Researchers have identified a novel brain disorder that is neurodegenerative, but so early onset that it disrupts development, leading to disturbances in the formation and function of hindbrain structures.

The specific mutation leading to the condition is rare. But they suggest that the split between neurodevelopmental disorders, where neurons or circuits fail to form correctly, and neurodegenerative disorders, where neurons or circuits are damaged after they are formed, is not an absolute one.

“We tend to think of things as being degenerative or developmental,” Joseph Gleeson told BioWorld Today. But in the case of the disorder he and his colleagues looked at, circuits fail to form because degeneration starts basically as soon as brain development does.

Gleeson is at the University of California at San Diego and the corresponding author of one of two papers showing that mutations in the kinase CLP-1 can lead to the neurological syndrome. Both papers appeared back to back in the April 24, 2014, issue of Cell.

Gleeson said that the work also points to what he believes will be the future of disease classification. The syndrome the two teams – his, and another led by scientists from the Baylor College of Medicine and the Austrian Institute of Biotechnology – have identified is so rare, and so similar to other neurological disorders, that it could not have been identified through clinical observations alone.

Only by “starting from a genetic point of view were we able to recognize it as a unique entity,” Gleeson said.

“We both started with enormous cohorts of patients,” he added, sequencing several thousand consanguineous families, where the parents were blood relatives and had children with neurological disorders of unknown origin.

Those sequencing data pointed to CLP-1 mutations as a previously unrecognized cause of neurological disease. Children with two copies of a mutated CLP-1 gene had severe brain malformations and physical and intellectual disabilities.

Gleeson’s group used “induced neurons” or i-neurons to study the effects of the CLP-1 mutation on cells. Such i-neurons are generated from skin cells of patients, but unlike induced pluripotent stem cells (iPSCs), they do not go through a stem-cell like intermediate.

They showed that the molecular reason behind the clinical symptom was a problem in processing transfer RNAs (tRNAs), which bring amino acids to the protein translation machinery to add to proteins.

Like mRNAs, tRNAs need to be spliced to function. In their papers, the two groups showed that mutations in a particular kinase in the splicing pathway interfere with tRNA processing, resulting in a simultaneous buildup of toxic upstream products and a depletion of the downstream metabolites that are necessary for proper cell functioning.

A defect in tRNAs would affect pretty much every cell in the body, and Gleeson said that “we really do not understand why neurons are more vulnerable to this mutation.” But the most likely reason is that they need lots of protein synthesis: “These are very long-lived cells, they are large, and they have a lot of metabolic demands.”

The rarity of the mutation is such that there is little to no market incentive to develop a treatment that specifically addresses mutations in CLP-1.

But overall, problems with tRNA appear to be involved in other disorders as well, including pontocerebellar hypoplasia and ALS. And so, “the tRNA class of neurological disease could be an important one to go after,” Gleeson said.

Gleeson and his team plan to use the i-neurons to gain a better understanding of the range of diseases that might be due to underlying deficiencies in tRNA function. They also want to identify the other components of the pathway that includes CLP-1. CLP-1 is a kinase, and involved in cutting tRNAs; there must be a ligase that joins the exons back together, which could possibly be a therapeutic target as well.

Finally, the CLP-1 containing pathway is not the only pathways cells use to make tRNAs. There is a second pathway, although whether the two operate completely independently of one another or share a cast of characters is not yet clear.

If they are independent of each other, Gleeson said, “the obvious treatment could be to somehow ramp up the other arm . . . but we don’t know how to do that,” at least not yet.