The process or pathway which makes this glycosylation takes at least 100 steps, and specialized proteins called enzymes trigger each step.   Hundreds of enzymes are used in making the sugar chains and adding them to thousands of proteins.  Sometimes coordinated groups of enzymes work in a specific order to add some sugars, or cleave others from the maturing chain.  In individuals born with CDG, one of the many glycosylation enzymes in the pathway malfunctions.   However, the impact on the body structures and functions differs depending upon the altered enzyme.  CDG is caused by a genetically inherited change or malfunction of one of these enzymes.  If one of these enzymes malfunction then the cells in the body of a child or adult cannot glycosylate correctly.  This incorrect glycosylation is the underlying basis of the important medical issues in individuals with CDG.

Scientists investigating CDG (who are called glycobiologists) have identified 19 types of CDG each with its own unique defective enzyme identified.   Most of the glycosylation disorders have been identified in the synthesis of N-linked oligosaccharides. These oligosaccharides are assembled in a specific order to create different sugar chain patterns on proteins in every cell. Because of the important biologic functions of these oligosaccharides for protein stability and cell communication, incorrect synthesis may result in clinical problems in different organs of the body.  The very complexity of sugar chain assembly practically guarantees that more gylcosylation disorders will be discovered.

While CDG is a rare disease, a great deal of new scientific information indicates that it may be more common than originally thought.  There are approximately 500 cases of all types of CDG worldwide, it is probably only a few percent of the total patients.   It is safe to say that the entire group of CDGs is severely underdiagnosed.  CDG patients are often misdiagnosed early on because their symptoms resemble other generic disorders.  CDG-Ia patients are sometimes mistaken for having inherited mitochondrial disorders or ataxic cerebral palsy.

Current research aimed at "boosting" glycosylation pathways are under development in cellular models.   However, it is hoped that a stimulation of glycosylation at the cellular level may eventually compensate for defects and restore normal glycosylation levels.   New research has identified several types of CDG and is focused on both the causes and possible treatments for this condition as well as appropriate medical management of children and adults affected with these disorders.

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History of CDG; A Personal Account by Dr. Jaeken

Jaak Jaeken, MD, Ph.D. In 1980, Dr. Jaeken published his first description of the disease, but it would be 15 years before the case of the twin sisters would be solved.

The story of CDG started in 1978 when I was asked to investigate monozygous (identical) twin sisters with psychomotor retardation (developmental delay).  I was intrigued by finding in both an unusual association of serum protein abnormalities namely decreased thyroxyine-binding globulin (TBG) levels and increased arylsulphatase A (ASA) activities.   The measurement of serum ASA activity was (and is still) part of our metabolic screening program.   The increase of ASA activity was only small (2-3 times the mean normal level) but it was reproducible and the patients did not take any medication.   So I found this an important feature of their disease and my next question was: is there just more serum ASA or is ASA, in addition, structurally abnormal. Another question was:  is there a structural abnormality common to ASA, TBG and maybe other proteins.   I thought that an electrophoresis or isoelectrofocusing (IEF) of ASA might help to answer these questions but J.  Kint, lysosomal specialist from Ghent, told me that the normally very low serum ASA activity would prohibit the use of such technique.

In 1983 an IEF technique for serum transferrin was published by H.G. van Eijk and co-workers and this seemed to me a dreamed occasion to look into this problem.  In a nice collaboration with this Rotterdam haematologist, it turned out that my patients had a cathodal shift of their serum transferrin IEF profile pointing to a deficiency of sialic acid, a terminal and negatively charged sugar.   This was the key observation providing insight into the biochemical basis of CDG (a defective cotranslational modification more specifically in glycosylation) and yielding at the same time a powerful diagnostic test (laboratory test used to make the diagnosis of CDG) that is still the method of choice for CDG screening.   However it was not until 1995 that E. Van Schaftingen and I were able to pinpoint the basic defect of CDG-Ia, by far the most prevalent CDG.   This occurred as follows.  The work of Wada et al (reported in 1992) showing that in these patients part of serum transferrin was completely devoid of glycans, strongly suggested that the defect was in an early glycosylation step.   After defects in several early steps were excluded, I asked E. Van Schaftingen to look at a few other early glycosylation reactions in particular phosphoglucomutase.   This led to a new breakthrough by his discovery of a deficient activity of phosphomannomutase, an enzyme not previously reported in man.  Indeed, until then it was thought that the transformation of mannose 6-phosphate into mannose 1-phosphate, and that of glucose 6-phosphate into glucose 1-phosphate was carried out by one and the same enzyme, phosphoglucomutase.

