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1.
Epileptic Disord ; 22(3): 327-335, 2020 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-32597768

RESUMO

Epilepsy of infancy with migrating focal seizures (EIMFS) is now a well-recognized early-onset syndrome included in the ILAE classification of the epilepsies. KCNT1 gain-of-function variants are identified in about half of patients. In the remaining cases, the underlying genetic component is far more heterogeneous with sporadic mutations occasionally reported in SCN1A, SCN2A, SLC12A5, TBC1D24, PLCB1, SLC25A22, and KCNQ2. Here, we report, for the first time, a homozygous deleterious variant in the FARS2 gene, identified using a 115-gene panel for monogenic epilepsies, in a patient with EIMFS. This boy was the second child born to healthy consanguineous parents. The first seizures occurred at six weeks of age. The patient rapidly developed severe epilepsy with focal discharges on EEG, migrating from one brain region to another, highly suggestive of EIMFS. At five months of age, he had daily multifocal clonic seizures and erratic myoclonic fits, which were not consistently related to spikes or spike-and-wave discharges. Neurological status was severely abnormal from onset and the patient died at 10 months of age from respiratory distress. Using the gene panel, a homozygous missense variant of FARS2 was identified, at Chr6 (GRCh37):g.5404829C>T, c.667C>T (NM_001318872.1), inherited from both parents, leading to an arginine-to-cysteine substitution, p.(Arg223Cys). FARS2 is a member of the mitochondrial aminoacyl tRNA transferase (ARS) enzymes. ARS variants are increasingly recognized causes of early-onset epileptic and neurodevelopmental encephalopathies, however, the associated epileptic phenotype is not completely described. This case shows that FARS2-related seizures can mimic EIMFS in the early stage of the disease. Furthermore, in the setting of migrating focal seizures of infancy, FARS2 should be considered as a further candidate gene, and increased lactate level and occurrence of refractory myoclonic seizures are possible key features to suspect FARS deficiency.

2.
Pediatr Neurol ; 109: 56-62, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32387008

RESUMO

BACKGROUND: Mutations in the X-linked gene WDR45 cause neurodegeneration with brain iron accumulation type 5. Global developmental delay occurs at an early age with slow progression to dystonia, parkinsonism, and dementia due to progressive iron accumulation in the brain. METHODS: We present 17 new cases and reviewed 106 reported cases of neurodegeneration with brain iron accumulation type 5. Detailed information related to developmental history and key time to event measures was collected. RESULTS: Within this cohort, there were 19 males. Most individuals were molecularly diagnosed by whole-exome testing. Overall 10 novel variants were identified across 11 subjects. All individuals were affected by developmental delay, most prominently in verbal skills. Most individuals experienced a decline in motor and cognitive skills. Although most individuals were affected by seizures, the spectrum ranged from provoked seizures to intractable epilepsy. The imaging findings varied as well, often evolving over time. The classic iron accumulation in the globus pallidus and substantia nigra was noted in half of our cohort and was associated with older age of image acquisition, whereas myelination abnormalities were associated with younger age. CONCLUSIONS: WDR45 mutations lead to a progressive and evolving disorder whose diagnosis is often delayed. Developmental delay and seizures predominate in early childhood, followed by a progressive decline of neurological function. There is variable expressivity in the clinical phenotypes of individuals with WDR45 mutations, suggesting that this gene should be considered in the diagnostic evaluation of children with myelination abnormalities, iron deposition, developmental delay, and epilepsy depending on the age at evaluation.

3.
BMC Med Genet ; 21(1): 10, 2020 01 08.
Artigo em Inglês | MEDLINE | ID: mdl-31914951

RESUMO

BACKGROUND: The role of deleterious copy number variations in schizophrenia is well established while data regarding pathogenic variations remain scarce. We report for the first time a case of schizophrenia in a child with a pathogenic mutation of the chromodomain helicase DNA binding protein 2 (CHD2) gene. CASE PRESENTATION: The proband was the second child of unrelated parents. Anxiety and sleep disorders appeared at the age of 10 months. He presented febrile seizures and, at the age of 8, two generalized tonic-clonic seizures. At the age of 10, emotional withdrawal emerged, along with a flat affect, disorganization and paranoid ideation, without seizures. He began to talk and giggle with self. Eventually, the patient presented daily auditory and visual hallucinations. The diagnosis of childhood onset schizophrenia (DSM V) was then evoked. Brain imaging was unremarkable. Wakefulness electroencephalography showed a normal background and some bilateral spike-wave discharges that did not explain the psychosis features. A comparative genomic hybridization array (180 K, Agilent, Santa Clara, CA, USA) revealed an 867-kb 16p13.3 duplication, interpreted as a variant of unknown significance confirmed by a quantitative PCR that also showed its maternal inheritance. Risperidone (1,5 mg per day), led to clinical improvement. At the age of 11, an explosive relapse of epilepsy occurred with daily seizures of various types. The sequencing of a panel for monogenic epileptic disorders and Sanger sequencing revealed a de novo pathogenic heterozygous transition in CHD2 (NM_001271.3: c.4003G > T). CONCLUSIONS: This case underlines that schizophrenia may be, sometimes, underpinned by a Mendelian disease. It addresses the question of systematic genetic investigations in the presence of warning signs such as a childhood onset of the schizophrenia or a resistant epilepsy. It points that, in the absence of pathogenic copy number variation, the investigations should also include a search for pathogenic variations, which means that some of the patients with schizophrenia should benefit from Next Generation Sequencing tools. Last but not least, CHD2 encodes a member of the chromodomain helicase DNA-binding (CHD) family involved in chromatin remodeling. This observation adds schizophrenia to the phenotypic spectrum of chromodomain remodeling disorders, which may lead to innovative therapeutic approaches.


