Targeted treatment trials for tuberous sclerosis and autism: no longer a dream.
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ABSTRACT:
SUBMITTER: Sahin M
PROVIDER: S-EPMC3715752 | biostudies-literature | 2012 Oct
REPOSITORIES: biostudies-literature
Publications
Targeted treatment trials for tuberous sclerosis and autism: no longer a dream.
Current opinion in neurobiology 20120504 5
Genetic disorders that present with a high incidence of autism spectrum disorders (ASD) offer tremendous potential both for elucidating the underlying neurobiology of ASD and identifying therapeutic drugs and/or drug targets. As a result, clinical trials for genetic disorders associated with ASD are no longer a hope for the future but rather an exciting reality whose time has come. Tuberous sclerosis complex (TSC) is one such genetic disorder that presents with ASD, epilepsy, and intellectual di ...[more]
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Project description:Tuberous sclerosis complex (TSC) is a genetic disorder with a high prevalence of autism spectrum disorder (ASD). Tremendous progress in understanding the pathogenesis of TSC has been made in recent years, along with initial trials of medical treatment aimed specifically at the underlying mechanism of the disorder. At the cellular level, loss of TSC1 or TSC2 results in upregulation of the mechanistic target of rapamycin (mTOR) pathway. At the circuitry level, TSC and mTOR play crucial roles in axonal, dendritic, and synaptic development and function. In this review, we discuss the molecular mechanism underlying TSC, and how this disease results in aberrant neural connectivity at multiple levels in the central nervous system, leading to ASD symptoms. We then review recent advances in mechanism-based treatments of TSC, and the promise that these treatments provide for future mechanism-based treatment of ASD. Because of these recent advances, TSC represents an ideal model for how to make progress in understanding and treating the mechanisms that underlie ASD in general.
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Project description:Approximately 50% of patients with the genetic disease tuberous sclerosis complex present with autism spectrum disorder. Although a number of studies have investigated the link between autism and tuberous sclerosis complex, the etiology of autism spectrum disorder in these patients remains unclear. Abnormal cerebellar function during critical phases of development could disrupt functional processes in the brain, leading to development of autistic features. Accordingly, the authors review the potential role of cerebellar dysfunction in the pathogenesis of autism spectrum disorder in tuberous sclerosis complex. The authors also introduce conditional knockout mouse models of Tsc1 and Tsc2 that link cerebellar circuitry to the development of autistic-like features. Taken together, these preclinical and clinical investigations indicate the cerebellum has a profound regulatory role during development of social communication and repetitive behaviors.
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Project description:ObjectiveTo determine the extent to which deficits associated with autism spectrum disorder (ASD) in toddlers with tuberous sclerosis complex (TSC) overlap with those in toddlers with nonsyndromic ASD (nsASD) and to examine cognitive function and epilepsy severity in toddlers with TSC and comorbid ASD. This is the endpoint analysis from a longitudinal investigation of ASD risk factors in children with TSC.MethodsMeasures included the Autism Diagnostic Observation Schedule (ADOS), the Mullen Scales of Early Learning, and clinical epilepsy variables. A repeated-measures analysis of variance was performed with between-subjects factor of group (typically developing, TSC/no ASD, TSC/ASD, nsASD) and within-subjects factors of individual ADOS item scores in the social communication and repetitive behavior/restricted interest domains. Within the TSC group, comparisons of epilepsy characteristics and cognitive domains were performed using independent-samples t tests.ResultsChildren with TSC/ASD demonstrated a profile of social communication impairment that had complete convergence with nsASD. Measured social communication impairments included gestures, pointing, eye contact, responsive social smile, and shared enjoyment. This convergence was observed despite the high comorbidity between ASD and cognitive impairment in TSC.ConclusionsThis study supports the clinical diagnosis of ASD in young children with TSC and demonstrates remarkable convergence of autism symptoms between TSC/ASD and nsASD. Our results strongly suggest the need for early intervention in toddlers with TSC, with treatment strategies targeting social communication function as well as broader developmental domains, before the onset of autism symptoms.
