RESUMEN
BACKGROUND: Behavioural sleep problems are common in children with autism spectrum disorder (ASD); however, evidence for the efficacy of behavioural sleep interventions is limited. This study examined the efficacy of a brief behavioural sleep intervention in autistic children. It was hypothesised that the intervention would reduce overall child sleep problems (primary outcome), in addition to improvements in children's social, emotional, cognitive, academic functioning, and quality of life, and parent/caregivers' stress, quality of life, and mental health (secondary outcomes). METHODS: A randomised controlled trial was conducted with participants randomised via a computer-generated sequence to the sleeping sound intervention (n = 123) or treatment as usual (n = 122) group. Participants comprised 245 children with an ASD diagnosis. Inclusion criteria were as follows: confirmation of DSM IV or DSM-5 diagnosis of ASD, participants aged between 5 and 13 years and parent/caregiver report of moderate-severe sleep problems. Exclusion criteria were as follows: parent/caregiver intellectual disability or lacking sufficient English to complete questionnaires; and child participant with co-occurring medical conditions known to impact sleep. The intervention group received the sleeping sound intervention (2 × 50-min face-to-face sessions plus follow-up phone call) by a trained clinician. RESULTS: Change in children's sleep problems was measured by the Children's Sleep Habits Questionnaire (CSHQ) at 3 months post randomisation. Parents/caregivers of children in the intervention group reported a reduction in child sleep problems at 3 months post randomisation (effect size: E.S -0.7). There were also small effects in a number of child (internalising symptoms, emotional behavioural disturbance and quality of life) and parent/caregiver (mental health, parenting stress and quality of life) outcomes; however, these did not remain significant when controlling for multiple comparisons. CONCLUSIONS: The sleeping sound ASD intervention is an efficacious and practical way to reduce sleep problems for autistic children. This brief behavioural intervention has the potential to be embedded easily into the Australian healthcare system.
Asunto(s)
Trastorno del Espectro Autista , Trastorno Autístico , Trastornos del Sueño-Vigilia , Niño , Humanos , Preescolar , Adolescente , Trastorno del Espectro Autista/complicaciones , Trastorno del Espectro Autista/terapia , Trastorno del Espectro Autista/psicología , Calidad de Vida , Trastorno Autístico/complicaciones , Australia , Sueño , Trastornos del Sueño-Vigilia/terapia , Trastornos del Sueño-Vigilia/complicaciones , Instituciones AcadémicasRESUMEN
OBJECTIVE: We tested 2 hypotheses regarding age at onset within familial epilepsies: (1) family members with epilepsy tend to have similar ages at onset, independent of epilepsy syndrome; and (2) age at onset is younger in successive generations after controlling for sampling bias. METHODS: We analyzed clinical data collected by the Epi4K Consortium (303 multiplex families, 1,120 individuals). To test hypothesis 1, we used both linear mixed models commonly used for heritability analysis and Cox regression models with frailty terms to assess clustering of onset within families after controlling for other predictors. To test hypothesis 2, we used mixed effects models, pairwise analyses, and survival analysis to address sampling-related bias that may mimic anticipation. RESULTS: Regarding hypothesis 1, age at seizure onset was significantly heritable (intraclass correlation coefficient = 0.17, p < 0.001) after adjusting for epilepsy type, sex, site, history of febrile seizure, and age at last observation. This finding remained significant after adjusting for epilepsy syndromes, and was robust across statistical methods in all families and in generalized families. Regarding hypothesis 2, the mean age at onset decreased in successive generations (p < 0.001). After adjusting for age at last observation, this effect was not significant in mixed effects models (p = 0.14), but remained significant in pairwise (p = 0.0003) and survival analyses (p = 0.02). INTERPRETATION: Age at seizure onset is an independent familial trait, and may have genetic determinants distinct from the determinants of particular epilepsy syndromes. Younger onsets in successive generations can be explained in part by sampling bias, but the presence of genetic anticipation cannot be excluded. ANN NEUROL 2019.