Assuntos
Variações do Número de Cópias de DNA/genética , Proteínas de Ligação a DNA/genética , Esquizofrenia/genética , Encéfalo/metabolismo , Encéfalo/patologia , Criança , Cromatina/genética , Montagem e Desmontagem da Cromatina/genética , Eletroencefalografia , Feminino , Heterozigoto , Humanos , Masculino , Mutação , Fenótipo , Esquizofrenia/fisiopatologia , Convulsões Febris/genética , Convulsões Febris/patologia
4.
Neuropediatrics ; 50(5): 308-312, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31226716

RESUMO

Mutations that disrupt the TBC1D24 presynaptic protein have been implicated in various neurological disorders including epilepsy, chronic encephalopathy, DOORS (deafness, onychodystrophy, osteodystrophy, mental retardation, and seizures) syndrome, nonsyndromic hearing loss, and myoclonus. We present the case of a 22-month-old male with infantile-onset paroxysmal episodes of facial and limb myoclonus. The episodes were linked to biallelic variants in exon 2 of the TBC1D24 gene that lead to amino acid changes (c.304C >T/p.Pro102Ser and c.410T > C/p.Val137Ala), each variant being inherited from a parent. Follow-up imaging in adolescence revealed widened right cerebellar sulci. We discuss the evolving landscape of TBC1D24 associated phenotypes; this case adds to a growing body of evidence linking this gene to movement disorders in children.

5.
Epilepsy Behav ; 96: 23-27, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-31077938

RESUMO

INTRODUCTION: Tuberous sclerosis complex (TSC) is a multisystemic genetic disease with high clinical variability and age-related manifestations. These characteristics add to the complexity of transition to adulthood. This study aimed to explore the perception of medical follow-up and transition experience in a large group of patients with TSC who presented epilepsy in childhood. METHOD: This multicenter French study included patients with TSC aged 18 years or older who developed epilepsy before the age of 16 years. A questionnaire specifically designed for the study explored patients' opinion through 270 questions covering different aspects of their social, familial, professional, and medical courses. RESULTS: The questionnaire was sent to 72 patients, and 60 patients were included in the study (83% response rate) with a mean age of 32 years (18-55 years). Cognitive impairment was present in 80% of patients, and half of questionnaires were completed by the family. Pediatric care was coordinated by the child neurologist and was more regular and multidisciplinary than adult care. Epilepsy had the best follow-up followed by renal issues. Unmet needs were identified for psychiatric and behavioral disorders, both in children and adults. Respondents considered the help in achieving autonomy better in adult care. Only 50% of patients with a normal intellectual development had clear knowledge about their disease and the need for a regular monitoring. Two-thirds of respondents estimated that they had a transition experience between 16.5 and 21-year-old, considered as good in 60% of them. Seventy percent felt continuity between pediatric and adult care, and only 3% of respondents felt that their care would have been better if they were still followed in pediatric healthcare system. The change of care structure and/or caregivers was the most stressful factor during transition and transfer. CONCLUSION: This study highlights persistent issues in the regularity and coordination of the follow-up of patients with TSC despite established international guidelines. Although most patients had a positive transition experience, there is still an urgent need to optimize transition programs. This would be essential to maintain care continuity between pediatric and adult health systems, especially for patients with TSC with epilepsy and high rate of cognitive and psychiatric impairments.

6.
J Clin Invest ; 129(3): 1240-1256, 2019 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-30620337

RESUMO

Sphingolipid imbalance is the culprit in a variety of neurological diseases, some affecting the myelin sheath. We have used whole-exome sequencing in patients with undetermined leukoencephalopathies to uncover the endoplasmic reticulum lipid desaturase DEGS1 as the causative gene in 19 patients from 13 unrelated families. Shared features among the cases include severe motor arrest, early nystagmus, dystonia, spasticity, and profound failure to thrive. MRI showed hypomyelination, thinning of the corpus callosum, and progressive thalamic and cerebellar atrophy, suggesting a critical role of DEGS1 in myelin development and maintenance. This enzyme converts dihydroceramide (DhCer) into ceramide (Cer) in the final step of the de novo biosynthesis pathway. We detected a marked increase of the substrate DhCer and DhCer/Cer ratios in patients' fibroblasts and muscle. Further, we used a knockdown approach for disease modeling in Danio rerio, followed by a preclinical test with the first-line treatment for multiple sclerosis, fingolimod (FTY720, Gilenya). The enzymatic inhibition of Cer synthase by fingolimod, 1 step prior to DEGS1 in the pathway, reduced the critical DhCer/Cer imbalance and the severe locomotor disability, increasing the number of myelinating oligodendrocytes in a zebrafish model. These proof-of-concept results pave the way to clinical translation.