The year before (1994) our group, in collaboration with H. Schachter from Toronto and G. Spik from Lille, reported the basic defect (N-acetylglucosaminyltransferase II deficiency) of a CDG with a completely different serum transferrin IEF pattern (that we have call the type 2 pattern).   This discovery was based on our finding of a mono-antennary N-acetyllactosamine type glycan on structural analysis of serum transferrin oligosaccharides (as seen in a subtype of patients with congenital dyserythropoietic anaemia type II with reported N-acetylglucosaminyltransferase II deficiency).   This was the first identified Golgi glycosylation defect and is now labeled CDG-IIa.

As time went on, we and others were confronted with a growing group of patients showing an unexplained CDG type, ie. children with abnormal transferring IEF but normal phosphmannomutase (not CDG-Ia).   On the other hand, I was aware of the fact that in yeast defects are known in nearly all steps of the glycosylation pathway.  Therefore I asked M. Aebi, a famous yeast specialist from Zurich, to collaborate and apply his yeast techniques to the elucidation of untyped CDG cases.  Particularly his use of lipid linked (dolichol-linked) oligosaccharides proved to be very useful.   This collaboration led to the identification of the first ER glycosylation defect (CDG-Ic) in 1998 and many others subsequently.  Also in 1998 three groups, including ours, published phosphomannose isomerase deficiency, CDG-Ib, a CDG that responds to mannose treatment.   Unfortunately, this still remains the only well treatable CDG among the 22 known N- and O-glycosylation diseases.

Recent review
Jaeken J, Carchon H. Congenital disorders of glycosylation (CDG), a booming chapter of pediatrics. Curr Opin Pediatr 2004 Aug;16(4):434-9.
*with permission from European Journal of Paediatric Neurology, 2004, volume 8, nr 6.

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Some children with CDG have serious life-threatening medical problems during their infancy.  Mortality in CDG-Ia children is about 20% during the first few years, but they stabilize after childhood.  Individuals with CDG require expert medical care, sometimes from multiple subspecialists.   Children and adults with CDG have varying degrees of disability, including cognitive impairment, speech difficulties, poor balance and motor skills.  As children with CDG- Ia grow older, they exhibit developmental delay, vision problems, seizures, and stroke-like episodes.   However, many are conversational with speech impairment and have very charming personalities.   Most are wheelchair bound because it is easier and safer for them to get around and they have progressive involvement of their skeleton.   Some live at home, some are in assisted living settings.

A growing number of newly diagnosed patients do not present with a classic CDG I profile, and many of them have a significantly milder form of disease.  Current treatment for CDG patients is supportive therapy and treatment of symptoms and sequelae.

There is no specific medicine to treat CDG, except for CDG-Ib and some CDG-IIc patients.   CDG-Ib presents with protein-losing enteropathy, coagulopathy and liver disease without neurological involvement.   These patients have significant gastrointestinal problems, but are neurologically and intellectually normal.   The effective therapy for CDG-Ib is oral mannose.   Mannose therapy reverses the hypoglycemia and coagulopathy within a few weeks, and within 1-2 months plasma protein levels become normal and protein-losing enteropathy disappears.   Fucose supplements have been used to treat patients with CDG-IIc who have a defective GDP-Fucose transporter. Infections cease and health improves.  Unfortunately, fucose does not improve or reverse the developmental delay.

