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1.
Zhonghua Er Ke Za Zhi ; 57(7): 532-537, 2019 Jul 02.
Artigo em Chinês | MEDLINE | ID: mdl-31269553

RESUMO

Objective: To analyze the clinical phenotypes of epilepsies in children with GABRB2 variants. Methods: Data of 8 epileptic patients with heterozygous GABRB2 variants were retrospectively collected at the Department of Pediatrics, Peking University First Hospital from April 2016 to December 2018. The clinical, electroencephalographic, neuroimaging characteristics, therapeutic and follow-up were analyzed. Results: Eight patients (4 boys, 4 girls) with heterozygous GABRB2 gene pathogenic variants were enrolled. Eight patients had different GABRB2 variants, among whom 2 patients inherited the variants from either parent, and the other 6 patients had de novo variants. Seven variants were novel. Ages at seizure onset ranged from 1 day to 22 months after birth, and the median age was 6 months. The seizure was first observed within one month of age in 2 patients, 1-6 months in 2 patients, 7-12 months in 2 patients, and beyond 1 year of age in 2 patients. Multiple seizure types were observed, including focal seizures in 6 patients, generalized tonic clonic seizures (GTCS) in 4 patients, myoclonic seizures in 3 patients, and epileptic spasm in 2 patients. Developmental delay was present in 6 patients. In 8 patients, Dravet syndrome was diagnosed in 3 patients, febrile seizures plus and West syndrome in 2 patients, respectively, Ohtahara syndrome in 1 patient. Six patients had epilepsy with fever sensitivity, and status epilepticus developed in all these patients. The ages at the last follow-up ranged from 8 months to 11 years, and the follow-up data showed that 5 patients were seizure-free, and 2 patients still had seizures, and 1 patient died of recurrent status epilepticus complicated with fungal infection. Conclusions: Epilepsies associated with GABRB2 variants were characterized by an onset in infancy, and the clinical features were heterogenous in seizure types and severities. Most patients had multiple seizures with fever sensitivity, and status epilepticus was common. Their seizures were easily induced by fever or infection. Additionally, the majority of the patients had varying degrees of developmental delay.


Assuntos
Epilepsias Mioclônicas/genética , Epilepsia/genética , Receptores de GABA-A/genética , Idade de Início , Criança , Pré-Escolar , Eletroencefalografia , Epilepsias Mioclônicas/diagnóstico , Epilepsia/diagnóstico , Feminino , Humanos , Lactente , Masculino , Mutação , Estudos Retrospectivos , Convulsões , Espasmos Infantis/genética
2.
Nat Commun ; 10(1): 2506, 2019 06 07.
Artigo em Inglês | MEDLINE | ID: mdl-31175295

RESUMO

Although there are many known Mendelian genes linked to epileptic or developmental and epileptic encephalopathy (EE/DEE), its genetic architecture is not fully explained. Here, we address this incompleteness by analyzing exomes of 743 EE/DEE cases and 2366 controls. We observe that damaging ultra-rare variants (dURVs) unique to an individual are significantly overrepresented in EE/DEE, both in known EE/DEE genes and the other non-EE/DEE genes. Importantly, enrichment of dURVs in non-EE/DEE genes is significant, even in the subset of cases with diagnostic dURVs (P = 0.000215), suggesting oligogenic contribution of non-EE/DEE gene dURVs. Gene-based analysis identifies exome-wide significant (P = 2.04 × 10-6) enrichment of damaging de novo mutations in NF1, a gene primarily linked to neurofibromatosis, in infantile spasm. Together with accumulating evidence for roles of oligogenic or modifier variants in severe neurodevelopmental disorders, our results highlight genetic complexity in EE/DEE, and indicate that EE/DEE is not an aggregate of simple Mendelian disorders.


