Johns Hopkins researchers have identified genetic mutations that appear to cause or contribute to more than half of all non-inherited or sporadic cases of the deadly muscle disease amyotrophic lateral sclerosis, or Lou Gehrig's disease.
"If these mutations really are specific to ALS, and we can develop a test to detect them, that could help us make the diagnosis and begin treatment much earlier in the course of the disease," says Jeffrey Rothstein, associate professor of neurology.
The newly identified mutations involve a protein called EAAT2, which normally deactivates and recycles glutamate, a chemical certain nerve cells use to send messages to each other.
Hopkins researchers had previously shown that many ALS patients have little or no EAAT2 in certain areas of the brain and spinal cord, creating an excess of glutamate that kills the nerves that control muscles.
This usually leads to paralysis and death in two to five years. Nearly 30,000 people currently have the disease, and 95 percent of them are thought to have the sporadic form.
The Hopkins team first found evidence of the mutation in a patient who had the inherited form of ALS and unusually reduced levels of EAAT2. The problem, the researchers discovered, was an error in the way the patient's nerve cells were translating the DNA code for EAAT2 into RNA.
Cells use RNA as the blueprint for building a protein. As they translate DNA into RNA, they normally cut out useless bits of DNA, called introns, and paste together the active parts, called exons. If the introns are not properly removed, they disrupt the blueprint and prevent the cell from making the protein properly.
"In this patient," Rothstein explains, "there were problems in the cutting and pasting. Some of the useless introns in the EAAT2 gene were being kept, while an exon was discarded. That produced defective RNA that led to a defective EAAT2 protein or no protein at all."
The team searched for and found similar mutations in 65 percent of ALS patients they surveyed. The bad RNA either produced a useless version of EAAT2 or suppressed production of normal EAAT2.
When researchers studied where the mutated EAAT2 RNA was present in the body, they found it only in areas where motor nerve cells were dying: in the spine and muscle control areas in the brain.
Scientists could not find the mutations in brain tissue from 12 normal subjects or 16 patients with Huntington's disease, Alz-heimer's disease or spinal muscular atrophy, an inherited disorder similar to ALS.
Rothstein's group next looked for a cause of the RNA problems and unexpectedly found that when the cells translated the genetic material, they cut and pasted randomly instead of at specific spots.
Something may be wrong in the biochemical machinery the body uses to decode the EAAT2 gene, Rothstein speculates.
It's also possible that there is an acquired or inherited mutation in the introns of EAAT2 that gives the wrong cues during the editing process, Rothstein says.
The new finding is among the first to be partially funded by the Cal Ripken/Lou Gehrig Fund for Neuromuscular Research, a fund for research into ALS and other neuromuscular diseases created in 1995 when Ripken broke Gehrig's long-standing record for consecutive games played.
Other funding organizations included the National Institutes of Health, the Muscular Dystrophy Association and the ALS Association.