congenital disorder of glycosylation

What are Congenital Disorders of Glycosylation (CDG)?

Congenital disorders of glycosylation (CDG) are a group of rare genetic disorders that affect how sugars attach to proteins and fats in the body [4]. This umbrella term encompasses over 130 different diseases, each caused by defects in various steps along the process of glycan synthesis [2].

Characteristics and Symptoms

Individuals with CDG may exhibit a range of symptoms, including developmental delays, imbalance, muscle weakness, nerve damage, vision issues, gastrointestinal problems, poor growth, and liver disease [3]. Some affected individuals may also display distinctive facial features, such as a high forehead, triangular face, large ears, and thin upper lip [5].

Types and Causes

CDG is characterized by defective activity of enzymes that participate in glycosylation. This can occur due to mutations in genes involved in the synthesis of oligosaccharides, leading to a range of clinical manifestations [8]. The condition is often inherited, with some forms being more severe than others.

Example: SRD5A3-CDG

One specific type of CDG is SRD5A3-congenital disorder of glycosylation (SRD5A3-CDG), which primarily causes neurological and vision problems [9]. This condition highlights the diverse range of symptoms associated with CDG.

References:

• [1] IJ Chang, "Congenital disorders of glycosylation," 2018.
• [2] IJ Chang, "Congenital disorders of glycosylation are a genetically and clinically heterogeneous group of >130 diseases caused by defects in various steps along glycan synthesis," 2018.
• [3] Jun 12, 2024 — Developmental delays. · Imbalance. · Muscle weakness. · Nerve damage. · Vision issues. · Gastrointestinal problems. · Poor growth. · Liver disease.
• [4] Congenital disorders of glycosylation (CDG) is a group of rare genetic disorders that affect how sugars attach to proteins and fats in the body.
• [5] Distinctive facial features are sometimes present in affected individuals, including a high forehead, a triangular face , large ears, and a thin upper lip .
• [6] IJ Chang, "Congenital disorders of glycosylation are a genetically and clinically heterogeneous group of >130 diseases caused by defects in various steps along glycan synthesis," 2018.
• [7] A fast growing group of inborn errors of metabolism characterized by defective activity of enzymes that participate in glycosylation.
• [8] DM Krasnewich, "Congenital disorders of glycosylation (CDGs) are a group of over 100 monogenic human diseases with defects in the synthesis of oligosaccharides,"
• [9] Sep 27, 2021 — SRD5A3-congenital disorder of glycosylation (SRD5A3-CDG) is an inherited condition that primarily causes neurological and vision problems.

Diagnostic Tests for Congenital Disorders of Glycosylation (CDG)

Congenital disorders of glycosylation (CDG) are a group of rare genetic disorders that affect the addition of sugar building blocks, called glycans, to proteins in cells throughout the body. Diagnostic tests play a crucial role in identifying CDG and determining the underlying cause.

Recommended First-Tier Test

The recommended first-tier test to screen for congenital disorders of glycosylation (CDG) is a biochemical test that analyzes transferrin and apolipoprotein C-III [9]. This test is often considered the standard first-screen test for N-linked protein glycosylation disorders [5].

Isoelectric Focusing/Polyacrylamide Gel Electrophoresis (IEF)

Still common screening tests for most CDG types, including CDG Ia, are isoelectric focusing/polyacrylamide gel electrophoresis (IEF) [1]. IEF demonstrates the abnormal glycosylation of transferrin.

Serum Transferrin Isoelectrofocusing

Analysis via serum transferrin isoelectrofocusing is often considered the standard first-screen test for N-linked protein glycosylation disorders; however, it may not be sufficient to diagnose all types of CDG [5].

Genetic Testing

The Invitae Congenital Disorders of Glycosylation Panel analyzes genes that are associated with congenital disorders of glycosylation (CDGs) [6]. This panel can help identify the underlying genetic cause of CDG.

Blood Test for N-Glycosylation Defects

A simple blood test to analyze the glycosylation status of transferrin can help diagnose or confirm many cases of CDG due to N-glycosylation defects [7].

These diagnostic tests are essential in identifying congenital disorders of glycosylation and determining the underlying cause. Early diagnosis and treatment can significantly improve patient outcomes.

References: [1] Marklová, E. (2007). Congenital Disorders of Glycosylation: A Review. [5] [6] Invitae Congenital Disorders of Glycosylation Panel [7] May 11, 2021 — For CDG due to N-glycosylation defects, a simple blood test to analyze the glycosylation status of transferrin can help diagnose or confirm many cases. [9] The recommended first-tier test to screen for congenital disorders of glycosylation (CDG) is a biochemical test that analyzes transferrin and apolipoprotein C-III.

Available Therapies for Congenital Disorders of Glycosylation (CDG)

Congenital disorders of glycosylation (CDG) are a group of rare genetic disorders that affect the addition of sugar building blocks, called glycans, to proteins in cells throughout the body. While there is no known cure for CDG, various treatment options have been explored to manage symptoms and improve quality of life.

• Oral Galactose Therapy: Oral galactose supplementation has been shown to improve seizure control in some patients with CDG (Verheijen et al., 2020 [6]). This therapy involves administering a daily dose of galactose, which can help restore normal glycosylation patterns.
• Oral Manganese Therapy: Individualized oral manganese therapy has also been used to manage seizures and other symptoms in patients with CDG (Verheijen et al., 2020 [6]).
• Acetazolamide: Acetazolamide, a medication approved for treating retinal complications, epilepsy, and other diseases, has been repurposed for the treatment of CDG (Brasil et al., 2022 [5]). This therapy involves administering acetazolamide to manage specific symptoms.
• Epalrestat: Epalrestat, an aldose reductase inhibitor used to treat diabetic neuropathy, is being explored as a potential treatment for PMM2-CDG (International clinical guidelines for the management of phosphomannomutase 2-congenital disorder of glycosylation [10]).
• Nutritional Therapies: Nutritional therapies, such as oral mannose supplementation, have been used to manage symptoms in patients with CDG (Monticelli et al., 2023 [9]). These therapies aim to restore normal glycosylation patterns by providing essential nutrients.

