Publications by authors named "Anna Rita Ferrari"

20 Publications

  • Page 1 of 1

Clinical and electroencephalographic correlates of psychiatric features in children with frontal lobe epilepsy.

Epilepsy Behav 2019 03 4;92:283-289. Epub 2019 Feb 4.

Department of Developmental Neuroscience, IRCCS Stella Maris Foundation, Pisa, Italy. Electronic address:

Background And Objective: Frontal lobe epilepsy (FLE) is often associated with psychiatric features, although the factors predisposing to the concurrence of these conditions have yet to be determined, especially in younger children. We aimed at defining possible clinical and electroencephalography (EEG) features that may enhance the psychiatric risk in pediatric FLE.

Method: We performed a structured psychiatric assessment of 59 children with FLE, using both categorical and dimensional approaches, correlated psychopathology with epilepsy data, and cognitive development.

Results: About 1/3 of patients with FLE displayed intellectual disability (ID), and more than 2/3 displayed psychiatric disorders, including depression, disruptive behaviors, anxiety, and bipolar/psychotic disorders. Psychiatric dimensions such as impulse control problems, attentional deficits, social problems, and aggressive behaviors were frequent features of FLE. Intellectual disability was associated with an earlier onset of psychiatric disorders and more frequent disruptive behavior disorders and aggressiveness. Long-standing epilepsy and bilateral or anterior frontal EEG abnormalities also increased the risk of psychopathology. Finally, right-hemisphere lesions were associated with disruptive behavior disorders, fast EEG rhythms with attention/memory problems, and phases of seizure remission with impulse control problems.

Conclusions: Clinical and EEG markers of increased psychopathological risk may help in defining consistent at-risk subgroups within FLE and improving early diagnosis, prognosis, and treatment. Categorical and dimensional approaches to psychiatric diagnosis may generate new research hypotheses and support the investigation of the complex pathophysiological bases shared by different neurodevelopmental disturbances.
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http://dx.doi.org/10.1016/j.yebeh.2019.01.008DOI Listing
March 2019

Relapsing-Remitting Course of Cystic Leukoencephalopathy.

Pediatr Neurol 2018 12 24;89:63-65. Epub 2018 Aug 24.

Molecular Medicine and Neurogenetics, IRCCS Stella Maris, Pisa, Italy. Electronic address:

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http://dx.doi.org/10.1016/j.pediatrneurol.2018.08.021DOI Listing
December 2018

Internalizing and externalizing symptoms in preschool and school-aged children with epilepsy: Focus on clinical and EEG features.

Epilepsy Behav 2018 02 15;79:68-74. Epub 2017 Dec 15.

Department of Developmental Neuroscience, IRCCS Stella Maris Foundation, Via dei Giacinti 2, Calambrone, 56128 Pisa, Italy. Electronic address:

Introduction: Psychiatric and behavioral problems are frequent comorbidities of epilepsy, although their clinical and electroencephalographic (EEG) correlates remain uncertain. In this study, we have assessed the frequency of psychopathological problems in a cohort of children with epilepsy, and established their main clinical and EEG-associated features.

Methods: One hundred fifty-nine young patients with epilepsy were recruited and assessed through the Child Behavior Checklist for preschool-aged children (CBCL 1 1/2-5) or for school-aged children (CBCL 6-18). Child Behavior Checklist (CBCL) results were then correlated to the main clinical and EEG data.

Results: We found emotional and behavioral problems in about half of the children in our sample. Internalizing, social, and attention problems were more common than externalizing features. Moderate intellectual disability, a nonidiopathic etiology of epilepsy, a poor control of seizures, and antiepileptic polytherapies, as well as an early age at seizure-onset and a longer duration of the disorder, were all associated with specific behavioral and emotional problems. A temporal site of interictal EEG abnormalities also enhanced the risk for psychiatric comorbidities, especially in the externalizing domain.

Conclusions: Several clinical and EEG features are associated with an increased risk for emotional and behavioral comorbidities in children with epilepsy. Their identification may foster an early diagnosis and appropriate care, limiting the worsening of psychiatric symptoms and their impact on quality of life and health status. A better understanding of the underlying clinical and molecular mechanisms is needed to further improve prevention and treatment interventions.
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http://dx.doi.org/10.1016/j.yebeh.2017.10.004DOI Listing
February 2018

Complex Phenotype of a Boy With De Novo 16p13.3-13.2 Interstitial Deletion.

Child Neurol Open 2016 Jan-Dec;3:2329048X16676153. Epub 2016 Dec 16.

Department of Developmental Neuroscience, IRCCS Fondazione Stella Maris, Pisa, Italy.

