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1.
Eur J Paediatr Neurol ; 23(6): 808-818, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31582194

RESUMO

OBJECTIVE: To quantify gait abnormalities in people with Dravet syndrome (DS). METHODS: Individuals with a confirmed diagnosis of DS were enrolled, and stratified according to knee flexion at initial contact (IC) and range of motion (ROM) during stance (atypical crouch: knee flexion >20° at IC and knee ROM >15° during stance; straight: knee flexion <20° at IC). A 1D ANOVA (α = 0.05) was used to test statistical differences among the joint kinematics and spatio-temporal parameters of the cohort and an age-matched control group. Clinical (neurological and orthopaedic evaluation) and anamnestic data (seizure type, drugs, genetic mutation) were collected; distribution between the two gait phenotypes was assessed with the Fisher exact test and, for mutation, with the chi-squared test (p < 0.05). Linear regression between maximum knee flexion and normalised walking speed was calculated. RESULTS: Seventy-one subjects were enrolled and evaluated with instrumented gait analysis. Fifty-two were included in final analysis (mean age 13.8 ± 7.3; M 26). Two gait patterns were detected: an atypical crouch gait (34.6%) with increased ankle, knee and hip flexion during stance, and reduced walking speed and stride length not associated with muscle-tendon retractions; and a pattern resembling those of healthy age-matched controls, but still showing reduced walking speed and stride length. No differences in clinical or anamnestic data emerged between the two groups. SIGNIFICANCE: Objectively quantified gait in DS shows two gait patterns with no clear-cut relation to clinical data. Kinematics abnormalities may be related to stabilization issues. These findings may guide rehabilitative and preventive measures.

2.
Epileptic Disord ; 21(S1): 22-30, 2019 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-31162114

RESUMO

Encephalopathy related to Status Epilepticus during slow Sleep (ESES) is a peculiar electro-clinical condition, with variable etiologies, characterized by an age-dependent phenomenon of extreme activation of epileptic activity during sleep, i.e. "status epilepticus during sleep", that is strictly associated with the appearance of cognitive and behavioral disturbances. Even though the peculiar EEG picture is fundamental for the diagnosis of ESES, clear-cut and shared diagnostic criteria for defining the EEG boundaries of this syndrome are still lacking. The diagnosis of ESES can be further complicated by the variability of the EEG findings, that during the course of the disease can change from diffuse to more or less focal and viceversa, depending both on the spontaneous clinical evolution of this condition and/or on the effects of medications. Given the complexity and the heterogeneity of EEG parameters during the ESES course, it is important to correlate the EEG findings with the concomitant cognitive and behavioral status, possibly taking into account not only the spike-wave index, but also other parameters, such as for instance the topography of the epileptic abnormalities, their patterns of spread, and their fluctuations over time. Moreover, the epileptiform activity not only during sleep, but also during wakefulness, the presence of focal slowing, the organization of the EEG background and a derangement of the sleep architecture may play a role in determining the clinical picture.

3.
Neurology ; 92(11): e1238-e1249, 2019 Mar 12.
Artigo em Inglês | MEDLINE | ID: mdl-30737342

RESUMO

OBJECTIVE: The aim of this study was to expand the spectrum of epilepsy syndromes related to STX1B, encoding the presynaptic protein syntaxin-1B, and establish genotype-phenotype correlations by identifying further disease-related variants. METHODS: We used next-generation sequencing in the framework of research projects and diagnostic testing. Clinical data and EEGs were reviewed, including already published cases. To estimate the pathogenicity of the variants, we used established and newly developed in silico prediction tools. RESULTS: We describe 17 new variants in STX1B, which are distributed across the whole gene. We discerned 4 different phenotypic groups across the newly identified and previously published patients (49 patients in 23 families): (1) 6 sporadic patients or families (31 affected individuals) with febrile and afebrile seizures with a benign course, generally good drug response, normal development, and without permanent neurologic deficits; (2) 2 patients with genetic generalized epilepsy without febrile seizures and cognitive deficits; (3) 13 patients or families with intractable seizures, developmental regression after seizure onset and additional neuropsychiatric symptoms; (4) 2 patients with focal epilepsy. More often, we found loss-of-function mutations in benign syndromes, whereas missense variants in the SNARE motif of syntaxin-1B were associated with more severe phenotypes. CONCLUSION: These data expand the genetic and phenotypic spectrum of STX1B-related epilepsies to a diverse range of epilepsies that span the International League Against Epilepsy classification. Variants in STX1B are protean and contribute to many different epilepsy phenotypes, similar to SCN1A, the most important gene associated with fever-associated epilepsies.

