Identification of risk factors for autism spectrum disorder in tuberous sclerosis complex

Department of Neurology, Massachusetts General Hospital, Boston, USA.
Neurology (Impact Factor: 8.29). 03/2011; 76(11):981-7. DOI: 10.1212/WNL.0b013e3182104347
Source: PubMed


The 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).
A 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.
Of 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.
The 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.

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Available from: Elizabeth A Thiele, Oct 07, 2015
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    • "Tuberous sclerosis complex is also associated with autism spectrum disorder (ASD). Estimated prevalence rates of TSC in people with ASD range from 1% up to 14% in individuals who also experience seizures and 40 to 45% of individuals with TSC may meet criteria for an ASD [24-27]. The most systematic evaluation of ASD in TSC was conducted by Bolton et al., [28]. "
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    ABSTRACT: Research reporting prevalence rates of self-injurious and aggressive behaviour in people with tuberous sclerosis complex (TSC) is limited. No studies have compared rates of these behaviours in TSC with those in other syndrome groups matched for degree of disability or investigated risk markers for these behaviours in TSC. Data from the Challenging Behaviour Questionnaire were collected for 37 children, aged 4 to 15 years, with TSC. Odds ratios were used to compare rates of self-injury and aggression in children with TSC with children with idiopathic autism spectrum disorder (ASD), fragile X, Cornelia de Lange and Down syndromes. Characteristics were measured using the Mood Interest and Pleasure Questionnaire, the Activity Questionnaire, the Social Communication Questionnaire, the Repetitive Behaviour Questionnaire, the Wessex Behaviour Schedule and the revised Non-communicating Children Pain Checklist. Mann-Whitney U analyses were used to compare characteristics between individuals with self-injury and aggression and those not showing these behaviours. Rates of self-injury and aggression in TSC were 27% and 50%, respectively. These are high but not significantly different from rates in children with Down syndrome or other syndrome groups. Both self-injury and aggression were associated with stereotyped and pain-related behaviours, low mood, hyperactivity, impulsivity and repetitive use of language. Children who engaged in self-injury also had lower levels of interest and pleasure and showed a greater degree of 'insistence on sameness' than children who did not self-injure. Aggression was associated with repetitive behaviour. The majority of these associations remained significant when the association with level of adaptive functioning was controlled for. Behavioural profiles can be used to identify those most at risk of developing self-injury and aggression. Further research is warranted to understand the influence of such internal factors as mood, ASD symptomatology and pain on challenging behaviour in people with intellectual disability.
    Journal of Neurodevelopmental Disorders 05/2014; 6(1):10. DOI:10.1186/1866-1955-6-10 · 3.27 Impact Factor
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    • "Some patients have normal cognitive function, but as many as 40 % have learning disabilities, and more than 60–80 % suffer from epilepsy at some point in their life (Shepherd and Stephenson 1992; Holmes and Stafstrom 2007; Crino et al. 2006). A number of studies have also shown that up to 50 % of individuals with TSC may also develop ASD (Harrison and Bolton 1997; Guttierez et al. 1998; Muzykewicz et al. 2007), but the risk factors for ASD in these patients are not clearly understood (Numis et al. 2011). While many studies have described the clinical characteristics of children with TSC and ASD, few studies have investigated the functional mechanisms that underline the association between the two disorders. "
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    ABSTRACT: The electrophysiological correlates of cognitive deficits in tuberous sclerosis complex (TSC) are not well understood, and modulations of neural dynamics by neuroanatomical abnormalities that characterize the disorder remain elusive. Neural oscillations (rhythms) are a fundamental aspect of brain function, and have dominant frequencies in a wide frequency range. The spatio-temporal dynamics of these frequencies in TSC are currently unknown. Using a novel signal decomposition approach this study investigated dominant cortical frequencies in 10 infants with TSC, in the age range 18-30 months, and 12 age-matched healthy controls. Distinct spectral characteristics were estimated in the two groups. High-frequency [in the high-gamma (>50 Hz) and ripple (>80 Hz) ranges], non-random EEG components were identified in both TSC and healthy infants at 18 months. Additional components in the lower gamma (30-50 Hz) ranges were also identified, with higher characteristic frequencies in TSC than in controls. Lower frequencies were statistically identical in both sub-groups. A significant shift in the high-frequency spectral content of the EEG was observed as a function of age, independently of task performance, possibly reflecting an overall maturation of developing neural circuits. This shift occurred earlier in healthy infants than in TSC, i.e., by age 20 months the highest dominant frequencies were in the high gamma range, whereas in TSC dominant frequencies above 100 Hz were still measurable. At age 28-30 months a statistically significant decrease in dominant high frequencies was observed in both TSC and healthy infants, possibly reflecting increased myelination and neuronal connection strengthening with age. Although based on small samples, and thus preliminary, the findings in this study suggest that dominant cortical rhythms, a fundamental aspect of neurodynamics, may be affected in TSC, possibly leading to impaired information processing in the brain.
    Journal of Autism and Developmental Disorders 07/2013; 45(2). DOI:10.1007/s10803-013-1887-7 · 3.06 Impact Factor
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    • "Due to the heterogeneous nature of autism spectrum disorders, it is not surprising that multiple gene families have been implicated in the pathology of autism [9-11] with 50 gene or gene variants accounting for approximately 30% of autism spectrum cases [11]. Many of these candidate genes overlap with those of other disorders with autistic behavioral deficits including tuberous sclerosis [12], fragile X syndrome (FXS) [13], Rett syndrome [14], and Angelman syndrome [15]. "
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    ABSTRACT: Candidate genes associated with idiopathic forms of autism overlap with other disorders including fragile X syndrome. Our laboratory has previously shown reduction in fragile X mental retardation protein (FMRP) and increase in metabotropic glutamate receptor 5 (mGluR5) in cerebellar vermis and superior frontal cortex (BA9) of individuals with autism. In the current study we have investigated expression of four targets of FMRP and mGluR5 signaling - homer 1, amyloid beta A4 precursor protein (APP), ras-related C3 botulinum toxin substrate 1 (RAC1), and striatal-enriched protein tyrosine phosphatase (STEP) - in the cerebellar vermis and superior frontal cortex (BA9) via SDS-PAGE and western blotting. Data were analyzed based on stratification with respect to age (children and adolescents vs. adults), anatomic region of the brain (BA9 vs. cerebellar vermis), and impact of medications (children and adolescents on medications (n = 4) vs. total children and adolescents (n = 12); adults on medications (n = 6) vs. total adults (n = 12)). There were significant increases in RAC1, APP 120 kDa and APP 80 kDa proteins in BA9 of children with autism vs. healthy controls. None of the same proteins were significantly affected in cerebellar vermis of children with autism. In BA9 of adults with autism there were significant increases in RAC1 and STEP 46 kDa and a significant decrease in homer 1 vs. controls. In the vermis of adult subjects with autism, RAC1 was significantly increased while APP 120, STEP 66 kDa, STEP 27 kDa, and homer 1 were significantly decreased when compared with healthy controls. No changes were observed in vermis of children with autism. There was a significant effect of anticonvulsant use on STEP 46 kDa/beta-actin and a potential effect on homer 1/NSE, in BA9 of adults with autism. However, no other significant confound effects were observed in this study. Our findings provide further evidence of abnormalities in FMRP and mGluR5 signaling partners in brains of individuals with autism and open the door to potential targeted treatments which could help ameliorate the symptoms of autism.
    Molecular Autism 06/2013; 4(1):21. DOI:10.1186/2040-2392-4-21 · 5.41 Impact Factor
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