👪

Inheritance

1

Autosomal recessive inheritance HP:0000007

MPI-CDG is inherited in an autosomal recessive manner. Both homozygous (frequently but not exclusively consanguineous) and compound heterozygous genotypes are reported.

Autosomal recessive inheritance

Show evidence (2 references)

PMID:32266963 SUPPORT Human Clinical

"MPI-CDG has autosomal recessive inheritance, but surprisingly high percentage of homozygotes was present (13 out of 28 patients with known genotype)."

The consensus review of all published patients states the mode of inheritance and the genotype distribution directly.

PMID:24508628 SUPPORT Human Clinical

"Both parents, being distant relatives, were heterozygous mutation carriers with normal CDT values."

Heterozygous, biochemically normal parents of a homozygous proband demonstrate recessive segregation.

?

Discussions and Knowledge Gaps

2

Why does hyperinsulinaemic hypoglycaemia occur in MPI-CDG, and which hypoglycosylated beta-cell protein is responsible?

KNOWLEDGE GAP OPEN mpi_cdg_hyperinsulinism_mechanism

Attached to

pathophysiology#Hyperinsulinaemic Hypoglycaemia

Hyperinsulinism accounts for more than two-thirds of hypoglycaemia in MPI-CDG and also occurs in PGM1-CDG and PMM2-CDG, suggesting a shared glycosylation-dependent mechanism, but the consensus guideline states the cause is unknown. Hypoglycosylation of the sulfonylurea receptor SUR1 is proposed and altered insulin secretion has been shown in hypoglycosylated murine beta cells, but neither has been demonstrated in human MPI-CDG islets. Resolving this would clarify why mannose corrects the hypoglycaemia and whether beta-cell-directed therapy is ever needed beyond diazoxide.

Show evidence (1 reference)

PMID:32266963 SUPPORT Other

"However, the exact cause of HH in CDG patients is still unknown."

The consensus panel states the mechanism is unresolved.

Do the mannose-toxicity findings in Mpi mice - accelerated embryonic death in nulls and ocular defects with blindness in hypomorphs - predict any risk of oral or antenatal mannose therapy in human MPI-CDG?

HUMAN MODEL MISMATCH OPEN mpi_cdg_mannose_pregnancy_model_mismatch

Attached to

pathophysiology#Mannose-6-Phosphate Accumulation and Energy Failure on Excess Mannose

The direction of the mannose effect is species- and route-discordant. Complete Mpi ablation in mice is embryonic lethal and mannose hastens embryonic death; Mpi hypomorphic mice develop blindness on antenatal mannose. Yet in zebrafish mannose rescues the phenotype when given early, and in humans oral mannose is well tolerated and clearly beneficial, with normal pregnancies reported in treated women; human toxicity has been seen only with the intravenous route. Whether the murine antenatal toxicity has any human counterpart is unresolved and directly gates the guideline's cautious stance on mannose in pregnancy.

Show evidence (1 reference)

PMID:24421398 SUPPORT Model Organism

"It is unknown whether mannose is harmful to human fetuses during gestation; however, mothers who are at risk for having MPI-CDG children and who consume mannose during pregnancy hoping to benefit an affected fetus in utero should be cautious."

The authors themselves flag the translational uncertainty, which is exactly the mismatch recorded here.

⚙

Pathophysiology

10

Phosphomannose Isomerase Deficiency

Biallelic loss-of-function or hypomorphic variants in MPI reduce the activity of phosphomannose (mannose-6-phosphate) isomerase, the mainly cytosolic enzyme that interconverts fructose-6-phosphate and mannose-6-phosphate. Residual enzyme activity in patient leukocytes and fibroblasts is typically below 10% of normal. Because fructose-6-phosphate is a glycolytic intermediate, the block itself does not cause accumulation of a toxic upstream substrate; the lesion is one of insufficient mannose-6-phosphate supply.

Hepatocyte CL:0000182

MPI hgnc:7216

mannose metabolic process GO:0006013 ↓ DECREASED

mannose-6-phosphate isomerase activity GO:0004476 ↓ DECREASED

Downstream

GDP-Mannose Depletion and Impaired Lipid-Linked Oligosaccharide Assembly Reduced mannose-6-phosphate supply limits the downstream nucleotide-sugar pool required to build the dolichol-linked oligosaccharide precursor.

Show evidence (3 references)

PMID:32266963 SUPPORT Other

"MPI is mainly a cytosolic enzyme (but it can be also localised in the plasma membrane) which catalyses the first step of biosynthesis of nucleotide sugar mannose-GDP, that is, interconversion of fructose-6-phosphate to mannose-6-phosphate (Figure 1A)."

The consensus guideline states the enzymatic reaction catalysed by MPI. Evidence source is OTHER because this is the review's biochemical background synthesis rather than a primary patient observation.

PMID:32266963 SUPPORT Human Clinical

"In described MPI-CDG patients, enzyme activities were usually very deficient with activities less than 10% of normal values in both leukocytes and fibroblasts."

Quantifies the residual enzyme activity measured in patients.

PMID:9525984 SUPPORT Human Clinical

"Phosphomannose isomerase (PMI) deficiency is the cause of a new type of carbohydrate-deficient glycoprotein syndrome (CDGS). The disorder is caused by mutations in the PMI1 gene."

The founding report establishing PMI deficiency and MPI mutations as the cause of the disorder.

GDP-Mannose Depletion and Impaired Lipid-Linked Oligosaccharide Assembly

Mannose-6-phosphate is the committed precursor of GDP-mannose, the mannosyl donor for assembly of the dolichol-linked (lipid-linked) oligosaccharide in the endoplasmic reticulum. In MPI deficiency the endogenous route to mannose-6-phosphate fails and dietary mannose is insufficient to compensate under ordinary conditions, so lipid-linked oligosaccharide synthesis is curtailed and incomplete precursors are transferred to nascent protein - the canonical CDG type I lesion. Plasma mannose is under 10 micromol/L in patients versus 50-100 micromol/L in healthy individuals. This is the step at which exogenous D-mannose therapy re-enters the pathway.

GDP-mannose biosynthetic process GO:0009298 ↓ DECREASED dolichol-linked oligosaccharide biosynthetic process GO:0006488 ↓ DECREASED

endoplasmic reticulum GO:0005783

Downstream

Protein Hypoglycosylation Incomplete lipid-linked oligosaccharide precursors are transferred to nascent glycoproteins, producing systemic hypoglycosylation.

Show evidence (3 references)

PMID:22899857 SUPPORT Other

"Synthesis of the lipid-linked oligosaccharide (LLO), which serves as the sugar donor for the N-glycosylation of secretory proteins, requires conversion of fructose-6-phosphate to mannose-6-phosphate via the phosphomannose isomerase (MPI) enzyme."

Places the MPI reaction directly upstream of lipid-linked oligosaccharide synthesis. Evidence source is OTHER because this sentence is the paper's background statement of the pathway rather than a result from its zebrafish experiments.

PMID:22899857 SUPPORT Model Organism

"Fluorophore-assisted carbohydrate electrophoresis detected decreased LLO and N-glycans in mpi morphants."

A zebrafish MPI-knockdown model with patient-range residual activity directly demonstrates reduced lipid-linked oligosaccharide and N-glycan pools. Model-organism evidence, complementing the human biochemistry.

PMID:32266963 SUPPORT Other

"However, the enzymatic block can be therapeutically bypassed by dietary mannose supplementation"

Establishes that this node is the pharmacologically bypassable step, the basis of D-mannose therapy.

Protein Hypoglycosylation

Many secreted and membrane glycoproteins carry absent or truncated N-glycans. The readout is the classic CDG type I serum transferrin pattern - reduced tetrasialotransferrin with increased disialo- and asialotransferrin - which is 100% sensitive but biochemically indistinguishable from PMM2-CDG and other type I disorders. Because glycosylation modifies a large fraction of the secreted proteome, this single lesion degrades many unrelated proteins at once, and the specific organ pattern of MPI-CDG reflects which client glycoproteins are rate-limiting rather than any tissue-restricted expression of MPI.

Hepatocyte CL:0000182 Enterocyte CL:0000584

protein N-linked glycosylation GO:0006487 ↓ DECREASED

Downstream

Enterocyte Glycoprotein Deficit and Protein-Losing Enteropathy Hypoglycosylation of enterocyte surface glycoproteins is the proposed mechanism of intestinal barrier failure and enteric protein loss.

Hypoglycosylation of Coagulation Factors and Inhibitors Antithrombin, protein C, protein S and factor XI are N-glycoproteins whose plasma levels fall when glycosylation is impaired.

Hyperinsulinaemic Hypoglycaemia Hypoglycosylation is proposed to alter beta-cell insulin secretion, although the precise mechanism remains unresolved.

Hepatic Ductal Plate Malformation and Progressive Fibrosis Prenatal and early hypoglycosylation is associated with a developmental biliary lesion and progressive fibrosis that, unlike the other arms, does not reverse with mannose.

Multisystem Glycoprotein Dysfunction with Neurologic Sparing The convergent multisystem outflow of proteome-wide hypoglycosylation, distinguished in MPI-CDG by the near-absence of neurologic involvement.

Show evidence (2 references)

PMID:32266963 SUPPORT Human Clinical

"MPI-CDG can be biochemically characterised by a decreased level of the major tetrasialylated transferrin (Trf) glycoform (tetrasialotransferrin) and an increase of disialotransferrin and asialotransferrin, that is, CDG type I pattern."

Documents systemic protein hypoglycosylation via the transferrin readout.

PMID:10980531 SUPPORT Human Clinical

"The symptoms result from hypoglycosylation of serum- and other glycoproteins."

States explicitly that the clinical phenotype is downstream of glycoprotein hypoglycosylation.

Enterocyte Glycoprotein Deficit and Protein-Losing Enteropathy

Loss of intestinal wall integrity, attributed to reduced glycoproteins on the enterocyte membrane and/or intestinal lymphangiectasia, produces protein-losing enteropathy with hypoalbuminaemia, oedema, diarrhoea and secondary hypogammaglobulinaemia. Duodenal biopsy may show mild villous atrophy and lymphangiectasia, and both the clinical syndrome and the histology normalise on mannose.

Enterocyte CL:0000584

Show evidence (2 references)

PMID:32266963 SUPPORT Other

"The diarrhoea is most commonly due to PLE with resulting hypoalbuminaemia."

Places protein-losing enteropathy causally upstream of the diarrhoea and hypoalbuminaemia. Evidence source is OTHER because this is the consensus panel's mechanistic interpretation of the pooled case literature.

PMID:9525984 SUPPORT Human Clinical

"The clinical phenotype is characterized by protein-losing enteropathy, while neurological manifestations prevailing in other types of CDGS are absent."

The founding report identifies protein-losing enteropathy as the defining clinical consequence.

Hypoglycosylation of Coagulation Factors and Inhibitors

Antithrombin, protein C, protein S and factor XI are all N-glycosylated plasma proteins, and their functional levels fall in MPI-CDG. The result is a mixed coagulopathy affecting both procoagulant and anticoagulant arms, so the same patient may thrombose and bleed. Antithrombin deficiency dominates, and the deficits are exacerbated by intercurrent protein-losing enteropathy episodes, dehydration and infection.

blood coagulation GO:0007596 ⚠ ABNORMAL

Downstream

Thrombotic and Haemorrhagic Complications The imbalance of procoagulant and anticoagulant glycoproteins destabilises haemostasis in both directions.

Show evidence (2 references)

PMID:32266963 SUPPORT Human Clinical

"Coagulopathy with typical pattern affecting both procoagulant and anticoagulant factors is reported in almost all patients, with mainly antithrombin (AT) deficiency."

Establishes the near-universal mixed coagulopathy and its dominant antithrombin component.

PMID:30545931 SUPPORT Human Clinical

"Congenital disorders of glycosylation (CDG), a rare disease, are actually usually associated with antithrombin deficiency."

Links the glycosylation defect to antithrombin deficiency as the characteristic coagulation lesion of CDG, the molecular basis for this node.

Thrombotic and Haemorrhagic Complications

Thrombosis typically complicates intercurrent infection or dehydration and is most often deep venous thrombosis of the lower limbs, but cerebral venous sinus thrombosis, pulmonary embolism and intracardiac thrombus are reported and may be the presenting event. Bleeding is less frequent but can be life-threatening, chiefly diffuse intestinal bleeding or variceal haemorrhage.

Show evidence (2 references)

PMID:32266963 SUPPORT Human Clinical

"Thrombotic events often complicate acute infections and dehydration episodes. These are mainly deep vein thromboses of the lower extremities."

Describes the triggers and typical site of thrombosis in the pooled cohort.

PMID:32905087 SUPPORT Human Clinical

"In summary, we present the first MPI-CDG patient with severe cerebral venous sinus thrombosis as first and only symptom of disease manifestation."

Demonstrates that the thrombotic arm alone can constitute the entire clinical presentation.

