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1.
Zhonghua Er Ke Za Zhi ; 58(2): 118-122, 2020 Feb 02.
Artigo em Chinês | MEDLINE | ID: mdl-32102148

RESUMO

Objective: To summarize the clinical phenotypes of epilepsy in patients with GABRA1 gene variants. Methods: A total of 11 epileptic patients (4 boys and 7 girls) who were treated in the Department of Pediatrics, Peking University First Hospital from March 2016 to July 2019 and detected with GABRA1 gene heterozygous pathogenic variants by targeted next-generation sequencing were enrolled. The features of clinical manifestations, electroencephalogram (EEG), and neuroimaging were analyzed retrospectively. Results: A total of 11 epileptic patients carried GABRA1 gene pathogenic variants, of whom 10 were de novo variants and the other one was inherited from the patient's mother. Two patients had the same variants. Six variants were novel. Ages at seizure onset ranged from 3 to 14 months, and the median age was 8 months. The seizure was first observed within 1 year in 10 patients and beyond 1 year of age in 1 patient. Multiple seizure types were observed, including focal seizures in 10 patients, generalized tonic clonic seizures (GTCS) in 3 patients, myoclonic seizures in 3 patients, and epileptic spasm in 2 patients. There were 5 patients with multiple seizure types. Sensitivity to fever was observed in 9 patients, among whom 6 patients had a history of status epilepticus. Two patients had photoparoxysmal response. Five patients had abnormal EEG background, and 6 patients had abnormal discharges in EEG during interictal phase. Brain magnetic resonance imaging (MRI) was normal in all patients. Developmental delay in various degrees was present in 9 patients. Among the 11 patients, Dravet syndrome was diagnosed in 5 patients, West syndrome in 2 patients, undiagnosed early-onset epileptic encephalopathy in 1 patient, and focal epilepsy in the other 3 patients. The ages at the last follow-up ranged from 8 months to 12 years. During follow-up, 8 patients were seizure-free for 6 months to 8 years, and 1 patient had discontinuation of medication. Conclusions: In epilepsy associated with GABRA1 gene variants, de novo pathogenic variants are more common than inherited. Most epilepsy caused by GABRA1 gene variants occurs in infancy. Most patients have multiple seizures and focal seizures are common. Most patients have a comparatively favorable prognosis, but they may still have varied degrees of developmental delay.


Assuntos
Encéfalo/diagnóstico por imagem , Deficiências do Desenvolvimento/genética , Epilepsia/diagnóstico , Epilepsia/genética , Convulsões/etiologia , Criança , Pré-Escolar , Deficiências do Desenvolvimento/etiologia , Eletroencefalografia , Epilepsia/diagnóstico por imagem , Feminino , Humanos , Lactente , Masculino , Neuroimagem , Fenótipo , Receptores de GABA-A , Estudos Retrospectivos , Espasmos Infantis/diagnóstico
2.
Medicine (Baltimore) ; 98(44): e17749, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31689829

RESUMO

RATIONALE: Early infantile epileptic encephalopathy (EIEE) 65 was recently shown to be caused by the cytoplasmic FMRP interacting protein 2 (CYFIP2) mutation. To date, only 5 cases have been reported in two articles, and all the outcomes in all cases were poor. PATIENT CONCERNS: In this study, we reported an 8-month-old girl with a 1 month-long history of seizures and developmental delay. Over 1 month later, she developed epileptic spasms in clusters with hypsarrhythmia on electroencephalography. DIAGNOSIS: The patient was diagnosed with EIEE 65 and trio-based whole-exome sequencing revealed a causative de novo CYFIP2 mutation c.260G >T (p.Arg87Leu). INTERVENTIONS: The proband was successively treated with multiple antiepileptic drugs, including levetiracetam, phenobarbital, VitB6, topiramate, methylprednisolone, prednisone, valproic acid and vigabatrin. OUTCOMES: After resistance to multiple anti-epileptic drugs over 2 months of treatment, she finally achieved seizure-free several days after vigabatrin administration and her developmental delay steadily improved. LESSONS: OUR: case confirmed that CYFIP2 was the pathogenic gene of EIEE 65. We also first demonstrated vigabatrin might be effective for control of seizures and helpful for the improved outcomes of these patients.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/genética , Mutação/genética , Espasmos Infantis/genética , Anticonvulsivantes/uso terapêutico , Diagnóstico Precoce , Feminino , Humanos , Lactente , Espasmos Infantis/diagnóstico , Espasmos Infantis/tratamento farmacológico , Resultado do Tratamento
3.
Int J Mol Sci ; 20(20)2019 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-31618813

RESUMO

Rett syndrome (RTT) and CDKL5 deficiency disorder (CDD) are two rare X-linked developmental brain disorders with overlapping but distinct phenotypic features. This review examines the impact of loss of methyl-CpG-binding protein 2 (MeCP2) and cyclin-dependent kinase-like 5 (CDKL5) on clinical phenotype, deficits in synaptic- and circuit-homeostatic mechanisms, seizures, and sleep. In particular, we compare the overlapping and contrasting features between RTT and CDD in clinic and in preclinical studies. Finally, we discuss lessons learned from recent clinical trials while reviewing the findings from pre-clinical studies.