4.
Epileptic Disord ; 20(5): 428-433, 2018 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-30378547

RESUMO

Mutations in the CDKL5 (cyclin-dependent kinase-like-5) gene are known to determine early-onset drug resistant epilepsies and severe cognitive impairment with absent language, hand stereotypies, and deceleration of head growth. Reflex seizures are epileptic events triggered by specific stimuli and diaper changing is a very rare triggering event, previously described in individual cases of both focal and unclassified epilepsy, as well as in Dravet syndrome. Our aim was to describe diaper changing-induced reflex seizures as one of the presenting features in a case of CDKL5-related epilepsy, providing video-EEG documentation and focusing discussion on hyperexcitability determined by the disease. [Published with video sequence on www.epilepticdisorders.com].

5.
Epilepsia ; 59(12): 2260-2271, 2018 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-30451291

RESUMO

OBJECTIVE: PCDH19-related epilepsy is an epileptic syndrome with infantile onset, characterized by clustered and fever-induced seizures, often associated with intellectual disability (ID) and autistic features. The aim of this study was to analyze a large cohort of patients with PCDH19-related epilepsy and better define the epileptic phenotype, genotype-phenotype correlations, and related outcome-predicting factors. METHODS: We retrospectively collected genetic, clinical, and electroencephalogram (EEG) data of 61 patients with PCDH19-related epilepsy followed at 15 epilepsy centers. All consecutively performed EEGs were analyzed, totaling 551. We considered as outcome measures the development of ID, autistic spectrum disorder (ASD), and seizure persistence. The analyzed variables were the following: gender, age at onset, age at study, genetic variant, fever sensitivity, seizure type, cluster occurrence, status epilepticus, EEG abnormalities, and cognitive and behavioral disorders. Receiver operating characteristic curve analysis was performed to evaluate the age at which seizures might decrease in frequency. RESULTS: At last follow-up (median = 12 years, range = 1.9-42.1 years), 48 patients (78.7%) had annual seizures/clusters, 13 patients (21.3%) had monthly to weekly seizures, and 12 patients (19.7%) were seizure-free for ≥2 years. Receiver operating characteristic analysis showed a significant decrease of seizure frequency after the age of 10.5 years (sensitivity = 81.0%, specificity = 70.0%). Thirty-six patients (59.0%) had ID and behavioral disturbances. ASD was present in 31 patients. An earlier age at epilepsy onset emerged as the only predictive factor for ID (P = 0.047) and ASD (P = 0.014). Conversely, age at onset was not a predictive factor for seizure outcome (P = 0.124). SIGNIFICANCE: We found that earlier age at epilepsy onset is related to a significant risk for ID and ASD. Furthermore, long-term follow-up showed that after the age of 10 years, seizures decrease in frequency and cognitive and behavioral disturbances remain the primary clinical problems.

6.
Neurology ; 91(12): e1112-e1124, 2018 Sep 18.
Artigo em Inglês | MEDLINE | ID: mdl-30171078

RESUMO

OBJECTIVE: To delineate the electroclinical features of SCN8A infantile developmental and epileptic encephalopathy (EIEE13, OMIM #614558). METHODS: Twenty-two patients, aged 19 months to 22 years, underwent electroclinical assessment. RESULTS: Sixteen of 22 patients had mildly delayed development since birth. Drug-resistant epilepsy started at a median age of 4 months, followed by developmental slowing, pyramidal/extrapyramidal signs (22/22), movement disorders (12/22), cortical blindness (17/22), sialorrhea, and severe gastrointestinal symptoms (15/22), worsening during early childhood and plateauing at age 5 to 9 years. Death occurred in 4 children, following extreme neurologic deterioration, at 22 months to 5.5 years. Nonconvulsive status epilepticus recurred in 14 of 22 patients. The most effective antiepileptic drugs were oxcarbazepine, carbamazepine, phenytoin, and benzodiazepines. EEG showed background deterioration, epileptiform abnormalities with a temporo-occipital predominance, and posterior delta/beta activity correlating with visual impairment. Video-EEG documented focal seizures (FS) (22/22), spasm-like episodes (8/22), cortical myoclonus (8/22), and myoclonic absences (1/22). FS typically clustered and were prolonged (<20 minutes) with (1) cyanosis, hypomotor, and vegetative semiology, sometimes unnoticed, followed by (2) tonic-vibratory and (3) (hemi)-clonic manifestations ± evolution to a bilateral tonic-clonic seizure. FS had posterior-temporal/occipital onset, slowly spreading and sometimes migrating between hemispheres. Brain MRI showed progressive parenchymal atrophy and restriction of the optic radiations. CONCLUSIONS: SCN8A developmental and epileptic encephalopathy has strikingly consistent electroclinical features, suggesting a global progressive brain dysfunction primarily affecting the temporo-occipital regions. Both uncontrolled epilepsy and developmental compromise contribute to the profound impairment (increasing risk of death) during early childhood, but stabilization occurs in late childhood.