Assuntos
Variação Genética , Espasmos Infantis/genética , Proteínas Adaptadoras de Transporte Vesicular/genética , Grupo com Ancestrais do Continente Asiático/genética , Estudos de Casos e Controles , DNA (Citosina-5-)-Metiltransferases/genética , Epilepsias Mioclônicas/genética , Fatores de Troca do Nucleotídeo Guanina/genética , Humanos , Lactente , Japão , Síndrome de Lennox Gastaut/genética , Modelos Logísticos , Mutação , Neurofibromina 1/genética , Polimorfismo de Nucleotídeo Único , Análise de Componente Principal , Canais de Cátion TRPM/genética , Sequenciamento Completo do Exoma
3.
Nat Commun ; 10(1): 2655, 2019 06 14.
Artigo em Inglês | MEDLINE | ID: mdl-31201320

RESUMO

CDKL5 deficiency disorder (CDD) is characterized by epilepsy, intellectual disability, and autistic features, and CDKL5-deficient mice exhibit a constellation of behavioral phenotypes reminiscent of the human disorder. We previously found that CDKL5 dysfunction in forebrain glutamatergic neurons results in deficits in learning and memory. However, the pathogenic origin of the autistic features of CDD remains unknown. Here, we find that selective loss of CDKL5 in GABAergic neurons leads to autistic-like phenotypes in mice accompanied by excessive glutamatergic transmission, hyperexcitability, and increased levels of postsynaptic NMDA receptors. Acute, low-dose inhibition of NMDAR signaling ameliorates autistic-like behaviors in GABAergic knockout mice, as well as a novel mouse model bearing a CDD-associated nonsense mutation, CDKL5 R59X, implicating the translational potential of this mechanism. Together, our findings suggest that enhanced NMDAR signaling and circuit hyperexcitability underlie autistic-like features in mouse models of CDD and provide a new therapeutic avenue to treat CDD-related symptoms.


Assuntos
Síndromes Epilépticas/patologia , Neurônios GABAérgicos/patologia , Proteínas Serina-Treonina Quinases/genética , Receptores de N-Metil-D-Aspartato/metabolismo , Transdução de Sinais/genética , Espasmos Infantis/patologia , Animais , Comportamento Animal/efeitos dos fármacos , Códon sem Sentido , Modelos Animais de Doenças , Síndromes Epilépticas/tratamento farmacológico , Síndromes Epilépticas/genética , Antagonistas de Aminoácidos Excitatórios/farmacologia , Antagonistas de Aminoácidos Excitatórios/uso terapêutico , Feminino , Humanos , Masculino , Memantina/farmacologia , Memantina/uso terapêutico , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Prosencéfalo/citologia , Prosencéfalo/efeitos dos fármacos , Prosencéfalo/patologia , Proteínas Serina-Treonina Quinases/deficiência , Receptores de N-Metil-D-Aspartato/antagonistas & inibidores , Espasmos Infantis/tratamento farmacológico , Espasmos Infantis/genética , Resultado do Tratamento
4.
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
5.
Eur J Paediatr Neurol ; 23(3): 418-426, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30853297

RESUMO

The human WW Domain Containing Oxidoreductase (WWOX) gene was originally described as a tumor suppressor gene. However, recent reports have demonstrated its cardinal role in the pathogenesis of central nervous systems disorders such as epileptic encephalopathy, intellectual disability, and spinocerebellar ataxia. We report on six patients from three unrelated families of full or partial Yemenite Jewish ancestry exhibiting early infantile epileptic encephalopathy and profound developmental delay. Importantly, four patients demonstrated facial dysmorphism. Exome sequencing revealed that four of the patients were homozygous for a novel WWOX c.517-2A > G splice-site variant and two were compound heterozygous for this variant and a novel c.689A > C, p.Gln230Pro missense variant. Complementary DNA sequencing demonstrated that the WWOX c.517-2A > G splice-site variant causes skipping of exon six. A carrier rate of 1:177 was found among Yemenite Jews. We provide the first detailed description of patients harboring a splice-site variant in the WWOX gene and propose that the clinical synopsis of WWOX related epileptic encephalopathy should be broadened to include facial dysmorphism. The increased frequency of the c.517-2A > G splice-site variant among Yemenite Jews coupled with the severity of the phenotype makes it a candidate for inclusion in expanded preconception screening programs.