March 23, 2001 Issue of Science Magazine, Vol. 291 no. 5512 (The American Association for the Advancement of Science) published an article on the subject of Carbohydrates and Glycobiology. "PROFILE Saving Lives With Sugar" describes a collaboration between Hudson Freeze and his Burnham Institute colleagues and his chief collaborator Thorsten Marquardt of the Pediatric Clinic in Munster, Germany that led to a treatment for type Ib. 

Hudson Freeze, Ph.D. Hoping to use mannose to treat CDG, Freeze asked the U.S. Food and Drug/Administration (FDA) for permission to test the safety of mannose therapy on healthy volunteers.  In 1995, the FDA agreed.  His biggest passion is getting the word out about potential treatments for these disorders.

About 10 years ago, Hudson Freeze and his Burnham Institute colleagues noticed that cells from one of the slime molds showed biochemical similarities to cells taken from a child with a disorder in the ways cells manipulate sugars. The cells were not PMI-deficient, they were defective in other ways that looked like what they saw in CDG-Ia cells, before they knew what caused Ia.  On a hunch, they added mannose and it corrected the Ia cells promting them to seek FDA approved trials among healthy volunteers in their lab.

Shortly after, Dr. Freeze and his team began their initial safety tests with mannose, he received a call from a physician in Germany, Dr. Thorsten Marquardt.   One of the doctor's patients, a young boy, who had lost 40 units (pints) of blood and had some CDG-X type.   Dr. Freeze told him of the mannose results, soon mannose was given to the child and they figured out his defect a few weeks later.  Six months later, Dr. Freeze learned that the boy was completely fine.  They published their findings in the April 1998 issue of the Journal of Clinical Investigation.  This finding was significant it gave glycobiologists a new perspective on multisystem diseases that they had no way of understanding before.  Since then other children have received life saving treatment.

This condition is known as Congenital Disorder of Glycosylation Type-Ib.  Individuals with CDG-Ib lack an enzyme called phosphomannose isomerase that converts the sugar fructose-6-phosphate to mannose-6-phosphate.   The mannose compound is a critical intermediate needed to synthesize N-linked glycosylated proteins, which are involved in myriad biochemical functions.  Freeze, who was studying a strain of Dictyostelium engineered to produce no phosphomannose isomerase, discovered that adding mannose to the mutants' culture medium corrected this deficit by allowing Dityostelium to use an alternative route for making mannose-6-phosphate.

It is important to point out that there is no evidence that healthy people require mannose supplements.  Vendors of complex nutraceutical mannose fail to point out that natural plant polysaccharides they sell are nondigestible. From time to time the cdg listserv is approached by vendors attempting to sell glyconutritional supplements.  There is no evidence that taking these supplements benefit individuals with CDG.

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The CDG's are divided into groups I and II based on the location in the biochemical pathway which the defect occurs.   Defective genes are lettered in chronological order of their discovery.

Type I CDGs (CDG-I) disable genes that make a large sugar chain precursor for N-linked glycosylation or attach it to proteins.  As shown in the table, there are 12 types.  Some defects occur in enzymes that mobilize small sugar units or the enzymes that add them to the proteins.

Type II CDGs (CDG-II) have defects in enzymes that remodel the sugar chains after they are added to protein.   These include glycosidases that trim the excess sugars or, glycosyl transferases that remodel them.  Some defects are in transporters that deliver the activated sugars to the glycosylation factory in the cell called the GOLGI.

There are potentially hundreds of genes involved in these processes.  Some of the Type II CDG'S may also impair assembly of other classes of sugar chains called glycolipids and glycosaminoglycans.   It is likely that serious mutations in any of these genes will cause CDG.

CDG research is quickly evolving, types are now recognized to include Ia through IL and IIa through IIf. Many are so new that only 1 or 2 patients are known. In addition, type Ix or IIx refers to cases of CDG that have new or unknown enzyme defects. Scientists are working now to identify other types of CDG.