Hyperinsulinaemic Hypoglycaemia

Hypoglycaemia affects most patients and is most often hyperinsulinaemic. The mechanism is unresolved; hypoglycosylation of beta-cell membrane proteins such as the sulfonylurea receptor SUR1 has been proposed, supported by altered insulin secretion in hypoglycosylated murine beta cells. A minority of patients are hypoglycaemic without hyperinsulinism. Hypoglycaemia responds to mannose in both groups.

Pancreatic beta cell CL:0000169

positive regulation of insulin secretion GO:0032024 ⚠ ABNORMAL

Show evidence (2 references)

PMID:32266963 SUPPORT Human Clinical

"The most common cause of hypoglycaemia in these patients was hyperinsulinism (HH), which is present in more than two-third of hypoglycaemic patients."

Establishes hyperinsulinism as the predominant hypoglycaemia mechanism.

PMID:32266963 PARTIAL Other

"However, the exact cause of HH in CDG patients is still unknown."

Explicitly flags the mechanism of hyperinsulinism as unresolved, so this node's proposed beta-cell mechanism is only partially supported.

Hepatic Ductal Plate Malformation and Progressive Fibrosis

Essentially all patients have some degree of liver involvement. The characteristic lesion is a developmental one - an excess of dilated bile duct structures in a ductal plate configuration, mimicking congenital hepatic fibrosis, together with hepatomegaly, fibrosis and sometimes steatosis. Because it is a congenital/developmental abnormality rather than an ongoing glycosylation-dependent process, it does not reverse with mannose and can progress to portal hypertension, oesophageal varices and hepatopulmonary syndrome. This mannose-refractory arm is the principal determinant of long-term morbidity.

Hepatocyte CL:0000182

Show evidence (3 references)

PMID:32266963 SUPPORT Human Clinical

"However, the most characteristic lesion mimics those seen in congenital hepatic fibrosis, with an excess of dilated bile duct structures in ductal plate configuration in the portal tracts"

Identifies the characteristic hepatic histopathology.

PMID:32266963 SUPPORT Other

"As the typical histological lesions represent congenital/developmental abnormalities of the liver (ie, ductal plate malformation), they do not respond to mannose therapy."

States the mechanistic reason the hepatic arm is refractory to mannose.

PMID:33098580 SUPPORT Human Clinical

"Liver fibrosis persisted despite treatment, but two patients showed improved liver architecture during follow-up."

Long-term treated follow-up confirms persistence of fibrosis on therapy.

Multisystem Glycoprotein Dysfunction with Neurologic Sparing

The convergent multisystem outflow of hypoglycosylation in MPI-CDG is hepatic, gastrointestinal, endocrine, coagulation and immune, but - unlike almost every other CDG - not neurologic. Cognitive development and brain imaging are typically normal, cerebellar hypoplasia is absent, and the dysmorphic, fat-pad, inverted-nipple and skeletal features of PMM2-CDG do not occur. A proposed explanation is that circulating maternal and dietary mannose partially rescues glycosylation in developing cerebral tissue, consistent with the zebrafish finding that mannose rescue is effective only within an early developmental window.

protein N-linked glycosylation GO:0006487 ⚠ ABNORMAL

Show evidence (3 references)

PMID:32266963 SUPPORT Human Clinical

"In contrast with PMM2-CDG, facial dysmorphia, atypical fat pads, inverted nipples, and skeletal deformities are not present in MPI-CDG patients."

Documents the absence of the classic CDG dysmorphic pattern in MPI-CDG.

PMID:32266963 SUPPORT Human Clinical

"no cerebellar hypoplasia was noted, as it is typical in other CDG."

Neuroimaging in reported patients shows the absence of the cerebellar hypoplasia characteristic of other CDG subtypes.

PMID:32266963 PARTIAL Other

"The exogenous mannose pathway is also a possible explanation for the absence of developmental impairment in MPI-CDG as circulating maternal mannose reduces the prenatal glycosylation defect in cerebral tissues."

The maternal-mannose rescue account of neurologic sparing is presented by the consensus panel as a hypothesis, hence PARTIAL support.

Mannose-6-Phosphate Accumulation and Energy Failure on Excess Mannose

An iatrogenic mechanism specific to MPI deficiency: because mannose-6-phosphate cannot be isomerised back to fructose-6-phosphate, an excessive mannose load (notably intravenous mannose) allows intracellular mannose-6-phosphate to accumulate. Mannose-6-phosphate inhibits hexokinase, phosphoglucose isomerase and glucose-6-phosphate dehydrogenase, suppressing glycolysis and depleting ATP - the "honeybee effect". This underlies reported seizures and stupor during intravenous mannose therapy and the paradoxical worsening of Mpi-null mouse embryos given mannose, and is the reason intravenous mannose is not recommended for stable patients.

Show evidence (3 references)

PMID:16339137 SUPPORT Model Organism

"Our results in vitro suggest that mannose toxicity in Mpi(-/-) embryos is caused by Man-6-P accumulation, which inhibits glucose metabolism and depletes intracellular ATP."

The Mpi-null mouse establishes the mechanism of mannose-6-phosphate toxicity. Model-organism evidence; the human counterpart is the intravenous-mannose case report below.

PMID:16339137 SUPPORT In Vitro

"In cell lysates, Man-6-P inhibited hexokinase (70%), phosphoglucose isomerase (65%), and glucose-6-phosphate dehydrogenase (85%), but not phosphofructokinase."

Biochemical assays identify the specific glycolytic enzymes inhibited by mannose-6-phosphate.

PMID:21240668 SUPPORT Human Clinical

"We caution that, in patients with MPI-CDG, life-threatening central nervous system disturbances may occur with intravenous mannose treatment."

Human clinical confirmation that intravenous mannose can cause severe neurological deterioration in MPI-CDG.

⬡

Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.

●

Phenotypes

30

Blood 2

Deep venous thrombosis Deep venous thrombosis HP:0002625

Show evidence (2 references)

PMID:32266963 SUPPORT Human Clinical

"Thrombotic events often complicate acute infections and dehydration episodes. These are mainly deep vein thromboses of the lower extremities."

Identifies deep venous thrombosis as the typical thrombotic event.

PMID:37124179 SUPPORT Human Clinical

"portal hypertension (4/9), epilepsy (2/17), thrombosis (12/14)"

Records thrombosis in 12/14 assessed patients, the higher of the two conflicting denominators noted in the description.

Decreased circulating immunoglobulin concentration OCCASIONAL Decreased circulating immunoglobulin concentration HP:0004313

Show evidence (1 reference)

PMID:32266963 SUPPORT Human Clinical

"Immunoglobulin deficiency due to PLE (characteristic by decreased levels of IgG but normal levels of IgA and IgM) was described in six patients."

Six of 35 patients (approximately 17%) maps to the OCCASIONAL band.

Cardiovascular 2

Portal hypertension Portal hypertension HP:0001409

Show evidence (2 references)

PMID:32266963 SUPPORT Human Clinical

"The rare but serious complications are portal hypertension with or without oesophageal varices and hepatopulmonary syndrome."

Identifies portal hypertension as an uncommon but serious hepatic complication.

PMID:33098580 SUPPORT Human Clinical

"On treatment, two patients developed severe portal hypertension, two developed venous thrombosis, and 1 displayed altered kidney function."

Two of nine treated patients developed severe portal hypertension during long-term follow-up.

Splenomegaly FREQUENT Splenomegaly HP:0001744

Show evidence (2 references)

PMID:37124179 SUPPORT Human Clinical

"prolonged coagulation (26/30), splenomegaly (13/21), non-pitting edema (14/20)"

Splenomegaly in 13/21 assessed patients (62%) supports the FREQUENT band.

PMID:32266963 SUPPORT Human Clinical

"Hepatomegaly is the most common clinical sign, sometimes associated with splenomegaly that is not initially present in the case of early diagnosis, but that appears in the first year of life."

Documents splenomegaly appearing during the first year of life.

Digestive 6

Protein-losing enteropathy VERY_FREQUENT Protein-losing enteropathy HP:0002243

Show evidence (2 references)

PMID:9525984 SUPPORT Human Clinical

"The clinical phenotype is characterized by protein-losing enteropathy, while neurological manifestations prevailing in other types of CDGS are absent."

The founding report defines protein-losing enteropathy as the characteristic phenotype.

PMID:37124179 SUPPORT Human Clinical

"chronic diarrhea (41/46), vomiting (23/27), hepatomegaly (39/44), hepatic fibrosis (20/37), protein-losing enteropathy (30/36), elevated serum transaminases (24/34), hyperinsulinemic-hypoglycemia (24/34), hypoalbuminemia (33/38), prolonged coagulation (26/30), splenomegaly (13/21), non-pitting..."

Protein-losing enteropathy in 30/36 assessed patients (83%) supports the VERY_FREQUENT band (80-100%).

Chronic diarrhea VERY_FREQUENT Chronic diarrhea HP:0002028

Temporal: CHRONIC

Show evidence (2 references)

PMID:32266963 SUPPORT Human Clinical

"Diarrhoea is the most common gastrointestinal symptom."

Establishes diarrhoea as the leading gastrointestinal feature.

PMID:37124179 SUPPORT Human Clinical

"chronic diarrhea (41/46), vomiting (23/27), hepatomegaly (39/44), hepatic fibrosis (20/37), protein-losing enteropathy (30/36)"

Chronic diarrhoea in 41/46 assessed patients (89%) supports the VERY_FREQUENT band.

Hepatomegaly VERY_FREQUENT Hepatomegaly HP:0002240

Show evidence (2 references)

PMID:32266963 SUPPORT Human Clinical

"Hepatomegaly is the most common clinical sign, sometimes associated with splenomegaly that is not initially present in the case of early diagnosis, but that appears in the first year of life."

Names hepatomegaly as the most common hepatic sign.

PMID:37124179 SUPPORT Human Clinical

"chronic diarrhea (41/46), vomiting (23/27), hepatomegaly (39/44), hepatic fibrosis (20/37)"

Hepatomegaly in 39/44 assessed patients (89%) supports the VERY_FREQUENT band.

Hepatic fibrosis FREQUENT Hepatic fibrosis HP:0001395

Course: PROGRESSIVE

Show evidence (3 references)

PMID:32266963 SUPPORT Human Clinical

"Liver involvement in MPI-CDG is one of the most common features. Patients often present with mild hepatopathy, hepatomegaly, and hepatic fibrosis."

Names hepatic fibrosis among the common hepatic features.

PMID:37124179 SUPPORT Human Clinical

"hepatomegaly (39/44), hepatic fibrosis (20/37), protein-losing enteropathy (30/36)"

Hepatic fibrosis in 20/37 assessed patients (54%) supports the FREQUENT band.

PMID:33098580 SUPPORT Human Clinical

"Liver fibrosis persisted despite treatment, but two patients showed improved liver architecture during follow-up."

Confirms persistence and progression of fibrosis under treatment.

Esophageal varix Esophageal varix HP:0002040

Show evidence (1 reference)

PMID:32266963 SUPPORT Human Clinical

"The main complication in adulthood is the portal hypertension with oesophageal varices."

Names oesophageal varices as the adult hepatic complication.

Hepatic steatosis OCCASIONAL Hepatic steatosis HP:0001397

Show evidence (1 reference)

PMID:32266963 SUPPORT Human Clinical

"or steatosis."

Steatosis is cited on liver biopsy for three of the reviewed patients (approximately 9%), consistent with the OCCASIONAL band.

Genitourinary 1

Enlarged kidney OCCASIONAL Enlarged kidney HP:0000105

Show evidence (1 reference)

PMID:32266963 PARTIAL Human Clinical

"Mild tubular acidosis, nephromegaly, renal cysts, and severe hypertrophic cardiomyopathy were described in sporadic cases; the connection with MPI-CDG is unclear."

Six of 35 patients had renal findings (OCCASIONAL band), but the guideline explicitly states the causal connection is unclear, hence PARTIAL support.

Immune 1

Recurrent infections Recurrent infections HP:0002719

Show evidence (1 reference)

PMID:32266963 SUPPORT Human Clinical

"One patient suffered from high frequency of unusual and severe specific infections (HSV encephalitis, bronchiolitis obliterans, cryptosporidial diarrhoea, candidal urinary tract infection) and a high frequency of respiratory infections."

Documents the recurrent-infection phenotype; frequency is deliberately omitted because only individual cases are reported.

Metabolism 4

Hypoalbuminemia VERY_FREQUENT Hypoalbuminemia HP:0003073

Show evidence (2 references)

PMID:32266963 SUPPORT Human Clinical

"The diarrhoea is most commonly due to PLE with resulting hypoalbuminaemia."

Directly links protein-losing enteropathy to hypoalbuminaemia.

PMID:37124179 SUPPORT Human Clinical

"hypoalbuminemia (33/38), prolonged coagulation (26/30), splenomegaly (13/21), non-pitting edema (14/20), failure to thrive (13/36)"

Hypoalbuminaemia in 33/38 assessed patients (87%) supports the VERY_FREQUENT band.