7.
Neurotherapeutics ; 15(4): 1112-1126, 2018 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-30112700

RESUMO

Epilepsy of infancy with migrating focal seizures (EIMFS) is a rare early-onset developmental epileptic encephalopathy resistant to anti-epileptic drugs. The most common cause for EIMFS is a gain-of-function mutation in the KCNT1 potassium channel gene, and treatment with the KCNT1 blocker quinidine has been suggested as a rational approach for seizure control in EIMFS patients. However, variable results on the clinical efficacy of quinidine have been reported. In the present study, we provide a detailed description of the clinical, genetic, in vitro, and in vivo electrophysiological profile and pharmacological responses to quinidine of 2 EIMFS unrelated patients with a heterozygous de novo KCNT1 mutation: c.2849G>A (p.R950Q) in patient 1 and c.2677G>A (p.E893K) in patient 2. When expressed heterologously in CHO cells, KCNT1 channels carrying each variant showed gain-of-function effects, and were more effectively blocked by quinidine when compared to wild-type KCNT1 channels. On the basis of these in vitro results, add-on quinidine treatment was started at 3 and 16 months of age in patients 1 and 2, respectively. The results obtained reveal that quinidine significantly reduced seizure burden (by about 90%) and improved quality of life in both patients, but failed to normalize developmental milestones, which persisted as severely delayed. Based on the present experience, early quinidine intervention associated with heart monitoring and control of blood levels is among the critical factors for therapy effectiveness in EIMFS patients with KCNT1 gain-of-function mutations. Multicenter studies are needed to establish a consensus protocol for patient recruitment, quinidine treatment modalities, and outcome evaluation, to optimize clinical efficacy and reduce risks as well as variability associated to quinidine use in such severe developmental encephalopathy.

8.
Seizure ; 51: 1-5, 2017 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-28743048

RESUMO

Myoclonic status in non-progressive encephalopathy (MSNPE) is characterized by the recurrence of long-lasting atypical status epilepticus associated with attention impairment and continuous polymorphous jerks, mixed with other complex abnormal movements, in infants suffering from a non-progressive encephalopathy. The ketogenic diet (KD) has been used as an alternative to antiepileptic drugs (AEDs) for patients with refractory epileptic encephalopathies. PURPOSE: In this study we assess the efficacy and tolerability of the KD in patients with MSNPE. METHODS: Between March 1, 1980 and August 31, 2013, 99 patients who met the diagnostic criteria of MSNPE were seen (58 patients in Verona and 41 patients in Buenos Aires). Six of these 99 patients were placed on the KD using the Hopkins protocol and followed for a minimum period of 24 months. RESULTS: Twelve months after initiating the diet, three patients had a 75%-99% decrease in seizures, two had a 50%-74% decrease in seizures, and the remaining child had a less than 50% seizure reduction. In five patients with a seizure reduction of more than 50%, the myoclonic status epilepticus disappeared within 6 months after starting the diet. All patients had very good tolerability and no adverse events were identified. In most of the patients AEDs were reduced. CONCLUSION: The KD is a promising therapy for MSNPE, with most of our patients showing a more than 50% seizure reduction. In patients that responded well to the diet cognitive performance and quality of life also improved.


Assuntos
Dieta Cetogênica/métodos , Epilepsias Mioclônicas/dietoterapia , Criança , Pré-Escolar , Feminino , Humanos , Masculino
9.
Case Rep Pediatr ; 2017: 8189790, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-29391961

RESUMO

Introduction: The type I is the most common Chiari malformation in children. In this condition, the lower part of the cerebellum, but not the brain stem, extends into the foramen magnum at the base of the skull leading to disturbances in cerebrospinal fluid circulation and to direct compression of nervous tissue. Case report: We describe a 4-year-old Caucasian female child with febrile seizures, headache, parasomnias, and a delay of speech. The child underwent a magnetic resonance imaging to investigate these neurological signs, disclosing a Chiari malformation type 1. The polysomnography showed a mild-moderate sleep-disordered breathing, increased number of central sleep apneas, and generalized spike waves at sleep onset. Conclusions: Seizures have been seldom described in CM1 patients. The main reasons for performing MRI in this case were frequent seizures, a delay of speech, and headache, leading to an unexpected diagnosis of CM1. Polysomnography detected a discrete SDB.

