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ABSTRACT: OBJECTIVE: To perform a clinical and genetic study of a family with benign familial infantile seizures (BFIS) and, upon finding a PRRT2 gene mutation, to study a cohort of probands with a similar phenotype. We extended the study to all available family members to find out whether PRRT2 mutations cosegregated with additional symptoms. METHODS: We carried out a clinical and genealogic study of a 3-generation family and of 32 additional probands with BFIS (11 families), infantile convulsions and paroxysmal choreoathetosis (ICCA) (9 families), BFIS/generalized epilepsy with febrile seizures plus (5 families), and sporadic benign neonatal or infantile seizures (7 probands/families). We performed a genetic study consisting of linkage analysis and PRRT2 screening of the 33 probands/families. RESULTS: We obtained a positive linkage in the 16p11.3-q23.1 chromosomal region in the large BFIS family. Mutation analysis of PRRT2 gene revealed a c.649dupC (p.Arg217Profs*8) in all affected individuals. PRRT2 analysis of the 32 additional probands showed mutations in 10, 8 familial and 2 sporadic, probands. Overall we found PRRT2 mutations in 11 probands with a mutation rate of 11 out of 33 (33%). BFIS co-occurred with migraine and febrile seizures in 2 families, with childhood absence epilepsy in one family and with hemiplegic migraine in one family. CONCLUSION: Our results confirm the predominant role of PRRT2 mutations in BFIS and expand the spectrum of PRRT2-associated phenotypes to include febrile seizures, childhood absence seizures, migraine, and hemiplegic migraine.
Neurology 10/2012; · 8.31 Impact Factor
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ABSTRACT: Pitt-Hopkins syndrome (PTHS) is an emerging condition characterized by severe intellectual disability (ID), typical facial gestalt, and additional features, such as breathing abnormalities. Because of the overlapping phenotype of severe ID with absent speech, epilepsy, microcephaly, large mouth, and constipation, differential diagnosis of PTHS with respect to Angelman, Rett, and Mowat-Wilson syndromes represents a relevant clinical issue, and many patients are currently undergoing genetic tests for different conditions that are assumed to fall within the PTHS clinical spectrum. During a search for TCF4 mutations in 78 patients with a suspected PTHS, haploinsufficiency of TCF4 was identified in 18. By evaluating clinical features of patients with a proven TCF4 mutation with those of patients without, we noticed that, in addition to the typical facial gestalt, the PTHS phenotype results from the various combination of the following characteristics: ID with severe speech impairment, normal growth parameters at birth, postnatal microcephaly, breathing abnormalities, motor incoordination, ocular anomalies, constipation, seizures, typical behavior, and subtle brain abnormalities. On the basis of these observations, here we propose a clinically based score system as useful tool for driving a first choice molecular test for PTHS. This scoring system is also proposed for a clinically based diagnosis of PTHS in absence of a proven TCF4 mutation.
American Journal of Medical Genetics Part A 06/2012; 158A(7):1604-11. · 2.39 Impact Factor
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Domenica Battaglia,
Daniela Chieffo,
Giampiero Tamburrini, Donatella Lettori,
Emma Losito,
Giuseppa Leo,
Domiziana Ranalli,
Cristina Giansanti,
Eleonora Antichi,
Massimo Caldarelli,
Concezio Di Rocco,
Francesco Guzzetta
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ABSTRACT: The aim of this study was to provide information on the neuropsychological evolution of children with symptomatic epilepsy who have undergone surgical resection of posterior (occipitoparietal) lesions. Twelve children with epilepsy with parietal and/or occipital lesions were enrolled in the study and followed after surgical resection: full clinical and epileptic examinations were performed before and after surgery, as was a neuropsychological study of both general and specific cognitive abilities. Epilepsy evolution was generally good (Engel classification IA in nine cases) with persistent selective neurological impairments (eye field defects, sensory unilateral spatial neglect) in some cases, consistent with the lesion site. Neuropsychological defects before surgery in the absence of refractory epilepsy were minimal with a normal global cognitive competence; yet, the relatively low performance scores with some impairment of specific cognitive skills were strictly correlated with defects in visual perceptive skills in both right- and left-sided lesions. Surgery seems to have improved performance abilities, whereas other abnormal specific skills did not change with the exception of working memory that in some cases was defective before surgery and normalized after lesion removal. Our study in this particular cohort of children with epileptogenic occipitoparietal lesions thus confirmed a trend toward a benign epileptic and neurodevelopmental outcome after surgical resection of the lesion.
