Congenital Disorders of Glycosylation

Congenital Disorders of Glycosylation

National Organization for Rare Disorders, Inc.

Important

It is possible that the main title of the report Congenital Disorders of Glycosylation is not the name you expected. Please check the synonyms listing to find the alternate name(s) and disorder subdivision(s) covered by this report.

Synonyms

  • CDG
  • CDG syndrome
  • carbohydrate-deficient glycoprotein syndromes

Disorder Subdivisions

  • None

General Discussion

Summary

Congenital disorders of glycosylation (CDG) is an umbrella term for an expanding group of rare metabolic disorders that share similar but not identical genetic changes (mutations) and biochemical activity. These disorders involve a normal, but complex, chemical process known as glycosylation. Glycosylation is the process by which sugar chains (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 varied important functions within the body and are essential for the normal growth and function of numerous tissues and organs. Glycosylation involves many different genes, which encode 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 virtually any part of the body, although most cases usually have 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 in infancy. Individual CDG are caused by a mutation to a specific gene. Most CDG are inherited as autosomal recessive conditions.



Introduction

CDG were first reported in the medical literature in 1980 by Dr. Jaak Jaeken, et al. More than 50 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, researchers 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. CDG are a rapidly growing disease family and information about these disorders is constantly changing.

Symptoms

The CDG encompass a wide variety of disorders. The specific symptoms present, severity and prognosis can vary greatly depending upon the specific type of CDG and the presence and extent of associated symptoms. The specific symptoms and 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 prevents physicians from developing an accurate picture of associated symptoms and prognosis. Therefore, it is important to note that affected individuals will not 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 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, there are some symptoms that are common to multiple subtypes of CDG. Many subtypes of CDG have a significant neurological component involving the central nervous system. Common neurological symptoms include diminished muscle tone (hypotonia), seizures, delays in attaining developmental milestones (developmental delay), 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 heavy or prolonged bleeding (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 dysmorphy). 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 may include an underactive thyroid (hypothyroidism), 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 are broken down into subgroups including two main groups of protein glycosylation 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 chain patterns, which are then attached to proteins on various cells. Disorders of N-glycosylation develop due to an enzyme deficiency or malfunction somewhere along the N-glycosylation pathway.



In the older classification, disorders of N-glycosylation were further subdivided into defects of oligosaccharide assembly and transfer (CDG-1) and defects in oligosaccharide trimming and processing that occurs after they are bound to proteins (CDG-2). This sub-classification has been discontinued in the new classification system.



Generally, these disorders of N-glycosylation occur in infants and are characterized by abnormalities affecting the central and peripheral nervous systems as well as the gastrointestinal, immune and coagulation systems. Disorders of N-glycosylation include:



PMM2-CDG - This disorder is the most common type of CDG. More than 700 individuals have been identified with PMM2-CDG. The disorder is generally 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 type 1a. 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 type 1b. 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 delays 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 36 individuals have been diagnosed with ALG6-CDG. This disorder was formerly known as CDG type 1C.



The remaining subtypes of CDG associated with N-linked glycosylation have only been reported in a handful of cases. They include:



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 may 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 type 1D.



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 also experienced moderate to severe psychomotor retardation and impaired immunity. This disorder was formerly known as CDG type 1G.



ALG8-CDG - Individuals with this form of CDG have developed different symptoms. Three individuals developed a severe form with multiorgan failure. Another individual 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 type 1h.



ALG1-CDG - Individuals 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 type 1k.



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 - Six individuals with this form of CDG have been identified. Symptoms include hypotonia, feeding difficulties, vision problems, and hearing loss. Severe psychomotor retardation and drug-resistant seizures have also occurred. This disorder was formerly known as CDG type 1n.



MAGT1-CDG - This form of CDG has only been reported in a family with four affected children, two girls and two boys. The girls and their mother had mild nonprogressive cognitive impairment. The two boys had more severe cognitive impairment. This form of CDG is inherited as an X-linked trait (see Causes section below).



MGAT2-CDG - This form of CDG has been reported in four individuals. Neurological symptoms included seizures, abnormal hand movements, psychomotor retardation and behavioral problems. Additional symptoms can occur including facial dysmorphology, skeletal malformations, gastrointestinal abnormalities and growth delays. This disorder was formerly known as CDG type 2a.



DISORDERS OF PROTEIN O-GLYCOSYLATION

Some CDG are classified as disorders of O-linked 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. 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 three individuals of one family. Affected individual developed a prematurely aged appearance, fine curly hair, sparse eyebrows, loose but elastic (hyperelastic) skin, abnormally loose or mobile joints (joint hyperlaxity), microcephaly and the classical 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 can be fatal before birth (prenatally).



B3GALTL-CDG - Affected individuals 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.