Assuntos
Síndromes Epilépticas/diagnóstico , Síndromes Epilépticas/etiologia , Síndromes Epilépticas/terapia , Síndrome de Rett/diagnóstico , Síndrome de Rett/etiologia , Síndrome de Rett/terapia , Espasmos Infantis/diagnóstico , Espasmos Infantis/etiologia , Espasmos Infantis/terapia , Animais , Ensaios Clínicos como Assunto , Diagnóstico Diferencial , Gerenciamento Clínico , Suscetibilidade a Doenças , Humanos , Proteína 2 de Ligação a Metil-CpG/genética , Proteína 2 de Ligação a Metil-CpG/metabolismo , Mutação , Fenótipo , Proteínas Serina-Treonina Quinases/genética , Proteínas Serina-Treonina Quinases/metabolismo , Pesquisa Médica Translacional
4.
Zh Nevrol Psikhiatr Im S S Korsakova ; 119(7. Vyp. 2): 74-82, 2019.
Artigo em Russo | MEDLINE | ID: mdl-31532594

RESUMO

OBJECTIVE: To study clinical and neurophysiological data of early infantile epileptic encephalopathy type 14 caused by KCNT1 mutations. MATERIAL AND METHODS: For the period 2017 to 2019, 3 non-relative girls with clinical characteristics of epilepsy of infancy with migrating focal seizures (EIMFS) and mutations in the KCNT1 gene are identified and studied. DNA sequencing was performed using the Hereditary epilepsy panel (Next Generation Sequencing on platform IlluminaNextSeq 500, USA). Dynamical video-EEG monitoring was done with "Encephalan-Video" RM-19/26 ("Medicom MTD", Russia). RESULTS AND CONCLUSION: De novo KCNT1 mutations are identified and studied in three unrelated Russian girls: M.V., 3 years and 3 month old, T.V., 9 month old and M.A., 5 month old. M.V. has the previously unknown mutation in exon 12 (chr9:138656907C>T) with amino acid substitution Arg356Trp. T.V. has the previously described mutation in chromosome 9: 138651532G>A with amino acid substitution Gly288Ser (OMIM: 608167.0010). M.U. has the previously unknown mutation in exon 15 (chr9:138660712A>G) with amino acid substitution Asp480Gly. M.V. has seizure onset at the age of 4 month with behavioral arrest seizures and tonic versive seizures. T.V. developed seizures at 4,5 month in the manner of behavior arrest and ophthalmo-clonic seizures with hyperemia of face. M.U. has neonatal seizures with bilateral tonic-clonic seizures, cyanosis and further development of status epilepticus of alternating hemiconvulsive seizures. Further all the girls develop polymorphic seizures of multiregional genesis up to migrating status epilepticus with typical electro-clinical pattern of EIMFS. Therefore, KCNT1 is likely to be a major gene causing this rare and severe epileptic syndrome.


Assuntos
Epilepsia , Proteínas do Tecido Nervoso , Canais de Potássio , Convulsões , Espasmos Infantis , Eletroencefalografia , Feminino , Humanos , Lactente , Mutação , Proteínas do Tecido Nervoso/genética , Canais de Potássio/genética , Federação Russa , Convulsões/etiologia , Convulsões/genética , Espasmos Infantis/diagnóstico , Espasmos Infantis/genética
6.
Int J Mol Sci ; 20(14)2019 Jul 10.
Artigo em Inglês | MEDLINE | ID: mdl-31295832

RESUMO

Kv7.2 subunits encoded by the KCNQ2 gene provide a major contribution to the M-current (IKM), a voltage-gated K+ current crucially involved in the regulation of neuronal excitability. Heterozygous missense variants in Kv7.2 are responsible for epileptic diseases characterized by highly heterogeneous genetic transmission and clinical severity, ranging from autosomal-dominant Benign Familial Neonatal Seizures (BFNS) to sporadic cases of severe epileptic and developmental encephalopathy (DEE). Here, we describe a patient with neonatal onset DEE, carrying a previously undescribed heterozygous KCNQ2 c.418G > C, p.Glu140Gln (E140Q) variant. Patch-clamp recordings in CHO cells expressing the E140Q mutation reveal dramatic loss of function (LoF) effects. Multistate structural modelling suggested that the E140Q substitution impeded an intrasubunit electrostatic interaction occurring between the E140 side chain in S2 and the arginine at position 210 in S4 (R210); this interaction is critically involved in stabilizing the activated configuration of the voltage-sensing domain (VSD) of Kv7.2. Functional results from coupled charge reversal or disulfide trapping experiments supported such a hypothesis. Finally, retigabine restored mutation-induced functional changes, reinforcing the rationale for the clinical use of Kv7 activators as personalized therapy for DEE-affected patients carrying Kv7.2 LoF mutations.


