Scientists uncover the cause of a rare fatal nerve disease

By Dr. Liji Thomas, MDOct 4 2019

Pelizaeus-Merzbacher syndrome is a rare neurologic condition, classified as a leukodystrophy, that affects around 1 in 200,000 to 500,000 people. Mostly, these are baby boys. The disease prevents the normal development of white matter in the nervous system.

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The condition is due to the brain’s exaggerated reaction to iron. For decades nobody knew that this was the cause. Now, a new study published in the journal Cell Stem Cell will reveal how the discovery was made, and how simply adding a chemical that binds to iron, so it can be removed from the cell, enables the sick cells to grow back dramatically.

It's unbelievably satisfying to identify a potential treatment for such a devastating disorder.”

Researcher Marius Wernig

The description is right, given the symptoms and signs in infancy itself, the baby shows abnormal movements of the head and the eyes feels floppy with weak muscle tone and is developmentally delayed. The condition is progressive, and most patients may succumb to it by the time they enter their teens. The cause of this syndrome is any of several mutations occurring in the PLP1 gene, which takes part in myelin synthesis. The substance called myelin is fatty and forms an insulating layer over the long fibers extending from one nerve cell to another, called the axonal myelin sheath. The functions of myelin include both insulations as well as facilitating faster conduction of nerve impulses.

How does the mutation act?

To understand how the gene was responsible for the disease, the researchers took skin cells from one of the patients and converted them to induced pluripotent stem cells. Pluripotent simply means the ability to do more than one kind of thing. A stem cell, meanwhile, is a cell that can form any kind of tissue because it has not yet become any specific type of cell. When you put these terms together, you can picture the type of cell the researchers were playing with – a cell that can change into almost any type of body cell provided it is stimulated properly.

These cells were then stimulated by culture conditions that caused them to differentiate into oligodendrocytes – a type of neuron that has only a few cell extensions, or branch-like dendrites, and which produce myelin.

The stem cells grown from the patient with a PLP1 mutation were unable to complete this conversion into oligodendrocytes. Instead, they died. On the other hand, when the defective gene was corrected, the stem cells grew and developed into normally functioning oligodendrocytes – both in culture and in living slices of the human brain.

Now, these cells were transplanted into mouse brains from animals that had problems with myelination. The researchers saw that the corrected cells developed normally, and also helped the myelination process to continue as expected. On the other hand, most cells in which the mutation persisted died after they were transplanted.

On looking at the defective cells, they found that they were showing unmistakable signs of excessive iron exposure. The addition of a chelating agent, which binds iron before it enters the cell, allowed the cells to recover their ability to differentiate into normal myelin-producing oligodendrocytes.

To confirm these findings, the researchers injected the chelator into baby mice a week old, which had a severe PLP1 mutation. As a result of this mutation, the mice typically died at about five weeks of age. However, when these mice were given the chelator, a higher percentage of cells survived, and the amount of myelin formed in the brain also increased. The overall survival also increased, though only slightly.

Conclusion

The current study built on earlier work on reprogramming skin cells into pluripotent stem cells, done by Wernig in 2007. This important achievement ensured a sufficient supply of functional nerve cells so that neurologic disorders could be studied in greater detail – including autism spectrum disorder (ASD) and schizophrenia.

As a researcher you hope that something you discover will eventually contribute in some way -- perhaps decades later -- to patient care, but this happened so much sooner than we anticipated. It's exciting to think that we could soon be testing this approach in patients.”

Marius Wernig

The team is planning to test out the drug in children with this condition in the form of a clinical trial to find out if the disease progression can be slowed or even stopped by preventing iron exposure in the brain cells.