Related Diseases
Pelizaeus-Merzbacher Disease
Symptoms
Cause
Inheritance
Pelizaeus-Merzbacher disease (PMD) is named for two German physicians: Dr. Pelizaeus, who in 1885 described five boys in a single family with involuntary oscillatory eye movement, spasticity in the limbs, very limited head and trunk control, and delay in cognitive development; and Dr. Merzbacher, who in 1910, reexamined this family, which then included 14 affected individuals including two girls, and found that all affected family members shared a common female ancestor. In addition, he noted that the disease was passed exclusively through the female line without father-to-son transmission. Analysis of brain tissue from one affected individual showed that most of the central white matter generally lacked staining for myelin, the fat and protein based substance that acts as an insulator for nerve conductors in the Central Nervous System (CNS).
Symptoms
PMD usually begins during infancy and signs of the disease may be present at birth or in the first few weeks of life. The first recognizable sign is a form of involuntary oscillatory movements of the eyes called nystagmus. Some infants have stridor (labored and noisy breathing). Infants may show hypotonia (lack of muscle tone; floppiness) which may eventually evolve into spasticity (a type of increased muscle tone or stiffness of the muscles and joints). Motor and intellectual milestones are delayed, however the intellectual delay is often more apparent than real, if care and time are taken to evaluate the children. Children are often non-verbal. Head and trunk control may be impaired and wavering or tremor of the upper body when sitting is commonly seen (titubation). Seizures occur only rarely in affected children.
PMD is a leukodystrophy, a disease that affects the formation of the myelin sheath, the fat and protein covering--which acts as an insulator--on neural fibers (axons) in the central nervous system, which is the brain and spinal cord. It is a rare condition caused by mutations affecting the gene for the proteolipid protein 1 (PLP1). PLP1 constitutes about half of the protein of myelin and is its most abundant constituent other than the fatty lipids.
The types of mutations that are known to cause PMD fall into three general categories: null, point mutations and duplications. A mutation (any alteration of the DNA) that affects only a single base (one letter) is called a point mutation. Other types of mutations can occur as well, including insertions (additions of DNA into a gene), deletions (removal of all or part of a gene), and duplications where entire genes are present in one or more additional copies.
The point and other small mutations usually cause the substitution of one of the amino acids for another somewhere in the protein or prevent PLP1 from reaching its full length. This probably results in the protein being unable to fold into the correct shape or to interact with other myelin constituents. These mutant proteins are toxic to the octopus-like cells called oligodendrocytes, whose job it is to make myelin, and prevent them from making normal myelin. These cells operate by actually myelinating several axons at once. They develop tentacle-like appendages that wrap around neighboring axons providing the insulation needed for proper nerve function. However, in just the past two years or so it has been discovered that most PMD cases are caused by duplications of the entire PLP1 gene, accounting for 50-75% of the cases. This seems to be the case for PMD families around the world and we still do not understand why it occurs. We currently believe that the duplication results in too much otherwise normal proteolipid protein being made. This excessive PLP1 also appears to be toxic to oligodendrocytes. Complete lack of PLP1 results in a so-called ‘null’ syndrome that is usually less severe than the syndrome caused by PLP1 duplications or most of the PLP1 point mutations.
PMD may affect individuals of any ethnic background. It differs from Tay-Sachs and most of the other allied diseases in that it follows an X-linked pattern of inheritance and therefore affects males more often and more severely than females. The term “X-linked” refers to the location of the PLP1 gene on the X chromosome. The degree to which a person experiences symptoms depends on the nature of the PLP1 mutation that they have. Males, with only one X chromosome bearing the faulty gene, have little or no functional PLP1, and whatever PLP1 they can make may have toxic effects on their oligodendrocytes, causing them to degenerate in the most severely affected boys. Females with one normal gene and one faulty gene are said to be carriers. The absence or presence of symptoms in female carriers is related to the degree to which their oligodendrocytes are affected by the PLP1 gene abnormality. In most cases, any degenerating oligodendrocytes are replaced by cells that make normal PLP1, and female carriers are usually healthy.
The first male in a family to be diagnosed with PMD is often the son of an unsuspecting female carrier with no symptoms of the disease. A woman who is a carrier of PMD has a 25% chance with each pregnancy of having an affected child; in other words, on average, half of her sons will be affected. She may have a daughter who is a carrier, a daughter who is not a carrier, a son without the disease, or a son with the disease. A male with PMD disease who has children will have daughters who are carriers but sons will not be affected with PMD.
Currently only DNA analysis is available for PLP1 duplications, deletions and point mutations. While it is reasonable to first check for PLP1 duplications in a child suspected of having PMD, it is important to make sure that the point mutations are also looked for if duplications are not detected. Point mutation testing is not automatically done when duplication testing is negative. To learn more about PMD carrier testing please visit the Pelizaeus-Merzbacher Disease Foundation.
During the 2005 National Organization of Rare Diseases, Jayne Gershkowitz, Executive Director of NTSAD, and Kim Crawford, Member Services Director of NTSAD, met two dedicated gentlemen on the Board of Directors of the Pelizaeus-Merzbacher Disease Foundation (PMDF): Don Hobson and Robert Gasperetti. Don and Rob are both attended NTSAD’s 28th Annual Family Conference and Kim thoroughly enjoyed PMD Foundation Annual Conference.
There are many similarities between PMD, Canavan and other allied leukodystrophies and lysosomal storage disorders. NTSAD and the PMDF are currently discussing possible areas of collaboration to further our shared objectives of finding a treatment for PMD and other allied leukodystrophies and supporting the families who face the daily struggle of caring for a loved one with a rare, progressive neurological disorder.
*Special thanks to the www.pmdfoundation.org website for the educational materials that helped
prepare this.
Additional Informational Links
The following online resources may be helpful in learning more about Pelizaeus-Merzbacher Disease or locating support: