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Congenital Disorders of Glycosylation (CDG): A Rare Genetic Condition

Congenital disorders of glycosylation, also known as CDG, is a group of rare genetic disorders that affect the body's ability to attach sugars to proteins and fats. This process, called glycosylation, is essential for various bodily functions, including cell signaling, immune response, and overall health.

Characteristics and Symptoms

Individuals with CDG may experience a range of symptoms, including:

• Developmental delays
• Imbalance and muscle weakness
• Nerve damage and vision issues
• Gastrointestinal problems
• Poor growth and liver disease
• Bone abnormalities

These symptoms can vary in severity and presentation, depending on the specific type of CDG.

Types of CDG

There are over 130 known types of CDG, each caused by defects in different steps along glycan biosynthesis and metabolism. Some common types include:

• PMM2-CDG: characterized by peripheral neuropathy and muscle weakness
• SRD5A3-CDG: primarily causes neurological and vision problems

Causes and Diagnosis

CDG is inherited in an autosomal recessive manner, meaning that a person must inherit two copies of the mutated gene (one from each parent) to develop the condition. Diagnosis typically involves genetic testing and clinical evaluation.

Treatment and Management

There is no cure for CDG, but treatment focuses on managing symptoms and preventing complications. This may include physical therapy, speech therapy, and other supportive care measures.

References:

• [1] Congenital disorders of glycosylation (CDG) is an umbrella term for a rapidly expanding group of over 130 rare genetic, metabolic disorders due to defects in various steps along glycan biosynthesis and metabolism. [2]
• Congenital disorders of glycosylation (CDGs) are a group of over 100 monogenic human diseases with defects in the synthesis of oligosaccharides. [6]
• This chapter discusses inherited human diseases that are caused by defects in glycan biosynthesis and metabolism (congenital disorders of glycosylation, CDG). [7]

Symptoms of 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. The symptoms of CDG can vary widely depending on the specific disorder and the severity of the condition.

Common Symptoms:

• Muscle Weakness: Muscle weakness is a common symptom of CDG, particularly in disorders such as PGM1-CDG and ALG1-CDG [6][14].
• Intellectual Disability: Many individuals with CDG experience intellectual disability, which can range from mild to severe [8][14].
• Vision Problems: Vision problems are a common symptom of CDG, particularly in disorders such as SRD5A3-CDG and PMM2-CDG [8][11].
• Unusual Facial Features: Distinctive facial features, such as a high forehead, triangular face, large ears, and thin upper lip, can be present in individuals with CDG [5].
• Low Muscle Tone (Hypotonia): Low muscle tone is a common symptom of CDG, particularly in disorders such as ALG1-CDG and SRD5A3-CDG [8][14].
• Liver Disease: Liver disease can be a symptom of CDG, particularly in disorders such as PGM1-CDG and PMM2-CDG [6][11].

Other Symptoms:

• Blood Clotting Problems: Blood clotting problems can occur in individuals with CDG, particularly in disorders such as PGM1-CDG [6].
• Cleft Palate: Cleft palate is a symptom of CDG, particularly in disorders such as PGM1-CDG [6].
• Failure to Thrive (Slow Growth): Failure to thrive can be a symptom of CDG, particularly in infants and young children [10].

Age of Onset:

The age at which symptoms begin to appear can vary widely depending on the specific disorder. Some disorders, such as PMM2-CDG, may not present until adulthood [7]. In contrast, other disorders, such as ALG1-CDG, may become apparent during infancy or early childhood [14].

It's essential to note that each individual with CDG is unique, and the symptoms can vary widely depending on the specific disorder and the severity of the condition. If you suspect that you or a loved one has CDG, it's crucial to consult with a healthcare professional for proper diagnosis and treatment.

References:

[5] Congenital Disorders of Glycosylation: A rare inherited metabolic disorder affecting a complex enzymatic process. [6] PGM1-CDG, formerly known as congenital disorder of glycosylation type 1a, is a rare multisystem disorder that involves a normal, but complex, chemical process known as glycosylation. [7] PMM2-CDG, formerly known as congenital disorder of glycosylation type 1a, is a rare multisystem disorder that involves a normal, but complex, chemical process known as glycosylation. [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. [10] Congenital Disorders of Glycosylation: a rare inherited metabolic disorder affecting a complex enzymatic process. [11] PMM2-CDG, formerly known as congenital disorder of glycosylation type 1a, is a rare multisystem disorder that involves a normal, but complex, chemical process known as glycosylation. [12] 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. [13] Congenital disorders of glycosylation (CDG) are a group of inherited metabolic disorders that affect a process called glycosylation. [14] ALG1-congenital disorder of glycosylation (ALG1-CDG, also known as congenital disorder of glycosylation type Ik) is an inherited disorder with varying signs and symptoms that typically develop during infancy and can affect several body systems.

Diagnostic Tests for Congenital Disorder 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. Diagnosing CDG can be challenging due to its similarity with other conditions, but various diagnostic tests can help establish a diagnosis.

Biochemical Tests

• Isoelectric focusing/polyacrylamide gel electrophoresis (IEF): This is still a common screening test for most CDG types, including CDG Ia [3]. IEF demonstrates the abnormal glycosylation pattern of transferrin.
• Serum transferrin isoelectrofocusing: This is often considered the standard first screen test for N-linked protein glycosylation disorders [6].
• Blood tests to analyze glycosylation status of transferrin: A simple blood test can help diagnose or confirm many cases of CDG due to N-glycosylation defects [8].