Assuntos
Animais Geneticamente Modificados , Encéfalo , Cloridrato de Fingolimode/farmacologia , Doenças Desmielinizantes Hereditárias do Sistema Nervoso Central , Proteínas de Peixe-Zebra , Peixe-Zebra , Animais , Animais Geneticamente Modificados/genética , Animais Geneticamente Modificados/metabolismo , Encéfalo/enzimologia , Encéfalo/patologia , Modelos Animais de Doenças , Ácidos Graxos Dessaturases/genética , Ácidos Graxos Dessaturases/metabolismo , Doenças Desmielinizantes Hereditárias do Sistema Nervoso Central/tratamento farmacológico , Doenças Desmielinizantes Hereditárias do Sistema Nervoso Central/enzimologia , Doenças Desmielinizantes Hereditárias do Sistema Nervoso Central/genética , Doenças Desmielinizantes Hereditárias do Sistema Nervoso Central/patologia , Humanos , Locomoção/efeitos dos fármacos , Oligodendroglia/enzimologia , Oligodendroglia/patologia , Peixe-Zebra/genética , Peixe-Zebra/metabolismo , Proteínas de Peixe-Zebra/genética
7.
Genet Med ; 21(3): 553-563, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-29997391

RESUMO

PURPOSE: To investigate the genetic basis of congenital ataxias (CAs), a unique group of cerebellar ataxias with a nonprogressive course, in 20 patients from consanguineous families, and to identify new CA genes. METHODS: Singleton -exome sequencing on these 20 well-clinically characterized CA patients. We first checked for rare homozygous pathogenic variants, then, for variants from a list of genes known to be associated with CA or very early-onset ataxia, regardless of their mode of inheritance. Our replication cohort of 180 CA patients was used to validate the new CA genes. RESULTS: We identified a causal gene in 16/20 families: six known CA genes (7 patients); four genes previously implicated in another neurological phenotype (7 patients); two new candidate genes (2 patients). Despite the consanguinity, 4/20 patients harbored a heterozygous de novo pathogenic variant. CONCLUSION: Singleton exome sequencing in 20 consanguineous CA families led to molecular diagnosis in 80% of cases. This study confirms the genetic heterogeneity of CA and identifies two new candidate genes (PIGS and SKOR2). Our work illustrates the diversity of the pathophysiological pathways in CA, and highlights the pathogenic link between some CA and early infantile epileptic encephalopathies related to the same genes (STXBP1, BRAT1, CACNA1A and CACNA2D2).


Assuntos
Ataxia/genética , Ataxia Cerebelar/genética , Espasmos Infantis/genética , Adolescente , Ataxia/fisiopatologia , Criança , Pré-Escolar , Estudos de Coortes , Exoma/genética , Feminino , França , Heterogeneidade Genética , Predisposição Genética para Doença/genética , Genótipo , Humanos , Masculino , Mutação/genética , Fenótipo , Sequenciamento Completo do Exoma/métodos , Adulto Jovem
8.
Brain Dev ; 40(9): 768-774, 2018 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-29861155

RESUMO

OBJECTIVE: Heterozygous mutations in the ATP1A3 gene are responsible for various neurological disorders, ranging from early-onset alternating hemiplegia of childhood to adult-onset dystonia-parkinsonism. Next generation sequencing allowed the description of other phenotypes, including early-onset epileptic encephalopathy in two patients. We report on three more patients carrying ATP1A3 mutations with a close phenotype and discuss the relationship of this phenotype to alternating hemiplegia of childhood. METHODS: The patients' DNA underwent next generation sequencing. A retrospective analysis of clinical case records is reported. RESULTS: Each of the three patients had an unreported heterozygous de novo sequence variant in ATP1A3. These patients shared a similar phenotype characterized by early-onset attacks of movement disorders, some of which proved to be epileptic, and severe developmental delay. (Hemi)plegic attacks had not been considered before genetic testing. SIGNIFICANCE: Together with the two previously reported cases, our patients confirm that ATP1A3 mutations are associated with a phenotype combining features of early-onset encephalopathy, epilepsy and dystonic fits, as in the most severe forms of alternating hemiplegia of childhood, but in which (hemi)plegic attacks are absent or only suspected retrospectively.


Assuntos
Epilepsia/genética , Transtornos dos Movimentos/genética , Mutação , Convulsões/genética , ATPase Trocadora de Sódio-Potássio/genética , Adolescente , Encéfalo/fisiopatologia , Criança , Pré-Escolar , Epilepsia/diagnóstico , Epilepsia/fisiopatologia , Feminino , Hemiplegia/genética , Hemiplegia/fisiopatologia , Humanos , Masculino , Transtornos dos Movimentos/diagnóstico , Transtornos dos Movimentos/fisiopatologia , Convulsões/diagnóstico , Convulsões/fisiopatologia
9.
Eur J Paediatr Neurol ; 22(1): 82-92, 2018 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-28947381

