Abstract
Background: Children with tuberous sclerosis complex (TSC), caused by pathogenic variants in TSC1/TSC2, are at risk for intellectual disability. TSC2 pathogenic variants appear to increase the risk, compared with TSC1. However, the effect of TSC2 pathogenic variants on early and specific domains of development hasn't been studied. Using an extensively phenotyped group, we aimed to characterize differences in early intellectual development between genotypes. Methods: The study group (n = 92) included participants with TSC enrolled in a multicenter study involving genetic testing and detailed prospective phenotyping including the Mullen Scales of Early Learning, a validated measure of cognition, language, and motor development in babies and preschool children. Mean T-scores at 24 months for each Mullen Scales of Early Learning domain were calculated for children with, versus without, a TSC2 pathogenic variant. Multivariable linear regression models were used to compare the groups, adjusting for seizures. Results: T-scores on every Mullen Scales of Early Learning domain were significantly worse in the TSC2 group. Below average composite scores were present in three-fourths of the TSC2 group, compared with one-fourth of those without TSC2. Having a TSC2 pathogenic variant was associated with lower composite Mullen Scales of Early Learning scores, even when corrected for seizures. Conclusions: In a well-characterized patient population with standardized assessment of multiple aspects of development, we found that having a TSC2 pathogenic variant was associated with significantly lower Mullen Scales of Early Learning scores at age 24 months, independent of seizures. These data suggest that a baby with a TSC2 pathogenic variant is at high risk for significant developmental delays by 24 months.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 58-63 |
| Number of pages | 6 |
| Journal | Pediatric neurology |
| Volume | 96 |
| DOIs | |
| State | Published - Jul 1 2019 |
Funding
Funding: This work was supported by Autism Center of Excellence Network [ 1U01NS082320-01 ], the Developmental Synaptopathies Consortium [ 1U54NS092090-01 ], and the Department of Defense [ W81XWH1810537 ]. The Developmental Synaptopathies Consortium [ U54NS092090 ] is part of the Rare Diseases Clinical Research Network (RDCRN), an initiative of the Office of Rare Diseases Research (ORDR), National Center for Advancing Translational Sciences (NCATS). Research reported in this publication was supported by the National Institute of Neurological Disorders and Stroke of the National Institutes of Health (NINDS), Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD), National Institute of Mental Health (NIMH), and National Center for Advancing Translational Sciences (NCATS). We are indebted to the generosity of the families and patients in TSC clinics across the United States who contributed their time and effort to this study. We would also like to thank the Tuberous Sclerosis Alliance for their continued support in TSC research. Funding: This work was supported by Autism Center of Excellence Network [1U01NS082320-01], the Developmental Synaptopathies Consortium [1U54NS092090-01], and the Department of Defense [W81XWH1810537]. The Developmental Synaptopathies Consortium [U54NS092090] is part of the Rare Diseases Clinical Research Network (RDCRN), an initiative of the Office of Rare Diseases Research (ORDR), National Center for Advancing Translational Sciences (NCATS). Research reported in this publication was supported by the National Institute of Neurological Disorders and Stroke of the National Institutes of Health (NINDS), Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD), National Institute of Mental Health (NIMH), and National Center for Advancing Translational Sciences (NCATS). Members of the Tuberous Sclerosis Autism Center of Excellence Research Network (TACERN): Principal Investigators: Sahin, M1; Krueger, D2; Bebin, M3; Wu, JY4; Northrup, H5; Co-Investigators: Warfield S1; Peters J1; Scherrer B1; Goyal M3; Project managers: Filip-Dhima R1; Dies K1; Bruns S2; Neuropsychological assessment team: Hanson E1; Bing N2; Kent B2; O'Kelley S3; Williams ME9; Pearson D5; Data Coordinating Center at UAB: Cutter G6; TS Alliance: Roberds S7; Autism Speaks: Murray DS8; Affiliations for TACERN: 1Boston Children's Hospital, Boston, MA, 2Cincinnati Children's Hospital Medical Center, Cincinnati, OH, 3University of Alabama at Birmingham, Birmingham, AL, 4University of California, Los Angeles, Los Angeles, CA, 5McGovern Medical School, University of Texas Health Science Center at Houston, Houston, TX, 6University of Alabama at Birmingham, Data Coordinating Center, Birmingham, AL, 7Tuberous Sclerosis Alliance, Silver Spring, Maryland 8Autism Speaks, New York, New York 9Keck School of Medicine of USC, University of Southern California, Children's Hospital Los Angeles, Los Angeles, CA.
Keywords
- Cognition
- Developmental delay
- Genotype
- Genotype-phenotype correlation
- Mullen scales of early learning (MSEL)
- Phenotype
- Tuberous sclerosis complex (TSC)
ASJC Scopus subject areas
- Pediatrics, Perinatology, and Child Health
- Neurology
- Developmental Neuroscience
- Clinical Neurology