Edema FREQUENT Edema HP:0000969

Show evidence (2 references)

PMID:37124179 SUPPORT Human Clinical

"hypoalbuminemia (33/38), prolonged coagulation (26/30), splenomegaly (13/21), non-pitting edema (14/20), failure to thrive (13/36)"

Non-pitting oedema in 14/20 assessed patients (70%) supports the FREQUENT band (30-79%).

PMID:22899857 SUPPORT Human Clinical

"Individuals who are deficient in MPI present with bleeding, diarrhea, edema, gastrointestinal bleeding and liver fibrosis."

This modelling paper's clinical summary of the human disorder lists oedema among the presenting features; the quoted statement is about human patients, not the zebrafish model.

Elevated circulating hepatic transaminase concentration FREQUENT Elevated circulating hepatic transaminase concentration HP:0002910

Show evidence (2 references)

PMID:37124179 SUPPORT Human Clinical

"protein-losing enteropathy (30/36), elevated serum transaminases (24/34), hyperinsulinemic-hypoglycemia (24/34)"

Elevated transaminases in 24/34 assessed patients (71%) supports the FREQUENT band.

PMID:32266963 SUPPORT Human Clinical

"Gamma-glutamyl transferase (GGT) and bilirubin levels are often normal."

Documents the sparing of GGT and bilirubin that defines the characteristic liver-enzyme pattern.

Hypoglycemia FREQUENT Hypoglycemia HP:0001943

Show evidence (2 references)

PMID:32266963 SUPPORT Human Clinical

"Hypoglycaemia has been observed in the majority of reported MPI-CDG patients."

"Majority" maps to the FREQUENT band (30-79%).

PMID:32266963 SUPPORT Human Clinical

"Hypoglycaemia is frequently associated with MPI-CDG and, it can be a presenting and rarely even the only sign."

Confirms hypoglycaemia can be the sole presenting manifestation.

Nervous System 1

Seizure OCCASIONAL Seizure HP:0001250

Show evidence (2 references)

PMID:32266963 SUPPORT Human Clinical

"Seizures were documented in six patients, but they were secondary in all cases and no chronical antiepileptic treatment was necessary."

Six of 35 patients (approximately 17%) maps to the OCCASIONAL band, and the statement establishes that seizures are always secondary.

PMID:37124179 SUPPORT Human Clinical

"portal hypertension (4/9), epilepsy (2/17), thrombosis (12/14)"

Epilepsy in 2/17 assessed patients (12%) independently supports the OCCASIONAL band.

Growth 2

Failure to thrive FREQUENT Failure to thrive HP:0001508

Show evidence (2 references)

PMID:32266963 SUPPORT Human Clinical

"The gastrointestinal impairment often leads to malnutrition/failure to thrive, which were reported in two-thirds of patients, although the anthropometric measurements were available in only half of them."

"Two-thirds of patients" maps to the FREQUENT band (30-79%).

PMID:37124179 SUPPORT Human Clinical

"non-pitting edema (14/20), failure to thrive (13/36), portal hypertension (4/9)"

Failure to thrive in 13/36 assessed patients (36%) in the larger review also falls in the FREQUENT band, at its lower end.

Growth delay OCCASIONAL Growth delay HP:0001510

Show evidence (1 reference)

PMID:32266963 SUPPORT Human Clinical

"Growth restriction was documented in four patients."

Four of the 35 reviewed patients (approximately 11%) maps to the OCCASIONAL band (5-29%).

Other 11

Episodic vomiting VERY_FREQUENT Episodic vomiting HP:0002572

Temporal: RECURRENT

Show evidence (2 references)

PMID:32266963 SUPPORT Human Clinical

"The presenting symptoms were mainly combination of gastrointestinal involvement (cyclic vomiting, PLE and failure to thrive, n = 26), hypoglycaemia (n = 15), hepatic involvement (elevation of transaminases, hepatomegaly, liver fibrosis, n = 14), and coagulation complications (laboratory..."

Cyclic vomiting is named among the presenting gastrointestinal features.

PMID:37124179 SUPPORT Human Clinical

"chronic diarrhea (41/46), vomiting (23/27), hepatomegaly (39/44)"

Vomiting in 23/27 assessed patients (85%) supports the VERY_FREQUENT band.

Villous atrophy Villous atrophy HP:0011473

Severity: MILD

Show evidence (1 reference)

PMID:32266963 SUPPORT Human Clinical

"Duodenal biopsies, when performed, reveal a mild villous atrophy"

Documents the duodenal histology reported in MPI-CDG.

Intestinal lymphangiectasia Intestinal lymphangiectasia HP:0002593

Show evidence (1 reference)

PMID:32266963 SUPPORT Human Clinical

"and less frequently lymphangiectasia."

Reports lymphangiectasia on duodenal biopsy in a subset of patients.

Malformation of the hepatic ductal plate Malformation of the hepatic ductal plate HP:0006563

Show evidence (1 reference)

PMID:32266963 SUPPORT Human Clinical

"However, the most characteristic lesion mimics those seen in congenital hepatic fibrosis, with an excess of dilated bile duct structures in ductal plate configuration in the portal tracts"

Directly describes the ductal plate malformation on liver biopsy.

Hyperinsulinemic hypoglycemia FREQUENT Hyperinsulinemic hypoglycemia HP:0000825

Show evidence (2 references)

PMID:32266963 SUPPORT Human Clinical

"The most common cause of hypoglycaemia in these patients was hyperinsulinism (HH), which is present in more than two-third of hypoglycaemic patients."

Hyperinsulinism in more than two-thirds of the hypoglycaemic patients.

PMID:37124179 SUPPORT Human Clinical

"elevated serum transaminases (24/34), hyperinsulinemic-hypoglycemia (24/34), hypoalbuminemia (33/38)"

Hyperinsulinaemic hypoglycaemia in 24/34 assessed patients (71%) supports the FREQUENT band.

Reduced antithrombin III activity VERY_FREQUENT Reduced antithrombin III activity HP:0001976

Show evidence (3 references)

PMID:32266963 SUPPORT Human Clinical

"Coagulopathy with typical pattern affecting both procoagulant and anticoagulant factors is reported in almost all patients, with mainly antithrombin (AT) deficiency."

"Almost all patients" maps to the VERY_FREQUENT band (80-100%), with antithrombin named as the principal deficiency.

PMID:37124179 SUPPORT Human Clinical

"hypoalbuminemia (33/38), prolonged coagulation (26/30), splenomegaly (13/21)"

Prolonged coagulation in 26/30 assessed patients (87%) corroborates the VERY_FREQUENT band for the coagulopathy of which antithrombin deficiency is the dominant component.

PMID:32905087 SUPPORT Human Clinical

"CDG screening should be included into the routine diagnostic work‐up in all patients presenting with unexplained coagulation disorder, especially when comprising AT deficiency."

Reinforces antithrombin deficiency as the characteristic and diagnostically actionable coagulation abnormality.

Reduced protein C activity FREQUENT Reduced protein C activity HP:0005543

Show evidence (1 reference)

PMID:32266963 SUPPORT Human Clinical

"Deficit in protein C (PC) and in factor XI (FXI) is also frequently observed, and protein S (PS) can also be decreased."

"Frequently observed" maps to the FREQUENT band.

Reduced factor XI activity FREQUENT Reduced factor XI activity HP:0001929

Show evidence (1 reference)

PMID:32266963 SUPPORT Human Clinical

"Deficit in protein C (PC) and in factor XI (FXI) is also frequently observed, and protein S (PS) can also be decreased."

"Frequently observed" maps to the FREQUENT band.

Cerebral venous sinus thrombosis Cerebral venous sinus thrombosis HP:0033724

Show evidence (1 reference)

PMID:32905087 SUPPORT Human Clinical

"In summary, we present the first MPI-CDG patient with severe cerebral venous sinus thrombosis as first and only symptom of disease manifestation."

Case report documenting cerebral venous sinus thrombosis as the presenting event.

Type I transferrin isoform profile VERY_FREQUENT Type I transferrin isoform profile HP:0003642

Show evidence (1 reference)

PMID:32266963 SUPPORT Human Clinical

"This pattern is 100% sensitive but non-specific (eg, indistinguishable from PMM2-CDG) and it has been reported in all MPI-CDG patients except those diagnosed post-mortem on basis of symptoms and/or MPI gene analysis in parents or siblings."

Reported in all living ascertained patients, supporting VERY_FREQUENT.

Normal cognitive development

Show evidence (3 references)

PMID:32266963 SUPPORT Human Clinical

"All the remaining patients have normal psychomotor development and intellect."

Confirms preserved cognition in the great majority of patients. No HPO term is bound because HPO codes abnormalities, not preserved function.

PMID:37124179 SUPPORT Human Clinical

"None of the patients was reported to have an intellectual disability (0/28)."

Zero of 28 assessed patients had intellectual disability in the expanded review.

PMID:9525984 SUPPORT Human Clinical

"The clinical phenotype is characterized by protein-losing enteropathy, while neurological manifestations prevailing in other types of CDGS are absent."

The founding report already noted the absence of neurological manifestations that dominate other CDG subtypes.

🧬

Genetic Associations

1

MPI

Gene: MPI hgnc:7216 relationship_type: CAUSATIVE variant_origin: GERMLINE

Show evidence (5 references)

PMID:10980531 SUPPORT Human Clinical

"CDG-Ib is caused by a deficiency of mannose-6-phosphate isomerase (synonym: phosphomannose isomerase, EC 5.3.1.8), due to mutations in the MPI gene."

Establishes MPI as the disease gene.

PMID:10980531 SUPPORT Human Clinical

"The gene is composed of 8 exons and spans only 5 kb."

Defines the genomic structure that underpins routine sequencing.

PMID:32266963 SUPPORT Human Clinical

"The most common variants are c.656G > A (p. Arg219Gln), c.457G > A (p.Arg152Gln), and c.884G > A (p.Arg295His), which all together form about one half of all alleles."

Identifies the recurrent variants and their allelic burden.

+ 2 more references

💊

Medical Actions

10

Oral D-mannose supplementation

Action: Pharmacotherapy NCIT:C15986

Agent: D-mannose CHEBI:16024

Oral D-mannose is the disease-specific therapy and the reason MPI-CDG is one of the few treatable CDGs. Exogenous mannose is phosphorylated by hexokinase to mannose-6-phosphate, entering the N-glycosylation pathway downstream of the MPI block. The recommended dose is 150-170 mg/kg per dose, four to five times daily, started as soon as the diagnosis is made and continued lifelong. It corrects the digestive symptoms, hypoglycaemia and coagulopathy, but it does not treat the hepatic disease. Clinical response usually begins within a week while biochemical abnormalities take months to stabilise. Abdominal pain and diarrhoea are the main side effects. Poor compliance is associated with relapse.

Mechanism Target:

BYPASSES GDP-Mannose Depletion and Impaired Lipid-Linked Oligosaccharide Assembly — Dietary mannose is converted to mannose-6-phosphate by hexokinase, re-supplying the GDP-mannose pool without requiring MPI activity.

Show evidence (2 references)

PMID:21240668 SUPPORT Human Clinical

"Dietary supplementation of mannose can reverse clinical symptoms by entering the N-glycosylation pathway downstream of MPI."

States the bypass mechanism explicitly.

PMID:22899857 SUPPORT Other

"MPI-CDG patients can be treated with oral mannose supplements, which is converted to mannose-6-phosphate through a minor complementary metabolic pathway, restoring protein glycosylation and ameliorating most symptoms, although liver disease continues to progress."

Names the complementary metabolic pathway that bypasses the block and notes its hepatic limitation. Evidence source is OTHER because this is the paper's background statement about human patients.

Target Phenotypes: Protein-losing enteropathy HP:0002243 Hypoglycemia HP:0001943 Reduced antithrombin III activity HP:0001976

Show evidence (7 references)

PMID:9525984 SUPPORT Human Clinical

"Daily oral mannose administration is a successful therapy for this new type of CDG syndrome classified as CDGS type Ib."

The founding report establishing oral mannose as effective therapy.

PMID:32266963 SUPPORT Other

"Oral mannose is recommended treatment for digestive symptoms, coagulopathy and hypoglycaemia, although it does not treat the liver symptoms in MPI-CDG."

Consensus recommendation delimiting exactly which disease arms respond.

PMID:32266963 SUPPORT Other

"The recommended mannose dose ranges from 150 to 170 mg/kg/dose four to five times daily."

Consensus dosing recommendation.

+ 4 more references

Diazoxide for hyperinsulinaemic hypoglycaemia

Action: Pharmacotherapy NCIT:C15986

Agent: diazoxide CHEBI:4495

Patients with confirmed hyperinsulinism and hypoglycaemia not controlled by mannose and feeding measures may need diazoxide, at reported doses of 4-15 mg/kg/day in three divided doses. Diazoxide is contraindicated in pregnancy.

Target Phenotypes: Hyperinsulinemic hypoglycemia HP:0000825

Show evidence (1 reference)

PMID:32266963 SUPPORT Other

"Patients with confirmed hyperinsulinaemia and hypoglycaemia might additionally need diazoxide treatment (reported doses vary from 4 to 15 mg/kg/day divided to three doses). The diazoxide is contraindicated in pregnancy."

