NORD gratefully acknowledges Grace M. Hobson, PhD, Principal Research Scientist Emeritus, Alfred I. DuPont Hospital for Children, Nemours Biomedical Research, for assistance in the preparation of this report.
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. It is one of the leukodystrophies in which disease is due 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 cannot function normally without it. In PMD, 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, late onset loss of motor abilities, and progressive deterioration of intellectual function. The neurologic signs of PMD are usually slowly progressive.
PMD is associated with abnormalities (mutations or variants) in the PLP1 gene. Several forms of the disorder have been identified including classic PMD; connatal (meaning "at birth") PMD; transitional PMD; and PLP1 null syndrome. Forms of complicated spastic paraparesis and pure spastic paraparesis (designated SPG2) and hypomyelination of early myelinating structures (HEMS) are also caused by mutations of the PLP1 gene.
The signs of PMD may vary widely from person to person. 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 are present at birth or are observed 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 PMD is more rapid and severe than the classic form and is often fatal during childhood.
Transitional PMD is a form of disease that is 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. In some cases, these signs resolve with age.
PMD is inherited as an X-linked recessive genetic disorder that affects mostly males. X-linked genetic disorders are conditions caused by an abnormal gene on the X chromosome. Females that have a disease gene present on one of their two X chromosomes are carriers for that disorder. Female carriers usually do not display symptoms because one of their two X chromosomes 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 PMD 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 in which females can be affected but less severely than the affected males in the family.
Male PMD patients usually do not reproduce, but males with X-linked disorders who do reproduce 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 with the PLP1 gene on it 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 at Xq22.2 and called the proteolipid protein gene or PLP1. Approximately 5 to 20% of males with a syndrome consistent with PMD do not have a mutation in the PLP1 gene. Some of these patients have a mutation of the GJC2 gene (autosomal recessive) that causes a Pelizaeus-Merzbacher-like disease (PMLD), which is clinically indistinguishable from PMD. Others have mutations in a growing list of other leukodystrophy genes that are being discovered (see Related Disorders).
Spastic paraplegia 2 (SPG2), hypomyelination of early myelinating structures (HEMS) and PMD result from different mutations of the same gene (allelic disorders) on the X chromosome, the PLP1 gene.
The classical and connatal forms of PMD affect males far more often than females. In rare cases, heterozygous females will exhibit some of the signs associated with the disorder. However, in the milder forms of PMD and the allelic SPG2, carrier females may be affected.
PMD is a rare disorder. Its prevalence in the general population is unknown but estimated as approximately 1 in 100,000 in the USA.
A diagnosis of PMD 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 PMD. 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 PMD and their families.
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