2.1 Spastic Paraplegia Type 5A

At least 37 mutations in the CYP7B1 gene have been found to cause spastic paraplegia type 5A. This condition is characterized by muscle stiffness (spasticity) and severe weakness of the lower limbs (paraplegia), typically beginning in adolescence. Most CYP7B1 gene mutations change single protein building blocks (amino acids) in the oxysterol 7-alpha-hydroxylase enzyme. Such changes reduce the enzyme's activity. Other mutations result in a complete loss of functional enzyme.

Reduced oxysterol 7-alpha-hydroxylase enzyme activity does not seem to affect cholesterol breakdown or bile acid production in the liver. Another pathway in the liver can perform these functions, which may explain why reduction of oxysterol 7-alpha-hydroxylase activity does not impact liver function.

In the brain, a decrease in enzyme activity results in an accumulation of cholesterol and alters neurosteroid production triggered by oxysterol 7-alpha-hydroxylase. Abnormal levels of neurosteroids impairs cell survival, likely leading to nerve cell death. The abnormal buildup of cholesterol in the brain probably also contributes to the death of nerve cells. The loss of these cells results in the deterioration of nervous system functions (neurodegeneration) and causes the movement problems, weakness, and other signs and symptoms characteristic of spastic paraplegia type 5A.