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Juvenile myoclonic epilepsy (JME) is a common generalized epilepsy syndrome considered the prototype of idiopathic generalized epilepsy. To date, generalized and focal seizures have been the fundamental concepts for classifying seizure types. In several studies, focal features of JME have been reported predominantly in the frontal lobe. However, results in previous studies are inconsistent. Therefore, we investigated the origin of epileptiform discharges in JME. We performed electroencephalography source localization using a distributed model with standardized low-resolution brain electromagnetic tomography. In 20 patients with JME, standardized low-resolution brain electromagnetic tomography images corresponding to the midpoint of the ascending phase and the negative peak of epileptiform discharges were obtained from a total of 362 electroencephalography epochs (181 epochs at each timepoint). At the ascending phase, the maximal current source density was located in the frontal lobe (58.6%), followed by the parietal (26.5%) and occipital lobes (8.8%). At the negative peak, the maximal current source density was located in the frontal lobe (69.1%), followed by the parietal (11.6%) and occipital lobes (9.4%). In the ascending phase, 41.4% of discharges were located outside the frontal lobe, and 30.9% were in the negative peak. Frontal predominance of epileptiform discharges was observed; however, source localization extending to various cortical regions also was identified. This widespread pattern was more prominent in the ascending phase (P = .038). The study results showed that JME includes widespread cortical regions over the frontal lobe. The current concept of generalized epilepsy and pathophysiology in JME needs further validation.
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Epilepsia Generalizada , Epilepsia Mioclónica Juvenil , Fenómenos Electromagnéticos , Epilepsia Generalizada/diagnóstico por imagen , Lóbulo Frontal/diagnóstico por imagen , Humanos , Epilepsia Mioclónica Juvenil/diagnóstico por imagen , Convulsiones , TomografíaRESUMEN
BACKGROUND: By definition, the background EEG is normal in juvenile myoclonic epilepsy (JME) patients and not accompanied by other developmental and cognitive problems. However, some recent studies using quantitative EEG (qEEG) reported abnormal changes in the background activity. QEEG investigation in patients undergoing anticonvulsant treatment might be a useful approach to explore the electrophysiology and anticonvulsant effects in JME. METHODS: We investigated background EEG activity changes in patients undergoing valproic acid (VPA) treatment using qEEG analysis in a distributed source model. In 17 children with JME, non-parametric statistical analysis using standardized low-resolution brain electromagnetic tomography was performed to compare the current density distribution of four frequency bands (delta, theta, alpha, and beta) between untreated and treated conditions. RESULTS: VPA reduced background EEG activity in the low-frequency (delta-theta) bands across the frontal, parieto-occipital, and limbic lobes (threshold log-F-ratio = ±1.414, p < 0.05; threshold log-F-ratio= ±1.465, p < 0.01). In the delta band, comparative analysis revealed significant current density differences in the occipital, parietal, and limbic lobes. In the theta band, the analysis revealed significant differences in the frontal, occipital, and limbic lobes. The maximal difference was found in the delta band in the cuneus of the left occipital lobe (log-F-ratio = -1.840) and the theta band in the medial frontal gyrus of the left frontal lobe (log-F-ratio = -1.610). CONCLUSIONS: This study demonstrated the anticonvulsant effects on the neural networks involved in JME. In addition, these findings suggested the focal features and the possibility of functional deficits in patients with JME.
