Pediatrics

Disorders of glycosylation

OVERVIEW: What every practitioner needs to know

Are you sure your patient has a disorder of glycosylation? What are the typical findings for this disease?

Congenital disorders of glycosylation (CDG), formerly called carbohydrate-deficient glycoprotein syndrome, are a rapidly expanding family of multisystem genetic diseases caused by defects in the biosynthesis of the glycan moiety of glycoproteins and other glycoconjugates. These disorders comprise defects in protein N- and O-glycosylation.

Deficiencies of N-glycosylation represent multisystem diseases with involvement of the central and peripheral nervous systems as well as the gastrointestinal, endocrine, immune, and coagulation/anticoagulation systems. The genetic transmission of CDG is autosomal recessive, with the exception of the hereditary multiple exostoses syndromes, which are autosomal dominant conditions.

When evaluating a child with neurologic abnormalities, CDG should be in the differential diagnosis of every patient, given the very broad phenotype of these disorders. Furthermore, any child with unexplained hypoglycemia (especially in the context of hyperinsulinism), with or without liver problems, should undergo CDG testing, as CDG type Ib is the only CDG disorder treatable so far without any neurologic symptoms.

Disorders affecting O-glycosylation defects are associated with different forms of muscular dystrophy such as Walker-Warburg syndrome, muscle-eye-brain disease, Fukuyama congenital muscular dystrophy, limb-girdle muscular dystrophy type 2I, and congenital muscular dystrophy type 1D. In addition, progeria syndromes and bone disorders such as hereditary multiple exostoses syndrome are caused by alterations in O-xylose–linked glycosaminoglycan formation.

Given the broad phenotypic spectrum of CDGs, there are no specific clinical findings pointing toward its diagnosis. In patients with eye, brain and skeletal muscle abnormalities, O-glycosylation disorders involving abnormal posttranslational processing of alpha-dystroglycan should be considered.

Recently, patients with cutis laxa and neurologic deficits have been found to have combined N- and O-glycosylation defects.

CDG should be considered in infants and children with any of the following:

  1. Neurologic abnormalities, such as developmental delay, seizures, and hypotonia; coagulation abnormalities; liver disease

  2. Hypoglycemia, impaired neutrophil mobility, neuronal migration abnormalities, neonatal intracranial hemorrhage, cutis laxa, inverted nipples, abnormal fat pad distribution

What other disease/condition shares some of these symptoms?

The differential diagnosis of CDG is very broad and includes disorders associated with neurologic abnormalities, coagulation defects, hypoglycemia with or without liver involvement, and eye and skeletal muscle abnormalities.

What caused this disease to develop at this time?

So far, almost all the patients with CDG have presented with clinical abnormalities within the first year of life. CDG type Ib, which does not present with any developmental abnormalities, may not be seen until the first 2-3 years of life.

What laboratory studies should you request to help confirm the diagnosis? How should you interpret the results?

A relatively inexpensive screening test for CDG requires only a small amount of serum and has used isoelectric focusing in the past and currently uses electrospray-ionization mass spectrometry (ESI-MS) to evaluate the glycosylated state of transferrin in the serum. This testing method has greatly facilitated the detection of N-linked glycosylation defects. The ESI-MS assay reliably identifies underglycosylation of transferrin and allows discrimination between defects of oligosaccharide assembly and transfer, termed CDG-I, and defects of N-linked glycan processing, termed CDG-II.

It is important to emphasize that galactosemia, hereditary fructose intolerance, and chronic alcohol abuse (but not liver dysfunction per se) are the only conditions that have been shown to lead to secondary glycosylation abnormalities associated with an abnormal transferrin pattern.

Once the screening test results prove suggestive of an N-glycosylation disorder, further biochemical studies on fibroblasts and/or gene sequencing are performed to establish the exact defect.

Disorders of O-glycosylation are not detected by this screening test. Thus, the clinical constellation of skeletal muscle, eye, and neurologic abnormalities should prompt consideration of defects in alpha-dystroglycan processing. In general, skeletal muscle biopsy specimens reveal abnormal immunolabeling of alpha-dystroglycan, which is then followed by gene sequencing of various genes associated with these muscle-eye-brain disorders.

Would imaging studies be helpful? If so, which ones?

Brain magnetic resonance imaging studies are necessary to detect structural abnormalities such as cerebellar hypoplasia and neuronal migration disorders.

Confirming the diagnosis

Evaluation for CDGs should start with screening of blood samples as described above, followed by biochemical and/or gene testing if results are positive.

If you are able to confirm that the patient has a disorder of glycosylation, what treatment should be initiated?

Treatment of patients with CDGs at this point is exclusively supportive. Careful management and support of these patients is necessary. Developmental delays, seizures, respiratory problems, and feeding difficulties need to be managed.

The only treatable form of CDG is CDG type Ib, which generally presents with hypoglycemia with or without liver disease, but no neurologic deficits. The patients are treated with mannose supplementation, which prevents future episodes of hypoglycemia and improves liver disease (if it has not progressed beyond treatment).

What are the adverse effects associated with each treatment option?

Mannose supplementation has no side effects

What are the possible outcomes of disorders of glycosylation?

The outcome of CDGs depends on the individual. Given the often severe multisystem involvement, CDGs often have a life-threatening trajectory.

What causes this disease and how frequent is it?

Most of these disorders are autosomal recessive in origin, with only a few exceptions (see above). Overall these disorders are very rare.

What complications might you expect from the disease or treatment of the disease?

Neurologic abnormalities often cause severe seizure disorders. Furthermore, feeding difficulties, coagulation defects, and respiratory problems need close monitoring.

How can disorders of glycosylation be prevented?

In case of identification of a primary gene defect, prenatal counseling can be offered to pregnant women.

What is the evidence?

Leroy, JG. "Congenital disorders of N-glycosylation including diseases associated with O- and as well as N-glycosylation defects". Pediatr Res. vol. 60. 2006. pp. 643-56.

Jaeken, J. "Komrower Lecture. Congenital disorders of glycosylation (CDG): it's all in it!". J Inherit Metab Dis. vol. 26. 2003. pp. 99-118.

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