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

Abstract

Objective: 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). Methods: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. Results: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. Conclusions: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. Neurology Tuberous sclerosis complex (TSC) is an autosomal dominant disorder resulting from mutations in the TSC1 or the TSC2 gene.1,2 Neurologic involvement occurs in more than 90% of individuals and comprises several distinct lesions.3 Seizure disorders are present in 70%-90% of patients and often develop within the first year of life.4 Developmental and behavioral disorders, including autism spectrum disorders (ASD), are also frequently diagnosed in TSC.ASD are characterized by impaired social interaction, restricted interests, and repetitive behaviors. ASD affects between 17% and 63% of patients with TSC, a prevalence dramatically higher than that of the general population. 5,6 Studies suggest that mental retardation and early onset of epilepsy in TSC, in particular infantile spasms, are associated with the development of ASD in this group. 7,8 In addition, there is evidence of an association between temporal lobe epileptiform foci with ASD in TSC.9 However, investigations seeking to implicate TSC genetics 10 -12 or neuropathology [13][14][15][16][17][18][19] in ASD have yielded inconclusive results. Discrepancies between investigations may result, in part, from varying methods used to diagnose ASD. To date, no

Genotype and cognitive phenotype of patients with tuberous sclerosis complex

“…19,39,40 However, the nearly identical IQ/DQs in men and women in our large TSC1 and TSC2 cohorts are more consistent with previous data on the prevalence of autism, ADHD and other neuropsychiatric disorders in the TSC population, 41,42 suggesting that genetic effects override gender effects.…”

“…Thus far, no associations have been found between specific TSC mutation types and cognitive outcomes, 10,19 although there are reports on associations with epilepsy and psychiatric features. 10, [19][20][21][22] As most of these studies have limited power or do not address all mutation types of interest, more extensive investigations are warranted to determine potential correlations between genotype and neurocognitive phenotype in TSC. Furthermore, as mTOR-inhibitors are now under investigation to prevent or reverse neurocognitive morbidity in TSC, more specific information on genotype-phenotype associations will assist clinicians and caregivers in these important treatment decisions.…”

Early developmental pathways to autism spectrum disorder in tuberous sclerosis complex

“…No single clinical feature, however, is predictive of ASD outcome. For example, there are children with TSC who develop ASD even without a history of seizures (Numis et al, 2011, Boronat et al, 2014.…”

Discovery of Rare Mutations in Autism: Elucidating Neurodevelopmental Mechanisms

“…The term CHARGE is an acronym for the syndrome's six core features: C, coloboma of the iris/retina; H, heart defects; A, atresia of the choanae; R, retardation of growth/development; G, genital abnormalities; and E, ear abnormalities. Occurring once in every 8500-10,000 live births [42,43], CHARGE syndrome also involves a range of secondary features, including deafness, laryngomalacia, vestibulocochlear defects, facial [80][81][82][83][84][85][86][87] CHARGE = C, coloboma of the iris/retina; H, heart defects; A, atresia of the choanae; R, retardation of growth/development; G, genital abnormalities; and E, ear abnormalities; PI3K = phosphoinositide 3-kinase; AKT = protein kinase B; MAPK = mitogen-activated protein kinase; mTOR = mammalian target of rapamycin nerve palsy, and oral clefts [44][45][46][47]. Many individuals with CHARGE syndrome are reported to exhibit autistic-like behaviors, with an estimated 27.5% meeting classification for autism [45].…”

“…TSC is associated with a variety of cognitive and developmental deficits, including ID, ADHD, and epilepsy. TSC is estimated to affect as many as 1 in 5800 newborns [82], approximately 40% of whom are diagnosed with ASD [83,84].…”