RESUMO

OBJECTIVES: Neurodevelopmental outcome of apparently isolated agenesis of the corpus callosum (ACC) remains a major concern with uncertain prognosis. Despite "normal" IQ reported in a majority of patients, the rates of learning disabilities and severe outcome (ranging from 0% to 20%) are not clearly established. METHODS: A large population-based series was investigated based on a longitudinal follow-up until school age, using Wechsler Intelligence scales at 3, 5, and 7 years. RESULTS: Fifty women were referred to a tertiary referral unit for an "apparently" isolated ACC confirmed by ultrasound, foetal MRI, and karyotyping or array CGH. Twelve pregnancies were terminated, one foetus died in utero, one pregnancy outcome was unknown, and 36 babies were born. Two were lost to follow-up. Thirty-four children could be classified into three groups. Group 1 comprised two children (6%) with severe intellectual disability (one Mowat-Wilson syndrome and one ASD). Group 2 comprised 10 children (29%) who had learning disabilities and borderline intellectual functioning (VIQ and/or PIQ scores >70 and <85); three patients had hypopituitarism with additional MRI anomalies revealed after birth. Group 3 comprised 22 children (65%) who had both VIQ and PIQ >85 (-1 SD) with a normal school level. Longitudinal follow-up revealed weaker PIQ in younger children which improved with age. CONCLUSION: Our data indicate that intellectual ability is normal (IQ > 85) in approximately two thirds and borderline in just over a quarter of patients. However, a low risk of severe cognitive impairment exists, and this information should be shared with couples during prenatal counselling.


Assuntos
Agenesia do Corpo Caloso/complicações , Deficiência Intelectual/epidemiologia , Deficiência Intelectual/etiologia , Criança , Feminino , Seguimentos , Humanos , Lactente , Estudos Longitudinais , Gravidez , Estudos Prospectivos
10.
Brain ; 140(5): 1316-1336, 2017 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-28379373

RESUMO

Mutations in SCN2A, a gene encoding the voltage-gated sodium channel Nav1.2, have been associated with a spectrum of epilepsies and neurodevelopmental disorders. Here, we report the phenotypes of 71 patients and review 130 previously reported patients. We found that (i) encephalopathies with infantile/childhood onset epilepsies (≥3 months of age) occur almost as often as those with an early infantile onset (<3 months), and are thus more frequent than previously reported; (ii) distinct phenotypes can be seen within the late onset group, including myoclonic-atonic epilepsy (two patients), Lennox-Gastaut not emerging from West syndrome (two patients), and focal epilepsies with an electrical status epilepticus during slow sleep-like EEG pattern (six patients); and (iii) West syndrome constitutes a common phenotype with a major recurring mutation (p.Arg853Gln: two new and four previously reported children). Other known phenotypes include Ohtahara syndrome, epilepsy of infancy with migrating focal seizures, and intellectual disability or autism without epilepsy. To assess the response to antiepileptic therapy, we retrospectively reviewed the treatment regimen and the course of the epilepsy in 66 patients for which well-documented medical information was available. We find that the use of sodium channel blockers was often associated with clinically relevant seizure reduction or seizure freedom in children with early infantile epilepsies (<3 months), whereas other antiepileptic drugs were less effective. In contrast, sodium channel blockers were rarely effective in epilepsies with later onset (≥3 months) and sometimes induced seizure worsening. Regarding the genetic findings, truncating mutations were exclusively seen in patients with late onset epilepsies and lack of response to sodium channel blockers. Functional characterization of four selected missense mutations using whole cell patch-clamping in tsA201 cells-together with data from the literature-suggest that mutations associated with early infantile epilepsy result in increased sodium channel activity with gain-of-function, characterized by slowing of fast inactivation, acceleration of its recovery or increased persistent sodium current. Further, a good response to sodium channel blockers clinically was found to be associated with a relatively small gain-of-function. In contrast, mutations in patients with late-onset forms and an insufficient response to sodium channel blockers were associated with loss-of-function effects, including a depolarizing shift of voltage-dependent activation or a hyperpolarizing shift of channel availability (steady-state inactivation). Our clinical and experimental data suggest a correlation between age at disease onset, response to sodium channel blockers and the functional properties of mutations in children with SCN2A-related epilepsy.


Assuntos
Epilepsia/tratamento farmacológico , Epilepsia/genética , Epilepsia/fisiopatologia , Canal de Sódio Disparado por Voltagem NAV1.2/genética , Canal de Sódio Disparado por Voltagem NAV1.2/fisiologia , Transtornos do Neurodesenvolvimento/genética , Bloqueadores dos Canais de Sódio/uso terapêutico , Adolescente , Adulto , Idade de Início , Criança , Pré-Escolar , Dinamarca/epidemiologia , Epilepsia/epidemiologia , Feminino , Humanos , Lactente , Masculino , Mutação , Fenótipo , Adulto Jovem
11.
J Pediatr ; 185: 160-166.e1, 2017 06.
Artigo em Inglês | MEDLINE | ID: mdl-28284480

