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1.
Epilepsy Behav ; 98(Pt A): 201-206, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31382177

RESUMO

OBJECTIVE: We have previously shown that cannabidiol (CBD; Epidiolex®) significantly affects levels of clobazam/N-desmethylclobazam, rufinamide, topiramate, zonisamide, and eslicarbazepine. In the present study, we tested whether the presence of concomitant clobazam affected seizure frequency and severity (treatment response) 12 weeks after initiation of therapy with CBD in patients with treatment-resistant epilepsy (TRE). The secondary questions were whether the presence of any of the other antiepileptic drugs (AEDs) had an effect on seizure frequency or severity at 12, 24, or 48 weeks after therapy initiation. METHODS: One hundred and thirty-two adults and children with TRE receiving CBD were studied prospectively. Participants were separated into two groups - either taking (CBD + clobazam) or not taking concomitant clobazam (CBD - clobazam). In the secondary analyses, participants were divided into groups depending on whether they were taking at least 1/4 of the other AEDs shown to interact with CBD (iAED). Seizure counts and Chalfont Seizure Severity Scale (CSSS) were obtained at baseline, 12, 24, and 48 weeks. Groups were compared at each respective time point in the study using generalized estimating equations (GEE) analyses. RESULTS: All groups demonstrated statistically significant reductions in seizure frequency and severity from baseline (all P < 0.05). When participants on CBD + clobazam were compared with CBD - clobazam, there were no significant differences in seizure frequency and severity reduction between the groups at 12 weeks (both P > 0.05). When comparing groups with iAEDs vs. group without iAEDs, independent of coadministration of clobazam, no differences in treatment response were observed (all P > 0.05). Longitudinal analyses up to 48 weeks after therapy initiation did not reveal any differences in treatment response between groups. CONCLUSION: These analyses suggest that concomitant to CBD, AEDs may not have an effect on reducing seizure frequency and severity in patients with TRE.

2.
Epilepsy Behav ; 97: 105-110, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31220785

RESUMO

Cognitive dysfunction is a common comorbidity in adults with treatment-resistant epilepsy (TRE). Recently, cannabidiol (CBD) has demonstrated efficacy in epilepsy treatment. However, our understanding of CBD's cognitive effects in epilepsy is limited. We examined long-term cognitive effects of CBD in adults with TRE as part of an ongoing prospective, open-label safety study. Twenty-sevenadults with TRE (mean age: 34[SD +14], female 52%) enrolled in the UAB CBD program completed standardized cognitive testing (NIH Toolbox Cognition Battery (NIHTB-CB)) at pre-CBD administration baseline and at one-yearfollow-up. Participants were receiving stable CBD dose at the time of one-year testing (mean=36.5mg/kg/day). The NIHTB-CB consisted of two global composite scales (Fluid and Crystallized) and seven individual tests measuring aspects of working memory, episodic memory, executive function, processing speed, and language. All participants had recorded Chalfont Seizure Severity Scale (CSSS) scores at each visit. Statistical analyses consisted of t-test, Pearson correlation coefficient, and linear regression. At baseline, cognitive test performance was below average for both global composite scales (Fluid: 71 [±18] range: 46-117) and Crystallized (76 [±15] range: 59-112)]. Longitudinal analysis revealed no significant group change across the two global composite scales. Of the seven individual cognitive tests, none changed significantly over time. No correlation was found between the cognitive change scores and CBD dose (all P's≥0.21). Change in cognitive test performance was not associated change in seizure severity rating. These findings are encouraging and indicate that long-term administration of pharmaceutical grade CBD is overall cognitively well-tolerated in adults with TRE.