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Epilepsia Mioclónica Juvenil , Ácido Valproico , Encéfalo/diagnóstico por imagen , Niño , Electroencefalografía , Fenómenos Electromagnéticos , Lóbulo Frontal , Humanos , Epilepsia Mioclónica Juvenil/tratamiento farmacológico , Tomografía , Ácido Valproico/uso terapéuticoRESUMEN
Background: Craniofrontonasal syndrome is a rare, X-linked disorder in which heterozygous females ironically reported the majority of patients and is caused by in the EFNB1 gene located at chromosome Xq13.1. Unlike previous reports, we present a female infant with a de novo EFNB1 missense mutation that was demonstrated in clinical diagnosis as global developmental delay (GDD) and brain anomaly without frontonasal dysplasia or other malformation. Case Presentation: This study reports the genetic analysis of a 4-month-old female infant presenting brain anomaly and GDD. She was the only child of unrelated parents. Early developmental was characterized by delays in fine motor, achieving gross motor, language, and social-cognitive milestones. She could not control her head or hold objects until 4 months of age. Brain magnetic resonance imaging revealed schizencephaly and dysgenesis of corpus callosum. Trio-based whole-exome sequencing revealed a heterozygous c.943C>T (p.Pro315Ser) in the EFNB1. Sanger sequencing confirmed this heterozygous alteration occurring in a dominant de novo manner, as a consequence of phenotypic and genotypic wild type in both parents. Conclusion: EFNB1 mutation is considered for a child with schizencephaly, and further study focusing on phenotyping is required to understand the possible contribution of environmental impact and genetic modifier in the expression of EFNB1.
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The lowest threshold lasing mode in a rounded D-shape microcavity is theoretically analyzed and experimentally demonstrated. To identify the lowest threshold lasing mode, we investigate threshold conditions of different periodic orbits by considering the linear gain condition due to the effective pumping region and total loss consisting of internal and scattering losses in ray dynamics. We compare the ray dynamical result with resonance mode analysis, including gain and loss. We find that the resonance modes localized on the pentagonal marginally unstable periodic orbit have the lowest threshold in our fabrication configuration. Our findings are verified by obtaining the path lengths and far-field patterns of lasing modes.
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We study a lasing of mode groups in a fully chaotic rounded D-shape InGaAsP semiconductor microcavity laser when an electrode is smaller than a cavity (inward gap). Although there are numerous unstable periodic orbits supporting resonances, a mode group localized on period-5 unstable periodic orbit is more competitive than the others for our laser configuration of the inward gap. By means of theoretical and numerical analyses with ray and wave dynamics, we show that the analyses well agree with our experimental results.
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Developments in next-generation sequencing (NGS) techogies have assisted in clarifying the diagnosis and treatment of developmental delay/intellectual disability (DD/ID) via molecular genetic testing. Advances in DNA sequencing technology have not only allowed the evolution of targeted panels but also, and more currently enabled genome-wide analyses to progress from research era to clinical practice. Broad acceptance of accuracy- guided targeted gene panel, whole-exome sequencing (WES), and whole-genome sequencing (WGS) for DD/ID need prospective analyses of the increasing cost-effectiveness versus conventional genetic testing. Choosing the appropriate sequencing method requires individual planning. Data are required to guide best-practice recommendations for genomic testing, regarding various clinical phenotypes in an etiologic approach. Targeted panel testing may be recommended as a first-tier testing approach for children with DD/ID. Family-based trio testing by WES/WGS can be used as a second test for DD/ ID in undiagnosed children who previously tested negative on a targeted panel. The role of NGS in molecular diagnostics, treatment, prediction of prognosis will continue to increase further in the coming years. Given the rapid pace of changes in the past 10 years, all medical providers should be aware of the changes in the transformative genetics field.
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OBJECTIVE: Variations in hormone levels are a direct effect of epileptic discharges in both animals and humans, and seizure can affect the hypothalamus-pituitary-thyroid axis. The purpose of this study was to determine which parameters could affect the alternation of thyroid hormones in children experiencing seizure. METHODS: We retrospectively reviewed the medical records of 181 pediatric patients with seizure and compared three thyroid hormones (serum thyroid-stimulating hormone [TSH], free thyroxine [fT4], and triiodothyronine [T3]) between initial (admission to hospital) and follow-up (2 weeks later) testing. RESULTS: Multivariable logistic regression models were used to determine which six parameters (gender, age, seizure accompanying with fever, seizure type, seizure duration, and anti-epileptic drug medication) could help to explain the higher initial TSH levels in pediatric seizure. Only seizure duration in patients with an increase in TSH levels was significantly longer compared with patients with normal TSH at the time of initial testing. CONCLUSION: Neuronal excitability by seizure can cause thyroid hormonal changes, which likely reflects changes in hypothalamic function.
