NORD gratefully acknowledges Jaak Jaeken, MD, PhD, Em. Professor of Pediatrics, Center for Metabolic Disease, University Hospital Gasthuisberg, Belgium, for assistance in the preparation of this report.
The CDG encompass a wide variety of disorders and symptoms. Their severity and prognosis vary greatly depending upon the specific type of CDG. The specific symptoms and their severity can vary even among individuals with the same subtype and even among members of the same family. In addition, most subtypes of CDG have only been reported in a handful of individuals, which renders it difficult for physicians from developing an accurate picture of associated symptoms and prognosis. It is important to note that affected individuals will not always have all of the symptoms discussed below. Affected individuals should talk to their physician and medical team about their specific case, associated symptoms and overall prognosis.
Because of the limited number of individuals and the overall lack of knowledge about many of the subtypes of CDG, NORD only provides very brief descriptions of most of these disorders. Most of the CDG do not have a specific clinical picture. As these disorders become better known and more affected individuals are identified, researchers should be able to obtain a better clinical understanding of the CDG. NORD does have individual reports on several of the better known disorders, which is noted in the individual descriptions below. In such cases, simply use the specific disorder name as your search term in the Rare Disease Database.
Despite the wide variety in presentation, many subtypes of CDG have a significant neurological component involving the central nervous system. Common neurological symptoms include diminished muscle tone (hypotonia), seizures, deficits in attaining developmental milestones (developmental disability), varying degrees of cognitive impairment, and underdevelopment of the cerebellum (cerebellar hypoplasia), which can cause problems with balance and coordination. Additional common symptoms include abnormal fat distribution, defects in blood clotting that can cause abnormal bleeding or clotting (coagulation defects), gastrointestinal symptoms such as vomiting and diarrhea, eye abnormalities such as crossed eyes (strabismus) and retinal degeneration, and abnormal or distinctive facial features (facial dysmorphism). Feeding difficulties leading to failure to thrive is also common. Failure to thrive is defined as the failure to grow and gain weight as would be expected based upon age and gender.
Additional symptoms include liver abnormalities, heart abnormalities such as disease of the heart muscle (cardiomyopathy), stroke-like episodes, and excessive loss of proteins from the gastrointestinal tract (protein-losing enteropathy), which can cause swelling due to fluid retention (edema). Fluid accumulation around the lungs or hearts (pleural or pericardial effusions) has also been reported.
The CDG comprising the disorders of protein glycosylation are broken down into two groups known as disorders of N-glycosylation and O-glycosylation.
DISORDERS OF PROTEIN N-GLYCOSYLATION
Most subtypes of CDG are classified as disorders of N-glycosylation, which involves carbohydrates called N-linked oligosaccharides. These oligosaccharides are created in a specific order to create specific sugar trees, which are then attached to proteins on various cells. Disorders of N-glycosylation are due to an enzyme deficiency or other malfunction somewhere along the N-glycosylation pathway.
As long as the defect is not identified, disorders of N-glycosylation are subdivided into defects of oligosaccharide assembly and transfer (CDG-Ix) and defects in oligosaccharide trimming and processing that occur after they are bound to proteins (CDG-IIx). As soon as the defect in an individual patient is clarified, a CDG name is given according to the current nomenclature.
Disorders of N-glycosylation include:
PMM2-CDG – This disorder is the most common type of CDG. 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. PMM2-CDG can be associated with a wide variety of symptoms and varying severity. This disorder was formerly known as CDG-Ia. NORD has an individual report on PMM2-CDG.
