Early white matter development is abnormal in tuberous sclerosis complex patients who develop autism spectrum disorder

Abstract

BackgroundAutism 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.MethodsTSC 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.ResultsSubjects 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.ConclusionsUnderconnectivity 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.

Is autism driven by epilepsy in infants with Tuberous Sclerosis Complex?

“…25 Abnormalities in early white matter development have been found in patients with TSC who developed ASD. 33 Refractory epilepsy with persistent seizures may aggravate the neurodevelopmental phenotype, disrupting white matter connectivity, especially in brain circuits involved in social behavior and cognition. 34 Therefore, seizures may represent a superimposed injury to an already abnormal myelogenic process.…”

Prediction of Neurodevelopment in Infants With Tuberous Sclerosis Complex Using Early EEG Characteristics

“…Besides clinical and quantitative EEG features, other characteristics, such as the pathogenic TSC variant, the epilepsy course (including the development of refractory epilepsy or epileptic spasms), MRI features and early development, can help to identify young infants with TSC at risk of developmental comorbidities (6,12,16,(42)(43)(44)(45)(46)(47).…”

Tuberous Sclerosis Complex as Disease Model for Investigating mTOR-Related Gliopathy During Epileptogenesis

“…The hypothesis that a dysfunctional white matter and hence abnormal neural circuitry account for the neurological manifestations in TSC has been further investigated by a plethora of studies. Interestingly, TSC patients with ASD have more crucial white matter abnormalities compared to patients without ASD (143,144).…”