RARE Daily

Researchers Identify Cause of Rare Deadly Neurological Disease

October 4, 2019

A deadly neurological disease that primarily affects infant boys is caused by increased sensitivity to iron in the brain, according to a new study by researchers at the Stanford School of Medicine, the University of California-San Francisco and the University of Cambridge.

The researchers also found that a drug that binds to and removes iron enhances the survival of cells involved in the disorder, and they are planning to conduct a clinical trial in Europe in children with the condition, called Pelizaeus-Merzbacher disease, to determine whether the drug can halt or slow its progression.

Pelizaeus-Merzbacher disease is a genetic disorder that affects the brain and spinal cord caused by the inability to form myelin, the outer covering of nerve cells, due to mutations in the PLP1 gene. It is a type of leukodystrophy characterized by problems with coordination, motor skills, and learning. It is passed through families in an X-linked recessive pattern, primarily affecting males, and occurring in about 1 in every 200,000 to 500,000 people. The age of onset and the severity of the symptoms vary greatly depending on the type of disease. People with the disease are usually diagnosed in infancy after displaying abnormal head and eye movements, poor muscle tone and developmental delays. The disease is progressive and is often fatal by the early teenage years.

The study was published online October 3 in Cell Stem Cell. “The rescue of diseased cells grown in the laboratory was dramatic,” said Marius Wernig, senior author and professor of pathology at Stanford. “It’s unbelievably satisfying to identify a potential treatment for such a devastating disorder.”

Until now, it was unclear how mutations in PLP1 caused the disease. Nobuta used skin cells from a patient with a specific mutation in PLP1 to create induced pluripotent stem cells, which can become nearly any cell in the body when exposed to the proper conditions. She then grew the stem cells under conditions that would stimulate their development into myelin-producing cells called oligodendrocytes.

Nobuta found that stem cells with the disease-associated mutation died before becoming functional oligodendrocytes. In contrast, cells in which the mutation had been corrected developed normally in a laboratory dish and on human brain slices. When transplanted into the brains of mice with a myelination disorder, the corrected cells not only developed normally but also contributed to the myelination of neurons in the animals. In contrast, most of the cells with the uncorrected mutation died after transplant.

“When Hiroko studied the cells more closely, she found that they exhibited many hallmarks of iron toxicity,” Rowitch said. “Adding a molecule that can chelate, or bind, iron outside the cell restored the cells’ ability to become mature, functional oligodendrocytes.”

The researchers injected the drug into week-old mice with a mutation in PLP1 that causes a very severe form of the disease. These mice usually die about 35 days after birth. They found that the drug reduced the levels of cell death and stimulated the formation of new myelin in the brain. They also saw a slight increase in how long the animals survived.

The study and its findings are an extension of earlier work by Wernig, who in 2007 was the first to show that it’s possible to directly reprogram mouse skin cells into pluripotent stem cells — the first step toward creating functional neurons in quantities sufficient to study neurological disorders such as schizophrenia and autism.

Photo: Marius Wernig, senior author and professor of pathology at Stanford

Author: Rare Daily Staff

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