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MPI-CDG (CDG-Ib)

Disorders of N-linked Protein Glycosylation / MPI-CDG (CDG-Ib)

Lay Summary

MPI-CDG, formerly known as CDG-Ib, is a rare but treatable inherited condition that mainly affects the liver and gastrointestinal system. To date, 35 cases of MPI-CDG have been reported in the literature. MPI-CDG is classified as a disorder of N-linked protein glycosylation. MPI-CDG is caused when an individual has mutations in both copies of the MPI gene which provides instructions for making an enzyme that generates the sugar mannose-6-phosphate. Mannose-6 phosphate is required for generating molecules that donate mannose sugars onto growing sugar chains during N-glycosylation. Mutations in the MPI gene cause some proteins to have incomplete or absent sugar chains. Individuals affected by MPI-CDG can present a range of symptoms, but common clinical features include liver and gastrointestinal abnormalities, blood clotting defects, and low blood glucose levels; these symptoms typically present in infancy. Several screening tests are available for MPI-CDG, but a definitive diagnosis is achieved through genetic testing.  Early diagnosis is crucial for MPI-CDG, as it is a potentially life-threatening disease, but is treatable through dietary supplements of mannose.

Overview

Mannose phosphate isomerase congenital disorder of glycosylation (MPI-CDG) is a rare autosomal recessive disorder that arises from defects in the MPI gene. MPI encodes the enzyme: mannose phosphate isomerase (MPI)1. MPI converts fructose-6-phosphate to mannose-6-phosphate, which is needed for N-glycosylation2. Mannose-6-phosphate is necessary for the generation of GDP-mannose and dolichol-phosphate-mannose: the mannose donors used in the construction of the lipid-linked oligosaccharide during N-glycosylation.  Deficiency in MPI results in insufficient N-glycosylation of proteins.

MPI-CDG was first clinically reported in 19803, but it was not until 1998 that genetic mutations in MPI were first described4,5,6. Collectively, 40 MPI-CDG cases have been reported in the literature, with 28 cases that have been confirmed by genetic testing1–30. Onset of symptoms can present from infancy, where common clinical features include liver, gastrointestinal and blood clotting abnormalities—although symptoms and severity vary between affected individuals1. MPI-CDG are typically diagnosed through a combination of biochemical (transferrin analysis), enzymatic (assessment of MPI), and genetic testing. As MPI affects N-glycosylation, transferrin isoform analysis is usually performed during diagnosis, with cases presenting abnormal transferrin isoform patterns (typically type I)30. However, genetic testing typically provides a definitive diagnosis. MPI-CDG can be treated with mannose therapy, which involves dietary supplements of the monosaccharide: mannose.

Synonyms

Inheritance

MPI-CDG is an autosomal recessive disorder, meaning an affected individual inherits one defective copy of the gene from each asymptomatic parent.

Gene Function

The MPI gene encodes mannose phosphate isomerase (MPI), also known as phosphomannose isomerase. Isomerase enzymes alter the structure of molecules by rearranging their atoms, generating a different molecule (or isomer)31. MPI is typically found in the cytosol, where it catalyzes the conversion of fructose-6-phsophate to mannose-6-phosphate30.

Mannose-6-phosphate is needed to generate mannose-1-phosphate, which a precursor of the nucleotide sugar GDP-mannose32. Nucleotide sugars are also called glycosyl donors or sugar donors because they enable sugars to be added onto other molecules. The generation of mannose containing glycosyl donors is particularly important for N-glycosylation of proteins, which involves the attachment of a mannose-rich glycan to the amino acid asparagine on a protein33.

Monosaccharide Interconversion

The monosaccharide mannose is an important component of glycans that are attached to various proteins and lipids. Before mannose can be incorporated into glycans, it must be converted to GDP-mannose in the cytoplasm (Figure 1) 34. Several steps are required to generate GDP-mannose from mannose, which includes the generation of mannose-6-phosphate. Mannose-6-phosphate can be generated by two ways: 1) by MPI converting fructose-6-phosphate to mannose-6-phosphate or 2) by an enzyme (hexokinase) adding phosphate to mannose forming mannose-6-phosphate32. Once generated, the PMM2 enzyme converts mannose-6-phosphate to mannose-1-phosphate, which is used to synthesize GDP-mannose, the mannose donor in the cytoplasm. GDP-mannose is also a precursor for dolichol-P-mannose, the mannose donor used inside the ER35.

