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Last updated:
May 11, 2021
Years published: 2012, 2015, 2021
NORD gratefully acknowledges Etienne Leveille, MD Candidate, McGill University School of Medicine, and Hudson Freeze PhD, Professor and Director, Human Genetics Program; Director, Sanford Children’s Health Research Center, Sanford-Burnham-Prebys Medical Discovery Institute, for assistance in the preparation of this report.
Summary
Congenital disorders of glycosylation (CDG) is an umbrella term for a rapidly expanding group of over 130 rare genetic, metabolic disorders due to defects in a complex chemical process known as glycosylation. Glycosylation is the process by which sugar ‘trees’ (glycans) are created, altered and attached to 1000’s of 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 to severe, disabling or life-threatening. CDG are usually apparent from infancy. Individual CDG are caused by changes (mutations) in a specific gene. Most CDG are inherited as autosomal recessive conditions, but some are X-linked or dominant. Others may arise spontaneously (de novo).
Introduction
CDG were first reported in the medical literature in 1980 by Dr. Jaak Jaeken and colleagues. More than 130 different forms of CDG have been identified in the ensuing years. Recently, Jaeken and colleagues proposed a classification system that names each type by the official abbreviation of the abnormal gene followed by a dash and CDG. For example, congenital disorder of glycosylation type 1a is now known as PMM2-CDG because a mutation in the PMM2 gene causes this type of CDG. Major categories of CDG are based on the glycosylation pathway or molecule that is affected. For instance, disorders of protein glycosylation are broken down into two groups known as disorders of N-glycosylation and disorders of O-glycosylation. Other types of CDG include disorders of glycosphingolipid and GPI-anchor glycosylation, and disorders of multiple glycosylation and other pathways. These four categories of CDG are described below.
Disorders of protein N-glycosylation
Most types of CDG are classified as disorders of N-glycosylation, which involve carbohydrates called N-linked oligosaccharides (glycans). Disorders of N-glycosylation are due to an enzyme deficiency or other malfunction somewhere along the N-glycosylation pathway. This category of CDG can be further divided into two subtypes: defects of oligosaccharide assembly and transfer (type 1) and defects in oligosaccharide trimming and processing that occur after they are bound to proteins (type 2). Disorders of protein N-glycosylation notably include PMM2-CDG, the most common type of CDG. (For more information on this disorder, choose “PMM2-CDG” as your search term in the Rare Disease Database.)
Disorders of protein O-glycosylation
Disorders of O-glycosylation are due to an enzyme deficiency or other malfunction somewhere along the O-glycosylation pathway. 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. For instance, some disorders of O-linked glycosylation are also classified as forms of muscular dystrophy. These disorders are collectively termed the dystroglycanopathies. The NORD database has individual reports on Walker-Warburg syndrome and Fukuyama muscular dystrophy, as well as 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 disorders involve defects in the synthesis of large molecules called glycosaminoglycans (GAGs) which are the sugar components of proteoglycans.
Disorders of glycosphingolipid and GPI-anchor glycosylation
As their name indicates, these disorders involve defects in the glycosylation of two types of lipid-containing molecules: glycosphingolipids (GSL) and glycosylphosphatidylinositol (GPI) anchors. These glycolipids have a wide range of functions in the body. Disorders associated with a defect in their production can therefore have a wide range of manifestations, as it is the case for disorders of protein glycosylation. There are over 20 types of GPI anchor disorders, but just a couple in GSL synthesis.
Defects of multiple glycosylation and other pathways
Some CDG occur due to defects that impact and alter multiple glycosylation pathways. For example, some individuals may have defects affecting both the N-linked and O-linked glycosylation pathways. These can also include defects in the organization, delivery, or trafficking of proteins within cells. These disorders usually have manifestations similar to other categories of congenital disorders of glycosylation.
CDG encompass a wide variety of disorders and symptoms. Their severity and prognosis vary greatly depending upon the specific type of CDG, even among individuals with the same type or from the same family. In addition, most types of CDG have only been reported in a handful of individuals, which makes it difficult for physicians to have an accurate picture of associated symptoms and prognosis. In most cases, these disorders become apparent in infancy. 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.