10.
Epilepsy Res ; 128: 83-93, 2016 12.
Artigo em Inglês | MEDLINE | ID: mdl-27816898

RESUMO

OBJECTIVE: Ring chromosome 20 syndrome is characterized by severe, drug resistant childhood onset epilepsy, often accompanied by cognitive impairment. We characterized the electro-clinical phenotype and the long-term course of epilepsy in a large series. METHODS: We reviewed the electro-clinical phenotype of 25 patients (aged 8-59 years), and assessed the relationship between epilepsy severity and clinical and/or genetic variables. We also searched for reports of patients diagnosed with r(20) syndrome in the literature, included those whose clinical information was sufficiently accurate, and compared their clinical features with the ones of our patients. RESULTS: Epilepsy exhibited an age dependent course. When seizure onset occurred in childhood (21 patients), terrifying hallucinations associated with focal motor seizures, often sleep-related (8 patients), or dyscognitive seizures (13 patients), were prominent features, often evolving into epileptic encephalopathy associated with non-convulsive status epilepticus (11 patients). In the long-term, progressive stabilization of drug resistant epilepsy associated with non-convulsive status epilepticus, focal seizures with motor and autonomic features, and eyelid myoclonia were noticed. Epilepsy onset in adolescence (3 patients) was accompanied by a milder developmental course, dyscognitive seizures and non-convulsive status epilepticus, and no cognitive decline. Only three older patients became seizure free (>5 years) We found statistically significant correlations between age at epilepsy onset and cognitive level. Although in the study cohort the relationship between r(20) ratio, age at epilepsy onset and cognitive level was non-statistically significant, it reached significance evaluating the larger cohort of patients previously published. SIGNIFICANCE: In ring(20) syndrome, epilepsy has an age dependent course and a worse outcome when age at seizure onset is earlier. The r(20) ratio and severity of cognitive impairment appear to be directly related to each other and inversely correlated with the age at epilepsy onset.


Assuntos
Epilepsia/complicações , Epilepsia/fisiopatologia , Cromossomos em Anel , Adolescente , Adulto , Fatores Etários , Anticonvulsivantes/uso terapêutico , Encéfalo/fisiopatologia , Criança , Progressão da Doença , Eletroencefalografia , Epilepsia/genética , Epilepsia/psicologia , Feminino , Seguimentos , Estudos de Associação Genética , Humanos , Masculino , Pessoa de Meia-Idade , Fenótipo , Estudos Retrospectivos , Índice de Gravidade de Doença , Adulto Jovem
11.
Epilepsia ; 57(11): 1808-1816, 2016 11.
Artigo em Inglês | MEDLINE | ID: mdl-27762437

RESUMO

OBJECTIVE: To describe the clinical, neuropsychological, and psychopathologic features of a cohort of children with a new diagnosis of symptomatic or presumed symptomatic focal epilepsy at time of recruitment and through the first month. The selected population will be followed for 2-5 years after enrollment to investigate the epilepsy course and identify early predictors of drug resistance. METHODS: In this observational, multicenter, nationwide study, children (age 1 month-12.9 years) with a new diagnosis of symptomatic or presumed symptomatic focal epilepsy were consecutively enrolled in 15 Italian tertiary childhood epilepsy centers. Inclusion criteria were as follows: (1) diagnosis of symptomatic focal epilepsy due to acquired and developmental etiologies, and presumed symptomatic focal epilepsy; (2) age at diagnosis older than 1 month and <13 years; and (3) written informed consent. Children were subdivided into three groups: ≤3 years, >3 to 6 years, and >6 years. Clinical, electroencephalography (EEG), neuroimaging, and neuropsychological variables were identified for statistical analyses. RESULTS: Two hundred fifty-nine children were enrolled (116 female and 143 male). Median age: 4.4 years (range 1 month-12.9 years); 46.0% (n = 119) of children were younger than 3 years, 24% (61) from 3 to 6 years of age, and 30% (79) older than 6 years. Neurologic examination findings were normal in 71.8%. Brain magnetic resonance imaging (MRI) was abnormal in 59.9%. Children age ≤3 years experienced the highest seizure frequency in the first month after recruitment (p < 0.0001). Monotherapy in the first month was used in 67.2%. Cognitive tests at baseline revealed abnormal scores in 30%; behavioral problems were present in 21%. At multivariate analysis, higher chances to exhibit more than five seizures in the first month after epilepsy onset was confirmed for younger children and those with temporal lobe epilepsy. SIGNIFICANCE: In this prospective cohort study, an extensive characterization of epilepsy onset in children with symptomatic or presumed symptomatic focal epilepsies is reported in relation to the age group and the localization of the epileptogenic zone.