Asunto(s)
Epilepsia/diagnóstico , Epilepsia/genética , Familia , Adolescente , Edad de Inicio , Niño , Preescolar , Femenino , Humanos , Lactante , Modelos Lineales , Masculino , Linaje , Síndrome , Adulto JovenRESUMEN
Juvenile myoclonic epilepsy (JME) is a common syndrome of genetic generalized epilepsies (GGEs). Linkage and association studies suggest that the gene encoding the bromodomain-containing protein 2 (BRD2) may increase risk of JME. The present methylation and association study followed up a recent report highlighting that the BRD2 promoter CpG island (CpG76) is differentially hypermethylated in lymphoblastoid cells from Caucasian patients with JME compared to patients with other GGE subtypes and unaffected relatives. In contrast, we found a uniform low average percentage of methylation (<4.5%) for 13 CpG76-CpGs in whole blood cells from 782 unrelated European Caucasians, including 116 JME patients, 196 patients with genetic absence epilepsies, and 470 control subjects. We also failed to confirm an allelic association of the BRD2 promoter single nucleotide polymorphism (SNP) rs3918149 with JME (Armitage trend test, P = 0.98), and we did not detect a substantial impact of SNP rs3918149 on CpG76 methylation in either 116 JME patients (methylation quantitative trait loci [meQTL], P = 0.29) or 470 German control subjects (meQTL, P = 0.55). Our results do not support the previous observation that a high DNA methylation level of the BRD2 promoter CpG76 island is a prevalent epigenetic motif associated with JME in Caucasians.
Asunto(s)
Islas de CpG/genética , Metilación de ADN , Epilepsia Mioclónica Juvenil/genética , Regiones Promotoras Genéticas/genética , Factores de Transcripción/genética , Epilepsia Tipo Ausencia/epidemiología , Epilepsia Tipo Ausencia/genética , Europa (Continente) , Femenino , Humanos , Leucocitos/química , Masculino , Epilepsia Mioclónica Juvenil/sangre , Epilepsia Mioclónica Juvenil/epidemiología , Polimorfismo de Nucleótido SimpleRESUMEN
OBJECTIVE: The cause of mesial temporal lobe epilepsy (MTLE) is often unknown. We ascertained to what extent newly diagnosed nonlesional MTLE actually represents familial MTLE (FMTLE). METHODS: We identified all consecutive patients presenting to the Austin Health First Seizure Clinic with MTLE and normal magnetic resonance imaging (MRI) or MRI evidence of hippocampal sclerosis over a 10-year period. Patients' first-degree relatives and pairwise age- and sex-matched controls underwent a comprehensive epilepsy interview. Each interview transcript was reviewed independently by 2 epileptologists, blinded to relative or control status. Reviewers classified each subject as follows: epilepsy, specifying if MTLE; manifestations suspicious for epilepsy; or unaffected. Physiological déjà vu was noted. RESULTS: Forty-four patients were included. At the Clinic, MTLE had been recognized to be familial in 2 patients only. Among 242 subjects interviewed, MTLE was diagnosed in 9 of 121 relatives versus 0 of 121 controls (p = 0.008). All affected relatives had seizures with intense déjà vu and accompanying features; 6 relatives had not been previously diagnosed. Déjà vu experiences that were suspicious, but not diagnostic, of MTLE occurred in 6 additional relatives versus none of the controls (p = 0.04). Physiological déjà vu was common, and did not differ significantly between relatives and controls. After completing the relatives' interviews, FMTLE was diagnosed in 8 of 44 patients (18.2%). INTERPRETATION: FMTLE accounts for almost one-fifth of newly diagnosed nonlesional MTLE, and it is largely unrecognized without direct questioning of relatives. Relatives of patients with MTLE may experience déjà vu phenomena that clinically lie in the "borderland" between epileptic seizures and physiological déjà vu. Ann Neurol 2017;82:166-176.
