NF1 Attention, Learning & Development Research

Developing new treatments for attention deficits and learning disabilities in children with NF1

Microsoft Word - Document2Nearly two-thirds of all children with NF1 exhibit problems with attention and impulsivity. 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. These investigations are designed to understand the molecular and cellular basis for attention deficits in NF1.

Spearheaded by Dr. David Wozniak in the Department of Psychiatry, these experiments have already led to the development of behavioral tests in mice suitable for preclinical drug evaluation. Working with Dr. Robert Mach in the Department of Radiology, Drs. Gutmann and Wozniak have recently applied positron emission tomography (PET) imaging to the preclinical evaluation of promising drugs for attention deficit. Future studies will combine imaging and behavior assessments to identify and test new candidate treatments for NF1-associated attention deficit.

Additional reading

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. 8: e66024, 2013.

Diggs-Andrew KA, Tokuda K, Izumi Y, Zorumski CF, Wozniak DF, Gutmann DH. Dopamine deficiency underlies learning deficits in neurofibromatosis-1 mice. Ann Neurol. 73: 309-15, 2013.

Diggs-Andrews KA, Gutmann DH. Modeling cognitive dysfunction in neurofibromatosis-1. Trends Neurosci. 36: 237-47, 2013.

Brown JA, Xu J, Diggs-Andrews KA, Wozniak DF, Mach RH, Gutmann DH. PET imaging for attention deficit preclinical drug testing in neurofibromatosis-1 mice. Exp Neurol. 232: 333-8, 2011.

Brown JA, Emnett RJ, White C, Yuede C, Conyers S, O’Malley K, Wozniak DF, Gutmann DH. Reduced striatal dopamine underlies the attention system dysfunction in neurofibromatosis-1 mutant mice. Human Mol Genet. 19: 4515-28, 2010.

Defining the spectrum of clinical problems in children and adults with NF1

While much clinical research has focused on tumors, children with NF1 can have a variety of problems with behavior, motor coordination and attention.

To better understand the impact of these issues on the lives of children with NF1, several investigators at the Washington University NF Center have initiated clinical studies to define the spectrum of attention deficits, developmental delays, short stature and sleep problems in children with NF1. These initial studies will provide researchers with a more in-depth understanding of these clinical features and will lead to future investigations aimed at developing more personalized treatments for children with NF1 who have these specific problems.

Additional reading

Madubata CC, Olsen MA, Stwalley DL, Gutmann DH, Johnson KJ. Neurofibromatosis type 1 and chronic neurological conditions in the United States: An administrative claims analysis. Genet Med. (in press)

Soucy EA, Wessel LE, Gao F, Albers AC, Gutmann DH, Dunn CM. A pilot study for evaluation of hypotonia in children with neurofibromatosis type 1. J Child Neurol. (in press).

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. 28: 1400-5, 2013.

Ostendorf AP, Gutmann DH, Weisenberg JL. Epilepsy in individuals with NF1. Epilepsia. 54: 1810-4, 2013.

Johnson KJ, Hussain I, Williams K, Cantens R, Mueller NL, Gutmann DH. Development of an international internet-based neurofibromatosis type 1 patient registry. Contemp Clin Trials. 34: 305-11, 2013.

Templer AK, Titus JB, Gutmann DH. A neuropsychological perspective on attention problems in neurofibromatosis type 1. J. Atten Disord. 17: 489-96, 2013.

Wessel LE, Gao F, Gutmann DH, Dunn CM. Longitudinal analysis of developmental delays in children with neurofibromatosis type 1. J Child Neurol. 28: 1689-93, 2013.

Wessel LE, Albers AC, Gutmann DH, Dunn CM. The association between hypotonia and brain tumors in children with neurofibromatosis type 1. J Child Neurol. 28: 1664-7, 2013.

Soucy EA, van Oppen D, Nejedly NL, Gao F, Gutmann DH, Hollander AS. Height assessments in children with neurofibromatosis type 1. J Child Neurol. 28: 303-7, 2013.

Isenberg JC, Templer A, Gao F, Titus JB, Gutmann DH. Attention skills in children with neurofibromatosis type 1. J Child Neurol. 28: 45-9, 2013.

Johnson KJ, Hussain I, Williams K, Santens R, Mueller NL, Gutmann DH. Development of an international internet-based neurofibromatosis type 1 patient registry. Contemp Clin Trials. 34:305-11, 2013.

Soucy EA, Gao F, Gutmann DH, Dunn CM. Developmental delays in children with neurofibromatosis type 1. J Child Neurol. 27: 641-4, 2012.

Function of the NF1 gene in brain nerve cells

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Individuals with NF1 are prone to learning disabilities, behavioral problems, seizures and motor delays – all indicative of impairments in normal nerve cell (neuron) function. Dr. Gutmann and his colleagues are leading studies to understand how the Nf1 protein (neurofibromin) controls the function of neurons in the brain.

These investigations have revealed that reduced neurofibromin function in the brain leads to impaired neuron lengths and survival, which reflects the role of neurofibromin in controlling cyclic AMP levels. Current efforts are directed at defining the mechanism underlying neurofibromin cyclic AMP regulation in neurons and identifying drugs capable of restoring normal neuron function.

Additional reading

Brown JA, Diggs-Andrews KA, Gianino SM, Gutmann DH. Neurofibromatosis-1 heterozygosity impairs CNS neuronal morphology in a cAMP/PKA/ROCK-dependent manner. Molecular and Cellular Neuroscience. 49: 13-22, 2012.

Brown JA, Gianino SM, Gutmann DH. Defective cAMP generation underlies the sensitivity of central nervous system neurons to neurofibromatosis-1 heterozygosity. J Neurosci. 30: 5579-89, 2010.

Hegedus B, Hughes WF, Garbow JR, Gianino SM, Banerjee D, Kim K, Ellisman MH, Brantley MA, Gutmann DH. Optic nerve dysfunction in a mouse model of neurofibromatosis-1 optic glioma. J Neuropathol Exp Neurol. 68: 542-51, 2009.