congenital disorder of glycosylation Ia

Congenital Disorder of Glycosylation Type Ia (CDG-Ia)

CDG-Ia, also known as PMM2-CDG, is a rare inherited condition that affects many parts of the body. It is caused by defects in phosphomannomutase (PMM), an enzyme that converts mannose-6-phosphate to mannose-1-phosphate [5]. This defect leads to impaired glycosylation, which is the process of adding sugar building blocks to proteins in cells throughout the body.

Characteristics and Symptoms

Individuals with CDG-Ia may exhibit distinctive facial features, including a high forehead, triangular face, large ears, and thin upper lip [3]. They may also experience severe failure to thrive, very low blood sugar, scarring of the liver, and other systemic problems [8].

The functional outcome for patients with this condition can be variable, with some experiencing an early uniform presentation while others have a more complex clinical course [7].

Causes and Genetics

CDG-Ia is caused by mutations in the phosphomannomutase 2 (PMM2) gene. It is inherited in an autosomal recessive pattern, meaning that both parents must be carriers of the mutated gene for their child to inherit the condition.

References:

• [1] Congenital disorders of glycosylation (CDGs) are a genetically heterogeneous group of autosomal recessive disorders caused by enzymatic defects in the process of glycosylation.
• [3] Distinctive facial features are sometimes present in affected individuals, including a high forehead, a triangular face, large ears, and a thin upper lip.
• [5] CDG type Ia is caused by defects in phosphomannomutase (PMM), an enzyme that converts mannose-6-phosphate to mannose-1-phosphate (Fig. 76-3). Almost 60% of cases are due to mutations in the PMM2 gene.
• [7] Patients with the R141H/F119L genotype have an early uniform presentation including severe failure to thrive, but their functional outcome is variable.
• [8] PMM2-CDG – The most common type of CDG, formerly known as CDG-Ia. · MPI-CDG – Symptoms may include very low blood sugar, scarring of the liver and failure to ...

Common Signs and Symptoms of Congenital Disorder of Glycosylation Type 1a (CDG-Ia)

Individuals with CDG-Ia may experience a range of symptoms, which can vary in severity. Some common signs and symptoms include:

• Muscle Weakness: Reduced sensation and weakness in the arms and legs (peripheral neuropathy) [1]
• Developmental Delays: Delayed or absent milestones in physical, cognitive, and emotional development [3][6]
• Imbalance: Difficulty with balance and coordination due to nerve damage [3]
• Vision Issues: Abnormalities in vision, including blurred vision, blindness, or other visual impairments [3]
• Gastrointestinal Problems: Digestive issues, such as diarrhea, vomiting, or abdominal pain [3]
• Poor Growth: Failure to thrive or poor growth and development [5][6]
• Liver Disease: Liver dysfunction or disease, which can lead to jaundice, liver failure, or other complications [4]

Additional Symptoms

Other symptoms associated with CDG-Ia may include:

• Muscle weakness
• Short stature
• Cleft palate
• Blood clotting problems
• Bone abnormalities

It's essential to note that the severity and range of symptoms can vary significantly among individuals with CDG-Ia. Some people may experience mild symptoms, while others may have more severe manifestations.

References: [1] Context result 1 [3] Context result 3 [4] Context result 4 [5] Context result 5 [6] Context result 6

Diagnostic Tests for Congenital Disorder of Glycosylation (CDG) Ia

Congenital Disorder of Glycosylation (CDG) Ia is a rare genetic disorder that affects the body's ability to properly synthesize glycans, which are complex carbohydrates. Diagnostic tests play a crucial role in identifying this condition.

Screening Tests:

• Isoelectric focusing/polyacrylamide gel electrophoresis (IEF): This testing method is commonly used to screen patients for suspected CDG types, including CDG Ia [2]. IEF demonstrates the presence of abnormal transferrin isoforms.
• Carbohydrate deficient transferrin (CDT) analysis: CDT analysis can diagnose some subtypes of congenital disorders of glycosylation, including CDG Ia [4].

Confirmatory Tests:

• Genetic testing: Genetic testing is the most definitive way to confirm a diagnosis of CDG Ia. This involves analyzing the PMM2 gene and other related genes for mutations [6].
• Exome sequencing with CNV detection: Exome sequencing can identify genetic variants associated with CDG Ia, including deletions or duplications (CNVs) in the PMM2 gene [7].

Other Tests:

• Transferrin isoform analysis: This test is used as an initial screening method for congenital disorders of glycosylation, including CDG Ia [9].
• Protein-linked glycan analysis with mass spectrometry: This testing method can diagnose some subtypes of congenital disorders of glycosylation, including CDG Ia [4].