Consensus recommendation with dose and the pregnancy contraindication.

Anticoagulation for thrombotic events

Action: Pharmacotherapy NCIT:C15986

Agent: heparin CHEBI:28304

Thrombosis is treated with unfractionated or low-molecular-weight heparin. Vitamin K antagonists require caution because of bleeding risk in the setting of digestive ulceration and oesophageal varices, and factor XI concentrate and recombinant factor VIIa are not recommended because unbalanced haemostasis makes thrombosis likely.

Target Phenotypes: Deep venous thrombosis HP:0002625 Cerebral venous sinus thrombosis HP:0033724

Show evidence (3 references)

PMID:32266963 SUPPORT Other

"In case of thrombosis, treatment by unfractionated heparin or low-molecular-weight heparin can be used."

Consensus first-line anticoagulation recommendation.

PMID:32266963 SUPPORT Other

"Infusion of factor XI concentrate or recombinant factor VIIa (rFVIIa) is not recommended due to the high risk of thrombotic events caused by unbalanced haemostasis."

Records the explicit agents-to-avoid recommendation for bleeding management.

PMID:32905087 SUPPORT Human Clinical

"Immediately after diagnosis of cerebral venous sinus thrombosis, therapy with unfractionated heparin was initiated and changed to low molecular weight heparin 2 weeks later."

Worked clinical example of the anticoagulation strategy.

Heparin for refractory protein-losing enteropathy

Action: Pharmacotherapy NCIT:C15986

Agent: heparin CHEBI:28304

Experimental heparin therapy has been used for severe protein-losing enteropathy in a patient with serious adverse reactions to mannose, on the rationale that heparin binds inflammatory cytokines that damage intestinal tight junctions. The bleeding risk in patients with coagulopathy, portal hypertension or varices must be weighed against the benefit; this is not routine disease-modifying treatment.

Target Phenotypes: Protein-losing enteropathy HP:0002243

Show evidence (1 reference)

PMID:32266963 PARTIAL Human Clinical

"Experimental heparin treatment of severe PLE was described in patient with serious adverse reactions after mannose."

Single-patient experimental use, hence PARTIAL support.

Liver transplantation

Action: Liver transplantation Ontology label: Liver Transplantation NCIT:C15271

Liver transplantation has been performed in selected patients, notably for hepatopulmonary syndrome secondary to portal hypertension. It restored exercise tolerance, pulmonary function, coagulation parameters and the transferrin isoelectric focusing pattern, although MPI enzyme activity and glycosylation of non-liver-derived glycoproteins remained deficient.

Target Phenotypes: Hepatic fibrosis HP:0001395 Portal hypertension HP:0001409

Show evidence (2 references)

PMID:24982104 SUPPORT Human Clinical

"After transplantation her physical exercise tolerance, pulmonary functions, and metabolic parameters became fully restored."

Reports the first successful liver transplantation in a CDG patient.

PMID:32266963 SUPPORT Other

"Liver transplantation has been performed in one patient and could be necessary in selected cases (such as in patients with hepatopulmonary syndrome due to portal hypertension)."

Consensus positioning of transplantation as a selected-case option.

Nutritional support

Action: nutritional support Ontology label: Nutritional Support NCIT:C15433

Severely undernourished patients with chronic diarrhoea or recurrent vomiting may need parenteral nutrition, nasogastric or gastrostomy feeding at presentation, and intravenous albumin before mannose achieves biochemical correction. Frequent feeds and complex dietary carbohydrate also help control hyperinsulinaemic hypoglycaemia.

Target Phenotypes: Failure to thrive HP:0001508 Hypoalbuminemia HP:0003073

Show evidence (2 references)

PMID:32266963 SUPPORT Other

"At presentation, severely undernourished patients with chronic diarrhoea or recurrent vomiting may require parenteral nutrition."

Consensus recommendation for nutritional rescue at presentation.

PMID:32266963 SUPPORT Other

"Hyperinsulinaemic hypoglycaemia can be also managed by frequent feedings and by adding complex carbohydrates to the diet."

Consensus dietary management of the endocrine arm.

Immunoglobulin replacement

Action: immunoglobulin therapy Ontology label: Immunoglobulin Therapy NCIT:C62710

Patients with significant hypogammaglobulinaemia secondary to protein-losing enteropathy should receive regular intravenous or subcutaneous immunoglobulin replacement.

Target Phenotypes: Decreased circulating immunoglobulin concentration HP:0004313

Show evidence (1 reference)

PMID:32266963 SUPPORT Other

"IV or SC immunoglobulins should be administered regularly in patients with hypogammaglobulinaemia."

Consensus recommendation for immunoglobulin replacement in the PLE-associated hypogammaglobulinaemia of MPI-CDG.

Multisystem surveillance programme

Category: Monitoring

Because the hepatic arm progresses independently of mannose and the coagulopathy fluctuates with intercurrent illness, the consensus guideline specifies scheduled surveillance rather than symptom-driven review: six-monthly liver chemistry (transaminases, GGT, bilirubin, alpha-fetoprotein, prothrombin time) plus liver ultrasound; annual elastography where transaminases remain elevated; annual and then at least three-yearly oesophageal endoscopy once portal hypertension is present, with echocardiography and oximetry for portopulmonary hypertension and hepatopulmonary syndrome; a broad annual haemostasis panel, repeated around infection, dehydration and any invasive procedure; albumin at a frequency set by the presence and severity of protein-losing enteropathy and the treatment response; and glucose, thyroid/IGF-axis, renal, immunoglobulin and nutritional review.

Show evidence (3 references)

PMID:32266963 SUPPORT Other

"To the best of our knowledge, all the patients have liver involvement even at minimal stage, so the liver tests (transaminases, GGT, bilirubin, alpha-fetoprotein, prothrombin time) and liver ultrasound (in search for liver fibrosis, steatosis, ductal plate malformations, or signs of portal..."

Consensus hepatic surveillance schedule, justified by the near-universal liver involvement.

PMID:32266963 SUPPORT Other

"Broad haemostatic study including fibrinogen, prothrombin time, partial thromboplastin time, factor VIII, factor IX, factor XI, AT, PC, and PS, complete blood count and differential should be performed at diagnosis and then annually."

Consensus haemostasis surveillance schedule.

PMID:32266963 SUPPORT Other

"oesophageal endoscopy should be performed each year at the beginning of the follow-up and thereafter depending on the endoscopic findings, but at least every 3 years."

Consensus variceal-surveillance interval for patients with portal hypertension.

Hepatoprotective avoidance measures

Action: supportive care Ontology label: Supportive Care NCIT:C15747

Because the hepatic lesion is irreversible and progressive and unresponsive to mannose, further liver injury should be actively prevented: vaccination against hepatitis A and B, avoidance of hepatotoxic drugs, and abstinence from alcohol.

Target Phenotypes: Hepatic fibrosis HP:0001395

Show evidence (1 reference)

PMID:32266963 SUPPORT Other

"As the liver involvement in MPI-CDG is irreversible and progressive, the further liver damage should be prevented by vaccination against hepatotropic viruses (hepatitises A and B), avoidance of hepatotoxic drugs, and alcohol abstinence."

Consensus "agents and circumstances to avoid" recommendation.

Genetic counseling

Action: genetic counseling Ontology label: Genetic Counseling NCIT:C15240

Identification of the causative variants supports carrier testing of family members, prenatal diagnosis and genetic counselling; psychological support for families is also recommended at the time of diagnosis.

Show evidence (1 reference)

PMID:32266963 SUPPORT Other

"The identification of disease-causing variants enables accurate prenatal diagnosis, determination of carrier status of family members, and genetic counselling."

Consensus recommendation for genetic counselling following molecular diagnosis.

🔬

Biochemical Markers

2

CDG type I transferrin pattern (ABNORMAL)

Context: Serum or plasma transferrin isoelectric focusing (or HPLC/capillary electrophoresis quantifying carbohydrate-deficient transferrin) shows reduced tetrasialotransferrin with increased disialo- and asialotransferrin. This is the first-line screen but cannot distinguish MPI-CDG from PMM2-CDG or other type I disorders.

Pathograph Readouts

Readout Of Protein Hypoglycosylation Positive Diagnostic

The cathodal transferrin shift directly reports systemic N-glycosylation deficiency.

Show evidence (2 references)

PMID:32266963 SUPPORT Human Clinical

"MPI-CDG can be biochemically characterised by a decreased level of the major tetrasialylated transferrin (Trf) glycoform (tetrasialotransferrin) and an increase of disialotransferrin and asialotransferrin, that is, CDG type I pattern."

Defines the biochemical signature.

PMID:32266963 SUPPORT Human Clinical

"The CDT% in MPI-CDG patients rises above 6% but often up to 40% to 50% of asialo-/and disialotransferrins."

Quantifies the carbohydrate-deficient transferrin elevation, relevant to the recurring misdiagnosis as alcohol misuse.

Deficient MPI enzyme activity in leukocytes or fibroblasts (ABNORMAL)

Context: Spectrophotometric MPI assay in freshly isolated leukocytes or fibroblasts is the second-line confirmatory test, typically showing under 10% of normal activity; obligate carriers show intermediate values of 30-83% (median 50%).

Pathograph Readouts

Readout Of Phosphomannose Isomerase Deficiency Negative Diagnostic

Directly measures the deficient enzyme defining the disorder.

Show evidence (2 references)

PMID:32266963 SUPPORT Human Clinical

"In described MPI-CDG patients, enzyme activities were usually very deficient with activities less than 10% of normal values in both leukocytes and fibroblasts."

Quantifies the diagnostic enzyme deficit.

PMID:24508628 SUPPORT Human Clinical

"Probing for the underlying enzyme defect(s) using cultured skin fibroblasts demonstrated normal activity of phosphomannomutase, whereas the activity of phosphomannose isomerase (MPI) was reduced (0.64 mU/mg protein, reference 2.1-6.9), pointing to CDG of the MPI subtype (formerly called CDG-Ib)."

Worked example of the fibroblast enzyme assay discriminating MPI-CDG from PMM2-CDG.

🔀

Differential Diagnoses

5

Conditions with similar clinical presentations that must be differentiated from MPI-congenital disorder of glycosylation:

PMM2-congenital disorder of glycosylation Not Yet Curated MONDO:0008907

Overlapping Features The commonest CDG and the closest biochemical mimic: PMM2-CDG produces an identical CDG type I transferrin pattern but is dominated by neurologic disease (developmental delay, cerebellar hypoplasia) with dysmorphism, inverted nipples and abnormal fat pads, none of which occur in MPI-CDG. Discrimination requires enzyme assay or molecular testing.

Show evidence (2 references)

PMID:32266963 SUPPORT Human Clinical

"In contrast with PMM2-CDG, facial dysmorphia, atypical fat pads, inverted nipples, and skeletal deformities are not present in MPI-CDG patients."

States the clinical discriminators from the principal differential.

PMID:24508628 SUPPORT Human Clinical

"Probing for the underlying enzyme defect(s) using cultured skin fibroblasts demonstrated normal activity of phosphomannomutase, whereas the activity of phosphomannose isomerase (MPI) was reduced (0.64 mU/mg protein, reference 2.1-6.9), pointing to CDG of the MPI subtype (formerly called CDG-Ib)."

Demonstrates how the two are separated enzymatically.

Chronic excessive alcohol consumption

Overlapping Features Elevated carbohydrate-deficient transferrin is a routine biomarker of heavy drinking, and asymptomatic MPI-CDG adults have been misdiagnosed as alcohol abusers on the basis of a markedly raised CDT. A negative phosphatidylethanol and the type-1 glycoform pattern point instead to CDG.

Show evidence (1 reference)

PMID:24508628 SUPPORT Human Clinical

"If asymptomatic MPI-CDG subjects undergo CDT screening, their highly elevated test results may be wrongly interpreted as caused by excessive alcohol consumption."

Documents the specific diagnostic pitfall.

Other causes of protein-losing enteropathy

Overlapping Features Protein-losing enteropathy has many causes - gastrointestinal infection, severe coeliac disease, inflammatory bowel disease, other metabolic disorders including ALG6-CDG, and intestinal lymphangiectasia in Noonan and Turner syndromes. One MPI-CDG patient was managed as Crohn disease for 13 years before mannose produced prompt improvement.

Show evidence (1 reference)

PMID:32266963 SUPPORT Other

"MPI-CDG should be included in the differential diagnosis of patients with a PLE."

Consensus statement positioning MPI-CDG within the protein-losing enteropathy differential.

Congenital hepatic fibrosis in autosomal recessive polycystic kidney disease

Overlapping Features The ductal plate malformation of MPI-CDG closely resembles the hepatic lesion of congenital hepatic fibrosis in ARPKD, which is a key histopathological differential on liver biopsy.

Show evidence (1 reference)

PMID:32266963 SUPPORT Other

"Bile duct involvement in MPI-CDG with ductal plate malformation is very similar to those observed in Congenital Hepatic Fibrosis in Autosomal Recessive Polycystic Kidney Disease."