RESUMO

OBJECTIVE: To evaluate the role that chromosomal micro-rearrangements play in patients with both corpus callosum abnormality and intellectual disability, we analyzed copy number variations (CNVs) in patients with corpus callosum abnormality/intellectual disability STUDY DESIGN: We screened 149 patients with corpus callosum abnormality/intellectual disability using Illumina SNP arrays. RESULTS: In 20 patients (13%), we have identified at least 1 CNV that likely contributes to corpus callosum abnormality/intellectual disability phenotype. We confirmed that the most common rearrangement in corpus callosum abnormality/intellectual disability is inverted duplication with terminal deletion of the 8p chromosome (3.2%). In addition to the identification of known recurrent CNVs, such as deletions 6qter, 18q21 (including TCF4), 1q43q44, 17p13.3, 14q12, 3q13, 3p26, and 3q26 (including SOX2), our analysis allowed us to refine the 2 known critical regions associated with 8q21.1 deletion and 19p13.1 duplication relevant for corpus callosum abnormality; report a novel 10p12 deletion including ZEB1 recently implicated in corpus callosum abnormality with corneal dystrophy; and) report a novel pathogenic 7q36 duplication encompassing SHH. In addition, 66 variants of unknown significance were identified in 57 patients encompassed candidate genes. CONCLUSIONS: Our results confirm the relevance of using microarray analysis as first line test in patients with corpus callosum abnormality/intellectual disability.


Assuntos
Agenesia do Corpo Caloso/genética , Variações do Número de Cópias de DNA , Deficiência Intelectual/genética , Adolescente , Adulto , Fatores de Transcrição Hélice-Alça-Hélice Básicos/genética , Proteínas de Ciclo Celular/genética , Criança , Pré-Escolar , Deleção Cromossômica , Duplicação Cromossômica , Cromossomos Humanos Par 10 , Cromossomos Humanos Par 19 , Cromossomos Humanos Par 3 , Cromossomos Humanos Par 7 , Cromossomos Humanos Par 8 , Feminino , Proteínas Hedgehog/genética , Humanos , Masculino , Análise em Microsséries , Polimorfismo de Nucleotídeo Único , Estudos Prospectivos , Adulto Jovem , Homeobox 1 de Ligação a E-box em Dedo de Zinco/genética
12.
Epilepsy Res ; 131: 64-69, 2017 03.
Artigo em Inglês | MEDLINE | ID: mdl-28273610

RESUMO

OBJECTIVE: Recent studies have suggested that the early introduction of a ketogenic diet (KD) could improve seizure control in myoclono-astatic epilepsy (MAE). This multicenter study sought to identify the benefits of KD use on seizure control and epilepsy and on developmental outcomes in children with resistant MAE. METHODS: Fifty children who were diagnosed with severe MAE in the French network of Reference Centers for Rare Epilepsies and who were treated with KD between 2000 and 2013 were included in this study. The seizure frequency and EEG recordings were assessed two weeks before KD introduction, 2 and 6 months after, and during the last follow-up, which also included an assessment of developmental outcome. RESULTS: Patients had a median follow up of 52 months (range 13-136) and received 4.3 antiepileptic drugs [2-9] before KD introduction. Fifty-four percent (54%) of our patients were seizure-free after 6 months of KD or more, and 86% experienced more than a 70% seizure reduction after 2 months of KD. Forty-four percent (44%) of them had a clear benefit of early KD treatment (after four AEDs failed). Early KD treatment did not result in a greater seizure reduction (p=0.055), but significantly resulted in remission (p<0.028). Fifty percent of patients with resistant MAE had normal development outcomes. Earlier KD treatment, after three AEDs failed, was correlated with a better cognitive outcome (p<0.01). SIGNIFICANCE: Early introduction of KD treatment in resistant MAE has a strong, persistent anticonvulsant effect with long-term remission and better cognitive outcomes.


Assuntos
Dieta Cetogênica/métodos , Epilepsia Resistente a Medicamentos/dietoterapia , Epilepsia Resistente a Medicamentos/epidemiologia , Epilepsias Mioclônicas/dietoterapia , Epilepsias Mioclônicas/epidemiologia , Pré-Escolar , Dieta Cetogênica/tendências , Epilepsia Resistente a Medicamentos/diagnóstico , Eletroencefalografia/tendências , Epilepsias Mioclônicas/diagnóstico , Feminino , Seguimentos , França/epidemiologia , Humanos , Lactente , Masculino , Estudos Retrospectivos , Resultado do Tratamento
13.
Eur J Hum Genet ; 25(3): 376-380, 2017 02.
Artigo em Inglês | MEDLINE | ID: mdl-28051072

RESUMO

We report on two consanguineous sibs affected with severe intellectual disability and autistic features due to a homozygous missense variant of GRIN1. Massive parallel sequencing was performed using a gene panel including 450 genes related to intellectual disability and autism spectrum disorders. We found a homozygous missense variation of GRIN1 (c.679G>C; p.(Asp227His)) in the two affected sibs, which was inherited from both unaffected heterozygous parents. Heterozygous variants of GRIN1, encoding the GluN1 subunit of the NMDA receptor, have been reported in patients with neurodevelopmental disorders including epileptic encephalopathy, severe intellectual disability, and movement disorders. The p.(Asp227His) variant is located in the same aminoterminal protein domain as the recently published p.(Arg217Trp), which was found at the homozygous state in two patients with a similar phenotype of severe intellectual disability and autistic features but without epilepsy. In silico predictions were consistent with a deleterious effect. The present findings further expand the clinical spectrum of GRIN1 variants and support the existence of hypomorphic variants causing severe neurodevelopmental impairment with autosomal recessive inheritance.


