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Congenital disorder of glycosylation Ia
PMM2-CDG is a rare inherited metabolic disorder, typically presenting in infancy or early childhood. It can lead to a wide range of health issues affecting the brain, liver, gut, and other organs, with varying severity among individuals.
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Overview
PMM2-CDG is the most common subtype of a group of conditions called congenital disorders of glycosylation (CDG). These disorders affect a process known as glycosylation, which involves adding complex sugar chains to proteins and lipids. This process is crucial for many biological functions, including proper protein folding, cell communication, and immune responses [PMID:32684494].
In PMM2-CDG, an enzyme called phosphomannomutase 2 (PMM2) does not work correctly. This enzyme plays a vital role in the early steps of N-glycosylation. When glycosylation is disrupted, proteins and lipids cannot function as they should, leading to a wide array of symptoms across different body systems. The condition typically manifests in infancy or early childhood, but milder forms may be recognised later in life.
Symptoms & clinical features
The symptoms of PMM2-CDG are highly variable, even within the same family. Common features often include developmental delay, intellectual disability, and difficulties with balance and coordination (ataxia) [PMID:32684494]. Many affected individuals experience neurological problems, such as seizures and reduced muscle tone (hypotonia).
Other typical symptoms can involve problems with the digestive system, including chronic diarrhoea, vomiting, and issues with nutrient absorption. Liver dysfunction, blood clotting abnormalities, and hormone imbalances have also been reported. Some individuals may have distinctive facial features, skeletal abnormalities, or problems with vision or hearing. The severity of these symptoms can range from mild to life-threatening.
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Affected organs
PMM2-CDG can impact almost any organ system due to the fundamental role of glycosylation in cellular function. The central nervous system is frequently affected, leading to issues with brain development and function. The liver can be compromised, potentially causing impaired function and coagulopathy (blood clotting problems). The gastrointestinal tract often experiences issues such as protein-losing enteropathy.
Endocrine glands, which produce hormones, may also be affected, leading to conditions like hypothyroidism or hypogonadism. The immune system can be weakened, increasing susceptibility to infections. Additionally, the heart and kidneys may sometimes be involved to varying degrees.
Risks & severity
The severity of PMM2-CDG varies significantly. Some individuals experience severe, life-threatening complications early in life, while others have milder symptoms that are managed successfully into adulthood [PMID:32684494]. The most critical period for many individuals is during infancy and early childhood, where severe neurological and multi-organ involvement can occur.
Survival into adulthood is possible, especially for individuals with less severe presentations. However, long-term complications can include progressive neurological deterioration, liver fibrosis, and ongoing developmental challenges. There is no precise age of onset, though symptoms typically become apparent in the first few years of life. The exact prevalence of PMM2-CDG in the UK population is not precisely known, but estimates suggest around 1 in 20,000 births.
Genetic causes
PMM2-CDG is caused by pathogenic variants in the PMM2 gene. This gene provides instructions for making the phosphomannomutase 2 enzyme. This enzyme converts mannose-6-phosphate to mannose-1-phosphate, a critical step in the N-glycosylation pathway [PMID:17918342].
When amendments in the PMM2 gene occur, the enzyme either works incorrectly or is produced in insufficient amounts. This leads to a reduced ability to form the N-glycans (sugar chains) that are essential for the proper structure and function of many proteins and lipids. Consequently, various cellular processes are disrupted throughout the body.
- PMM2 phosphomannomutase 2
Inheritance pattern
PMM2-CDG is inherited in an autosomal recessive pattern. This means that an individual must inherit two altered copies of the PMM2 gene-one from each parent-to develop the condition. If a person inherits only one altered copy and one typical copy of the gene, they are considered a carrier. Carriers typically do not show symptoms of the condition themselves but can pass the altered gene copy to their children [PMID:17918342].
When both parents are carriers of a pathogenic PMM2 variant, there is a 25% chance with each pregnancy that their child will inherit two altered copies and develop PMM2-CDG. There is a 50% chance the child will be a carrier, and a 25% chance the child will inherit two typical gene copies and not be affected or a carrier.
When both parents are carriers, each child has a 25% chance of being affected, 50% of being a carrier, and 25% of being unaffected.
Diagnosis & testing
Diagnosing PMM2-CDG typically begins with observing a combination of clinical symptoms suggesting a CDG. Initial screening tests may include measuring transferrin isoforms in the blood, which can show an abnormal glycosylation pattern characteristic of CDG-Ia.