Known Deficiency by Type

Disorder

Gene

Enzyme

OMIM

Key Features

CDG-Ia	PMM 2	Phosphomannomutase II	212065	Developmental delay, hypotonia, esotropia, lipodystrophy, cerebellar hypoplasia, stroke-like episodes, seizures
CDG-Ib	MPI	Phosphomannose Isomerase	602579	Hepatic fibrosis, protein losing enteropathy, coagulopathy, hypoglycemia
CDG-Ic	ALG6	Glucosyltransferase I Dol-P-Glc: Man9GlcNAc2-PP-Dol Glucosyltransferase	603147	Moderate developmental delay, hypotonia, esotropia, epilepsy
CDG-Id	ALG3	Dol-P-Man: Man5GlcNAc2-PP-Dol Mannosyltransferase	601110	Profound psychomotor delay, optic atrophy, acquired microcephaly, iris colobomas; hypsarrhythmia
CDG-Ie	DPM 1	Dol-P-Man Synthase I GDP-Man: Dol-P-Mannosyltransferase	608799	Profound psychomotor delay, severe developmental delay, optic atrophy, acquired microcephaly, epilepsy, hypotonia, mild dysmorphism, coagulopathy
CDG-If	MPDU1	MPDU1/Lec35	609180	Short stature, icthyosis, psychomotor retardation, pigmentary retinopathy
CDG-Ig	ALG12	Dol-P-Man: Man7GlcNAc2PP-Dol Mannosyltransferase	607143	Hypotonia, facial dysmorphism, psychomotor retardation, acquired microcephaly. Frequent infections
CDG-Ih	ALG8	Glucosyltransferase II Dol-P-Glc: Glc1Man9GlcNAc2-PP-Dol Glucosyltransferase	608104	Hepatomegaly, protein-losing enteropathy, renal failure, hypoalbuminemia, edema, ascites
CDG-Ii	ALG2	Mannosyltransferase II GDP-Man: Man1GlcNAc2-PP-Dol Mannosyltransferase	607906	Normal at birth; developmental delay, hypomyelination, intractable seizures, iris colobomas, hepatomegaly, coagulopathy
CDG-Ij	DPAGT1	UDP-GlcNAc: dolichol phosphate N-acetylglucosamine 1-phosphate transferase	608093	Severe developmental delay, hypotonia, seizures, microcephaly, exotropia
CDG-Ik	ALG1	Mannosyltransferase I GDP-Man: GlcNAc2-PP-Dol Mannosyltransferase	608540	Severe psychomotor retardation, hypotonia, acquired microcephaly, intractable seizures, fever, coagulopathy, nephrotic syndrome, early death
CDG-IL	ALG9	Mannosyltransferase Dol-P-Man: Man6 and 8GlcNAc2-PP-Dol Mannosyltransferase	608776	Severe microcephaly, hypotonia, seizures, hepatomegaly
CDG-IIa	MGAT2	GlcNAc-Transferase 2 (GnT II)	212066	developmental delay, dysmorphism, stereotypies, seizures
CDG-IIb	GLS1	Glucosdase I	606056	Dysmorphism, hypotonia, seizures, hepatomegaly, hepatic fiborsis (death at 2.5 months)
CDG-IIc	SLC35C1 /FUCT1	GDP-Fucose Transporter	266265	Recurrent infections, persistent neutrophilia, developmental delay, microcephaly, hypotonia (normal Tf)
CDG-IId	B4GALT1	b1,4 galactosyltransferase	607091	Hypotonia (myopathy), spontaneous hemorrhage, Dandy-Walker malformation
CDG-IIe	COG7	Conserved oligomeric Golgi complex subunit 7	608779	Fatal in early infancy; dysmorphism, hypotonia, intractable seizures, hepatomegaly, progressive jaundice, recurrent infections, cardiac failure.
CDG-IIf	SLC35A1	CMP-Sialic acid transporter	--	Thrombocytopenia, no neurologic symptoms, normal Tf, abnormal platelet glycoproteins

The table is adapted from information provided in the "Encyclopedia of Biological Chemistry", from Elsevier Vol 1 pp34-39 and "Pediatric Neurology: Principles and Practice" 4th Edition.

