Rare neurological disease shines light on health of essential nerve cells

Ian Duncan is a Scotsman with the iron discipline and stamina of a competitive marathoner, triathlete and cross-country skier. As a neuroscientist at the School of Veterinary Medicine at the University of Wisconsin-Madison, he’s applied his tenacity to a rare genetic disorder.

Known as Pelizaeus Merzbacher disease or PMD, it’s a devastating neurological condition that, in its most severe form, kills infants weeks after birth.

Thirty years ago, Duncan noticed a genetic mutation in dogs that was practically identical to the disease in humans. Now, in the online edition of the journal Neurobiology of Disease, Duncan has laid out the results of his marathon pursuit of PMD.

His work underscores the benefits of patience and persistence in the discovery of unexpected results that may point toward new therapies.

Like multiple sclerosis, PMD is a disease that interferes with myelin, the insulation needed for normal communication in the nervous system. The genetic mutation that blocks the formation of myelin is found on the X chromosome, so the disease occurs only in males.

Studies of the dogs are crucial, Duncan says, since PMD is so rare in humans - occurring in one male birth in roughly 200,000.

Duncan says his studies have yielded discoveries that could help fight the grievous illness.

What is Pelizaeus-Merzbacher disease?

Pelizaeus-Merzbacher disease is an inherited condition involving the brain and spinal cord (central nervous system). This disease is one of a group of genetic disorders called leukodystrophies. Leukodystrophies are characterized by degeneration of myelin, which is the covering that protects nerves and promotes the efficient transmission of nerve impulses. Pelizaeus-Merzbacher disease is caused by an inability to form myelin (dysmyelination). As a result, individuals with this condition have impaired intellectual functions, such as language and memory, and delayed motor skills, such as coordination and walking. Typically, motor skills are more severely affected than intellectual function; motor skills development tends to occur more slowly and usually stops in a person’s teens, followed by gradual deterioration.

Rare neurological disease shines light on health of essential nerve cells Pelizaeus-Merzbacher disease is divided into classic and connatal types. Although these two types differ in severity, their features can overlap.

Classic Pelizaeus-Merzbacher disease is the more common type. Within the first year of life, those affected with classic Pelizaeus-Merzbacher disease typically experience weak muscle tone (hypotonia), involuntary movements of the eyes (nystagmus), and delayed development of motor skills such as crawling or walking. As the child gets older, nystagmus usually stops but other movement disorders develop, including muscle stiffness (spasticity), problems with movement and balance (ataxia), and involuntary jerking (choreiform movements).

Connatal Pelizaeus-Merzbacher disease is the more severe of the two types. Symptoms can begin in infancy and include problems feeding, a whistling sound when breathing, progressive spasticity leading to joint deformities (contractures) that restrict movement, speech difficulties (dysarthria), ataxia, and seizures. Those affected with connatal Pelizaeus-Merzbacher disease show little development of motor skills and intellectual function.

How common is Pelizaeus-Merzbacher disease?
The prevalence of Pelizaeus-Merzbacher disease is estimated to be 1 in 200,000 to 500,000 males in the United States. This condition rarely affects females.

First, Duncan determined that in dogs, myelin in the spinal cord is gradually generated after birth, proving that the cells that make myelin survive and work in some regions. “The brain is acting differently than the spinal cord,” Duncan says. “It’s striking, on day one there is no myelin. But after some months the spinal cord develops myelin and by two years it is almost normal, but the brain is not, and the lack of myelin is the cause of death.”

In these dogs, and presumably in human PMD, there are abnormally few myelin-forming cells, or oligodendrocytes, in the brain and spinal cord. “For reasons we don’t know, the spinal cord repairs because the number of those cells increases with time, but this doesn’t happen in the brain.”

Second, nerve fibers called axons totally lacking myelin have survived for more than two years in the dogs, flouting the accepted wisdom that axons cannot survive without myelin. (Axons are fibers that connect nerve cells to each other, and to muscles.) If lack of myelin is not a death sentence for the axon, the clinical picture for many myelin-related diseases is much brighter, Duncan says.

PMD Epidemiology

  This is a rare disease with an international incidence that is probably between 0.1 and 1 per 100,000 of the population.
  As an X-linked disease it would be natural to expect that males are affected and females are carriers but females do have features of the disease (see ‘Female carriers’, below).
  This disease affects all ethnic groups.

Third, the recognition that myelin-making cells are still active is shifting Duncan’s focus toward drugs that can increase their number and activity.

“There is hope that several drugs already on the market could stimulate the production of more myelin,” he says. “That could help PMD patients - both human and canine - and potentially MS patients as well.”

That concept is already being tested in MS patients in a phase 1 trial at the University of California, San Francisco.

Unlike MS, PMD is a genetic disorder, suggesting the need for gene therapy. However, Duncan suspects that simply increasing the number of myelin-producing cells early in PMD might cause myelin formation in the brain as well as the spinal cord, eliminating the need for gene therapy.

Finally, Duncan says, his studies make clear that oligodendrocytes - cells that create a protective sheath around myelin - develop differently in the spinal cord than in the brain.

“It’s a big surprise,” he says. “Neurologists have focused on the brain, which is bigger and easier to image.”

Duncan says the dog model of PMD is “strikingly similar to the human disease which we are unable to study in any detail. This is a naturally occurring disease, and our study of it will generate treatments for dogs and for humans alike.”

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David Tenenbaum, 608-265-8549, .(JavaScript must be enabled to view this email address)

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Ian Duncan
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608-263-9828

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University of Wisconsin-Madison

Journal - Neurobiology of Diseas

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