Despite the wide variety in presentation, many types of CDG have a significant neurological component involving the brain and/or spine (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). Although facial dysmorphism can occur in any type of CDG, it is most often associated with disorders of O-glycosylation. Feeding difficulties leading to failure to thrive are also common. Failure to thrive is defined as the failure to grow and gain weight as would be expected based upon age and gender. Another factor that can contribute to failure to thrive is excessive loss of proteins from the gastrointestinal tract (protein-losing enteropathy) which can also cause swelling due to fluid retention (edema). Fluid accumulation around the lungs or heart (pleural or pericardial effusions) has also been reported. Additional symptoms include various abnormalities of the kidneys, liver and heart; skeletal abnormalities including bony overgrowth or deformities; abnormalities of muscle fibers that can cause pain and weakness (myopathy); skin changes such as scaly skin or rashes; stroke-like episodes; and deficiencies of the immune system (immunodeficiency). As mentioned, the manifestations of CDG vary greatly between affected individuals. However, certain patterns of features are more frequently seen in certain types. For instance, patients with PGM1-CDG (a type 1 disorder of N-glycosylation) frequently have hypoglycemia, hormonal dysregulations, growth delay, seizures, cleft lip and/or palate, a uvula that is split in two (bifid uvula), myopathy and bleeding.
As discussed above, CDG are caused by a deficiency or lack of specific enzymes or other proteins involved in the formation of sugar trees (glycans) and their binding to other proteins or lipids (glycosylation). Glycosylation is an extensive and complex process that modifies 1000’s of proteins. 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 in 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. Not all CDG types are caused by mutations in enzymes. Sometimes they result from mutations in proteins that transport, organize or direct other molecules within cells.
Most forms of CDG are inherited in an autosomal recessive pattern. 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 abnormal gene and, therefore, have an affected child is 25% with each pregnancy. The risk to have a child who is a carrier like the parents is 50% with each pregnancy. The chance for a child to receive normal genes from both parents is 25%. The risk is the same for males and females.
Certain forms of CDG are inherited in an autosomal dominant pattern. 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 in the affected individual. The risk of passing the abnormal gene from affected parent to offspring is 50% for each pregnancy. The risk is the same for males and females. However, if an affected child has a new mutation that is not carried by either parent, other children of the same parents are much less likely to develop the disease.
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 types are identified, more cases should be recognized. The most common type (PMM2-CDG) has been reported in more than 1,000 individuals, but the real frequency is probably much higher.
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.
Sequencing an individual’s DNA is rapidly becoming an early test when physicians suspect a genetic abnormality. The speed and accuracy of the test can save a lot of time and expense and provides a provisional diagnosis. This sequencing approach can spot an abnormality in the DNA, but not every variant is harmful (pathogenic). In fact, most are not, so it is important to find an independent way to assess the impact.
For CDG due to N-glycosylation defects, a simple blood test to analyze the glycosylation status of transferrin can help diagnose or confirm many (not all) types. Transferrin is a glycoprotein found in the blood plasma 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 separation molecules such as proteins or enzymes based upon their electrical charge. This allows detection of abnormal serum transferrin. IEF is the standard test for diagnosing CDG due to a defect of N-glycosylation. Another test known as mass spectrometry may be used to detect abnormal transferrin. It is much more sensitive than IEF and can sometimes narrow down or confirm suspected defects.
Further testing may include measuring the activity of a specific type of enzyme or using other methods. However, for most types no enzyme assay has been developed. Molecular genetic testing is needed to identify mutations that can cause CDG and therefore confirm the genetic diagnosis.
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 affected child’s treatment.
The specific therapeutic procedures and interventions for individuals with a CDG will vary depending upon numerous factors including the specific symptoms, severity of the disorder, an individual’s age and overall health and tolerance to 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 their 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, certain disorders have an existing therapy and others are in development. Some examples are provided below:
Individuals with PMM2-CDG treated with acetazolamide showed improvement on standardized evaluation tests. It was clearly effective for improving motor cerebellar functions. Larger trials are underway. Acetazolamide has been used since the 1950’s and is approved for use in multiple disorders including glaucoma and epilepsy. Trials are also planned for another drug, epalrestat, which is approved in Japan to treat diabetic neuropathies. Some reports claim that mannose can improve PMM2-CDG transferrin and clinical features, however, this not accurate. While mannose is unlikely to be harmful, its use is discouraged because it offers false hope.
