Improving Developmental Abilities in Infants With Tuberous Sclerosis Complex: A Pilot Behavioral Intervention Study.
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ABSTRACT:
SUBMITTER: McDonald NM
PROVIDER: S-EPMC7255424 | biostudies-literature | 2020 Apr-Jun
REPOSITORIES: biostudies-literature
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Improving Developmental Abilities in Infants With Tuberous Sclerosis Complex: A Pilot Behavioral Intervention Study.
McDonald Nicole M NM Hyde Carly C Choi April Boin AB Gulsrud Amanda C AC Kasari Connie C Nelson Charles A CA Jeste Shafali S SS
Infants and young children 20200401 2
Tuberous sclerosis complex (TSC) is a rare genetic syndrome that confers risk for neurodevelopmental disorders, including autism spectrum disorder and intellectual disability. Delays in social communication and early cognitive abilities are observable as early as 9 months of age in children with TSC; however, there have been no studies of early behavioral intervention in TSC. We conducted a pilot study of an evidence-based, parent-mediated behavioral intervention focused on improving early socia ...[more]
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Project description:We performed a longitudinal cohort study of infants with tuberous sclerosis complex (TSC), with the overarching goal of defining early clinical, behavioral, and biological markers of autism spectrum disorder (ASD) in this high-risk population.Infants with TSC and typically developing controls were recruited as early as 3 months of age and followed longitudinally until 36 months of age. Data gathered at each time point included detailed seizure history, developmental testing using the Mullen Scales of Early Learning, and social-communication assessments using the Autism Observation Scale for Infants. At 18 to 36 months, a diagnostic evaluation for ASD was performed using the Autism Diagnostic Observation Schedule.Infants with TSC demonstrated delays confined to nonverbal abilities, particularly in the visual domain, which then generalized to more global delays by age 9 months. Twenty-two of 40 infants with TSC were diagnosed with ASD. Both 12-month cognitive ability and developmental trajectories over the second and third years of life differentiated the groups. By 12 months of age, the ASD group demonstrated significantly greater cognitive delays and a significant decline in nonverbal IQ from 12 to 36 months.This prospective study characterizes early developmental markers of ASD in infants with TSC. The early delay in visual reception and fine motor ability in the TSC group as a whole, coupled with the decline in nonverbal ability in infants diagnosed with ASD, suggests a domain-specific pathway to ASD that can inform more targeted interventions for these high-risk infants.
| S-EPMC4117170 | biostudies-literature
Project description:BACKGROUND:Research in rare genetic syndromes associated with ASD is often hampered by the wide geographic distribution of families and the presence of medical comorbidities, such as epilepsy, that may preclude travel to clinical sites. These challenges can limit the sample size and generalizability of the cohorts included in both natural history studies and clinical trials. Tuberous sclerosis complex (TSC) is a rare genetic syndrome that confers an elevated risk for autism spectrum disorder (ASD), with social communication delays identified in this population as early as 12?months of age. Early identification of risk necessitates parallel testing of early intervention, prompting the first randomized controlled clinical trial of behavioral intervention for infants with TSC (NCT03422367). However, considerable early recruitment challenges have mandated the systematic identification of enrollment barriers followed by modification of the study design to address these barriers. METHODS:Caregivers were interviewed regarding barriers to enrollment (phase 1). Adaptations to the intervention were made to address these barriers (phase 2). Outcomes based on this modification to the study design were defined by enrollment rate and participant demographics. RESULTS:Qualitative reports from caregivers indicated that distance and time were the primary barriers to clinical trial enrollment. The intervention was then modified to a remote model, with at-home, parent-delivered intervention, and weekly video conferencing with interventionists at the study sites. Enrollment increased 10-fold (from 3 to 30 participants) within 1?year and included a more diverse and clinically representative cohort of infants. CONCLUSION:The design and implementation of more scalable methods to disseminate research remotely can substantially improve access to clinical trials in rare neurodevelopmental disorders. The lessons learned from this trial can serve as a model for future studies not only in rare conditions, but in other populations that lack adequate access, such as families with limited financial or clinical resources. Continued efforts will further refine delivery methods to enhance efficiency and ease of these delivery systems for families.
