INDIANA U. (US) — Stopping the production of a chain-like molecule the body uses to store glucose could lead to treatment for a rare but deadly disease in teenagers.
Lafora disease strikes early in the teen years with epileptic seizures and then other neurological symptoms that become progressively worse. It is always fatal, usually within 10 years.
The disease occurs when a genetic mutation causes excessive amounts of phosphate to build up in a molecule called glycogen. Glycogen stores glucose when it’s not needed to provide energy for cellular activities. The
excess phosphate causes unnatural glycogen structures to appear in the body, including the brain, resulting in progressive neurological problems.
“It’s a very harrowing disease and there’s no treatment right now, says Peter Roach, professor of biochemistry and molecular biology at Indiana University. “It’s thankfully rare, but for the families affected it’s tragic.”
In a paper in journal Cell Metabolism, Roach identifies where the extra phosphate comes from, and how it is chemically linked to the glycogen molecules.
The disease is caused by a mutation to one of two genes, one leading to a defective version of a protein called laforin. In previous research, Roach showed that laforin’s role is to remove phosphate residues from glycogen. When the body cannot produce laforin, the phosphate levels in glycogen build up, resulting in Lafora disease.
Up until now, scientists were puzzled by the source of the phosphate. The answer, Roach says, is found in the enzyme that cells normally use to build up the glycogen molecules.
When there are extra glucose molecules in the body, such as after a meal, the enzyme, like a tiny molecular machine, hooks the glucose molecules onto the glycogen chain and phosphates that are attached to the glucose are discarded.
But once every 10,000 cycles or so, a phosphate molecule remains attached when the enzyme hooks the glucose molecule onto the glycogen chain. The job of laforin is to correct for those errors. Without the laforin, phosphates build up and the deadly disease is the result.
Animal experiments suggest that a treatment to counteract the laforin mutation could be compounds that would block the production of glycogen, Roach says.
Although a lack of glycogen could have side effects—such as greater propensity to develop diabetes—they might be acceptable in the face of such a deadly alternative. Such an approach is only a theoretical possibility at this point, Roach says.
Researchers at the University of Georgia contributed to the study, that was funded by the National Institutes of Health and the American Heart Association.
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