Interstitial deletions encompassing chromosome 16p13.3-13.2 are rarely described in the literature, whereas terminal deletions or duplications involving this region are slightly more frequently described. The authors describe a boy harboring a de novo 16p13.3-13.2 interstitial deletion, with intellectual disability, verbal dyspraxia, epilepsy, and a distinctive brain magnetic resonance finding, namely a nodular heterotopia. The authors found partial genotype-phenotype correspondences regarding epilepsy and intellectual disability, which have been associated with 16p1 region. Conversely, nodular heterotopia and verbal dyspraxia have not been clearly related to this region. These data are in agreement with the emerging concept that similar copy number variants may be the general risk factors for distinct disorders. Verbal dyspraxia, which has not responded to speech therapy, is the child's most disabling trait. In view of the above, genetic studies should be appraised in cases of serious speech difficulties, especially if they are associated with intellectual disability and epilepsy.
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http://dx.doi.org/10.1177/2329048X16676153DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5417293PMC
December 2016

The syndrome of polymicrogyria, thalamic hypoplasia, and epilepsy with CSWS.

Neurology 2016 Mar 4;86(13):1250-9. Epub 2016 Mar 4.

From the Pediatric Neurology Unit and Laboratories, A. Meyer Children's Hospital (E.B., M.F., F.Z., E.P., C.B., R.G.), and Department of Statistics, Computer Science and Applications "G. Parenti" (L.G.), University of Florence; Department of Translational Research and New Surgical and Medical Technologies (M.C.), University of Pisa; Unit of Neuroradiology (M.C.), Pisa University Hospital "Azienda Ospedaliero-Universitaria Pisana"; Child Neurology and Psychiatry Unit (A. Posar, M.S.), IRCCS Institute of Neurological Sciences of Bologna; Departments of Biomedical and Neuromotor Sciences (A. Posar, M.S.) and Medical and Surgical Sciences (A. Parmeggiani, G.A.), University of Bologna; Child Neurology and Psychiatry Unit (A. Parmeggiani), Policlinico S. Orsola-Malpighi, Bologna; IRCCS Stella Maris Foundation (E.B., A.R.F., R.G.), Calambrone, Pisa, Italy; and the Epilepsy Unit, Department of Neurology (J.S.-P.), Hospital Vall Hebron, Barcelona, Spain.

Objective: We explored the long-term follow-up of continuous spike-and-wave complexes during sleep (CSWS) in polymicrogyria and the anatomic volumetric variables that influence the risk of developing this age-related epileptic encephalopathy.

Methods: We performed prospective follow-up of 27 patients with polymicrogyria/CSWS (mean follow-up 14.3 years; range 2-31 years) and comparative volumetric analysis of the polymicrogyric hemispheres and ipsilateral thalami vs 3 subgroups featuring polymicrogyria without CSWS, benign rolandic epilepsy (BRE), and headache. Receiver operator characteristic analysis of the power of volumetric values was determined to predict CSWS.

Results: CSWS peaked between 5 and 7 years (mean age at onset 4.7 years). Remission occurred within 2 years from onset in 21%, within 4 years in 50%, and by age 13 years in 100%. We found smaller thalamic and hemispheric volumes in polymicrogyria/CSWS with respect to polymicrogyria without CSWS (p = 0.0021 for hemispheres; p = 0.0003 for thalami), BRE, and controls with headache (p < 0.0001). Volumes of the malformed hemispheres and ipsilateral thalami reliably identified the risk of incurring CSWS, with a 68-fold increased risk for values lower than optimal diagnostic cutoffs (436,150 mm(3) for malformed hemispheres or 4,616 mm(3) for ipsilateral thalami; sensitivity 92.54%; specificity 84.62%). The risk increased by 2% for every 1,000 mm(3) reduction of the polymicrogyric hemispheres and by 15% for every 100 mm(3) reduction of ipsilateral thalami.

Conclusions: The polymicrogyria/CSWS syndrome is likely caused by a cortico-thalamic malformation complex and is characterized by remission of epilepsy within early adolescence. Early assessment of hemispheric and thalamic volumes in children with polymicrogyria and epilepsy can reliably predict CSWS.
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http://dx.doi.org/10.1212/WNL.0000000000002526DOI Listing
March 2016

Temporal lobe connects regression and macrocephaly to autism spectrum disorders.

Eur Child Adolesc Psychiatry 2016 Apr 30;25(4):421-9. Epub 2015 Jul 30.

Department of Developmental Neuroscience, IRCCS Stella Maris Foundation, Via dei Giacinti 2 - Calambrone, 56128, Pisa, Italy.