Assuntos
Encefalopatias/genética , Deficiências do Desenvolvimento/genética , Predisposição Genética para Doença , Variação Genética , Canal de Potássio KCNQ2/genética , Domínios e Motivos de Interação entre Proteínas/genética , Espasmos Infantis/genética , Substituição de Aminoácidos , Biomarcadores , Encefalopatias/diagnóstico , Encefalopatias/terapia , Pré-Escolar , Deficiências do Desenvolvimento/diagnóstico , Deficiências do Desenvolvimento/terapia , Eletroencefalografia , Estudos de Associação Genética , Humanos , Lactente , Recém-Nascido , Canal de Potássio KCNQ2/química , Mutação com Perda de Função , Imagem por Ressonância Magnética , Masculino , Modelos Moleculares , Neuroimagem , Conformação Proteica , Espasmos Infantis/diagnóstico , Espasmos Infantis/terapia , Relação Estrutura-Atividade , Avaliação de Sintomas
7.
J Genet ; 98(2)2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-31204721

RESUMO

Neuronal migration disorders (NMDs) are a heterogeneous group of conditions caused by the abnormal migration of neuroblasts in the developing brain and nervous system, resulting in severe developmental impairment, intractable epilepsy and intellectual disability (Spalice et al. 2009). To date, many genes have been identified as the leading cause of migration defects, i.e. agyria/pachygyria, polymicrogyria, heterotopias, agenesis of the corpus callosum and agenesis of the cranial nerves (Spalice et al. 2009). Here, we present a patient with early infantile epileptic encephalopathy (Ohtahara syndrome) with seizure onset on the first dayof life, severe developmental delay and an abnormal brain MRI with excessive folding of small, fused gyri and bilateral perisylvian polymicrogyria, suggestive of neuronal migration disorder. To clarify the unknown aetiology, we conducted whole-exome sequencing, which detected a de novo missense variant (c.5308A>T; p.(Met1770Leu)) in the SCN2A gene. This is a report of SCN2A gene variant identified in a patient with neuronal migration disorder which could further expand the phenotypic spectrum of these genetic disorders.


Assuntos
Mutação , Canal de Sódio Disparado por Voltagem NAV1.2/genética , Neuroimagem , Fenótipo , Espasmos Infantis/diagnóstico , Espasmos Infantis/genética , Sequência de Aminoácidos , Diagnóstico Diferencial , Humanos , Lactente , Imagem por Ressonância Magnética , Masculino , Malformações do Desenvolvimento Cortical do Grupo II/diagnóstico , Neuroimagem/métodos
8.
Epileptic Disord ; 21(3): 271-277, 2019 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-31225800

RESUMO

To further characterise CDKL5-related disorder, previously classified as an early-onset seizure variant of Rett syndrome, which is currently considered a specific and independent early-infantile epileptic encephalopathy. We describe the epileptic phenotype and neurocognitive development in three girls with CDKL5 mutations showing severe neurodevelopmental impairment, with different epileptic phenotypes and severity. The patients differed regarding age at epilepsy onset, seizure frequency, duration of "honeymoon periods", as well as EEG features. The "honeymoon period", defined as a seizure-free period longer than two months, represented, in our case series, a good indicator of the epilepsy outcome, but not of the severity of developmental impairment. However, even during the "honeymoon period", the interictal EEG showed epileptiform abnormalities, slowing, or a disappearance of physiological pattern. The natural history of CDKL5 disorder was compared between the three girls, focusing on the relationship between electroclinical features and neurological development. Our findings suggest that CDKL5 mutations likely play a direct role in psychomotor development, whereas epilepsy is one of the clinical features associated with this complex disorder.


Assuntos
Epilepsia/terapia , Mutação/genética , Proteínas Serina-Treonina Quinases/genética , Espasmos Infantis/genética , Criança , Eletroencefalografia/métodos , Epilepsia/genética , Síndromes Epilépticas/diagnóstico , Síndromes Epilépticas/genética , Síndromes Epilépticas/terapia , Feminino , Humanos , Fenótipo , Síndrome de Rett/genética , Convulsões/genética , Espasmos Infantis/diagnóstico , Espasmos Infantis/terapia
9.
Neurocase ; 25(1-2): 59-61, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31046567

RESUMO

The CDKL5 disorder is characterized by early onset epilepsy, stereotypical hand movement, absent speech and severe hypotonia. Herein, we report epileptic encephalopathy with continuous spike-and-wave during sleep (CSWS) in apatient with CDKL5 disorder. She admitted with complaints of frequently recurring generalized tonic and myoclonic seizures. The diagnoses were confirmed by de novo CDKL5 mutation, c.197_198delCT (p.L67QfsX23). Interictal EEG revealed generalized spike and slow-wave activity, occurring intermittently in wakefulness but present for at least 85% of non-REM sleep, consistent with the diagnosis of CSWS. To our knowledge, this is the first report of CSWS associated with CDKL5 disorder.