MPI-CDG – This form of CDG is distinct from other forms because neurological symptoms are usually absent. The disorder is characterized by profoundly low levels of blood sugar (hypoglycemia), scarring (fibrosis) of the liver, failure to thrive, and cyclic vomiting. Some individuals may develop recurrent blood clots (thromboses), gastrointestinal bleeding, and protein-losing enteropathy. Additional symptoms can include vomiting, diarrhea, abdominal pain, and an enlarged liver (hepatomegaly). The specific symptoms vary greatly even among members of the same family. Approximately 25 individuals have been diagnosed with MPI-CDG. This disorder was formerly known as CDG-Ib. It is the only CDG with an efficient treatment (oral mannose). Without this treatment affected individuals usually die from liver failure.
ALG6-CDG – Affected infants may experience mild to moderate neurological impairment. Specific symptoms may include deficits in attaining developmental milestones, hypotonia, seizures, and inability to control voluntary movements (ataxia). Some individuals may have strabismus and degeneration of the retina. At least one reported case was associated with dilated cardiomyopathy. Approximately 54 individuals have been diagnosed with ALG6-CDG. This disorder was formerly known as CDG-Ic.
ALG3-CDG – Affected individuals develop delays in attaining milestones that require the coordination of muscular and mental activity (psychomotor retardation), a defect of the colored portion of the eye (iris coloboma), and degeneration of the optic nerve and certain structures of the brain. Hypotonia and seizure may also occur. Some infants develop postnatal microcephaly, a condition characterized by head circumference that is smaller than would be expected based upon age and gender. Abnormalities of the hands and feet have also been reported. Approximately 11 individuals have been reported with ALG3-CDG. This disorder was formerly known as CDG-Id.
ALG12-CDG – Individuals with this form of CDG have developed hypotonia, dysmorphic facial features, frequent upper respiratory infections, feeding difficulties and progressive microcephaly. Affected individuals (8 reported) also experienced moderate to severe psychomotor disability and impaired immunity. This disorder was formerly known as CDG-Ig.
ALG8-CDG – Individuals (10 reported) with this form of CDG have developed different symptoms. Some developed a severe form with multiorgan failure. Others had significant involvement of the central nervous system and kidney (renal) disease. One individual had milder symptoms including hepatomegaly, protein-losing enteropathy and kidney disease. This disorder was formerly known as CDG-Ih.
ALG1-CDG – Individuals (some 19 reported) with this form of CDG have developed epilepsy, hypotonia and severe psychomotor retardation. Additional symptoms were reported some individuals including dysmorphic features, liver dysfunction, coagulation defects, kidney disease, cardiomyopathy and abnormalities of the immune system. This disorder was formerly known as CDG-Ik.
ALG9-CDG – Two children with this form of CDG developed microcephaly, hypotonia, developmental delays and seizures. Enlargement of the liver (hepatomegaly) also occurred. A third child also developed kidney cysts and pericardial effusions and experienced failure to thrive.
RFT1-CDG – Eight individuals with this form of CDG have been identified. Symptoms include hypotonia, feeding difficulties, vision problems, and hearing loss. Severe psychomotor disability and drug-resistant seizures have also occurred. This disorder was formerly known as CDG-In.
MAGT1-CDG – To be dropped (not sure that this is a CDG)
MGAT2-CDG – This form of CDG has been reported in five individuals. Neurological symptoms included seizures, abnormal hand movements, psychomotor disability and behavioral problems. Additional symptoms can occur including facial dysmorphology, skeletal malformations, gastrointestinal abnormalities and growth delays. This disorder was formerly known as CDG-IIa.
Other protein N-glycosylation disorders are: GMPPA-CDG, GMPPB-CDG, DPAGT1-CDG, ALG13-CDG, ALG2-CDG, ALG11-CDG, ALG14-CDG, TUSC3-CDG, DDOST-CDG, STT3A-CDG, STT3B-CDG, SSR4-CDG, MOGS-CDG and MAN1B1-CDG
DISORDERS OF PROTEIN O-GLYCOSYLATION
Some of these disorders are better known than the N-linked forms and many have more traditional names. In some cases, they have also been classified as subtypes of other umbrella groups (e.g., muscular dystrophy). In general, disorders of O-linked glycosylation show more dysmorphic features. These disorders include:
EXT1/EXT2-CDG – These subtypes of CDG (also named hereditary multiple exostoses) are characterized by multiple bony growths or tumors (exostoses) on the growing end of the long bones of the legs, arms and fingers and toes. These bony growths are covered by cartilage and usually continue to grow until puberty. Exostoses can lead to bone deformities, skeletal abnormalities, nerve compression, reduced range of motion of joints, and short stature. Malignancy occurs in about 5 %. They are caused by mutations of the EXT1 and EXT2 genes. NORD has an individual report on this disorder.