Interictal electroencephalogram (EEG) abnormalities are frequently associated with autism spectrum disorders (ASD), although their relationship with the clinical features of ASD, particularly the regressive onset, remains controversial. The aim of this study was to investigate whether the characteristics of interictal EEG abnormalities might help to distinguish and predict definite phenotypes within the heterogeneity of ASD. We reviewed the awake and sleep interictal EEGs of 220 individuals with idiopathic ASD, either with or without a history of seizures. EEG findings were analyzed with respect to a set of clinical variables to explore significant associations. A brain morphometry study was also carried out on a subgroup of patients. EEG abnormalities were seen in 154/220 individuals (70%) and were mostly focal (p < 0.01) with an anterior localization (p < 0.001). They were detected more frequently during sleep (p < 0.01), and were associated with a regressive onset of ASD (p < 0.05), particularly in individuals with focal temporal localization (p < 0.05). This association was also stronger in regressive patients with concurrent macrocephaly, together with a relative volumetric reduction of the right temporal cortex (p < 0.05). Indeed, concurrence of temporal EEG abnormalities, regression and macrocephaly might possibly define a distinct endophenotype of ASD. EEG-based endophenotypes could be useful to untangle the complexity of ASD, helping to establish anatomic or pathophysiologic subtypes of the disorder.
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http://dx.doi.org/10.1007/s00787-015-0746-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4820486PMC
April 2016

Dysgraphia as a Mild Expression of Dystonia in Children with Absence Epilepsy.

PLoS One 2015 1;10(7):e0130883. Epub 2015 Jul 1.

Pediatric Neurology and Neurogenetics Unit and Laboratories, Neuroscience Department, A. Meyer Children's Hospital, University of Florence, 50139, Florence, Italy; IRCCS Stella Maris Foundation, 56128, Pisa, Italy.

Background: Absence epilepsy (AE) is etiologically heterogeneous and has at times been associated with idiopathic dystonia.

Objectives: Based on the clinical observation that children with AE often exhibit, interictally, a disorder resembling writer's cramp but fully definable as dysgraphia, we tested the hypothesis that in this particular population dysgraphia would represent a subtle expression of dystonia.

Methods: We ascertained the prevalence of dysgraphia in 82 children with AE (mean age 9.7) and average intelligence and compared them with 89 age-, gender- and class-matched healthy children (mean age 10.57) using tests for handwriting fluency and quality, based on which we divided patients and controls into four subgroups: AE/dysgraphia, AE without dysgraphia, controls with dysgraphia and healthy controls. We compared the blink reflex recovery cycle in children belonging to all four subgroups.

Results: We identified dysgraphia in 17/82 children with AE and in 7/89 controls (20.7 vs 7.8%; P = 0.016) with the former having a 3.4-times higher risk of dysgraphia regardless of age and gender (odd ratio: 3.49; 95% CI 1.2, 8.8%). The AE/dysgraphia subgroup performed worse than controls with dysgraphia in one test of handwriting fluency (P = 0.037) and in most trials testing handwriting quality (P< 0.02). In children with AE/dysgraphia the blink reflex showed no suppression at short interstimulus intervals, with a difference for each value emerging when comparing the study group with the three remaining subgroups (P<0.001).

Conclusions: In children with AE, dysgraphia is highly prevalent and has a homogeneous, distinctive pathophysiological substrate consistent with idiopathic dystonia.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0130883PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4488862PMC
April 2016

Late-onset epileptic spasms: clinical evidence and outcome in 34 patients.

J Child Neurol 2015 Feb 6;30(2):153-9. Epub 2014 Jun 6.

Epilepsy and Clinical Neurophysiology Laboratory, Department of Clinical Neuroscience, IRCCS Stella Maris Foundation, Calambrone, Pisa, Italy

To evaluate the diverse presentation and course of late-onset epileptic spasms in relation to etiology, we analyzed the clinical, electroencephalographic (EEG), and prognostic features in 34 patients. We divided the patient sample into cryptogenic or symptomatic based on etiology. An association emerged between symmetric spasms at onset and focal interictal EEG abnormalities in cryptogenic patients, and onset with focal or generalized seizures before displaying asymmetric spasms, and multifocal or diffuse EEG abnormalities, in the symptomatic group. Despite an overall poor prognosis, symptomatic patients starting with generalized seizures seem to have a relatively more favorable outcome. The high occurrence of intellectual disability, and sometimes psychomotor regression, confirmed this rare and poorly understood heterogeneous clinical condition as a severe form of epileptic encephalopathy that deserves further study.
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http://dx.doi.org/10.1177/0883073814532547DOI Listing
February 2015

Somatic overgrowth predisposes to seizures in autism spectrum disorders.