3.
Epilepsy Behav ; 95: 131-136, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31048098

RESUMO

OBJECTIVE: The objective of this study was to determine the relationship between cannabidiol (CBD) dose, CBD plasma level, and seizure control in a large open-label single-center study. METHODS: All participants with treatment-refractory epilepsy participating in our expanded access program (EAP) were approached for participation. Highly purified grade CBD (Epidiolex®) dosing was weight-based and could be increased every 2 weeks by 5 mg/kg/day up to a maximum dosage of 50 mg/kg/day depending on tolerance and seizure control. Seizure counts were obtained at each visit with frequency calculated per 2-week periods. Cross-sectional plasma peak levels of CBD were obtained ~4 h after dosing in consecutively presenting patients. RESULTS: We evaluated 56 adults and 44 children (100 total; 54 female) at two time points - one before initiating CBD and one at the time of CBD plasma level testing. There was a positive linear correlation between CBD dosage (range from 5 to 50 mg/kg/day) and level (range from 7.1-1200 ng/mL) in all participants (r = 0.640; p < 0.001). The quantile regression model supported the notion of increased CBD levels being associated with improvement in seizure frequency after adjusting for age - specifically, a 100 ng/mL increase in CBD level was associated with approximately two counts reduction in seizure frequency per time period (1.87 96% confidence interval [CI] 0.34-3.39; p = 0.018). In participants with the same CBD level, differences in seizure improvement did not depend on age (p = 0.318). CONCLUSIONS: In this open-label study, we found evidence of a linear correlation between CBD dosage and plasma levels, and that higher dose/levels are associated with a higher response rate for seizure improvement. Children and adults responded to CBD similarly. However, seizure control response rates suggest children may respond to lower dosages/plasma levels than adults. Findings reported in this study are specific to Epidiolex® and should not be extrapolated to other CBD products.

4.
Epilepsy Behav ; 96: 114-121, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31129526

RESUMO

Patients with treatment-resistant epilepsy (TRE) frequently exhibit memory and attention deficits that contribute to their poor personal and societal outcomes. We studied the effects of adjunct treatment with pharmaceutical grade cannabidiol (CBD) oral solution (Epidiolex®; Greenwich Biosciences, Inc.) on attention control processes related to stimulus conflict resolution in patients with TRE. Twenty-two patients with TRE underwent 3 T magnetic resonance imaging (MRI) before receiving (PRE) and after achieving a stable dose of CBD (ON). Functional MRI (fMRI) data were collected while patients performed 2 runs of a flanker task (FT). Patients were instructed to indicate via button press the congruent (CON) and incongruent (INC) conditions. We performed t-tests to examine with FT attention control processes at PRE and ON visits and to compare the 2 visits using derived general linear model (GLM) data (INC - CON). We performed generalized psychophysiological interaction (gPPI) analyses to assess changes in condition-based functional connectivity on FT. Median time between fMRI visits was 10 weeks, and median CBD dose at follow-up was 25 mg/kg/d. From PRE to ON, participants experienced improvements in seizure frequency (SF) (p = 0.0009), seizure severity (Chalfont Seizure Severity Scale (CSSS); p < 0.0001), and mood (Total Mood Disturbance (TMD) score from Profile of Mood States (POMS); p = 0.0026). Repeated measures analysis of variance showed nonsignificant improvements in executive function from 34.6 (23.5)% to 41.9 (22.4)% CON accuracy and from 34.2 (25.7)% to 37.6 (24.4)% INC accuracy (p = 0.199). Change in CON accuracy was associated with change in INC accuracy (rS = 0.81, p = 0.0005). Participants exhibited CBD-induced increases in fMRI activation in the right superior frontal gyrus (SFG) and right insula/middle frontal gyrus (MFG) and decrease in activation for both regions at ON relative to PRE (corrected p = 0.05). The subset of patients who improved in FT accuracy with CBD showed a negative association between change in right insula/MFG activation and change in accuracy for the INC condition (rS = -0.893, p = 0.0068). The gPPI analysis revealed a CBD-induced decrease in condition-based functional connectivity differences for the right SFG seed region (corrected p = 0.05). Whole-brain regression analysis documented a negative association of change in right insula/MFG condition-based connectivity with change in INC accuracy (corrected p = 0.005). Our results suggest that CBD modulates attention control processing in patients with TRE by reducing right SFG and right insula/MFG activation related to stimulus conflict resolution and by dampening differences in condition-based functional connectivity of the right SFG. Our study is the first to provide insight into how CBD affects the neural substrates involved in attention processing and how modulation of the activity and functional connectivity related to attentional control processes in the right insula/MFG may be working to improve cognitive performance in TRE.