B4GALT7-CDG – This subtype of CDG has been reported in 27 patients. Affected individual can develop a prematurely aged appearance, fine curly hair, sparse eyebrows, loose but elastic (hyperelastic) skin, abnormally loose or mobile joints (joint hyperlaxity), microcephaly and features of Ehlers-Danlos syndrome. This disorder is also known as the progeroid form of Ehlers-Danlos syndrome.
GALNT3-CDG – Individuals with this subtype of CDG experience progressive calcium deposits in the skin and subcutaneous tissue, which eventually form large masses. These recurrent, painful masses can lead to secondary infection of the skin and bone and ulcerative lesions in the affected area. Additional symptoms can occur. Mutations of the GALNT3 gene are the cause of this so-called hyperphosphatemic familial tumoral calcinosis.
SLC35D1-CDG – Loss of function mutations of the SLC35D1 gene cause Schneckenbecken dysplasia, a skeletal disorder characterized by flattened bones of the vertebral column (platyspondyly), short ribs, abnormally short and wide bones of the lower legs (fibulae), and malformation of the long bones. In addition, the large, broad bone (ilium) that forms the upper portion of the pelvis may be small and underdeveloped. This disorder usually fatal before birth (prenatally).
B3GALTL-CDG – Affected individuals (48 reported) develop eye abnormalities primarily affecting the front portion of the eye known as the anterior chamber. Such abnormalities include clouding of the transparent structure that covers the front of the eyeball (corneal opacities) and adhesions affecting the colored portion of the eye (iris). Additional symptoms include disproportionate short stature, developmental delay, varying degrees of cognitive impairment, distinctive facial features including cleft lip and/or palate, and a wide variety of abnormalities affecting other organ systems. The disorder is also known as Peters-plus syndrome.
LFNG-CDG – Individuals with this form of CDG have abnormalities affecting the development of bones of the spine and associated muscles. Mutations of the SCDO3 gene are the cause of this spondylocostal dysostosis type 3.
Some disorders of O-linked glycosylation are also classified as forms of muscular dystrophy. Such disorders include forms of congenital muscular dystrophy (CMD) including POMT1-CDG, POMT2-CDG, POMGNT1-CDG, LARGE-CDG (Walker-Warburg syndrome, muscle-eye-brain disease, and limb-girdle muscular dystrophies). In these particular disorders, improper glycosylation of a protein (dystroglycan) found on the membrane of muscle, eye and brain cells occurs. These disorders are collectively termed the dystroglycanopathies. NORD has individual reports on Walker-Warburg syndrome and Fukuyama muscular dystrophy and general overviews on congenital muscular dystrophy and limb-girdle muscular dystrophy. For more information on these disorders choose the specific disorder name as your search term in the Rare Disease Database.
Other protein O-glycosylation disorders include: EOGT-CDG, B3GALT6-CDG, B3GAT3-CDG, CHSY1-CDG, B3GALNT2-CDG, POFUT1-CDG, POGLUT1-CDG, and SLC35D1-CDG
DEFECTS OF GLYCOSPHINOGLIPID AND GPI-ANCHOR GLYCOSYLATION
CDG that are caused by abnormalities of lipid glycosylation have recently been identified. Three forms of this subtype have been reported. Researchers expect additional forms to be recognized in the future.
