X;2) has been previously reported in a patient with epilepsy. The 2q37 microduplication was inherited from her mother, who never experienced epileptic seizures, thus this imbalance is not "" sufficient to cause epilepsy. It can be hypothesized that the epileptic phenotype is provoked by the simultaneous presence of 22q11.2 deletion and 2q37 duplication. It has been shown that rare additional copy-number variations (CNVs) outside the 22q11.2 region may modulate the risk of congenital heart defects. It is possible that also for the epileptic phenotype, the additional CNVs may represent an important modifying factor underlying the variable expressivity and incomplete penetrance in the 22q11DS.
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http://dx.doi.org/10.3389/fped.2017.00048DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5359231PMC
March 2017

A 6.5 mb deletion at 3q24q25.2 narrows Wisconsin syndrome critical region to a 750 kb interval: A potential role for MBNLI.

Am J Med Genet A 2017 Jan 18;173(1):280-284. Epub 2016 Oct 18.

Unita' di Genetica Medica, A.O.U. Pisana, Ospedale S.Chiara, Pisa, Italy.

We report on a patient with a 6.5 Mb interstitial de novo deletion in 3q24q25.2, characterized by array CGH. The patient is a 4-year and 2-month-old girl, who presented to us with mild developmental delay, absence of language, facial dysmorphism, hirsutism, strabismus, and Dandy-Walker Malformation. The main clinical signs typical of WS (Wisconsin syndrome) are evident in the patient. The molecular mapping of WS in 3q23q25 allowed geneticists to define the syndrome more accurately. Comparing the present patient's phenotype with that of cases with a molecular characterization so far reported, it was possible to narrow the critical region for WS to an interval of 750 Kb, where two genes (MBNL1 and TMEM14E) are harbored. The potential role of MBNL1 in causing the WS phenotype is discussed. © 2016 Wiley Periodicals, Inc.
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http://dx.doi.org/10.1002/ajmg.a.38002DOI Listing
January 2017