Asunto(s)
Déjà Vu , Epilepsia del Lóbulo Temporal/congénito , Salud de la Familia , Adolescente , Adulto , Anciano , Estudios de Casos y Controles , Niño , Epilepsia del Lóbulo Temporal/diagnóstico , Epilepsia del Lóbulo Temporal/diagnóstico por imagen , Epilepsia del Lóbulo Temporal/genética , Femenino , Humanos , Imagen por Resonancia Magnética , Masculino , Persona de Mediana Edad , Adulto JovenRESUMEN
AIM: Loss-of-function mutations in SLC2A1, encoding glucose transporter-1 (GLUT-1), lead to dysfunction of glucose transport across the blood-brain barrier. Ten percent of cases with hypoglycorrhachia (fasting cerebrospinal fluid [CSF] glucose <2.2mmol/L) do not have mutations. We hypothesized that GLUT1 deficiency could be due to non-coding SLC2A1 variants. METHOD: We performed whole exome sequencing of one proband with a GLUT1 phenotype and hypoglycorrhachia negative for SLC2A1 sequencing and copy number variants. We studied a further 55 patients with different epilepsies and low CSF glucose who did not have exonic mutations or copy number variants. We sequenced non-coding promoter and intronic regions. We performed mRNA studies for the recurrent intronic variant. RESULTS: The proband had a de novo splice site mutation five base pairs from the intron-exon boundary. Three of 55 patients had deep intronic SLC2A1 variants, including a recurrent variant in two. The recurrent variant produced less SLC2A1 mRNA transcript. INTERPRETATION: Fasting CSF glucose levels show an age-dependent correlation, which makes the definition of hypoglycorrhachia challenging. Low CSF glucose levels may be associated with pathogenic SLC2A1 mutations including deep intronic SLC2A1 variants. Extending genetic screening to non-coding regions will enable diagnosis of more patients with GLUT1 deficiency, allowing implementation of the ketogenic diet to improve outcomes.
Asunto(s)
Errores Innatos del Metabolismo de los Carbohidratos/líquido cefalorraquídeo , Errores Innatos del Metabolismo de los Carbohidratos/genética , Epilepsia/líquido cefalorraquídeo , Epilepsia/genética , Transportador de Glucosa de Tipo 1/genética , Glucosa/líquido cefalorraquídeo , Proteínas de Transporte de Monosacáridos/deficiencia , Adulto , Preescolar , Exoma , Femenino , Humanos , Lactante , Masculino , Proteínas de Transporte de Monosacáridos/líquido cefalorraquídeo , Proteínas de Transporte de Monosacáridos/genética , Linaje , Análisis de SecuenciaRESUMEN
Genetic generalized epilepsies (GGEs) have a lifetime prevalence of 0.3% and account for 20-30% of all epilepsies. Despite their high heritability of 80%, the genetic factors predisposing to GGEs remain elusive. To identify susceptibility variants shared across common GGE syndromes, we carried out a two-stage genome-wide association study (GWAS) including 3020 patients with GGEs and 3954 controls of European ancestry. To dissect out syndrome-related variants, we also explored two distinct GGE subgroups comprising 1434 patients with genetic absence epilepsies (GAEs) and 1134 patients with juvenile myoclonic epilepsy (JME). Joint Stage-1 and 2 analyses revealed genome-wide significant associations for GGEs at 2p16.1 (rs13026414, P(meta) = 2.5 × 10(-9), OR[T] = 0.81) and 17q21.32 (rs72823592, P(meta) = 9.3 × 10(-9), OR[A] = 0.77). The search for syndrome-related susceptibility alleles identified significant associations for GAEs at 2q22.3 (rs10496964, P(meta) = 9.1 × 10(-9), OR[T] = 0.68) and at 1q43 for JME (rs12059546, P(meta) = 4.1 × 10(-8), OR[G] = 1.42). Suggestive evidence for an association with GGEs was found in the region 2q24.3 (rs11890028, P(meta) = 4.0 × 10(-6)) nearby the SCN1A gene, which is currently the gene with the largest number of known epilepsy-related mutations. The associated regions harbor high-ranking candidate genes: CHRM3 at 1q43, VRK2 at 2p16.1, ZEB2 at 2q22.3, SCN1A at 2q24.3 and PNPO at 17q21.32. Further replication efforts are necessary to elucidate whether these positional candidate genes contribute to the heritability of the common GGE syndromes.