Assuntos
Face/anormalidades , Deficiência Intelectual/genética , Espasmos Infantis/genética , Proteínas Supressoras de Tumor/genética , Oxidorredutase com Domínios WW/genética , Feminino , Estudos de Associação Genética , Humanos , Judeus/genética , Masculino , Mutação , Linhagem , Iêmen
7.
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
8.
Metab Brain Dis ; 34(2): 557-563, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30637540

RESUMO

D-glycerate 2 kinase (DGK) is an enzyme that mediates the conversion of D-glycerate, an intermediate metabolite of serine and fructose metabolism, to 2-phosphoglycerate. Deficiency of DGK leads to accumulation of D-glycerate in various tissues and its massive excretion in urine. D-glyceric aciduria (DGA) is an autosomal recessive metabolic disorder caused by mutations in the GLYCTK gene. The clinical spectrum of DGA is highly variable, ranging from severe progressive infantile encephalopathy to a practically asymptomatic condition. We describe a male patient from a consanguineous Arab family with infantile onset of DGA, characterized by profound psychomotor retardation, progressive microcephaly, intractable seizures, cortical blindness and deafness. Consecutive brain MR imaging showed an evolving brain atrophy, thinning of the corpus callosum and diffuse abnormal white matter signals. Whole exome sequencing identified the homozygous missense variant in the GLYCTK gene [c.455 T > C, NM_145262.3], which affected a highly conserved leucine residue located at a domain of yet unknown function of the enzyme [p.Leu152Pro, NP_660305]. In silico analysis of the variant supported its pathogenicity. A review of the 15 previously reported patients, together with the current one, confirms a clear association between DGA and severe neurological impairment. Yet, future studies of additional patients with DGA are required to better understand the clinical phenotype and pathogenesis.


Assuntos
Encefalopatias/metabolismo , Epilepsia/metabolismo , Hiperoxalúria Primária/metabolismo , Fosfotransferases (Aceptor do Grupo Álcool)/metabolismo , Encefalopatias/genética , Criança , Epilepsia/diagnóstico , Epilepsia/genética , Ácidos Glicéricos/metabolismo , Humanos , Hiperoxalúria Primária/genética , Lactente , Masculino , Mutação/genética , Fenótipo , Fosfotransferases (Aceptor do Grupo Álcool)/genética , Espasmos Infantis/genética , Espasmos Infantis/metabolismo
9.
Hum Genet ; 138(2): 187-198, 2019 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-30656450

RESUMO

Developmental and epileptic encephalopathies (DEEs) are genetically heterogenous conditions, often characterized by early onset, EEG interictal epileptiform abnormalities, polymorphous and drug-resistant seizures, and neurodevelopmental impairments. In this study, we investigated the genetic defects in two siblings who presented with severe DEE, microcephaly, spastic tetraplegia, diffuse brain hypomyelination, cerebellar atrophy, short stature, and kyphoscoliosis. Whole exome next-generation sequencing (WES) identified in both siblings a homozygous non-sense variant in the ACTL6B gene (NM_016188:c.820C>T;p.Gln274*) coding for a subunit of the neuron-specific chromatin remodeling complex nBAF. To further support these findings, a targeted ACTL6B sequencing assay was performed on a cohort of 85 unrelated DEE individuals, leading to the identification of a homozygous missense variant (NM_016188:c.1045G>A;p.Gly349Ser) in a patient. This variant did not segregate in the unaffected siblings in this family and was classified as deleterious by several prediction softwares. Interestingly, in both families, homozygous patients shared a rather homogeneous phenotype. Very few patients with ACTL6B gene variants have been sporadically reported in WES cohort studies of patients with neurodevelopmental disorders and/or congenital brain malformations. However, the limited number of patients with incomplete clinical information yet reported in the literature did not allow to establish a strong gene-disease association. Here, we provide additional genetic and clinical data on three new cases that support the pathogenic role of ACTL6B gene mutation in a syndromic form of DEE.


