Pelizaeus-Merzbacher disease

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Pelizaeus-Merzbacher disease


Pelizaeus-Merzbacher disease (PMD) is a neurological condition that affects myelin, the insulation surrounding the nerves in the brain and spinal cord.


PMD was named for two German doctors, F. Pelizaeus and L. Merzbacher, who first described the condition in the late 1800s. The severity of characteristics in PMD can range from mild to severe. PMD primarily affects males, but occasionally females have mild or moderate symptoms. PMD is also called a leukodystrophy, meaning that it affects the myelin, sometimes called the white matter, in the brain and spinal cord. The brain and the spinal cord together are called the central nervous system.

Genetic profile

PMD is caused by a mutation or change in the proteolipid protein gene (PLP). The PLP gene has the instructions to make proteolipid protein, one of the proteins that make up myelin in the central nervous system. When there is a mutation in the PLP gene, the myelin is not formed properly or is not made at all, resulting in PMD.

Genes are organized on structures called chromosomes . There are hundreds to thousands of genes on each chromosome. There are 46 chromosomes in each cell of the body. These are grouped into 23 pairs. The first 22 pairs are the same in both males and females. The 23rd pair is called the sex chromosomes; having one X chromosome and one Y chromosome causes a person to be male; having two X chromosomes causes a person to be female. A fetus acquires one member of each pair from the mother's egg and one member from the father's sperm.

The PLP gene is located on the X chromosome. Since males have only one X chromosome, they have only one copy of the PLP gene. Thus, a male with a mutation in his PLP gene will have PMD. Females have two X chromosomes and therefore have two copies of the PLP gene. If they have a mutation in one copy of their PLP genes, they may only have mild symptoms of PMD or no symptoms at all. This is because their normal copy of the PLP gene does make normal myelin. Females who have one copy of the PLP gene with a mutation and one normal copy are called carriers.


PMD is passed on through families by X-linked recessive inheritance . This means that affected males are related through females in the family. A male does not pass PMD on to his sons. Females pass on one of their X chromosomes to their sons or daughters. If the normal X chromosome is passed on, her son or daughter will be unaffected and cannot pass PMD onto their children. However, if the X chromosome with the PLP mutation is passed on, a daughter will be a carrier while the son would have PMD. Therefore, a female PLP mutation carrier has a 50%, or one in two chance of having a normal child (son or daughter), a 25%, or one in four chance of having a carrier daughter, and a 25%, or one in four chance of having an affected son.

Males with PMD usually do not reproduce and therefore do not pass PMD on.


Different types of mutations or changes in the PLP gene cause PMD. Everyone in a family who has the condition or is a carrier has the exact same PLP mutation. The most common type of mutation is a duplication (doubling) of the PLP gene. This means that two copies of the PLP gene are present on one X chromosome. Having this extra copy causes the myelin to be abnormal and leads to PMD. About 50–75% of people with PMD have a PLP duplication. The duplication usually causes a severe form of PMD. Another 15–20% of people with PMD have point mutations within their PLP gene. A point mutation is like a typo in the gene. This typo changes the message of the gene and also causes the myelin to be abnormal. A few patients with PMD have a deletion of the PLP gene as their cause of PMD. This means that they have no copies of the PLP gene if they are male or one copy if they are female. Another 5–20% of patients have characteristics of PMD, but no mutation has been found in their PLP gene. Scientists are working to determine the cause of disease in these people.


PMD has been described in people from all over the world and from many different ethnic backgrounds. The condition is rare and estimated to affect approximately one in 300,000 individuals in the United States.

Signs and symptoms

There is a range in the severity of symptoms of PMD. Rough categories have been set up based on the age of onset and severity of symptoms. However, many patients do not fall neatly into one of these categories and instead fall somewhere in between. Patients with different severities have been seen in the same family.

In the most severe form of PMD, symptoms are first noticed shortly after birth or in infancy. This is called connatal PMD. One of the first signs usually noticed is nystagmus, a side-to-side jerking of the eyes. This does not usually cause problems with vision. Patients can have significant mental retardation and never learn to walk, talk, or care for themselves. They may have noisy breathing called stridor and difficulty sucking. Seizures may be present in these children. They are often small for their age and have trouble gaining weight. Early on, they have floppy muscles called hypotonia, but later develop spasticity, which is stiffness or tightness in the muscles and joints.

Those patients who have classical PMD, which is less severe than the connatal type, usually have nystagmus. Nystagmus develops within the first few months of life. Other symptoms typically develop within the first few years. These children also have hypotonia that turns into spasticity. Sometimes these patients will learn to walk. However, they may need a wheelchair as their spasticity increases. Shaking of the head and neck called titubation may occur. Although these children often have moderate mental retardation, they often learn to talk and often understand more than is evident by their speech.

A less severe type of PMD is called the PLP null syndrome. Those affected do not usually have nystagmus and their spasticity may be mild. Symptoms develop in early childhood. This group of patients may also have a peripheral neuropathy, which is a problem with the nerves that run from the spinal cord through the body. This can cause weakness and problems with sensation (telling if something is hot or cold, for example). These patients usually talk and walk. They may have mild to moderate mental retardation.