Names the histopathological mimic.

Liver-predominant congenital disorders of glycosylation

Overlapping Features TMEM199-CDG, CCDC115-CDG and ATP6AP1-CDG also present with liver disease as the predominant symptom and belong in the differential of an abnormal transferrin pattern with hepatopathy.

Show evidence (1 reference)

PMID:32266963 SUPPORT Other

"including other CDGs, especially those where the liver involvement is present as a predominant symptom (TMEM199-CDG, CCDC115-CDG, and ATP6AP1-CDG)."

Names the liver-predominant CDG differentials.

🔬

Clinical Trials

1

NCT03404869 PHASE_II UNKNOWN

Open-label, single-group Phase 1/2 study of ORL-1M (D-mannose) in patients with CDG-Ib, sponsored by Orpha Labs, with an estimated enrolment of five participants under 18 years. The primary outcome was improvement in hypoglycaemia, diarrhoea and vomiting at six months and the secondary outcome improved serum transferrin glycosylation at 30 days. The registry record was last known to be recruiting and no results have been posted.

Target Phenotypes: Hypoglycemia HP:0001943 Chronic diarrhea HP:0002028 Episodic vomiting HP:0002572

Show evidence (1 reference)

clinicaltrials:NCT03404869 SUPPORT Human Clinical

"Study of ORL-1M in Patients With CDG-Ib"

The ClinicalTrials.gov record confirms a registered interventional study of the D-mannose product ORL-1M in CDG-Ib (MPI-CDG). Only the study title is available in the cached registry summary, so the detailed design described above is drawn from the registry record and is not quoted here.

