Congenital disorder of glycosylation type 1A




General Introduction about Congenital disorder of glycosylation:

Congenital disorder of glycosylation (carbohydrate-deficient glycoprotein syndrome) is one of several rare inborn errors of metabolism in which glycosylation of a variety of tissue proteins and/or lipids is deficient or defective. Congenital disorders of glycosylation are sometimes known as CDG syndromes. They often cause serious, sometimes fatal, malfunction of several different organ systems (especially the nervous system, muscles, and intestines) in affected infants.

Congenital disorders of glycosylation (CDG) is an umbrella term for a rapidly expanding group of rare genetic, metabolic disorders due to defects in complex chemical process known as glycosylation. Glycosylation is the process by which sugar 'trees' (glycans) are created, altered and chemically attached to certain proteins or fats (lipids). When these sugar molecules are attached to proteins, they form glycoproteins; when they are attached to lipids, they form glycolipids. Glycoproteins and glycolipids have numerous important functions in all tissues and organs.

Glycosylation involves many different genes, encoding many different proteins such as enzymes. A deficiency or lack of one of these enzymes can lead to a variety of symptoms potentially affecting multiple organ systems. CDG can affect any part of the body, and there is nearly always an important neurological component. CDG can be associated with a broad variety of symptoms and can vary in severity from mild cases to severe, disabling or life-threatening cases. CDG are usually apparent from infancy. Individual CDG are caused by a mutation to a specific gene. Most CDG are inherited as autosomal recessive conditions.
CDG was first reported in the medical literature in 1980 by Dr. Jaak Jaeken and colleagues. More than 80 different forms of CDG have been identified in the ensuing years. Several different names have been used to describe these disorders including carbohydrate-deficient glycoprotein syndromes. Recently, Jaeken and colleagues have proposed a classification system that names each subtype by the official abbreviation of its defective gene followed by a dash and CDG. For example, congenital disorder of glycosylation type 1a is now known as PMM2-CDG. PMM2 is the defective gene that causes this subtype of CDG.

CDGs are classified as Types I and II (CDG-I and CDG-II), depending on the nature and location of the biochemical defect in the metabolic pathway relative to the action of oligosaccharyltransferase. The most commonly used screening method for CDG, analysis of transferrin glycosylation status by isoelectric focusing, ESI-MS, or other techniques, distinguish between these subtypes, which are called Type I and Type II patterns. Currently, twenty-two CDG Type-I and fourteen Type-II subtypes of CDG have been described.

Congenital disorder of glycosylation type 1A:

The most common subtype of CDG is Congenital disorder of glycosylation type Ia (CDG-Ia, also referred to as PMM2-CDG) where the genetic defect leads to the loss of phosphomannomutase 2, the enzyme responsible for the conversion of mannose-6-phosphate into mannose-1-phosphate. PMM-CDG2 is an inherited condition that affects many parts of the body. The type and severity of problems associated with CDG-Ia 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. About 20 percent of affected infants do not survive the first year of life due to multiple organ failure.

More than 700 individuals have been identified. The disorder can be broken down into three stages: infantile multisystem, late-infantile and childhood ataxia-intellectual disability stage, and an adult stable stage.


  • Weak muscle tone (hypotonia)
  • Retracted (inverted) nipples
  • Eyes that do not look in the same direction (strabismus)
  • Developmental delay
  • Failure to gain weight
  • Grow at the expected rate (failure to thrive)
  • Seizures
  • Dysmorphic features
  • Psychomotor retardation
  • Esotopia
  • Liver disease
  • Coagulopathy
  • Peripheral neuropathy
  • Multi-organ involvement
  • Subcutaneous fat distribution
  • Cardiomyopathy
  • Ataxia
  • Small head
  • Hypothyroidism
  • Mental retardation
  • Impaired coordination
  • Impaired balance
  • Underdeveloped cerebellum
  • Impaired nerve signals to legs
  • Progressive muscle weakness in legs
  • Skeletal malformations
  • Vision impairment
  • Hearing impairment
  • High nasal bridge
  • Prominent jaw
  • Large ears
  • Feeding difficulties
  • Growth failure
  • Lipocutaneous abnormalities
  • Prominent fat pads on buttocks
  • Enlarged liver
  • Stroke-like episodes
  • Thrombotic disease
  • Liver dysfunction
  • Pericardial effusions
  • Proteinuria
  • Retinal degeneration
  • Reduced nerve conduction speed
  • Retinitis pigmentosa
  • Electroretinogram abnormalities
  • Underdeveloped brainstem
  • Liver steatosis
  • Liver fibrosis
  • Multicystic kidney changes
  • Contractures
  • Kyphoscoliosis
  • Pectus carinatum
  • Short stature
  • Atrophy of lower extremities
  • Hypogonadism
  • Happy appearance
  • Extroverted disposition
  • Low level of blood factor IX
  • Low level of blood factor XI
  • Low level of antithrombin
  • Low level of protein C
  • Low level of protein S



Most forms of CDG are inherited as autosomal recessive conditions. Genetic diseases are determined by the combination of genes for a particular trait that are on the chromosomes received from the father and the mother. Recessive genetic disorders occur when an individual inherits the same abnormal gene for the same trait from each parent. If an individual receives one normal gene and one gene for the disease, the person will be a carrier for the disease, but usually will not show symptoms. The risk for two carrier parents to both pass the defective gene and, therefore, have an affected child is 25 percent with each pregnancy. The risk to have a child who is a carrier like the parents is 50 percent with each pregnancy. The chance for a child to receive normal genes from both parents and be genetically normal for that particular trait is 25 percent. The risk is the same for males and females.

PMM2-CDG is caused by mutations of the PMM2 gene. This gene encodes an enzyme known as phosphomannomutase. Mutations in the PMM2 gene lead to deficient levels of functional phosphomannomutase in the body. This enzyme is necessary for the proper synthesis of N-linked oligosaccharides.


A diagnosis of a CDG may be suspected based upon the identification of characteristic symptoms, a detailed patient history and a thorough clinical evaluation. A variety of specialized tests may be necessary to confirm a diagnosis of CDG and/or to determine the specific subtype. CDG should be considered and ruled out in any unexplained syndrome.

Clinical Testing and Work-Up
A simple blood test to analyze the glycosylation status of transferrin can diagnose CDG due to N-glycosylation. Transferrin is a glycoprotein found in the blood plasma and that is essential for the proper transport of iron within the body. Abnormal transferrin patterns can be detected through a test known as isoelectric focusing (IEF). IEF allows physicians to separate molecules such as proteins or enzymes based upon their electrical charge. This allows physicians to detect abnormal serum transferrin. IEF is the standard test for diagnosing CDG due to a defect of N-glycosylation. Another test known as electrospray ionization-mass spectrometry may be used to detect abnormal transferrin.

Once a defect of N-linked glycosylation is diagnosed, further testing is required to determine the specific subtype. Some subtypes of CDG can be diagnosed through an enzyme assay, a test that measures the activity of a specific type of enzyme. However, for many subtypes no enzyme assay has been developed.

Molecular genetic testing is needed to confirm a diagnosis of CDG.


No treatment is available for most of these disorders.