Epilepsy & Behavior 02/2012; 23(2):131-7. · 2.34 Impact Factor
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Giuseppe Marangi,
Stefania Ricciardi,
Daniela Orteschi,
Serena Lattante,
Marina Murdolo,
Bruno Dallapiccola,
Chiara Biscione,
Rosetta Lecce,
Pietro Chiurazzi,
Corrado Romano, [......],
Cinzia Magnani,
Paolo Bonanni,
Federica Martinez,
Gigliola Serra,
Domenica Battaglia, Donatella Lettori,
Gessica Vasco,
Anna Baroncini,
Cecilia Daolio,
Marcella Zollino
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ABSTRACT: Pitt-Hopkins syndrome (PTHS) is characterized by severe intellectual disability, typical facial gestalt and additional features, such as breathing anomalies. Following the discovery of the causative haploinsufficiency of transcription factor 4 (TCF4), about 60 patients have been reported. We looked for TCF4 mutations in 63 patients with a suspected PTHS. Haploinsufficiency of TCF4 was identified in 14 patients, as a consequence of large 18q21.2 chromosome deletions involving TCF4 (2 patients), gene mutations (11 patients) and a t(14q;18q) balanced translocation disrupting TCF4 (one patient). By evaluating the clinical features of these patients, along with literature data, we noticed that, in addition to the typical facial gestalt, the PTHS phenotype results from the various combinations of the following characteristics: intellectual disability with severe speech impairment, normal growth parameters at birth, postnatal microcephaly, breathing anomalies, motor incoordination, ocular anomalies, constipation, seizures, typical behavior and subtle brain abnormalities. Although PTHS is currently considered to be involved in differential diagnosis with Angelman and Rett syndromes, we found that combining the facial characteristics with a detailed analysis of both the physical and the neurological phenotype, made molecular testing for PTHS the first choice. Based on striking clinical criteria, a diagnosis of PTHS was made clinically in two patients who had normal TCF4. This report deals with the first series of PTHS patients of Italian origin.
American Journal of Medical Genetics Part A 07/2011; 155A(7):1536-45. · 2.39 Impact Factor
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Giuseppe Marangi,
Stefania Ricciardi,
Daniela Orteschi,
Serena Lattante,
Marina Murdolo,
Bruno Dallapiccola,
Chiara Biscione,
Rosetta Lecce,
Pietro Chiurazzi,
Corrado Romano, [......],
Cinzia Magnani,
Paolo Bonanni,
Federica Martinez,
Gigliola Serra,
Domenica Battaglia, Donatella Lettori,
Gessica Vasco,
Anna Baroncini,
Cecilia Daolio,
Marcella Zollino
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ABSTRACT: Pitt-Hopkins syndrome (PTHS) is characterized by severe intellectual disability, typical facial gestalt and additional features, such as breathing anomalies. Following the discovery of the causative haploinsufficiency of transcription factor 4 (TCF4), about 60 patients have been reported. We looked for TCF4 mutations in 63 patients with a suspected PTHS. Haploinsufficiency of TCF4 was identified in 14 patients, as a consequence of large 18q21.2 chromosome deletions involving TCF4 (2 patients), gene mutations (11 patients) and a t(14q;18q) balanced translocation disrupting TCF4 (one patient). By evaluating the clinical features of these patients, along with literature data, we noticed that, in addition to the typical facial gestalt, the PTHS phenotype results from the various combinations of the following characteristics: intellectual disability with severe speech impairment, normal growth parameters at birth, postnatal microcephaly, breathing anomalies, motor incoordination, ocular anomalies, constipation, seizures, typical behavior and subtle brain abnormalities. Although PTHS is currently considered to be involved in differential diagnosis with Angelman and Rett syndromes, we found that combining the facial characteristics with a detailed analysis of both the physical and the neurological phenotype, made molecular testing for PTHS the first choice. Based on striking clinical criteria, a diagnosis of PTHS was made clinically in two patients who had normal TCF4. This report deals with the first series of PTHS patients of Italian origin. © 2011 Wiley-Liss, Inc.
American Journal of Medical Genetics Part A 06/2011; 155(7):1536 - 1545. · 2.39 Impact Factor
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ABSTRACT: Aim of this study is to report a detailed profile of neuropsychological development in children with Dravet syndrome.
Twelve children with Dravet syndrome were longitudinally assessed using a detailed clinical and neuropsychological evaluation. Six had typical features of severe myoclonic epilepsy in infancy (SMEI) whereas the other six resulted borderline. All twelve underwent serial neuropsychological assessments with neurodevelopmental scales and further assessment of specific cognitive abilities.
Our results reported an apparent normal development before disease onset, a general evolution in two main stages, more active the first one and with a general trend towards a clinical stabilization afterwards. The onset of cognitive decline was generally later than what is reported in other series; furthermore, the impairment of cognitive development is less severe, especially in borderline cases. As to specific cognitive competence, attention, visual motor integration, visual perception as well as executive functions are the most impaired abilities; language appears less involved, with a predominance of phonological defects.