5.
Epilepsy Behav ; 95: 10-17, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31003195

RESUMO

Treatment-resistant epilepsy (TRE) is associated with low quality of life (QOL). Cannabidiol (CBD) may improve QOL, but it is unclear if such improvements are independent of improvements in seizure control. Our aim was to compare QOL at baseline and after 1 year of treatment with CBD. We hypothesized that QOL would improve independent of changes in seizure frequency (SF) or severity, mood, or adverse events. We assessed QOL using Quality of Life in Epilepsy-89 (QOLIE-89) in an open-label study of purified CBD (Epidiolex®) for the treatment of TRE. All participants received CBD, starting at 5 mg/kg/day and titrated to 50 mg/kg/day in increments of 5 mg/kg/day. We collected QOLIE-89 in adult participants at enrollment and after 1 year of treatment, or at study exit if earlier. We analyzed if the change in QOLIE-89 total score could be explained by the change in SF, seizure severity (Chalfont Seizure Severity Scale, CSSS), mood (Profile of Moods States, POMS), or adverse events (Adverse Event Profile, AEP). Associations among the variables were assessed using bivariate tests and multiple regression. Fifty-three participants completed enrollment and follow-up testing, seven at study termination. Mean QOLIE-89 total score improved from enrollment (49.4 ±â€¯19) to follow-up (57 ±â€¯21.3; p = .004). We also saw improvements in SF, POMS, AEP, and CSSS (all p ≤ .01). Multivariable regression results showed QOLIE-89 at follow-up associated with improvements in POMS at follow-up (p = .020), but not with AEP, CSSS, or SF (p ≥ .135). Improvement in QOL after treatment with CBD is associated with better mood but not with changes in SF, seizure severity, or AEP. Cannabidiol may have beneficial effects on QOL and mood that are independent of treatment response.

6.
Epilepsy Res ; 154: 13-20, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31022635

RESUMO

BACKGROUND: Since 2014, patients with severe treatment-resistant epilepsies (TREs) have been receiving add-on cannabidiol (CBD) in an ongoing, expanded access program (EAP), which closely reflects clinical practice. We conducted an interim analysis of long-term efficacy and tolerability in patients with Lennox-Gastaut syndrome (LGS) or Dravet syndrome (DS) who received CBD treatment through December 2016. METHODS: Children and adults with LGS/DS taking stable doses of antiepileptic drugs (AEDs) at baseline were included from 25 EAP sites across the United States. During the 4-week baseline period, parents/caregivers kept diaries of all countable seizure types. Patients received a pharmaceutical formulation of highly purified CBD (Epidiolex®; 100 mg/mL) in oral solution at 2-10 mg/kg/day, titrated until tolerability limit or a maximum dose of 25-50 mg/kg/day. Patient visits were every 2-4 weeks. The percentage change from baseline in median monthly convulsive (ie, major motor) and total seizures was evaluated at 12-week intervals through 96 weeks. The percentages of patients who had ≥50%, ≥75%, and 100% reduction in monthly seizures relative to the baseline period were also evaluated. Adverse events (AEs) were monitored and summarized for the safety analysis set (SAS) through 144 weeks. RESULTS: Of the 607 patients in the SAS, 58 had DS and 94 had LGS (N = 152); 455 patients had other TREs. Twenty-eight percent of LGS/DS patients withdrew, primarily owing to lack of efficacy (20%). LGS/DS patients were taking a median of 3 (0-10) concomitant AEDs. Median treatment duration was 78.3 (range, 4.1-146.4) weeks. Between weeks 12 and 96, median CBD dose ranged from 21 to 25 mg/kg/day. At 12 weeks, add-on CBD reduced median monthly major motor seizures by 50% and total seizures by 44%, with consistent reductions in both seizure types through 96 weeks. At 12 weeks, the proportions of patients with ≥50%, ≥75%, and 100% reductions in major motor seizures were 53%, 23%, and 6%; the proportions with corresponding reductions in total seizures were 46%, 26%, and 5%. Responder rates for both seizure types were consistent through 96 weeks. CBD had an acceptable safety profile; the most common AEs were somnolence (30%) and diarrhea (24%). CONCLUSIONS: Results from this interim analysis support add-on CBD as an effective long-term treatment option in LGS or DS.

