Behavioral and cognitive outcomes for clinical trials in children with neurofibromatosis type 1

Vaart, Thijs van der; Rietman, André B.; Plasschaert, Ellen; Legius, Eric; Elgersma, Ype; Moll, Henriëtte A.

doi:10.1212/wnl.0000000000002118

Cited by 29 publications

(30 citation statements)

References 33 publications

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“…In addition, MEK inhibitors rescued the plasticity phenotype of CS mice but failed to rescue the cognitive deficits. A review of treatment trials [van der Vaart et al, 2016] in genetic cognitive disorders has shown very limited efficacy, and there is need for larger scale studies, international collaboration and improved reporting and design, particularly with predefinition of outcome measures.…”

Section: Proceedingsmentioning

confidence: 99%

The Fourth International Symposium on Genetic Disorders of the Ras/MAPK pathway

Stevenson

Schill²,

Schoyer³

et al. 2016

American J of Med Genetics Pt A

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The RASopathies are a group of disorders due to variations of genes associated with the Ras/MAPK pathway. Some of the RASopathies include neurofibromatosis type 1 (NF1), Noonan syndrome, Noonan syndrome with multiple lentigines, cardiofaciocutaneous (CFC) syndrome, Costello syndrome, Legius syndrome, and capillary malformation–arteriovenous malformation (CM-AVM) syndrome. In combination, the RASopathies are a frequent group of genetic disorders. This report summarizes the proceedings of the 4th International Symposium on Genetic Disorders of the Ras/MAPK pathway and highlights gaps in the field.

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Section: Proceedingsmentioning

confidence: 99%

The Fourth International Symposium on Genetic Disorders of the Ras/MAPK pathway

Stevenson

Schill²,

Schoyer³

et al. 2016

American J of Med Genetics Pt A

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“…Notably, correlated abnormal behaviors are rescued by treatment with statins ( Li et al, 2005 ) and dopamine re-uptake inhibitors ( Brown et al, 2010 ), respectively. Nevertheless, mixed results in clinical studies ( Bearden et al, 2016 ; van der Vaart et al, 2013 , 2016 ), along with possible memory-associated side effects ( Strom et al, 2015 ), have precluded definitive recommendation of the use of statins in NF1 patients. Therefore, better understanding of molecular mechanisms underlying NF1 neurological issues is crucial to establish successful treatment regimens.…”

Section: Introductionmentioning

confidence: 99%

Oligodendrocyte Nf1 Controls Aberrant Notch Activation and Regulates Myelin Structure and Behavior

et al. 2017

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SUMMARY The RASopathy neurofibromatosis type 1 (NF1) is one of the most common autosomal dominant genetic disorders. In NF1 patients, neurological issues may result from damaged myelin, and mice with a neurofibromin gene (Nf1) mutation show white matter (WM) defects including myelin decompaction. Using mouse genetics, we find that altered Nf1 gene-dose in mature oligodendrocytes results in progressive myelin defects and behavioral abnormalities mediated by aberrant Notch activation. Blocking Notch, upstream mitogen-activated protein kinase (MAPK), or nitric oxide signaling rescues myelin defects in hemizygous Nf1 mutants, and pharmacological gamma secretase inhibition rescues aberrant behavior with no effects in wild-type (WT) mice. Concomitant pathway inhibition rescues myelin abnormalities in homozygous mutants. Notch activation is also observed in Nf1+/− mouse brains, and cells containing active Notch are increased in NF1 patient WM. We thus identify Notch as an Nf1 effector regulating myelin structure and behavior in a RASopathy and suggest that inhibition of Notch signaling may be a therapeutic strategy for NF1.

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“…Diffusion tensor imaging (DTI) has been used to examine white matter microstructure in NF1. Fractional anisotropy (FA) is higher in heavily myelinated fiber tracts than in other brain regions (Feldman et al, 2010), and is reduced in NF1 children compared to typically developing children; 60-70% of NF1 children exhibit abnormalities in white matter, including reduced FA (Aydin et al, 2016;Brown et al, 2010;Karlsgodt et al, 2012;Koini et al, 2017;Nemmi et al, 2019;van der Vaart et al, 2016). All these changes lack treatment.…”

Section: Introductionmentioning

confidence: 99%

Brain-wide structural and functional disruption in mice with oligodendrocyte specificNf1deletion is rescued by inhibition of NOS

Asleh

Shofty

Cohen

et al. 2020

Preprint

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Neurofibromin gene (NF1) mutation causes Neurofibromatosis type 1 (NF1), a disorder in which brain white matter deficits identified by neuroimaging are common, yet of unknown cellular etiology. In mice, Nf1 loss in adult oligodendrocyte causes myelin decompaction, and increases oligodendrocyte nitric oxide (NO) levels. Nitric oxide synthase (NOS) inhibitors rescue this pathology. Whether oligodendrocyte pathology is sufficient to affect brainwide structure and account for NF1 imaging findings is unknown. Here, we show that Nf1 gene inactivation in adult oligodendrocytes (Plp-Nf1 fl/+ mice) results in a motor coordination deficit. Magnetic resonance imaging in awake mice shows that fractional anisotropy is reduced in Plp-Nf1 fl/+ corpus callosum and that interhemispheric functional connectivity in motor cortex is also reduced, consistent with disrupted myelin integrity. Further, NOS-specific inhibition rescued both measures. These results demonstrate that oligodendrocyte defects account for aspects of brain dysfunction in NF1, which can be identified by neuroimaging and ameliorated by NOS inhibition. Significance statementThis study assesses the effects of myelin decompaction on motor behavior and brain-wide structural and functional connectivity, and the effect of nitric oxide synthase (NOS) inhibition by N-nitro-L-arginine methyl ester (L-NAME) on these imaging measures. We report that inducible oligodendrocyte-specific inactivation of the Nf1 gene, which causes myelin decompaction, results in reduced motor coordination. Using diffusion-based MRI we show reduced myelin integrity and using functional MRI we show reduced functional connectivity in awake passive mice. L-NAME administration results in rescue of the pathology at the mesoscopic level using imaging procedures that can be directly applied to humans to study treatment efficacy in clinical trials.

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Behavioral and cognitive outcomes for clinical trials in children with neurofibromatosis type 1

Cited by 29 publications

References 33 publications

The Fourth International Symposium on Genetic Disorders of the Ras/MAPK pathway

The Fourth International Symposium on Genetic Disorders of the Ras/MAPK pathway

Oligodendrocyte Nf1 Controls Aberrant Notch Activation and Regulates Myelin Structure and Behavior

Brain-wide structural and functional disruption in mice with oligodendrocyte specificNf1deletion is rescued by inhibition of NOS

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