The first step of N-glycosylation is the building of a mannose-rich lipid-linked oligosaccharide (LLO) comprised of a 14-sugar oligosaccharide and dolichol pyrophosphate (Dol-PP). The oligosaccharide component, also referred to as the oligosaccharide precursor, is subsequently transferred en bloc to an asparagine (Asn; N) residue of a protein inside the ER. The synthesis of the LLO occurs through a stepwise process that occurs both in the cytoplasm and inside the ER, and thus requires both GDP-mannose and Dol-P-mannose as glycosyl donors33.

Figure 1. Role of MPI in glycosylation.
MPI converts fructose-6-phosphate into mannose-6-phosphate, which is needed for N-glycosylation. Mannose-6-phosphate is needed for cells to produce activated forms of mannose (GDP-mannose and Dol-P-mannose), which are used to generate the lipid-linked oligosaccharide (LLO) during N-glycosylation, as well as N-glycan chain elongation.

Disease Mechanism

Defects in MPI reduce the ability of MPI to generate mannose-6-phsophate, which leads to abnormal N-glycans2. Deficient MPI are unable or at a reduced capacity of converting fructose-6-phohsphate to mannose-6-phosphate. Fructose-6-phosphate can be used in a different pathway (glycolytic pathway), reducing accumulation in cells, which may limit neurological effects in individuals with MPI-CDG36. However, reduced activity of MPI by gene mutations can lead to abnormal N-glycans structures and levels on proteins30. As mannose-6-phosphate can also be generated through a separate enzymatic pathway, providing cells with more mannose (such as by mannose dietary supplements) can increase levels of GDP-mannose, generating normal N-glycans and alleviating symptoms37.

Mutations

To date, 21 pathogenic variants have been identified in the MPI gene, with the most common variant detected being p.Arg219Gln (c.656G > A). Of these pathogen variants, 17 are missense variants, 2 are frameshift variants, 1 is a nonsense variant, and 1 is a splice variant2,30. Individuals with MPI-CDG can also be found to have different mutations in each copy of the MPI gene (known as compound heterozygosity)5,9.

Some variants can also yield clinically asymptomatic MPI-CDG10. However, the extent of enzymatic activity does not appear to predict disease severity30.

Signs & Symptoms

Clinical Presentation

Affected individuals typically present clinical features from infancy, with disease characterised by liver and gastrointestinal abnormalities. MPI-CDG symptoms can include:

In addition, while affected individuals are not typically associated with neurological symptoms, some individuals can have seizures30.

Biochemical Abnormalties

Individuals with MPI-CDG can often present with elevated liver enzymes (arylsulfatase A and transaminases), blood clotting (coagulation) abnormalities, low blood albumin (hypoalbuminemia) levels, and low blood glucose levels (hypoglycemia). In addition, affected individuals can also present reduced hormone levels (hypothyroidism)30.

Classification

MPI-CDG is classified as a disorder of N-linked protein glycosylation. More specifically, it is a disorder of monosaccharide interconversion.

Under the former CDG classification system, MPI-CDG is classified as a Type I CDG, which arise due to defects in the synthesis of N-glycoproteins that occur before the glycan is transferred from the LLO onto the protein.

Diagnosis

MPI should be suspected when individuals present liver and gastrointestinal symptoms, without displaying central nervous system defects20—although, minor neurological defects can also be found in affected individuals39. To date, common symptoms include diarrhoea, low blood sugar levels, failure to thrive, protein-losing enteropathy, liver pathologies and antithrombin deficiencies27.

Screening in suspected patients typically begins with a blood test to analyze serum transferrin isoforms. Direct assessment of MPI enzymatic activity may also be used and is often performed after a transferrin analysis displays a type I pattern. Genetic testing is used to definitively diagnose MPI-CDG30.

Transferrin Analysis

Individuals with MPI-CDG show a characteristic type I pattern by transferrin isoelectric focusing (TIEF) or mass spectrometry analysis of transferrin30. Type I patterns are observed in CDG that arise due to defects in LLO assembly and are characterized by a decrease in tetrasialo-transferrin and an increase in di-sialo and a-sialo transferrin isoforms30.

MPI Enzymatic Acitivity

Defects in MPI enzyme activity can be assessed by enzyme analysis. Typically, enzyme analysis is performed on patient fibroblasts or leukocytes30.

Biomarkers

Several biomarkers have been identified for MPI-CDG which may aid in diagnosis.

N-Tetrasaccharide (Neu5Acα2,6Galβ1,4-GlcNAcβ1,4GlcNA)
N-tetrasaccharide (Neu5Acα2,6Galβ1,4-GlcNAcβ1,4GlcNA) has been found at higher levels in plasma from patients with MPI-CDG compared to unaffected controls, with N-tetrasaccharide levels reducing after mannose treatment. This N-tetrasaccharide was also found at higher levels in patients with ALG1-CDG and PMM2-CDG40.