Assuntos
Transtorno do Espectro Autista/genética , Deficiência Intelectual/genética , Mutação de Sentido Incorreto , Proteínas do Tecido Nervoso/genética , Receptores de N-Metil-D-Aspartato/genética , Transtorno do Espectro Autista/diagnóstico , Criança , Pré-Escolar , Consanguinidade , Feminino , Homozigoto , Humanos , Deficiência Intelectual/diagnóstico , Masculino , Irmãos , Síndrome
14.
Am J Hum Genet ; 99(6): 1368-1376, 2016 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-27889060

RESUMO

Early-onset epileptic encephalopathy (EOEE) represents a heterogeneous group of severe disorders characterized by seizures, interictal epileptiform activity with a disorganized electroencephalography background, developmental regression or retardation, and onset before 1 year of age. Among a cohort of 57 individuals with epileptic encephalopathy, we ascertained two unrelated affected individuals with EOEE associated with developmental impairment and autosomal-recessive variants in AP3B2 by means of whole-exome sequencing. The targeted sequencing of AP3B2 in 86 unrelated individuals with EOEE led to the identification of an additional family. We gathered five additional families with eight affected individuals through the Matchmaker Exchange initiative by matching autosomal-recessive mutations in AP3B2. Reverse phenotyping of 12 affected individuals from eight families revealed a homogeneous EOEE phenotype characterized by severe developmental delay, poor visual contact with optic atrophy, and postnatal microcephaly. No spasticity, albinism, or hematological symptoms were reported. AP3B2 encodes the neuron-specific subunit of the AP-3 complex. Autosomal-recessive variations of AP3B1, the ubiquitous isoform, cause Hermansky-Pudlak syndrome type 2. The only isoform for the δ subunit of the AP-3 complex is encoded by AP3D1. Autosomal-recessive mutations in AP3D1 cause a severe disorder cumulating the symptoms of the AP3B1 and AP3B2 defects.


Assuntos
Complexo 3 de Proteínas Adaptadoras/genética , Subunidades beta do Complexo de Proteínas Adaptadoras/genética , Epilepsia/complicações , Epilepsia/genética , Genes Recessivos/genética , Mutação , Atrofia Óptica/complicações , Atrofia Óptica/genética , Idade de Início , Criança , Pré-Escolar , Deficiências do Desenvolvimento/genética , Feminino , Humanos , Lactente , Recém-Nascido , Masculino , Microcefalia/genética , Linhagem , Síndrome
15.
Neurology ; 87(1): 77-85, 2016 07 05.
Artigo em Inglês | MEDLINE | ID: mdl-27281533

RESUMO

OBJECTIVE: To evaluate the phenotypic spectrum associated with mutations in TBC1D24. METHODS: We acquired new clinical, EEG, and neuroimaging data of 11 previously unreported and 37 published patients. TBC1D24 mutations, identified through various sequencing methods, can be found online (http://lovd.nl/TBC1D24). RESULTS: Forty-eight patients were included (28 men, 20 women, average age 21 years) from 30 independent families. Eighteen patients (38%) had myoclonic epilepsies. The other patients carried diagnoses of focal (25%), multifocal (2%), generalized (4%), and unclassified epilepsy (6%), and early-onset epileptic encephalopathy (25%). Most patients had drug-resistant epilepsy. We detail EEG, neuroimaging, developmental, and cognitive features, treatment responsiveness, and physical examination. In silico evaluation revealed 7 different highly conserved motifs, with the most common pathogenic mutation located in the first. Neuronal outgrowth assays showed that some TBC1D24 mutations, associated with the most severe TBC1D24-associated disorders, are not necessarily the most disruptive to this gene function. CONCLUSIONS: TBC1D24-related epilepsy syndromes show marked phenotypic pleiotropy, with multisystem involvement and severity spectrum ranging from isolated deafness (not studied here), benign myoclonic epilepsy restricted to childhood with complete seizure control and normal intellect, to early-onset epileptic encephalopathy with severe developmental delay and early death. There is no distinct correlation with mutation type or location yet, but patterns are emerging. Given the phenotypic breadth observed, TBC1D24 mutation screening is indicated in a wide variety of epilepsies. A TBC1D24 consortium was formed to develop further research on this gene and its associated phenotypes.


Assuntos
Proteínas de Transporte/genética , Epilepsia/genética , Epilepsia/fisiopatologia , Animais , Encéfalo/diagnóstico por imagem , Encéfalo/fisiopatologia , Proteínas de Transporte/metabolismo , Crescimento Celular , Células Cultivadas , Criança , Pré-Escolar , Estudos de Coortes , Eletroencefalografia , Epilepsia/diagnóstico por imagem , Epilepsia/psicologia , Feminino , Estudos de Associação Genética , Humanos , Lactente , Masculino , Proteínas de Membrana , Camundongos , Mutação , Proteínas do Tecido Nervoso , Neuritos/fisiologia , Exame Físico , Adulto Jovem
16.
J Med Genet ; 53(8): 511-22, 2016 08.
Artigo em Inglês | MEDLINE | ID: mdl-26989088

