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.
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
||Developmental delay, hypotonia, esotropia, lipodystrophy, cerebellar hypoplasia, stroke-like episodes, seizures
||Hepatic fibrosis, protein losing enteropathy, coagulopathy, hypoglycemia
Dol-P-Glc: Man9GlcNAc2-PP-Dol Glucosyltransferase
|Moderate developmental delay, hypotonia, esotropia, epilepsy
||Dol-P-Man: Man5GlcNAc2-PP-Dol Mannosyltransferase
||Profound psychomotor delay, optic atrophy, acquired microcephaly, iris colobomas; hypsarrhythmia
||Dol-P-Man Synthase I
|Profound psychomotor delay, severe developmental delay, optic atrophy, acquired microcephaly, epilepsy, hypotonia, mild dysmorphism, coagulopathy
||Short stature, icthyosis, psychomotor retardation, pigmentary retinopathy
||Dol-P-Man: Man7GlcNAc2PP-Dol Mannosyltransferase
||Hypotonia, facial dysmorphism, psychomotor retardation, acquired microcephaly. Frequent infections
Dol-P-Glc: Glc1Man9GlcNAc2-PP-Dol Glucosyltransferase
|Hepatomegaly, protein-losing enteropathy, renal failure, hypoalbuminemia, edema, ascites
GDP-Man: Man1GlcNAc2-PP-Dol Mannosyltransferase
|Normal at birth; developmental delay, hypomyelination, intractable seizures, iris colobomas, hepatomegaly, coagulopathy
||UDP-GlcNAc: dolichol phosphate
N-acetylglucosamine 1-phosphate transferase
|Severe developmental delay, hypotonia, seizures, microcephaly, exotropia
GDP-Man: GlcNAc2-PP-Dol Mannosyltransferase
|Severe psychomotor retardation, hypotonia, acquired microcephaly, intractable seizures, fever, coagulopathy, nephrotic syndrome, early
Dol-P-Man: Man6 and 8GlcNAc2-PP-Dol Mannosyltransferase
|Severe microcephaly, hypotonia, seizures, hepatomegaly
||GlcNAc-Transferase 2 (GnT II)
||developmental delay, dysmorphism, stereotypies, seizures
||Dysmorphism, hypotonia, seizures, hepatomegaly, hepatic fiborsis (death at 2.5 months)
||Recurrent infections, persistent neutrophilia, developmental delay, microcephaly, hypotonia (normal Tf)
||Hypotonia (myopathy), spontaneous hemorrhage, Dandy-Walker malformation
||Conserved oligomeric Golgi complex subunit 7
||Fatal in early infancy; dysmorphism, hypotonia, intractable seizures, hepatomegaly, progressive jaundice, recurrent infections, cardiac failure.
||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.
Signs and Symptoms
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)
- 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
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.
Mayo Medical Laboratories
Request: Carbohydrate Deficient Transferrin, serum. Test code 82414.
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.
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.
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
- look for means of improving the symptoms