Asunto(s)
Epilepsia Generalizada/genética , Estudio de Asociación del Genoma Completo , Alelos , Epilepsia Tipo Ausencia/genética , Predisposición Genética a la Enfermedad/genética , Proteínas de Homeodominio/genética , Humanos , Epilepsia Mioclónica Juvenil/genética , Canal de Sodio Activado por Voltaje NAV1.1/genética , Proteínas Serina-Treonina Quinasas/genética , Receptor Muscarínico M3/genética , Proteínas Represoras/genética , Caja Homeótica 2 de Unión a E-Box con Dedos de ZincRESUMEN
The availability of glucose, and its glycolytic product lactate, for cerebral energy metabolism is regulated by specific brain transporters. Inadequate energy delivery leads to neurologic impairment. Haploinsufficiency of the glucose transporter GLUT1 causes a characteristic early onset encephalopathy, and has recently emerged as an important cause of a variety of childhood or later-onset generalized epilepsies and paroxysmal exercise-induced dyskinesia. We explored whether mutations in the genes encoding the other major glucose (GLUT3) or lactate (MCT1/2/3/4) transporters involved in cerebral energy metabolism also cause generalized epilepsies. A cohort of 119 cases with myoclonic astatic epilepsy or early onset absence epilepsy was screened for nucleotide variants in these five candidate genes. No epilepsy-causing mutations were identified, indicating that of the major energetic fuel transporters in the brain, only GLUT1 is clearly associated with generalized epilepsy.
Asunto(s)
Epilepsia/genética , Epilepsia/metabolismo , Variación Genética/genética , Transportador de Glucosa de Tipo 1/fisiología , Glucosa/metabolismo , Mutación/genética , Niño , Preescolar , Estudios de Cohortes , Metabolismo Energético/fisiología , Epilepsia/diagnóstico , Femenino , Humanos , Lactante , MasculinoRESUMEN
AIM: To show that atypical multifocal Dravet syndrome is a recognizable, electroclinical syndrome associated with sodium channel gene (SCN1A) mutations that readily escapes diagnosis owing to later cognitive decline and tonic seizures. METHOD: Eight patients underwent electroclinical characterization. SCN1A was sequenced and copy number variations sought by multiplex ligation-dependent probe amplification. RESULTS: All patients were female (age range at assessment 5-26y) with median seizure onset at 6.5 months (range 4-19mo). The initial seizure was brief in seven and status epilepticus only occurred in one; three were febrile. Focal seizures occurred in four patients and bilateral convulsion in the other four. All patients developed multiple focal seizure types and bilateral convulsions, with seizure clusters in six. The most common focal seizure semiology (six out of eight) comprised unilateral clonic activity. Five also had focal or asymmetric tonic seizures. Rare or transient myoclonic seizures occurred in six individuals, often triggered by specific antiepileptic drugs. Developmental slowing occurred in all: six between 3 years and 8 years, and two around 1 year 6 months. Cognitive outcome varied from severe to mild intellectual disability. Multifocal epileptiform discharges were seen on electroencephalography. Seven out of eight patients had SCN1A mutations. INTERPRETATION: Atypical, multifocal Dravet syndrome with SCN1A mutations may not be recognized because of later cognitive decline and frequent tonic seizures.