7.
Am Psychol ; 74(3): 356-367, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30945897

RESUMO

The Tuberous Sclerosis Complex Autism Center of Excellence Network (TACERN) is a 6-site collaborative conducting longitudinal research on infants with tuberous sclerosis complex (TSC), focused on identifying early biomarkers for autism spectrum disorder (ASD). A multidisciplinary research team that includes the specialties of psychology, neurology, pediatrics, medical genetics, and speech-language pathology, its members work together to conduct studies on neurological status, brain structure and function, neurodevelopmental phenotype, and behavioral challenges in this population. This article provides insights into the roles of the multidisciplinary multisite team and lessons learned from the collaboration, in terms of research as well as training of future researchers and clinicians. In addition, the authors detail the major findings to date, including those related to the identification and measurement of early symptoms of ASD, relationship between seizures and early development, and early biomarkers for epilepsy and developmental delay in infants and young children with TSC. (PsycINFO Database Record (c) 2019 APA, all rights reserved).

8.
Am J Hum Genet ; 104(4): 701-708, 2019 Apr 04.
Artigo em Inglês | MEDLINE | ID: mdl-30879638

RESUMO

Developmental delay and intellectual disability (DD and ID) are heterogeneous phenotypes that arise in many rare monogenic disorders. Because of this rarity, developing cohorts with enough individuals to robustly identify disease-associated genes is challenging. Social-media platforms that facilitate data sharing among sequencing labs can help to address this challenge. Through one such tool, GeneMatcher, we identified nine DD- and/or ID-affected probands with a rare, heterozygous variant in the gene encoding the serine/threonine-protein kinase BRSK2. All probands have a speech delay, and most present with intellectual disability, motor delay, behavioral issues, and autism. Six of the nine variants are predicted to result in loss of function, and computational modeling predicts that the remaining three missense variants are damaging to BRSK2 structure and function. All nine variants are absent from large variant databases, and BRSK2 is, in general, relatively intolerant to protein-altering variation among humans. In all six probands for whom parents were available, the mutations were found to have arisen de novo. Five of these de novo variants were from cohorts with at least 400 sequenced probands; collectively, the cohorts span 3,429 probands, and the observed rate of de novo variation in these cohorts is significantly higher than the estimated background-mutation rate (p = 2.46 × 10-6). We also find that exome sequencing provides lower coverage and appears less sensitive to rare variation in BRSK2 than does genome sequencing; this fact most likely reduces BRSK2's visibility in many clinical and research sequencing efforts. Altogether, our results implicate damaging variation in BRSK2 as a source of neurodevelopmental disease.

9.
Am J Hum Genet ; 103(6): 1022-1029, 2018 12 06.
Artigo em Inglês | MEDLINE | ID: mdl-30526861

RESUMO

Developmental and epileptic encephalopathies (DEEs) are a group of severe epilepsies characterized by refractory seizures and developmental impairment. Sequencing approaches have identified causal genetic variants in only about 50% of individuals with DEEs.1-3 This suggests that unknown genetic etiologies exist, potentially in the ∼98% of human genomes not covered by exome sequencing (ES). Here we describe seven likely pathogenic variants in regions outside of the annotated coding exons of the most frequently implicated epilepsy gene, SCN1A, encoding the alpha-1 sodium channel subunit. We provide evidence that five of these variants promote inclusion of a "poison" exon that leads to reduced amounts of full-length SCN1A protein. This mechanism is likely to be broadly relevant to human disease; transcriptome studies have revealed hundreds of poison exons,4,5 including some present within genes encoding other sodium channels and in genes involved in neurodevelopment more broadly.6 Future research on the mechanisms that govern neuronal-specific splicing behavior might allow researchers to co-opt this system for RNA therapeutics.


Assuntos
Epilepsias Mioclônicas/genética , Epilepsia/genética , Éxons/genética , Variação Genética/genética , Canal de Sódio Disparado por Voltagem NAV1.1/genética , Adulto , Criança , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Transtornos do Neurodesenvolvimento/genética , Canais de Sódio/genética , Transcriptoma/genética
10.
Epilepsy Res ; 148: 1-7, 2018 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-30296632

