Corticosterone methyloxidase deficiency, also known as aldosterone synthase deficiency, is a disorder characterized by excessive amounts of sodium released in the urine (salt wasting), along with insufficient release of potassium in the urine, usually beginning in the first few weeks of life. This imbalance leads to low levels of sodium and high levels of potassium in the blood (hyponatremia and hyperkalemia, respectively). Individuals with corticosterone methyloxidase deficiency can also have high levels of acid in the blood (metabolic acidosis).

Mutations in the CYP11B2 gene cause corticosterone methyloxidase deficiency. This gene provides instructions for making an enzyme called aldosterone synthase. The aldosterone synthase enzyme is found in the adrenal glands, which are located on top of the kidneys.

Aldosterone synthase helps produce a hormone called aldosterone. Aldosterone regulates blood pressure by maintaining proper salt and fluid levels in the body. The aldosterone synthase enzyme is involved in a series of three chemical reactions that produce aldosterone from other (precursor) molecules: the conversion of 11-deoxycorticosterone to corticosterone, the conversion of corticosterone to 18-hydroxycorticosterone, and the conversion of 18-hydroxycorticosterone to aldosterone.

The CYP11B2 gene mutations that cause corticosterone methyloxidase deficiency lead to insufficient production of aldosterone, which impairs the kidneys' ability to reabsorb salt (sodium chloride or NaCl) into the blood and release potassium in the urine. As a result, excessive amounts of salt in the form of charged atoms (ions) of sodium (Na+) and chlorine (Cl-) leave the body in the urine, while not enough potassium is released. The resulting imbalance of ions in the body underlies the signs and symptoms of corticosterone methyloxidase deficiency.

Normal Function

The CYP11B2 gene provides instructions for making an enzyme called aldosterone synthase (previously known as corticosterone methyloxidase). This enzyme is found in the adrenal glands, which are located on top of the kidneys. Aldosterone synthase is a member of the cytochrome P450 family of enzymes. These enzymes are involved in the formation and breakdown of various molecules within cells.

Aldosterone synthase helps produce a hormone called aldosterone. Aldosterone helps control blood pressure by maintaining proper salt and fluid levels in the body. The aldosterone synthase enzyme is involved in a series of three chemical reactions that produce aldosterone from other (precursor) molecules: the conversion of 11-deoxycorticosterone to corticosterone, the conversion of corticosterone to 18-hydroxycorticosterone, and the conversion of 18-hydroxycorticosterone to aldosterone.

Health Conditions Related to Genetic Changes

Corticosterone methyloxidase deficiency

At least 30 CYP11B2 gene mutations that cause corticosterone methyloxidase deficiency (also known as aldosterone synthase deficiency) have been identified. These mutations lead to insufficient production of aldosterone, which impairs the kidneys' ability to reabsorb salt (sodium chloride or NaCl) into the blood and release potassium in the urine. As a result, excessive amounts of salt in the form of charged atoms (ions) of sodium (Na+) and chlorine (Cl-) leave the body in the urine, while not enough potassium is released. The resulting imbalance of ions in the body underlies the signs and symptoms of this disorder, which include nausea, vomiting, dehydration, low blood pressure, extreme tiredness (fatigue), and muscle weakness.

Familial hyperaldosteronism

A genetic change affecting the CYP11B2 gene causes familial hyperaldosteronism type I, a disorder that leads to high blood pressure (hypertension). This change joins (fuses) the section of the CYP11B2 gene that contains the instructions for making aldosterone synthase to a section of a nearby gene called CYP11B1. The added part of the CYP11B1 gene contains a section called a promoter region, which normally helps start the production of an enzyme called 11-beta-hydroxylase from the CYP11B1 gene.

By binding to the CYP11B1 gene's promoter region, a hormone called adrenocorticotropic hormone (ACTH) normally triggers production of the 11-beta-hydroxylase enzyme. In the fusion gene, ACTH binding abnormally triggers production of aldosterone synthase. High levels of aldosterone synthase result in excessive aldosterone production, which leads to the hypertension associated with familial hyperaldosteronism type I.

Other disorders

Normal variations (polymorphisms) of the CYP11B2 gene have been associated with increased risk of cardiovascular problems including hypertension, stroke caused by a lack of blood flow to the brain (ischemic stroke), and a heart rhythm abnormality called atrial fibrillation in people with heart failure. Researchers suggest that differences in blood pressure control resulting from the CYP11B2 gene variations may lead to increased risk of these cardiovascular problems.

Other Names for This Gene

• ALDOS
• aldosterone synthase
• aldosterone-synthesizing enzyme
• C11B2_HUMAN
• CPN2
• CYP11B
• CYP11BL
• CYPXIB2
• cytochrome P-450Aldo
• cytochrome P-450C18
• cytochrome P450 11B2, mitochondrial
• cytochrome P450 11B2, mitochondrial precursor
• cytochrome P450, family 11, subfamily B, polypeptide 2
• cytochrome P450, subfamily XIB (steroid 11-beta-hydroxylase), polypeptide 2
• mitochondrial cytochrome P450, family 11, subfamily B, polypeptide 2
• P-450C18
• P450aldo
• P450C18
• steroid 11-beta-monooxygenase
• steroid 11-beta/18-hydroxylase
• steroid 18-hydroxylase, aldosterone synthase, P450C18, P450aldo

Genomic Location

The hyponatremia, hyperkalemia, and metabolic acidosis associated with corticosterone methyloxidase deficiency can cause nausea, vomiting, dehydration, low blood pressure, extreme tiredness (fatigue), and muscle weakness. Affected infants often experience failure to thrive, which means they do not gain weight and grow at the expected rate. Severe cases of corticosterone methyloxidase deficiency can result in seizures and coma and can be life-threatening. However, affected individuals who survive infancy generally have a normal life expectancy, and the signs and symptoms of the disorder typically become milder or disappear by adulthood.

Corticosterone methyloxidase deficiency is a rare disorder; its prevalence is unknown. Researchers have described two types of the condition: Type I is more common in the Amish population of Lancaster, Pennsylvania, while type II is more common in people of Iranian Jewish ancestry. The two types have similar signs and symptoms but can be distinguished by laboratory testing.

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.