Challenges and Limitations

While these treatment options show promise, it is essential to note that the management of CDG remains a significant challenge. The heterogeneity of CDG symptoms and the limited availability of effective treatments make it difficult for physicians to provide optimal care (International clinical guidelines for the management of phosphomannomutase 2-congenital disorder of glycosylation [10]).

Future Directions

Further research is needed to develop more effective treatment options for CDG. The exploration of new therapies, such as epalrestat and nutritional supplements, holds promise for improving patient outcomes. Additionally, the development of diagnostic tools and classification systems will aid in the identification and management of CDG (Monticelli et al., 2023 [9]).

References: [5] Brasil et al. (2022). Repurposing the aldose reductase inhibitor and diabetic neuropathy drug epalrestat for the congenital disorder of glycosylation PMM2-CDG. Dis. Model. Mech., 12. [6] Verheijen et al. (2020). International clinical guidelines for the management of phosphomannomutase 2-congenital disorder of glycosylation. [9] Monticelli et al. (2023). Congenital disorders of glycosylation: a review of the literature and current treatment options. [10] International clinical guidelines for the management of phosphomannomutase 2-congenital disorder of glycosylation.

Differential Diagnosis of Congenital Disorders of Glycosylation (CDG)

Congenital disorders of glycosylation (CDG) are a group of rare genetic disorders that can be challenging to diagnose. The differential diagnosis for CDG involves considering various symptoms and conditions that may mimic the presentation of CDG.

Symptoms to Consider

• Unexplained hypoglycemia
• Chronic diarrhea
• Liver disease
• Coagulopathy
• Neurologic dysfunction
• Skeletal deformities
• Polyhydramnios or Ballantyne syndrome (in prenatal cases)

These symptoms can be indicative of CDG, but they can also be caused by other conditions. A comprehensive differential diagnosis should consider the following:

Other Conditions to Consider

• Metabolic disorders (e.g., Pompe disease, Gaucher disease)
• Genetic disorders (e.g., muscular dystrophy, spinal muscular atrophy)
• Infections (e.g., sepsis, meningitis)
• Autoimmune disorders (e.g., lupus, rheumatoid arthritis)

Diagnostic Approaches

To diagnose CDG, a combination of clinical evaluation, laboratory tests, and genetic analysis may be necessary. The following approaches can be considered:

• Analysis of transferrin glycoforms
• Glycan biosynthesis and metabolism assays
• Genetic testing for specific CDG-causing genes (e.g., PMM2, ALG6)
• Imaging studies (e.g., MRI, CT scans) to evaluate organ involvement

Key Takeaways

The differential diagnosis for congenital disorders of glycosylation involves considering a range of symptoms and conditions that may mimic the presentation of CDG. A comprehensive diagnostic approach, including laboratory tests and genetic analysis, is essential for accurate diagnosis.

References:

• [1] Congenital disorders of glycosylation (CDG), formerly named carbohydrate deficient glycoprotein syndrome, are rare hereditary disorders. [7]
• [2] A group of rare genetic disorders of carbohydrate metabolism characterized by neurologic dysfunction; often affects other organ systems. [8]
• [3] Thus, CDG Ib should be considered in the differential diagnosis of patients with unexplained hypoglycemia, chronic diarrhea, liver disease, or coagulopathy ... [9]
• [4] Congenital disorders of glycosylation (CDG) are a group of clinically heterogeneous disorders characterized by defects in the synthesis of glycans and their attachment to proteins and lipids. ... Laboratory diagnosis of congenital disorders of glycosylation type I by analysis of transferrin glycoforms. Mol Diagn Ther. (2007) 11:303–11. [10]
• [5] Congenital disorders of glycosylation (CDG) are a large group of rare genetic disorders that affect the addition of sugar building blocks, called glycans, to proteins in cells throughout the body. ... so a combination of unexplained health problems can be an indication of the disorder. Symptoms of CDG in infancy and childhood may include: low ... [11]
• [6] The goals of this overview on congenital disorders of glycosylation are the following: Goal 1. Describe the clinical characteristics of congenital disorders of N-linked glycosylation. ... CDG is increasingly being considered in the differential diagnosis for varied symptoms across multiple age groups and clinical specialties. [12]
• [7] This chapter discusses inherited human diseases that are caused by defects in glycan biosynthesis and metabolism (congenital disorders of glycosylation, CDGs). Representative examples are described of genetic defects in the major glycan families and what lessons we can learn from them about glycobiology. Among genetic disorders of glycosylation, those caused by somatic mutations are described ... [13]
• [8] Congenital disorders of glycosylation (CDG) are a group of clinically heterogeneous disorders characterized by defects in the synthesis of glycans and their attachment to proteins and lipids. This manuscript aims to provide a classification of the clinical presentation, diagnostic methods, and treatment of CDG based on the literature review and ... [14]
• [9] Congenital disorders of glycosylation (CDG) are a group of clinically heterogeneous disorders characterized by defects in the synthesis of glycans and their attachment to proteins and lipids. ... Early and accurate diagnosis of CDG is crucial for timely implementation of appropriate therapies and improving clinical outcomes. However, causative ... [15]