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Pelizaeus Merzbacher disease

NORD is very grateful to James Garbern, MD, PhD, FAAN, deceased, Department of Neurology & Center for Molecular Medicine & Genetics, Wayne State University, for assistance in the preparation of this report.

Synonyms of Pelizaeus Merzbacher disease

  • Pelizaeus-Merzbacher disease
  • PMD
  • sclerosis, diffuse familial brain
  • sudanophilic leukodystrophy, Pelizaeus-Merzbacher type

Disorder Subdivisions

  • acute infantile Pelizaeus-Merzbacher brain sclerosis
  • autosomal dominant Pelizaeus-Merzbacher brain sclerosis
  • classical x-linked Pelizaeus-Merzbacher brain sclerosis
  • late onset Pelizaeus-Merzbacher brain sclerosis

General Discussion

Pelizaeus-Merzbacher disease (PMD) is a rare X-linked genetic disorder affecting the central nervous system that is associated with abnormalities of the white matter of the brain and spinal cord. Symptoms develop due to lack of the fatty covering (myelin sheath) of nerve cell fibers. Many areas of the central nervous system may be affected, including the deep portions of the cerebrum (subcortical), cerebellum, brain stem and spinal cord. Signs may include the impaired ability to coordinate movement (ataxia), involuntary muscle spasms (spasticity) that result in slow, stiff movements of the legs, delays in reaching developmental milestones, and late onset loss of motor abilities and progressive deterioration of intellectual function. The neurologic signs of Pelizaeus-Merzbacher disease are usually slowly progressive.

Pelizaeus-Merzbacher disease is associated with abnormalities (mutations) in the PLP1 gene. Several forms of the disorder have been identified including classic PMD; connatal PMD; transitional PMD; and PLP1 null syndrome. Forms of complicated spastic paraparesis and pure spastic paraparesis (designated SPG2) are also caused by the PLP1 gene.


The signs of Pelizaeus-Merzbacher disease may vary widely from case to case. The signs of the classical form of PMD usually begin during early infancy, typically before 2 months of age. Initially, affected infants may fail to develop normal control of the head and eyes, specifically abnormal head bobbing and rapid, involuntary, jerky eye movements (nystagmus). Abnormally slow growth may also be an early sign.

As affected infants and children age, additional signs may become apparent, including muscle tremors, weakness, facial grimacing, lack of muscle tone (hypotonia), impaired ability to coordinate voluntary movements (ataxia), and/or impairment in the acquisition of skills requiring the coordination of muscular and mental activities (psychomotor retardation) including delays in reaching developmental milestones such as sitting, standing, and walking.

Affected individuals may also develop involuntary muscle spasms (spasticity) that result in slow, stiff movements of the legs and potentially partial paralysis of the arms and legs (spastic quadriparesis); abnormal, permanent fixation of certain joints (contractures); progressive degeneration of the nerves that lead to the eyes (optic atrophy); and/or difficulty speaking (dysarthria).

In some cases, as affected children age, nystagmus may disappear. Some children may also develop skeletal deformities Secondary to the severe spasticity that typically develops over time.

The signs of connatal PMD begin during the first few weeks of life. This form of the disorder is characterized by weakness, spasticity, stridor, nystagmus, and seizures. Severe dysphagia may also occur, necessitating gastrostomy feeding. Affected infants may also exhibit deterioration of mental functions and failure to reach developmental milestones such as speaking and walking. The progression of this form of Pelizaeus-Merzbacher disease is more rapid and severe than the classic form and is often fatal during childhood.

Transitional PMD is a form of Pelizaeus-Merzbacher disease intermediate between the classical and connatal forms. The signs are similar to those of the classical and connatal forms of the disorder. However, the rate of progression is faster than the classical form but slower than the connatal form. The PLP1 null syndrome is characterized by mild spastic quadriparesis, mild ataxia, absence of nystagmus during infancy and a mild demyelinating peripheral neuropathy. Patients with this form typically learn to walk, but deteriorate more rapidly beginning in late adolescence or early adulthood.

Female carriers of PMD-related PLP1 mutations may have mild to moderate signs of the disease.


Pelizaeus-Merzbacher disease is inherited as an X-linked genetic disorder. X-linked genetic disorders are conditions caused by an abnormal gene on the X chromosome and occur mostly in males. Females that have a disease gene present on one of their X chromosomes are carriers for that disorder. Carrier females usually do not display symptoms because females have two X chromosomes and one is inactivated so that the genes on that chromosome are nonfunctioning. It is usually the X chromosome with the abnormal gene that is inactivated. Males have one X chromosome that is inherited from their mother and if a male inherits an X chromosome that contains a disease gene he will develop the disease. Female carriers of an X-linked disorder have a 25% chance with each pregnancy to have a carrier daughter like themselves, a 25% chance to have a non-carrier daughter, a 25% chance to have a son affected with the disease and a 25% chance to have an unaffected son. Females from families where males have a milder phenotype, such as SPG2 or the PLP1 null syndrome, should be more cautiously counseled. In some of these families the disorder behaves more like an X-linked dominant disorder with reduced penetrance.

Males with X-linked disorders pass the disease gene to all of their daughters who will be carriers. A male cannot pass an X-linked gene to his sons because males always pass their Y chromosome instead of their X chromosome to male offspring.