{ }

Source YAML

click to show

name: MPI-congenital disorder of glycosylation
creation_date: "2026-08-01T00:00:00Z"
description: >-
  MPI-congenital disorder of glycosylation (MPI-CDG, formerly CDG-Ib) is an
  ultra-rare autosomal recessive congenital disorder of N-linked glycosylation
  caused by biallelic pathogenic variants in MPI, encoding phosphomannose
  (mannose-6-phosphate) isomerase. Loss of MPI blocks the endogenous conversion
  of fructose-6-phosphate to mannose-6-phosphate, depleting GDP-mannose for
  lipid-linked oligosaccharide assembly and producing a CDG type I
  hypoglycosylation pattern. MPI-CDG is the outlier of the CDG family in two
  respects: the phenotype is dominantly hepatic-intestinal and endocrine
  (protein-losing enteropathy, congenital hepatic fibrosis with ductal plate
  malformation, hyperinsulinaemic hypoglycaemia, mixed coagulopathy) with
  sparing of cognitive development, and the enzymatic block can be bypassed
  therapeutically by oral D-mannose, making it one of the few treatable CDGs.
  Liver disease is the notable mannose-refractory arm.
category: Mendelian
parents:
- hereditary disease
synonyms:
- MPI-CDG
- CDG-Ib
- CDG1B
- congenital disorder of glycosylation type Ib
- carbohydrate deficient glycoprotein syndrome type Ib
- phosphomannose isomerase deficiency
- mannose phosphate isomerase deficiency
disease_term:
  preferred_term: MPI-congenital disorder of glycosylation
  term:
    id: MONDO:0011257
    label: MPI-congenital disorder of glycosylation
notes: >-
  GeneReviews baseline: no dedicated GeneReviews chapter exists for MPI-CDG
  (PubMed searches for "MPI-CDG", "phosphomannose isomerase" and "CDG-Ib"
  combined with GeneReviews return no hits); the only related chapter,
  "Congenital Disorders of N-Linked Glycosylation and Multiple Pathway Overview"
  (PMID:20301507), is a retired archival overview whose abstract carries no
  MPI-specific clinical content. The 2020 international consensus guideline
  (PMID:32266963), which systematically reviewed all 35 then-published patients
  organ system by organ system, and the 2023 literature review of 52 patients
  (PMID:37124179) are used here as the equivalent expert-curated phenotype
  baseline. Frequency bands are taken from the 2023 review's explicit
  numerators/denominators where available; those denominators vary by feature
  because not every feature was assessed in every published patient, and both
  cohorts are subject to publication and ascertainment bias.
inheritance:
- name: Autosomal recessive inheritance
  inheritance_term:
    preferred_term: Autosomal recessive inheritance
    term:
      id: HP:0000007
      label: Autosomal recessive inheritance
  description: >-
    MPI-CDG is inherited in an autosomal recessive manner. Both homozygous
    (frequently but not exclusively consanguineous) and compound heterozygous
    genotypes are reported.
  evidence:
  - reference: PMID:32266963
    reference_title: "Consensus guideline for the diagnosis and management of mannose phosphate isomerase-congenital disorder of glycosylation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      MPI-CDG has autosomal recessive inheritance, but surprisingly high percentage of homozygotes was present (13 out of 28 patients with known genotype).
    explanation: >-
      The consensus review of all published patients states the mode of
      inheritance and the genotype distribution directly.
  - reference: PMID:24508628
    reference_title: "Asymptomatic phosphomannose isomerase deficiency (MPI-CDG) initially mistaken for excessive alcohol consumption."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Both parents, being distant relatives, were heterozygous mutation carriers with normal CDT values.
    explanation: >-
      Heterozygous, biochemically normal parents of a homozygous proband
      demonstrate recessive segregation.
prevalence:
- population: Worldwide
  measure_type: CASES_IN_LITERATURE
  prevalence_class: NOT_YET_DOCUMENTED
  notes: >-
    The 2020 international consensus guideline systematically reviewed the
    entire published literature and identified 35 patients from 30 families; no
    population prevalence estimate is available.
  evidence:
  - reference: PMID:32266963
    reference_title: "Consensus guideline for the diagnosis and management of mannose phosphate isomerase-congenital disorder of glycosylation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      MPI-CDG is a rare autosomal recessive disorder with only 35 patients described so far. The prevalence is not known.
    explanation: >-
      Directly states the total number of reported cases and the absence of a
      prevalence estimate.
- population: Worldwide
  measure_type: CASES_IN_LITERATURE
  prevalence_class: NOT_YET_DOCUMENTED
  notes: >-
    An expanded 2023 literature review raised the cumulative published total to
    52 patients from 17 countries, confirming panethnic distribution rather than
    restriction to the Saguenay-Lac-Saint-Jean founder population in which the
    earliest cluster was described.
  evidence:
  - reference: PMID:37124179
    reference_title: "Mannose phosphate isomerase gene mutation leads to a congenital disorder of glycosylation: A rare case report and literature review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Including the present case, a total of 52 patients from hospitals across 17 countries were diagnosed with MPI-CDG.
    explanation: >-
      Gives the updated cumulative case count and geographic spread.
  - reference: PMID:32266963
    reference_title: "Consensus guideline for the diagnosis and management of mannose phosphate isomerase-congenital disorder of glycosylation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The disease is panethnic, 14 patients originated from Europe
    explanation: >-
      The consensus cohort description establishes panethnic distribution.
progression:
- phase: Infantile-onset hepatic-intestinal and endocrine presentation
  age_range: birth to 15 years, with onset before age 2 in most patients
  notes: >-
    Symptoms begin in infancy in the large majority of patients, most often as
    diarrhoea and vomiting with hepatomegaly, hypoglycaemia and coagulopathy.
    The gastrointestinal and hypoglycaemic course is episodic, with infection,
    fasting or dehydration precipitating exacerbations. Diagnostic delay is
    substantial (median 2.15 years, range 0-30 years).
  evidence:
  - reference: PMID:32266963
    reference_title: "Consensus guideline for the diagnosis and management of mannose phosphate isomerase-congenital disorder of glycosylation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The onset of disease symptoms was in infancy in large majority of patients (93%) with the average age of onset being at 1.2 years
    explanation: >-
      Establishes infantile onset in the pooled published cohort.
  - reference: PMID:37124179
    reference_title: "Mannose phosphate isomerase gene mutation leads to a congenital disorder of glycosylation: A rare case report and literature review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Age at disease onset ranged from birth to 15 years, with an onset under 2 years in most patients (43/50).
    explanation: >-
      Quantifies onset age across the expanded 52-patient literature review.
- phase: Untreated course and mortality
  notes: >-
    Untreated disease carries substantial early mortality, concentrated in
    infancy and early childhood, with hepatic failure and sepsis among the
    identified causes. Most reported deaths predate recognition of the disorder
    and availability of mannose.
  evidence:
  - reference: PMID:32266963
    reference_title: "Consensus guideline for the diagnosis and management of mannose phosphate isomerase-congenital disorder of glycosylation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The mortality rate was 23.5%, and all the eight patients died in their infancy and early childhood (at the age from 4 months to 5 years, median age 2.2 years).
    explanation: >-
      Quantifies mortality in the pooled published cohort.
- phase: Treated long-term course with residual hepatic and vascular risk
  notes: >-
    On D-mannose the digestive, hypoglycaemic and coagulation manifestations
    remit, but liver fibrosis persists and portal hypertension, venous
    thrombosis and impaired renal function can still emerge in adolescence and
    adulthood. Lifelong treatment and surveillance are required.
  evidence:
  - reference: PMID:37124179
    reference_title: "Mannose phosphate isomerase gene mutation leads to a congenital disorder of glycosylation: A rare case report and literature review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The majority of patients (26/30) showed clinical symptoms, and laboratory results improved after oral mannose administration.
    explanation: >-
      Quantifies treatment response across the reviewed literature.
  - reference: PMID:33098580
    reference_title: "Long term outcome of MPI-CDG patients on D-mannose therapy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      On treatment, two patients developed severe portal hypertension, two developed venous thrombosis, and 1 displayed altered kidney function.
    explanation: >-
      The longest published follow-up series documents the residual long-term
      complications despite D-mannose therapy.
pathophysiology:
- name: Phosphomannose Isomerase Deficiency
  biological_scale: MOLECULAR
  role: trigger
  description: >-
    Biallelic loss-of-function or hypomorphic variants in MPI reduce the
    activity of phosphomannose (mannose-6-phosphate) isomerase, the mainly
    cytosolic enzyme that interconverts fructose-6-phosphate and
    mannose-6-phosphate. Residual enzyme activity in patient leukocytes and
    fibroblasts is typically below 10% of normal. Because fructose-6-phosphate
    is a glycolytic intermediate, the block itself does not cause accumulation
    of a toxic upstream substrate; the lesion is one of insufficient
    mannose-6-phosphate supply.
  genes:
  - preferred_term: MPI
    term:
      id: hgnc:7216
      label: MPI
  molecular_functions:
  - preferred_term: mannose-6-phosphate isomerase activity
    modifier: DECREASED
    term:
      id: GO:0004476
      label: mannose-6-phosphate isomerase activity
  biological_processes:
  - preferred_term: mannose metabolic process
    modifier: DECREASED
    term:
      id: GO:0006013
      label: mannose metabolic process
  chemical_entities:
  - preferred_term: D-mannose 6-phosphate
    modifier: DECREASED
    term:
      id: CHEBI:17369
      label: D-mannose 6-phosphate
  cell_types:
  - preferred_term: Hepatocyte
    term:
      id: CL:0000182
      label: hepatocyte
  evidence:
  - reference: PMID:32266963
    reference_title: "Consensus guideline for the diagnosis and management of mannose phosphate isomerase-congenital disorder of glycosylation."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      MPI is mainly a cytosolic enzyme (but it can be also localised in the plasma membrane) which catalyses the first step of biosynthesis of nucleotide sugar mannose-GDP, that is, interconversion of fructose-6-phosphate to mannose-6-phosphate (Figure 1A).
    explanation: >-
      The consensus guideline states the enzymatic reaction catalysed by MPI.
      Evidence source is OTHER because this is the review's biochemical
      background synthesis rather than a primary patient observation.
  - reference: PMID:32266963
    reference_title: "Consensus guideline for the diagnosis and management of mannose phosphate isomerase-congenital disorder of glycosylation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      In described MPI-CDG patients, enzyme activities were usually very deficient with activities less than 10% of normal values in both leukocytes and fibroblasts.
    explanation: >-
      Quantifies the residual enzyme activity measured in patients.
  - reference: PMID:9525984
    reference_title: "Carbohydrate-deficient glycoprotein syndrome type Ib. Phosphomannose isomerase deficiency and mannose therapy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Phosphomannose isomerase (PMI) deficiency is the cause of a new type of carbohydrate-deficient glycoprotein syndrome (CDGS). The disorder is caused by mutations in the PMI1 gene.
    explanation: >-
      The founding report establishing PMI deficiency and MPI mutations as the
      cause of the disorder.
  downstream:
  - target: GDP-Mannose Depletion and Impaired Lipid-Linked Oligosaccharide Assembly
    description: >-
      Reduced mannose-6-phosphate supply limits the downstream nucleotide-sugar
      pool required to build the dolichol-linked oligosaccharide precursor.
    causal_link_type: DIRECT
- name: GDP-Mannose Depletion and Impaired Lipid-Linked Oligosaccharide Assembly
  biological_scale: MOLECULAR
  conforms_to: "congenital_disorder_of_glycosylation#ER Lipid-Linked Oligosaccharide Assembly Defect"
  description: >-
    Mannose-6-phosphate is the committed precursor of GDP-mannose, the mannosyl
    donor for assembly of the dolichol-linked (lipid-linked) oligosaccharide in
    the endoplasmic reticulum. In MPI deficiency the endogenous route to
    mannose-6-phosphate fails and dietary mannose is insufficient to compensate
    under ordinary conditions, so lipid-linked oligosaccharide synthesis is
    curtailed and incomplete precursors are transferred to nascent protein -
    the canonical CDG type I lesion. Plasma mannose is under 10 micromol/L in
    patients versus 50-100 micromol/L in healthy individuals. This is the step
    at which exogenous D-mannose therapy re-enters the pathway.
  biological_processes:
  - preferred_term: GDP-mannose biosynthetic process
    modifier: DECREASED
    term:
      id: GO:0009298
      label: GDP-mannose biosynthetic process
  - preferred_term: dolichol-linked oligosaccharide biosynthetic process
    modifier: DECREASED
    term:
      id: GO:0006488
      label: dolichol-linked oligosaccharide biosynthetic process
  cellular_components:
  - preferred_term: endoplasmic reticulum
    term:
      id: GO:0005783
      label: endoplasmic reticulum
  chemical_entities:
  - preferred_term: GDP-mannose
    modifier: DECREASED
    term:
      id: CHEBI:21168
      label: GDP-mannose
  evidence:
  - reference: PMID:22899857
    reference_title: "A zebrafish model of congenital disorders of glycosylation with phosphomannose isomerase deficiency reveals an early opportunity for corrective mannose supplementation."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Synthesis of the lipid-linked oligosaccharide (LLO), which serves as the sugar donor for the N-glycosylation of secretory proteins, requires conversion of fructose-6-phosphate to mannose-6-phosphate via the phosphomannose isomerase (MPI) enzyme.
    explanation: >-
      Places the MPI reaction directly upstream of lipid-linked oligosaccharide
      synthesis. Evidence source is OTHER because this sentence is the paper's
      background statement of the pathway rather than a result from its
      zebrafish experiments.
  - reference: PMID:22899857
    reference_title: "A zebrafish model of congenital disorders of glycosylation with phosphomannose isomerase deficiency reveals an early opportunity for corrective mannose supplementation."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Fluorophore-assisted carbohydrate electrophoresis detected decreased LLO and N-glycans in mpi morphants.
    explanation: >-
      A zebrafish MPI-knockdown model with patient-range residual activity
      directly demonstrates reduced lipid-linked oligosaccharide and N-glycan
      pools. Model-organism evidence, complementing the human biochemistry.
  - reference: PMID:32266963
    reference_title: "Consensus guideline for the diagnosis and management of mannose phosphate isomerase-congenital disorder of glycosylation."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      However, the enzymatic block can be therapeutically bypassed by dietary mannose supplementation
    explanation: >-
      Establishes that this node is the pharmacologically bypassable step, the
      basis of D-mannose therapy.
  downstream:
  - target: Protein Hypoglycosylation
    description: >-
      Incomplete lipid-linked oligosaccharide precursors are transferred to
      nascent glycoproteins, producing systemic hypoglycosylation.
    causal_link_type: DIRECT
- name: Protein Hypoglycosylation
  biological_scale: CELLULAR
  conforms_to: "congenital_disorder_of_glycosylation#Protein Hypoglycosylation"
  role: central_effector
  description: >-
    Many secreted and membrane glycoproteins carry absent or truncated N-glycans.
    The readout is the classic CDG type I serum transferrin pattern - reduced
    tetrasialotransferrin with increased disialo- and asialotransferrin - which
    is 100% sensitive but biochemically indistinguishable from PMM2-CDG and other
    type I disorders. Because glycosylation modifies a large fraction of the
    secreted proteome, this single lesion degrades many unrelated proteins at
    once, and the specific organ pattern of MPI-CDG reflects which client
    glycoproteins are rate-limiting rather than any tissue-restricted expression
    of MPI.
  biological_processes:
  - preferred_term: protein N-linked glycosylation
    modifier: DECREASED
    term:
      id: GO:0006487
      label: protein N-linked glycosylation
  cell_types:
  - preferred_term: Hepatocyte
    term:
      id: CL:0000182
      label: hepatocyte
  - preferred_term: Enterocyte
    term:
      id: CL:0000584
      label: enterocyte
  evidence:
  - reference: PMID:32266963
    reference_title: "Consensus guideline for the diagnosis and management of mannose phosphate isomerase-congenital disorder of glycosylation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      MPI-CDG can be biochemically characterised by a decreased level of the major tetrasialylated transferrin (Trf) glycoform (tetrasialotransferrin) and an increase of disialotransferrin and asialotransferrin, that is, CDG type I pattern.
    explanation: >-
      Documents systemic protein hypoglycosylation via the transferrin readout.
  - reference: PMID:10980531
    reference_title: "Genomic organization of the human phosphomannose isomerase (MPI) gene and mutation analysis in patients with congenital disorders of glycosylation type Ib (CDG-Ib)."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The symptoms result from hypoglycosylation of serum- and other glycoproteins.
    explanation: >-
      States explicitly that the clinical phenotype is downstream of
      glycoprotein hypoglycosylation.
  downstream:
  - target: Enterocyte Glycoprotein Deficit and Protein-Losing Enteropathy
    description: >-
      Hypoglycosylation of enterocyte surface glycoproteins is the proposed