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Excitabilidad Cortical/fisiología , Epilepsia/fisiopatología , Glándula Tiroides/metabolismo , Tirotropina/sangre , Adolescente , Anticonvulsivantes/uso terapéutico , Niño , Preescolar , Epilepsia/sangre , Epilepsia/tratamiento farmacológico , Femenino , Estudios de Seguimiento , Humanos , Hipotálamo/fisiopatología , Lactante , Masculino , Estudios Retrospectivos , Pruebas de Función de la Tiroides , Glándula Tiroides/inervación , Tirotropina/metabolismo , Tiroxina/sangre , Tiroxina/metabolismo , Factores de Tiempo , Triyodotironina/sangre , Triyodotironina/metabolismoRESUMEN
Localizing the source of epileptiform discharges in generalized epilepsy has been controversial for the past few decades. Recent neuroimaging studies have shown that epileptiform discharges in generalized epilepsy can be localized to a particular region. Childhood absence epilepsy (CAE) is the most common generalized epilepsy in childhood and is considered the prototype of idiopathic generalized epilepsy (IGE). To better understand electrophysiological changes and their development in CAE, we investigated the origin of epileptiform discharges. We performed distributed source localization with standardized, low-resolution, brain electromagnetic tomography (sLORETA). In 16 children with CAE, sLORETA images corresponding to the midpoint of the ascending phase and the negative peak of the spike were obtained from a total of 242 EEG epochs (121 epochs at each timepoint). Maximal current source density (CSD) was mostly located in the frontal lobe (69.4%). At the gyral level, maximal CSD was most commonly in the superior frontal gyrus (39.3%) followed by the middle frontal gyrus (14.0%) and medial frontal gyrus (8.7%). At the hemisphere level, maximal CSD was dominant in the right cerebral hemisphere (63.6%). These results were consistent at the midpoint of the ascending phase and the negative peak of the spike. Our results demonstrated that the major source of epileptiform discharges in CAE was the frontal lobe. These results suggest that the frontal lobe is involved in generating CAE. This finding is consistent with recent studies that have suggested selective cortical involvement, especially in the frontal regions, in IGE.
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Mapeo Encefálico/métodos , Encéfalo/fisiopatología , Electroencefalografía/métodos , Epilepsia Tipo Ausencia/diagnóstico , Epilepsia Tipo Ausencia/fisiopatología , Niño , Femenino , Humanos , Masculino , Modelos Teóricos , Procesamiento de Señales Asistido por ComputadorRESUMEN
BACKGROUND: Several neuroimaging studies have reported neurophysiological alterations in patients with benign childhood epilepsy with centrotemporal spikes (BCECTS). However, reported outcomes have been inconsistent, and the progression of these changes in the brain remains unresolved. Moreover, background electroencephalography (EEG) in cases of BCECTS has not been performed often. METHODS: We investigated background EEG activity changes after six months of oxcarbazepine treatment to better understand the neurophysiological alterations and progression that occur in BCECTS. In 18 children with BCECTS, non-parametric statistical analyses using standardized low resolution brain electromagnetic tomography (sLORETA) were performed to compare the current density distribution of four frequency bands (delta, theta, alpha, and beta) between untreated and treated conditions. RESULTS: Background EEG activity for the delta frequency band was significantly decreased in the fronto-temporal and limbic regions of the left hemisphere after oxcarbazepine treatment (threshold log-F-ratio = ±2.729, P < 0.01). The maximum current density difference was found in the parahippocampal gyrus of the left limbic lobe (Montreal Neurological Institute coordinate [x, y, z = 25, - 20, - 10], Brodmann area 28) (log-F-ratio = 3.081, P < 0.01). CONCLUSIONS: Our results indicate the involvement of the fronto-temporal and limbic cortices in BCECTS, and limbic lobe involvement, including the parahippocampal gyrus, was noted. In addition to evidence of the involvement of the fronto-temporal and limbic cortices in BCECTS, this study also found that an antiepileptic drug could reduce the delta frequency activity of the background EEG in these regions.