Assuntos
Encéfalo/diagnóstico por imagem , Transtornos Cognitivos/etiologia , Epilepsias Parciais/complicações , Adolescente , Distribuição por Idade , Criança , Pré-Escolar , Transtornos Cognitivos/diagnóstico , Estudos de Coortes , Eletroencefalografia , Epilepsias Parciais/diagnóstico por imagem , Feminino , Humanos , Lactente , Recém-Nascido , Imagem por Ressonância Magnética , Masculino , Testes Neuropsicológicos , Estudos Prospectivos
12.
Seizure ; 42: 1-6, 2016 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-27632409

RESUMO

PURPOSE: A small case series with a neurodegenerative disorder involving central nervous system and related to Seipin mutations was recently reported. Herein we describe clinical and EEG features of three patients presenting with Progressive Myoclonus Epilepsy (PME) and Congenital Generalized Lipodystrophy type 2 (CGL2) related to novel Seipin mutations. METHODS: The EEG-clinical picture was evaluated at epilepsy onset and in the follow-up period. The molecular analysis of BSCL2, Laforin and Malin genes was performed to patients and/or their parents by Denaturing High Performance Liquid Chromatography and automated nucleotide sequencing. Skin specimens collected from a patient were processed for histochemical and ultrastructural analysis. RESULTS: The CGL2-PME syndrome co-segregated with two different BSCL2 genotypes: the homozygosity for c.782_783dupG involving exon 8 (two cases), or the compound heterozygosity for c.782_783dupG/c.828_829delAA (one case). Periodic-Acid Schiff positive osmiophilic material in the cytoplasm of fibrocytes and eccrine-gland cells were found in skin specimens. The lack of Lafora's bodies in skin specimens and the molecular analysis excluding mutations in Laforin and Malin genes ruled out Lafora disease. CONCLUSION: The spectrum of CGL2 associated to BSCL2 gene mutations may include PMEs. Selected mutations in BSCL2 gene seem to be related to PMEs in patients with CGL2 phenotype.


Assuntos
Encéfalo/fisiopatologia , Subunidades gama da Proteína de Ligação ao GTP/genética , Lipodistrofia Generalizada Congênita/genética , Lipodistrofia Generalizada Congênita/fisiopatologia , Epilepsias Mioclônicas Progressivas/genética , Epilepsias Mioclônicas Progressivas/fisiopatologia , Encéfalo/diagnóstico por imagem , Proteínas de Transporte/genética , Criança , Diagnóstico Diferencial , Evolução Fatal , Feminino , Humanos , Lipodistrofia Generalizada Congênita/diagnóstico , Lipodistrofia Generalizada Congênita/patologia , Masculino , Epilepsias Mioclônicas Progressivas/diagnóstico , Epilepsias Mioclônicas Progressivas/patologia , Proteínas Tirosina Fosfatases não Receptoras/genética , Pele/metabolismo , Pele/patologia
13.
Dev Med Child Neurol ; 58(10): 1085-91, 2016 10.
Artigo em Inglês | MEDLINE | ID: mdl-27172925

RESUMO

AIM: Epilepsy is commonly observed in congenital disorders of glycosylation (CDG), but no distinctive electroclinical pattern has been recognized. We aimed at identifying a characteristic clinical presentation that might help targeted diagnostic work-up. METHOD: Based on the initial observation of an index case with CDG and migrating partial seizures, we evaluated 16 additional children with CDG and analysed their clinical course, biochemical, genetic, electrographic, and imaging findings. RESULTS: Four of 17 consecutively observed children with CDG (three females, one male) were first referred between the first and fourth month of life, after early onset of migrating partial seizures. All four patients manifested developmental delay, microcephaly, and multi-organ involvement. Magnetic resonance imaging disclosed cerebral and cerebellar atrophy. Isoelectrofocusing of transferrin, enzymatic studies, and lipid-linked oligosaccharide analysis indicated CDG-I. Genetic testing demonstrated either homozygous or compound heterozygous variants involving the ALG3 gene in patients 1 and 3, the RFT1 gene in patient 2, and the ALG1 gene in patient 4. At last follow-up, patients 1 and 2 were 5 and 3(1/2) years old. Patients 3 and 4 had died due to respiratory failure during pneumonia and refractory status epilepticus respectively. INTERPRETATION: Children with migrating partial seizures and concomitant multisystem involvement should be investigated for CDG.