PLoS One 2013 23;8(9):e75015. Epub 2013 Sep 23.

Epilepsy, Neurophysiology and Neurogenetics Unit, IRCCS Stella Maris Foundation, Pisa, Italy.

Background: Comorbidity of Autism Spectrum Disorders with seizures or abnormal EEG (Autism-Epilepsy Phenotype) suggests shared pathomechanisms, and might be a starting point to identify distinct populations within the clinical complexity of the autistic spectrum. In this study, we tried to assess whether distinct subgroups, having distinctive clinical hallmarks, emerge from this comorbid condition.

Methods: Two-hundred and six individuals with idiopathic Autism Spectrum Disorders were subgrouped into three experimental classes depending on the presence of seizures and EEG abnormalities. Neurobehavioral, electroclinical and auxological parameters were investigated to identify differences among groups and features which increase the risk of seizures. Our statistical analyses used ANOVA, post-hoc multiple comparisons, and the Chi-squared test to analyze continuous and categorical variables. A correspondence analysis was also used to decompose significant Chi-squared and reduce variables dimensions.

Results: The high percentage of children with seizures (28.2% of our whole cohort) and EEG abnormalities (64.1%) confirmed that the prevalence of epilepsy in Autism Spectrum Disorders exceeds that of the general population. Seizures were associated with severe intellectual disability, and not with autism severity. Interestingly, tall stature (without macrocephaly) was significantly associated with EEG abnormalities or later onset seizures. However, isolated macrocephaly was equally distributed among groups or associated with early onset seizures when accompanied by tall stature.

Conclusions: Tall stature seems to be a phenotypic "biomarker" of susceptibility to EEG abnormalities or late epilepsy in Autism Spectrum Disorders and, when concurring with macrocephaly, predisposes to early onset seizures. Growth pattern might act as an endophenotypic marker in Autism-Epilepsy comorbidity, delineating distinct pathophysiological subtypes and addressing personalized diagnostic work-up and therapeutic approaches.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0075015PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3781047PMC
August 2014

Language regression associated with autistic regression and electroencephalographic (EEG) abnormalities: a prospective study.

J Child Neurol 2014 Jun 4;29(6):855-9. Epub 2013 Apr 4.

Unité de Neurologie et de Neuroréhabilitation Pédiatrique CHUV, Lausanne, Switzerland.

We report a boy, referred at 25 months following a dramatic isolated language regression antedating autistic-like symptomatology. His sleep electroencephalogram (EEG) showed persistent focal epileptiform activity over the left parietal and vertex areas never associated with clinical seizures. He was started on adrenocorticotropic hormone (ACTH) with a significant improvement in language, behavior, and in EEG discharges in rapid eye movement (REM) sleep. Later course was characterized by fluctuations/regressions in language and behavior abilities, in phase with recrudescence of EEG abnormalities prompting additional ACTH courses that led to remarkable decrease in EEG abnormalities, improvement in language, and to a lesser degree, in autistic behavior. The timely documentation of regression episodes suggesting an "atypical" autistic regression, striking therapy-induced improvement, fluctuation of symptomatology over time could be ascribed to recurrent and persisting EEG abnormalities.
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http://dx.doi.org/10.1177/0883073813482767DOI Listing
June 2014

Epilepsy in Mowat-Wilson syndrome: delineation of the electroclinical phenotype.

Am J Med Genet A 2013 Feb 15;161A(2):273-84. Epub 2013 Jan 15.

Child Neurology and Psychiatry Unit, S Orsola Malpighi Hospital, University of Bologna, Bologna, Italy.

Mowat-Wilson syndrome (MWS) is a genetic disease caused by heterozygous mutations or deletions of the ZEB2 gene and is characterized by distinctive facial features, epilepsy, moderate to severe intellectual disability, corpus callosum abnormalities and other congenital malformations. Epilepsy is considered a main manifestation of the syndrome, with a prevalence of about 70-75%. In order to delineate the electroclinical phenotype of epilepsy in MWS, we investigated epilepsy onset and evolution, including seizure types, EEG features, and response to anti-epileptic therapies in 22 patients with genetically confirmed MWS. Onset of seizures occurred at a median age of 14.5 months (range: 1-108 months). The main seizure types were focal and atypical absence seizures. In all patients the first seizure was a focal seizure, often precipitated by fever. The semiology was variable, including hypomotor, versive, or focal clonic manifestations; frequency ranged from daily to sporadic. Focal seizures were more frequent during drowsiness and sleep. In 13 patients, atypical absence seizures appeared later in the course of the disease, usually after the age of 4 years. Epilepsy was usually quite difficult to treat: seizure freedom was achieved in nine out of the 20 treated patients. At epilepsy onset, the EEGs were normal or showed only mild slowing of background activity. During follow-up, irregular, diffuse frontally dominant and occasionally asymmetric spike and waves discharges were seen in most patients. Sleep markedly activated these abnormalities, resulting in continuous or near-to-continuous spike and wave activity during slow wave sleep. Slowing of background activity and poverty of physiological sleep features were seen in most patients. Our data suggest that a distinct electroclinical phenotype, characterized by focal and atypical absence seizures, often preceded by febrile seizures, and age-dependent EEG changes, can be recognized in most patients with MWS.
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http://dx.doi.org/10.1002/ajmg.a.35717DOI Listing
February 2013

