Three genetic alterations linked to rare epilepsy and movement disorders successfully identified in mice

In a new study at the University of Maryland School of Medicine (UMSOM), three genetic alterations associated with rare epilepsy and movement disorders were successfully mirrored in mice and their symptoms treated, Physiology Professor Andrea Meredith, PhD, and her colleagues collaborators conducted the stud.

The disorder -- a KCNMA1-linked channelopathy, named after the gene affected -- is associated with involuntary collapse episodes, with patients hunched over due to loss of posture and muscle ton.

"Most patients with kcnma1-related channel disease do not inherit the disease from their parents," said D.

Once they have identified the mechanisms behind these symptoms, they can be ready to test therapies to treat the disease, D.

Along with collapse seizures, those with mutations in the KCNMA1 gene may experience seizures and developmental delay.

To test this idea, the researchers genetically modified groups of mice, each carrying one of three different mouse mutations in KCNMA1 patients, all linked to the diseas.

"In neurological research, mouse disease models help us better identify specific aspects of brain activity that may contribute to epilepsy or motor problems in patients," said author Peter Crino, MD, P.

While none of the mice carrying the KCNMA1 patient mutation developed spontaneous seizures in some patients, two of the mutations caused mice to have seizures faster than healthy mice when given a seizure-inducing dru.

Next, the researchers administered a stimulant called dextroamphetamine, which is commonly used as a drug for ADHD, to the mice with the most severe movement disorder.

"Patients with the same KCNMA1 mutation also responded positively to stimulants," D.

Because the mutant mice exhibited the main symptoms of the disease, the researchers wanted to explore what was going on at the molecular leve.

The findings of D.

"We hope to help as many patients as possible by identifying those who respond to this treatment," D.

This clinical trial may further answer other questions about which KCNMA1 mutations might cause the main symptoms in patient.

"Animal models of disease are the cornerstone of understanding disease and treatment," said Mark .
Gladwin, vice president of medical affairs at UM Baltimore and John .
and Akiko .
Bowers Endowed Professor and Dean of the University of Maryland School of Medicin.
"Utilizing modern molecular biology tools , D.
Meredith and her team have created a mouse with a rare human disease that may help find new treatment.
Finding treatments for children with rare diseases is a major focus of our scientific investigatio.
"

Additional authors on this paper include postdoc Park Su Mi, PhD; laboratory technician Cooper Roach, MS; Phillip Iffland II, PhD, assistant professor of neurology; Hans Moldenhauer, PhD; graduate student Katia Matychak, PhD; graduate student Amber Plante, PhD; and research associates Abby Lieberman, both from the University of Maryland School of Medicin.

This research was supported by the National Heart, Lung, and Blood Institute (R01-HL102758), the National Institute of General Medical Sciences (T32-GM008181), the S&R Foundation Ryuji Ueno Ion Channel Research Award, the National Institute of Neurological Disorders and Stroke (NS114122), and the University of Maryland Funding from the Baltimore Institute for Clinical and Translational Research (Voucher 376.
This research was funded by the Clinical Translational Science Award (1UL1TR003098) from the National Center for Translational Science Advancemen.