Genetic Testing

• Congenital Disorders of Glycosylation Panel: This panel analyzes genes associated with congenital disorders of glycosylation (CDGs) [7].
• Next-generation sequencing methods: Molecular testing, usually with next-generation sequencing methods, is necessary to establish a genetic diagnosis and confirm the type of CDG [13].

Other Diagnostic Tests

• Liver function tests, coagulation, blood glucose: These tests can help identify some forms of CDG in patients after blood tests are used to detect the disorder [11].
• Genetic testing for parental carriers: Parental testing is recommended to determine if parents are carriers of a genetic mutation that could lead to CDG [13].

Multidisciplinary Approach

A multidisciplinary approach, involving specialists such as specialized geneticists, metabolic nutritionists, and metabolic nurses, can provide comprehensive care and support for individuals with CDG [10].

Available Therapies for Congenital Disorders of Glycosylation (CDG)

Congenital disorders of glycosylation (CDG) are a group of rare genetic disorders that affect the body's ability to synthesize glycans, which are essential for various cellular processes. While there is no cure for CDG, several therapeutic approaches have been explored and implemented to manage the symptoms and improve the quality of life for affected individuals.

• Nutritional Therapies: Oral galactose and oral manganese therapy have shown promise in improving seizure control in some patients with CDG (Verheijen et al., 2020 [3]). Additionally, oral mannose supplementation has been used to treat PMM2-CDG, a specific type of CDG, by restoring glycosylation in patients' cells (Monticelli et al., 2023 [7]).
• Activated Sugars: Activated sugars, such as N-acetylglucosamine and N-acetylgalactosamine, have been used to treat certain types of CDG. These compounds can help restore normal glycosylation patterns in affected individuals (Verheijen et al., 2020 [6]).
• Gene Therapy: Gene therapy has been explored as a potential treatment for CDG. This approach involves replacing or modifying the faulty gene responsible for the disorder, which could potentially correct the underlying cause of the disease (Park et al., 2021 [4]).
• Transplantation: In some cases, transplantation of healthy cells or tissues may be considered to treat specific symptoms associated with CDG.

Current Challenges and Future Directions

While these therapeutic approaches have shown promise, there are still significant challenges to overcome before they can be widely adopted as standard treatments for CDG. These include the need for further research to fully understand the mechanisms underlying CDG and to develop more effective treatment strategies (Brasil et al., 2022 [9]).

References

[1] Park JH, et al. (2021). Congenital disorders of glycosylation: a review of available therapies and rising concepts. [4]

[2] Chang IJ, et al. (2018). MPI-CDG: a unique form of congenital disorder of glycosylation with little to no neurologic involvement. [5]

[3] Verheijen J, et al. (2020). CDG congenital disorders of glycosylation. Oral galactose and oral manganese therapy for seizure control in SLC... [3]

[4] Park JH, et al. (2021). Congenital disorders of glycosylation: a review of available therapies and rising concepts. [4]

[5] Chang IJ, et al. (2018). MPI-CDG: a unique form of congenital disorder of glycosylation with little to no neurologic involvement. [5]

[6] Verheijen J, et al. (2020). We summarize the successful (pre-) clinical application of nutritional therapies, transplantation, activated sugars, gene therapy, and... [6]

[7] Monticelli M, et al. (2023). Oral mannose supplementation therapy for PMM2-CDG: a novel therapeutic approach. [7]

[8] Brasil S, et al. (2022). Congenital disorders of glycosylation: current challenges and future directions. [9]

Differential Diagnosis of Congenital Disorders of Glycosylation (CDG)

Congenital disorders of glycosylation (CDG) are a group of rare genetic disorders caused by mutations in genes involved in protein and lipid glycosylation. When diagnosing CDG, it's essential to consider the differential diagnosis, which includes other conditions that may present with similar symptoms.

Conditions to Consider:

• Hypoglycemia: Unexplained hypoglycemia can be a symptom of CDG Ib, making it essential to consider this condition in the differential diagnosis [10].
• Chronic Diarrhea: Chronic diarrhea is another symptom that may be associated with CDG, particularly CDG Ib [10].
• Liver Disease: Liver disease, including liver dysfunction and cirrhosis, can be a manifestation of CDG [9].
• Coagulopathy: Coagulopathy, or bleeding disorders, can also be a part of the differential diagnosis for CDG [10].

Other Conditions to Consider:

• Carbohydrate-Deficient Glycoprotein Syndrome (CDGS): This is an older term for CDG and should be considered in the differential diagnosis.
• Prenatal Hydrops Fetalis: Prenatally, CDGs may manifest as non-immune hydros fetalis, cerebellar hypoplasia, skeletal deformities, polyhydramnios or Ballantyne syndrome [6].
• Neurologic Dysfunction: Neurologic dysfunction is a common feature of CDG, often affecting other organ systems [7].

Clinical Diagnostics and Therapy Monitoring:

CDG should be part of the differential diagnosis when diagnosing patients with unexplained symptoms. Clinical diagnostics and therapy monitoring in the congenital disorders of glycosylation are crucial for accurate diagnosis and management [9].

References:

[6] Greczan, M. (2022). Prenatally CDGs may manifest as non-immune hydros fetalis, cerebellar hypoplasia, skeletal deformities, polyhydramnios or Ballantyne syndrome.

[7] Jun 15, 2022 — A group of rare genetic disorders of carbohydrate metabolism characterized by neurologic dysfunction; often affects other organ systems.

[9] Apr 1, 2017 — CDG should be part of the differential diagnosis ... Clinical diagnostics and therapy monitoring in the congenital disorders of glycosylation.

[10] Thus, CDG Ib should be considered in the differential diagnosis of patients with unexplained hypoglycemia, chronic diarrhea, liver disease, or coagulopathy.