Assuntos
Epilepsia/etiologia , Epilepsia/fisiopatologia , Síndromes Epilépticas/complicações , Espasmos Infantis/complicações , Criança , Eletroencefalografia , Epilepsia/diagnóstico , Síndromes Epilépticas/diagnóstico , Feminino , Humanos , Espasmos Infantis/diagnóstico
10.
Dev Period Med ; 23(1): 15-20, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30954976

RESUMO

OBJECTIVE: Introduction: Epileptic spasms are seizures usually associated with a severe developmental epilepsy syndrome with onset in the first year of life, peaking between 3 and 10 months of age [12]. A variety of disorders can cause epileptic spasms, with the etiology driving management, prognosis, and overall outcome. Preexisting brain damage has been demonstrated in 60% to 90% of the cases reflecting pre-, peri-, or postnatal brain injury that may usually be determined by history and clinical neurologic examination. Cerebral malformations may account for up to 30% of the cases [2]. Prenatal alcohol exposure can permanently damage the brain, affecting important structures, such as the cerebellum, corpus callosum as well as specific cell populations in many other regions of the brain. No one knows what a "safe" amount of alcohol consumption during pregnancy may be[3]. Objective: The aim of this article is to present a clinical case of a large brain temporal lobe malformation which was recognized after a very early onset of spasms registered on video EEG-monitoring followed by MRI findings and to put forward the assumption that regular consumption of light alcoholic drinks even in low doses could contribute to irreversible brain damage in the fetus. PATIENTS AND METHODS: Material and methods: All patient data were collected from the NICU and Newborn Pathology Department of Lviv City Children's Clinical Hospital Health Record Department, and included the hospital and clinic records by the staff neurologist, neurophysiologist, and pediatrician, as well as EEG records in the postneonatal period. The mother was interviewed to clarify the pregnancy course data. The mother's consent was obtained for publication. RESULTS: Results: Asymmetric spasms, which were recognized as seizures on the 4th day of the child's life while recording video EEG, urged the physicians towards further diagnostic investigations. Primarily the child was diagnosed with neonatal abstinence syndrome on the 2nd day of life based on clinical and patient history data, but on the following day episodes of myoclonic jerks and jitteriness were noticed and video EEG monitoring started. Upon analysis of video- EEG, myoclonic seizures and spasms were reported showing asymmetry in the amplitude of ictal EEG. MRI was recommended and performed to explain focal EEG findings, and a large brain left temporal lobe malformation was seen. CONCLUSION: Conclusions: Spasms in the form of seizures are rarely reported in the neonatal period. Their recognition has to lead to urgent brain imaging study to look for the underlying cause and to implement timely, appropriate corrections in the treatment strategy. Although brain malformations can have many causes, taking careful antenatal, perinatal and family history has ruled out many usual etiologies. Maternal alcohol consumption during pregnancy may potentially have contributed to the condition.


Assuntos
Epilepsia do Lobo Temporal/etiologia , Efeitos Tardios da Exposição Pré-Natal/diagnóstico , Espasmos Infantis/etiologia , Lobo Temporal/patologia , Eletroencefalografia , Epilepsia do Lobo Temporal/diagnóstico , Epilepsia do Lobo Temporal/patologia , Etanol , Feminino , Humanos , Recém-Nascido , Imagem por Ressonância Magnética , Gravidez , Efeitos Tardios da Exposição Pré-Natal/diagnóstico por imagem , Efeitos Tardios da Exposição Pré-Natal/patologia , Espasmos Infantis/diagnóstico , Espasmos Infantis/patologia , Lobo Temporal/diagnóstico por imagem
11.
Nat Commun ; 10(1): 1477, 2019 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-30931947

RESUMO

Phenotypic and biochemical categorization of humans with detrimental variants can provide valuable information on gene function. We illustrate this with the identification of two different homozygous variants resulting in enzymatic loss-of-function in LDHD, encoding lactate dehydrogenase D, in two unrelated patients with elevated D-lactate urinary excretion and plasma concentrations. We establish the role of LDHD by demonstrating that LDHD loss-of-function in zebrafish results in increased concentrations of D-lactate. D-lactate levels are rescued by wildtype LDHD but not by patients' variant LDHD, confirming these variants' loss-of-function effect. This work provides the first in vivo evidence that LDHD is responsible for human D-lactate metabolism. This broadens the differential diagnosis of D-lactic acidosis, an increasingly recognized complication of short bowel syndrome with unpredictable onset and severity. With the expanding incidence of intestinal resection for disease or obesity, the elucidation of this metabolic pathway may have relevance for those patients with D-lactic acidosis.


Assuntos
Acidose Láctica/diagnóstico , Lactato Desidrogenases/genética , Ácido Láctico/metabolismo , Mutação com Perda de Função , Síndrome do Intestino Curto/metabolismo , Espasmos Infantis/diagnóstico , Acidose Láctica/genética , Adulto , Animais , Consanguinidade , Diagnóstico Diferencial , Homozigoto , Humanos , Lactente , Lactato Desidrogenases/deficiência , Masculino , Espasmos Infantis/genética , Peixe-Zebra
12.
Res Dev Disabil ; 89: 114-119, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30974259

