Understanding Attention and Learning in NF1

Defining the role of the NF1 gene in normal brain development

The observation that children with NF1 have learning, memory and behavioral problems suggests that the Nf1 gene neurofibromin is important in brain development and function.

Microsoft Word - Document2To better understand the role of neurofibromin in normal brain development, Dr. Gutmann and his colleagues are using novel strains of genetically-engineered mice, as well as human induced pluripotent stem cells (hiPSCs). These studies are aimed at determining the mechanism by which neurofibromin regulates the growth of progenitor cells (neural stem cells) and their differentiation into neurons, astrocytes and oligodendrocytes. The goal of these studies is to determine exactly how neurofibromin regulates normal brain development and function with an eye towards future treatments that leverage these new insights.

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Developing new treatments for learning, behavioral, motor and sleep deficits in children with NF1

Microsoft Word - Document2Many children with NF1 have learning difficulties, behavioral problems (autism, attention deficit), motor delays, and sleep disturbances. In an effort to develop new treatments for these common problems, cross-disciplinary studies at the Washington University NF Center are leveraging Nf1 genetically-engineered mice to complement human clinical studies led by Dr. Stephanie Morris and her colleagues in children with NF1.

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Eby NS, Griffith JL, Gutmann DH, Morris SM. Adaptive functioning in children with neurofibromatosis type 1: relationship to cognition, behavior, and magnetic resonance imaging. Dev Med Child Neurol. 2019 Aug;61(8):972-978. doi: 10.1111/dmcn.14144. Epub 2019 Jan 18. PMID: 30659594.

Anastasaki C, Rensing N, Johnson KJ, Wong M, Gutmann DH. Neurofibromatosis type 1 (Nf1)-mutant mice exhibit increased sleep fragmentation. J Sleep Res. 2019 Aug;28(4):e12816. doi: 10.1111/jsr.12816. Epub 2019 Jan 4. PMID: 30609083.

Morris SM, Gutmann DH. A genotype-phenotype correlation for quantitative autistic trait burden in neurofibromatosis 1. Neurology. 2018 Feb 20;90(8):377-379. doi: 10.1212/WNL.0000000000005000. Epub 2018 Jan 24. PMID: 29367450.

Vogel AC, Gutmann DH, Morris SM. Neurodevelopmental disorders in children with neurofibromatosis type 1. Dev Med Child Neurol. 2017 Nov;59(11):1112-1116. doi: 10.1111/dmcn.13526. Epub 2017 Aug 27. PMID: 28845518.

Maloney SE, Chandler KC, Anastasaki C, Rieger MA, Gutmann DH, Dougherty JD. Characterization of early communicative behavior in mouse models of neurofibromatosis type 1. Autism Res. 2018 Jan;11(1):44-58. doi: 10.1002/aur.1853. Epub 2017 Aug 26. PMID: 28842941.

Morris SM, Acosta MT, Garg S, Green J, Huson S, Legius E, North KN, Payne JM, Plasschaert E, Frazier TW, Weiss LA, Zhang Y, Gutmann DH, Constantino JN. Disease Burden and Symptom Structure of Autism in Neurofibromatosis Type 1: A Study of the International NF1-ASD Consortium Team (INFACT). JAMA Psychiatry. 2016 Dec 1;73(12):1276-1284. doi: 10.1001/jamapsychiatry.2016.2600. PMID: 27760236.

Constantino JN, Zhang Y, Holzhauer K, Sant S, Long K, Vallorani A, Malik L, Gutmann DH. Distribution and Within-Family Specificity of Quantitative Autistic Traits in Patients with Neurofibromatosis Type I. J Pediatr. 2015 Sep;167(3):621-6.e1. doi: 10.1016/j.jpeds.2015.04.075. Epub 2015 Jun 4. PMID: 26051969.

Omrani A, van der Vaart T, Mientjes E, van Woerden GM, Hojjati MR, Li KW, Gutmann DH, Levelt CN, Smit AB, Silva AJ, Kushner SA, Elgersma Y. HCN channels are a novel therapeutic target for cognitive dysfunction in Neurofibromatosis type 1. Mol Psychiatry. 2015 Nov;20(11):1311-21. doi: 10.1038/mp.2015.48. Epub 2015 Apr 28. PMID: 25917366.

Anastasaki C, Woo AS, Messiaen LM, Gutmann DH. Elucidating the impact of neurofibromatosis-1 germline mutations on neurofibromin function and dopamine-based learning. Hum Mol Genet. 2015 Jun 15;24(12):3518-28. doi: 10.1093/hmg/ddv103. Epub 2015 Mar 18. PMID: 25788518.

Licis AK, Vallorani A, Gao F, Chen C, Lenox J, Yamada KA, Duntley SP, Gutmann DH. Prevalence of Sleep Disturbances in Children With Neurofibromatosis Type 1. J Child Neurol. 2013 Nov;28(11):1400-1405. Epub 2013 Sep 23. PMID: 24065580.

Wozniak DF, Diggs-Andrews KA, Conyers S, Yuede CM, Dearborn JT, Brown JA, Tokuda K, Izumi Y, Zorumski CF, Gutmann DH. Motivational disturbances and effects of L-dopa administration in neurofibromatosis-1 model mice. PLoS One. 2013 Jun 10;8(6):e66024. doi: 10.1371/journal.pone.0066024. Print 2013. PMID: 23762458.

Diggs-Andrews KA, Tokuda K, Izumi Y, Zorumski CF, Wozniak DF, Gutmann DH. Dopamine deficiency underlies learning deficits in neurofibromatosis-1 mice. Ann Neurol. 2013 Feb;73(2):309-15. doi: 10.1002/ana.23793. Epub 2012 Dec 7. PMID: 23225063.

Wessel LE, Gao F, Gutmann DH, Dunn CM. Longitudinal analysis of developmental delays in children with neurofibromatosis type 1. J Child Neurol. 2013 Dec;28(12):1689-93. doi: 10.1177/0883073812462885. Epub 2012 Oct 30. PMID: 23112244.

Isenberg JC, Templer A, Gao F, Titus JB, Gutmann DH. Attention skills in children with neurofibromatosis type 1. J Child Neurol. 2013 Jan;28(1):45-9. doi: 10.1177/0883073812439435. Epub 2012 Apr 10. PMID: 22496119.

Soucy EA, Gao F, Gutmann DH, Dunn CM. Developmental delays in children with neurofibromatosis type 1. J Child Neurol. 2012 May;27(5):641-4. doi: 10.1177/0883073811423974. Epub 2011 Dec 21. PMID: 22190506.