Two recipients of NARSAD Independent Investigator Grants report new research results suggesting a promising new approach to treat a serious neurological disorder called MECP2 duplication syndrome. The disorder mainly affects males and includes symptoms seen in a related autism spectrum disorder (ASD) called Rett syndrome.

Like Rett syndrome, which for reasons that remain unclear affects almost exclusively males, MECP2 duplication syndrome has been traced, at least in part, to faulty expression of a gene called MECP2. Ninety-five percent of patients with Rett syndrome have mutations in the MECP2 gene that render it non-functional. That means the MeCP2 protein, important in the nervous system, is not produced. In contrast, in MECP2 duplication syndrome the gene is overactive, causing too much of the protein to be produced in nerve cells.

Elisa S. Na, Ph.D. and Lisa M. Monteggia, Ph.D., both of The University of Texas Southwestern Medical Center, led a team that overexpressed the MECP2 gene in a mouse model. The mice displayed anxiety, motor coordination deficits and could not remember objects to which they had just been introduced. In people, MECP2 overexpression syndrome is marked by symptoms of progressive spasticity, poor social interaction skills and mental retardation.

Drs. Na, Monteggia and colleagues chronically treated MECP2-overexpressing mice with low doses of a candidate medication called picrotoxin (PTX). Other researchers have used it in mice to reduce symptoms resembling those seen in Down Syndrome. As reported in the journal Neuropsychopharmacology on March 12th, PTX treatment similarly improved symptoms in the MECP2-overexpressing mice; specifically, their deficits in motor coordination were reduced and episodic memory improved.

PTX blocks the action of a type of nerve-cell receptor called GABA_A—a docking port for inhibitory neurotransmitters—on the surface of nerve cells. The researchers suspect that an excess of inhibition causes pathology seen in MECP2 overexpression syndrome. Giving affected mice PTX, they suggest, may “rebalance” this abnormality in nerve-signal transmission and restore impaired neural plasticity.

The researchers call their results an encouraging “proof of principle,” not just of PTX, but more broadly of a new class of potential medications that would block GABA_A receptors. They report that such medications “may represent a potential treatment approach for patients with MECP2 duplication syndrome.”

Read the abstract of the paper.