Assuntos
Anormalidades Múltiplas/diagnóstico , Defeitos Congênitos da Glicosilação/diagnóstico , Deficiências do Desenvolvimento/diagnóstico , Epilepsias Parciais/diagnóstico , Microcefalia/diagnóstico , Anormalidades Múltiplas/etiologia , Pré-Escolar , Defeitos Congênitos da Glicosilação/complicações , Deficiências do Desenvolvimento/etiologia , Epilepsias Parciais/etiologia , Feminino , Humanos , Lactente , Masculino , Microcefalia/etiologia
14.
Epilepsia ; 56(5): 692-8, 2015 May.
Artigo em Inglês | MEDLINE | ID: mdl-25847462

RESUMO

OBJECTIVE: To present the clinical features and the results of laboratory investigations in three patients with spinal muscular atrophy associated with progressive myoclonic epilepsy (SMA-PME), a rare condition caused by mutations in the N-acylsphingosine amidohydrosilase 1 (ASAH1) gene. METHODS: The patients were submitted to clinical evaluation, neurophysiologic investigations (that included wakefulness and sleep electroencephalography [EEG], video-polygraphic recording with jerk-locked back-averaging, multimodal evoked potentials, and electromyography), brain magnetic resonance imaging (MRI), biochemical screening, muscle and skin biopsies, and molecular genetic analysis. RESULTS: The main clinical features were onset in childhood with proximal muscular weakness, generalized epilepsy with absences and myoclonic seizures, cognitive impairment of variable degree; the course was progressive with muscle wasting and uncontrolled epileptic seizures. In one patient, earlier onset before the age of 2 years was associated with a more complex clinical picture, with abnormal eye movements, progressive cognitive impairment, and a more rapid and severe course. EEG/polygraphic data were consistent with PME, demonstrating generalized spike-and-wave discharges, evidence of positive and negative myoclonia, and prominent photosensitivity. In one patient, transcranial magnetic stimulation showed a hyperexcitable motor cortex, whereas somatosensory evoked potentials were unaffected. Possible involvement of the central acoustic and visual pathways was suggested by abnormal auditory and visual evoked potentials. Muscle biopsies showed typical signs of neurogenic damage. Molecular genetic analysis showed mutations of the ASAH1 gene. SIGNIFICANCE: Our data indicate that SMA-PME associated with ASAH1 mutations is a genetically distinct condition with specific clinical and neurophysiologic features. Further studies are warranted to explore the role of the ASAH1 gene in muscle and brain function.


Assuntos
Ceramidase Ácida/genética , Atrofia Muscular Espinal/complicações , Atrofia Muscular Espinal/genética , Mutação/genética , Epilepsias Mioclônicas Progressivas/complicações , Epilepsias Mioclônicas Progressivas/genética , Adolescente , Criança , Pré-Escolar , Análise Mutacional de DNA , Eletroencefalografia , Potenciais Evocados/genética , Feminino , Humanos , Neuroimagem , Estimulação Transcraniana por Corrente Contínua
15.
Epilepsia ; 55(11): 1748-53, 2014 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-25266480

RESUMO

OBJECTIVE: Mutations involving the cyclin-dependent kinase-like 5 (CDKL5) gene cause an early onset epileptic encephalopathy (EE) with severe neurologic impairment and a skewed 12:1 female-to-male ratio. To date, 18 mutations have been described in boys. We analyzed our cohort of boys with early onset EE to assess the diagnostic yield of our molecular approach. METHODS: We studied 74 boys who presented early onset severe seizures, including infantile spasms and developmental delay, in the setting of EE, using Sanger sequencing, next-generation sequencing (NGS) and multiplex ligation-dependent probe amplification (MLPA). RESULTS: We identified alterations involving CDKL5 in four boys (5.4%) using NGS in one and MLPA in three. Three of four mutations were indicative of somatic mosaicism. SIGNIFICANCE: CDKL5 gene mutations accounted for 5.4% of boys with early onset EE. Somatic mosaic mutations might be even more represented than germline mutations, probably because their less deleterious effect enhances viability of the male embryo. The molecular approach used for CDKL5 screening remarkably influences the diagnostic yield in boys. Diagnosis is optimized by Sanger sequencing combined with array-based methods or MLPA; alternatively, NGS targeted resequencing designed to also detect copy number alterations, may be performed.


