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Postnatal Cytomegalovirus Infection May Increase the Susceptibility of Tuberous Sclerosis Complex to Autism Spectrum Disorders.

ABSTRACT: Autism spectrum disorder (ASD), a highly hereditary and heterogeneous neurodevelopmental disorder, is influenced by genetic and environmental factors. Tuberous sclerosis complex (TSC) is a common syndrome associated with ASD. Cytomegalovirus (CMV) infection is an environmental risk factor for ASD. The similarities in pathological and mechanistic pathways of TSC and CMV intrigued us to investigate whether CMV and TSC interacted in ASD's occurrence. We detected CMV IgG seroprevalence of 308 TSC patients from our prospective cohort (September 2011 to March 2021) and 93 healthy children by magnetic particle indirect chemiluminescence immunoassay. A total of 206 TSC patients enrolled were divided into ASD and non-ASD groups, and the relationship between ASD and CMV seroprevalence was analyzed. Nested PCR and Western blot were used to detect CMV DNAs and proteins in cortical malformations of seven TSC patients with and without ASD. No difference was found in CMV seroprevalence between TSC patients and healthy children (74.0% versus 72.0%, P = 0.704). Univariate analysis showed the seroprevalence in TSC patients with ASD was higher than that in TSC patients without ASD (89.2% versus 75.1%, P = 0.063), and multifactorial analysis showed that CMV seroprevalence was a risk factor for ASD in TSC patients (OR = 3.976, 95% CI = 1.093 to 14.454). Moreover, CMV was more likely to be detected in the cortical malformations in TSC patients with ASD but not in those without ASD. The findings demonstrated that CMV may increase the susceptibility of TSC to ASD. IMPORTANCE CMV is an environmental risk factor for ASD, but its role in syndromic autism with known genetic etiology has been rarely studied. The pathogenesis of ASD is related to the interaction between environmental and genetic factors. This study demonstrated that CMV can contribute to the occurrence of ASD related to TSC, a common genetic syndrome associated with ASD. Our findings provided support for the theory of gene-environment interaction (G × E) in pathogenesis of ASD and a new perspective for the prevention and therapy for TSC related ASD.

SUBMITTER: Yang XY

PROVIDER: S-EPMC9241718 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Tuberous sclerosis complex (TSC) is a rare genetic disorder that confers a high risk for autism spectrum disorders (ASD), with behavioral predictors of ASD emerging early in life. Deviations in structural and functional neural connectivity are highly implicated in both TSC and ASD. For the first time, we explore whether electroencephalographic (EEG) measures of neural network function precede or predict the emergence of ASD in TSC. We determine whether altered brain function (a) is present in infancy in TSC, (b) differentiates infants with TSC based on ASD diagnostic status, and (c) is associated with later cognitive function. We studied 35 infants with TSC (N = 35), and a group of typically developing infants (N = 20) at 12 and 24 months of age. Infants with TSC were later subdivided into ASD and non-ASD groups based on clinical evaluation. We measured features of spontaneous alpha oscillations (6-12 Hz) that are closely associated with neural network development: alpha power, alpha phase coherence (APC), and peak alpha frequency (PAF). Infants with TSC demonstrated reduced interhemispheric APC compared to controls at 12 months of age, and these differences were found to be most pronounced at 24 months in the infants who later developed ASD. Across all infants, PAF at 24 months was associated with verbal and nonverbal cognition at 36 months. Associations between early network function and later neurodevelopmental and cognitive outcomes highlight the potential utility of early scalable EEG markers to identify infants with TSC requiring additional targeted intervention initiated very early in life. Autism Res 2019, 12: 1758-1773. © 2019 International Society for Autism Research, Wiley Periodicals, Inc. LAY SUMMARY: Approximately half of infants with tuberous sclerosis complex (TSC) develop autism. Here, using EEG, we find that there is a reduction in communication between brain regions during infancy in TSC, and that the infants who show the largest reductions are those who later develop autism. Being able to identify infants who show early signs of disrupted brain development may improve the timing of early prediction and interventions in TSC, and also help us to understand how early brain changes lead to autism.

Project description:BACKGROUND:Autism spectrum disorder (ASD) is prevalent in tuberous sclerosis complex (TSC), occurring in approximately 50% of patients, and is hypothesized to be caused by disruption of neural circuits early in life. Tubers, or benign hamartomas distributed stochastically throughout the brain, are the most conspicuous of TSC neuropathology, but have not been consistently associated with ASD. Widespread neuropathology of the white matter, including deficits in myelination, neuronal migration, and axon formation, exist and may underlie ASD in TSC. We sought to identify the neural circuits associated with ASD in TSC by identifying white matter microstructural deficits in a prospectively recruited, longitudinally studied cohort of TSC infants. METHODS:TSC infants were recruited within their first year of life and longitudinally imaged at time of recruitment, 12 months of age, and at 24 months of age. Autism was diagnosed at 24 months of age with the ADOS-2. There were 108 subjects (62 TSC-ASD, 55% male; 46 TSC+ASD, 52% male) with at least one MRI and a 24-month ADOS, for a total of 187 MRI scans analyzed (109 TSC-ASD; 78 TSC+ASD). Diffusion tensor imaging properties of multiple white matter fiber bundles were sampled using a region of interest approach. Linear mixed effects modeling was performed to test the hypothesis that infants who develop ASD exhibit poor white matter microstructural integrity over the first 2 years of life compared to those who do not develop ASD. RESULTS:Subjects with TSC and ASD exhibited reduced fractional anisotropy in 9 of 17 white matter regions, sampled from the arcuate fasciculus, cingulum, corpus callosum, anterior limbs of the internal capsule, and the sagittal stratum, over the first 2 years of life compared to TSC subjects without ASD. Mean diffusivity trajectories did not differ between groups. CONCLUSIONS:Underconnectivity across multiple white matter fiber bundles develops over the first 2 years of life in subjects with TSC and ASD. Future studies examining brain-behavior relationships are needed to determine how variation in the brain structure is associated with ASD symptoms.