There are some people who have PLP mutations who are very mildly affected. They have spasticity and sometimes have other problems such as a spastic bladder. Intelligence is normal or mildly impaired. Although these individuals have mutations in the PLP gene, their condition is given a different name, spastic paraplegia 2 (SPG2).


When problems are first noticed in an infant or a child, they will usually be referred to a pediatric neurologist who is specially trained in diseases of the nerves and muscles in children. At the initial evaluation, the neurologist will perform a clinical examination to evaluate the child's development and how well the nerves and muscles work. At this time, a thorough family history should be taken to determine if there are others in the family that are affected and if so, how they are related.

One of the initial tests that may be ordered is magnetic resonance imaging (MRI). In this test, pictures of the brain are taken and the amount of white matter in the brain is measured. In people with PMD, the amount of white matter is usually significantly reduced compared to normal. However, a decrease in white matter is seen in other neurological conditions and is not specific to PMD. Therefore, an MRI can be helpful in making the diagnosis of PMD, but if changes are seen on MRI, it does not confirm the diagnosis of PMD. Changes in the white matter may only be seen after one to two years of age when the brain has matured.

If no one else in the family is known to be affected, testing may be performed to rule out conditions other than PMD. Often PMD may not initially be suspected when no one else is affected in the family. It is not uncommon for people to be misdiagnosed initially. Sometimes the diagnosis of PMD is made only after a second affected child is born into a family.

Genetic testing

The only way to be absolutely sure that someone has PMD is by genetic testing , usually done by a blood test. First, the genetic material is evaluated to see if a PLP gene duplication is present. If this test is negative, additional testing can be done to look for other mutations in the gene. In 80% of people who have clear symptoms of PMD, a mutation can be found in the PLP gene. If a mutation in the PLP gene has been identified in a family member, testing on another child suspected of having PMD is possible to look at the mutation known to cause PMD in the family.

Treatment and management

There is no treatment or cure for PMD. Medical management is aimed at making life as full as possible and keeping people free from illness. Different types of therapy might be suggested. An occupational therapist can suggest adaptive devices to make it easier for an affected person to get around his or her home and perform everyday activities such as eating and using the bathroom. For example they may suggest installing bars to use in the bathroom or shower or special utensils for eating. Physical therapy can be helpful for reducing spasticity. Some patients with PMD require a feeding tube to help take in more calories. There are also medications that can assist in treating spasticity and seizures.

Prenatal testing

Testing during pregnancy to determine whether an unborn child is affected is possible if genetic testing in a family has identified a specific PLP mutation. This can be done at 10–12 weeks gestation by a procedure called chorionic villus sampling (CVS), which involves removing a tiny piece of the placenta and examining the cells. It can also be done by amniocentesis after 16 weeks gestation by removing a small amount of the amniotic fluid surrounding the baby and analyzing the cells in the fluid. Each of these procedures has a small risk of miscarriage associated with them. Couples interested in these options should have genetic counseling to carefully explore all of the benefits and limitations of these procedures.

Another procedure, called preimplantation diagnosis, allows a couple to have a child that is unaffected with the genetic condition in their family. This procedure is experimental and not available for all conditions. Those interested in learning more about this procedure should check with their doctor or genetic counselor.


The prognosis for patients with PMD varies in part due to the severity of the symptoms. The quality of care that patients receive also makes a difference in their quality of life. Boys with connatal PMD may die in infancy or early childhood, although some have survived into their 30s. Those with classic PMD or with the PLP null syndrome usually reach adulthood, and some have survived into their 70s. The symptoms of PMD usually progress very slowly and some people have a plateau of their symptoms over time. Some people may seem to get worse over time but it is likely to be due to factors such as growth spurts, poor nutrition, or frequent illness and not because of progression of the disease. Most patients with PMD die from pulmonary or breathing difficulties.



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Garbern, J., F. Cambi, M. Shy, and J. Kamholz. "The molecular pathogenesis of Pelizaeus-Merzbacher disease." Archives of Neurology 56 (October 1999): 1210–14.

Yool, D.A., J.M. Edgar, P. Montague, and S. Malcolm. "The proteolipid protein gene and myelin disorders in man and animal models." Human Molecular Genetics 9, no. 6 (2000): 987–992.


National Organization for Rare Disorders (NORD). PO Box 8923, New Fairfield, CT 06812-8923. (203) 746-6518 or (800) 999-6673. Fax: (203) 746-6481. <>.

PMD Foundation. Contact: Mike Laprocido, (609) 636-2482.

United Leukodystrophy Foundation. 2304 Highland Dr., Sycamore, IL 60178. (815) 895-3211 or (800) 728-5483. Fax: (815) 895-2432. <>.


"Clinical Programs." PMD Website at Wayne State University.<>.

GeneClinics. <>.

Online Mendelian Inheritance in Men. <>.

Karen M. Krajewski, MS, CGC