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Anticonvulsivantes/uso terapéutico , Epilepsia Rolándica , Neuroimagen/métodos , Oxcarbazepina/uso terapéutico , Tomografía/métodos , Encéfalo/diagnóstico por imagen , Niño , Estudios de Cohortes , Electroencefalografía , Epilepsia Rolándica/diagnóstico por imagen , Epilepsia Rolándica/tratamiento farmacológico , Epilepsia Rolándica/fisiopatología , HumanosRESUMEN
BACKGROUND: To validate the clinical application of chromosomal microarray analysis (CMA) as a first-tier clinical diagnostic test and to determine the impact of CMA results on patient clinical management, we conducted a multicenter prospective study in Korean patients diagnosed as having developmental delay/intellectual disability (DD/ID), autism spectrum disorders (ASD), and multiple congenital anomalies (MCA). METHODS: We performed both CMA and G-banding cytogenetics as the first-tier tests in 617 patients. To determine whether the CMA results directly influenced treatment recommendations, the referring clinicians were asked to complete a 39-item questionnaire for each patient separately after receiving the CMA results. RESULTS: A total of 122 patients (19.8%) had abnormal CMA results, with either pathogenic variants (N=65) or variants of possible significance (VPS, N=57). Thirty-five well-known diseases were detected: 16p11.2 microdeletion syndrome was the most common, followed by Prader-Willi syndrome, 15q11-q13 duplication, Down syndrome, and Duchenne muscular dystrophy. Variants of unknown significance (VUS) were discovered in 51 patients (8.3%). VUS of genes putatively associated with developmental disorders were found in five patients: IMMP2L deletion, PTCH1 duplication, and ATRNL1 deletion. CMA results influenced clinical management, such as imaging studies, specialist referral, and laboratory testing in 71.4% of patients overall, and in 86.0%, 83.3%, 75.0%, and 67.3% of patients with VPS, pathogenic variants, VUS, and benign variants, respectively. CONCLUSIONS: Clinical application of CMA as a first-tier test improves diagnostic yields and the quality of clinical management in patients with DD/ID, ASD, and MCA.
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Anomalías Múltiples/diagnóstico , Trastorno del Espectro Autista/diagnóstico , Bandeo Cromosómico/métodos , Cromosomas/genética , Discapacidades del Desarrollo/diagnóstico , Discapacidad Intelectual/diagnóstico , Anomalías Múltiples/genética , Adolescente , Adulto , Trastorno del Espectro Autista/genética , Niño , Preescolar , Hibridación Genómica Comparativa , Discapacidades del Desarrollo/genética , Femenino , Eliminación de Gen , Duplicación de Gen , Humanos , Lactante , Recién Nacido , Discapacidad Intelectual/genética , Cariotipo , Masculino , Estudios Prospectivos , República de Corea , Adulto JovenRESUMEN
The child with global developmental delay (GDD)/intellectual disability (ID) is deserving of the appropriate evaluation available for improving the health and well-being of patients and their families. To better elucidate the diagnostic approach of genetic tests for patients with GDD and/or ID, we evaluated the results in a cohort of 75 patients with clinical features of GDD and/or ID who were referred for diagnostic workup. A total of 75 children were investigated for GDD or ID in the pediatric neurology department. Ten patients (13%, 10/75) with a clinically recognizable syndrome were diagnosed by single-gene analysis. Next, chromosomal microarray was performed as a first-tier test, and 25 patients (33%, 25/75) showed structural abnormalities. Then, two fragile X syndrome (3%, 2/75) were confirmed by FMR1 gene fragment analysis. Thirty-eight remaining patients received a gene panel by next-generation sequencing. Eight patients were found to have an underlying genetic etiology: CHD8, ZDHHC9, MBD5, CACNA1H, SMARCB1, FOXP1, NSD1, and PAX6. As a result, 45 patients (60%, 45/75) had been diagnosed by genetic tests. Among 30 undiagnosed patients, brain structural abnormalities related to GDD/ID were observed in eight patients (11%, 8/75). However, in 22 patients (29%, 22/75), the causes of GDD/ID remained uncertain. A genetic diagnostic approach of GDD/ID by sequential molecular analysis can help in the planning of treatment, assigning the risk of occurrence in siblings, and providing emotional relief for the family.