ST3GAL5-CDG – Affected individuals (some 46 reported) have developed infantile-onset seizures (epilepsy). At the onset of seizures, normal development is hindered and developmental deficits or regression (loss of previously acquired skills) may occur. Individuals can develop a variety of eye abnormalities including eye deviation, degeneration of the optic nerve (optic atrophy), loss of vision and potentially blindness. This form of CDG is also known as Amish infantile epilepsy.
PIGM-CDG – This form of CDG is characterized by seizures and blood clots affecting the hepatic veins Three patients have been reported.
PIGN-CDG – This form of CDG is potentially associated with wide and varied symptoms. Affected individuals may have severe neurological disease including hypotonia, seizures, and developmental delays. They may also have rapid, involuntary eye movements (nystagmus), dysmorphic facial features and multiple congenital anomalies affecting multiple systems of the body including gastrointestinal, genitourinary, and cardiac systems. PIGN-CDG has been reported in several families.
PIGV-CDG – This form of CDG is characterized by neurological abnormalities including cognitive impairment and seizures and additional symptoms including facial dysmorphism, skeletal abnormalities and hyperphosphatasia. PIGV mutations are the cause of this rare disorder also known as Mabry syndrome (some 18 patients described).
Other CDG of this group include: PIGA-CDG, PIGL-CDG, and B4GALNT1-CDG.
DEFECTS OF MULTIPLE GLYCOSYLATION AND OTHER PATHWAYS
Some CDG occur due to combined defects of glycosylation. For example, some individuals may have defects affecting both the N-linked and O-linked glycosylation pathways. Disorders in this group include:
DPM1-CDG – Reported in 12 children, this form of CDG is characterized by severe neurological involvement including developmental impairment, seizures and a variety of eye (ocular) abnormalities. This disorder was formerly known as CDG-Ie.
MPDU1-CDG – Four children have been reported with this form of CDG. Symptoms have included severe psychomotor retardation, episodes of increased muscle tone (hypertonia), and a scaly, reddish skin condition. One child exhibited transient growth hormone deficiency and short stature. This disorder was formerly known as CDG-If.
SLC35C1-CDG – Nine individuals have been reported with this disorder, which is characterized by growth retardation, psychomotor abnormalities and dysmorphic facial features. Affected individuals also experience recurrent bacterial infections. This disorder was formerly known as CDG-IIc and is also known as leukocyte adhesion deficiency type II. NORD has a general report on the leukocyte adhesion deficiencies.
DOLK-CDG (DOLK-CDG) – Seventeen affected infants developed hypotonia and ichthyosis, a general term for a group of scaly skin disorders, seizures, progressive microcephaly, failure to thrive and/or cardiomyopathy. This disorder was formerly known as CDG-Im.
SRD5A3-CDG – This form of CDG has been reported in 11 individuals and is characterized by congenital eye abnormalities, hypotonia, developmental impairment. Abnormalities affecting the skin including ichthyosis, dry skin, erythroderma and atopic dermatitis may also occur. Some individuals have developed cerebellar ataxia.
COG1-8-CDG – These CDG subtypes involve the conserved oligomeric Golgi (COG) complex, an eight subunit protein complex consisting of several related proteins labeled COG1 through COG8. These proteins are required for the proper development and function of the Golgi complex. The Golgi complex (or apparatus) is a structure found in most cells and contributes to the process of glycosylation. Although the full function of the Golgi complex is not completely understood, it changes, sorts, packages and transports proteins. Defects have been identified in the COG 1, 2, 4, 5, 6, 7, and 8 subunits. Common symptoms include intellectual disability, feeding problems, growth retardation, hypotonia, microcephaly and degeneration of the cerebellum (cerebellar atrophy).