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The symptoms and severity of CDG vary from child to child.  Some of the symptoms become more prominent at different ages.   Most types of CDG are associated with minor differences in facial and body features, neurological problems, slow growth, clotting problems, liver and/or intestinal problems.   Some of the children have significant medical problems during infancy.   Physicians should suspect CDG in children who present with the following signs and symptoms:

hypotonia (low muscle tone)

failure to thrive (slow growth)

developmental delay

hepatopathy (liver disease)

coagulopathy (bleeding tendancies)

esotropia (crossed eyes)

seizures

cerebellar hypoplasia (changes in the brain that can be seen on developmental delayI)

At a later age, adolescence or adulthood, affected individuals may have these additional clinical features:

• ataxia (poor balance)
• dysarthria (slurred speech)
• absent puberty in females
• retinitis pigmentosa (pigment in the retina of the eye)
• progressive scoliosis (curvature of the spine)
• joint contractures

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Individuals who exhibit signs and symptoms of CDG should be referred for diagnostic testing to confirm they have this condition.  Most CDG patients can be diagnosed by a simple blood test to analyze the glycosylation status of transferrin (Tf).   Abnormal Tf is detected by isoelectric focusing (IEF), or by electrospray ionization-mass spectrometry (ESI-MS).   Once CDG is diagnosed, further testing is required to determine the type of CDG.

Diagnosis of CDG Physician Information:
Test Name:  Carbohydrate Deficient Transferrin Test
Method:     ESI-MS method superior to IEF, CE (Capillary Electrophoresis), or HPLC (High Performance Liquid Chromatography)
Laboratory:  Mayo Medical Laboratories Test (82414); CPT Code 82373
Requirments:  Requires: 0.1 ml of serum
Detection:  Will detect all known CDG-I types, many CDG-x.  Will not detect: CDG-IIb, CDG IIc, CDG-IIf.  Test may need to be rerun if done less than 2 weeks of age.

Physician Contact:
Mayo Medical Laboratories
Request: Carbohydrate Deficient Transferrin, serum. Test code 82414.
Phone: 1-800-533-1710
Fax: 1-507-284-4542
E-mail: mml@mayo.edu
Web:  www.mayoreferenceservices.org/mrs/index.asp

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Many families who have a child with CDG want to know what their risk is of having another child with CDG with another pregnancy.   This risk can be assessed by knowing that CDG is a recessively inherited disease.   This means that, although each parent carries two genes for the CDG function, one of them doesn't work correctly. The functional single gene in the parent protects them from having CDG.   A child with CDG has inherited two of these non-working genes, one from each parent.  Usually there is a 1:4 risk of having a second child with CDG-Ia, but recent work shows that the ratio is closer to 1:3.  This higher incidence is surprising, and so far, it has only been shown for CDG-Ia.  Families are encouraged to contact a genetics consultant.   A genetics doctor/counselor can help to explain the genetic risk for each family and the risk in future pregnancies.

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Excerpt from "CDG Summary of Features and Management", read entire article

The management issues relevant to children with CDG, appropriate for all types except CDG-Ib, include:

Failure to thrive:  Infants and children with most types of CDG have failure to thrive as one of their major medical problems.  These children can be nourished with any type of formula for maximal caloric intake although early in life they seem to do better on elemental formulas.  This diagnosis is not associated with any dietary restrictions, they can tolerate carbohydrates, fats and protein.   Their feeding may be progressed as is tolerated by their oral motor function.  Some of the children require a naso-gastric or gastrostomy tube placement for nutritional support which is most often removed as the child gains oral motor skills.