RESUMO

After initially successful treatment of infantile spasms, the long-term cumulative risk of relapse approaches 50%, and there is no established protocol to mitigate this risk. Although vigabatrin may be an effective means to prevent relapse, there is little guidance as to ideal duration and dosage. Using a cohort of children with infantile spasms and tuberous sclerosis complex (TSC), we evaluated the potential association of post-response VGB treatment and the rate of infantile spasms relapse. Patients with infantile spasms and clinical response to vigabatrin were identified among a multicenter prospective observational cohort of children with TSC. For each patient we recorded dates of infantile spasms onset, response to vigabatrin, relapse (if any), and quantified duration and dosage of vigabatrin after response. Time to relapse as a function of vigabatrin exposure was evaluated using survival analyses. We identified 50 children who responded to VGB. During a median follow-up of 16.6 months (IQR 10.3-22.9), 12 (24%) patients subsequently relapsed after a median of 7.8 months (IQR 3.1-9.6). Relapse occurred after VGB discontinuation in four patients, and during continued VGB treatment in the remaining eight cases. In survival analyses, risk of relapse was unaffected by the presence or absence of VGB treatment (HR 0.31, 95%CI 0.01-28.4, P = 0.61), but weighted-average dosage was associated with marked reduction in relapse risk: Each 50 mg/kg/d increment in dosage was associated with 61% reduction in risk (HR 0.39, 95%CI 0.17 - 0.90, P = 0.026). This study suggests that the risk of infantile spasms relapse in TSC may be reduced by high-dose vigabatrin treatment.

11.
Ann Neurol ; 84(5): 788-795, 2018 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-30269351

RESUMO

NBEA is a candidate gene for autism, and de novo variants have been reported in neurodevelopmental disease (NDD) cohorts. However, NBEA has not been rigorously evaluated as a disease gene, and associated phenotypes have not been delineated. We identified 24 de novo NBEA variants in patients with NDD, establishing NBEA as an NDD gene. Most patients had epilepsy with onset in the first few years of life, often characterized by generalized seizure types, including myoclonic and atonic seizures. Our data show a broader phenotypic spectrum than previously described, including a myoclonic-astatic epilepsy-like phenotype in a subset of patients. Ann Neurol 2018;84:796-803.

12.
PLoS One ; 13(9): e0201005, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30192751

RESUMO

INTRODUCTION: The EXIST-2 (NCT00790400) study demonstrated the superiority of everolimus over placebo for the treatment of renal angiomyolipomas associated with tuberous sclerosis complex (TSC) or sporadic lymphangioleiomyomatosis (LAM). This post hoc analysis of EXIST-2 study aimed to assess angiomyolipoma tumor behavior among patients who submitted to continued radiographic examination following discontinuation of everolimus in the noninterventional follow-up phase. METHODS: For patients who discontinued everolimus at the completion of extension phase for reasons other than angiomyolipoma progression, a single CT/MRI scan of the kidney was collected after 1 year of treatment discontinuation. Changes from baseline and from the time of everolimus discontinuation in the sum of volumes of target angiomyolipoma lesions were assessed in the non-interventional follow-up phase (data cutoff date, November 6, 2015). RESULTS: Of the 112 patients who received ≥1 dose of everolimus and discontinued treatment by the end of extension phase, 34 (30.4%) were eligible for participation in the non-interventional follow-up phase. Sixteen of 34 patients were evaluable for angiomyolipoma tumor behavior as they had at least one valid efficacy assessment (i.e. kidney CT/MRI scan) after everolimus discontinuation. During the non-interventional follow-up phase, compared with baseline, two patients (12.5%) experienced angiomyolipoma progression (angiomyolipoma-related bleeding [n = 1], increased kidney volume [n = 1]). Five patients out of 16 (31.3%) experienced angiomyolipoma progression when compared with the angiomyolipoma tumor assessment at everolimus discontinuation. The median (range) percentage change in angiomyolipoma tumor volume (cm3) from baseline was -70.56 (-88.30; -49.64) at time of everolimus discontinuation (n = 11), and -50.55 (-79.40; -23.16) at week 48 (n = 7) after discontinuation of everolimus. One patient death was reported due to angiomyolipoma hemorrhage. CONCLUSIONS: Angiomyolipoma lesions displayed an increase in volume following discontinuation of everolimus in patients with renal angiomyolipoma or sporadic LAM associated with TSC, but there was no evidence of rapid regrowth. TRIAL REGISTRATION: ClinicalTrials.gov NCT00790400.