RESUMO

OBJECTIVE: We aimed to delineate the neurodevelopmental spectrum associated with SYNGAP1 mutations and to investigate genotype-phenotype correlations. METHODS: We sequenced the exome or screened the exons of SYNGAP1 in a total of 251 patients with neurodevelopmental disorders. Molecular and clinical data from patients with SYNGAP1 mutations from other centres were also collected, focusing on developmental aspects and the associated epilepsy phenotype. A review of SYNGAP1 mutations published in the literature was also performed. RESULTS: We describe 17 unrelated affected individuals carrying 13 different novel loss-of-function SYNGAP1 mutations. Developmental delay was the first manifestation of SYNGAP1-related encephalopathy; intellectual disability became progressively obvious and was associated with autistic behaviours in eight patients. Hypotonia and unstable gait were frequent associated neurological features. With the exception of one patient who experienced a single seizure, all patients had epilepsy, characterised by falls or head drops due to atonic or myoclonic seizures, (myoclonic) absences and/or eyelid myoclonia. Triggers of seizures were frequent (n=7). Seizures were pharmacoresistant in half of the patients. The severity of the epilepsy did not correlate with the presence of autistic features or with the severity of cognitive impairment. Mutations were distributed throughout the gene, but spared spliced 3' and 5' exons. Seizures in patients with mutations in exons 4-5 were more pharmacoresponsive than in patients with mutations in exons 8-15. CONCLUSIONS: SYNGAP1 encephalopathy is characterised by early neurodevelopmental delay typically preceding the onset of a relatively recognisable epilepsy comprising generalised seizures (absences, myoclonic jerks) and frequent triggers.

17.
Epilepsia ; 57(4): 648-59, 2016 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-26873267

RESUMO

OBJECTIVE: To describe the epileptic phenotype of Tsc1(+/-) mice pups in comparison with age-related seizures in human tuberous sclerosis complex (TSC). METHODS: Tsc1(+/-) and control mice underwent intracranial electroencephalography (EEG) recording at postnatal ages (P)8 to P33, with linear silicon probe implanted in the somatosensory cortex of one or both hemispheres for 8-24 h. Ictal events were classified visually by independent analyzers; distinct EEG patterns were related to age and analyzed to quantify field potential characteristics and signal dynamics between hemispheres. We collected retrospectively 20 infants with prenatally diagnosed TSC and EEG before seizure onset, and analyzed the electroclinical course of epilepsy, taking into account a first-line treatment by vigabatrin. RESULTS: Spontaneous seizures were disclosed in 55% of Tsc1(+/-) mice at P9-18. Three ictal patterns were identified: from P9 to P12 "spike clusters" consisted of recurring large spikes without clinical correlate; "spasm-like" discharges dominated from P13 to P16 consisting of high amplitude large field potential superimposed with or followed by fast activity repeated every 2-10 s for at least 20 s, accompanied by rhythmic limb contractions; from P14 to P18 a "tonic-clonic like" pattern comprised rhythmic spikes of increasing amplitude with tonic-clonic movements. Early onset "spike clusters" were mainly unilateral, whereas "spasm-like" and "tonic-clonic like" patterns were bilateral. Interhemispheric propagation was significantly faster for "tonic-clonic like" than for "spasm-like" events. In infants diagnosed prenatally with TSC, clusters of sharp waves or spikes preceded the first seizure, and vigabatrin prevented the development of seizures. Patients treated after seizure onset developed spasms or focal seizures that were pharmacoresistant in 66.7% of cases. SIGNIFICANCE: Tsc1(+/-) mice pups exhibit an age-dependent seizure pattern sequence mimicking early human TSC epilepsy features. Spike clusters before seizure onset in TSC should be considered as a first stage of epilepsy reinforcing the concept of preventive antiepileptic therapy.


Assuntos
Epilepsia/metabolismo , Esclerose Tuberosa/metabolismo , Proteínas Supressoras de Tumor/biossíntese , Adolescente , Fatores Etários , Animais , Criança , Pré-Escolar , Epilepsia/genética , Epilepsia/patologia , Feminino , Seguimentos , Regulação da Expressão Gênica , Humanos , Lactente , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Estudos Retrospectivos , Esclerose Tuberosa/genética , Esclerose Tuberosa/patologia , Proteína 1 do Complexo Esclerose Tuberosa , Proteínas Supressoras de Tumor/genética
18.
Eur J Hum Genet ; 24(7): 1001-8, 2016 07.
Artigo em Inglês | MEDLINE | ID: mdl-26486472

RESUMO

West syndrome (WS), defined by the triad of infantile spasms, pathognomonic hypsarrhythmia and developmental regression, is a rare epileptic disease affecting about 1:3500 live births. To get better insights on the genetic of this pathology, we exome-sequenced the members of a consanguineous family affected with isolated WS. We identified a homozygous variant (c.1825G>T/p.(Ala609Ser)) in the GUF1 gene in the three affected siblings. GUF1 encodes a protein essential in conditions that counteract faithful protein synthesis: it is able to remobilize stuck ribosomes and transiently inhibit the elongation process to optimize protein synthesis. The variant identified in the WS family changes an alanine residue conserved in all eukaryotic organisms and positioned within the tRNA-binding moiety of this nuclear genome-encoded mitochondrial translational elongation factor. Yeast complementation assays show that the activity of GUF1(A609S) is modified in suboptimal environments. We suggest a new link between improper assembly of respiratory chain complexes and WS.