Asunto(s)
Trastornos del Conocimiento/etiología , Epilepsias Mioclónicas/complicaciones , Epilepsias Mioclónicas/diagnóstico , Discapacidad Intelectual/etiología , Mutación , Canal de Sodio Activado por Voltaje NAV1.1/genética , Adolescente , Adulto , Edad de Inicio , Niño , Desarrollo Infantil , Trastornos del Conocimiento/genética , Variaciones en el Número de Copia de ADN , Electroencefalografía , Epilepsias Mioclónicas/genética , Epilepsias Mioclónicas/fisiopatología , Femenino , Humanos , Discapacidad Intelectual/genética , Datos de Secuencia Molecular , Convulsiones/genética , Convulsiones/fisiopatologíaRESUMEN
Disordered sleep is common in autistic children. This study aimed to evaluate the cost-effectiveness of a brief behavioural sleep intervention, the 'Sleeping Sound intervention', in primary school-aged autistic children in Australia. A cost-effectiveness analysis was undertaken alongside a randomised controlled trial over a 6-month follow-up period from both a societal and healthcare sector perspective. Resources used by participants were collected from a resource-use questionnaire and administrative data; intervention costs were determined from study records. Mean costs and quality-adjusted life-years (QALYs) were compared between the intervention and treatment as usual (TAU) groups. Uncertainty analysis using bootstrapping and sensitivity analyses were conducted. The sample included 245 children, with 123 participants randomised to the intervention group and 122 to TAU. The mean total costs were higher for the Sleeping Sound intervention with a mean difference of A$745 (95% CI 248; 1242; p = 0.003) from a healthcare sector perspective and A$1310 (95% CI 584; 2035, p < 0.001) from a societal perspective. However, the intervention also resulted in greater QALYs compared with TAU, with a mean difference of 0.038 (95% CI 0.004; 0.072; p = 0.028). The incremental cost-effectiveness ratio was A$24,419/QALY (95% CI 23,135; 25,703) from a healthcare sector perspective and A$41,922/QALY (95% CI 39,915; 43,928) from a societal perspective; with a probability of being cost-effective of 93.8% and 74.7%, respectively. Findings remained robust in the sensitivity analyses. The Sleeping Sound intervention offers a cost-effective approach in improving sleep in primary school-aged autistic children.Trial registration The trial was registered with the International Trial Registry (ISRCTN14077107).
RESUMEN
Mutations of the SCN1A subunit of the sodium channel is a cause of genetic epilepsy with febrile seizures plus (GEFS(+) ) in multiplex families and accounts for 70-80% of Dravet syndrome (DS). DS cases without SCN1A mutation inherited have predicted SCN9A susceptibility variants, which may contribute to complex inheritance for these unexplained cases of DS. Compared with controls, DS cases were significantly enriched for rare SCN9A genetic variants. None of the multiplex febrile seizure or GEFS(+) families could be explained by highly penetrant SCN9A mutations.
Asunto(s)
Epilepsias Mioclónicas/genética , Mutación/genética , Canal de Sodio Activado por Voltaje NAV1.7/genética , Convulsiones Febriles/genética , Canales de Sodio/genética , Predisposición Genética a la Enfermedad , Genotipo , Humanos , LinajeRESUMEN
OBJECTIVE: To investigate the longitudinal associations between COVID-19 induced stress (related to COVID-19 restrictions/changes), attention-deficit/hyperactivity disorder (ADHD) symptoms, oppositional symptoms, and mental health outcomes (negative affect, anxiety, depression, and irritability) in children with ADHD during the COVID-19 pandemic. METHOD: Parents of 140 Australian children with ADHD (aged 5-17 years) completed an online survey in May 2020 during stay-at-home restrictions and 12-months later. RESULTS: Baseline COVID-19 stress was associated with increased total ADHD symptom severity (ß = .21, p = .007) and hyperactivity/impulsivity symptoms (ß = .23, p = .002) at 12-months, after accounting for covariates (i.e., child age, gender, ADHD medication, socio-economic status, and baseline symptoms). Despite some indication of associations between baseline COVID-19 stress and 12-month oppositional symptoms and negative affect, these were attenuated when adjusting for baseline symptoms. CONCLUSIONS: The study provides initial evidence of the medium-term impacts of pandemic-related stress for children with ADHD.
