Abstract
SATB2-associated syndrome (SAS) is a multisystemic disorder characterized by developmental delay often with concurrent autistic tendencies. This study aimed to characterize cellular metabolic pathways and energy metabolism from cells derived from individuals with SAS. The cellular production of NADH (nicotinamide adenine dinucleotide, reduced form) as determined by the Phenotype Mammalian MicroArrays was measured in lymphoblastoid cell lines derived from 11 subjects with a molecularly confirmed diagnosis of SAS and compared to a control population of 50 age-matched typically developing individuals. All patients were evaluated clinically by a multidisciplinary team. Eleven individuals (five in a screening cohort and six in the validation cohort, mean age 6.1 years) were recruited to the study. All individuals had developmental delay and the diagnosis of autism was previously established in five of them. Key metabolic findings included reduced NADH production in the presence of phosphorylated carbohydrates (with corresponding increased production in the presence of alternative carbon-based energy sources), increased response to certain hormones (β-estradiol in particular), and significantly reduced levels of NADH in wells containing tryptophan. The individual analysis revealed no particular differences among the SAS subjects based on molecular findings or phenotypic features. In conclusion, individuals with SAS have a common and recognizable metabolic profile. A lower capacity to utilize glucose as an energy substrate could be contributing to the neurodevelopment phenotype of SAS. The identified abnormalities offer previously unexplored insight into the potential pathophysiology of common SAS phenotypic features.
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The datasets generated during and/or analysed during the current study are available from the corresponding author on reasonable request.
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Acknowledgements
This work was supported in part by a research grant from the SATB2 Gene Foundation awarded to Y.Z. The authors would like to thank all participating families.
Funding
This study was funded in in part by a research grant from the SATB2 Gene Foundation awarded to Y.Z.
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All authors contributed to the study conception and design. Material preparation and data collection by Yuri Zarate and Katherine Bosanko. Experiments and Data analysis were performed by Sujata Srikanth, Rini Pauly, Lauren Cascio, and Luigi Boccuto. Data analysis was performed by Jenny-Li Örsell. The first draft of the manuscript was written by Yuri A. Zarate, Jenny-Li Örsell, and Luigi Boccuto. All authors commented on previous versions of the manuscript. All authors read and approved the final manuscript.
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Y.Z. serves in the Medical Scientific Advisory Board for the SATB2 gene foundation. All other authors have no relevant financial or non-financial interests to disclose.
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The study was performed in accordance with the ethical standards as laid down in the 1964 Declaration of Helsinki and its later amendments or comparable ethical standards. The study was approved by the Institutional Review Board (IRB) of the University of Arkansas for Medical Sciences and the Self Regional IRB.
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Zarate, Y.A., Örsell, JL., Bosanko, K. et al. Individuals with SATB2-associated syndrome with and without autism have a recognizable metabolic profile and distinctive cellular energy metabolism alterations. Metab Brain Dis 36, 1049–1056 (2021). https://doi.org/10.1007/s11011-021-00706-7
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DOI: https://doi.org/10.1007/s11011-021-00706-7