Oral motor dysfunction with persistent vomiting:  Many children with different types of CDG have difficulty with coordinating their suck and swallow.  Parents may become very anxious when the children are young because feeding can be difficult for some of the children and these children may also grow very slowly.   This anxiety is heightened by the commonly seen reflux and many of the children have persistent vomiting.  Thickening feeds, maintenance of an upright position after eating and antacids can be helpful. The involvement of a gastroenterologist and nutritionist to manage this is often necessary.  Should the child have a gastrostomy tube placed for nutritional support, it is important to strongly encourage the child to continue to eat by mouth, if there is a sufficiently low risk of aspiration.  Continued speech and oral motor therapy is essential.  This will not only smooth the transition to oral feeds but will also encourage speech when the child is developmentally ready.

Developmental delay: Typically parents begin to recognize the developmental delays in their children with CDG around four months of age.   At this point early intervention with occupational therapy, physical therapy and speech therapy should be instituted.  As the child grows and the developmental gap widens between these children and their unaffected peers, parents need continued counseling and support.

Abnormal liver function:   In many of the types of CDG liver function tests (AST and ALT) begin to rise in the first year of life.   The AST and ALT may peak in the 1000-1500 range before it begins to return to normal.   Typically, the ALT and AST return to normal by age 3-5 in children with CDG-Ia and remain normal throughout the remainder of their lives.

Coagulopathy (changes in blood clotting):  Many patients with CDG have low levels of factors in the coagulation cascade.  The clinical importance of this rarely manifests in every day activities, but must be acknowledged if an individual with CDG undergoes surgery.   Consultation with a hematologist to document the coagulation status and factor levels of the patient and to discuss with situation with the surgeon is important.  Infusion of fresh frozen plasma corrects the factor deficiency and clinical bleeding when indicated.

Parents should also know that some infants with CDG-Ia never experience a hospital visit while others may be hospitalized a number of times in their first year.

Strabismus:  Aggressive intervention by a pediatric ophthalmologist early in life is important to preserve vision in these children who have so many other issues.  Many children with CDG with esotropia (crossed eyes) have had successful corrective surgery.  Some children just require patching and glasses.

Pericardial effusion:  Many children with CDG-Ia have pericardial effusions and most do not cause any medical issues and resolve early in life.  An initial echocardiogram, to detect pericardial effusions, is warranted with followup, as needed, by a cardiologist.

Hypothyroidism:  Children with CDG who have elevated TSH and low free T4 are currently being treated with thyroid hormone.  Assessment by a pediatric endocrinologist may be useful in some circumstances.

Seizures:  Children with CDG-Ia may have seizures in their 2nd or 3rd year of life which are easily controlled with medication.  Other children with other types of CDG (CDG-Id and Ih) have intractable seizures, this situation is much less common.

Stroke-like episodes:  Transient loss of neurologic function or a stroke-like episode may occur as early as 4 years of age in a child with CDG but most occur later.  Some parents say that there is association with head trauma (falls), dehydration or fever, although a formal study has never been done.  Some of the children have seizures around the time of the event.  Supportive therapy for the children as they recover, including good hydration by IV if necessary, and physical therapy during the recovery period is important.  Full recovery may only take be a week, but may extend to several months in some cases.

Additional management issues of adults with CDG include:

Orthopedic issues:  Thorax shortening, scoliosis/kyphosis- Appropriate orthopedic and physical medicine management, with well supported wheel chairs, appropriate transfer devices for the home, and continued physical therapy is important.   Some children and adults have had surgical treatment of their spinal curvature with variable success.

Independent living issues: Young adults with CDG and their parents need to have issues of independent living addressed as they grow older.   Aggressive education throughout the school years in functional life skills and even vocational training will support the transition to the years after schooling is completed.   Independence in self care and the tasks of daily living should be encouraged as much as is physically possible.   Support and provision of resources to parents of a disabled adult is an important part of the management of the care of these patients.

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Ongoing Research and Findings

Research is underway to:

identify further types of CDG and determine their symptoms and outcomes

identify glycosylation defects that lead to CDG and determine if there are ways to alter these defects within cells of affected children

look for means of improving the symptoms

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