22q11.2 Microduplication syndrome and epilepsy with continuous spikes and waves during sleep (CSWS). A case report and review of the literature.

Epilepsy Behav 2012 Dec 13;25(4):567-72. Epub 2012 Nov 13.

Epilepsy, Neurophysiology and Neurogenetics Unit, IRCCS Stella Maris Foundation, Via dei Giacinti 2, 56128 Calambrone, Pisa, Italy.

Chromosome 22q11.2 microduplication syndrome is characterized by a variable and usually mild phenotype and by incomplete penetrance. Neurological features of the syndrome may entail intellectual or learning disability, motor delay, and other neurodevelopmental disorders. However, seizures or abnormal EEG are reported in a few cases. We describe a 6-year-old girl with microduplication of chromosome 22q11.2 and epilepsy with continuous spikes and waves during sleep (CSWS). Her behavioral disorder, characterized by hyperactivity, impulsiveness, attention deficit, and aggressiveness, became progressively evident a few months after epilepsy onset, suggesting a link with the interictal epileptic activity characterizing CSWS. We hypothesize that, at least in some cases, the neurodevelopmental deficit seen in the 22q11.2 microduplication syndrome could be the consequence of a disorder of cerebral electrogenesis, suggesting the need for an EEG recording in affected individuals. Moreover, an array-CGH analysis should be performed in all individuals with cryptogenic epilepsy and CSWS.
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http://dx.doi.org/10.1016/j.yebeh.2012.09.035DOI Listing
December 2012

CDKL5 gene-related epileptic encephalopathy: electroclinical findings in the first year of life.

Dev Med Child Neurol 2011 Apr 11;53(4):354-60. Epub 2011 Feb 11.

Paediatric Neurology Unit and Laboratories, A. Meyer Children's Hospital, University of Florence, Florence, Italy.

Aim: Cyclin-dependent kinase-like 5 (CDKL5) gene abnormalities cause an early-onset epileptic encephalopathy. We performed video-electroencephalography (video-EEG) monitoring early in the course of CDKL5-related epileptic encephalopathy in order to examine the early electroclinical characteristics of the condition.

Method: We used video-EEG to monitor six infants (five females, one male) with CDKL5-related epileptic encephalopathy (five mutations; one deletion), at ages 45 days to 12 months and followed them up to the ages of 14 months to 5 years (mean age 23 mo). We focused our analysis on the first year of life. The results were evaluated against those of a comparison group of nine infants (aged below 1y) with epileptic encephalography who had tested negative for CDKL5 mutations and deletions.

Results: One infant exhibited normal background activity, three exhibited moderate slowing, and two exhibited a suppression burst pattern. Two participants had epileptic spasms and four had a stereotyped complex seizure pattern, which we defined as a 'prolonged' generalized tonic-clonic event consisting of a tonic-tonic/vibratory contraction, followed by a clonic phase with series of spasms, gradually translating into repetitive distal myoclonic jerks. Seizure duration ranged from 2 to 4 minutes. The EEG correlate of each clinical phase included an initial electrodecremental event (tonic vibratory phase), irregular series of sharp waves and spike slow waves (clonic phase with series of spasms), and bilateral rhythmic sharp waves (time locked with myoclonus).

Interpretation: Infants with CDKL5-related early epileptic encephalopathy can present in the first year of life with an unusual electroclinical pattern of 'prolonged' generalized tonic-clonic seizures.
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http://dx.doi.org/10.1111/j.1469-8749.2010.03889.xDOI Listing
April 2011

Contractions in the second polyA tract of ARX are rare, non-pathogenic polymorphisms.

Am J Med Genet A 2011 Jan 10;155A(1):164-7. Epub 2010 Dec 10.