Assuntos
Actinas/genética , Montagem e Desmontagem da Cromatina , Proteínas Cromossômicas não Histona/genética , Proteínas de Ligação a DNA/genética , Doenças Genéticas Inatas/diagnóstico por imagem , Microcefalia/genética , Transtornos do Neurodesenvolvimento/genética , Quadriplegia/genética , Espasmos Infantis/genética , Criança , Pré-Escolar , Cromatina/genética , Metilação de DNA/genética , Feminino , Doenças Genéticas Inatas/genética , Humanos , Lactente , Recém-Nascido , Masculino , Microcefalia/diagnóstico por imagem , Transtornos do Neurodesenvolvimento/diagnóstico por imagem , Linhagem , Quadriplegia/diagnóstico por imagem , Espasmos Infantis/diagnóstico por imagem
10.
J Hum Genet ; 64(4): 347-350, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30626896

RESUMO

We report the second case of early infantile epileptic encephalopathy (EIEE) arising from a homozygous truncating variant of NECAP1. The boy developed infantile-onset tonic-clonic and tonic seizures, then spasms in clusters. His electroencephalogram (EEG) showed a burst suppression pattern, leading to the diagnosis of Ohtahara syndrome. Whole-exome sequencing revealed the canonical splice-site variant (c.301 + 1 G > A) in NECAP1. In rodents, Necap1 protein is enriched in neuronal clathrin-coated vesicles and modulates synaptic vesicle recycling. cDNA analysis confirmed abnormal splicing that produced early truncating mRNA. There has been only one previous report of a mutation in NECAP1 in a family with EIEE; this was a nonsense mutation (p.R48*) that was cited as EIEE21. Decreased mRNA levels and the loss of the WXXF motif in both the families suggests that loss of NECAP1 function is a common pathomechanism for EIEE21. This study provided additional support that synaptic vesicle recycling plays a key role in epileptogenesis.


Assuntos
Subunidades alfa do Complexo de Proteínas Adaptadoras/genética , Convulsões/genética , Espasmos Infantis/genética , Encéfalo/diagnóstico por imagem , Encéfalo/fisiopatologia , Homozigoto , Humanos , Lactente , Masculino , Mutação , Convulsões/diagnóstico por imagem , Convulsões/fisiopatologia , Espasmos Infantis/diagnóstico por imagem , Espasmos Infantis/fisiopatologia
11.
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
12.
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
13.
Discov Med ; 26(143): 147-153, 2018 10.
Artigo em Inglês | MEDLINE | ID: mdl-30586538

RESUMO

The sortilin-related VPS10 domain-containing receptor 3 (SORCS3) is a type-I receptor transmembrane protein and a member of the vacuolar protein sorting 10 receptor family. Proteins of this family are defined to have a vacuolar protein sorting 10 domain at the N-terminus. They play important roles as a sorting agency within the cells and transport a variety of intracellular proteins between the Golgi apparatus, endosome, lysosome, secretory granules, and plasma membrane. They are also involved in signal transduction. Clinically, they have been implicated in the pathophysiology of multiple sclerosis and Alzheimer's disease. Here, we report details on two brothers deceased at 20 months and 2 years of age, respectively, with a neurological phenotype including infantile spasms, intellectual disability, global developmental delay, microcephaly, hypotonia, spastic quadriplegia, and delayed myelination. Whole exome sequencing and autozygome analysis showed homozygous missense variant in the SORCS3 gene. The pathogenicity is supported by functional studies in the patient mesenchymal stem cells. Patients' cells showed less proliferation capability than normal cells. In addition, making the same mutation in normal cells revealed a viability defect in them. This is the first study on human subjects with a SORCS3 gene defect and supports the important role of SORCS3 in the central nervous system.