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Discapacidades del Desarrollo/diagnóstico , Pruebas Genéticas , Discapacidad Intelectual/diagnóstico , Adolescente , Niño , Preescolar , Estudios de Cohortes , Discapacidades del Desarrollo/genética , Femenino , Secuenciación de Nucleótidos de Alto Rendimiento , Humanos , Lactante , Discapacidad Intelectual/genética , Masculino , AnamnesisRESUMEN
Emission characteristics of an oval-shaped microcavity laser are studied. In experiments, modes localized on periodic orbits emit unidirectionally with a narrow in-plane divergence angle of about 12 deg. The origin of high directionality is elucidated by means of classical ray dynamics. Wave calculations show that the Q-factors of the resonances are higher than 108. We explain this extraordinary high Q-factor in relation with a dynamical barrier region where Kolmogorov-Arnold-Moser curves significantly obstruct leakages of resonances.
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Ataxia/genética , ADN Mitocondrial/genética , Mitocondrias/genética , Mutación/genética , Enfermedades del Sistema Nervioso/genética , Retinitis Pigmentosa/genética , Adolescente , Ataxia/sangre , Ataxia/diagnóstico por imagen , Niño , ADN Mitocondrial/sangre , Familia , Femenino , Humanos , Imagen por Resonancia Magnética , Masculino , Enfermedades del Sistema Nervioso/sangre , Enfermedades del Sistema Nervioso/diagnóstico por imagen , Linaje , Fenotipo , Retinitis Pigmentosa/sangre , Retinitis Pigmentosa/diagnóstico por imagen , Adulto JovenRESUMEN
BACKGROUND: Headache is a common complaint in children and adolescents. Recently, an increased prevalence of headache in children and adolescents has been reported. METHODS: We retrospectively reviewed the medical records of children and adolescents attending the Headache Clinic of Daejeon St. Mary's Hospital during the period from January 2005 through December 2016. RESULTS: The study population consisted of 2466 children, aged between 3 and 18 years (mean age: 10.9). Our study showed an increase in the number of patients visiting the hospital with headaches during the past decade. Compared with 2005, the number of patients with headache increased three-fold in 2016. Interestingly, the proportion of boys, preschool children, and other primary headaches revealed a steady and statistically significant increase. CONCLUSION: Due to a steady increase in pediatric headaches, the earlier the problem is recognized and properly diagnosed and a treatment plan is established, the greater the likelihood of a better lifelong outcome. Studies are needed to estimate recent trend in prevalence and to identify the demographic and socioeconomic factors predicting the occurrence of headache.
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Cefalea/epidemiología , Adolescente , Niño , Preescolar , Femenino , Humanos , Masculino , Prevalencia , República de Corea/epidemiología , Estudios RetrospectivosRESUMEN
BACKGROUND: Neonatal seizures remain a significant clinical problem, and therapeutic options are still not diverse with limited efficacy. Levetiracetam (LEV) is a relatively new and wide spectrum anti-seizure medication with favorable pharmacokinetics and safety profile. In the recent decades, LEV has been increasingly used for the treatment of neonatal seizures. The aim of this study was to describe the experience of using LEV as the first line anti-seizure medication for preterm infants. METHODS: A retrospective analysis of 37 preterm infants who were treated with LEV as the first-line anti-seizure medication was performed. RESULTS: Mean gestational age of the 37 preterm infants was 31.5 ± 1.9 weeks (range, 26 to 36+ 6 weeks). Twenty-one infants (57%) were seizure-free while given LEV at the end of the first week, and no additional anti-seizure medication was required. Loading doses of LEV ranged from 40 to 60 mg/kg (mean 56 mg/kg) and the maintenance dose ranged from 20 to 30 mg/kg (mean 23 mg/kg). No adverse effect was observed. CONCLUSIONS: Levetiracetam can be a good and safe choice for treatment of neonatal seizures in preterm infants. Prospective double blind controlled studies are needed in the future.
