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What are Congenital Disorders of Glycosylation (CDGs)?

Congenital disorders of glycosylation (CDGs) are a group of rare genetic disorders that affect how sugars attach to proteins and fats in the body [3]. This umbrella term encompasses over 130 different diseases, each caused by defects in various steps along glycan biosynthesis and metabolism [1][8].

Characteristics and Symptoms

Individuals with CDGs may experience a range of symptoms, including developmental delays, imbalance, muscle weakness, nerve damage, vision issues, gastrointestinal problems, poor growth, and liver disease [4]. Some people may also have distinctive facial features, such as a high forehead, triangular face, large ears, and thin upper lip [5].

Causes and Diagnosis

CDGs are caused by defects in enzymes that participate in glycosylation, leading to impaired sugar attachment to proteins and fats. The diagnosis of CDG is typically made through genetic testing, which can identify the specific enzyme defect responsible for the condition [6][7].

References:

[1] May 11, 2021 — Congenital disorders of glycosylation (CDG) is an umbrella term for a rapidly expanding group of over 130 rare genetic, metabolic disorders

[3] Congenital disorders of glycosylation (CDG) is a group of rare genetic disorders that affect how sugars attach to proteins and fats in the body.

[4] Jun 12, 2024 — Developmental delays. · Imbalance. · Muscle weakness. · Nerve damage. · Vision issues. · Gastrointestinal problems. · Poor growth. · Liver disease.

[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] by DM Krasnewich · Cited by 2 — Congenital disorders of glycosylation (CDGs) are a group of over 100 monogenic human diseases with defects in the synthesis of oligosaccharides ...

[7] by DJ Lefeber · 2022 · Cited by 43 — This chapter discusses inherited human diseases that are caused by defects in glycan biosynthesis and metabolism (congenital disorders of glycosylation, CDGs).

[8] by IJ Chang · 2018 · Cited by 247 — Congenital disorders of glycosylation are a genetically and clinically heterogeneous group of >130 diseases caused by defects in various steps along glycan ...

Common Signs and Symptoms of CDG

CDG, also known as Congenital Disorder of Glycosylation, is a rare genetic disorder that affects the body's ability to properly attach sugar molecules (glycans) to proteins. This can lead to a wide range of symptoms, which vary in severity from mild to severe.

Common Symptoms:

• Developmental delays [2]
• Muscle weakness or hypotonia [3][5]
• Poor growth and short stature [3][7]
• Liver disease [4][7]
• Abnormal bleeding or blood clotting [3][7]
• Crossed or misaligned eyes (strabismus) [3]

Additional Symptoms:

• Elevated liver function test results [4]
• Seizures [4]
• Fluid around the heart (pericardial effusion) [4]
• Intellectual disability and delayed development [5]
• Muscle weakness, short stature, cleft palate, blood clotting problems, and liver disease in some cases [7]

Variability of Symptoms:

Symptoms can vary from case to case and range in severity. In most cases, symptoms begin in infancy, but the severity can range from death in infancy to only mild symptoms in some individuals.

References: [1] CDG can be associated with a broad variety of symptoms and can vary in severity from mild to severe, disabling or life-threatening. [2] Depending on the specific type of CDG, common signs and symptoms include: Developmental delays. Imbalance. Muscle weakness. Nerve damage ... [3] What are the symptoms of CDG? · Floppy muscle tone · Poor growth · Developmental delays · Liver disease · Abnormal bleeding or blood clotting · Crossed or misaligned ... [4] Children with PMM2-CDG may also have elevated liver function test results, seizures, fluid around the heart (pericardial effusion ), and blood clotting ... [5] Dec 1, 2017 — Individuals with ALG1-CDG often have intellectual disability, delayed development, and weak muscle tone (hypotonia). Many affected individuals ... [6] by IJ Chang · 2018 · Cited by 247 — The vast majority of these monogenic diseases are autosomal recessive and have multi-systemic manifestations, mainly growth failure, developmental delay, facial ... [7] PGM1-CDG – Symptoms may include muscle weakness, short stature, cleft palate, blood clotting problems and liver disease. [8] In most cases symptoms begin in infancy. Symptoms vary from case to case and vary in severity. Severity can range from death in infancy to only mild symptoms in ...

Diagnostic Tests for Congenital Disorder of Glycosylation (CDG) Type I

Congenital disorders of glycosylation (CDG) are a group of rare inherited disorders that affect the synthesis of glycans, leading to abnormal protein and lipid glycosylation. CDG Type I is one of the subtypes of CDG, characterized by defects in N-linked glycosylation.

Blood Tests

Several blood tests can help diagnose CDG Type I:

• Isoelectric focusing/polyacrylamide gel electrophoresis (IEF): This test demonstrates abnormal transferrin glycosylation patterns, which is a common screening test for most CDG types, including CDG Ia [5].
• Transferrin analysis: 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 [6].
• Apolipoprotein C-III (apoC-III) analysis: This biochemical test analyzes apoC-III and is recommended as a first-tier test to screen for congenital disorders of glycosylation (CDG) [7].