Assuntos
Deficiência Intelectual/genética , Receptores de Neuropeptídeos/genética , Espasmos Infantis/genética , Pré-Escolar , Consanguinidade , Humanos , Lactente , Deficiência Intelectual/complicações , Masculino , Mutação , Linhagem , Irmãos , Espasmos Infantis/complicações
15.
Epileptic Disord ; 20(6): 541-544, 2018 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-30530441

RESUMO

A male neonate presented with seizures at 18 hours of life, characterized by tonic posturing with eye deviation to the right, apnoea, bradycardia, and oxygen desaturation. Initial structural, metabolic, and infectious work-up was unremarkable. He continued to have seizures refractory to a variety of antiepileptic medications. A phenobarbital coma was trialled, leading to cessation of clinical seizures but continuation of electrographic status epilepticus. On EEG, ictal discharges originated from both the right and left hemispheres, migrating to the opposite hemisphere, consistent with encephalopathy of infancy with migrating focal seizures. At this time, he developed septic shock and was trialled on a ketamine infusion and ketogenic diet. Due to his poor prognosis, a goals of care discussion was carried out with the family, leading to withdrawal of care and his subsequent death at one month and seven days. A posthumous genetic panel revealed a de novo KCNQ2 p.Ser247Leu variant, considered likely to be pathogenic. This is the third reported case of a KCNQ2 mutation associated with an encephalopathy of infancy with migrating focal seizures phenotype. We discuss potential cellular mechanisms underlying this unique KCNQ2 phenotype, as well as future therapeutic considerations.


Assuntos
Canal de Potássio KCNQ2/genética , Mutação , Convulsões/genética , Espasmos Infantis/genética , Encéfalo/fisiopatologia , Análise Mutacional de DNA , Eletroencefalografia , Humanos , Recém-Nascido , Masculino , Prognóstico , Convulsões/fisiopatologia , Espasmos Infantis/fisiopatologia
16.
BMC Neurol ; 18(1): 150, 2018 Sep 20.
Artigo em Inglês | MEDLINE | ID: mdl-30236064

RESUMO

BACKGROUND: Noonan syndrome-like disorder with loose anagen hair-2 (NSLH2) is an extremely rare disease caused by a heterozygous mutation in the PPP1CB gene on chromosome 2p23. The syndrome causes not only numerous dysmorphic features but also hypotonia, developmental delay, and even intellectual disability. We report the first case of NSLH2 in Asia and the 16th in the world. Moreover, the first case of PPP1CB-related infantile spasms. The clinical and therapeutic significance is outlined in this paper. CASE PRESENTATION: We found a male infant presented with severe intractable epileptic spasms. Although certain clinical features of somatic dysmorphism were noted, numerous laboratory and neuroimaging studies failed to identify the cause. To determine the underlying etiology, whole-exome sequencing was conducted. We identified a de novo heterozygous mutation, NM_206876.1: c.548A > C (p.Glu183Ala), in the PPP1CB gene. His seizures were almost refractory to conventional antiepileptic drugs but relative seizure control was eventually achieved with a ketogenic diet. CONCLUSION: This result expands the clinical spectrum of NSLH2 and strengthens the association between the PPP1CB gene and epileptic seizures. Furthermore, we suggest that the ketogenic diet can offer seizure reduction in particular drug-resistant epilepsy syndromes. Additional studies are warranted to clarify the pathogenic mechanisms underlying this PPP1CB mutation in epileptic seizures.


Assuntos
Doenças do Recém-Nascido/genética , Proteína Fosfatase 1/genética , Espasmos Infantis/genética , Anormalidades Craniofaciais/genética , Deficiências do Desenvolvimento/genética , Dieta Cetogênica , Heterozigoto , Humanos , Lactente , Recém-Nascido , Deficiência Intelectual/genética , Masculino , Hipotonia Muscular/genética , Mutação , Neuroimagem , Espasmos Infantis/dietoterapia
17.
Epileptic Disord ; 20(4): 313-318, 2018 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-30078785

