The Learning Disabilities Network (LeaDNet): Using neurofibromatosis type 1 (NF1) as a paradigm for translational research

Abstract

Learning disabilities and other cognitive disorders represent one of the most important unmet medical needs and a significant source of lifelong disability. To accelerate progress in this area, an international consortium of researchers and clinicians, the Learning Disabilities Network (LeaDNet), was established in 2006. Initially, LeaDNet focused on neurofibromatosis type 1 (NF1), a common single gene disorder with a frequency of 1:3,000. Although NF1 is best recognized as an inherited tumor predisposition syndrome, learning, cognitive, and neurobehavioral deficits account for significant morbidity in this condition and can have a profound impact on the quality of life of affected individuals. Recently, there have been groundbreaking advances in our understanding of the molecular, cellular, and neural systems underpinnings of NF1-associated learning deficits in animal models, which precipitated clinical trials using a molecularly targeted treatment for these deficits. However, much remains to be learned about the spectrum of cognitive, neurological, and psychiatric phenotypes associated with the NF1 clinical syndrome. In addition, there is a pressing need to accelerate the identification of specific clinical targets and treatments for thesephenotypes. The successeswith NF1 have allowed LeaDNet investigators to broaden their initial focus to other genetic disorders characterized by learning disabilities and cognitive deficits including other RASopathies (caused by changes in the Ras signaling pathway). The ultimate mission of LeaDNet is to leverage an international translational consortium of clinicians and neuroscientists to integrate bench-to-bedside knowledge across a broad range of cognitive genetic disorders, with the goal of accelerating the development of rational and biologically based treatments.

The RASopathies

“…One common feature of the RASopathies is some degree of neurocognitive involvement, which is an attractive target for treatment (1). The first randomized, placebo-controlled, double-blind clinical trial examined the effect of a 12-week simvastatin treatment on cognitive function in children with NF1 (30).…”

Neuropsychological Functioning in Individuals with Noonan Syndrome: a Systematic Literature Review with Educational and Treatment Recommendations

“…However, results of initial trials using simvastatin did not support short-term efficacy in providing clear functional benefits (Krab et al 2008;van der Vaart et al 2013). NF1 treatment trials to evaluate statin drugs using larger, more carefully selected samples are ongoing (Acosta et al 2012). Importantly, there is now evidence to demonstrate that drugs targeting the same mechanism can be effective in ameliorating cognitive deficits in mouse models of NS (Lee et al 2014), suggesting a potential avenue for future therapeutic exploration.…”

“…Some researchers have advised that to optimally translate scientific advances into clinical interventions, a collaborative framework to include neuroscientists and clinicians from diverse institutions must be developed (Acosta et al 2012). The complexity of the challenges facing evaluation of clinical therapies (e.g., measurement considerations, recruitment of sufficient numbers of participants) will require interdisciplinary contributions and multi-site partnerships.…”

Modeling cognitive dysfunction in neurofibromatosis-1

“…Clinical studies examining cognitive problems in NF1 have revealed a left shift in average IQ, ranging from low-to-normal IQs, with specific learning deficits observed in 30–70% of children [1, 14, 15]. Additionally, children with NF1 exhibit poor performance on tasks of reading, spelling and mathematics, impaired expressive and receptive language skills, deficits in visuospatial and visuoperceptual skills, and defects in executive function (planning and concept formation) [1, 16, 17]. While less common, there is also an increased incidence of autistic spectrum disorder in children with NF1 [18].…”