Asunto(s)
Trastorno por Déficit de Atención con Hiperactividad , COVID-19 , Humanos , Niño , Trastorno por Déficit de Atención con Hiperactividad/psicología , Salud Mental , Pandemias , Australia/epidemiologíaRESUMEN
Dravet syndrome is an epilepsy syndrome of infantile onset, frequently caused by SCN1A mutations or deletions. Its prevalence, long-term evolution in adults and neuropathology are not well known. We identified a series of 22 adult patients, including three adult post-mortem cases with Dravet syndrome. For all patients, we reviewed the clinical history, seizure types and frequency, antiepileptic drugs, cognitive, social and functional outcome and results of investigations. A systematic neuropathology study was performed, with post-mortem material from three adult cases with Dravet syndrome, in comparison with controls and a range of relevant paediatric tissue. Twenty-two adults with Dravet syndrome, 10 female, were included, median age 39 years (range 20-66). SCN1A structural variation was found in 60% of the adult Dravet patients tested, including one post-mortem case with DNA extracted from brain tissue. Novel mutations were described for 11 adult patients; one patient had three SCN1A mutations. Features of Dravet syndrome in adulthood include multiple seizure types despite polytherapy, and age-dependent evolution in seizure semiology and electroencephalographic pattern. Fever sensitivity persisted through adulthood in 11 cases. Neurological decline occurred in adulthood with cognitive and motor deterioration. Dysphagia may develop in or after the fourth decade of life, leading to significant morbidity, or death. The correct diagnosis at an older age made an impact at several levels. Treatment changes improved seizure control even after years of drug resistance in all three cases with sufficient follow-up after drug changes were instituted; better control led to significant improvement in cognitive performance and quality of life in adulthood in two cases. There was no histopathological hallmark feature of Dravet syndrome in this series. Strikingly, there was remarkable preservation of neurons and interneurons in the neocortex and hippocampi of Dravet adult post-mortem cases. Our study provides evidence that Dravet syndrome is at least in part an epileptic encephalopathy.
Asunto(s)
Encéfalo/patología , Trastornos del Conocimiento/patología , Epilepsias Mioclónicas/patología , Proteínas del Tejido Nervioso/genética , Canales de Sodio/genética , Adulto , Anciano , Encéfalo/fisiopatología , Trastornos del Conocimiento/genética , Trastornos del Conocimiento/fisiopatología , Progresión de la Enfermedad , Epilepsias Mioclónicas/genética , Epilepsias Mioclónicas/fisiopatología , Femenino , Humanos , Masculino , Persona de Mediana Edad , Mutación , Canal de Sodio Activado por Voltaje NAV1.1 , SíndromeRESUMEN
This study examined the sustained and moderating effects of a behavioural sleep intervention for autistic children in a randomised controlled trial. Autistic children (5-13 years) with sleep problems were randomised to the Sleeping Sound intervention or Treatment as Usual (TAU). At 12-month follow-up (n = 150), caregivers of children in the Sleeping Sound group reported greater reduction in child sleep problems compared to TAU (p < .001, effect size: - 0.4). The long-term benefits of the intervention were greater for children taking sleep medication, children of parents who were not experiencing psychological distress, and children with greater autism severity. The Sleeping Sound intervention demonstrated sustained improvements in child sleep. Identified moderators may inform treatment by indicating which subgroups may benefit from further support.
RESUMEN
OBJECTIVE: To examine the impact of COVID-19 restrictions among children with attention-deficit/hyperactivity disorder (ADHD). METHODS: Parents of 213 Australian children (5-17 years) with ADHD completed a survey in May 2020 when COVID-19 restrictions were in place (i.e., requiring citizens to stay at home except for essential reasons). RESULTS: Compared to pre-pandemic, children had less exercise (Odds Ratio (OR) = 0.4; 95% CI 0.3-0.6), less outdoor time (OR = 0.4; 95% 0.3-0.6), and less enjoyment in activities (OR = 6.5; 95% CI 4.0-10.4), while television (OR = 4.0; 95% CI 2.5-6.5), social media (OR = 2.4; 95% CI 1.3-4.5), gaming (OR = 2.0; 95% CI 1.3-3.0), sad/depressed mood (OR = 1.8; 95% CI 1.2-2.8), and loneliness (OR = 3.6; 95% CI 2.3-5.5) were increased. Child stress about COVID-19 restrictions was associated with poorer functioning across most domains. Most parents (64%) reported positive changes for their child including more family time. CONCLUSIONS: COVID-19 restrictions were associated with both negative and positive impacts among children with ADHD.