Children's Hospital A. Meyer, University of Florence, Firenze, Italy.

Aristaless related homeobox (ARX) is a transcription factor containing highly conserved octapeptide, homeobox, acidic, and aristaless domains, as well as four polyA tracts. The most frequent ARX mutation found to date in patients with X-linked infantile spasms, Partington syndrome or X-linked mental retardation, is a duplication of 24 bp in exon 2, resulting in the expansion of the second polyA tract. Although the pathogenic role of this expansion has been well characterized, the effect of contractions in the same polyA tract is still debated since different reports have associated contractions to either mental retardation or a normal phenotype. Here, we report two unrelated girls with epilepsy and mental retardation who inherited from their unaffected parents, of either sex, a deletion of 24 bp (c.441_464del), resulting in a contraction of eight alanines in the second polyA tract of ARX. Segregation studies revealed the c.441_464del also in two healthy relatives of one of the patients. This finding supports the hypothesis that this contraction represents a rare, benign polymorphism.
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http://dx.doi.org/10.1002/ajmg.a.33753DOI Listing
January 2011

Bilateral frontoparietal polymicrogyria, Lennox-Gastaut syndrome, and GPR56 gene mutations.

Epilepsia 2009 Jun 6;50(6):1344-53. Epub 2008 Oct 6.

Pediatric Neurology and Neurogenetics Unit, Children's Hospital A. Meyer-University of Florence, Florence, Italy.

Purpose: Bilateral frontoparietal polymicrogyria (BFPP) has been reported in sporadic patients and in recessive pedigrees. Eleven mutations in GPR56, a gene encoding an evolutionarily dynamic G-protein-coupled receptor, have been identified in 29 patients from 18 families. The clinical features of BFPP include severe mental retardation, motor and language impairment, and epilepsy. No detailed description of the epilepsy is available for the patients reported to date. We report three consanguineous families in which four affected individuals with BFPP and GPR56 mutations had Lennox-Gastaut syndrome.

Methods: Family studies, brain magnetic resonance imaging (MRI), electroencephalography (EEG)-video recordings, and mutation analysis.

Results: In Family 1, with one affected proband, we found an R565W change in the second extracellular loop of GPR56, involving a highly conserved aminoacidic residue. In Family 2, with one affected proband, we found an R79X change affecting the protein N-terminus and predicted to cause a premature truncation with loss of the G-protein-coupled receptor proteolytic site. In family 3, with two affected siblings, we found an R33P substitution in the protein N-terminus, involving a highly conserved aminoacidic residue. Epilepsy, present in all four patients, had started between ages 1 and 8 years, with infantile spasms in one patient and with de novo Lennox-Gastaut syndrome in the remaining three. All patients had Lennox-Gastaut syndrome when last observed, at ages 13 to 32 years.

Discussion: Several genes, when mutated, can cause malformations of cortical development that have been associated with the Lennox-Gastaut syndrome. BFPP caused by GPR56 mutations represents an additional, although rare, genetically determined cause of Lennox-Gastaut syndrome.
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http://dx.doi.org/10.1111/j.1528-1167.2008.01787.xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4271835PMC
June 2009

Idiopathic epilepsies with seizures precipitated by fever and SCN1A abnormalities.

Epilepsia 2007 Sep 11;48(9):1678-1685. Epub 2007 Jun 11.

Epilepsy, Neurophysiology and Neurogenetic Unit, Institute of Child Neurology and Psychiatry, IRCCS Stella Maris Foundation, Calambrone, Pisa, ItalyNeurogenetic Laboratory, Pediatric Hospital A. Meyer, Florence, ItalyUnidade de Neuropediatria, Seviço de Pediatria, Hospital Geral de Santo António, Porto, PortugalChild Neurology Unit, Pediatric Hospital A. Meyer, Florence, ItalyPediatric Neurology Unit, Hospital Dona Estefania, Lisbon, PortugalClinical Neurophysiology and Developmental Neuropsychiatry, School of Life and Health Sciences, Aston University, The Birmingham Children's Hospital NHS Trust, Birmingham, United KingdomNeurosciences Unit, Institute of Child Health and Great Ormond Street Hospital for Children NHS Trust, London, United KingdomPediatric Neurology Unit, Clínica Universitaria de Navarra, Pamplona, SpainCambridge Institute for Medical Research and Department of Medical Genetics, University of Cambridge, Cambridge, United KingdomDepartment of Neurosciences, Division of Neurology, Bellaria Hospital, Bologna, ItalyChild Neurology and Psychiatry Unit, Ospedale S. Chiara, Trento, ItalyUniversity of Florence, Florence, Italy.