Confirmation of PMM2-CDG involves genetic testing to identify pathogenic variants in the PMM2 gene. Families are usually referred to a Clinical Genetics service or a metabolic specialist for evaluation. The NHS Genomic Medicine Service offers genomic testing, and PMM2-CDG falls under test directory codes such as R133 (Inherited metabolic disorders - gene panel). Genetic counselling is offered alongside testing to discuss the implications of results for the individual and their wider family.
Management & lifestyle
Managing PMM2-CDG focuses on addressing specific symptoms and providing supportive care, as there is currently no cure. A multidisciplinary team of specialists, including neurologists, hepatologists, gastroenterologists, and developmental paediatricians, is often involved. Regular monitoring of organ function, such as liver and kidney health, neurological status, and growth, is important.
Treatments may include managing seizures with anti-epileptic medications, dietary modifications to address malabsorption, and physical and occupational therapy to support development and motor skills. Early intervention programmes can be beneficial for individuals with developmental delays. In some cases, specific hormone deficiencies may be treated with hormone replacement. Management plans are individualised and evolve as the patient ages.
UK care pathway
In the UK, suspected cases of PMM2-CDG are typically referred into the NHS Genomic Medicine Service pathway. Referrals are generally made by paediatricians or specialist consultants to a regional Clinical Genetics service or a metabolic diseases specialist centre. These services facilitate genomic testing, often using gene panels covered by NHS R-codes like R133, to confirm a diagnosis. Following diagnosis, individuals and families are supported by clinical geneticists and genetic counsellors who provide information, discuss inheritance patterns, and guide complex care coordination.
Frequently asked questions
What is glycosylation and why is it important?
Glycosylation is a vital biological process where sugar chains (glycans) are attached to proteins and lipids. These sugar modifications are essential for many cellular functions, including proper protein folding, cell recognition, and immune system responses, affecting how cells and organs work throughout the body.
What is the life expectancy for someone with PMM2-CDG?
The life expectancy for individuals with PMM2-CDG is highly variable. Some severe forms can lead to significant health challenges and early mortality, particularly in infancy. However, others with milder presentations may live into adulthood with appropriate supportive care, though they might experience ongoing health issues.
Can PMM2-CDG be treated?
Currently, there is no cure for PMM2-CDG. Treatment focuses on managing the specific symptoms an individual experiences. This can involve therapies for neurological issues, dietary adjustments for digestive problems, and physical therapies to support development, aiming to improve quality of life.
If I am a carrier, will my children have PMM2-CDG?
If you are a carrier of a PMM2 variant, you typically do not have the condition yourself. For your child to have PMM2-CDG, they would need to inherit an altered PMM2 gene from both parents. If your partner is also a carrier, there is a 25% chance with each pregnancy that your child will be affected.
How common is PMM2-CDG?
PMM2-CDG is considered a rare condition. While exact figures in the UK are not readily available, global estimates suggest its prevalence to be approximately 1 in 20,000 births, making it the most common form of congenital disorders of glycosylation.
References
- Midena G, Pilotto E. Case Report: Multiple Retinal Astrocytic Hamartomas in Congenital Disorder of Glycosylation-Ia. Frontiers in medicine. 2022. PMID: 35237617
- Richard E, Vega AI, Pérez B. Congenital disorder of glycosylation Ia: new differentially expressed proteins identified by 2-DE. Biochemical and biophysical research communications. 2009. PMID: 19101518
- Işıkay S, Başpınar O, Yılmaz K. A case of congenital disorder of glycosylation ia presented with recurrent pericardial effusion. Iranian journal of pediatrics. 2014. PMID: 25793077
- Sala G, Dupré T, Seta N. Increased biosynthesis of glycosphingolipids in congenital disorder of glycosylation Ia (CDG-Ia) fibroblasts. Pediatric research. 2002. PMID: 12409508
- Miller BS, Duffy MM, Addo OY. rhIGF-1 Therapy for Growth Failure and IGF-1 Deficiency in Congenital Disorder of Glycosylation Ia (PMM2 Deficiency). Journal of investigative medicine high impact case reports. 2013. PMID: 26425584
- Grünert SC, Marquardt T, Lausch E. Unsuccessful intravenous D-mannose treatment in PMM2-CDG. Orphanet journal of rare diseases. 2019. PMID: 31640729
- Blank C, Smith LA, Hammer DA. Recurrent infections and immunological dysfunction in congenital disorder of glycosylation Ia (CDG Ia). Journal of inherited metabolic disease. 2006. PMID: 16826448
- Dahl R, Bravo Y, Sharma V. Potent, selective, and orally available benzoisothiazolone phosphomannose isomerase inhibitors as probes for congenital disorder of glycosylation Ia. Journal of medicinal chemistry. 2011. PMID: 21539312