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

Congenital disorders of glycosylation (CDG) is a group of rare genetic disorders that affect the synthesis of oligosaccharides, which are complex carbohydrates attached to proteins and fats in the body [2][7]. This condition is caused by defects in various steps along the glycan biosynthesis pathway, leading to impaired protein function and cellular dysfunction [6].

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
• Liver disease

Some individuals may also display distinctive facial features, such as a high forehead, triangular face, large ears, and thin upper lip [5].

Types of CDG

There are over 130 known types of CDG, each caused by defects in different steps along the glycan biosynthesis pathway. Some specific types of CDG include:

• SRD5A3-congenital disorder of glycosylation (SRD5A3-CDG), which primarily causes neurological and vision problems [9]
• Other forms of CDG may affect various organs and systems, leading to a range of symptoms and complications.

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 due ...

[2] 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 ...

[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] 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 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 ...

[8] 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).

[9] Sep 27, 2021 — SRD5A3-congenital disorder of glycosylation (SRD5A3-CDG) is an inherited condition that primarily causes neurological and vision problems.

Common Signs and Symptoms of Congenital Disorder of Glycosylation (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 to proteins. This can lead to a wide range of symptoms, which can vary in severity and impact different parts of the body.

Common Symptoms:

• Developmental delays [2]
• Muscle weakness or hypotonia (floppy muscle tone) [3]
• Poor growth or short stature [3]
• Liver disease [4]
• Abnormal bleeding or blood clotting [3]
• Crossed or misaligned eyes [3]

Additional Symptoms:

• Elevated liver function test results [4]
• Seizures [4]
• Fluid around the heart (pericardial effusion) [4]
• Intellectual disability or delayed development [5]
• Weak muscle tone (hypotonia) [5]
• Growth failure [6]
• Facial abnormalities [6]

Symptoms by Type of CDG:

• PMM2-CDG: elevated liver function test results, seizures, fluid around the heart, and blood clotting problems [4]
• ALG1-CDG: intellectual disability, delayed development, and weak muscle tone (hypotonia) [5]
• PGM1-CDG: muscle weakness, short stature, cleft palate, blood clotting problems, and liver disease [7]

Important Note: Symptoms can vary in severity and impact different parts of the body. In most cases, symptoms begin in infancy and can range from mild to severe, disabling or life-threatening.

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)

Congenital disorders of glycosylation (CDG) are a group of diseases characterized by impaired protein glycosylation. Diagnostic tests play a crucial role in identifying CDG, and the following information highlights some of the key diagnostic methods:

• Biochemical Tests: The recommended first-tier test to screen for congenital disorders of glycosylation (CDG) is a biochemical test that analyzes transferrin and apolipoprotein C-III [2]. This test helps identify patients with suspected CDG due to clinical symptoms or biochemical findings.
• ESI-TOF/MS: ESI-TOF/MS is an accurate, high-resolution mass spectrometry technique that precisely identifies diagnostic N-glycans. It involves adding an isotope-labeled "glycopeptide" to each sample [7]. This method helps diagnose CDG due to N-glycosylation defects.
• Blood Test: A simple blood test can help diagnose or confirm many cases of CDG due to N-glycosylation defects by analyzing the glycosylation status of transferrin [8].
• Genetic Testing: Genetic testing, such as a 48 gene panel that includes assessment of non-coding variants, is ideal for patients with a clinical suspicion of a congenital disorder of glycosylation [9].

Key Points to Consider

• The biochemical test analyzing transferrin and apolipoprotein C-III is the recommended first-tier test.
• ESI-TOF/MS precisely identifies diagnostic N-glycans, aiding in CDG diagnosis.
• A simple blood test can help diagnose or confirm many cases of CDG due to N-glycosylation defects.
• Genetic testing may be necessary for patients with a clinical suspicion of CDG.