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Anticonvulsivantes/efectos adversos , Anticonvulsivantes/uso terapéutico , Enfermedades del Prematuro/tratamiento farmacológico , Levetiracetam/efectos adversos , Levetiracetam/uso terapéutico , Convulsiones/tratamiento farmacológico , Anticonvulsivantes/administración & dosificación , Peso al Nacer , Encéfalo/diagnóstico por imagen , Femenino , Edad Gestacional , Humanos , Recién Nacido , Recien Nacido Prematuro , Levetiracetam/administración & dosificación , Imagen por Resonancia Magnética , Masculino , Fenobarbital/uso terapéutico , Estudios Retrospectivos , Convulsiones/diagnóstico por imagenRESUMEN
Background: Differential diagnosis of developmental delay (DD) and/or intellectual disability (ID) is challenging because of the diversity of phenotypic manifestations as DD/ID patients usually have combined congenital malformations, autism-spectrum disorders, and/or seizure disorder. Thus, unbiased genomic approaches are needed to discover genetic alterations leading to DD and/or ID. Objective: The aim of this study was to investigate the clinical usefulness of targeted next-generation sequencing (NGS) to investigate genetic causes in 35 Korean patients with unexplained DD/ID. Methods: Targeted next-generation sequencing (NGS) using the TruSight One Panel was analyzed in 35 patients with unexplained DD/ID. Sanger sequencing was used to confirm candidate variants, and to define genetic inheritance mode of candidate variant as familial segregation testing. Results: Of 35 patients with DD and/or ID, 10 were found to have underlying genetic etiology and carried X-linked recessive inheritance of ZDHHC9 or autosomal dominant inheritance of SMARCB1, CHD8, LAMA5, NSD1, PAX6, CACNA1H, MBD5, FOXP1, or KCNK18 mutations. No autosomal recessive inherited mutation was identified in this study. As a result, the diagnostic yield of DD/ID by targeted NGS was 29% (10/35), mostly involving may be de novo mutation present in the proband only. A total of seven may be de novo mutations, one paternally inherited, and one maternally inherited mutations that had been reported previously to concede the genetic pathogenesis as known DD and/or ID genes were found in nine patients with available inheritance pattern except LAMA5. Mutations in nine causative genes were detected in patients with similar DD/ID phenotypes in the OMIM database, providing support for genetic evidence as the cause of DD and/or ID. Conclusion: Targeted NGS through singleton analysis with phenotype-first approaches was able to explain 10 out of 35 DD/ID cases. However, the excavation of plausible genetic causes may be de novo, and X-linked disease-causative variants in DD/ID-associated genes requires further genetic analysis.
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Mutations in SCN8A, which codes for the voltage-gated sodium channel NaV1.6, have been described in relation to infantile onset epilepsy with developmental delay and cognitive impairment. Here, we report the case of an infant and her father with early onset benign familial infantile epilepsy, but without cognitive or neurological impairment. In this patient, diagnostic exome sequencing (DES) identified a heterozygous mutation (c.4427G>A; p.Gly1476Asp) in the SCN8A gene. This mutation, confirmed by Sanger sequencing, effects a highly conserved amino acid. In-silico analysis predicts that this mutation may be pathogenic. To our knowledge, this is the first clinical report on Korean benign familial infantile epilepsy with a SCN8A mutation. We were able to achieve good seizure control in our patients with sodium channel blockers. This result suggests the application of DES will be valuable for the diagnosis of patients with infantile epilepsy but no cognitive impairment.