On the other hand, 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 most symptoms following mannose therapy. This therapy is life-saving, but close monitoring of affected individuals is required because few individuals have been diagnosed (and thus treated) for MPI-CDG. In some individuals, liver disease did not improve when given mannose.
A few individuals with SLC35C1-CDG have been treated with fucose. This therapy depends upon the nature of the underlying mutation of the SLC35C1 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 production of protein from the PIGM gene and is able to help manage seizures associated with this form of CDG.
Individuals with PGM1-CDG can be treated with D-galactose supplementation, which is usually well tolerated and associated with decreased bleeding, improvement of laboratory markers and increased quality of life in some patients. Larger trials are underway. Other disorders, such as SLC35A2-CDG may respond to D-galactose supplementation, but these results are at very preliminary.
CAD-CDG is caused by mutations that limit the body’s ability to make uridine, an important molecule for many cellular functions. Symptoms include developmental delay and seizures among other issues. Providing uridine supplements (triacetyl uridine) shows remarkable improvement within days of starting therapy and prolonged treatment gives further improvements.
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.
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. Blood clotting abnormalities (coagulopathies) require special attention if affected individuals need surgery, but rarely pose problems during normal daily activities. Early developmental intervention is also 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. Genetic counseling is also important for affected individuals and their families.
Support groups include CDG CARE which provides a wealth of information, updates, conferences, newsletters and support for families affected by CDG. They are also a component of a consortium of 10 clinical institutions in the US (Frontiers of Congenital Disorders of Glycosylation Consortium) examining the natural history, biomarkers and therapy for CDG.
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 CDG 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. 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.
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
Some current clinical trials also are posted on the following page on the NORD website:
https://rarediseases.org/living-with-a-rare-disease/find-clinical-trials/
For information about clinical trials sponsored by private sources, in the main, contact:
www.centerwatch.com
For information about clinical trials conducted in Europe, contact:
https://www.clinicaltrialsregister.eu/
RareConnect offers a safe patient-hosted online community for patients and caregivers affected by this rare disease. For more information, visit www.rareconnect.org.
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
Peanne R, de Lonlay P, Foulquier F, Kornak U, Lefeber DJ, Morava E, et al. Congenital disorders of glycosylation (CDG): Quo vadis? Eur J Med Genet. 2018;61(11):643-63.
Ng BG, Freeze HH. Human genetic disorders involving glycosylphosphatidylinositol (GPI) anchors and glycosphingolipids (GSL). J Inherit Metab Dis. 2015;38(1):171-8.
Morava E. Galactose supplementation in phosphoglucomutase-1 deficiency; review and outlook for a novel treatable CDG. Mol Genet Metab. 2014;112(4):275-9.
Ohba C, Okamoto N, Murakami Y, et al. PIGN mutations cause congenital anomalies, developmental delay, hypotonia, epilepsy, and progressive cerebellar atrophy. Neurogenetics. 2014;15:85-92. https://www.ncbi.nlm.nih.gov/pubmed/24253414
Maydan G, Noyman I, Har-Zahav A, et al. Multiple congenital anomalies-hypotonia-seizures syndrome is caused by a mutation in PIGN. J Med Genet. 2011;48:383-389. https://www.ncbi.nlm.nih.gov/pubmed/21493957
Jaeken J. Congenital disorders of glycosylation. Ann NY Acad Sci. 2010;1214:190-198. https://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. https://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. https://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. https://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. https://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. https://www.jbc.org/content/283/12/7354
Vodopiutz J, Bodamer OA. Congenital disorders of glycosylation – a challenging group of IEMs. J Inherit Metab Dis. 2008;31:267-269. https://www.springerlink.com/content/6717655243k8h001/fulltext.pdf
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. https://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. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2860379/pdf/nihms191323.pdf
Matthijs G. Euroglycanet: a European network focused on congenital disorders of glycosylation. Eur J Hum Genet. 2005;13:395-397. https://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]. https://www.nature.com/ng/journal/v36/n6/pdf/ng1358.pdf
INTERNET
Sparks SE, Krasnewich DM. Congenital Disorders of N-Linked Glycosylation and Multiple Pathway Overview. 2005 Aug 15 [Updated 2017 Jan 12]. In: Adam MP, Ardinger HH, Pagon RA, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2021. Available from: https://www.ncbi.nlm.nih.gov/books/NBK1332/ Accessed April 28, 2021.
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