RESUMO

Mutation of the gene encoding ubiquitin-like modifier-activating enzyme 5 (UBA5) causes autosomal recessive early-onset epileptic encephalopathy. UBA5 acts as an E1-activating enzyme in the ubiquitin-fold modifier 1 pathway, which is important for unfolded protein elimination and regulation of apoptosis, and has been linked to human diseases. We identified biallelic mutations in UBA5 in a Japanese boy with intractable West syndrome, profound failure to thrive, and severe cerebral and cerebellar atrophy. The boy presented with epileptic spasms and hypsarrhythmia at the age of three months. He was diagnosed with West syndrome, however, treatments with adrenocorticotropic hormone and several antiepileptic drugs were ineffective. MRI findings were initially normal, but subsequently showed a progression of cerebellar and cerebral atrophy. By the age of seven years, he had not achieved any developmental milestones; he had daily epileptic spasms and tonic seizures and profound failure to thrive. Gene analysis revealed novel compound heterozygous mutations in UBA5; a microdeletion encompassing the entire UBA5 gene and a putative disease-causing missense mutation in the catalytic domain. These biallelic variants may have caused loss of function, accounting for the observed clinical symptoms. Intractable infantile epileptic spasms, failure to thrive, and severe neurological impairment may be characteristic of patients with UBA5 mutations.


Assuntos
Cerebelo/patologia , Cérebro/patologia , Insuficiência de Crescimento , Espasmos Infantis , Enzimas Ativadoras de Ubiquitina/genética , Atrofia/patologia , Cerebelo/diagnóstico por imagem , Cérebro/diagnóstico por imagem , Criança , Insuficiência de Crescimento/genética , Insuficiência de Crescimento/patologia , Insuficiência de Crescimento/fisiopatologia , Humanos , Lactente , Imagem por Ressonância Magnética , Masculino , Mutação , Espasmos Infantis/genética , Espasmos Infantis/patologia , Espasmos Infantis/fisiopatologia
18.
Semin Pediatr Neurol ; 26: 28-32, 2018 07.
Artigo em Inglês | MEDLINE | ID: mdl-29961512

RESUMO

Epileptic encephalopathies are childhood brain disorders characterized by a variety of severe epilepsy syndromes that differ by the age of onset and seizure type. Until recently, the cause of many epileptic encephalopathies was unknown. Whole exome or whole genome sequencing has led to the identification of several causal genes in individuals with epileptic encephalopathy, and the list of genes has now expanded greatly. Genetic testing with epilepsy gene panels is now done quite early in the evaluation of children with epilepsy, following brain imaging, electroencephalogram, and metabolic profile. Early infantile epileptic encephalopathy (EIEE1; OMIM #308350) is the earliest of these age-dependent encephalopathies, manifesting as tonic spasms, myoclonic seizures, or partial seizures, with severely abnormal electroencephalogram, often showing a suppression-burst pattern. In this case study, we describe a 33-month-old female child with severe, neonatal onset epileptic encephalopathy. An infantile epilepsy gene panel test revealed 2 novel heterozygous variants in the MECP2 gene; a 70-bp deletion resulting in a frameshift and truncation (p.Lys377ProfsX9) thought to be pathogenic, and a 6-bp in-frame deletion (p.His371_372del), designated as a variant of unknown significance. Based on this test result, the diagnosis of atypical Rett syndrome (RTT) was made. Family-based targeted testing and segregation analysis, however, raised questions about the pathogenicity of these specific MECP2 variants. Whole exome sequencing was performed in this family trio, leading to the discovery of a rare, de novo, missense mutation in GNAO1 (p. Leu284Ser). De novo, heterozygous mutations in GNAO1 have been reported to cause early infantile epileptic encephalopathy-17 (EIEE17; OMIM 615473). The child's severe phenotype, the family history and segregation analysis of variants and prior reports of GNAO1-linked disease allowed us to conclude that the GNAO1 mutation, and not the MECP2 variants, was the cause of this child's neurological disease. With the increased use of genetic panels and whole exome sequencing, we will be confronted with lists of gene variants suspected to be pathogenic or of unknown significance. It is important to integrate clinical information, genetic testing that includes family members and correlates this with the published clinical and scientific literature, to help one arrive at the correct genetic diagnosis.


