Bringing the HEET: The Argument for High-Efficacy Early Treatment for Pediatric-Onset Multiple Sclerosis.

Pediatric-onset multiple sclerosis (POMS) is rarer than adult-onset disease, and represents a different diagnostic and treatment challenge to clinicians. We review POMS clinical and radiographic presentations, and explore important differences between POMS and adult-onset MS natural histories and long-term outcomes. Despite having more active disease, current treatment guidelines for patients with POMS endorse the off-label use of lower-efficacy disease-modifying therapies (DMTs) as first line. We review the available MS DMTs, their evidence for use in POMS, and the contrasting treatment strategies of high-efficacy early treatment and escalation therapy. We introduce a new treatment approach, the "high-efficacy early treatment", or HEET strategy, based on using directly observed, high-efficacy intravenously infused DMTs as first-line therapies. Like other proposed POMS treatment strategies, HEET will need to be prospectively studied, and all treatment decisions should be determined by an experienced neurologist, the patient, and his/her parents.

Engrailed2 modulates cerebellar granule neuron precursor proliferation, differentiation and insulin-like growth factor 1 signaling during postnatal development.

BACKGROUND: The homeobox transcription factor Engrailed2 (En2) has been studied extensively in neurodevelopment, particularly in the midbrain/hindbrain region and cerebellum, where it exhibits dynamic patterns of expression and regulates cell patterning and morphogenesis. Because of its roles in regulating cerebellar development and evidence of cerebellar pathology in autism spectrum disorder (ASD), we previously examined an ENGRAILED2 association and found evidence to support EN2 as a susceptibility gene, a finding replicated by several other investigators. However, its functions at the cell biological level remain undefined. In the mouse, En2 gene is expressed in granule neuron precursors (GNPs) just as they exit the cell cycle and begin to differentiate, raising the possibility that En2 may modulate these developmental processes. METHODS: To define En2 functions, we examined proliferation, differentiation and signaling pathway activation in En2 knockout (KO) and wild-type (WT) GNPs in response to a variety of extracellular growth factors and following En2 cDNA overexpression in cell culture. In vivo analyses of cerebellar GNP proliferation as well as responses to insulin-like growth factor-1 (IGF1) treatment were also conducted. RESULTS: Proliferation markers were increased in KO GNPs in vivo and in 24-h cultures, suggesting En2 normally serves to promote cell cycle exit. Significantly, IGF1 stimulated greater DNA synthesis in KO than WT cells in culture, a finding associated with markedly increased phospho-S6 kinase activation. Similarly, there was three-fold greater DNA synthesis in the KO cerebellum in response to IGF1 in vivo. On the other hand, KO GNPs exhibited reduced neurite outgrowth and differentiation. Conversely, En2 overexpression increased cell cycle exit and promoted neuronal differentiation. CONCLUSIONS: In aggregate, our observations suggest that the ASD-associated gene En2 promotes GNP cell cycle exit and differentiation, and modulates IGF1 activity during postnatal cerebellar development. Thus, genetic/epigenetic alterations of EN2 expression may impact proliferation, differentiation and IGF1 signaling as possible mechanisms that may contribute to ASD pathogenesis.