Asunto(s)
Trastorno por Déficit de Atención con Hiperactividad , COVID-19 , Adolescente , Trastorno por Déficit de Atención con Hiperactividad/epidemiología , Australia/epidemiología , Niño , Humanos , Salud Mental , Pandemias , SARS-CoV-2RESUMEN
Microdeletion at chromosomal position 15q13.3 has been described in intellectual disability, autism spectrum disorders, schizophrenia and recently in idiopathic generalized epilepsy (IGE). Using independent IGE cohorts, we first aimed to confirm the association of 15q13.3 deletions and IGE. We then set out to determine the relative occurrence of sporadic and familial cases and to examine the likelihood of having seizures for individuals with the microdeletion in familial cases. The 15q13.3 microdeletion was identified in 7 of 539 (1.3%) unrelated cases of IGE using quantitative PCR or SNP arrays and confirmed by array comparative genomic hybridization analysis using probes specific to the 15q13.3 region. The inheritance of this lesion was tracked using family studies. Of the seven microdeletions identified in probands, three were de novo, two were transmitted from an unaffected parent and in two cases the parents were unavailable. Non-penetrance of the microdeletion was identified in 4/7 pedigrees and three pedigrees included other family members with IGE who lacked the 15q13.3 deletion. The odds ratio is 68 (95% confidence interval 29-181), indicating a pathogenic lesion predisposing to epilepsy with complex inheritance and incomplete penetrance for the IGE component of the phenotype in multiplex families.
Asunto(s)
Deleción Cromosómica , Cromosomas Humanos Par 15/genética , Epilepsia/genética , Estudios de Cohortes , Epilepsia/congénito , Femenino , Predisposición Genética a la Enfermedad , Humanos , Masculino , Linaje , Población Blanca/genéticaRESUMEN
Familial adult myoclonic epilepsy 1 (FAME1), first recognised in Japanese families, was recently shown to be caused by a TTTCA repeat insertion in intron 4 of SAMD12 on chromosome 8. We performed whole genome sequencing on two families with FAME, one of Sri Lankan origin and the other of Indian origin, and identified a TTTCA repeat insertion in SAMD12 in both families. Haplotype analysis revealed that both families shared the same core ancestral haplotype reported in Japanese and Chinese families with FAME1. Mutation dating, based on the length of shared haplotypes, estimated the age of the ancestral haplotype to be ~670 generations, or 17,000 years old. Our data extend the geographic range of this repeat expansion to Southern Asia and potentially implicate an even broader regional distribution given the age of the variant. This finding suggests patients of Asian ancestry with suspected FAME should be screened for the SAMD12 TTTCA expansion.
Asunto(s)
Epilepsias Mioclónicas/genética , Efecto Fundador , Proteínas del Tejido Nervioso/genética , Femenino , Haplotipos , Humanos , India , Masculino , Mutación , Linaje , Sri LankaRESUMEN
INTRODUCTION: Sleep problems are a characteristic feature of children with autism spectrum disorder (ASD) with 40% to 80% of children experiencing sleep difficulties. Sleep problems have been found to have a pervasive impact on a child's socio-emotional functioning, as well as on parents' psychological functioning. The Sleeping Sound ASD project aims to evaluate the efficacy of a brief behavioural sleep intervention in reducing ASD children's sleep problems in a fully powered randomised controlled trial (RCT). Intervention impact on child and family functioning is also assessed. METHODS AND ANALYSIS: The RCT aims to recruit 234 children with a diagnosis of ASD, aged 5-13 years, who experience moderate to severe sleep problems. Participants are recruited from paediatrician clinics in Victoria, Australia, and via social media. Families interested in the study are screened for eligibility via phone, and then asked to complete a baseline survey online, assessing child sleep problems, and child and family functioning. Participants are then randomised to the intervention group or treatment as usual comparator group. Families in the intervention group attend two face-to-face sessions and a follow-up phone call with a trained clinician, where families are provided with individually tailored behavioural sleep strategies to help manage the child's sleep problems. Teacher reports of sleep, behavioural and social functioning are collected, and cognitive ability assessed to provide measures blind to treatment group. The primary outcome is children's sleep problems as measured by the Children's Sleep Habits Questionnaire at 3 months post-randomisation. Secondary outcomes include parent and child quality of life; child social, emotional, behavioural and cognitive functioning; and parenting stress and parent mental health. Cost-effectiveness of the intervention is also evaluated. ETHICS AND DISSEMINATION: Findings from this study will be published in peer-reviewed journals and disseminated at national and international conferences, local networks and online. TRIAL REGISTRATION NUMBER: ISRCTN14077107 (ISRCTN registry dated on 3 March 2017).
