|Donna Krasnewich M.D., Ph.D., is a board certified Clinical Biochemical Geneticist and Pediatrician. She trained at Wayne State University School of Medicine in Detroit, Michigan and received her M.D. and Ph.D. in Pharmacology in 1986. After completing her Fellowship in Genetics at the National Institutes of Health (NIH) she joined the faculty of the National Human Genome Research Institutes (NHGRI) at NIH and is currently the Deputy Clinical Director of NHGRI where she sees children with developmental delay and continues her research on Congenital Disorders of Glycosylation.
|| Susan Sparks M.D., Ph.D., is a board certified Pediatrician completing her fellow- ship training in Clinical Genetics and Clinical Biochemical Genetics at the National Institutes of Health. She received her M.D. and Ph.D. in Molecular Biology and Pharmacology from the Chicago Medical School in 1997 and 1999. She has a strong research interest in glyco- sylation defects including Congenital Disorders of Glycosylation and Congenital Muscular Dystrophies.
CDG Summary of Features and Management
Donna Krasnewich M.D., Ph.D., National Institutes of Health, (email@example.com) and Susan Sparks M.D., Ph.D., National Institutes of Health, (firstname.lastname@example.org)
Article appeared in CDG Newsletter Summer 2004.
Congenital Disorders of Glycosylation (CDG), formerly known as Carbohydrate-deficient glycoprotein syndrome, are a group of disorders caused by the defective synthesis of N-linked oligosaccharides. These oligosaccharides are multiple sugars, linked together in a very specific pattern and attached to proteins and lipids. Because of the important biologic functions of the oligosaccharides in both glycoproteins and glycolipids incorrect synthesis of these compounds may result in clinical problems in different organs of the body. Clinical presentations, most commonly with onset of symptoms in infancy, range from significan neurologic impairment with multiple organ system involvement to low blood sugar and gastrointestinal symptoms with normal development. Over time it has become very clear that we only know the tip of the iceberg about how children with CDG present to their doctors. Some children have few problems, some more. We have a lot to learn.
The diagnosis is suggested by a spectrum of clinical features and confirmed by analysis of the N-linked glycosylation of a reporter glycoprotein, serum transferrin. The definitive diagnostic test for all types of CDG is isoelectric focusing or other isoform analysis (ie. capillary electrophoresis, GC/MS) of serum transferrin which reveals abnormal N-linked oligosaccharides linked to transferrin.
If an individual has an abnormal serum transferrin pattern the next step is to define the type of CDG. Each type of CDG is caused by a different defective step in the synthesis of N-linked oligosaccharides corresponding to a different deficient enzyme. CDG typing is done by assaying for enzyme activity of one of the fifteen known defective enzymes currently recognized, if available, or by analysis for mutations in the genes coding for these enzymes. This analysis can be performed on fibroblasts, white blood cell pellets, lymphobasts. Some of them can be done on amniocytes and chorionic villus samples for prenatal testing of another pregnancy in the family.
The laboratory diagnostic test for all types of CDG is the analysis of serum transferrin glycoforms, either called transferrin isoforms analysis or carbohydrate deficient transferrin by clinical laboratories. Abnormal serum transferrin glycoform analysis in an individual gives them the diagnosis of CDG.
The clinical spectrum of CDG is expanding with milder and more severe features being recognized. Many cases are probably still not diagnosed. On the other hand, the differential diagnosis of a child with developmental delay and low tone is lengthy making the physician's job difficult. Children with CDG may have any or all of the following clinical issues:
At a later age, in adolescence or adulthood, the presentation may include the following clinical features in addition to a suggestive history:
- developmental delay
- failure to thrive
- hepatic dysfunction (elevated transaminases)
- coagulopathy (low levels of clotting factors)
- abnormal fat pattern including increased suprapubic fat pad, skin dimpling and inverted nipples or subcutaneous fat pads having a
toughened, puffy, or uneven consistency
- cerebellar hypoplasia
- stroke-like episodes in a developmentally delayed child
- neurologic evidence of cerebellar dysfunction (ataxia, dysarthria, dysmetria)
- variable degrees of non-progressive cognitive impairment
- absent puberty in females, small testes in males
- retinitis pigmentosa
- progressive scoliosis with truncal shortening
- joint contractures
- stroke-like episodes
- peripheral neuropathy with or without muscle wasting
The management issues relevant to children with CDG, appropropriate for all types except CDG-Ib, include:
Additional management issues of adults with CDG 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. Feeding is difficult and when coupled with the slow growth of the children creates anxiety in the parents. 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 have had successful corrective surgery. Some children just require patching and glasses.
- Pericardial effusion-Many children with CDG-Ia have pericardial effusions and most are clinically benign 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.
- Seizures-Children with CDG-Ia may have seizures in their 2nd or 3rd year of life which are easily controlled with medication.
- While children with some 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. Anecdotally 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.
- 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.
This is just a brief discussion of things that we think about as physicians when we are caring for children with CDG. Also, as physicians, we know that parents know a lot more than we do about their children. Also, remember that not all that is written will be important for every child. Your care of and love for the child or adult with CDG in your family is their greatest asset.
Please let me know if you have any questions. Donna Krasnewich M.D., Ph.D.
National Institutes of Health (email@example.com), Susan Sparks M.D., Ph.D., National Institutes of Health (firstname.lastname@example.org)
Disclaimer: This is a forum for the free expression of ideas created by, and for, parents of children diagnosed with Congenital Disorder of Glycosylation. The information provided on this web site should NOT be used as a substitute for seeking professional medical diagnosis, treatment and care. You should not rely on any information in these pages to replace consultations with qualified health professionals.
The CDG Family Network, Attn: Cynthia Wren-Gray, P.O. Box 860847, Plano, Texas, 75074 Phone: 800-250-5273