Assuntos
Epilepsia/genética , Predisposição Genética para Doença , Mutação/genética , Proteínas Serina-Treonina Quinases/genética , Adolescente , Criança , Pré-Escolar , Deficiências do Desenvolvimento/genética , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Lactente , Masculino , Síndrome de Rett/genética
16.
Epilepsy Res ; 108(9): 1597-603, 2014 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-25218893

RESUMO

BACKGROUND: Epilepsy is a frequent and severe feature of Menkes disease (MD) but only few studies described the long-term evolution of these children. We report a series of 28 epileptic MD patients, with clinical characteristics, EEG abnormalities, brain malformations and long-term outcome. METHODS: EEG, clinical characteristics and neuroimaging features in 28 MD patients were analyzed at the onset of epilepsy and after long-term follow-up (at least 4 years). We subdivided the patients into two groups: Group 1, 16 patients who received a subcutaneous copper-histidine treatment, and Group 2 including 12 patients who did not get any therapies. RESULTS: The large majority of our patients presented at the onset of epilepsy focal seizures (FS) and infantile spasms (IS). Five patients had recurrent status epilepticus (SE). During the follow-up, patients showed multiple seizure types: 6 patients had generalized tonic clonic seizures (GCT), 6 patients presented IS, 10 children had FS, 11 had myoclonic jerks and 3 had SE. Therapy with various antiepileptic drugs had poor efficacy, except in three patients who showed seizure disappearance with consequent discontinuation of antiepileptic therapy. There was no difference of neurological outcome among the two groups analyzed. CONCLUSIONS: Epilepsy in MD is a difficult to treat problem. At the onset, the most frequent type of seizures are FC and IS; in the next months, other kinds of seizures can appear. Many children are drug resistant. Institution of replacement therapy with copper-histidine seems to be not beneficial for epilepsy.


Assuntos
Eletroencefalografia , Epilepsia/diagnóstico , Epilepsia/etiologia , Síndrome dos Cabelos Torcidos/complicações , Idade de Início , Anticonvulsivantes/uso terapêutico , Pré-Escolar , Humanos , Lactente , Estudos Longitudinais , Imagem por Ressonância Magnética , Masculino , Síndrome dos Cabelos Torcidos/tratamento farmacológico , Síndrome dos Cabelos Torcidos/mortalidade , Testes Neuropsicológicos , Estudos Retrospectivos , Tomógrafos Computadorizados
17.
Orphanet J Rare Dis ; 9: 72, 2014 May 05.
Artigo em Inglês | MEDLINE | ID: mdl-24886560

RESUMO

Joubert syndrome is a clinically and genetically heterogeneous ciliopathy characterized by a typical cerebellar and brainstem malformation (the "molar tooth sign"), and variable multiorgan involvement. To date, 24 genes have been found mutated in Joubert syndrome, of which 13 also cause Meckel syndrome, a lethal ciliopathy with kidney, liver and skeletal involvement. Here we describe four patients with mild Joubert phenotypes who carry pathogenic mutations in either MKS1 or B9D1, two genes previously implicated only in Meckel syndrome.


Assuntos
Doenças Cerebelares/genética , Transtornos da Motilidade Ciliar/genética , Encefalocele/genética , Anormalidades do Olho/genética , Doenças Renais Císticas/genética , Mutação , Doenças Renais Policísticas/genética , Proteínas/genética , Retina/anormalidades , Anormalidades Múltiplas , Adulto , Doenças Cerebelares/patologia , Cerebelo/anormalidades , Criança , Pré-Escolar , Transtornos da Motilidade Ciliar/patologia , Encefalocele/patologia , Anormalidades do Olho/patologia , Feminino , Humanos , Doenças Renais Císticas/patologia , Imagem por Ressonância Magnética , Masculino , Doenças Renais Policísticas/patologia , Retina/patologia , Retinite Pigmentosa , Índice de Gravidade de Doença
18.
Epilepsia ; 55(3): 403-13, 2014 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-24483620

RESUMO

OBJECTIVE: To identify the brain networks that are involved in the different electroencephalography (EEG) abnormalities in patients with ring chromosome 20 [r(20)] syndrome. We hypothesize the existence of both distinctive and common brain circuits for the paroxysmal high voltage sharp waves (hSWs), the seizures, and the slow-wave 3-7 Hz rhythm that characterize this condition. METHODS: Thirteen patients with [r(20)] syndrome were studied by means of EEG simultaneously recorded with functional magnetic resonance imaging (EEG-fMRI). EEG traces were reviewed in order to detect the pathologic interictal (hSWs) and ictal activities; the 3-7 Hz theta-delta power was derived using a fast Fourier transform. A group-level analysis was performed for each type of EEG abnormality separately using a fixed-effect model and a conjunction analysis. Finally, a second-level random-effect model was applied considering together the different EEG abnormalities, without distinction between hSW, seizures, or theta-delta rhythms. RESULTS: Subcontinuous theta-delta rhythm was recorded in seven patients, seizures in two, and hSWs in three patients. The main results are the following: (1) the slow-wave rhythm was related to blood oxygen level-dependent (BOLD) increases in the premotor, sensory-motor, and temporoparietal cortex, and to BOLD decrements involving the default mode (DMN) and the dorsal attention networks (DANs); (2) the ictal-related BOLD changes showed an early involvement of the prefrontal lobe; (3) increases in BOLD signal over the basal ganglia, either for interictal and ictal activities, were observed; (4) a common pattern of positive BOLD changes in the bilateral perisylvian regions was found across the different EEG abnormalities. SIGNIFICANCE: The BOLD increment in the perisylvian network and the decrease of the DMN and DAN could be the expression of the [r(20)] syndrome-related cognitive and behavioral deficits. The observed BOLD patterns are similar to the ones detected in other epileptic encephalopathies, suggesting that different epileptic disorders characterized by neurobehavioral regression are associated with dysfunction in similar brain networks. A PowerPoint slide summarizing this article is available for download in the Supporting Information section here.


