PLP1-related disorders are inherited conditions that affect the nervous system and cause neurological problems. They are part of a group of conditions called leukodystrophies.
PLP1-related disorders include Pelizaeus-Merzbacher disease (PMD) and spastic paraplegia type 2 (SPG2).
Pelizaeus-Merzbacher disease (PMD): PMD causes issues with movement and eye control. There are different forms of PMD: connatal, classic, and null syndrome. Connatal PMD is the most severe and usually starts at birth or early infancy. Symptoms include low muscle tone (hypotonia), unusual eye movements (nystagmus), breathing problems, feeding difficulties, and seizures. People with connatal PMD often have intellectual disabilities, motor delays, muscle stiffness (spasticity), and paralysis. They usually have limited language abilities and can’t walk. Classic PMD is the most common form, affecting about 70% of people with PMD. Symptoms often appear in the first year of life and include low muscle tone, abnormal eye movements, and delayed motor skills. While motor skills may develop in childhood, they tend to worsen with age. As the disease progresses, people may experience muscle stiffness, coordination problems (ataxia), involuntary muscle tensing (dystonia), and intellectual disabilities. Some individuals may be able to walk with help. PLP1 Null Syndrome is a milder form of PMD. Symptoms can include mild developmental delays, muscle weakness or numbness (peripheral neuropathy), mild muscle stiffness, balance and coordination problems, and mild intellectual disabilities.
Spastic Paraplegia Type 2 (SPG2): SPG2 causes muscle stiffness that gets worse over time and can lead to paralysis. There are two types of SPG2- Uncomplicated and Complicated. Uncomplicated affects only the lower limbs and does not affect thinking abilities. Symptoms usually start between ages 1 and 5, but sometimes they don’t appear until adulthood. Complicated affects the lower and upper limbs, the brain, and includes mild cognitive impairment and bladder control problems. Symptoms also typically start between ages 1 and 5.
There is no cure for PLP1-related disorders. Treatment focuses on managing symptoms and may involve a team of specialists, including neurologists, orthopedists, respiratory doctors, and gastroenterologists. Common treatments include medications to control seizures and reduce muscle stiffness, physical therapy, and mobility aids like wheelchairs. Some people may need speech and swallowing therapy or a feeding tube if they have severe swallowing difficulties.
These disorders are caused by pathogenic variants in the PLP1 gene and exhibit X-linked recessive inheritance. This means that one pathogenic variant is enough to cause the disease in both individuals assigned male at birth (who have one X chromosome and one Y chromosome) and individuals assigned female at birth (who have two X chromosomes) may experience symptoms depending on how many copies of the X chromosome that has the pathogenic variant are turned on in the cells.
PLP1-related disorders primarily affect males. However, some carrier females can have symptoms. Symptoms, if they occur, usually occur in adulthood and are mild to moderate. The most common symptoms are those associated with the PLP1 null syndrome or SPG2. Rarely carrier females are diagnosed with Pelizaeus-Merzbacher disease.
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Written August 2024