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Project description:Tuberous sclerosis complex (TSC) is a genetic multisystem disorder that affects the brain in almost every patient. It is caused by a mutation in the TSC1 or TSC2 genes, which regulate mammalian target of rapamycin (mTOR), a key player in control of cellular growth and protein synthesis. The most frequent neurological symptoms are seizures, which occur in up to 90% of patients and often are intractable, followed by autism spectrum disorders, intellectual disability, attention deficit-hyperactivity disorder, and sleep problems. Conventional treatment has frequently proven insufficient for neurological and behavioral symptoms, particularly seizure control. This review focuses on the role of TSC/mTOR in neuronal development and network formation and recent mechanism-based treatment approaches.We performed a literature review to identify ongoing therapeutic challenges and novel strategies.To achieve a better quality of life for many patients, current therapy approaches are directed at restoring dysregulated mTOR signaling. Studies in animals have provided insight into aberrant neuronal network formation caused by constitutive activation of the mTOR pathway, and initial studies in TSC patients using magnetic resonance diffusion tensor imaging and electroencephalogram support a model of impaired neuronal connectivity in TSC. Rapamycin, an mTOR inhibitor, has been used successfully in Tsc-deficient mice to prevent and treat seizures and behavioral abnormalities. There is recent evidence in humans of improved seizure control with mTOR inhibitors.Current research provides insight into aberrant neuronal connectivity in TSC and the role of mTOR inhibitors as a promising therapeutic approach.
| S-EPMC3959246 | biostudies-literature
Project description:Tuberous sclerosis (TSC) is an autosomally dominant neurocutaneous disease notable for its high comorbidity with autism in human patients. Studies of murine models of tuberous sclerosis have found defects in cognition and learning, but thus far have not uncovered deficits in social behaviors relevant to autism. To explore social communication and interaction in TSC2 heterozygous mice, we recorded ultrasonic vocalizations (USV) and found that although both wild-type (WT) and heterozygous pups born to WT dams showed similar call rates and patterns, baseline vocalization rates were elevated in pups born to heterozygous dams. Further analysis revealed several robust features of maternal potentiation in all but WT pups born to heterozygous dams. This lack of potentiation is suggestive of defects in mother-pup social interaction during or before the reunion period between WT pups and heterozygous dams. Intriguingly, male pups of both genotypes born to heterozygous dams showed particularly heightened call rates and burst patterns. Because our maternal retrieval experiments revealed that TSC2(+/-) dams exhibited improved defensive reactions against intruders and highly efficient pup retrieval performance, the alterations in their pups' USVs and maternal potentiation do not appear to result from poor maternal care. These findings suggest that a pup's interaction with its mother strongly influences the pup's vocal communication, revealing an intriguing dependence of this social behavior on TSC2 gene dosage of both parties involved. Our study of this murine model thus uncovers social abnormalities that arise from TSC haploinsufficiency and are suggestive of autism.
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Project description:ContextWe have previously shown that serum VEGF-D is elevated at baseline, correlates with kidney angiomyolipoma size at baseline and 12 months, and decreases with sirolimus treatment in adults with tuberous sclerosis complex (TSC). To further investigate the utility of serum VEGF-D for longer term monitoring of TSC kidney disease, we present VEGF-D level results with 24 month follow-up.ObjectiveTo compare 24 month VEGF-D levels in two subgroups of sirolimus treated patients (OFF SIROLIMUS AFTER 12 MONTHS or ON SIROLIMUS AFTER 12 MONTHS). DESIGN AND INTERVENTION(S): Serum VEGF-D was measured in samples collected from subjects enrolled in a phase 2 multicenter trial evaluating sirolimus for the treatment of kidney angiomyolipomas associated with TSC or TSC/LAM. All participants were treated with sirolimus from 0-12 months. During months 12-24, sirolimus was discontinued in one subgroup. The other subgroup was treated with additional sirolimus.SettingAdult TSC participants were recruited from six clinical sites in the United States (comprehensive TSC clinics, 5; urology clinic, 1).PatientsThere were 28 TSC patients who completed all 24 months of the study and serum samples were available at 24 months from 18/28 patients.Main outcome measure(s)We compared the percent change in VEGF-D levels (baseline to 24 months) in patients from the two treatment subgroups.ResultsAt 24 months, VEGF-D levels decreased by 67% compared with baseline (to 787 ± 426 pg/ml) in the ON SIROLIMUS AFTER 12 MONTHS group versus a 13% decrease (to 2971 ± 4014 pg/ml) in the OFF SIROLIMUS AFTER 12 MONTHS group (p=0.013, Mann-Whitney test). A similar trend was observed in kidney angiomyolipoma size but not in pulmonary function tests. Conclusions Serum VEGF-D may be useful for monitoring response to treatment with sirolimus and kidney angiomyolipoma size in patients with TSC, but confirmation is needed.Trial registrationClinical trials.gov NCT00126672.
