Pelizaeus-Merzbacher disease

Pelizaeus-Merzbacher disease (PMD) is a rare condition characterized by demyelination and progressive degeneration of the central nervous system (CNS), which includes the brain and spinal cord. This leads to decreased motor and cognitive function, as well as decreased coordination. There are three types of PMD: classic Pelizaeus-Merzbacher disease, transitional Pelizaeus-Merzbacher disease, and connatal Pelizaeus-Merzbacher disease. Classic PMD is the most common form and shares similar features with connatal PMD, though connatal PMD tends to cause more severe symptoms. Those with the severe form of PMD have a poorer prognosis, while those with the classic form of the condition may have an average life expectancy. 

PMD is classified within a group of genetic disorders called leukodystrophies. Leukodystrophies are movement disorders that cause defects in the white matter of the brain and spinal cord.  Other leukodystrophies include adrenoleukodystrophy (ALD), Canavan disease, Niemann-Pick disease, and cerebral adrenoleukodystrophy.

PMD is caused by a mutation in the PLP1 gene, an X-linked gene that controls proteolipid protein-1 (PLP1) synthesis. Mutations in the PLP1 gene cause an impaired ability of the body to produce myelin. Myelin, also known as the myelin sheath, is an insulating sleeve that covers the axons, or nerve fibers, of the CNS that help with electrical conduction and protection. PLP adheres and compacts myelin membranes together, playing an integral role in the stabilization of the myelin sheath to support nerve conduction down the axon terminal. Without the myelin sheath, signal conduction from the central and peripheral nervous system is impaired.

PMD more commonly affects genetic males than genetic females as genetic females have two X chromosomes. The unaffected X chromosome is usually able to compensate for the defective X chromosome, while genetic males only have one X chromosome, therefore they are unable to counteract the effects of the defective gene. Thus, PMD is said to follow an X-linked recessive inheritance pattern.

In the United States, the prevalence of PMD is around 1 in every 200,000 to 1 in every 500,000 individuals.

The signs and symptoms of PMD vary greatly but generally begin within the first year of life. With classic Pelizaeus-Merzbacher disease, the infant will typically initially experience problems with movement, specifically an inability to control the movements of the head. Symptoms may include unusual head bobbing and nystagmus, or rapid involuntary movements of the eyes. The infant may also have delayed growth, facial grimacing, a lack of muscle tone (i.e., hypotonia), and issues with coordination (i.e., ataxia). Over time they can develop more progressive problems such as muscle contractures, muscle spasms, skeletal deformities, and swallowing problems. Infants with PMD can also have developmental delays.

Connatal Pelizaeus-Merzbacher disease is a more severe form of PMD that is often present at birth and begins more rapidly with nystagmus, muscle spasticity, and seizures, and is commonly fatal during the first decade of life. Transitional PMD is usually a mix of classic and connatal features and usually progresses slower than connatal and faster than classic.