The only gene that has been found to be associated with PMD is located on the long arm of the X chromosome (Xq21.3-q22) and called the proteolipid protein gene or PLP1. Approximately 5-20% of males with a syndrome consistent with PMD do not have a mutation in the PLP1 gene so other genes may also be related to this condition. Mutations in the GJC2 (autosomal recessive), SLC16A2/MCT8 (X-linked) and HSPD1/HSP60 (autosomal recessive) genes are recently described causes of Pelizaeus-Merzbacher-like disease (PMLD). Other PMLD genes very likely remain to be discovered. Spastic paraplegia 2 (SPG2) and Pelizaeus-Merzbacher disease result from different mutations of the same gene (allelic disorders) on the X chromosome.

Affected Populations

The classical form of Pelizaeus-Merzbacher disease affects males far more often than females. In rare cases, heterozygous females will exhibit some of the signs associated with the disorder.

The recessively inherited cases of acute infantile (connatal) Pelizaeus-Merzbacher disease affect males and females in equal numbers. Adult-onset Pelizaeus-Merzbacher disease affects males and females in equal numbers and symptoms generally begin during the 3rd or 4th decade of life.

Pelizaeus-Merzbacher disease is a rare disorder. Its prevalence in the general population is unknown but estimated as approximately 1 in 100,000 in the USA.

Related Disorders

Symptoms of the following disorders can be similar to those of Pelizaeus-Merzbacher disease. Comparisons may be useful for a differential diagnosis:

Spastic paraplegia 2 (SPG2) and Pelizaeus-Merzbacher disease result from different mutations of the same gene (allelic disorders) on the X chromosome. This condition is characterized by progressive weakness (paraplegia) and increased muscle tone and stiffness (spasticity) of leg muscles. Initial findings typically include stiffness and relatively mild weakness of leg muscles, balance difficulties, involuntary eye movements (nystagmus), gradual deterioration of the nerves of the eyes (optic atrophy, and an unusually "clumsy" manner of walking). As the disorder progresses, walking may become increasingly difficult.

Leukodystrophies are a group of very rare, progressive, metabolic, genetic diseases that affect the brain, spinal cord and sometimes the peripheral nerves as well. Each type of leukodystrophy is caused by a specific gene abnormality that leads to abnormal development of one or more components (predominantly fats or proteins) that make up the white matter (myelin sheath) of the brain. The myelin sheath is the protective covering of the nerve and nerves can't function normally with out it. Each type of leukodystrophy affects a different part of the myelin sheath, leading to a range of neurological problems. (For more information on leukodystrophies, choose the specific disorder name as your search term in the Rare Disease Database.)

Multiple sclerosis is a chronic neuroimmunologic (both the nervous system and the immunological system are involved) disorder of the central nervous system involving the brain, spinal chord and optic nerves. By means of a mechanism not clearly understood, the protective fatty, insulating substance called the myelin sheath that covers the nerve is destroyed. The inflammatory attacks that produce the characteristic scarring (plaques or patches) of the myelin sheath occur randomly, vary in intensity, and at multiple sites. The course of the disease may advance, relapse, remit, or stabilize. The randomness of the location of plaques or patches affects the nerve's ability to transmit information (neurotransmission) and causes a wide range of neurological symptoms, which may vary from person to person. (For more information on this disorder choose "multiple sclerosis" as your search term in the Rare Disease Database.)

Standard Therapies

A diagnosis of Pelizaeus-Merzbacher disease may be suspected based upon a thorough clinical evaluation, a detailed patient history and a variety of specialized tests such as magnetic resonance imaging (MRI) to detect deficiency of white matter. Recognition of early myelination defects, such as lack of myelination in the cerebellum and brainstem, may aide in early diagnosis of the severe forms of PMD. Molecular genetic testing for the PLP1 gene is available to confirm the diagnosis.

Carrier testing is possible if a disease-causing mutation in the PLP1 gene has been identified in an affected family member.

Prenatal diagnosis and preimplantation genetic diagnosis is available if a PLP1 gene mutation is identified in an affected family member.

There is no standard treatment method or regimen for individuals with Pelizaeus-Merzbacher disease. Treatment is based upon specific symptoms present such as medications that prevent seizures or those used for movement disorders. Supportive care, including emotional support for family members, is recommended as needed.

Genetic Counseling is recommended for individuals affected with Pelizaeus-Merzbacher disease and their families.

Investigational Therapies

StemCells Inc., in conjunction with the UCSF Children's Hospital in San Francisco, is conducting a Phase I trial designed to assess the safety and preliminary effectiveness of HuCNS-SC cells (human neural stem cells) as a potential treatment for Pelizaeus-Merzbacher disease (PMD). The trial is expected to enroll four patients with the connatal type of PMD. For more information visit:

Information on current clinical trials is posted on the Internet at All studies receiving U.S. government funding, and some supported by private industry, are posted on this government web site.

For information about clinical trials being conducted at the NIH Clinical Center in Bethesda, MD, contact the NIH Patient Recruitment Office:

Toll-free: (800) 411-1222
TTY: (866) 411-1010

For information about clinical trials sponsored by private sources, contact:

Pelizaeus Merzbacher disease Resources

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Report last updated: 2010/04/08 00:00:00 GMT+0

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