RESUMO

BACKGROUND: This study aimed to investigate the clinical characteristics and neurodevelopmental outcomes of children with West syndrome (WS) by using the Bayley-III scale of infant development, as the first report from the Middle-East. METHODS: Between January 2013 and February 2016, we prospectively enrolled 67 consecutive patients with a confirmed diagnosis of WS from Isfahan, Iran. Cognition, language and motor outcomes of the studied subjects were evaluated with the Bayley Scales of Infant and Toddler Development-Third Edition (Bayley-III). RESULTS: Overall, 67 cases, including 34 (50.7%) boys and 33 (49.3%) girls (a male/female ratio of 1.03), were enrolled for the study. The mean age was 26.7 ± 12.9 months. Among the subjects, 50 (74.6%) patients had symptomatic WS, and 17 (25.4%) patients had cryptogenic WS. "Severe delay" was found in 76.9% of the patients regarding cognitive evaluation, 67.7% for language and communication abilities, and, 81.5% for motor function. The patients with cryptogenic WS were significantly more likely to have more favorable outcomes in motor (p = 0.035), cognitive (p = 0.035) and receptive language (p = 0.043) in comparison to those who had symptomatic WS. The patients with controlled seizures were significantly more likely to have more favorable outcomes in motor (p = 0.027) and cognition (p = 0.011) as compared to those with uncontrolled seizures. CONCLUSION: WS was associated with poor neurodevelopmental outcome in our study. Severe developmental delay was associated with two major factors: (i) presence of a specific underlying abnormality (symptomatic WS) and(ii) persistent seizures as a result of the former.


Assuntos
Cognição , Deficiências do Desenvolvimento , Desenvolvimento da Linguagem , Destreza Motora , Espasmos Infantis , Desenvolvimento Infantil , Pré-Escolar , Deficiências do Desenvolvimento/diagnóstico , Deficiências do Desenvolvimento/epidemiologia , Deficiências do Desenvolvimento/etiologia , Feminino , Humanos , Lactente , Irã (Geográfico)/epidemiologia , Masculino , Testes Neuropsicológicos , Espasmos Infantis/diagnóstico , Espasmos Infantis/epidemiologia , Espasmos Infantis/fisiopatologia , Espasmos Infantis/psicologia
13.
Ann Neurol ; 85(4): 514-525, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30779207

RESUMO

OBJECTIVE: To elucidate the biophysical basis underlying the distinct and severe clinical presentation in patients with the recurrent missense SCN1A variant, p.Thr226Met. Patients with this variant show a well-defined genotype-phenotype correlation and present with developmental and early infantile epileptic encephalopathy that is far more severe than typical SCN1A Dravet syndrome. METHODS: Whole cell patch clamp and dynamic action potential clamp were used to study T226M Nav 1.1 channels expressed in mammalian cells. Computational modeling was used to explore the neuronal scale mechanisms that account for altered action potential firing. RESULTS: T226M channels exhibited hyperpolarizing shifts of the activation and inactivation curves and enhanced fast inactivation. Dynamic action potential clamp hybrid simulation showed that model neurons containing T226M conductance displayed a left shift in rheobase relative to control. At current stimulation levels that produced repetitive action potential firing in control model neurons, depolarization block and cessation of action potential firing occurred in T226M model neurons. Fully computationally simulated neuron models recapitulated the findings from dynamic action potential clamp and showed that heterozygous T226M models were also more susceptible to depolarization block. INTERPRETATION: From a biophysical perspective, the T226M mutation produces gain of function. Somewhat paradoxically, our data suggest that this gain of function would cause interneurons to more readily develop depolarization block. This "functional dominant negative" interaction would produce a more profound disinhibition than seen with haploinsufficiency that is typical of Dravet syndrome and could readily explain the more severe phenotype of patients with T226M mutation. Ann Neurol 2019;85:514-525.


Assuntos
Epilepsias Mioclônicas/genética , Mutação com Ganho de Função/genética , Canal de Sódio Disparado por Voltagem NAV1.1/genética , Espasmos Infantis/genética , Animais , Células CHO , Cricetulus , Bases de Dados Genéticas , Epilepsias Mioclônicas/diagnóstico , Humanos , Espasmos Infantis/diagnóstico
14.
Invest Ophthalmol Vis Sci ; 60(1): 93-97, 2019 01 02.
Artigo em Inglês | MEDLINE | ID: mdl-30640974

RESUMO

Purpose: Germline and somatic mutations in CTNNB1 have been found in different types of human diseases. This follow-up study aimed to identify causative germline mutations in CTNNB1 and their associated ocular phenotypes through a comparative analysis of whole-exome sequencing data. Methods: Annotated sequence variations in CTNNB1 were selected from in-house data from whole-exome sequencing of genomic DNA prepared from leucocytes of 3280 unrelated probands with different forms of eye diseases. Potentially pathogenic variants in CTNNB1 were analyzed by multistep bioinformatics analyses. Clinical data from probands with pathogenic variants in CTNNB1 were collected, and potential genotype-phenotype correlations were analyzed. Results: Eleven rare variants that potentially affect the coding regions of CTNNB1 were detected in 11 of the 3280 samples, and four variants were considered to be potentially pathogenic. All four mutations, namely, c.999delC (p.Tyr333*), c.1104delT (p.His369Thrfs*2), c.1738_1742delinsACA (p.Leu580Thrfs*28), and c.1867C>T (p.Gln623*), were heterozygotes and considered to have a germline origin. Three of the four mutations are de novo mutations, and the status of the remaining mutation is unavailable. All four probands had the same class of closely related ocular diseases: one proband had FEVR, and three probands had Norrie-like retinopathy. The molecular results indicated that three probands showed systemic anomalies, as demonstrated by a follow-up survey, but relevant information for the remaining proband was unavailable. Conclusions: The data suggest that germline truncating mutations in CTNNB1 cause autosomal dominant syndromic FEVR or Norrie disease. Patients with mutations in CTNNB1, KIF11, or NDP may have similar or overlapping phenotypes, but this phenomenon needs to be studied further.