| S-EPMC3577773 | biostudies-literature
Project description:ObjectiveThe purpose of this study was to assess the prevalence of and to identify epidemiologic, genetic, electrophysiologic, and neuroanatomic risk factors for autism spectrum disorders (ASD) in a cohort of patients with tuberous sclerosis complex (TSC).MethodsA total of 103 patients with TSC were evaluated for ASD. A retrospective review of patients' records was performed, including mutational analysis. EEG reports were analyzed for the presence of ictal and interictal epileptiform features. Brain MRI scans were evaluated for TSC neuropathology, including tuber burden.ResultsOf the 103 patients with TSC, 40%were diagnosed with an ASD. On univariate analysis, patients with ASD were less likely to have mutations in the TSC1 gene. Patients with ASD also had an earlier age at seizure onset and more frequent seizures. On EEG, those with ASD had a significantly greater amount of interictal epileptiform features in the left temporal lobe only. On MRI, there were no differences in the regional distribution of tuber burden, although those with TSC2 and ASD had a higher prevalence of cyst-like tubers.ConclusionsThe development of ASD in TSC is not well understood. Given our findings, ASD may be associated with persistent seizure activity early in development in particular brain regions, such as those responsible for social perception and communication in the left temporal lobe. The presence of cyst-like tubers on MRI could provide a structural basis or marker for ASD pathology in TSC, although studies assessing their effect on cortical function are needed.
| S-EPMC3271577 | biostudies-literature
Project description:Tuberous sclerosis complex (TSC) is a genetic multisystem disorder characterized by the development of hamartomas in several organs. Mutations in the TSC1 and TSC2 tumor suppressor genes determin overactivation of the mammalian target of rapamycin (mTOR) signaling pathway and subsequent abnormalities in numerous cell processes. As a result, mTOR inhibitors such as sirolimus and everolimus have the potential to provide targeted therapy for TSC patients. Everolimus has been recently approved as a pharmacotherapy option for TSC patients with subependymal giant-cell astrocytomas (SEGAs) or renal angiomyolipomas (AMLs). However, clinical evidence suggests that this treatment can benefit other TSC-associated disease manifestations, such as skin manifestations, pulmonary lymphangioleiomyomatosis, cardiac rhabdomyomas, and epilepsy. Therefore, the positive effects that mTOR inhibition have on a wide variety of TSC disease manifestations make this a potential systemic treatment option for this genetic multifaceted disorder.
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Project description:To evaluate if short-term treatment with everolimus was safe and could improve neurocognition and behavior in children with TSC.This was a prospective, double-blind randomized, placebo-controlled two-center phase II study. Participants diagnosed with TSC and age 6-21 years were treated with 4.5 mg/m2 per day of oral everolimus (n = 32) or matching placebo (n = 15) taken once daily for 6 months. For efficacy, a comprehensive neurocognitive and behavioral evaluation battery was performed at baseline, 3 months, and 6 months. For safety, adverse events recorded continuously via patient diary were categorized and graded per NCI Common Toxicity Criteria for Adverse Events, version 3.0 (CTCAE 3.0). Analyses were performed on the intention-to-treat population (n = 47).Nearly all assessment measures failed to demonstrate significant differences between the two groups at the end of 6 months. Only one measure each of executive function (Cambridge Neuropsychological Test Automated Battery Stockings of Cambridge) favoring placebo (P = 0.025) and social cognition (Social Responsiveness Scale Social Cognition Subscale) favoring everolimus (P = 0.011) was observed. A total of 473 adverse events (AE) were reported. The average number of total AE per subject was similar for both placebo and everolimus. Most were mild or moderate in severity and serious AE were rare.While safe, oral everolimus administered once daily for 6 months did not significantly improve neurocognitive functioning or behavior in children with TSC.
| S-EPMC5740257 | biostudies-literature
Project description:ObjectiveTo evaluate the long-term benefit and safety of everolimus for the treatment of medically refractory epilepsy in patients with tuberous sclerosis complex (TSC).MethodsEverolimus was titrated over 4 weeks and continued an additional 8 weeks in a prospective, open-label, phase I/II clinical trial design. Participants demonstrating initial benefit continued treatment until study completion (48 months). The primary endpoint was percentage of patients with a ≥50% reduction in seizure frequency compared to baseline. Secondary endpoints assessed absolute seizure frequency, adverse events (AEs), behavior, and quality of life.ResultsOf the 20 participants who completed the initial study phase, 18 continued extended treatment. Fourteen of 18 (78%) participants completed the study, all but 1 of whom reported ≥50% reduction in seizure frequency at 48 months. All participants reported at least 1 AE, the vast majority (94%) of which were graded mild or moderate severity. Improvements in behavior and quality of life were also observed, but failed to achieve statistical significance at 48 months.ConclusionsImproved seizure control was maintained for 4 years in the majority of patients with TSC with medically refractory epilepsy treated with everolimus. Long-term treatment with everolimus is safe and well-tolerated in this population. Everolimus may be a therapeutic option for refractory epilepsy in TSC.Classification of evidenceThis study provides Class IV evidence that for patients with TSC with medically refractory epilepsy everolimus improves seizure control.
| S-EPMC5177677 | biostudies-literature