In our cohort the global development of patients appear less affected than in previous studies. Furthermore, our study points out an impairment of several specific cognitive skills even in patients with a developmental quotient apparently in the normal range. Language and other cognitive skill impairment such as attention, visuo-spatial organization, working memory and executive function appear consistent with what is usually found in cerebellar disorders.
Epilepsy research 06/2011; 95(1-2):86-93. · 2.48 Impact Factor
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Daniela Chieffo, Donatella Lettori,
Ilaria Contaldo,
Francesca Perrino,
Alessandra Graziano,
Concetta Palermo,
Antonio Mittica,
Giampiero Tamburrini,
Domenica Battaglia,
Concezio Di Rocco,
Francesco Guzzetta
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ABSTRACT: was to provide new data about the evolution of neuropsychological findings in patients with lesional frontal lobe epilepsy (FLE) operated on with lesion excision.
Twelve patients with lesional FLE underwent full clinical examination including neurological, neuropsychological and developmental assessments, high-resolution magnetic resonance imaging (MRI), ictal and interictal prolonged EEG monitoring and evaluation of seizure semeiology before and after surgery. The mean follow-up duration was 2 years and 10 months (range=14 months-7 years). Another group of lesional temporal lobe epilepsy, matched for the age at surgery and side of surgery, was likewise studied in order to compare neuropsychological patterns and to try to find out specific features in frontal lobe epilepsy evolution.
All patients resulted seizure free at outcome except one belonging to Engel's class II. Before surgery general intelligence was similar in FLE as well as in TLE group. Executive functions and motor coordination were frequently affected in FLE whereas patients with TLE often presented with deficits in naming, visual memory and visuo-spatial attention. After surgery there was a frequent decline of IQ in FLE group together with a slight deterioration, especially of executive functions in some patients. An improvement of behaviour was often observed in both groups.
As already reported in literature, neuropsychological pre-surgical data confirms the involvement of attention and executive functions in lesional FLE. No significant neuropsychological improvement was produced by surgery that determined in some cases a slight decline of general intelligence and specific frontal abilities. Yet, generally behaviour improved and seizures were controlled.
Brain & development 04/2011; 33(4):310-5. · 1.74 Impact Factor
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ABSTRACT: Aim of the study was to describe prospectively the early neuropsychological evolution including the first pre-cognitive stages of the Severe Myoclonic Epilepsy in Infancy (SMEI) or Dravet syndrome. Five cases, four of whom since before a diagnostic evidence of the Dravet syndrome, were followed up. Full clinical assessment including developmental, visual function and behaviour assessments were serially performed. In four cases, a variable onset age of cognitive decline assessed with developmental scales was preceded some months before by an impairment of visual function; the remaining patient during all the course of follow-up till 51 months of age showed a normal development without visual impairment. A cognitive decline with variable onset was generally confirmed in Dravet syndrome. The previous early impairment of visual function seems to herald the cognitive decline and provides useful prognostic information; furthermore, it possibly suggests some clues for a better understanding of the mechanisms of cognitive deterioration in this syndrome.
Epilepsy research 01/2011; 93(1):73-9. · 2.48 Impact Factor
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ABSTRACT: The aim of this study was to assess behavioral aspects of visual function and visuoperceptual abilities in patients with Panayiotopoulos syndrome (PS), and their possible associations with clinical and electroencephalography (EEG) findings in order to establish the possible effect of interictal paroxysmal activity on visual performance.
The cohort included 28 patients (14 male and 14 female) of ages ranging between 4 and 15 years. All patients underwent serial videopolygraphic studies and a detailed battery of tests assessing visual abilities, including assessment of acuity, stereopsis, visual fields, and visuoperceptual abilities; tests included the Movement Assessment Battery for Children, the Visuo Motor Integration tests, and evaluation of motion and form coherence threshold.
On the assessment of visual function, only 4 of the 28 (15%) had abnormal crowding acuity and one had abnormal stereopsis. On the visuoperceptual assessment, one patient had abnormal results on the Visuo Motor Integration tests, and one on the Movement Assessment Battery for Children, whereas 4 (15%) had abnormal results for form coherence threshold and one for motion threshold.
Our results suggest that, although most of our patients had focal or diffuse EEG abnormalities involving the occipital regions, abnormalities of visual and visuoperceptual function were relatively uncommon. Age at onset of seizure <5 years and EEG activation to eye closure and during sleep can be considered as factors that slightly increased the risk for developing visual abnormalities. Their presence, however, was not always associated with abnormal visual findings.
