Spastic paraplegia type 5A is one of a group of genetic disorders known as hereditary spastic paraplegias. These disorders are characterized by muscle stiffness (spasticity) and severe weakness in the lower limbs (paraplegia). Hereditary spastic paraplegias are often divided into two types: pure and complex. The pure types involve spasticity and weakness only in the lower limbs, while the complex types involve additional problems with other areas of the body; additional features can include changes in vision, changes in intellectual functioning, brain abnormalities, and disturbances in nerve function (neuropathy). Spastic paraplegia type 5A is usually a pure hereditary spastic paraplegia, although complex type features have been reported in some individuals, usually in those who have had the condition for many years.

In addition to spasticity and weakness, people with spastic paraplegia type 5A can lose the ability to sense the position of their limbs or detect vibrations with their lower limbs. They may also have muscle wasting (amyotrophy), reduced bladder control, or high arches of the feet (pes cavus). The signs and symptoms of spastic paraplegia type 5A usually appear in adolescence but can begin at any time between infancy and mid-adulthood. The condition slowly worsens over time, often leading affected individuals to require walking support or wheelchair assistance.

Spastic paraplegia type 5A is caused by mutations in the CYP7B1 gene. This gene provides instructions for making an enzyme called oxysterol 7-alpha-hydroxylase. In the brain, oxysterol 7-alpha-hydroxylase is involved in a pathway that converts cholesterol to hormones called neurosteroids. These neurosteroids increase nerve cell activity (excitability) and promote cell survival and communication between nerve cells. Oxysterol 7-alpha-hydroxylase helps maintain normal cholesterol levels in the brain and, by producing neurosteroids through altering existing hormones within the pathway, regulates the effects of neurosteroids on the brain.

CYP7B1 gene mutations that cause spastic paraplegia type 5A reduce or eliminate the activity of oxysterol 7-alpha-hydroxylase. 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 of spastic paraplegia type 5A.

Normal Function

The CYP7B1 gene is a member of the cytochrome P450 gene family. Enzymes produced from cytochrome P450 genes are involved in the formation and breakdown of various molecules and chemicals within cells. The CYP7B1 gene provides instructions for making an enzyme called oxysterol 7-alpha-hydroxylase. This enzyme is produced primarily in the liver and the brain. In the liver, oxysterol 7-alpha-hydroxylase is involved in the pathway that breaks down a waxy, fat-like substance called cholesterol to form a bile acid called chenodeoxycholic acid. Bile acids are a component of a digestive fluid called bile that digests fats.

In the brain, oxysterol 7-alpha-hydroxylase is also involved in a pathway that converts cholesterol to hormones called neurosteroids. Neurosteroids increase nerve cell activity (excitability) and promote cell survival and communication between nerve cells. The enzyme primarily converts the neurosteroid dehydroepiandrosterone (DHEA) into 7-hydroxy-DHEA. Oxysterol 7-alpha-hydroxylase helps maintain normal cholesterol levels in the brain and, by producing neurosteroids through altering existing hormones within the pathway, regulates the effects of neurosteroids on the brain.

Health Conditions Related to Genetic Changes

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.

Other Names for This Gene

• CBAS3
• CP7B
• cytochrome P450 7B1
• cytochrome P450, subfamily VIIB (oxysterol 7 alpha-hydroxylase), polypeptide 1
• oxysterol 7-alpha-hydroxylase

Genomic Location

This condition is inherited in an autosomal recessive pattern, which means both copies of the gene in each cell have mutations. The parents of an individual with an autosomal recessive condition each carry one copy of the mutated gene, but they typically do not show signs and symptoms of the condition.

Spastic paraplegia type 5A is a rare condition. Its prevalence is unknown.