Purpose: SCN1A is the most clinically relevant epilepsy gene, most mutations lead to severe myoclonic epilepsy of infancy (SMEI) and generalized epilepsy with febrile seizures plus (GEFS+). We studied 132 patients with epilepsy syndromes with seizures precipitated by fever, and performed phenotype-genotype correlations with SCN1A alterations.

Methods: We included patients with SMEI including borderline SMEI (SMEB), GEFS+, febrile seizures (FS), or other seizure types precipitated by fever. We performed a clinical and genetic study focusing on SCN1A, using dHPLC, gene sequencing, and MLPA to detect genomic deletions/duplications on SMEI/SMEB patients.

Results: We classified patients as: SMEI/SMEB = 55; GEFS+= 26; and other phenotypes = 51. SCN1A analysis by dHPLC/sequencing revealed 40 mutations in 37 SMEI/SMEB (67%) and 3 GEFS+ (11.5%) probands. MLPA showed genomic deletions in 2 of 18 SMEI/SMEB. Most mutations were de novo (82%). SMEB patients carrying mutations (8) were more likely to have missense mutations (62.5%), conversely SMEI patients (31) had more truncating, splice site or genomic alterations (64.5%). SMEI/SMEB with truncating, splice site or genomic alterations had a significantly earlier age of onset of FS compared to those with missense mutations and without mutations (p = 0.00007, ANOVA test). None of the remaining patients with seizures precipitated by fever carried SCN1A mutations.

Conclusion: We obtained a frequency of 71%SCN1A abnormalities in SMEI/SMEB and of 11.5% in GEFS+ probands. MLPA complements DNA sequencing of SCN1A increasing the mutation detection rate. SMEI/SMEB with truncating, splice site or genomic alterations had a significantly earlier age of onset of FS. This study confirms the high sensitivity of SCN1A for SMEI/SMEB phenotypes.
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http://dx.doi.org/10.1111/j.1528-1167.2007.01122.xDOI Listing
September 2007

Generalized epilepsy with febrile seizures plus (GEFS+): clinical spectrum in seven Italian families unrelated to SCN1A, SCN1B, and GABRG2 gene mutations.

Epilepsia 2004 Feb;45(2):149-58

Epilepsy, Neurophysiology, Neurogenetics Unit, IRCCS Fondazione Stella Maris, Pisa, Italy.

Purpose: We describe seven Italian families with generalized epilepsy with febrile seizures plus (GEFS+), in which mutations of SCN1A, SCN1B, and GABRG2 genes were excluded and compare their clinical spectrum with that of previously reported GEFS+ with known mutations.

Methods: We performed a clinical study of seven families (167 individuals). The molecular study included analysis of polymerase chain reaction (PCR) fragments of SCN1A and SCN1B exons by denaturing high-performance liquid chromatography (DHPLC) and direct sequencing of GABRG2 in all families. We excluded SCN1A, SCN1B, and GABRG2 genes with linkage analysis in a large pedigree and directly sequenced SCN2A in a family with neonatal-infantile seizures onset. We compared the epilepsy phenotypes observed in our families with those of GEFS+ families harboring mutations of SCN1A, SCN1B, and GABRG2 and estimated the percentage of mutations of these genes among GEFS+ cases by reviewing all published studies.

Results: Inheritance was autosomal dominant with 69% penetrance. Forty-one individuals had epilepsy: 29 had a phenotype consistent with GEFS+; seven had idiopathic generalized epilepsy (IGE); in three, the epilepsy type could not be classified; and two were considered phenocopies. Clinical phenotypes included FS+ (29.2%), FS (29.2%), IGE (18.2%), FS+ with focal seizures (13%) or absence seizures (2.6%), and FS with absence seizures (2.6%). Molecular study of SCN1A, SCN2A, SCN1B, and GABRG2 did not reveal any mutation. Results of our study and literature review indicate that mutations of SCN1A, SCN2A, SCN1B, and GABRG2 in patients with GEFS+ are rare.

Conclusions: The most frequently observed phenotypes matched those reported in families with mutations of the SCN1A, SCN1B, and GABRG2 genes. IGE and GEFS+ may overlap in some families, suggesting a shared genetic mechanism. The observation that 13% of affected individuals had focal epilepsy confirms previously reported rates and should prompt a reformulation of the "GEFS+" concept to include focal epileptogenesis.
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http://dx.doi.org/10.1111/j.0013-9580.2004.04303.xDOI Listing
February 2004

Influence of dosage, age, and co-medication on plasma topiramate concentrations in children and adults with severe epilepsy and preliminary observations on correlations with clinical response.