Assuntos
Subunidades alfa Gi-Go de Proteínas de Ligação ao GTP/genética , Síndrome de Rett/diagnóstico , Síndrome de Rett/genética , Espasmos Infantis/diagnóstico , Espasmos Infantis/genética , Pré-Escolar , Diagnóstico Diferencial , Erros de Diagnóstico , Feminino , Humanos , Proteína 2 de Ligação a Metil-CpG/genética , Fenótipo
19.
Neural Plast ; 2018: 9726950, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29977282

RESUMO

CDKL5 disorder is a severe neurodevelopmental disorder caused by mutations in the X-linked CDKL5 (cyclin-dependent kinase-like five) gene. CDKL5 disorder primarily affects girls and is characterized by early-onset epileptic seizures, gross motor impairment, intellectual disability, and autistic features. Although all CDKL5 female patients are heterozygous, the most valid disease-related model, the heterozygous female Cdkl5 knockout (Cdkl5 +/-) mouse, has been little characterized. The lack of detailed behavioral profiling of this model remains a crucial gap that must be addressed in order to advance preclinical studies. Here, we provide a behavioral and molecular characterization of heterozygous Cdkl5 +/- mice. We found that Cdkl5 +/- mice reliably recapitulate several aspects of CDKL5 disorder, including autistic-like behaviors, defects in motor coordination and memory performance, and breathing abnormalities. These defects are associated with neuroanatomical alterations, such as reduced dendritic arborization and spine density of hippocampal neurons. Interestingly, Cdkl5 +/- mice show age-related alterations in protein kinase B (AKT) and extracellular signal-regulated kinase (ERK) signaling, two crucial signaling pathways involved in many neurodevelopmental processes. In conclusion, our study provides a comprehensive overview of neurobehavioral phenotypes of heterozygous female Cdkl5 +/- mice and demonstrates that the heterozygous female might be a valuable animal model in preclinical studies on CDKL5 disorder.


Assuntos
Encéfalo/metabolismo , Modelos Animais de Doenças , Proteínas Serina-Treonina Quinases/genética , Proteínas Serina-Treonina Quinases/metabolismo , Síndrome de Rett/genética , Espasmos Infantis/genética , Animais , Comportamento Animal , Síndromes Epilépticas , Feminino , Heterozigoto , Camundongos Endogâmicos C57BL , Camundongos Knockout , Síndrome de Rett/metabolismo , Síndrome de Rett/psicologia , Transdução de Sinais , Espasmos Infantis/metabolismo , Espasmos Infantis/psicologia
20.
Int J Mol Sci ; 19(7)2018 Jul 06.
Artigo em Inglês | MEDLINE | ID: mdl-29986434

RESUMO

Early infantile epileptic encephalopathies (EIEEs) are a group of neurological disorders characterized by early-onset refractory seizures, severe electroencephalographic abnormalities, and developmental delay or intellectual disability. Recently, genetic studies have indicated that a significant portion of previously cryptogenic EIEEs are single-gene disorders. SPTAN1 is among the genes whose mutations are associated with EIEE development (OMIM# 613477). Here, a case of the c.6923_6928dup (p.Arg2308_Met2309dup) SPTAN1 mutation associated with a severe EIEE is reported. This case shows that mutations in the α20 repeat in the C-terminal of αII spectrin can be associated with EIEE. Duplication seems essential to cause EIEE. This causation is not demonstrated for amino acid deletions in the same spectrin residues. Reportedly, children with p.(Asp2303_Leu2305del) and p.(Gln2304_Gly2306del) deletions have childhood-onset epilepsy and no or marginal magnetic resonance imaging abnormalities, suggesting that not only the location but also the type of mutation plays a role in conditioning nervous system damage. Further studies are needed for a better understanding of the phenotype/genotype correlation in SPTAN1-related encephalopathies.


Assuntos
Proteínas de Transporte/genética , Proteínas dos Microfilamentos/genética , Mutação , Espasmos Infantis/genética , Encéfalo/fisiopatologia , Pré-Escolar , Eletroencefalografia , Estudos de Associação Genética , Triagem de Portadores Genéticos , Genótipo , Humanos , Imagem por Ressonância Magnética , Masculino , Fenótipo , Espasmos Infantis/sangue , Espasmos Infantis/diagnóstico por imagem
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