SCDO3-CDG - Individuals with this form of CDG have abnormalities affecting the development of bones of the spine and ribs. 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 Walker-Warburg syndrome, Fukuyama muscular dystrophy, muscle-eye-brain disease, and CMD type 1C and CMD type 1D. Limb-girdle muscular dystrophy 2I is also considered a disorder of O-linked glycosylation. In these particular disorders, improper glycosylation of a protein (dystroglycan) found on the membrane of muscle 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.



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.



SIAT9-CDG - Affected individuals have developed infantile-onset seizures (epilepsy). At the onset of seizures, normal development is hindered and developmental delays 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, which are the veins of the soft internal organs (viscera) of the body.



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.



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 several children, this form of CDG is characterized by severe neurological involvement including developmental delay, cognitive impairment, seizures and a variety of eye (ocular) abnormalities. This disorder was formerly known as CDG type 1e.



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 type 1f.



SLC35C1-CDG - Several individuals have been reported with this disorder, which is characterized by growth retardation, psychomotor abnormalities and facial dysmorphy. Affected individuals also experience recurrent bacterial infections. This disorder was formerly known as CDG type 2c and is also known as leukocyte adhesion deficiency type II. NORD has a general report on the leukocyte adhesion deficiencies.



DOLK-CDG (DOLK-CDG) - Four affected infants developed hypotonia and ichthyosis, a general term for a group of scaly skin disorders. Seizures, progressive microcephaly, failure to thrive and cardiomyopathy have also been reported. This disorder was formerly known as CDG type 1m.



SRD5A3-CDG - This form of CDG has been reported in 11 individuals and is characterized by congenital eye abnormalities, hypotonia, developmental delay and cognitive 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 some 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, 4, 5, 6, 7, and 8 subunits. Common symptoms include 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 delay, 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. 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).



ADDITIONAL FORMS OF CDG - There are additional forms of CDG. However, they have only been reported in one or two people and are not covered in this report.



CDG-x

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 CGD, 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.

Causes

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 receiver 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.



MAGT1-CDG is inherited as an X-linked recessive condition. X-linked recessive genetic disorders are conditions caused by an abnormal gene on the X chromosome. Females have two X chromosomes but one of the X chromosomes is "turned off" and all of the genes on that chromosome are inactivated. Females who have a disease gene present on one of their X chromosomes are carriers for that disorder. Carrier females usually do not display symptoms of the disorder because it is usually the X chromosome with the abnormal gene that is "turned off". Males have one X chromosome and if they inherit an X chromosome that contains a disease gene, they will develop the disease. Males with X-linked disorders pass the disease gene to all of their daughters, who will be carriers. Males can not pass an X-linked gene to their sons because males always pass their Y chromosome instead of their X chromosome to male offspring. Female carriers of an X-linked disorder have a 25 percent chance with each pregnancy to have a carrier daughter like themselves, a 25 percent chance to have a non-carrier daughter, a 25 percent to have a son affected with the disease, and a 25 percent chance to have an unaffected son.



As discussed above, CDG are caused by a deficiency or lack of specific enzymes involved in the binding of sugar molecules (glycans) 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 deficient 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.

Affected Populations

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 begin in infancy.

Standard Therapies

Diagnosis

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 CDGs 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. In some cases, a different 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 can confirm a diagnosis of CDG. Molecular genetic testing can detect mutations in specific genes known to cause CDGs, but is available only on a clinical basis.



Treatment

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 extent of the disorder, an individual's age and overall health, tolerance of certain medications or procedures, personal preference and other factors. 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. Although this therapy is effective, 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 type 2c) 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.



Some general therapies are common for infants and children with CDG including nutritional supplements to ensure maximum caloric intake. In addition, in some cases, 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 CDGs.



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 CDGs 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 may be of benefit for affected individuals and their families. Other treatment is symptomatic and supportive.

Investigational Therapies

Researchers are studying enzyme replacement therapy for the treatment of CDGs. 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 forms 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 produce 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. This is often the case in individuals with 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 minimize symptom severity and progression.



Researchers are also studying whether simple pharmacological agents can be developed that would bypass the underlying genetic defect in CDGs 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: prpl@cc.nih.gov



For information about clinical trials sponsored by private sources, in the main, contact:

www.centerwatch.com

References

TEXTBOOKS

Brodsky MC, ed. Pediatric Neuro-Ophthalmology, 2nd ed. New York, NY: Springer; 2010: 493-494.



Patterson MC. Congenital Disorders of Glycosylation. In: NORD Guide to Rare Disorders. Lippincott Williams & Wilkins. Philadelphia, PA. 2003:457-458.