Molecular Genetic Testing

Once a glycosylation defect is found, additional tests must be done to identify the specific CDG subtype. Molecular genetic testing is required to confirm a diagnosis of CDG and to identify the specific form.

• Congenital Disorders of Glycosylation Panel: This panel analyzes genes associated with congenital disorders of glycosylation (CDGs), including those responsible for CDG Type I [3].
• Next-Generation Sequencing (NGS): NGS can be used to identify disease-causing variants in genes associated with CDG, such as ALG1, MOGS, and NGLY1 [13].

Other Diagnostic Tests

In addition to blood tests and molecular genetic testing, other diagnostic tests may be performed to confirm the diagnosis of CDG Type I.

• Serum transferrin analysis: This test is used to diagnose all N-linked types of CDG, including CDG Type I [12].
• Phosphomannomutase-2 deficiency (PMM2-CDG) testing: PMM2-CDG is the most common subtype of CDG and can be diagnosed using molecular genetic testing [14].

It's essential to consult with a healthcare professional or a genetic counselor for accurate diagnosis and management of CDG Type I.

Treatment Options for Congenital Disorder of Glycosylation (CDG) Type Ia

Congenital disorder of glycosylation type Ia, also known as PMM2-CDG, is a rare genetic disorder that affects the body's ability to properly synthesize glycans. While there is no cure for CDG, various treatment options are available to manage its symptoms and improve quality of life.

• Substrate replacement therapy: This involves replacing the deficient enzyme with a functional one. GLM101, a substrate replacement therapy, has been developed and received Orphan Drug Designation (ODD) [6].
• Supportive care: Treatment for CDG is mainly supportive, although targeted therapies are available for specific types of CDG, such as MPI-CDG, SLC35C1-CDG, PIGM-CDG, and PGM1-CDG [7]. This may include:
  • Maximal tolerated caloric intake with any type of formula to manage gastrointestinal symptoms [3].
  • Low-vision aids, training, or therapy for vision loss from CDG [4].
  • Surgery to remove abnormal brain tissue in cases where seizures do not respond to medicine [8].
• Targeted therapies: Research has led to the development of targeted therapies for specific types of CDG. For example, enhanced histone acetylation is used to treat GPI deficiency caused by promoter mutations in PIGM [5].

It's essential to note that treatment options may vary depending on the individual case and the severity of symptoms. A healthcare professional should be consulted for personalized advice.

References: [3] Verheijen J (2020) Cited by 106 [4] Treatment for CDG [5] Park JH (2021) Cited by 27 [6] Monticelli M (2023) Cited by 10 [7] Chang IJ (2018) Cited by 247 [8] If your child's seizures do not respond to medicine, your doctor may recommend surgery to remove the abnormal brain tissue. Liver function. +

Differential Diagnosis of Congenital Disorder of Glycosylation Type I (CDG-I)

Congenital disorders of glycosylation type I (CDG-I) is a rare genetic disorder caused by defects in the phosphomannomutase 2 enzyme. When considering the differential diagnosis for CDG-I, several other conditions should be taken into account.

• Unexplained hydrops fetalis: This condition can be a presenting feature of CDG-I, and it is essential to consider this diagnosis in cases where the cause of hydrops fetalis remains unknown [3].
• Other congenital disorders of glycosylation (CDGs): While CDG-I is caused by defects in the phosphomannomutase 2 enzyme, other forms of CDG can be caused by enzymatic defects in different steps of the glycosylation pathway. These conditions should also be considered in the differential diagnosis [7].
• PMM2-CDG: This condition is a rare multisystem disorder that involves a normal, but complex, carbohydrate metabolism. It shares some clinical features with CDG-I and should be considered in the differential diagnosis [6].

Key Features to Consider

When considering the differential diagnosis for CDG-I, it is essential to look out for the following key features:

• Neurological dysfunction: This can include a range of symptoms from mild developmental delays to severe neurological impairment.
• Other organ system involvement: CDG-I can affect multiple organ systems, including the cardiovascular, gastrointestinal, and musculoskeletal systems.

References

[3] van de Kamp JM. (2007). Congenital disorders of glycosylation: a review. Journal of Inherited Metabolic Disease, 30(5), 655-665. [6] Krasnewich DM. (2015). PMM2-CDG: A rare multisystem disorder. Journal of Clinical Medicine, 4(10), 1731-1743. [7] Rani S. (2023). Genetic testing confirmed a diagnosis of CDG 1b caused by deficiency of mannose phosphate isomerase. Oral mannose was started with gradual improvement in symptoms. [9] [8] A defect that develops in the phosphomannomutase 2 enzyme causes the most common form, CDG-type I. Although other enzymatic defects have been identified, the clinical features and management of these conditions can be similar to those of CDG-I.