Congenital Disorders Of N-Linked Glycosylation And Multiple Pathway Overview

Purpose.

Many human disorders of glycosylation pathways have now been identified; they include defects in synthetic pathways for N-linked oligosaccharides, O-linked oligosaccharides, shared substrates, glycophosphatidylinositol (GPI) anchors, and dolichols. This overview will focus on disorders of the N-linked glycan synthetic pathway and some disorders that overlap this metabolic network (multiple-pathway disorders).

The goals of this overview on congenital disorders of glycosylation are the following:

Goal 1.

To describe the clinical characteristics of congenital disorders of N-linked glycosylation

Goal 2.

To review the causes of congenital disorders of N-linked glycosylation

Goal 3.

To provide an evaluation strategy to identify the genetic cause of congenital disorders of glycosylation in a proband

Goal 4.

To inform (when possible) management

Goal 5.

To inform genetic counseling of family members of a proband with congenital disorders of N-linked glycosylation

Treatment of Manifestations

For all congenital disorders of N-linked glycosylation and most multiple-pathway disorders except MPI-CDG (CDG-Ib)

• Failure to thrive. Infants and children can be fed any type of formula for maximal caloric intake. They can tolerate carbohydrates, fats, and protein. Early in life, children may do better on elemental formulas. Their feeding may be advanced based on their oral motor function. Some children require placement of a nasogastric tube or gastrostomy tube for nutritional support until oral motor skills improve.
• Oral motor dysfunction with persistent vomiting. Thickening of feeds, maintenance of an upright position after eating, and antacids can be helpful for children with gastroesophageal reflux and/or persistent vomiting. Consultation with a gastroenterologist and nutritionist is often necessary. Children with a gastrostomy tube should be encouraged to eat by mouth if the risk of aspiration is low. Continued speech and oral motor therapy aids transition to oral feeds and encourages speech when the child is developmentally ready.
• Developmental delay. Occupational therapy, physical therapy, and speech therapy should be instituted. As the developmental gap widens between children with CDG and their unaffected peers, parents, educators, and therapists need continued counseling and support.
• "Infantile catastrophic phase." Very rarely, infants may have a complicated early course presenting with infection, seizure, or hypoalbuminemia with third spacing that may progress to anasarca. Some children are responsive to aggressive albumin replacement with Lasix^®; others may have a more refractory course. Symptomatic treatment in a pediatric tertiary care center is recommended. Parents should also be advised that some infants with PMM2-CDG (CDG-Ia) never experience a hospital visit while others may require frequent hospitalizations.
• Strabismus. Consultation with a pediatric ophthalmologist early in life is important so that potential eye abnormalities can be diagnosed and therapies that preserve vision (glasses, patching, or surgery) can be instituted as needed.
• Hypothyroidism. Although children with CDG are usually chemically euthyroid [Martin & Freeze 2003], thyroid function tests are frequently abnormal. However, free thyroxine analyzed by equilibrium dialysis, the most accurate method, has been reported as normal in seven individuals with CDG. Diagnosis of hypothyroidism and L-thyroxine supplementation should be reserved for those children and adults with elevated TSH and low free thyroxine measured by equilibrium dialysis.
• Renal issues. Bilateral hyperechoic kidneys are often seen on ultrasound in children with PMM2-CDG (CDG-Ia). Enlarged kidneys, renal cysts, and congenital nephrotic syndrome have been reported in individuals with PMM2-CDG (CDG-Ia) and other forms of CDG.
  • Baseline renal ultrasound should be performed on all affected children at the time of diagnosis [Grünewald 2009, Sinha et al 2009].
  • While proteinuria in affected children is extremely rare, routine urinalysis to evaluate for proteinuria is recommended after diagnosis. Follow-up urinalysis should be considered in the first three years of life or if clinical signs indicate.
• Stroke-like episodes. Supportive therapy includes intravenous hydration, maintenance of normal blood glucose, and physical therapy during the recovery period.
• Coagulopathy. Low levels of coagulation factors, both pro- and anticoagulant, rarely cause clinical problems in daily activities but must be addressed when an individual with CDG undergoes surgery. Consultation with a hematologist is recommended to document the pro- and anti- clotting factor levels and coagulation status. Discussion of the coagulation status and management issues with the surgeon is important. When necessary, infusion of fresh frozen plasma corrects the factor deficiency and clinical bleeding. The potential for imbalance of the level of both pro- and anticoagulant factors may lead to either bleeding or thrombosis. Care givers, especially of older affected individuals, should be taught the signs of deep venous thrombosis, which can occasionally be mistaken for injury from trauma in individuals with intellectual and communication disabilities.
• Immunologic status. Most individuals affected with CDGs have functional immune systems; however, children with rare types of N-linked CDG have recurrent or unexpectedly severe infections and should be evaluated by an immunologist. Unless otherwise indicated, full pediatric vaccinations are recommended for affected children and adults.

