PMM2-congenital disorder of glycosylation (PMM2-CDG, also known as congenital disorder of glycosylation type Ia) is an inherited condition that affects many parts of the body. The type and severity of problems associated with PMM2-CDG vary widely among affected individuals, sometimes even among members of the same family.

Individuals with PMM2-CDG typically develop signs and symptoms of the condition during infancy. Affected infants may have weak muscle tone (hypotonia), retracted (inverted) nipples, an abnormal distribution of fat, eyes that do not look in the same direction (strabismus), developmental delay, and a failure to gain weight and grow at the expected rate (failure to thrive). Infants with PMM2-CDG also frequently have an underdeveloped cerebellum, which is the part of the brain that coordinates movement. Distinctive facial features are sometimes present in affected individuals, including a high forehead, a triangular face, large ears, and a thin upper lip. Children with PMM2-CDG may also have elevated liver function test results, seizures, fluid around the heart (pericardial effusion), and blood clotting disorders. About 20 percent of affected infants do not survive the first year of life due to multiple organ failure.

The most severe cases of PMM2-CDG are characterized by hydrops fetalis, a condition in which excess fluid builds up in the body before birth. Most babies with hydrops fetalis are stillborn or die soon after birth.

People with PMM2-CDG who survive infancy may have moderate intellectual disability, and some are unable to walk independently. Affected individuals may also experience stroke-like episodes that involve an extreme lack of energy (lethargy) and temporary paralysis. Recovery from these episodes usually occurs over a period of a few weeks to several months.

During adolescence or adulthood, individuals with PMM2-CDG have reduced sensation and weakness in their arms and legs (peripheral neuropathy), an abnormal curvature of the spine (kyphoscoliosis), impaired muscle coordination (ataxia), and joint deformities (contractures). Some affected individuals have an eye disorder called retinitis pigmentosa that causes vision loss. Females with PMM2-CDG have hypergonadotropic hypogonadism, which affects the production of hormones that direct sexual development. As a result, females with PMM2-CDG do not go through puberty. Affected males experience normal puberty but often have small testes.

PMM2-CDG is caused by mutations in the PMM2 gene. This gene provides instructions for making an enzyme called phosphomannomutase 2 (PMM2). The PMM2 enzyme is involved in a process called glycosylation, which attaches groups of sugar molecules (oligosaccharides) to proteins. Glycosylation modifies proteins so they can perform a wider variety of functions. Mutations in the PMM2 gene lead to the production of an abnormal PMM2 enzyme with reduced activity. Without a properly functioning PMM2 enzyme, glycosylation cannot proceed normally. As a result, incorrect oligosaccharides are produced and attached to proteins. The wide variety of signs and symptoms in PMM2-CDG are likely due to the production of abnormally glycosylated proteins in many organs and tissues.

Normal Function

The PMM2 gene provides instructions for making an enzyme called phosphomannomutase 2 (PMM2). This enzyme is involved in a process called glycosylation, which attaches groups of sugar molecules (oligosaccharides) to proteins. Oligosaccharides are made up of many small sugar molecules that are attached to one another in a long chain. Glycosylation modifies proteins so they can perform a wider variety of functions. In one of the early steps of glycosylation, the PMM2 enzyme converts a molecule called mannose-6-phosphate to mannose-1-phosphate. Subsequently, mannose-1-phosphate is converted into GDP-mannose, which can transfer its small sugar molecule called mannose to the growing oligosaccharide chain. Once the correct number of small sugar molecules are linked together to form the oligosaccharide, it can be attached to a protein.

Health Conditions Related to Genetic Changes

PMM2-congenital disorder of glycosylation

More than 115 mutations in the PMM2 gene have been found to cause PMM2-congenital disorder of glycosylation (PMM2-CDG, also known as congenital disorder of glycosylation type Ia). This is a severe condition that is characterized by developmental delay, weak muscle tone (hypotonia), abnormal distribution of fat, and various other signs and symptoms. The mutations that cause PMM2-CDG change the structure of the PMM2 enzyme in different ways; however, all of the mutations appear to result in reduced enzyme activity. Decreased activity of the PMM2 enzyme leads to a shortage of GDP-mannose within cells. As a result, there is not enough activated mannose to form oligosaccharides. Glycosylation cannot proceed normally because incorrect oligosaccharides are produced. The signs and symptoms in PMM2-CDG are likely due to the production of abnormally glycosylated proteins in many organs and tissues.

Other Names for This Gene

• CDG1a
• phosphomannomutase
• PMM
• PMM2_HUMAN

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.

More than 800 individuals with PMM2-CDG have been identified worldwide.