Asunto(s)
Trastorno del Espectro Autista/complicaciones , Trastorno del Espectro Autista/terapia , Terapia Conductista/métodos , Trastornos del Inicio y del Mantenimiento del Sueño/etiología , Trastornos del Inicio y del Mantenimiento del Sueño/terapia , Niño , Preescolar , Femenino , Humanos , Masculino , Calidad de Vida , Ensayos Clínicos Controlados Aleatorios como Asunto , Sueño , VictoriaRESUMEN
Brain glucose transport is dependent on glucose transporter 1 (GLUT1), encoded by the solute carrier family 2 member 1 (SLC2A1) gene. Mutations in SLC2A1 cause GLUT1 deficiency which is characterized by a broad spectrum of neurological phenotypes including generalized epilepsy, motor disorders, developmental delay and microcephaly. Recent case reports suggest SLC2A1 mutations can contribute to non-acquired focal epilepsy (NAFE) but interrogation of a large patient cohort has not been reported. We studied 200 patients with NAFE (126 with temporal lobe epilepsy) comprising 104 females and 96 males with a mean age of onset of 18 years. Polymerase chain reaction (PCR) and Sanger sequencing was performed to detect variants in all 10 coding exons and splice site regions of the SLC2A1 gene. We did not detect any pathogenic mutations in SLC2A1 in this cohort. Our data suggests that the frequency of GLUT1 mutations in NAFE is low. Limitations of this study include the mean age of onset and cohort size. Future research should focus on subpopulations of focal epilepsy with lower age of seizure onset particularly with co-existent movement disorders in which GLUT1 mutations may play a more important role.
Asunto(s)
Epilepsias Parciales/genética , Predisposición Genética a la Enfermedad/genética , Transportador de Glucosa de Tipo 1/genética , Mutación/genética , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Estudios de Cohortes , Análisis Mutacional de ADN , Electroencefalografía , Epilepsias Parciales/diagnóstico por imagen , Epilepsias Parciales/fisiopatología , Femenino , Transportador de Glucosa de Tipo 1/metabolismo , Humanos , Imagen por Resonancia Magnética , Masculino , Persona de Mediana Edad , Índice de Severidad de la Enfermedad , Adulto JovenRESUMEN
OBJECTIVE: Following our original description of generalized epilepsy with febrile seizures plus (GEFS+) in 1997, we analyze the phenotypic spectrum in 409 affected individuals in 60 families (31 new families) and expand the GEFS+ spectrum. METHODS: We performed detailed electroclinical phenotyping on all available affected family members. Genetic analysis of known GEFS+ genes was carried out where possible. We compared our phenotypic and genetic data to those published in the literature over the last 19 years. RESULTS: We identified new phenotypes within the GEFS+ spectrum: focal seizures without preceding febrile seizures (16/409 [4%]), classic genetic generalized epilepsies (22/409 [5%]), and afebrile generalized tonic-clonic seizures (9/409 [2%]). Febrile seizures remains the most frequent phenotype in GEFS+ (178/409 [44%]), followed by febrile seizures plus (111/409 [27%]). One third (50/163 [31%]) of GEFS+ families tested have a pathogenic variant in a known GEFS+ gene. CONCLUSION: As 37/409 (9%) affected individuals have focal epilepsies, we suggest that GEFS+ be renamed genetic epilepsy with febrile seizures plus rather than generalized epilepsy with febrile seizures plus. The phenotypic overlap between GEFS+ and the classic generalized epilepsies is considerably greater than first thought. The clinical and molecular data suggest that the 2 major groups of generalized epilepsies share genetic determinants.