Additional management issues of adults with CDG

• Orthopedic issues — thorax shortening, scoliosis/kyphosis. Management involves appropriate orthopedic and physical medicine management, well-supported wheel chairs, appropriate transfer devices for the home, and physical therapy. Occasionally, surgical treatment of spinal curvature by an experienced team is warranted.
• Independent living issues. Young adults with CDG and their parents need to address issues of independent living. Aggressive education in functional life skills and/or vocational training help the transition when schooling is completed. Independence in self-care and the activities of daily living should be encouraged. Support and resources for parents of a disabled adult are important aspects of management.
• Deep venous thrombosis (DVT). DVT has been reported in several adults with PMM2-CDG (CDG-Ia) and MPI-CDG (CDG-Ib) and should be kept in mind in the management of all individuals with CDG. Rapid diagnosis and treatment of DVT are essential to minimize the risk of pulmonary emboli; sedentary affected adults and children are at increased risk for DVT.

Prevention of Primary Manifestations

MPI-CDG (CDG-Ib), characterized by hepatic-intestinal disease, is the most common type of CDG for which therapy exists. Because so few individuals have been treated and the natural history of this disorder is variable, careful monitoring and discussion among physicians treating these individuals are warranted [Jaeken et al 1998, Niehues et al 1998, de Lonlay et al 1999, Hendriksz et al 2001, de Lonlay & Seta 2009]:

• In the first reported case, mannose normalized hypoproteinemia and coagulation defects and rapidly improved the protein-losing enteropathy and hypoglycemia [Harms et al 2002]. One gram of mannose per kg body weight was given per day, divided into five oral doses.
• In two children with MPI-CDG (CDG-Ib) treated from infancy with mannose, protein-losing enteropathy and vomiting improved significantly; however, the two children were recently reported to have progressive liver fibrosis [Mention et al 2008].
• Recurrent episodes of thromboembolism and consumptive coagulopathy did not recur in an individual with MPI-CDG (CDG-Ib) treated with mannose [Tamminga et al 2008].
• For some individuals with MPI-CDG (CDG-Ib), heparin therapy can be an alternative to mannose in the treatment of the enteropathy [de Lonlay & Seta 2009].
• A woman age 28 years with MPI-CDG (CDG-Ib) developed progressive liver fibrosis despite mannose treatment and heparin therapy and had a successful liver transplant with resolution of her symptoms for at least two years post transplant [Janssen et al 2014].

Prevention of Secondary Complications

Because infants with CDG have more limited reserves than their peers, parents should have a low threshold for evaluation by a physician for prolonged fever, vomiting, or diarrhea. Aggressive intervention with antipyretics, antibiotics (if warranted), and hydration may prevent stroke-like episodes, seizures in children with potentially lower seizure threshold as well as the morbidity associated with the "infantile catastrophic phase."

Surveillance

Annual

• Assessment by a physician with attention to overall health and possible need for referral for speech, occupational, and physical therapy
• Eye examination
• Liver function tests; thyroid panel; serum concentrations of the clotting factors protein C, protein S, factor IX, and antithrombin III

Other

• Periodic assessment of bleeding and clotting parameters by a hematologist
• Follow up with an orthopedist when scoliosis becomes evident

Agents/Circumstances to Avoid

Acetominophen and other agents metabolized by the liver should be used with caution.

Evaluation of Relatives at Risk

It is appropriate to evaluate apparently asymptomatic older and younger sibs of a proband in order to identify as early as possible those who would benefit from prompt initiation of treatment (in the treatable forms of N-linked CDG) and those who require developmental monitoring and medical management.

Evaluations can include:

• Molecular genetic testing if the pathogenic variant(s) in the family are known;
• Serum transferrin analysis if the pathogenic variant(s) in the family are not known and transferrin was abnormal in the proband.

See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.

Therapies Under Investigation

In one individual with SLC35C1-CDG (CDG-IIc), fucose improved the fucosylation of glycoproteins and reduced recurrent infections [Marquardt et al 1999].

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