Assuntos
Cegueira/congênito , Oftalmopatias Hereditárias/genética , Doenças Genéticas Ligadas ao Cromossomo X/genética , Mutação em Linhagem Germinativa , Doenças do Sistema Nervoso/genética , Degeneração Retiniana/genética , Doenças Retinianas/genética , Espasmos Infantis/genética , beta Catenina/genética , Cegueira/diagnóstico , Cegueira/genética , Análise Mutacional de DNA , Oftalmopatias Hereditárias/diagnóstico , Feminino , Angiofluoresceinografia , Seguimentos , Doenças Genéticas Ligadas ao Cromossomo X/diagnóstico , Humanos , Lactente , Masculino , Doenças do Sistema Nervoso/diagnóstico , Fenótipo , Degeneração Retiniana/diagnóstico , Doenças Retinianas/diagnóstico , Espasmos Infantis/diagnóstico , Sequenciamento Completo do Genoma
15.
Mol Genet Genomic Med ; 7(1): e00503, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30474316

RESUMO

BACKGROUND: Both familial exudative vitreoretinopathy (FEVR) and Norrie disease (ND) are hereditary retinal disorders which can cause severe visual impairment and blindness at a young age. The present study aimed to report the use of antenatal genetic testing and ultrasound in the diagnosis and counseling of FEVR and ND. METHODS: Amniocentesis and ultrasonography were performed in high-risk mothers, with children having FEVR or ND, to predict severe ocular abnormalities. RESULTS: Case 1: A homozygous NDP mutation (c.376T>C, NM_000266) was detected in the proband and his mother. Molecular prenatal analysis of the fetal DNA revealed no mutations. No ocular abnormalities were detected on ultrasonography. The pregnancy progressed uneventfully to a normal outcome. Case 2: A novel heterozygous FZD4 mutation (c.1010dupA, NM_012193) was detected in the proband and his mother. The same mutation was detected in the fetus, but ultrasonography showed no ocular abnormalities. A healthy baby boy with stage 1 FEVR was born after an uneventful pregnancy. Case 3: Deletions of exons 2 and 3 in the NDP were found in the proband and his mother. The same deletion mutation was detected in the female fetus, but the ultrasound scan was normal. The pregnancy progressed uneventfully to a normal outcome. CONCLUSIONS: To our knowledge, antenatal genetic analyses were used in conjunction with ultrasound for the first time, to diagnose FEVR and ND, and predict the postnatal prognoses in at-risk babies.


Assuntos
Cegueira/congênito , Oftalmopatias Hereditárias/genética , Doenças Genéticas Ligadas ao Cromossomo X/genética , Testes Genéticos/métodos , Doenças do Sistema Nervoso/genética , Degeneração Retiniana/genética , Doenças Retinianas/genética , Espasmos Infantis/genética , Ultrassonografia Pré-Natal/métodos , Adulto , Amniocentese/métodos , Cegueira/diagnóstico , Cegueira/genética , Pré-Escolar , Oftalmopatias Hereditárias/diagnóstico , Proteínas do Olho/genética , Feminino , Receptores Frizzled/genética , Doenças Genéticas Ligadas ao Cromossomo X/diagnóstico , Humanos , Lactente , Masculino , Mutação , Proteínas do Tecido Nervoso/genética , Doenças do Sistema Nervoso/diagnóstico , Degeneração Retiniana/diagnóstico , Doenças Retinianas/diagnóstico , Espasmos Infantis/diagnóstico
16.
Epilepsy Behav ; 90: 252-259, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30527252

RESUMO

PURPOSE: Differentiating between Dravet syndrome and non-Dravet SCN1A-related phenotypes is important for prognosis regarding epilepsy severity, cognitive development, and comorbidities. When a child is diagnosed with genetic epilepsy with febrile seizures plus (GEFS+) or febrile seizures (FS), accurate prognostic information is essential as well, but detailed information on seizure course, seizure freedom, medication use, and comorbidities is lacking for this milder patient group. In this cross-sectional study, we explore disease characteristics in milder SCN1A-related phenotypes and the nature, occurrence, and relationships of SCN1A-related comorbidities in both patients with Dravet and non-Dravet syndromes. METHODS: A cohort of 164 Dutch participants with SCN1A-related seizures was evaluated, consisting of 116 patients with Dravet syndrome and 48 patients with either GEFS+, febrile seizures plus (FS+), or FS. Clinical data were collected from medical records, semi-structured telephone interviews, and three questionnaires: the Functional Mobility Scale (FMS), the Pediatric Quality of Life Inventory (PedsQL) Measurement Model, and the Child or Adult Behavior Checklists (CBCL/ABCL). RESULTS: Walking disabilities and severe behavioral problems affect 71% and 43% of patients with Dravet syndrome respectively and are almost never present in patients with non-Dravet syndromes. These comorbidities are strongly correlated to lower quality-of-life (QoL) scores. Less severe comorbidities occur in patients with non-Dravet syndromes: learning problems and psychological/behavioral problems are reported for 27% and 38% respectively. The average QoL score of the non-Dravet group was comparable with that of the general population. The majority of patients with non-Dravet syndromes becomes seizure-free after 10 years of age (85%). CONCLUSIONS: Severe behavioral problems and walking disabilities are common in patients with Dravet syndrome and should receive specific attention during clinical management. Although the epilepsy course of patients with non-Dravet syndromes is much more favorable, milder comorbidities frequently occur in this group as well. Our results may be of great value for clinical care and informing newly diagnosed patients and their parents about prognosis.