Assuntos
Encéfalo/fisiopatologia , Eletroencefalografia/métodos , Imagem por Ressonância Magnética/métodos , Rede Nervosa/fisiopatologia , Adolescente , Adulto , Criança , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Cromossomos em Anel , Adulto Jovem
19.
Clin Neurophysiol ; 125(2): 239-49, 2014 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-23968845

RESUMO

OBJECTIVES: To evaluate the spectral and spatial features of the cortical rhythms in patients affected by ring chromosome 20 - [r(20)]-syndrome. METHODS: Twelve patients with [r(20)] syndrome were studied. As controls we enrolled 12 patients with idiopathic generalized epilepsy (IGE) and 12 healthy volunteers (HV). Blind source separation, spectral analyses and source reconstruction were applied in all cases in order to identify reliable spatio-temporal patterns of cortical activity. RESULTS: A theta-delta EEG rhythm was identified in [r(20)] patients, with spectral peak ranging between 3 and 7Hz and whose generators mapped over the sensory-motor cortices. A second peak laying at a frequency about double with respect to the first one was present in 6 cases. Analogue methodological approach in HV and IGE groups failed to show similar findings. CONCLUSIONS: EEG of [r(20)] patients reveals the existence of a highly reproducible EEG pattern arising from the sensory-motor system. SIGNIFICANCE: The recognition of this peculiar EEG pattern could help the diagnostic work-up. Additionally, our findings supports the existence of a parallelism between this EEG trait and the physiological "mu" rhythm which is generate by the sensory-motor system. Such link suggests a sensory-motor system dysfunction in [r(20)] patients.


Assuntos
Córtex Cerebral/fisiopatologia , Ritmo Delta/fisiologia , Epilepsia Generalizada/fisiopatologia , Cromossomos em Anel , Ritmo Teta/fisiologia , Adolescente , Adulto , Criança , Eletroencefalografia/métodos , Epilepsia Generalizada/genética , Feminino , Humanos , Processamento de Imagem Assistida por Computador , Masculino , Pessoa de Meia-Idade
20.
Epilepsia ; 54 Suppl 7: 66-9, 2013 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-24099057

RESUMO

PURPOSE: Absence epilepsy with onset before age 4 years, or early onset absence epilepsy (EOAE), has been rarely reported, and children with onset in the first year of life are considered almost exceptional. We aimed to report the clinical and electrophysiologic features of a cohort of children with absence epilepsy starting within the first year of life. METHODS: This was a multicenter study including patients with absence epilepsy starting within the first year of life and identified over a 20-year period (1991-2011). KEY FINDINGS: We identified 16 patients with absence epilepsy starting within the first year of life with a mean follow-up of 6.4 years. Mean age at seizure onset was 10.3 ± (standard deviation)1.4 months (range 8-12). Two patients experienced rare tonic-clonic seizures that started later than the absences. None of the subjects had episodes of absence status epilepticus. Eleven subjects were seizure-free with the first antiepileptic drug. In eight children, therapy was withdrawn after a mean 3.2 years of treatment. None evolved into a different form of idiopathic generalized epilepsy. SLC2A1 gene analysis in 12 children (75%) failed to reveal glucose transporter 1 deficiency. SIGNIFICANCE: EOAE, including patients with onset within the first year of life, should be no more considered a distinct idiopathic generalized epilepsy (IGE) syndrome, as it shows electroclinical features, response to therapy, and prognosis similar to childhood absence epilepsy. Moreover, early age of onset is not predictive of GLUT-1 deficiency and genetic analysis may be therefore avoided in patients meeting strict inclusion criteria.


Assuntos
Epilepsia Tipo Ausência/diagnóstico , Epilepsia Tipo Ausência/fisiopatologia , Adolescente , Idade de Início , Criança , Pré-Escolar , Estudos de Coortes , Eletroencefalografia/métodos , Epilepsia Tipo Ausência/epidemiologia , Feminino , Seguimentos , Humanos , Masculino
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