WHAT IS CDG?
Congenital Disorders of Glycosylation (CDG) are a group of rare inherited metabolic disorders that affect a complex enzymatic process called glycosylation. The process of glycosylation is critical to normal organ development throughout the body. It seems especially critical for the development and maturation of the nervous system. CDG only started to be recognized clinically in the 1980s. Through the determined effort of geneticists, researchers, clinicians and parents, CDG awareness has expanded greatly, creating opportunities for earlier and more accurate diagnosis and for proper categorization of the existing CDG subtypes. Despite increased understanding and awareness, the diagnosis of CDG can remain elusive. The diagnosis of CDG should be considered in any child with unexplained (and often profound) developmental delay, failure to thrive, stroke-like symptoms, seizures and cerebellar dysfunction. CDG affects most organ systems to varying degrees, so children will often display abnormalities in liver enzymes, digestion and absorption, glandular function (i.e. thyroid), blood clotting, and immunologic function (infectious susceptibility).
CDG-type IB presents with an entirely different clinical picture. Children are often “normal” neurologically but have profound issues with intestinal absorption and digestion. If recognized early, a rather simple therapy with a sugar called mannose may significantly improve the condition.
CDG is a rare disorder, with only approximately 1,000 cases diagnosed worldwide. It is our belief that there remain many undiagnosed and misdiagnosed CDG patients, and that the true number of cases remains unknown.
The Process of Glycosylation
Glycosylation is a complex biochemical enzymatic process in which sugar molecules are attached to proteins forming complexes called glycoproteins. Attachment of sugars to proteins directs the proteins to appropriate tissues leading to normal organ and child development.
The physiologic process of glycosylation is a complex process that takes upward of 100 steps. Each step in the process is catalyzed by special proteins called enzymes, which work in a very specific and exact order to add and delete sugar molecules to the protein. Individuals with CDG genetically lack one or more of these enzymes leading to dysfunctional glycoprotein development which then leads to the myriad of clinical manifestation seen in CDG patients. Depending upon which enzyme is involved; this leads to the different subtype category and its associated CDG clinical presentation.
Scientists investigating CDG (who are called glycobiologists) have identified 50 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 additional glycosylation disorders will continue to be discovered.
It is important to note that current researchers have created and implemented a new nomenclature that uses the gene name and adds CDSG. So, CDG 1A is PMM2-CDG, CDG 1B is MPI-CDG. With so many new CDGs being discovered, it will now be easier for professionals to track them, and important for families to become familiar with both forms of the current CDG terms.
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 1,000 cases of all types of CDG worldwide; however, it is likely that this is only a few percent of the total patients living with CDG. 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 genetic disorders. CDG 1A patients are sometimes mistaken for having inherited mitochondrial disorders or ataxic cerebral palsy.
Prognosis and Treatment
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 most CDG 1A children stabilize after childhood. Individuals with CDG require lifelong expert medical care from their team of physicians (usually comprised of geneticists, medical subspecialists and primary care). Patients with CDG have varying degrees of physical and cognitive disability, including cognitive impairment (mild to severe), speech and language difficulties, poor balance and motor control. As children with CDG IA grow older, they may exhibit ongoing developmental impairment, vision problems, seizure disorders, and stroke-like episodes. However, many are highly interactive, some are conversational and universally they have very charming and winsome personalities. Most are wheelchair bound because it is easier and safer for them to get around as they have ataxic poorly coordinated movement patterns as well as muscular atrophy in their skeletal muscles and scoliosis of their spine.
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 the disease. Current treatment for CDG patients is lifelong intensive supportive therapy (with all variety of therapies), treatment of symptoms, and very importantly prevention of medical problems thru excellent nutrition, scheduled immunizations and excellent health and hygienic practices.
There is no specific medicine to treat CDG, with the exception of 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.
Types of CDG
Congenital Disorders of Glycosylation (CDG) 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. 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, glycosyltransferases 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 CDGs 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 have been identified. In addition, type Ix or IIx refers to cases of CDG that have new or unknown enzyme defects. Scientists are continually working to identify new types of CDG.
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 CDG 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) presenting as elevated liver enzymes (ALT and AST)
- coagulopathy (bleeding tendencies early on and abnormal clotting as adults)
- esotropia (crossed eyes)
- cerebellar hypoplasia (changes in the brain that can be seen on brain imaging)
At a later age, adolescence or adulthood, affected individuals may have these additional clinical features:
- ataxia (poor balance and movement coordination)
- 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.
Excerpt from “CDG Summary of Features and Management”
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 everyday 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 follow-up, 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.