Ther Drug Monit 2003 Dec;25(6):700-8

IRCCS Stella Maris Foundation, University of Pisa, Pisa, Italy.

The influence of dosage, age, and co-medication on plasma topiramate (TPM) concentrations at steady state was investigated in 51 patients aged 3 to 30 years. All patients had chronic active epilepsy, and most were receiving concomitant medication with enzyme-inducing anticonvulsants (carbamazepine and phenobarbital). Plasma TPM concentrations were determined by a specific immunoassay in samples obtained before the morning dose. Thirty-five patients could be evaluated prospectively at different dose levels, and the relationship between plasma TPM concentration and dosage was linear over the assessed dose range (1.8 to 10.0 mg/kg) both in adults and in children. The influence of age on pharmacokinetic parameters could be assessed only for the 42 patients co-medicated with enzyme inducers. In these patients dose-normalized plasma TPM concentrations correlated positively with age (r = 0.59, P < 0.0001), where apparent oral clearance values (CL/F) were inversely related to age (r = 0.73, P < 0.0001). In particular, CL/F values in children aged less than 10 years (112 +/- 82 mL/kg/h, mean +/- SD, n = 14) were almost three times as high as those observed in patients aged >15 to 30 years (42 +/- 16 mL/kg/h, n = 17), whereas the CL/F value in children aged 10 to 15 years (66 +/- 22 mL/kg/h, n = 11) was intermediate between those found in the two other age groups. Patients not receiving enzyme-inducing AEDs showed lower CL/F values than did age- and gender-matched patients on enzyme-inducing co-medication. A preliminary evaluation of the relationship between plasma TPM concentration and therapeutic response could be made in 41 patients. No significant difference in drug concentration was detected between patients showing a greater than 50% reduction in seizure frequency compared with baseline (5.9 +/- 2.2 micrograms/mL, n = 30) and those having no clinical improvement (5.2 +/- 2.2 micrograms/mL, n = 11). Likewise, there was no consistent relationship between plasma TPM concentration and appearance of adverse effects. These results indicate that plasma TPM concentrations are linearly related to dosage both in adults and in children and that children aged <10 years require much greater body weight-adjusted dosage to achieve drug levels comparable to those observed in young adults. The marked increase in TPM clearance caused by enzyme-inducing co-medication was confirmed.
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http://dx.doi.org/10.1097/00007691-200312000-00008DOI Listing
December 2003

Plasma gabapentin concentrations in children with epilepsy: influence of age, relationship with dosage, and preliminary observations on correlation with clinical response.

Ther Drug Monit 2003 Feb;25(1):54-60

Department of Internal Medicine and Therapeutics, University of Pavia, Italy.

The influence of age and administered daily dosage on the plasma concentrations of gabapentin (GBP) at steady state was evaluated in a group of 41 children and young adults (aged 3-30 years) receiving long-term adjunctive treatment with GBP for the management of refractory partial-onset seizures. For each patient, peak and trough concentrations were determined by a specific high-performance liquid chromatography (HPLC) method in samples obtained before the morning dose and 2.5 hours later, respectively. To assess within-subject relationship between plasma concentration and dosage, 30 patients were evaluated at more than one dosage level. Within the assessed dose range, plasma GBP concentrations were linearly related to dose. Apparent oral clearance values (mean +/- SD) in children aged 6 years or less (4.8 +/- 0.9 mL/kg/min) were comparable with those observed in children aged 7 to 15 years (4.6 + 1.5 mL/kg/min) and moderately higher than those found in young adults (3.9 + 0.9 mL/kg/min), even though differences among groups failed to reach statistical significance. There was, however, a significant difference in CL/F between children aged 10 years or less and older children (5.1 +/- 1.1 vs. 3.8 +/- 1.2 mL/kg/min, P < 0.005). Of the 41 patients who entered the study, 22 discontinued treatment, mostly due to insufficient efficacy. No significant difference in plasma GBP concentration was detected between patients showing a greater than 50% reduction in seizure frequency (4.1 +/- 1.9 microg/mL, n = 11, mean +/- SD) and those having no significant clinical improvement (4.4 +/- 1.7 microg/mL, n = 30). These results indicate that in children given dosages up to 50 mg/kg/d (mean, 25 mg/kg/d), GBP pharmacokinetic analyses show no important deviation from linearity. The data also suggest that, on average, children may need moderately higher dosages to reach plasma GBP concentrations comparable with those found in adults. There seems to be a large variation in the plasma concentrations of the drug associated with a favorable therapeutic response.
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http://dx.doi.org/10.1097/00007691-200302000-00008DOI Listing
February 2003