Assuntos
GTP Fosfo-Hidrolases/genética , Homozigoto , Proteínas Mitocondriais/genética , Mutação de Sentido Incorreto , Fator G para Elongação de Peptídeos/genética , Espasmos Infantis/genética , Sítios de Ligação , Sequência Conservada , Exoma , Feminino , GTP Fosfo-Hidrolases/metabolismo , Teste de Complementação Genética , Humanos , Lactente , Masculino , Proteínas Mitocondriais/metabolismo , Linhagem , Fator 1 de Elongação de Peptídeos , Fator G para Elongação de Peptídeos/metabolismo , Ligação Proteica , Espasmos Infantis/patologia , Leveduras/genética
19.
Epilepsia ; 56(12): 1931-40, 2015 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-26514728

RESUMO

OBJECTIVE: Mutations in the syntaxin binding protein 1 gene (STXBP1) have been associated mostly with early onset epileptic encephalopathies (EOEEs) and Ohtahara syndrome, with a mutation detection rate of approximately 10%, depending on the criteria of selection of patients. The aim of this study was to retrospectively describe clinical and electroencephalography (EEG) features associated with STXBP1-related epilepsies to orient molecular screening. METHODS: We screened STXBP1 in a cohort of 284 patients with epilepsy associated with a developmental delay/intellectual disability and brain magnetic resonance imaging (MRI) without any obvious structural abnormality. We reported on patients with a mutation and a microdeletion involving STXBP1 found using array comparative genomic hybridization (CGH). RESULTS: We found a mutation of STXBP1 in 22 patients and included 2 additional patients with a deletion including STXBP1. In 22 of them, epilepsy onset was before 3 months of age. EEG at onset was abnormal in all patients, suppression-burst and multifocal abnormalities being the most common patterns. The rate of patients carrying a mutation ranged from 25% in Ohtahara syndrome to <5% in patients with an epilepsy beginning after 3 months of age. Epilepsy improved over time for most patients, with an evolution to West syndrome in half. Patients had moderate to severe developmental delay with normal head growth. Cerebellar syndrome with ataxic gait and/or tremor was present in 60%. SIGNIFICANCE: Our data confirm that STXBP1 mutations are associated with neonatal-infantile epileptic encephalopathies. The initial key features highlighted in the cohort of early epileptic patients are motor seizures either focal or generalized, abnormal initial interictal EEG, and normal head growth. In addition, we constantly found an ongoing moderate to severe developmental delay with normal head growth. Patients often had ongoing ataxic gait with trembling gestures. Altogether these features should help the clinician to consider STXBP1 molecular screening.


Assuntos
Epilepsia/genética , Proteínas Munc18/genética , Idade de Início , Encéfalo/patologia , Encéfalo/fisiopatologia , Criança , Pré-Escolar , Hibridização Genômica Comparativa , Eletroencefalografia , Epilepsias Mioclônicas/genética , Epilepsia/patologia , Epilepsia/fisiopatologia , Feminino , Humanos , Lactente , Imagem por Ressonância Magnética , Masculino , Mutação , Estudos Retrospectivos , Deleção de Sequência , Espasmos Infantis/genética
20.
Epilepsy Behav ; 48: 61-5, 2015 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-26057351

RESUMO

Hormonal therapy or ketogenic diet often permits overcoming the challenging periods of many epileptic encephalopathies (West and Lennox-Gastaut syndromes and encephalopathy with continuous spike-waves in slow sleep), but relapse affects over 20% of patients. We report here a monocenter pilot series of 42 consecutive patients in whom we combined oral steroids with the ketogenic diet for corticosteroid-resistant or -dependent epileptic encephalopathy. We retrospectively evaluated the effect on seizure frequency, interictal spike activity, neuropsychological course, and steroid treatment course. Twenty-three patients had West syndrome (WS), 13 had encephalopathy with continuous spike-waves in slow sleep (CSWS), and six others had miscellaneous epileptic encephalopathies. All patients succeeded to reach 0.8 to 1.6g/l ketone bodies in the urine following the usual KD regimen. For at least 6 months, 14/42 responded to the addition of the ketogenic diet: 4/23 with WS, 8/13 with CSWS, and 2/6 with miscellaneous epileptic encephalopathies. The addition of the KD allowed withdrawing steroids in all responders. Among them, 10/15 had been patients with steroid-dependent epileptic encephalopathy and 4/27 patients with steroid-resistant epileptic encephalopathy. Therefore, the ketogenic diet can be used successfully in combination with corticosteroids for epileptic encephalopathies. Patients presenting with steroid-dependent CSWS seem to be the best candidates.


Assuntos
Corticosteroides/uso terapêutico , Dieta Cetogênica , Epilepsia/dietoterapia , Epilepsia/tratamento farmacológico , Convulsões/tratamento farmacológico , Corticosteroides/farmacologia , Anticonvulsivantes/uso terapêutico , Eletroencefalografia/efeitos dos fármacos , Feminino , Humanos , Lactente , Síndrome de Lennox Gastaut/tratamento farmacológico , Masculino , Estudos Retrospectivos , Convulsões/diagnóstico , Sono/efeitos dos fármacos , Espasmos Infantis/diagnóstico , Espasmos Infantis/tratamento farmacológico , Resultado do Tratamento
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