Aspartylglucosaminidase
Increased levels of plasma aspartylglucosaminidase activity have been found in many different types of CDG, including MPI-CDG41.

Intercellular Adhesion Molecule 1 (ICAM-1)
Reduced intercellular adhesion molecule 1 (ICAM-1) protein levels have been found at the cell surface of fibroblasts from MPI-CDG patients, compared to controls. ICAM-1 levels increased after mannose treatment. ICAM-1 protein levels were also found reduced in other CDG, including PMM2-CDG and ALG1-CDG42.

Prognosis

MPI-CDG prognosis can vary among affected individuals, depending on disease severity. Some affected individuals can be asymptomatic in adulthood, with one individual reported in the medical literature in 2014 as being asymptomatic at 32 years old10. MPI-CDG symptoms can be effectively managed in individuals with mannose therapy4,6,16,18. However, MPI-CDG can be life-threatening, with premature death observed in untreated individuals presenting symptoms in early life20. Death can be linked to liver failure and sepsis in some affected individuals30. Liver abnormalities can persist even with mannose therapy, and poor compliance to mannose therapy can lead to MPI-CDG symptoms recurring (such as diarrhea and thrombosis)37.

Management

MPI-CDG may involve gastrointestinal management (such as albumin infusions or intravenous feeding), endocrine management (such as frequent feeding or intravenous glucose) liver transplants, mannose therapy, and blood clotting management. Affected individuals may also regularly undergo tests to monitor liver, gastrointestinal, endocrine, haematological, neurological, kidney and immune function, as well as mannose therapy monitoring30.

Therapies

In addition to managing symptoms, mannose therapy (mannose supplements) can be used to treat MPI-CDG. Mannose supplements can alleviate symptoms, improving N-glycosylation of proteins. This is achieved by providing more mannose for hexokinase to generate mannose-6-phosphate for GDP-mannose synthesis. As mannose therapy can have limited results on liver disease, liver transplants are another therapeutic option21,24.

Research Models

Several research models have been developed for studying MPI, including zebrafish, mice, and human cell lines43.

Fish (D. rerio)

Zebrafish models with reduced levels of MPI displayed decreased LLO and N-glycan levels, 50% embryonic lethality levels (by four days after fertilization), and abnormal features in the majority of the larvae that survived. However, normal phenotypes were obtained if mannose was added to the water within 24 hours after fertilization44.

Mouse (M. musculus)

Mpi-/- constitutive knockout mice
Mpi-/- knockout mice models displayed embryonic lethal phenotypes, as well as growth defects, which was linked to toxic accumulation of mannose-6-phosphate (studies included Mpi-/- primary embryonic fibroblasts)32.

Mpi hypomorphic mice
Mpi hypomorphic mice displayed roughly 15% embryonic lethality. Embryonic lethality was increased when mannose supplements were administered during pregnancy, and around half of the surviving pups developed eye defects45.

Human Cell Lines

Human colon adenocarcinoma cells (HT-29 cell line)
HT-29 cells were used and MPI levels were reduced using siRNAs. By labelling mannose, experiments showed that mannose was redirected to use by a separate enzyme (PMM2) when cells lacked MPI, increasing mannose-modified protein levels46.

Clinical Studies

Active

Clinical and Basic Investigations into Congenital Disorders of Glycosylation (NCT04199000)
The Frontiers in Congenital Disorder of Glycosylation Disorders Consortium (FCDGC) is conducting a 5-year natural history study on all CDG types, including MPI-CDG. The purpose of this study is to define the natural history and clinical symptoms of CDG, develop new diagnostic techniques, identify clinical biomarkers that can be used in future clinical trials and evaluate whether dietary treatments improve clinical symptoms and quality of life.

Unknown

Study of ORL-1M (D-mannose) in Patients With CDG-Ib (NCT03404869)
Orpha Labs is conducting an interventional study (clinical trial) on MPI-CDG. The purpose of this study is to assess ability of mannose to treat hypoglycemia, diarrhea and vomiting and improve serum transferrin glycosylation patterns in MPI-CDG patients.

Publications

MPI-CDG Scientific Articles on PubMed
Consensus guideline for the diagnosis and management of mannose phosphate isomerase-congenital disorder of glycosylation

Additional Resources

MPI-CDG on FCDGC
MPI-CDG Infographic
MPI-CDG Clinical Utility Gene Card
IEMbase
OMIM
OrphaNet
GARD
Genetic Testing Registry
ClinVar
NIH
GeneCards
UniProt

References

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