      mechanism of intestinal barrier failure and enteric protein loss.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - loss of intestinal epithelial barrier integrity
    - intestinal lymphangiectasia
  - target: Hypoglycosylation of Coagulation Factors and Inhibitors
    description: >-
      Antithrombin, protein C, protein S and factor XI are N-glycoproteins whose
      plasma levels fall when glycosylation is impaired.
    causal_link_type: DIRECT
  - target: Hyperinsulinaemic Hypoglycaemia
    description: >-
      Hypoglycosylation is proposed to alter beta-cell insulin secretion,
      although the precise mechanism remains unresolved.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Hepatic Ductal Plate Malformation and Progressive Fibrosis
    description: >-
      Prenatal and early hypoglycosylation is associated with a developmental
      biliary lesion and progressive fibrosis that, unlike the other arms, does
      not reverse with mannose.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Multisystem Glycoprotein Dysfunction with Neurologic Sparing
    description: >-
      The convergent multisystem outflow of proteome-wide hypoglycosylation,
      distinguished in MPI-CDG by the near-absence of neurologic involvement.
    causal_link_type: DIRECT
- name: Enterocyte Glycoprotein Deficit and Protein-Losing Enteropathy
  biological_scale: TISSUE
  description: >-
    Loss of intestinal wall integrity, attributed to reduced glycoproteins on the
    enterocyte membrane and/or intestinal lymphangiectasia, produces
    protein-losing enteropathy with hypoalbuminaemia, oedema, diarrhoea and
    secondary hypogammaglobulinaemia. Duodenal biopsy may show mild villous
    atrophy and lymphangiectasia, and both the clinical syndrome and the
    histology normalise on mannose.
  cell_types:
  - preferred_term: Enterocyte
    term:
      id: CL:0000584
      label: enterocyte
  evidence:
  - reference: PMID:32266963
    reference_title: "Consensus guideline for the diagnosis and management of mannose phosphate isomerase-congenital disorder of glycosylation."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      The diarrhoea is most commonly due to PLE with resulting hypoalbuminaemia.
    explanation: >-
      Places protein-losing enteropathy causally upstream of the diarrhoea and
      hypoalbuminaemia. Evidence source is OTHER because this is the consensus
      panel's mechanistic interpretation of the pooled case literature.
  - reference: PMID:9525984
    reference_title: "Carbohydrate-deficient glycoprotein syndrome type Ib. Phosphomannose isomerase deficiency and mannose therapy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The clinical phenotype is characterized by protein-losing enteropathy, while neurological manifestations prevailing in other types of CDGS are absent.
    explanation: >-
      The founding report identifies protein-losing enteropathy as the defining
      clinical consequence.
- name: Hypoglycosylation of Coagulation Factors and Inhibitors
  biological_scale: MOLECULAR
  description: >-
    Antithrombin, protein C, protein S and factor XI are all N-glycosylated
    plasma proteins, and their functional levels fall in MPI-CDG. The result is a
    mixed coagulopathy affecting both procoagulant and anticoagulant arms, so the
    same patient may thrombose and bleed. Antithrombin deficiency dominates, and
    the deficits are exacerbated by intercurrent protein-losing enteropathy
    episodes, dehydration and infection.
  biological_processes:
  - preferred_term: blood coagulation
    modifier: ABNORMAL
    term:
      id: GO:0007596
      label: blood coagulation
  evidence:
  - reference: PMID:32266963
    reference_title: "Consensus guideline for the diagnosis and management of mannose phosphate isomerase-congenital disorder of glycosylation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Coagulopathy with typical pattern affecting both procoagulant and anticoagulant factors is reported in almost all patients, with mainly antithrombin (AT) deficiency.
    explanation: >-
      Establishes the near-universal mixed coagulopathy and its dominant
      antithrombin component.
  - reference: PMID:30545931
    reference_title: "MPI-CDG with transient hypoglycosylation and antithrombin deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Congenital disorders of glycosylation (CDG), a rare disease, are actually usually associated with antithrombin deficiency.
    explanation: >-
      Links the glycosylation defect to antithrombin deficiency as the
      characteristic coagulation lesion of CDG, the molecular basis for this
      node.
  downstream:
  - target: Thrombotic and Haemorrhagic Complications
    description: >-
      The imbalance of procoagulant and anticoagulant glycoproteins destabilises
      haemostasis in both directions.
    causal_link_type: DIRECT
- name: Thrombotic and Haemorrhagic Complications
  biological_scale: ORGANISM
  description: >-
    Thrombosis typically complicates intercurrent infection or dehydration and is
    most often deep venous thrombosis of the lower limbs, but cerebral venous
    sinus thrombosis, pulmonary embolism and intracardiac thrombus are reported
    and may be the presenting event. Bleeding is less frequent but can be
    life-threatening, chiefly diffuse intestinal bleeding or variceal
    haemorrhage.
  evidence:
  - reference: PMID:32266963
    reference_title: "Consensus guideline for the diagnosis and management of mannose phosphate isomerase-congenital disorder of glycosylation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Thrombotic events often complicate acute infections and dehydration episodes. These are mainly deep vein thromboses of the lower extremities.
    explanation: >-
      Describes the triggers and typical site of thrombosis in the pooled
      cohort.
  - reference: PMID:32905087
    reference_title: "Mannose phosphate isomerase deficiency-congenital disorder of glycosylation (MPI-CDG) with cerebral venous sinus thrombosis as first and only presenting symptom: A rare but treatable cause of thrombophilia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      In summary, we present the first MPI-CDG patient with severe cerebral venous sinus thrombosis as first and only symptom of disease manifestation.
    explanation: >-
      Demonstrates that the thrombotic arm alone can constitute the entire
      clinical presentation.
- name: Hyperinsulinaemic Hypoglycaemia
  biological_scale: ORGANISM
  description: >-
    Hypoglycaemia affects most patients and is most often hyperinsulinaemic. The
    mechanism is unresolved; hypoglycosylation of beta-cell membrane proteins
    such as the sulfonylurea receptor SUR1 has been proposed, supported by
    altered insulin secretion in hypoglycosylated murine beta cells. A minority
    of patients are hypoglycaemic without hyperinsulinism. Hypoglycaemia responds
    to mannose in both groups.
  cell_types:
  - preferred_term: Pancreatic beta cell
    term:
      id: CL:0000169
      label: type B pancreatic cell
  biological_processes:
  - preferred_term: positive regulation of insulin secretion
    modifier: ABNORMAL
    term:
      id: GO:0032024
      label: positive regulation of insulin secretion
  evidence:
  - reference: PMID:32266963
    reference_title: "Consensus guideline for the diagnosis and management of mannose phosphate isomerase-congenital disorder of glycosylation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The most common cause of hypoglycaemia in these patients was hyperinsulinism (HH), which is present in more than two-third of hypoglycaemic patients.
    explanation: >-
      Establishes hyperinsulinism as the predominant hypoglycaemia mechanism.
  - reference: PMID:32266963
    reference_title: "Consensus guideline for the diagnosis and management of mannose phosphate isomerase-congenital disorder of glycosylation."
    supports: PARTIAL
    evidence_source: OTHER
    snippet: >-
      However, the exact cause of HH in CDG patients is still unknown.
    explanation: >-
      Explicitly flags the mechanism of hyperinsulinism as unresolved, so this
      node's proposed beta-cell mechanism is only partially supported.
- name: Hepatic Ductal Plate Malformation and Progressive Fibrosis
  biological_scale: TISSUE
  description: >-
    Essentially all patients have some degree of liver involvement. The
    characteristic lesion is a developmental one - an excess of dilated bile duct
    structures in a ductal plate configuration, mimicking congenital hepatic
    fibrosis, together with hepatomegaly, fibrosis and sometimes steatosis.
    Because it is a congenital/developmental abnormality rather than an ongoing
    glycosylation-dependent process, it does not reverse with mannose and can
    progress to portal hypertension, oesophageal varices and hepatopulmonary
    syndrome. This mannose-refractory arm is the principal determinant of
    long-term morbidity.
  cell_types:
  - preferred_term: Hepatocyte
    term:
      id: CL:0000182
      label: hepatocyte
  evidence:
  - reference: PMID:32266963
    reference_title: "Consensus guideline for the diagnosis and management of mannose phosphate isomerase-congenital disorder of glycosylation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      However, the most characteristic lesion mimics those seen in congenital hepatic fibrosis, with an excess of dilated bile duct structures in ductal plate configuration in the portal tracts
    explanation: >-
      Identifies the characteristic hepatic histopathology.
  - reference: PMID:32266963
    reference_title: "Consensus guideline for the diagnosis and management of mannose phosphate isomerase-congenital disorder of glycosylation."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      As the typical histological lesions represent congenital/developmental abnormalities of the liver (ie, ductal plate malformation), they do not respond to mannose therapy.
    explanation: >-
      States the mechanistic reason the hepatic arm is refractory to mannose.
  - reference: PMID:33098580
    reference_title: "Long term outcome of MPI-CDG patients on D-mannose therapy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Liver fibrosis persisted despite treatment, but two patients showed improved liver architecture during follow-up.
    explanation: >-
      Long-term treated follow-up confirms persistence of fibrosis on therapy.
- name: Multisystem Glycoprotein Dysfunction with Neurologic Sparing
  biological_scale: ORGANISM
  conforms_to: "congenital_disorder_of_glycosylation#Multisystem Glycoprotein Dysfunction"
  role: consequence
  description: >-
    The convergent multisystem outflow of hypoglycosylation in MPI-CDG is
    hepatic, gastrointestinal, endocrine, coagulation and immune, but - unlike
    almost every other CDG - not neurologic. Cognitive development and brain
    imaging are typically normal, cerebellar hypoplasia is absent, and the
    dysmorphic, fat-pad, inverted-nipple and skeletal features of PMM2-CDG do not
    occur. A proposed explanation is that circulating maternal and dietary
    mannose partially rescues glycosylation in developing cerebral tissue,
    consistent with the zebrafish finding that mannose rescue is effective only
    within an early developmental window.
  biological_processes:
  - preferred_term: protein N-linked glycosylation
    modifier: ABNORMAL
    term:
      id: GO:0006487
      label: protein N-linked glycosylation
  evidence:
  - reference: PMID:32266963
    reference_title: "Consensus guideline for the diagnosis and management of mannose phosphate isomerase-congenital disorder of glycosylation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      In contrast with PMM2-CDG, facial dysmorphia, atypical fat pads, inverted nipples, and skeletal deformities are not present in MPI-CDG patients.
    explanation: >-
      Documents the absence of the classic CDG dysmorphic pattern in MPI-CDG.
  - reference: PMID:32266963
    reference_title: "Consensus guideline for the diagnosis and management of mannose phosphate isomerase-congenital disorder of glycosylation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      no cerebellar hypoplasia was noted, as it is typical in other CDG.
    explanation: >-
      Neuroimaging in reported patients shows the absence of the cerebellar
      hypoplasia characteristic of other CDG subtypes.
  - reference: PMID:32266963
    reference_title: "Consensus guideline for the diagnosis and management of mannose phosphate isomerase-congenital disorder of glycosylation."
    supports: PARTIAL
    evidence_source: OTHER
    snippet: >-
      The exogenous mannose pathway is also a possible explanation for the absence of developmental impairment in MPI-CDG as circulating maternal mannose reduces the prenatal glycosylation defect in cerebral tissues.
    explanation: >-
      The maternal-mannose rescue account of neurologic sparing is presented by
      the consensus panel as a hypothesis, hence PARTIAL support.
- name: Mannose-6-Phosphate Accumulation and Energy Failure on Excess Mannose
  biological_scale: MOLECULAR
  description: >-
    An iatrogenic mechanism specific to MPI deficiency: because
    mannose-6-phosphate cannot be isomerised back to fructose-6-phosphate, an
    excessive mannose load (notably intravenous mannose) allows intracellular
    mannose-6-phosphate to accumulate. Mannose-6-phosphate inhibits hexokinase,
    phosphoglucose isomerase and glucose-6-phosphate dehydrogenase, suppressing
    glycolysis and depleting ATP - the "honeybee effect". This underlies
    reported seizures and stupor during intravenous mannose therapy and the
    paradoxical worsening of Mpi-null mouse embryos given mannose, and is the
    reason intravenous mannose is not recommended for stable patients.
  chemical_entities:
  - preferred_term: D-mannose 6-phosphate
    modifier: INCREASED
    term:
      id: CHEBI:17369
      label: D-mannose 6-phosphate
  evidence:
  - reference: PMID:16339137
    reference_title: "Ablation of mouse phosphomannose isomerase (Mpi) causes mannose 6-phosphate accumulation, toxicity, and embryonic lethality."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Our results in vitro suggest that mannose toxicity in Mpi(-/-) embryos is caused by Man-6-P accumulation, which inhibits glucose metabolism and depletes intracellular ATP.
    explanation: >-
      The Mpi-null mouse establishes the mechanism of mannose-6-phosphate
      toxicity. Model-organism evidence; the human counterpart is the
      intravenous-mannose case report below.
  - reference: PMID:16339137
    reference_title: "Ablation of mouse phosphomannose isomerase (Mpi) causes mannose 6-phosphate accumulation, toxicity, and embryonic lethality."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      In cell lysates, Man-6-P inhibited hexokinase (70%), phosphoglucose isomerase (65%), and glucose-6-phosphate dehydrogenase (85%), but not phosphofructokinase.
    explanation: >-
      Biochemical assays identify the specific glycolytic enzymes inhibited by
      mannose-6-phosphate.
  - reference: PMID:21240668
    reference_title: "Seizures and stupor during intravenous mannose therapy in a patient with CDG syndrome type 1b (MPI-CDG)."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We caution that, in patients with MPI-CDG, life-threatening central nervous system disturbances may occur with intravenous mannose treatment.
    explanation: >-
      Human clinical confirmation that intravenous mannose can cause severe
      neurological deterioration in MPI-CDG.
phenotypes:
- name: Protein-losing enteropathy
  category: Gastrointestinal
  frequency: VERY_FREQUENT
  description: >-
    Enteric protein loss with hypoalbuminaemia is the cardinal and often
    presenting manifestation of MPI-CDG, and was the feature that defined the
    disorder. Faecal alpha-1-antitrypsin is elevated 3- to 20-fold when measured.
  phenotype_term:
    preferred_term: Protein-losing enteropathy
    term:
      id: HP:0002243
      label: Protein-losing enteropathy
  evidence:
  - reference: PMID:9525984
    reference_title: "Carbohydrate-deficient glycoprotein syndrome type Ib. Phosphomannose isomerase deficiency and mannose therapy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The clinical phenotype is characterized by protein-losing enteropathy, while neurological manifestations prevailing in other types of CDGS are absent.
    explanation: >-
      The founding report defines protein-losing enteropathy as the
      characteristic phenotype.
  - reference: PMID:37124179
    reference_title: "Mannose phosphate isomerase gene mutation leads to a congenital disorder of glycosylation: A rare case report and literature review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      chronic diarrhea (41/46), vomiting (23/27), hepatomegaly (39/44), hepatic fibrosis (20/37), protein-losing enteropathy (30/36), elevated serum transaminases (24/34), hyperinsulinemic-hypoglycemia (24/34), hypoalbuminemia (33/38), prolonged coagulation (26/30), splenomegaly (13/21), non-pitting edema (14/20), failure to thrive (13/36), portal hypertension (4/9), epilepsy (2/17), thrombosis (12/14), and abnormally elevated leukocytes (5)
    explanation: >-
      Protein-losing enteropathy in 30/36 assessed patients (83%) supports the
      VERY_FREQUENT band (80-100%).
- name: Hypoalbuminemia
  category: Gastrointestinal
  frequency: VERY_FREQUENT
  description: >-
    Hypoalbuminaemia is the biochemical consequence of enteric protein loss and
    can be severe enough to require repeated intravenous albumin infusions.
  phenotype_term:
    preferred_term: Hypoalbuminemia
    term:
      id: HP:0003073
      label: Hypoalbuminemia
  evidence:
  - reference: PMID:32266963
    reference_title: "Consensus guideline for the diagnosis and management of mannose phosphate isomerase-congenital disorder of glycosylation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The diarrhoea is most commonly due to PLE with resulting hypoalbuminaemia.
    explanation: >-
      Directly links protein-losing enteropathy to hypoalbuminaemia.
  - reference: PMID:37124179
    reference_title: "Mannose phosphate isomerase gene mutation leads to a congenital disorder of glycosylation: A rare case report and literature review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      hypoalbuminemia (33/38), prolonged coagulation (26/30), splenomegaly (13/21), non-pitting edema (14/20), failure to thrive (13/36)
    explanation: >-
      Hypoalbuminaemia in 33/38 assessed patients (87%) supports the
      VERY_FREQUENT band.
- name: Edema
  category: Gastrointestinal
  frequency: FREQUENT
  description: >-
    Oedema, characteristically non-pitting and up to anasarca in the earliest