Project description:BACKGROUND:Renal angiomyolipoma occurs at a high frequency in patients with tuberous sclerosis complex (TSC) and is associated with potentially life-threatening complications. Despite this frequency and severity, there are no large population-based cohort studies. Here we present baseline and follow-up data of the international TuberOus SClerosis registry to increase disease Awareness (TOSCA) with an aim to provide detailed clinical characteristics of renal angiomyolipoma among patients with TSC. METHODS:Patients of any age with a documented clinic visit for TSC within 12 months or who were newly diagnosed with TSC before participation in the registry were eligible. Data specific to renal angiomyolipoma included physical tumour characteristics (multiple, bilateral, lesion size and growing lesions), clinical signs and symptoms, and management. The effects of age, gender and genotype on the prevalence of renal angiomyolipoma were also evaluated. RESULTS:Renal angiomyolipoma was reported in 51.8% of patients at baseline, with higher frequency in female patients (57.8% versus 42.2%). The median age at diagnosis was 12 years. Prevalence of angiomyolipoma was higher in patients with TSC2 compared with TSC1 mutations (59.2% versus 33.3%, P?<?0.01). Of the 1031 patients with angiomyolipoma at baseline, multiple lesions were reported in 88.4% and bilateral in 83.9% of patients, while the size of angiomyolipoma was >3 cm in 34.3% of patients. Most patients were asymptomatic (82%). Frequently reported angiomyolipoma-related symptoms included bleeding, pain, elevated blood pressure and impaired renal function. Embolization and mammalian target of rapamycin inhibitors were the two most common treatment modalities. CONCLUSIONS:The TOSCA registry highlights the burden of renal angiomyolipoma in patients with TSC and shows that renal manifestations are initially asymptomatic and are influenced by gender and genotype. Furthermore, the occurrence of significant problems from angiomyolipoma in a minority of younger patients suggests that surveillance should begin in infancy or at initial diagnosis.

Project description:BackgroundTuberous sclerosis complex (TSC) is a rare multisystem autosomal dominant disorder caused by pathogenic variants in either the TSC1 or TSC2 gene. Common manifestations of TSC have been grouped into major and minor clinical diagnostic criteria and assessed in clinical routine workup. However, case studies point towards the existence of rare disease manifestations and to the potential association of TSC with malignant tumors. In this study we sought to characterize rare manifestations and malignancies using a large cohort of patients.MethodsTuberOus SClerosis registry to increAse disease awareness (TOSCA) is a multicenter, international disease registry collecting clinical manifestations and characteristics of patients with TSC, both retrospectively and prospectively. We report rates and characteristics of rare manifestations and malignancies in patients with TSC who had enrolled in the TOSCA registry. We also examined these manifestations by age, sex, and genotype (TSC1 or TSC2).ResultsOverall, 2211 patients with TSC were enrolled in the study. Rare manifestations were reported in 382 (17.3%) study participants and malignancies in 65 (2.9%). Of these rare manifestations, the most frequent were bone sclerotic foci (39.5%), scoliosis (23%), thyroid adenoma (5.5%), adrenal angiomyolipoma (4.5%), hemihypertrophy and pancreatic neuroendocrine tumors (pNET; both 3.1%). These rare manifestations were more commonly observed in adults than children (66.2% vs. 22.7%), in females versus males (58.4% vs. 41.6%; except for scoliosis: 48.9% vs. 51.1%), and in those with TSC2 versus TSC1 (67.0% vs. 21.1%; except for thyroid adenoma: 42.9% vs. 57.1%). In the 65 individuals with reported malignancies, the most common were renal cell carcinoma (47.7%), followed by breast (10.8%) and thyroid cancer (9.2%). Although malignancies were more common in adult patients, 26.1% were reported in children and 63.1% in individuals < 40 years. TSC1 mutations were over-represented in individuals with malignancies compared to the overall TOSCA cohort (32.1% vs. 18.5%).ConclusionRare manifestations were observed in a significant proportion of individuals with TSC. We recommend further examination of rare manifestations in TSC. Collectively, malignancies were infrequent findings in our cohort. However, compared to the general population, malignant tumors occurred earlier in age and some tumor types were more common.

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Postnatal Cytomegalovirus Infection May Increase the Susceptibility of Tuberous Sclerosis Complex to Autism Spectrum Disorders.

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