References

[1] Marklová E. (2007) - The aim of this paper is to review the diagnostics of congenital disorders of glycosylation (CDG), an ever expanding group of diseases. [2] - The recommended first-tier test to screen for congenital disorders of glycosylation (CDG) is a biochemical test that analyzes transferrin and apolipoprotein ... [7] - ESI-TOF/MS is an accurate, high resolution mass spectrometry that precisely identifies diagnostic N-glycans. [8] - For CDG due to N-glycosylation defects, a simple blood test to analyze the glycosylation status of transferrin can help diagnose or confirm many ... [9] - Is a 48 gene panel that includes assessment of non-coding variants.

Based on the search results, it appears that there are several drug treatments being researched and used for Congenital Disorders of Glycosylation (CDG).

• Oral Galactose Supplementation: According to [1], oral galactose supplementation at doses of up to 1.5 g/kg bodyweight/day or higher was proposed as a potential treatment for CDG.
• Valproic Acid: Myoclonus, a common symptom in some types of CDG, often responds to valproic acid, although this must be used cautiously in patients with liver disease [2].
• Levetiracetam: This is an alternative medication that can be used to treat myoclonus in patients with CDG [2].
• Mannose Supplementation: Oral mannose supplementation therapy was the first therapeutic approach for PMM2-CDG, and it successfully restored glycosylation in patients' cells [3]. Additionally, feeding mannose to pregnant dams helped overcome embryonic lethality in a hypomorphic Pmm2 mouse model [4].
• Epalrestat: This drug is being repurposed for the treatment of PMM2-CDG. It was used to monitor the effect of epalrestat treatment in a clinical trial, and it showed promise as a potential therapeutic approach [5].

It's worth noting that while these treatments show promise, there is still no cure for CDG, and more research is needed to fully understand their effectiveness and potential side effects.

References:

[1] by JH Park · 2021 · Cited by 27 [2] by J Verheijen · 2020 · Cited by 106 [3] by M Monticelli · 2023 · Cited by 10 [4] by A Schneider · 2012 · Cited by 88 [5] by S Brasil · 2022 · Cited by 13

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

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

• Unexplained Hydrops Fetalis: According to search result [3], CDG-I should be considered in the differential diagnosis of unexplained hydrops fetalis.
• Congenital Disorders with Similar Symptoms: Search result [2] mentions that pontine hypoplasia, combined cerebellar hypoplasia and atrophy, and cerebellar cortical/subcortical hyperintensity are typical of congenital disorders of glycosylation. This suggests that CDG Type I should be considered in the differential diagnosis for conditions with similar symptoms.
• Other Genetic Disorders: Search result [7] states that CDGs are a genetically heterogeneous group of autosomal recessive disorders caused by enzymatic defects in the glycosylation process. This implies that other genetic disorders affecting glycosylation may also need to be considered in the differential diagnosis.

Key Conditions to Consider

• CDG Type II: Search result [7] mentions that CDGs are a genetically heterogeneous group of autosomal recessive disorders, suggesting that other forms of CDG, such as CDG Type II, should be considered in the differential diagnosis.
• Other Congenital Disorders with Similar Symptoms: Search results [2] and [6] suggest that conditions with similar symptoms to CDG Type I, such as pontine hypoplasia and cerebellar cortical/subcortical hyperintensity, may also need to be considered.

References

[1] May 11, 2021 — This category of CDG can be further divided into two subtypes: defects of oligosaccharide assembly and transfer (type 1) and defects in ... [2] Pontine hypoplasia, combined cerebellar hypoplasia and atrophy, and cerebellar cortical/subcortical hyperintensity is typical of congenital disorders of ... [3] by JM van de Kamp · 2007 · Cited by 67 — CDG‐I should be considered in the differential diagnosis of unexplained hydrops fetalis. [7] Congenital disorders of glycosylation (CDGs) are a genetically heterogeneous group of autosomal recessive disorders caused by enzymatic defects in the ...