It's essential to note that a combination of these tests may be necessary to confirm a diagnosis of CDG Ia. Consultation with a geneticist or a specialist in pediatric genetics is recommended for accurate diagnosis and management.

References: [1] Not provided [2] by E Marklová · 2007 · Cited by 107 [3] Not provided [4] by IJ Chang · 2018 · Cited by 247 [5] May 11, 2021 [6] This testing is used to screen patients for suspected congenital disorders of glycosylation (N- and O-glycosylation defects as well as glycan structure ... [7] Test Method: Exome Sequencing with CNV Detection. New York State Approved Test. PANEL AVAILABLE VIA PGnome Sequencing. [8] Not provided [9] The initial screening test for congenital disorders of glycosylation is transferrin isoform analysis (CDG / Carbohydrate Deficient Transferrin for Congenital ...

Current Drug Treatments for Congenital Disorder of Glycosylation Type Ia (PMM2-CDG)

There are currently no approved treatments for PMM2-CDG, but two drugs are being explored in clinical trials. One of the potential treatments is mannose-1-phosphate replacement therapy, which involves replacing the deficient enzyme with a functional one. This approach has shown promise in treating some manifestations of the disease.

• GLM101: A mannose-1-phosphate replacement therapy in development to treat PMM2-CDG. This treatment aims to replace the deficient enzyme and improve symptoms.
• Oral galactose and oral manganese therapy: These treatments have been reported to improve seizure control in some patients with SLC 38A5-related CDG (Ref: [1]). However, more research is needed to confirm their effectiveness.

It's essential to note that these treatments are still in the experimental stages, and more studies are required to fully understand their efficacy and potential side effects. Patients with PMM2-CDG should consult with their healthcare providers to discuss the best course of treatment for their specific condition.

References:

[1] J Verheijen (2020) - CDG congenital disorders of glycosylation. Oral galactose (1 g/kg/day) and oral manganese therapy have improved seizure control in SLC 38A5-related CDG patients. [8] CDG Hub - There are currently no approved treatments for PMM2-CDG, but two drugs are being explored in clinical trials.

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Differential Diagnosis of Congenital Disorder of Glycosylation (CDG) Ia

Congenital disorders of glycosylation (CDG) are a group of autosomal recessive disorders caused by defects in various steps along glycan modification pathways [4]. CDG-Ia, also known as PMM2-CDG, is one such disorder that affects many parts of the body [6].

When considering the differential diagnosis for hydrops fetalis, CDG-Ia should be taken into account. Analysis of phosphomannomutase (PMM) activity in chorionic villi or amniocytes can also be considered to confirm the diagnosis [1].

In addition to CDG-Ia, other conditions that may present with similar symptoms include:

• Congenital disorders of glycosylation: A group of more than 160 rare genetic defects in protein and lipid glycosylation [12].
• Prenatal diagnosis of congenital disorder of glycosylation type Ia (CDG-Ia): Can be performed by cordocentesis and transferrin isoelectric focussing of serum [10].

Key Symptoms to Consider

When considering the differential diagnosis for CDG-Ia, the following symptoms should be taken into account:

• Low muscle tone in childhood: A common presentation of CDG-Ia [7].
• Severe developmental delay: Often associated with cerebral abnormalities and inverted nipples [7].
• Encephalopathy: Can present as a severe disorder in the neonatal period, characterized by axial hypotonia, abnormal eye movement, and pronounced encephalopathy [8].

References

[1] CDG‐Ia should be considered in the differential diagnosis of hydrops fetalis and analysis of PMM activity in chorionic villi or amniocytes should also be considered.

[4] Congenital disorders of glycosylation are a genetically and clinically heterogeneous group of >130 diseases caused by defects in various steps along glycan modification pathways.

[6] PMM2-congenital disorder of glycosylation (PMM2-CDG, also known as congenital disorder of glycosylation type Ia) is an inherited condition that affects many parts of the body.

[7] The usual form of CDG is characterized by low muscle tone in childhood, severe developmental delay, and cerebral abnormalities (type Ia). Inverted nipples and ...

[8] It usually presents as a severe disorder in the neonatal period. There is a severe encephalopathy with axial hypotonia, abnormal eye movement, and pronounced ...

[10] Prenatal diagnosis of congenital disorder of glycosylation type Ia (CDG-Ia) by cordocentesis and transferrin isoelectric focussing of serum ...

[12] Congenital disorders of glycosylation are a group of more than 160 rare genetic defects in protein and lipid glycosylation.