ALG12-congenital disorder of glycosylation (ALG12-CDG, also known as congenital disorder of glycosylation type Ig) is an inherited disorder with varying signs and symptoms that can affect several body systems. Individuals with ALG12-CDG typically develop signs and symptoms of the condition during infancy. They may have problems feeding and difficulty growing and gaining weight at the expected rate (failure to thrive). In addition, affected individuals often have intellectual disability, delayed development, and weak muscle tone (hypotonia), and some develop seizures.

Some people with ALG12-CDG have physical abnormalities such as a small head size (microcephaly) and unusual facial features. These features can include folds of skin that cover the inner corners of the eyes (epicanthal folds), a prominent nasal bridge, and abnormally shaped ears. Some males with ALG12-CDG have abnormal genitalia, such as a small penis (micropenis) and undescended testes.

People with ALG12-CDG often produce abnormally low levels of proteins called antibodies (or immunoglobulins), particularly immunoglobulin G (IgG). Antibodies help protect the body against infection by attaching to specific foreign particles and germs, marking them for destruction. A reduction in antibodies can make it difficult for affected individuals to fight infections.

Less common abnormalities seen in people with ALG12-CDG include a weakened heart muscle (cardiomyopathy) and poor bone development, which can lead to skeletal abnormalities.

Mutations in the ALG12 gene cause ALG12-CDG. This gene provides instructions for making an enzyme that is involved in a process called glycosylation. During this process, complex chains of sugar molecules (oligosaccharides) are added to proteins and fats (lipids). Glycosylation modifies proteins and lipids so they can fully perform their functions. The enzyme produced from the ALG12 gene transfers a simple sugar called mannose to growing oligosaccharides at a particular step in the formation of the sugar chain. Once the correct number of sugar molecules are linked together, the oligosaccharide is attached to a protein or lipid.

ALG12 gene mutations lead to the production of an abnormal enzyme with reduced activity. Without a properly functioning enzyme, mannose cannot be added to the chain efficiently, and the resulting oligosaccharides are often incomplete. Although the short oligosaccharides can be transferred to proteins and fats, the process is not as efficient as with the full-length oligosaccharide. As a result, glycosylation is reduced. The wide variety of signs and symptoms in ALG12-CDG are likely due to impaired glycosylation of proteins and lipids that are needed for normal function of many organs and tissues, including the brain.

Normal Function

The ALG12 gene provides instructions for making an enzyme that is involved in a process called glycosylation. During this process, complex chains of sugar molecules (oligosaccharides) are attached to proteins and fats (lipids). Glycosylation modifies proteins so they can fully perform their functions. Oligosaccharides are made up of many sugar molecules that are attached to one another in a stepwise process, forming a complex chain. The enzyme produced from the ALG12 gene transfers a simple sugar called mannose to growing oligosaccharides at a particular step in the formation of the chain. Once the correct number of sugar molecules are linked together, the oligosaccharide is attached to a protein or lipid.

Health Conditions Related to Genetic Changes

ALG12-congenital disorder of glycosylation

At least 13 mutations in the ALG12 gene have been found to cause ALG12-congenital disorder of glycosylation (ALG12-CDG). This condition typically leads to delayed growth and development, weak muscle tone (hypotonia), and other signs and symptoms. Mutations in the ALG12 gene result in the production of an abnormal enzyme with little activity. Without a properly functioning enzyme, mannose cannot be added to the chain efficiently, and the resulting oligosaccharides are often incomplete. Although the short oligosaccharides can be transferred to proteins and lipids, the process is not as efficient as with the full-length oligosaccharide. As a result, glycosylation is reduced. The wide variety of signs and symptoms in ALG12-CDG are likely due to impaired glycosylation of proteins and lipids that are needed for normal function in many organs and tissues, including the brain.

Other Names for This Gene

• asparagine-linked glycosylation 12 homolog (S. cerevisiae, alpha-1,6-mannosyltransferase)
• asparagine-linked glycosylation 12 homolog (yeast, alpha-1,6-mannosyltransferase)
• asparagine-linked glycosylation 12, alpha-1,6-mannosyltransferase homolog
• asparagine-linked glycosylation protein 12 homolog
• CDG1G
• dol-P-Man dependent alpha-1,6-mannosyltransferase
• dol-P-Man:Man(7)GlcNAc(2)-PP-Dol alpha-1,6-mannosyltransferase
• dolichyl-P-Man:Man(7)GlcNAc(2)-PP-dolichol alpha-1,6-mannosyltransferase
• dolichyl-P-Man:Man(7)GlcNAc(2)-PP-dolichyl-alpha-1,6-mannosyltransferase
• dolichyl-P-mannose:Man-7-GlcNAc-2-PP-dolichyl-alpha-6-mannosyltransferase
• ECM39
• hALG12
• mannosyltransferase ALG12 homolog
• membrane protein SB87
• PP14673

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.

ALG12-CDG is a rare condition; its prevalence is unknown. Only a handful of affected individuals have been described in the medical literature.