13.
Epilepsy Behav ; 86: 131-137, 2018 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-30006259

RESUMO

OBJECTIVE: We studied our collective open-label, compassionate use experience in using cannabidiol (CBD) to treat epilepsy in patients with CDKL5 deficiency disorder and Aicardi, Doose, and Dup15q syndromes. METHODS: We included patients aged 1-30 years with severe childhood-onset epilepsy who received CBD for ≥10 weeks as part of multiple investigator-initiated expanded access or state access programs for a compassionate prospective interventional study: CDKL5 deficiency disorder (n = 20), Aicardi syndrome (n = 19), Dup15q syndrome (n = 8), and Doose syndrome (n = 8). These patients were treated at 11 institutions from January 2014 to December 2016. RESULTS: The percent change in median convulsive seizure frequency for all patients taking CBD in the efficacy group decreased from baseline [n = 46] to week 12 (51.4% [n = 35], interquartile range (IQR): 9-85%) and week 48 (59.1% [n = 27], IQR: 14-86%). There was a significant difference between the percent changes in monthly convulsive seizure frequency during baseline and week 12, χ2(2) = 22.9, p = 0.00001, with no difference in seizure percent change between weeks 12 and 48. Of the 55 patients in the safety group, 15 (27%) withdrew from extended observation by week 144: 4 due to adverse effects, 9 due to lack of efficacy, 1 withdrew consent, and 1 was lost to follow-up. SIGNIFICANCE: This open-label drug trial provides class III evidence for the long-term safety and efficacy of CBD administration in patients with treatment-resistant epilepsy (TRE) associated with CDKL5 deficiency disorder and Aicardi, Dup15q, and Doose syndromes. Adjuvant therapy with CBD showed similar safety and efficacy for these four syndromes as reported in a diverse population of TRE etiologies. This study extended analysis of the prior report from 12 weeks to 48 weeks of efficacy data and suggested that placebo-controlled randomized trials should be conducted to formally assess the safety and efficacy of CBD in these epileptic encephalopathies.

14.
Epilepsy Behav ; 85: 1-6, 2018 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-29886019

RESUMO

Intractable epilepsy can be challenging for patients and for their families. Disability rates in patients are high, causing tremendous physical and emotional burden on family caregivers. Additionally, caregivers may experience affiliate stigma, where they perceive and internalize the negative societal views of a condition and exhibit a psychological response. Affiliate stigma has been rarely studied in caregivers of those with intractable epilepsy. This study examined the relationship between affiliate stigma and the levels of burden experienced by caregivers, as well as how these levels may vary between those caring for children and adults. This cross-sectional approach used a self-administered survey offered to caregivers of family members with confirmed diagnoses of intractable epilepsy. We measured burden with the 30-item Carer's Assessment of Difficulties Index (CADI) and affiliate stigma with a six-item scale examining caregivers' perceptions of stigma directed toward themselves and their family members with epilepsy. Four nested ordinary-least-squares regression models were estimated using stigma scale scores to predict levels of perceived burden adjusting for demographic variables. Age of the patient with epilepsy was dichotomized (pediatric/adult) to assess a possible moderating effect of patient's age on the relationship between stigma and caregiver burden. Respondents (N = 136) were predominantly White (83%), female (75%), and married (69%), with an average age of 43 years. Patients with epilepsy were 52% male with ages ranging from 2 to 82 years. Each of the regression models yielded positive associations (p < 0.001) between perceived levels of caregiver burden and affiliate stigma. Additionally, the age of the family member with epilepsy moderated (p < 0.05) the effect, with the relationship stronger for caregivers of adults. In a highly select group of patients with refractory epilepsy recruited mostly from a cannabidiol (CBD) clinic, this study demonstrated that caregivers experience affiliate stigma, which is significantly associated with higher burden levels. Additionally, this study identified specific needs, which when met, may improve caregivers' physical and mental health.

15.
Genet Med ; 2018 Apr 12.
Artigo em Inglês | MEDLINE | ID: mdl-29790872

RESUMO

PurposeClinically relevant secondary variants were identified in parents enrolled with a child with developmental delay and intellectual disability.MethodsExome/genome sequencing and analysis of 789 "unaffected" parents was performed.ResultsPathogenic/likely pathogenic variants were identified in 21 genes within 25 individuals (3.2%), with 11 (1.4%) participants harboring variation in a gene defined as clinically actionable by the American College of Medical Genetics and Genomics. These 25 individuals self-reported either relevant clinical diagnoses (5); relevant family history or symptoms (13); or no relevant family history, symptoms, or clinical diagnoses (7). A limited carrier screen was performed yielding 15 variants in 48 (6.1%) parents. Parents were also analyzed as mate pairs (n = 365) to identify cases in which both parents were carriers for the same recessive disease, yielding three such cases (0.8%), two of which had children with the relevant recessive disease. Four participants had two findings (one carrier and one noncarrier variant). In total, 71 of the 789 enrolled parents (9.0%) received secondary findings.ConclusionWe provide an overview of the rates and types of clinically relevant secondary findings, which may be useful in the design and implementation of research and clinical sequencing efforts to identify such findings.Genetics in Medicine advance online publication, 12 April 2018; doi:10.1038/gim.2018.53.