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Pueblo Asiatico/genética , Síndromes Epilépticos/genética , Secuenciación del Exoma/métodos , Patrón de Herencia/genética , Mutación/genética , Canal de Sodio Activado por Voltaje NAV1.6/genética , Secuencia de Aminoácidos , Preescolar , Familia , Femenino , Humanos , Lactante , Masculino , Canal de Sodio Activado por Voltaje NAV1.6/química , LinajeRESUMEN
RATIONALE: Stroke is an uncommon disease in childhood with an estimated incidence of 1 to 6 per 100,000 and stenoocclusive arteriopathy is the main risk factor of recurrent pediatric arterial ischemic stroke (AIS). Dyslipidemia may influence strongly before puberty and in late adolescence when plasma levels are naturally highest. PATIENT CONCERNS: An 11-year-old male presented with acute onset seizure, a drowsy mentality, and right hemiplegia. DIAGNOSES: Magnetic resonance (MR) angiogram demonstrated occlusion of distal basilar artery and left vertebral arteries. Serum Lp(a) was significantly increased as 269ânmol/L (normal<75ânmol/L) only. Thus, he was diagnosed as pediatric AIS. INTERVENTIONS: He was started on aspirin (100âmg/day) for secondary stroke prevention and received nicotinic acid (2âg/day) as a Lp(a)-lowering agent. OUTCOMES: Consciousness gradually improved and the patient regained a normal orientation after 2 weeks. The Lp(a) level was reduced to 48ânmol/L after nicotinic acid administration. LESSONS: High Lp(a) level may be considered in the risk profile assessment of pediatric AIS. Niacin and certain inhibitors of cholesteryl ester transfer protein can be considered to reduce Lp(a).
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Dislipidemias/complicaciones , Arteriosclerosis Intracraneal/complicaciones , Lipoproteína(a)/sangre , Accidente Cerebrovascular/complicaciones , Niño , Dislipidemias/tratamiento farmacológico , Humanos , Masculino , Niacina/uso terapéutico , Factores de RiesgoRESUMEN
Methyl-CpG-binding domain 5 (MBD5)-associated neurodevelopmental disorder caused by 2q23.1 or MBD5-specific mutation has been recently identified as a genetic disorder associated with autism spectrum disorders. Phenotypic features of 2q23.1 deletion or disruption of MBD5 gene include severe intellectual disability, seizure, significant speech impairment, sleep disturbance, and autistic-like behavioural problems. Here we report a 7-year-old girl with intellectual disability and epilepsy without previous clinical diagnosis. Diagnostic exome sequencing identified a novel frameshift mutation c.254_255delGA (p.Arg85Asnfs*6) in the MBD5 gene of the proband and her father. The proband's father with normal intelligence showed subclinical manifestations observed in subsequent investigations. Clinical manifestations, disease course, and molecular findings of the involvement of MBD5 gene in this family suggest an unusual MBD5-related neurodevelopmental disorder. Moreover, this report demonstrates the critical role of next-generation sequencing technique in characterizing such a rare disorder with variable or no clinical manifestation and providing opportunity to develop effective preventive measures such as pre-implantation genetic diagnosis.
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Proteínas de Unión al ADN/genética , Epilepsia/genética , Mutación del Sistema de Lectura , Discapacidad Intelectual/genética , Adulto , Niño , Epilepsia/diagnóstico , Exoma , Femenino , Heterocigoto , Humanos , Discapacidad Intelectual/diagnóstico , Masculino , Linaje , Fenotipo , SíndromeRESUMEN
X-linked intellectual disability (XLID) is a genetically heterogeneous disorder involving more than 100 genes known to date. Here, we describe a Korean male infant with global developmental delay. He had neither facial dysmorphism nor skeletal abnormalities. Bayley scale of infant and toddler development third edition (Bayley-III) measured at age of 2 years revealed marked global developmental delays without Marfanoid habitus, structural brain abnormalities, or epilepsy. The patient's cognitive, motor, and language developmental ages were 8-9 months, 12 months, and 9 months, respectively. Targeted next-generation sequencing revealed a de novo mutation [NM_001008222.2(ZDHHC9): c.286C > T (p.(Arg96Trp))] in the affected patient. This mutation has been reported previously in a family XLID with Marfanoid features. Sanger sequencing analysis of the proband and his parents revealed that the missense mutation was present in the proband only (absent in his parents). This indicates that the mutation is de novo in origin. To the best of our knowledge, this is the first report describing sporadic XLID with de novo ZDHHC9 mutation identified by targeted next-generation sequencing.