| S-EPMC6977334 | biostudies-literature
Project description:BACKGROUND:Children with tuberous sclerosis complex (TSC), caused by pathogenic variants in TSC1/TSC2, are at risk for intellectual disability. TSC2 pathogenic variants appear to increase the risk, compared with TSC1. However, the effect of TSC2 pathogenic variants on early and specific domains of development hasn't been studied. Using an extensively phenotyped group, we aimed to characterize differences in early intellectual development between genotypes. METHODS:The study group (n = 92) included participants with TSC enrolled in a multicenter study involving genetic testing and detailed prospective phenotyping including the Mullen Scales of Early Learning, a validated measure of cognition, language, and motor development in babies and preschool children. Mean T-scores at 24 months for each Mullen Scales of Early Learning domain were calculated for children with, versus without, a TSC2 pathogenic variant. Multivariable linear regression models were used to compare the groups, adjusting for seizures. RESULTS:T-scores on every Mullen Scales of Early Learning domain were significantly worse in the TSC2 group. Below average composite scores were present in three-fourths of the TSC2 group, compared with one-fourth of those without TSC2. Having a TSC2 pathogenic variant was associated with lower composite Mullen Scales of Early Learning scores, even when corrected for seizures. CONCLUSIONS:In a well-characterized patient population with standardized assessment of multiple aspects of development, we found that having a TSC2 pathogenic variant was associated with significantly lower Mullen Scales of Early Learning scores at age 24 months, independent of seizures. These data suggest that a baby with a TSC2 pathogenic variant is at high risk for significant developmental delays by 24 months.
| S-EPMC6837240 | biostudies-literature
Project description: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.
| S-EPMC5703775 | biostudies-literature
Project description:OBJECTIVE:To identify whether abnormal electroencephalography (EEG) connectivity is present before the onset of epileptic spasms (ES) in infants with tuberous sclerosis complex (TSC). METHODS:Scalp EEG recordings were collected prospectively in infants diagnosed with TSC in the first year of life. This study compared the earliest recorded EEG from infants prior to ES onset (n = 16) and from infants who did not develop ES (n = 28). Five minutes of stage II or quiet sleep was clipped and filtered into canonical EEG frequency bands. Mutual information values between each pair of EEG channels were compared directly and used as a weighted graph to calculate graph measures of global efficiency, characteristic path length, average clustering coefficient, and modularity. RESULTS:At the group level, infants who later developed ES had increased EEG connectivity in sleep. They had higher mutual information values between most EEG channels in all frequency bands adjusted for age. Infants who later developed ES had higher global efficiency and average clustering coefficients, shorter characteristic path lengths, and lower modularity across most frequency bands adjusted for age. This suggests that infants who went on to develop ES had increased local and long-range EEG connectivity with less segregation of graph regions into distinct modules. SIGNIFICANCE:This study suggests that increased neural connectivity precedes clinical ES onset in a cohort of infants with TSC. Overconnectivity may reflect progressive pathologic network synchronization culminating in generalized ES. Further research is needed before scalp EEG connectivity measures can be used as a potential biomarker of ES risk and treatment response in pre-symptomatic infants with TSC.
| S-EPMC6687536 | biostudies-literature
Project description:ObjectiveEpilepsy develops in 70 to 90% of children with tuberous sclerosis complex (TSC) and is often resistant to medication. Recently, the concept of preventive antiepileptic treatment to modify the natural history of epilepsy has been proposed. EPISTOP was a clinical trial designed to compare preventive versus conventional antiepileptic treatment in TSC infants.MethodsIn this multicenter study, 94 infants with TSC without seizure history were followed with monthly video electroencephalography (EEG), and received vigabatrin either as conventional antiepileptic treatment, started after the first electrographic or clinical seizure, or preventively when epileptiform EEG activity before seizures was detected. At 6 sites, subjects were randomly allocated to treatment in a 1:1 ratio in a randomized controlled trial (RCT). At 4 sites, treatment allocation was fixed; this was denoted an open-label trial (OLT). Subjects were followed until 2?years of age. The primary endpoint was the time to first clinical seizure.ResultsIn 54 subjects, epileptiform EEG abnormalities were identified before seizures. Twenty-seven were included in the RCT and 27 in the OLT. The time to the first clinical seizure was significantly longer with preventive than conventional treatment [RCT: 364?days (95% confidence interval [CI] =?223-535) vs 124?days (95% CI = 33-149); OLT: 426?days (95% CI = 258-628) vs 106?days (95% CI = 11-149)]. At 24?months, our pooled analysis showed preventive treatment reduced the risk of clinical seizures (odds ratio [OR] = 0.21, p = 0.032), drug-resistant epilepsy (OR = 0.23, p = 0.022), and infantile spasms (OR = 0, p?<?0.001). No adverse events related to preventive treatment were noted.InterpretationPreventive treatment with vigabatrin was safe and modified the natural history of seizures in TSC, reducing the risk and severity of epilepsy. ANN NEUROL 2021;89:304-314.