16.
Hum Genet ; 2018 May 08.
Artigo em Inglês | MEDLINE | ID: mdl-29740699

RESUMO

Many genetic causes of developmental delay and/or intellectual disability (DD/ID) are extremely rare, and robust discovery of these requires both large-scale DNA sequencing and data sharing. Here we describe a GeneMatcher collaboration which led to a cohort of 13 affected individuals harboring protein-altering variants, 11 of which are de novo, in MED13; the only inherited variant was transmitted to an affected child from an affected mother. All patients had intellectual disability and/or developmental delays, including speech delays or disorders. Other features that were reported in two or more patients include autism spectrum disorder, attention deficit hyperactivity disorder, optic nerve abnormalities, Duane anomaly, hypotonia, mild congenital heart abnormalities, and dysmorphisms. Six affected individuals had mutations that are predicted to truncate the MED13 protein, six had missense mutations, and one had an in-frame-deletion of one amino acid. Out of the seven non-truncating mutations, six clustered in two specific locations of the MED13 protein: an N-terminal and C-terminal region. The four N-terminal clustering mutations affect two adjacent amino acids that are known to be involved in MED13 ubiquitination and degradation, p.Thr326 and p.Pro327. MED13 is a component of the CDK8-kinase module that can reversibly bind Mediator, a multi-protein complex that is required for Polymerase II transcription initiation. Mutations in several other genes encoding subunits of Mediator have been previously shown to associate with DD/ID, including MED13L, a paralog of MED13. Thus, our findings add MED13 to the group of CDK8-kinase module-associated disease genes.

17.
Clin Neurophysiol ; 129(7): 1458-1466, 2018 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-29673547

RESUMO

OBJECTIVES: We aim to establish that interictal fast ripples (FR; 250-500 Hz) are detectable on scalp EEG, and to investigate their association to epilepsy. METHODS: Scalp EEG recordings of a subset of children with tuberous sclerosis complex (TSC)-associated epilepsy from two large multicenter observational TSC studies were analyzed and compared to control children without epilepsy or any other brain-based diagnoses. FR were identified both by human visual review and compared with semi-automated review utilizing a deep learning-based FR detector. RESULTS: Seven out of 7 children with TSC-associated epilepsy had scalp FR compared to 0 out of 4 children in the control group (p = 0.003). The automatic detector has a sensitivity of 98% and false positive rate with average of 11.2 false positives per minute. CONCLUSIONS: Non-invasive detection of interictal scalp FR was feasible, by both visual and semi-automatic detection. Interictal scalp FR occurred exclusively in children with TSC-associated epilepsy and were absent in controls without epilepsy. The proposed detector achieves high sensitivity of FR detection; however, expert review of the results to reduce false positives is advised. SIGNIFICANCE: Interictal FR are detectable on scalp EEG and may potentially serve as a biomarker of epilepsy in children with TSC.

18.
Am J Med Genet A ; 176(4): 925-935, 2018 04.
Artigo em Inglês | MEDLINE | ID: mdl-29436146

RESUMO

SATB2-associated syndrome (SAS) is an autosomal dominant disorder characterized by significant neurodevelopmental disabilities with limited to absent speech, behavioral issues, and craniofacial anomalies. Previous studies have largely been restricted to case reports and small series without in-depth phenotypic characterization or genotype-phenotype correlations. Seventy two study participants were identified as part of the SAS clinical registry. Individuals with a molecularly confirmed diagnosis of SAS were referred after clinical diagnostic testing. In this series we present the most comprehensive phenotypic and genotypic characterization of SAS to date, including prevalence of each clinical feature, neurodevelopmental milestones, and when available, patient management. We confirm that the most distinctive features are neurodevelopmental delay with invariably severely limited speech, abnormalities of the palate (cleft or high-arched), dental anomalies (crowding, macrodontia, abnormal shape), and behavioral issues with or without bone or brain anomalies. This comprehensive clinical characterization will help clinicians with the diagnosis, counseling and management of SAS and help provide families with anticipatory guidance.