Epilepsia 07/2010; 51(7):1205-11. · 3.96 Impact Factor
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ABSTRACT: The authors report the study of a 30-month-old girl with refractory myoclonic epilepsy associated with mental retardation, growth delay, peculiar facial appearance, and minor physical anomalies. Extensive genetic studies were performed, including an array-based comparative genomic hybridization (array-CGH) that showed a cryptic interstitial deletion of 15q (5 Mb) affecting the 15q26.1-26.2 region. Partial deletions of the long arm of chromosome 15, including the 15q26 region, were observed in syndromic associations that typically include congenital diaphragmatic hernia, but neurologic features were poorly described and epileptic seizures were never reported. Our findings suggest that genes for seizures could be included in the 15q26.1q26.2 deletion interval.
Epilepsia 05/2009; 50(7):1810-5. · 3.96 Impact Factor
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ABSTRACT: Mechanisms inducing continuous spike-wave during slow sleep (CSWS) in encephalopathy with electrical status epilepticus during sleep are still unclear. Recently, some sporadic cases with early thalamic injury associated with CSWS have been reported. The aim of the study was to investigate in a population of patients with an early thalamic injury the presence of an activation of paroxysmal activities during sleep, their characteristics, and possible relations to neuroimaging and neuropsychological features.
Thirty-two patients with prenatal or perinatal thalamic injuries, mostly due to a vascular mechanisms, were fully examined, including neuroimaging, EEG monitoring, and cognitive follow-up.
Twenty-nine of 32 patients showed major sleep EEG activation. Among these 29 patients, two different groups were distinguished: the first included the more or less typical CSWS (12 cases), generally with symmetry of spike and waves (SWs) and often with no spindle at all. The other cases had an usual asymmetry of SWs and presence or reduction of spindles, plus other atypical features concerning synchronism and morphology of SWs. Behavioral disorders were significantly more present in patients with a true CSWS; their improvement (and in one case of the three thoroughly followed the improvement of cognitive competence) paralleled the disappearance of CSWS. The generally predominant injury of the lateral aspect of the thalamus included reticular nucleus and ventral nuclei. An imbalance of gamma-aminobutyric acid (GABA)(B)--versus GABA(A)--mediated receptors may be evoked as a cofactor predisposing to CSWS.
Epilepsia 07/2005; 46(6):889-900. · 3.96 Impact Factor
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Domenica Battaglia,
Giuseppe Zampino,
Marcella Zollino,
Paolo Mariotti,
Celeste Acquafondata, Donatella Lettori,
Marika Pane,
Isabella Vasta,
Giovanni Neri,
Charlotte Dravet,
Francesco Guzzetta
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ABSTRACT: Wolf-Hirschhorn syndrome (WHS) is a well-known clinical entity caused by partial deletion of the short arm of one chromosome 4 (4p- syndrome). Seizures occur in almost all the cases, but studies on the electroclinical disorder and its evolution are still scarce. We present a longitudinal study of the electroclinical features in 10 children with WHS.
Ten patients (five boys and five girls) underwent a detailed clinical assessment and a prolonged EEG study. Six of the 10 also had video-polygraphy.
Nine of the 10 patients had seizures; they were generalized or unilateral clonic and tonic-clonic, and atypical absences associated with myoclonic jerks. Age at onset of seizures varied from 1 day to 2.5 years. In all the patients, including the only one without seizures, two stereotyped EEG patterns were observed, consisting of (a) bursts of rhythmic (3-5 Hz), high-voltage slow waves located in the posterior regions and increased by sleep, or bursts of rapid spike-wave complexes in the centroparietal and parietooccipital regions; and (b) repetitive rapid posterior spikes. Sleep organization was constantly absent or very poor. The evolution of epilepsy was frequently good, with four seizure-free cases at the end of follow-up, two of them weaned from antiepileptic drugs (AEDs).
Seizure onset in WHS also can occur at neonatal age. At least two electrical stereotyped patterns of the epileptic disorder are associated with a relevant disorganization of the sleep states. Prognosis of epilepsy is generally good both for the seizure control and for its evolution.
Epilepsia 10/2003; 44(9):1183-90. · 3.96 Impact Factor
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ABSTRACT: We report the case of a male newborn with Ohtahara syndrome and right hemimegalencephaly who presented epileptic negative myoclonus in the first days of life.
Prolonged polygraphic studies were performed, as well as MRI and a full clinical examination.
EEG showed a constant and nonreactive pattern of burst suppression. There were several kinds of electro-clinical seizures (generalized myoclonia, short atonias, typical spasm and tonic spasms) at the beginning of the EEG's burst. The periods of EMG silence, lasting less than 300 ms, were associated with stereotyped EEG transients.
Epileptic negative myoclonus can be observed also in neonatal age. The short transient impairment of motor function observed in the newborn seems linked to the slow component of spike-wave discharge, but its mechanism is still not clear.
Epilepsia 10/2002; 43(9):1106-9. · 3.96 Impact Factor
