Spastic paraplegia type 2 is part of a group of genetic disorders known as hereditary spastic paraplegias. These disorders are characterized by progressive muscle stiffness (spasticity) and the development of paralysis of the lower limbs (paraplegia). Hereditary spastic paraplegias are divided into two types: pure and complex. The pure types involve the lower limbs. The complex types involve the lower limbs and can also affect the upper limbs to a lesser degree; the structure or functioning of the brain; and the nerves connecting the brain and spinal cord to muscles and sensory cells that detect sensations such as touch, pain, heat, and sound (the peripheral nervous system). Spastic paraplegia type 2 can occur in either the pure or complex form.

People with the pure form of spastic paraplegia type 2 experience spasticity in the lower limbs, usually without any additional features. People with the complex form of spastic paraplegia type 2 have lower limb spasticity and can also experience problems with movement and balance (ataxia); involuntary movements of the eyes (nystagmus); mild intellectual disability; involuntary, rhythmic shaking (tremor); and degeneration (atrophy) of the optic nerves, which carry information from the eyes to the brain. Symptoms usually become apparent between the ages of 1 and 5 years; those affected are typically able to walk and have a normal lifespan.

Mutations in the PLP1 gene cause spastic paraplegia 2. The PLP1 gene provides instructions for producing proteolipid protein 1 and a modified version (isoform) of proteolipid protein 1, called DM20. Proteolipid protein 1 and DM20 are primarily located in the brain and spinal cord (central nervous system) and are the main proteins found in myelin, the fatty covering that insulates nerve fibers. A lack of proteolipid protein 1 and DM20 can cause a reduction in the formation of myelin (dysmyelination) which can impair nervous system function, resulting in the signs and symptoms of spastic paraplegia type 2.

Normal Function

The PLP1 gene provides instructions for producing proteolipid protein 1 and a modified version (isoform) of that protein called DM20. Proteolipid protein 1 is found primarily in nerves in the brain and spinal cord (the central nervous system) and DM20 is produced mainly in nerves that connect the brain and spinal cord to muscles (the peripheral nervous system). These two proteins are found within the cell membrane of nerve cells, where they make up a large proportion of myelin and help myelin stay anchored to the cells. Myelin is the fatty covering that insulates nerve fibers and promotes the rapid transmission of nerve impulses.

Health Conditions Related to Genetic Changes

Pelizaeus-Merzbacher disease

There are more than 280 mutations in the PLP1 gene that have been found to cause Pelizaeus-Merzbacher disease. Pelizaeus-Merzbacher disease is an inherited condition involving the central nervous system that primarily affects males. Individuals with Pelizaeus-Merzbacher disease have neurological problems including abnormal eye movements (nystagmus) and other movement abnormalities. In addition, these individuals have difficulty walking or cannot walk.

An extra copy (duplication) of the PLP1 gene accounts for 50 to 70 percent of all Pelizaeus-Merzbacher disease mutations. In many cases, genes near the PLP1 gene are also duplicated, but having extra copies of these genes does not seem to impact the severity of the condition. In another 10 to 25 percent of cases, mutations change single protein building blocks (amino acids) in the proteolipid protein 1 and DM20 proteins and lead to excess or abnormal proteins that are often misfolded. Excess or abnormal proteins become trapped within cell structures and cannot travel to the cell membrane. The accumulation of excess proteins leads to swelling and breakdown of nerve fibers. In less than 2 percent of cases, a mutation that deletes the entire PLP1 gene causes Pelizaeus-Merzbacher disease. Such a deletion prevents production of proteolipid protein 1 and DM20 protein.

All of these PLP1 gene mutations prevent proteolipid protein 1 and DM20 from reaching the nerve cell membrane where they are needed to form myelin. Decreased myelin production leads to nerve fiber damage and the loss of nerve fibers that are covered by myelin (leukodystrophy), leading to impairment of nervous system function and the signs and symptoms of Pelizaeus-Merzbacher disease.

Spastic paraplegia type 2

More than 20 mutations in the PLP1 gene that cause spastic paraplegia type 2 have been identified. Spastic paraplegia type 2 is characterized by movement problems, particularly muscle stiffness (spasticity) in the lower limbs that worsens over time. Generally, PLP1 gene mutations that cause spastic paraplegia type 2 disrupt the production of the proteolipid 1 protein but do not interfere with the production of DM20. Changes in the proteolipid 1 protein appear to impair its function, resulting in reduced myelin production. It is thought that because there is some remaining myelin production, the signs and symptoms of spastic paraplegia type 2 are milder than those of Pelizaeus-Merzbacher disease (described above).

Other Names for This Gene

• lipophilin
• major myelin proteolipid protein
• MMPL
• MYPR_HUMAN
• PLP
• PLP/DM20

Genomic Location

This condition is inherited in an X-linked recessive pattern. A condition is considered X-linked if the mutated gene that causes the disorder is located on the X chromosome, one of the two sex chromosomes. In males (who have only one X chromosome), one altered copy of the gene in each cell is sufficient to cause the condition. Because females have two copies of the X chromosome, one altered copy of the gene in each cell usually leads to less severe symptoms in females than in males, or may cause no symptoms at all. A characteristic of X-linked inheritance is that fathers cannot pass X-linked traits to their sons.

In X-linked recessive inheritance, a female with one altered copy of the gene in each cell is called a carrier. She can pass on the gene, but generally does not experience signs and symptoms of the disorder. Some females who carry a PLP1 mutation, however, may experience muscle stiffness and a decrease in intellectual function. Females with one PLP1 mutation have an increased risk of experiencing progressive deterioration of cognitive functions (dementia) later in life.

The prevalence of all hereditary spastic paraplegias combined is estimated to be 2 to 6 in 100,000 people worldwide. Spastic paraplegia type 2 likely accounts for only a small percentage of all spastic paraplegia cases.