| S-EPMC7898885 | biostudies-literature
Project description:Tuberous Sclerosis Complex (TSC) is a multisystem genetic disorder with a high risk of early-onset epilepsy and a high prevalence of neurodevelopmental comorbidities, including intellectual disability and autism spectrum disorder (ASD). Therefore, TSC is an interesting disease model to investigate early biomarkers of neurodevelopmental comorbidities when interventions are favourable. We investigated whether early EEG characteristics can be used to predict neurodevelopment in infants with TSC. The first recorded EEG of 64 infants with TSC, enrolled in the international prospective EPISTOP trial (recorded at a median gestational age 42 4/7 weeks) was first visually assessed. EEG characteristics were correlated with ASD risk based on the ADOS-2 score, and cognitive, language, and motor developmental quotients (Bayley Scales of Infant and Toddler Development III) at the age of 24 months. Quantitative EEG analysis was used to validate the relationship between EEG background abnormalities and ASD risk. An abnormal first EEG (OR = 4.1, p-value = 0.027) and more specifically a dysmature EEG background (OR = 4.6, p-value = 0.017) was associated with a higher probability of ASD traits at the age of 24 months. This association between an early abnormal EEG and ASD risk remained significant in a multivariable model, adjusting for mutation and treatment (adjusted OR = 4.2, p-value = 0.029). A dysmature EEG background was also associated with lower cognitive (p-value = 0.029), language (p-value = 0.001), and motor (p-value = 0.017) developmental quotients at the age of 24 months. Our findings suggest that early EEG characteristics in newborns and infants with TSC can be used to predict neurodevelopmental comorbidities.
| S-EPMC7596378 | biostudies-literature
Project description:Tuberous sclerosis complex (TSC) is a multisystem tumor-forming disorder caused by loss of TSC1 or TSC2. Renal manifestations predominately include cysts and angiomyolipomas. Despite a well-described monogenic etiology, the cellular pathogenesis has remained elusive. Here, we report a novel genetically-engineered human renal organoid model which recapitulates pleiotropic features of TSC kidney disease in vitro and upon orthotopic xenotransplantation. We find that loss of TSC1/2 affects multiple developmental processes in the renal epithelial, stromal, and glial compartments. First, loss of TSC1/2 leads to an expanded stroma by favouring stromal cell fate acquisition and alters terminal stromal cell identity. Second, epithelial cells in the TSC1/2-/- organoids exhibit a rapamycin-insensitive epithelial-to-mesenchymal transition. Third, a melanocytic population forms exclusively in TSC1/2-/- organoids, branching from MITF+ Schwann cell precursors of a bona fide neural crest-to-Schwann cell differentiation trajectory. Together, these results illustrate the pleiotropic developmental consequences of biallelic inactivation of TSC1/2 and offer insight into the pathogenesis of TSC kidney lesions.
2022-07-05 | GSE182632 | GEO
Project description:Although not as common as other genetic renal diseases such as autosomal dominant polycystic kidney disease, patients with tuberous sclerosis complex frequently have significant renal involvement. Recent revelations in the cell biology of these renal disease manifestations as well as effective therapies for tuberous sclerosis complex-related renal issues have heralded hope of improved renal survival and improved quality of life for the TSC patient. This review specifically addresses some of the major renal manifestations of this disease.
| S-EPMC2992644 | biostudies-literature
Project description:ObjectiveIn this cohort analysis, we studied 1-year-old infants with tuberous sclerosis complex (TSC), correlating volumes of cerebellar structures with neurodevelopmental measures.MethodsWe analyzed data from a prospective biomarker study in infants with TSC (ClinicalTrials.gov NCT01780441). We included participants aged 12 months with an identified mutation of TSC1 or TSC2. Using MRI segmentation performed with the PSTAPLE algorithm, we measured relative volumes (structure volume divided by intracranial contents volume) of the following structures: right/left cerebellar white matter, right/left cerebellar exterior, vermal lobules I-V, vermal lobules VI-VII, and vermal lobules VIII-X. We correlated relative volumes to Mullen Scales of Early Learning (MSEL) scores.ResultsThere were 70 participants (mean age 1.03 [0.11] years): n = 11 had a TSC1 mutation; n = 59 had a TSC2 mutation. For patients with TSC2 mutation, for every percentage increase in total cerebellar volume, there was an approximate 10-point increase in MSEL composite score (β = 10.47 [95% confidence interval 5.67, 15.27], p < 0.001). For patients with TSC1 mutation, the relationship between cerebellar volume and MSEL composite score was not statistically significant (β = -10.88 [95% confidence interval -22.16, 0.41], p = 0.06). For patients with TSC2 mutation, there were positive slopes when regressing expressive language and visual reception skills with volumes of nearly all cerebellar structures (p ≤ 0.29); there were also positive slopes when regressing receptive language skills, gross motor skills, and fine motor skills with volumes of cerebellar right/left exterior (p ≤ 0.014).ConclusionsCerebellar volume loss-perhaps reflecting Purkinje cell degeneration-may predict neurodevelopmental severity in patients with TSC2 mutations.
| S-EPMC5921037 | biostudies-literature