PLP1-related disorders

What are PLP1-related Disorders?

PLP1-related disorders are inherited conditions that cause neurological symptoms and belong to a group of conditions called "leukodystrophies." The symptoms individuals with PLP1-related disorders experience are due to a problem with the body's nervous system. PLP1-related disorders are caused by harmful genetic changes (variants) in the PLP1 gene.

PLP1-related disorders include Pelizaeus-Merzbacher disease and spastic paraplegia type 2, described below. There is wide variability in the severity of PLP1-related disorders, with individuals in the same family even having different forms of the disease.

Pelizaeus-Merzbacher disease

The symptoms of Pelizaeus-Merzbacher disease, also called PMD, include abnormal eye movements and problems with movement. There are several forms of PMD, including connatal, classic, and null syndrome.

The connatal form is the most severe and accounts for 10-15% of cases of PMD. People often have symptoms at birth or in early infancy, including low muscle tone (hypotonia), abnormal eye movements (nystagmus), respiratory distress, feeding difficulties, and seizures. People with the connatal form of PMD have intellectual disability, motor delays, muscle stiffness (spasticity), and paralysis. Individuals have limited language abilities and typically cannot walk.

People with the classic form of PMD account for 70% of all cases and usually show symptoms within the first year of life. These include low muscle tone (hypotonia), abnormal eye movements (nystagmus), and delayed motor skills. Motor skills develop throughout childhood, but these skills are lost as the child ages. As the disease progresses, symptoms include stiff muscles (spasticity), problems with balance and coordination (ataxia), involuntary muscle tensing (dystonia), and intellectual disability. People with the classic form of PMD may learn to walk with assistance.

People with the PLP1 null syndrome show more mild symptoms of PMD. These can include mild developmental delays, mild muscle weakness or numbness (peripheral neuropathy), mild muscle stiffness (spasticity), problems with balance and coordination (ataxia), and mild intellectual disabilities.

Spastic paraplegia type 2

The symptoms of spastic paraplegia type 2, also called SPG2, are muscle stiffness (spasticity) that gets worse over time and paralysis (paraplegia). SPG2 occurs in two forms: uncomplicated and complicated. Uncomplicated SPG2 affects the lower limbs only and does not impact cognition. Symptoms usually start between 1 and 5 years of age, but a few people may not develop symptoms until adulthood. Complicated SPG2 affects the lower limbs, upper limbs, and brain, including mild cognitive impairment and bladder control issues. Symptoms typically start between 1 and 5 years of age.

Additional considerations for carriers

PLP1-related disorders are X-linked diseases, meaning the PLP1 gene is on the X chromosome. Males have just one copy of the X chromosome and the PLP1 gene, while females have two copies. Because of this, PLP1-related disorders primarily affect males. However, some females (known as 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.

How common are PLP1-related Disorders?

The incidence of Pelizaeus-Merzbacher disease is estimated to be between 1 in 200,000 to 1 in 500,000 male births in US. The exact incidence of spastic paraplegia type 2 is unknown. Approximately one hundred individuals have been diagnosed with spastic paraplegia type 2 worldwide. PLP1-related disorders may be more common in individuals from the Czech Republic.

How are PLP1-related Disorders treated?

There is no cure for PLP1-related disorders. Treatment for these conditions is directed at managing an individual's specific symptoms and typically involves a multidisciplinary team, which includes neurologists, orthopedists, respiratory medicine, and gastroenterologists. Common interventions may include medications to treat seizures or to reduce muscle stiffness, physical therapy, and devices to assist with mobility, such as a wheelchair. Speech and swallowing studies may be needed to assess swallowing difficulties, and severe symptoms may require a feeding tube.

What is the prognosis for an individual with PLP1-related Disorders?

The prognosis for people with PLP1-related disorders depends on the severity of symptoms and the specific presentation of the condition. People with the connatal form of PMD die between infancy and the third decade of life. Individuals with other forms of PMD or the complicated form of SPG2 have a shortened lifespan and may die between the third and seventh decade of life. People with uncomplicated SPG2 typically have a normal lifespan.