JOURNAL ARTICLES

Jaeken J. Congenital disorders of glycosylation. Ann NY Acad Sci. 2010;1214:190-198. http://onlinelibrary.wiley.com/doi/10.1111/j.1749-6632.2010.05840.x/pdf



Al-Owain M, Mohamed S, Kaya N, et al. A novel mutation and first report of dilated cardiomyopathy in ALG6-CDG (CDG-Ic). Orphanet J Rare Dis. 2010;5:7. http://www.ojrd.com/content/5/1/7



Jaeken J, Hennet T, Matthijs G, Freeze HH. CDG nomenclature: time for a change! Biochim Biophys Acta. 2009;1792:825-826. http://www.ncbi.nlm.nih.gov/pubmed/19765534



Haeuptle MA, Hennet T. Congenital disorders of glycosylation: an update on defects affecting biosynthesis of dolichol-linked oligosaccharides. Hum Mutat. 2009;30:1628-1641. http://www.ncbi.nlm.nih.gov/pubmed/19862844



Coman DJ. The congenital disorders of glycosylation are clinical chameleons. Eur J Hum Genet. 2008;16:2-4. http://www.nature.com/ejhg/journal/v16/n1/pdf/5201962a.pdf



Hess D, Keusch JJ, Oberstein SAL, Hennekam RCM, Hofsteenge J. Peters plus syndrome is a new congenital disorder of glycosylation and involves defective O-glycosylation of thrombospondin type 1 repeats. J Biol Chem. 2008;283:7354-7360. http://www.jbc.org/content/283/12/7354



Kranz C, Jungeblut C, Denecke J, et al. A defect in dolichol phosphate biosynthesis causes a new inherited disorder with death in early infancy. Am J Med Genet. 2007;80:433-440. http://www.ncbi.nlm.nih.gov/pubmed/17273964



Martin PT. The dystroglycanopathies: the new disorders of O-linked glycosylation. Semin Pediatr Neurol. 2005;12:152-158. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2860379/pdf/nihms191323.pdf



Vodopiutz J, Bodamer OA. Congenital disorders of glycosylation - a challenging group of IEMs. J Inherit Metab Dis. 208;31:267-269. http://www.springerlink.com/content/6717655243k8h001/fulltext.pdf



Matthijs G. Euroglycanet: a European network focused on congenital disorders of glycosylation. Eur J Hum Genet. 2005;13:395-397. http://www.nature.com/ejhg/journal/v13/n4/pdf/5201359a.pdf



Topaz O, Shurman DL, Bergman R, et al. Mutations in GALNT3, encoding a protein involved in O-linked glycosylation, cause familial tumoral calcinosis. Nat Genet. 2004;579-581[Epub]. http://www.nature.com/ng/journal/v36/n6/pdf/ng1358.pdf



FROM THE INTERNET

Sparks SE, Krasnewich DM. Updated:08/11/2011. Congenital Disorders of Glycosylation Overview. In: GeneReviews at GeneTests: Medical Genetics Information Resource (database online). Copyright, University of Washington, Seattle. 1997-2003. Available at http://www.genetests.org.



Seta N. The CDG Syndrome. Orphanet encyclopedia, September 2004. Available at: http://www.orpha.net/data/patho/Pro/en/CDGSyndrome-FRenPro3553.pdf Accessed on: November 27, 2011.

Resources

CLIMB (Children Living with Inherited Metabolic Diseases)

Climb Building

176 Nantwich Road

Crewe, CW2 6BG

United Kingdom

Tel: 4408452412173

Fax: 4408452412174

Email: enquiries@climb.org.uk

Internet: http://www.CLIMB.org.uk



The Arc

1825 K Street NW, Suite 1200

Washington, DC 20006

Tel: (202)534-3700

Fax: (202)534-3731

Tel: (800)433-5255

TDD: (817)277-0553

Email: info@thearc.org

Internet: http://www.thearc.org



CDG Family Network

PO Box 860847

Plano, TX 75074

Tel: (800)250-5273

Email: cdgaware@aol.com

Internet: http://www.cdgs.com



Genetic and Rare Diseases (GARD) Information Center

PO Box 8126

Gaithersburg, MD 20898-8126

Tel: (301)251-4925

Fax: (301)251-4911

Tel: (888)205-2311

TDD: (888)205-3223

Internet: http://rarediseases.info.nih.gov/GARD/



For a Complete Report

This is an abstract of a report from the National Organization for Rare Disorders, Inc.® (NORD). Cigna members can access the complete report by logging into myCigna.com. For non-Cigna members, a copy of the complete report can be obtained for a small fee by visiting the NORD website. The complete report contains additional information including symptoms, causes, affected population, related disorders, standard and investigational treatments (if available), and references from medical literature. For a full-text version of this topic, see http://www.rarediseases.org/search/rdblist.html.

This information does not replace the advice of a doctor. Healthwise, Incorporated disclaims any warranty or liability for your use of this information. Your use of this information means that you agree to the Terms of Use . How this information was developed to help you make better health decisions.

Healthwise, Healthwise for every health decision, and the Healthwise logo are trademarks of Healthwise, Incorporated.