Assuntos
Epilepsias Mioclônicas/epidemiologia , Epilepsias Mioclônicas/genética , Epilepsia/epidemiologia , Epilepsia/genética , Canal de Sódio Disparado por Voltagem NAV1.1/genética , Adolescente , Adulto , Idoso , Criança , Pré-Escolar , Estudos de Coortes , Comorbidade , Estudos Transversais , Epilepsias Mioclônicas/diagnóstico , Epilepsia/diagnóstico , Síndromes Epilépticas/diagnóstico , Síndromes Epilépticas/epidemiologia , Síndromes Epilépticas/genética , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Qualidade de Vida , Estudos Retrospectivos , Convulsões Febris/diagnóstico , Convulsões Febris/epidemiologia , Convulsões Febris/genética , Espasmos Infantis/diagnóstico , Espasmos Infantis/epidemiologia , Espasmos Infantis/genética , Inquéritos e Questionários , Resultado do Tratamento , Adulto Jovem
17.
Epilepsy Behav ; 90: 217-227, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30578097

RESUMO

OBJECTIVE: Behavior problems in Dravet syndrome (DS) are common and can impact the lives of patients tremendously. The current study aimed to give more insight into (1) the prevalence of a wide range of specific behavior difficulties and aspects of health-related quality of life (HRQoL) in patients with DS compared with the general population (gp) and patients with epilepsy without DS, (2) the relations between these behavior problems and different aspects of HRQoL, and (3) the associations between seizure frequency, cognitive impairment (CI), behavior problems, and HRQoL, based on a conceptual model. METHODS: One hundred and sixteen patients (aged between 2 and 67 years), affected by SCN1A-related seizures, were included in the study. Eighty-five were patients with DS, 31 were patients with epilepsy without DS. Behavior problems were measured using the Child/Adult Behavior Checklist (C/ABCL), HRQoL was measured using the Pediatric Quality of Life Inventory (PedsQL) Measurement Model. Other characteristics were obtained by clinical assessments, medical records, and semi-structured telephone interviews with parents. Comparisons between patients with DS, patients without DS, and the gp were calculated by the exact goodness of fit χ2 analyses, relations between subscales were analyzed using Pearson's correlations, and the conceptual model was tested in a path analysis. RESULTS: (1) Patients with DS show significantly more behavior problems compared with the gp and patients with epilepsy without DS. A total of 56.5% of patients with DS scored in the borderline and clinical ranges for total behavior problems. Problems with attention were most prevalent; 62.3% of patients with DS scored in the borderline and clinical ranges. Health-related quality of life was significantly lower for patients with DS compared with the gp and patients without DS. Physical and social functioning scores were especially low and decreased even more in the older age categories. (2) Problems with attention, aggression, and withdrawn behavior were most related to social functioning. Somatic problems and anxiety/depression were most related to emotional functioning. (3) Cognitive impairment and behavior problems were both independent predictors of poorer HRQoL in patients with DS, with behavior problems being the strongest predictor. Seizure frequency was only indirectly related to HRQoL, mediated by cognitive impairment. IMPLICATIONS: The high prevalence of behavior problems in DS and the significant impact on quality of life (QoL), independent of epilepsy-related factors, emphasize the need for active management and treatment of these problems and should be considered as part of the management plan.


Assuntos
Epilepsias Mioclônicas/genética , Epilepsias Mioclônicas/psicologia , Comportamento Problema/psicologia , Qualidade de Vida/psicologia , Adolescente , Adulto , Idoso , Criança , Pré-Escolar , Estudos de Coortes , Depressão/diagnóstico , Depressão/genética , Depressão/psicologia , Epilepsias Mioclônicas/diagnóstico , Epilepsia/diagnóstico , Epilepsia/genética , Epilepsia/psicologia , Síndromes Epilépticas/diagnóstico , Síndromes Epilépticas/genética , Síndromes Epilépticas/psicologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Canal de Sódio Disparado por Voltagem NAV1.1/genética , Síndrome de Rett/diagnóstico , Síndrome de Rett/genética , Síndrome de Rett/psicologia , Convulsões/diagnóstico , Convulsões/genética , Convulsões/psicologia , Ajustamento Social , Espasmos Infantis/diagnóstico , Espasmos Infantis/genética , Espasmos Infantis/psicologia , Inquéritos e Questionários , Adulto Jovem
18.
Arch Pediatr ; 26(1): 1-5, 2019 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-30554851

