Antonio Gambardella

Publications (253) View all

• Article: Low penetrance of autosomal dominant lateral temporal epilepsy in Italian families without LGI1 mutations.

  Roberto Michelucci, Elena Pasini, Sandro Malacrida, Pasquale Striano, Carlo Di Bonaventura, Patrizia Pulitano, Francesca Bisulli, Gabriella Egeo, Lia Santulli, Vito Sofia, [......], Manuela Fanciulli, Yerma Bartolini, Patrizia Riguzzi, Lilia Volpi, Fabrizio A de Falco, Anna Teresa Giallonardo, Oriano Mecarelli, Salvatore Striano, Paolo Tinuper, Carlo Nobile
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  ABSTRACT: PURPOSE: In relatively small series, autosomal dominant lateral temporal epilepsy (ADLTE) has been associated with leucine-rich, glioma-inactivated 1 (LGI1) mutations in about 50% of the families, this genetic heterogeneity being probably caused by differences in the clinical characteristics of the families. In this article we report the overall clinical and genetic spectrum of ADLTE in Italy with the aim to provide new insight into its nosology and genetic basis. METHODS: In a collaborative study of the Commission of Genetics of the Italian League Against Epilepsy (LICE) encompassing a 10-year period (2000-2010), we collected 33 ADLTE families, selected on the basis of the following criteria: presence of at least two members concordant for unprovoked partial seizures with prominent auditory and or aphasic symptoms, absence of any known structural brain pathology or etiology, and normal neurologic examination. The clinical, neurophysiologic, and neuroradiologic findings of all patients were analyzed and a genealogic tree was built for each pedigree. The probands' DNA was tested for LGI1 mutations by direct sequencing and, if negative, were genotyped with single-nucleotide polymorphism (SNP) array to search for disease-linked copy-number variation CNV. The disease penetrance in mutated and nonmutated families was assessed as a proportion of obligate carriers who were affected. KEY FINDINGS: The 33 families included a total of 127 affected individuals (61 male, 66 female, 22 deceased). The age at onset ranged between 2 and 60 years (mean 18.7 years). Ninety-one patients (72%) had clear-cut focal (elementary, complex, or secondarily generalized) seizures, characterized by prominent auditory auras in 68% of the cases. Other symptoms included complex visual hallucinations, vertigo, and déjà vu. Aphasic seizures, associated or not with auditory features, were observed in 20% of the cases, whereas tonic-clonic seizures occurred in 86% of the overall series. Sudden noises could precipitate the seizures in about 20% of cases. Seizures, which usually occurred at a low frequency, were promptly controlled or markedly improved by antiepileptic treatment in the majority of patients. The interictal electroencephalography (EEG) studies showed the epileptiform temporal abnormalities in 62% of cases, with a slight predominance over the left region. Magnetic resonance imaging (MRI) or computerized tomography (CT) scans were negative. LGI1 mutations (missense in nine and a microdeletion in one) were found in only 10 families (30%). The patients belonging to the mutated and not mutated groups did not differ except for penetrance estimate, which was 61.3% and 35% in the two groups, respectively (chi-square, p = 0.017). In addition, the disease risk of members of families with mutations in LGI1 was three times higher than that of members of LGI1-negative families (odds ratio [OR] 2.94, confidence interval [CI] 1.2-7.21). SIGNIFICANCE: A large number of ADLTE families has been collected over a 10-year period in Italy, showing a typical and homogeneous phenotype. LGI1 mutations have been found in only one third of families, clinically indistinguishable from nonmutated pedigrees. The estimate of penetrance and OR, however, demonstrates a significantly lower penetrance rate and relative disease risk in non-LGI1-mutated families compared with LGI1-mutated pedigrees, suggesting that a complex inheritance pattern may underlie a proportion of these families.
  Epilepsia 04/2013; · 3.96 Impact Factor
• Article: Failure to confirm association of a polymorphism in KCNMB4 gene with mesial temporal lobe epilepsy.