19.
Pediatr Nephrol ; 33(1): 101-109, 2018 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-28993887

RESUMO

BACKGROUND: Patients with tuberous sclerosis complex (TSC) often have multiple TSC-associated hamartomas, particularly in the brain and kidney. METHODS: This was a post hoc analysis of pediatric patients being treated for subependymal giant cell astrocytomas (SEGAs) during the phase 3, randomized, double-blind, placebo-controlled EXIST-1 trial. Patients were initially randomly assigned to receive everolimus 4.5 mg/m2/day (target blood trough 5-15 mg/dl) or placebo and could continue in an open-label extension phase. Angiomyolipoma response rates were analyzed in patients aged <18 years with ≥1 target angiomyolipoma lesion at baseline. Response was defined as the proportion of patients with a ≥50% reduction in the sum volume of target renal angiomyolipomata from baseline, in the absence of new target angiomyolipomata, a >20% increase in kidney volume from nadir, and angiomyolipoma-related bleeding ≥ grade 2. Tolerability was also assessed. RESULTS: Overall, this analysis included 33 patients. Renal angiomyolipoma response was achieved by 75.8% of patients (95% confidence interval, 57.7-88.9%), with sustained mean reductions in renal angiomyolipoma volume over nearly 4 years of treatment. In addition, most (≥80%) achieved clinically relevant reductions in angiomyolipoma volume (≥50%), beginning at week 24 and continuing for the remainder of the study. Everolimus was generally well tolerated in this subgroup, with most adverse events being grade 1 or 2 in severity. CONCLUSIONS: Although everolimus is currently not indicated for this use, this analysis from EXIST-1 demonstrates its long-term efficacy and safety for the treatment of renal angiomyolipoma in pediatric patients undergoing treatment for TSC-associated SEGA.


Assuntos
Angiomiolipoma/tratamento farmacológico , Antineoplásicos/uso terapêutico , Everolimo/uso terapêutico , Neoplasias Renais/tratamento farmacológico , Esclerose Tuberosa/complicações , Adolescente , Angiomiolipoma/complicações , Antineoplásicos/efeitos adversos , Astrocitoma/complicações , Astrocitoma/tratamento farmacológico , Criança , Pré-Escolar , Método Duplo-Cego , Everolimo/efeitos adversos , Feminino , Humanos , Rim/patologia , Neoplasias Renais/patologia , Masculino , Resultado do Tratamento , Esclerose Tuberosa/tratamento farmacológico
20.
Pediatrics ; 140(6)2017 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-29101226

RESUMO

OBJECTIVES: Tuberous sclerosis complex (TSC) is a neurocutaneous genetic disorder with a high prevalence of epilepsy and neurodevelopmental disorders. TSC can be challenging to diagnose in infants because they often do not show many clinical signs early in life. In this study, we describe the timing and pattern of presenting and diagnostic features in a prospective longitudinal study of infants with TSC. METHODS: Two multicenter, prospective studies enrolled 130 infants with definite TSC by clinical or genetic criteria and followed them longitudinally up to 36 months of age. Periodic study visits included medical and seizure histories, physical and neurologic examinations, and developmental assessments. Ages at which major and minor features of TSC and seizures were first identified were analyzed. RESULTS: The most common initial presenting features of TSC were cardiac rhabdomyomas (59%) and hypomelanotic macules or other skin findings (39%), and 85% of infants presented with either or both. Ultimately, the most prevalent diagnostic TSC features were hypomelanotic macules (94%), tubers or other cortical dysplasias (94%), subependymal nodules (90%), and cardiac rhabdomyomas (82%). Thirty-five percent of infants presented prenatally, 41% presented at birth or within the first month of life, and 74% met criteria for TSC diagnosis at or within 30 days of presentation. Seizure onset occurred before or at initial presentation in only 15% of infants, but 73% developed epilepsy within the first year of life. CONCLUSIONS: Infants with TSC can often be identified early, before the onset of neurologic sequelae, enabling earlier diagnosis, surveillance, and possibly disease-modifying treatment.


Assuntos
Esclerose Tuberosa/diagnóstico , Feminino , Humanos , Lactente , Estudos Longitudinais , Masculino , Prevalência , Estudos Prospectivos
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