ATP6V0A2-CDG – Mutations of the ATP6V0A2 gene have been shown to affect both N-linked and O-linked glycosylation. Mutations of this gene are also known to cause autosomal recessive cutis laxa (ARCL) and wrinkly skin syndrome. Affected individuals have developed a prematurely aged (progeroid) facial appearance, cognitive impairment, developmental disability, progressive microcephaly, seizures, and osteopenia, a condition characterized by decreased bone mineralization and bone loss.
SEC23B-CDG – The mutation of the SEC23B gene causes a disorder known as congenital dyserythropoietic anemia type 2 (or HEMPAS). This disorder is characterized by yellowing of the skin and whites of the eyes (jaundice), an abnormally large spleen (splenomegaly), gallstones (cholelithiasis), premature destruction of red blood cells (hemolysis) and low levels of circulating red blood cells (anemia).
Other CDG in this group include: GFPT1-CDG, DPM2-CDG, DPM3-CDG, B4GALT1-CDG, GNE-CDG, SLC35A1-CDG, SLC35A2-CDG, SLC35A3-CDG, SRD5A3-CDG, DHDDS-CDG, TMEM165-CDG, PGM1-CDG, and PGM3-CDG.
An increasing number of individuals have been reported with unidentified defects of glycosylation. Some of these individuals have signs and symptoms that are similar to other subtypes of CDG, while other individuals have signs and symptoms that have not been reported in CDG before. Such unidentified cases are collectively referred to as CDG-x.
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.
EXT1/EXT2-CDG is inherited as an autosomal dominant condition. Dominant genetic disorders occur when only a single copy of an abnormal gene is necessary for the appearance of the disease. The abnormal gene can be inherited from either parent, or can be the result of a new mutation (gene change) in the affected individual. The risk of passing the abnormal gene from affected parent to offspring is 50 percent for each pregnancy regardless of the sex of the resulting child.
As discussed above, CDG are caused by a deficiency or lack of specific enzymes involved in the formation of sugar trees (glycans) and their binding to other proteins or lipids (glycosylation). Glycosylation is an extensive and complex process. Hundreds of different genes and unique enzymes are involved in glycosylation. These genes contain instructions for creating (encoding) these enzymes. An individual with a CDG lacks functional levels of one of these enzymes because of a mutation to the corresponding gene. Due to lack of or diminished levels of these enzymes, glycosylation is impaired. Improper glycosylation is the underlying problem in individuals with CDG. The specific organs affected and the various symptoms that develop depend, in part, upon the specific gene and protein product involved.
For example, 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.
Congenital disorders of glycosylation affect males and females in equal numbers. The exact incidence or prevalence of these disorders is the general population is unknown. Researchers believe that many cases go unrecognized or misdiagnosed, making it difficult to determine their true frequency. As these disorders become better known and more subtypes are identified, more cases should be recognized. The most common type (PMM2-CDG) has been reported in more than 700 individuals. In most cases, these disorders become apparent in infancy.
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.
The treatment of most forms of CDG is directed toward the specific symptoms that are apparent in each individual. Treatment may require the coordinated efforts of a team of specialists. Pediatricians, neurologists, surgeons, cardiologists, speech pathologists, ophthalmologists, gastroenterologists, and other healthcare professionals may need to systematically and comprehensively plan an affect child’s treatment.
The specific therapeutic procedures and interventions for individuals with a CDG will vary, depending upon numerous factors including the specific symptoms present, the severity of the disorder, an individual’s age and overall health, and tolerance of certain medications or procedures. Decisions concerning the use of particular therapeutic interventions should be made by physicians and other members of the healthcare team in careful consultation with the patient and/or parents based upon the specifics of his or her case; a thorough discussion of the potential benefits and risks including possible side effects and long-term effects; patient preference; and other appropriate factors.
Although there is no specific therapy for most forms of CDG, three disorders have an existing therapy.