  Ida Manna, Angelo Labate, Laura Mumoli, Edoardo Ferlazzo, Umberto Aguglia, Aldo Quattrone, Antonio Gambardella
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  ABSTRACT: A recent study has implicated a tagging single nucleotide polymorphism (SNP) rs398702 located 3' of KCNMB4 (encoding calcium-activated potassium channel, subfamily M subunit beta 4) as a possible susceptibility allele for mesial temporal lobe epilepsy (mTLE). Such a finding warrants a further well-powered study in additional carefully phenotyped cohorts. Here we examined the role of the SNP (rs398702) in a cohort of 332 patients (182 women and 150 men; mean±SD age: 47.06±18.12) who had diagnoses of mTLE. None of the patients had a mass lesion, malformations of cortical development, or traumatic brain injury. Brain MRI study revealed hippocampal sclerosis (Hs) in 86/332 (26%) patients. Most patients (254/332, 76%) patients had drug-responsive mTLE. We also enrolled 335 healthy controls (164 women and 171 men; mean±SD age: 48.20±21.90), matched for age, sex and ethnicity. All patients and controls were Caucasian and were born in Italy. The genotype distribution of the SNP rs398702 in patients and controls was within Hardy-Weinberg equilibrium (p>0.05). There was no statistically significant difference in the genotype or allelic frequencies between patients and controls (p=0.878 and p=0.666 respectively). Moreover, such a variant did not influence the main clinical characteristics of mTLE, the presence of Hs or responsiveness to antiepileptic drugs. In conclusion, our data suggest that the rs398702 variant in the KCNMB4 gene is unlikely to influence significantly the risk of developing mTLE or its severity. They further highlight the importance of replication to confirm the validity of association study results.
  Epilepsy research 04/2013; · 2.48 Impact Factor
• Article: Divergent effects of the T1174S SCN1A mutation associated with seizures and hemiplegic migraine.

  Sandrine Cestèle, Angelo Labate, Raffaella Rusconi, Patrizia Tarantino, Laura Mumoli, Silvana Franceschetti, Grazia Annesi, Massimo Mantegazza, Antonio Gambardella
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  ABSTRACT: PURPOSE: To report the identification of the T1174S SCN1A (Na(V) 1.1) mutation in a three-generation family with both epileptic and familial hemiplegic migraine (FHM) phenotypes and clarify the pathomechanism. METHODS: The five affected individuals underwent detailed clinical analyses. Mutation analyses was performed by direct sequencing of SCN1A; functional studies by expression in tsA-201 cells. A computational model was used to compare the effects of T1174S with those of a typical FHM mutation (Q1489K). KEY FINDINGS: The proband had benign occipital epilepsy (BOE); two relatives had simple febrile seizures (FS) and later developed BOE. Two additional relatives had FHM without epilepsy or FS. All affected members and one obliged carrier carried the T1174S mutation. Functional effects were divergent: positive shift of the activation curve and deceleration of recovery from fast inactivation, consistent with loss of function, and increase of persistent current (I(NaP) ), consistent with gain of function. The I(NaP) increase was inhibited by dialysis of the cytoplasm, consistent with a modulation. Therefore, as shown by the computational model, T1174S could in some conditions induce overall loss of function, and in others gain of function; Q1489K induced gain of function in all the conditions. SIGNIFICANCE: Modulation of the properties of T1174S can lead to a switch between overall gain and loss of function, consistent with a switch between promigraine end epileptogenic effect and, thus, with coexistence of epileptic and FHM phenotypes in the same family. These findings may help to shed light on the complex genotype-phenotype relationship of SCN1A mutations.
  Epilepsia 02/2013; · 3.96 Impact Factor
• Article: Mutations in PRRT2 result in familial infantile seizures with heterogeneous phenotypes including febrile convulsions and probable SUDEP.

  Angelo Labate, Patrizia Tarantino, Grazia Palamara, Monica Gagliardi, Francesca Cavalcanti, Edoardo Ferlazzo, Miriam Sturniolo, Gemma Incorpora, Grazia Annesi, Umberto Aguglia, Antonio Gambardella
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  ABSTRACT: Mutations of PRRT2, which encodes proline-rich transmembrane protein 2, are associated with heterogeneous phenotypes including benign familial infantile seizures (BFIS) and/or familial paroxysmal kinesigenic dystonia (PKD). Here, we performed mutation screening of PRRT2 in six Italian families with BFIS/PKD phenotypes. The mutation, c.649dupC (p.Arg217ProfsX8), was found in two families with BFIS phenotype. In a third BFIS family, a missense mutation, c.718C/T (R240X), was identified. All these mutations co-segregated with the disease and were not observed in 100 controls of matched ancestry. In one BFIS family that carried the c.649dupC mutation, one affected member developed afebrile focal seizures and died at age of 14 years of probable sudden unexpected death in epilepsy, while his brother also had simple febrile convulsions (FC) and performed poorly on complex psychomotor functioning. In another family carrying the c.718C/T mutation, two of three affected members also had simple FC. This study enlarges the clinical spectrum related to PPRT2 mutations and underscores the complexity of the phenotypic consequences of mutations in this gene.
  Epilepsy research 01/2013; · 2.48 Impact Factor
• Article: Sacsin-Related Spastic Ataxia Caused by a Novel Missense Mutation p.Arg272His in a Patient from Sicily, Southern Italy.

  Valeria Dibilio, Francesca Cavalcanti, Alessandra Nicoletti, Giovanni Mostile, Elisa Bruno, Grazia Annesi, Patrizia Tarantino, Monica Gagliardi, Antonio Gambardella, Aldo Quattrone, Mario Zappia
  The Cerebellum 01/2013; · 3.21 Impact Factor