RESUMO

PURPOSE: To describe the management of infants with epileptic spasms (ESs) in a low-income country and identify factors predictive of their prognosis. MATERIAL AND METHODS: We conducted a retrospective study in a university hospital in Tunis, Tunisia, over a period of 10 years. We included infants with recurrent ESs. RESULTS: Thirty-eight patients were included. The median age at onset of ESs was 5 months. Typical hypsarrhythmia was found in 21 patients (55%). Brain MRI was done in 32 patients (84%) and metabolic work-up in 34 patients (89%). ESs were categorized as symptomatic in 58% of the patients. Vigabatrin was prescribed as the first-line drug in almost half of the patients. At the last follow-up, 63% of the patients were seizure-free and 82% had a psychomotor delay. The presence of other types of seizures was associated with uncontrolled epilepsy at the last follow-up (P=0.020). The persistence of spasms after the first-line treatment was associated with abnormal final psychomotor development (P=0.047). CONCLUSIONS: Investigation practices and final outcomes of our patients were comparable to data from high-income countries. Treatment practices have been standardized to be in line with international guidelines.


Assuntos
Padrões de Prática Médica/estatística & dados numéricos , Espasmos Infantis/diagnóstico , Anticonvulsivantes/uso terapêutico , Feminino , Hospitais Universitários , Humanos , Lactente , Masculino , Pobreza , Prognóstico , Estudos Retrospectivos , Fatores de Risco , Espasmos Infantis/tratamento farmacológico , Tunísia
19.
Conf Proc IEEE Eng Med Biol Soc ; 2018: 538-541, 2018 07.
Artigo em Inglês | MEDLINE | ID: mdl-30440453

RESUMO

Infantile spasms is a type of epilepsy characterized by clinical seizures termed "spasms" and often an electroencephalographic (EEG) pattern known as hypsarrhythmia. Multiple studies have shown that the interrater reliability for human visual recognition of hypsarrhythmia is poor. Quantitative measurements of this EEG pattern would provide objective basis for identification; however, the basic temporal and spectral characteristics of hypsarrhythmia have never been assessed. Thus, we measured EEG amplitude and power spectra in 21 infantile spasms patients before and after treatment, as well as 21 control subjects. The hypsarrhythmia EEG pattern was associated with (1) high broadband amplitude, especially in frontal and central brain regions, (2) high median power in the delta and alpha frequency bands, and (3) low spectral edge frequency. Our results indicate that hypsarrhythmia can be quantitatively distinguished from data without hypsarrhythmia. Introduction of these quantitative measures into clinical practice may increase diagnostic accuracy, expediting proper treatment and improving outcomes.


Assuntos
Encéfalo/fisiopatologia , Eletroencefalografia , Espasmos Infantis/diagnóstico , Estudos de Casos e Controles , Humanos , Lactente , Reprodutibilidade dos Testes
20.
J Med Genet ; 55(12): 803-813, 2018 12.
Artigo em Inglês | MEDLINE | ID: mdl-30287594

RESUMO

BACKGROUND: Progressive encephalopathy, hypsarrhythmia and optic atrophy (PEHO) has been described as a clinically distinct syndrome. It has been postulated that it is an autosomal recessive condition. However, the aetiology is poorly understood, and the genetic basis of the condition has not been fully elucidated. Our objective was to discover if PEHO syndrome is a single gene disorder. METHOD: Children with PEHO and PEHO-like syndrome were recruited. Clinical, neurological and dysmorphic features were recorded; EEG reports and MRI scans were reviewed. Where possible, exome sequencing was carried out first to seek mutations in known early infantile developmental and epileptic encephalopathy (DEE) genes and then to use an agnostic approach to seek novel candidate genes. We sought intra-interfamilial phenotypic correlations and genotype-phenotype correlations when pathological mutations were identified. RESULTS: Twenty-three children were recruited from a diverse ethnic background, 19 of which were suitable for inclusion. They were similar in many of the core and the supporting features of PEHO, but there was significant variation in MRI and ophthalmological findings, even between siblings with the same mutation. A pathogenic genetic variant was identified in 15 of the 19 children. One further girl's DNA failed analysis, but her two affected sisters shared confirmed variants. Pathogenic variants were identified in seven different genes. CONCLUSIONS: We found significant clinical and genetic heterogeneity. Given the intrafamily variation demonstrated, we question whether the diagnostic criteria for MRI and ophthalmic findings should be altered. We also question whether PEHO and PEHO-like syndrome represent differing points on a clinical spectrum of the DEE. We conclude that PEHO and PEHO-like syndrome are clinically and genetically diverse entities-and are phenotypic endpoints of many severe genetic encephalopathies.


Assuntos
Edema Encefálico/diagnóstico , Edema Encefálico/etiologia , Epilepsia/diagnóstico , Epilepsia/genética , Doenças Neurodegenerativas/diagnóstico , Doenças Neurodegenerativas/etiologia , Atrofia Óptica/diagnóstico , Atrofia Óptica/etiologia , Espasmos Infantis/diagnóstico , Espasmos Infantis/etiologia , Fatores Etários , Alelos , Biomarcadores , Pré-Escolar , Eletroencefalografia , Facies , Feminino , Estudos de Associação Genética , Predisposição Genética para Doença , Testes Genéticos , Genótipo , Humanos , Lactente , Recém-Nascido , Imagem por Ressonância Magnética , Masculino , Mutação , Linhagem , Fenótipo
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