Researchers do not fully understand what causes PLS, although it is thought it could be due to a combination of environmental and genetic factors. Studies are being done to evaluate the possible causes, although linking causality can be difficult due to the relatively low number of people who are diagnosed with PLS.

Juvenile PLS may be caused by the ALS2 gene, although this condition is very rare.

Juvenile primary lateral sclerosis (JPLS) ", also known as primary lateral sclerois (PLSJ)," is a rare genetic disorder, with a small number of reported cases, characterized by progressive weakness and stiffness of muscles in the arms, legs, and face. The disorder damages motor neurons, which are specialized nerve cells in the brain and spinal cord that control muscle movement.

Juvenile Primary Lateral Sclerosis is inherited in an autosomal recessive pattern, which means two copies of the gene in each cell are altered. Most often, parents of affected individuals each carry one copy of the altered gene, but do not show any signs or symptoms.

Mutations in the ALS2 gene, found on Chromosome 2, are responsible for causing Juvenile Primary Lateral Sclerosis. The ALS2 gene provides instructions for making a protein called alsin. Alsin is abundant in motor neurons, but its function is not fully understood. Mutations in the ALS2 gene in this disorder disrupt the instructions for producing alsin. As a result, alsin is unstable and decays rapidly, or it is disabled and cannot function properly. It is currently unknown how the loss of functional alsin protein causes the death of motor neurons and the symptoms of juvenile primary lateral sclerosis.

Patients can often live with PLS for many years and very often outlive their neurological disease and succumb to some unrelated condition. There is currently no effective cure, and the progression of symptoms varies. Some people may retain the ability to walk without assistance, but others eventually require wheelchairs, canes, or other assistive devices.