Individuals with MPI-CDG are treated with oral mannose. This therapy bypasses the underlying genetic defect in glycosylation that causes the disorder. Some individuals have experienced a near complete resolution of symptoms following mannose therapy. This therapy is life-saving, but close monitoring of affected individuals is required because so few individuals have been diagnosed (and thus treated) for MPI-CDG.
Some individuals with SLC35C1-CDG (CDG-IIc) have been treated with fucose. This therapy depends upon the nature of the underlying mutation of the SLC34C1 gene. Fucose therapy can be beneficial in treating recurrent infections associated with this form of CDG and improving health. However, fucose therapy does not help with other symptoms of this disorder.
Some individuals with PIGM-CDG have been treated with butyrate, which increases the transcription of PIGM and is able to help manage seizures associated with this form of CDG.
Symptomatic therapies are common for infants and children with CDG including nutritional supplements to ensure maximum caloric intake. In addition, some children may require the insertion of a tube through a small surgical opening in the stomach (gastrostomy) or a tube through the nose, down the esophagus and into the stomach (nasogastric tube). Many children with a CDG develop persistent vomiting and dysfunction of oral motor skills, which involve the muscles of the face and throat. A variety of therapies may be necessary to ensure proper feeding including agents to thicken food, antacids, and maintaining an upright position when eating. Maintaining proper nutrition and caloric intake is critical for infants with chronic disorders and often a particular challenge for infants and children with CDG.
Early developmental intervention is important to ensure that affected children reach their potential. Most affected children will benefit from occupational, physical and speech therapy. Additional medical, social, and/or vocational services including special remedial education may also be beneficial. Ongoing counseling and support for parents is beneficial as well.
Blood clotting abnormalities (coagulopathies) require special attention if affected individuals need surgery, but rarely pose problems during normal daily activities.
Additional therapies for CDG depend upon the specific abnormalities present and generally follow standard guidelines. For example, anti-seizure medications (anti-convulsants) may be used to treat seizures, thyroid hormone may be used to treat hypothyroidism, and surgery may be used to treat certain skeletal malformations.
Genetic counseling is important for affected individuals and their families.
Researchers are studying enzyme replacement therapy for the treatment of CDG. Enzyme replacement therapy involves replacing the missing enzyme in individuals who are deficient or lack the particular enzyme in question. Synthetic versions of missing enzymes have been developed and used to treat individuals with a certain form of a related group of disorders known as the lysosomal storage diseases.
Gene therapy is also been studied as another approach to therapy for individuals with CDGs or related disorders. In gene therapy, the defective gene present in a patient is replaced with a normal gene to enable the production of the active enzyme and prevent the development and progression of the disease in question. Given the permanent transfer of the normal gene, which is able to produce active enzyme at all sites of disease, this form of therapy is theoretically most likely to lead to a “cure”. However, at this time, there are many technical difficulties to resolve before gene therapy can succeed.
While some individuals have significantly deficient levels of a particular enzyme, other individuals may have residual enzyme activity, and thus a milder disease expression. Researchers are seeking ways to boost or improve any residual enzyme activity in such individuals in the hope that it can further decrease symptom severity and progression.
Researchers are also studying whether simple pharmacological agents can be developed that would bypass the underlying genetic defect in CDG allowing proper glycosylation to occur. Such agents may increase the production (synthesis) or activity of alternative enzymes that could carry out the functions normally performed by the deficient enzyme in question.
Information on current clinical trials is posted on the Internet at www.clinicaltrials.gov. All studies receiving U.S. government funding, and some supported by private industry, are posted on this government web site.
For information about clinical trials being conducted at the NIH Clinical Center in Bethesda, MD, contact the NIH Patient Recruitment Office:
Toll-free: (800) 411-1222
TTY: (866) 411-1010
Email: [email protected]
For information about clinical trials sponsored by private sources, in the main, contact:
For information about clinical trials conducted in Europe, contact:
RareConnect offers a safe patient-hosted online community for patients and caregivers affected by this rare disease. For more information, visit www.rareconnect.org.
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