PGM3-CDG

Other Names: Phosphoglucomutase 3 deficiency; CID due to PGM3 deficiency; PGM3-related congenital disorder of glycosylation; Combined immunodeficiency due to PGM3 deficiency; Immunodeficiency 23; Phosphoglucomutase deficiency type 3

PGM3-congenital disorder of glycosylation (PGM3-CDG) is an inherited condition that primarily affects the immune system but can also involve other areas of the body. The pattern and severity of this disorder's signs and symptoms typically vary.

Epidemiology

PGM3-CDG is a rare disorder, although its prevalence is unknown. Approximately 40 people with the condition have been described worldwide.

Cause

Mutations in the PGM3 gene cause PGM3-CDG. This gene provides instructions for making an enzyme called phosphoglucomutase 3 (PGM3). The PGM3 enzyme is involved in a process called glycosylation, which attaches groups of sugar molecules (oligosaccharides) to proteins. During this process, complex chains of sugar molecules (oligosaccharides) are added to proteins and fats (lipids). Glycosylation modifies proteins and lipids so they can perform a wider variety of functions.

Mutations in the PGM3 gene lead to the production of a PGM3 enzyme with reduced activity. Without a properly functioning enzyme, glycosylation cannot proceed normally. The wide variety of signs and symptoms in PGM3-CDG are likely due to impaired glycosylation of proteins and lipids that are needed for the normal function of many organs and tissues. Immune system proteins are highly dependent on glycosylation to function normally, which likely explains why people with PGM3-CDG have immune deficiency.

Inheritance

Autosomal recessive inheritance, a 25% chance

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.

Signs and symptoms

Most people with PGM3-CDG have impaired immune function (immune deficiency). Many have a shortage of white blood cells (leukopenia), which normally protect the body from infection. Because affected individuals lack the necessary immune cells to fight off certain bacteria, viruses, and fungi, they are prone to repeated and persistent infections that often occur in the lungs, ears, skin, or gastrointestinal tract. In severe cases of PGM3-CDG, impaired bone marrow function may lead to a decrease in the production of all blood cells, resulting in a condition called bone marrow failure. Affected individuals usually also have allergies, asthma, or an inflammatory skin condition called eczema. People with PGM3-CDG may develop autoimmunity, which occurs when the body attacks its own tissues and organs by mistake. Persistent illness may cause affected children to grow more slowly than other individuals.

Additionally, people with PGM3-CDG often have abnormally high levels of immune system proteins called antibodies (also known as immunoglobulins), particularly immunoglobulin E (IgE). Antibodies help protect the body against infection by attaching to specific foreign particles and germs, marking them for destruction. The effect of abnormal levels of antibodies in PGM3-CDG is unclear.

People with PGM3-CDG often have intellectual disability, delayed development, and weak muscle tone (hypotonia). Many affected individuals have skeletal abnormalities involving the ribs or bones in the hands, feet, or spine. Some people with this condition have distinct facial features, such as a flat or sunken appearance of the middle of the face (midface hypoplasia), small chin (micrognathia), full lips, downturned corners of the mouth, and wide nostrils that open to the front rather than downward. PGM3-CDG can also cause problems in the lungs, gastrointestinal tract, and kidneys.

Lifespan varies widely in people with PGM3-CDG; some do not survive past infancy while others live into late adulthood.

Diagnosis

Laboratory studies shows neutropenia and leukopenia, with particularly decreased levels of CD8 -positive T cells and CD27 (TNFRSF7; 186711) memory B cells, as well as increased IgE, IgG, and IgA. In vitro studies shows that stimulation of patient CD4 (186940)-positive T cells resulted in increased levels of certain cytokines, including IL4 (147780), IL5 (147850), IL13 (147683), and IL17 (IL17A; 603149), compared with controls. Stimulation of peripheral blood cells resulted in increased proliferation of CD4-positive and CD8-positive T cells compared with controls. There was also evidence of a glycosylation defect, with decreased UDP-GalNAc and hyposialylation of O-linked serum glycans. However, glycosylation of serum transferrin (TF; 190000) was normal.

NIH genetic and rare disease info

• NIH info on PGM3-CDG

PGM3-CDG is a rare disease.

PGM3-CDG Resources
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