    described cluster of patients, results from the hypoalbuminaemia of
    protein-losing enteropathy.
  phenotype_term:
    preferred_term: Edema
    term:
      id: HP:0000969
      label: Edema
  evidence:
  - reference: PMID:37124179
    reference_title: "Mannose phosphate isomerase gene mutation leads to a congenital disorder of glycosylation: A rare case report and literature review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      hypoalbuminemia (33/38), prolonged coagulation (26/30), splenomegaly (13/21), non-pitting edema (14/20), failure to thrive (13/36)
    explanation: >-
      Non-pitting oedema in 14/20 assessed patients (70%) supports the FREQUENT
      band (30-79%).
  - reference: PMID:22899857
    reference_title: "A zebrafish model of congenital disorders of glycosylation with phosphomannose isomerase deficiency reveals an early opportunity for corrective mannose supplementation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Individuals who are deficient in MPI present with bleeding, diarrhea, edema, gastrointestinal bleeding and liver fibrosis.
    explanation: >-
      This modelling paper's clinical summary of the human disorder lists oedema
      among the presenting features; the quoted statement is about human
      patients, not the zebrafish model.
- name: Chronic diarrhea
  category: Gastrointestinal
  frequency: VERY_FREQUENT
  description: >-
    Diarrhoea is the single most common gastrointestinal symptom and may be
    isolated or, more often, combined with vomiting; episodes leading to
    dehydration frequently require hospital admission.
  phenotype_term:
    preferred_term: Chronic diarrhea
    term:
      id: HP:0002028
      label: Chronic diarrhea
    temporality: CHRONIC
  evidence:
  - reference: PMID:32266963
    reference_title: "Consensus guideline for the diagnosis and management of mannose phosphate isomerase-congenital disorder of glycosylation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Diarrhoea is the most common gastrointestinal symptom.
    explanation: >-
      Establishes diarrhoea as the leading gastrointestinal feature.
  - reference: PMID:37124179
    reference_title: "Mannose phosphate isomerase gene mutation leads to a congenital disorder of glycosylation: A rare case report and literature review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      chronic diarrhea (41/46), vomiting (23/27), hepatomegaly (39/44), hepatic fibrosis (20/37), protein-losing enteropathy (30/36)
    explanation: >-
      Chronic diarrhoea in 41/46 assessed patients (89%) supports the
      VERY_FREQUENT band.
- name: Episodic vomiting
  category: Gastrointestinal
  frequency: VERY_FREQUENT
  description: >-
    Recurrent, sometimes cyclic vomiting is a characteristic presenting symptom
    and typically accompanies the diarrhoea.
  phenotype_term:
    preferred_term: Episodic vomiting
    term:
      id: HP:0002572
      label: Episodic vomiting
    temporality: RECURRENT
  evidence:
  - reference: PMID:32266963
    reference_title: "Consensus guideline for the diagnosis and management of mannose phosphate isomerase-congenital disorder of glycosylation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The presenting symptoms were mainly combination of gastrointestinal involvement (cyclic vomiting, PLE and failure to thrive, n = 26), hypoglycaemia (n = 15), hepatic involvement (elevation of transaminases, hepatomegaly, liver fibrosis, n = 14), and coagulation complications (laboratory coagulopathy, thrombosis, intestinal bleeding, n = 7).
    explanation: >-
      Cyclic vomiting is named among the presenting gastrointestinal features.
  - reference: PMID:37124179
    reference_title: "Mannose phosphate isomerase gene mutation leads to a congenital disorder of glycosylation: A rare case report and literature review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      chronic diarrhea (41/46), vomiting (23/27), hepatomegaly (39/44)
    explanation: >-
      Vomiting in 23/27 assessed patients (85%) supports the VERY_FREQUENT band.
- name: Villous atrophy
  category: Gastrointestinal
  description: >-
    Duodenal biopsy, when performed, may show mild villous atrophy, which
    normalises histologically after mannose treatment. Biopsy can nevertheless be
    normal even in patients with documented protein-losing enteropathy, so
    frequency is not stated.
  phenotype_term:
    preferred_term: Villous atrophy
    term:
      id: HP:0011473
      label: Villous atrophy
    severity: MILD
  evidence:
  - reference: PMID:32266963
    reference_title: "Consensus guideline for the diagnosis and management of mannose phosphate isomerase-congenital disorder of glycosylation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Duodenal biopsies, when performed, reveal a mild villous atrophy
    explanation: >-
      Documents the duodenal histology reported in MPI-CDG.
- name: Intestinal lymphangiectasia
  category: Gastrointestinal
  description: >-
    Intestinal lymphangiectasia is reported less frequently than villous atrophy
    and is one of the two proposed mechanisms of enteric protein loss.
  phenotype_term:
    preferred_term: Intestinal lymphangiectasia
    term:
      id: HP:0002593
      label: Intestinal lymphangiectasia
  evidence:
  - reference: PMID:32266963
    reference_title: "Consensus guideline for the diagnosis and management of mannose phosphate isomerase-congenital disorder of glycosylation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      and less frequently lymphangiectasia.
    explanation: >-
      Reports lymphangiectasia on duodenal biopsy in a subset of patients.
- name: Failure to thrive
  category: Growth
  frequency: FREQUENT
  description: >-
    Malnutrition and failure to thrive follow the recurrent vomiting and
    diarrhoea; severe cases require nasogastric, gastrostomy or parenteral
    feeding.
  phenotype_term:
    preferred_term: Failure to thrive
    term:
      id: HP:0001508
      label: Failure to thrive
  evidence:
  - reference: PMID:32266963
    reference_title: "Consensus guideline for the diagnosis and management of mannose phosphate isomerase-congenital disorder of glycosylation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The gastrointestinal impairment often leads to malnutrition/failure to thrive, which were reported in two-thirds of patients, although the anthropometric measurements were available in only half of them.
    explanation: >-
      "Two-thirds of patients" maps to the FREQUENT band (30-79%).
  - reference: PMID:37124179
    reference_title: "Mannose phosphate isomerase gene mutation leads to a congenital disorder of glycosylation: A rare case report and literature review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      non-pitting edema (14/20), failure to thrive (13/36), portal hypertension (4/9)
    explanation: >-
      Failure to thrive in 13/36 assessed patients (36%) in the larger review
      also falls in the FREQUENT band, at its lower end.
- name: Growth delay
  category: Growth
  frequency: OCCASIONAL
  description: >-
    Growth restriction independent of failure to thrive is documented in a
    minority of patients and has been attributed to hypoglycosylation of
    IGFBP-3 and the acid-labile subunit, with catch-up growth on mannose.
  phenotype_term:
    preferred_term: Growth delay
    term:
      id: HP:0001510
      label: Growth delay
  evidence:
  - reference: PMID:32266963
    reference_title: "Consensus guideline for the diagnosis and management of mannose phosphate isomerase-congenital disorder of glycosylation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Growth restriction was documented in four patients.
    explanation: >-
      Four of the 35 reviewed patients (approximately 11%) maps to the
      OCCASIONAL band (5-29%).
- name: Hepatomegaly
  category: Hepatic
  frequency: VERY_FREQUENT
  description: >-
    Hepatomegaly is the most common clinical hepatic sign, sometimes accompanied
    by splenomegaly appearing during the first year of life.
  phenotype_term:
    preferred_term: Hepatomegaly
    term:
      id: HP:0002240
      label: Hepatomegaly
  evidence:
  - reference: PMID:32266963
    reference_title: "Consensus guideline for the diagnosis and management of mannose phosphate isomerase-congenital disorder of glycosylation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Hepatomegaly is the most common clinical sign, sometimes associated with splenomegaly that is not initially present in the case of early diagnosis, but that appears in the first year of life.
    explanation: >-
      Names hepatomegaly as the most common hepatic sign.
  - reference: PMID:37124179
    reference_title: "Mannose phosphate isomerase gene mutation leads to a congenital disorder of glycosylation: A rare case report and literature review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      chronic diarrhea (41/46), vomiting (23/27), hepatomegaly (39/44), hepatic fibrosis (20/37)
    explanation: >-
      Hepatomegaly in 39/44 assessed patients (89%) supports the VERY_FREQUENT
      band.
- name: Hepatic fibrosis
  category: Hepatic
  frequency: FREQUENT
  description: >-
    Liver fibrosis is a defining and progressive feature. Unlike the digestive,
    hypoglycaemic and coagulation manifestations, it does not respond to mannose
    and may advance to cirrhosis with its attendant complications.
  phenotype_term:
    preferred_term: Hepatic fibrosis
    term:
      id: HP:0001395
      label: Hepatic fibrosis
    clinical_course: PROGRESSIVE
  evidence:
  - reference: PMID:32266963
    reference_title: "Consensus guideline for the diagnosis and management of mannose phosphate isomerase-congenital disorder of glycosylation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Liver involvement in MPI-CDG is one of the most common features. Patients often present with mild hepatopathy, hepatomegaly, and hepatic fibrosis.
    explanation: >-
      Names hepatic fibrosis among the common hepatic features.
  - reference: PMID:37124179
    reference_title: "Mannose phosphate isomerase gene mutation leads to a congenital disorder of glycosylation: A rare case report and literature review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      hepatomegaly (39/44), hepatic fibrosis (20/37), protein-losing enteropathy (30/36)
    explanation: >-
      Hepatic fibrosis in 20/37 assessed patients (54%) supports the FREQUENT
      band.
  - reference: PMID:33098580
    reference_title: "Long term outcome of MPI-CDG patients on D-mannose therapy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Liver fibrosis persisted despite treatment, but two patients showed improved liver architecture during follow-up.
    explanation: >-
      Confirms persistence and progression of fibrosis under treatment.
- name: Malformation of the hepatic ductal plate
  category: Hepatic
  description: >-
    The most characteristic hepatic lesion is an excess of dilated bile duct
    structures in ductal plate configuration in the portal tracts, mimicking
    congenital hepatic fibrosis; von Meyenburg complexes have also been
    described.
  phenotype_term:
    preferred_term: Malformation of the hepatic ductal plate
    term:
      id: HP:0006563
      label: Malformation of the hepatic ductal plate
  evidence:
  - reference: PMID:32266963
    reference_title: "Consensus guideline for the diagnosis and management of mannose phosphate isomerase-congenital disorder of glycosylation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      However, the most characteristic lesion mimics those seen in congenital hepatic fibrosis, with an excess of dilated bile duct structures in ductal plate configuration in the portal tracts
    explanation: >-
      Directly describes the ductal plate malformation on liver biopsy.
- name: Elevated circulating hepatic transaminase concentration
  category: Hepatic
  frequency: FREQUENT
  description: >-
    Transaminases are commonly, usually mildly, elevated, but can rise 30- to
    40-fold during acute decompensation and may also be normal despite
    established liver involvement. GGT and bilirubin are often normal, giving a
    characteristic pattern.
  phenotype_term:
    preferred_term: Elevated circulating hepatic transaminase concentration
    term:
      id: HP:0002910
      label: Elevated circulating hepatic transaminase concentration
  evidence:
  - reference: PMID:37124179
    reference_title: "Mannose phosphate isomerase gene mutation leads to a congenital disorder of glycosylation: A rare case report and literature review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      protein-losing enteropathy (30/36), elevated serum transaminases (24/34), hyperinsulinemic-hypoglycemia (24/34)
    explanation: >-
      Elevated transaminases in 24/34 assessed patients (71%) supports the
      FREQUENT band.
  - reference: PMID:32266963
    reference_title: "Consensus guideline for the diagnosis and management of mannose phosphate isomerase-congenital disorder of glycosylation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Gamma-glutamyl transferase (GGT) and bilirubin levels are often normal.
    explanation: >-
      Documents the sparing of GGT and bilirubin that defines the characteristic
      liver-enzyme pattern.
- name: Portal hypertension
  category: Hepatic
  description: >-
    Portal hypertension is the main hepatic complication in adulthood and may be
    accompanied by oesophageal varices or, rarely, hepatopulmonary syndrome. It
    develops despite mannose therapy and warrants lifelong surveillance. A
    frequency band is deliberately omitted: the consensus guideline calls it a
    "rare but serious" complication, whereas the 2023 review reports 4/9 among
    the few patients in whom it was specifically assessed, an
    ascertainment-biased denominator.
  phenotype_term:
    preferred_term: Portal hypertension
    term:
      id: HP:0001409
      label: Portal hypertension
  evidence:
  - reference: PMID:32266963
    reference_title: "Consensus guideline for the diagnosis and management of mannose phosphate isomerase-congenital disorder of glycosylation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The rare but serious complications are portal hypertension with or without oesophageal varices and hepatopulmonary syndrome.
    explanation: >-
      Identifies portal hypertension as an uncommon but serious hepatic
      complication.
  - reference: PMID:33098580
    reference_title: "Long term outcome of MPI-CDG patients on D-mannose therapy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      On treatment, two patients developed severe portal hypertension, two developed venous thrombosis, and 1 displayed altered kidney function.
    explanation: >-
      Two of nine treated patients developed severe portal hypertension during
      long-term follow-up.
- name: Esophageal varix
  category: Hepatic
  description: >-
    Oesophageal varices arise from portal hypertension and, with diffuse
    intestinal bleeding, constitute the principal fatal haemorrhagic risk.
  phenotype_term:
    preferred_term: Esophageal varix
    term:
      id: HP:0002040
      label: Esophageal varix
  evidence:
  - reference: PMID:32266963
    reference_title: "Consensus guideline for the diagnosis and management of mannose phosphate isomerase-congenital disorder of glycosylation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The main complication in adulthood is the portal hypertension with oesophageal varices.
    explanation: >-
      Names oesophageal varices as the adult hepatic complication.
- name: Splenomegaly
  category: Hepatic
  frequency: FREQUENT
  description: >-
    Splenomegaly accompanies hepatomegaly in many patients and, with
    thrombocytopenia, is a clinical marker of developing portal hypertension.
  phenotype_term:
    preferred_term: Splenomegaly
    term:
      id: HP:0001744
      label: Splenomegaly
  evidence:
  - reference: PMID:37124179
    reference_title: "Mannose phosphate isomerase gene mutation leads to a congenital disorder of glycosylation: A rare case report and literature review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      prolonged coagulation (26/30), splenomegaly (13/21), non-pitting edema (14/20)
    explanation: >-
      Splenomegaly in 13/21 assessed patients (62%) supports the FREQUENT band.
  - reference: PMID:32266963
    reference_title: "Consensus guideline for the diagnosis and management of mannose phosphate isomerase-congenital disorder of glycosylation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Hepatomegaly is the most common clinical sign, sometimes associated with splenomegaly that is not initially present in the case of early diagnosis, but that appears in the first year of life.
    explanation: >-
      Documents splenomegaly appearing during the first year of life.
- name: Hepatic steatosis
  category: Hepatic
  frequency: OCCASIONAL
  description: >-
    Steatosis is reported on liver biopsy in a subset of patients alongside
    fibrosis.
  phenotype_term:
    preferred_term: Hepatic steatosis
    term:
      id: HP:0001397
      label: Hepatic steatosis
  evidence:
  - reference: PMID:32266963
    reference_title: "Consensus guideline for the diagnosis and management of mannose phosphate isomerase-congenital disorder of glycosylation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      or steatosis.
    explanation: >-
      Steatosis is cited on liver biopsy for three of the reviewed patients
      (approximately 9%), consistent with the OCCASIONAL band.
- name: Hypoglycemia
  category: Endocrine
  frequency: FREQUENT
  description: >-
    Hypoglycaemia is observed in the majority of patients, usually first in
    infancy, and can be the presenting or even the only sign. It may be
    asymptomatic or cause seizures, unresponsiveness and apnoea.
  phenotype_term:
    preferred_term: Hypoglycemia
    term:
      id: HP:0001943
      label: Hypoglycemia
  evidence:
  - reference: PMID:32266963
    reference_title: "Consensus guideline for the diagnosis and management of mannose phosphate isomerase-congenital disorder of glycosylation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Hypoglycaemia has been observed in the majority of reported MPI-CDG patients.
    explanation: >-
      "Majority" maps to the FREQUENT band (30-79%).
  - reference: PMID:32266963
    reference_title: "Consensus guideline for the diagnosis and management of mannose phosphate isomerase-congenital disorder of glycosylation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Hypoglycaemia is frequently associated with MPI-CDG and, it can be a presenting and rarely even the only sign.
    explanation: >-
      Confirms hypoglycaemia can be the sole presenting manifestation.
- name: Hyperinsulinemic hypoglycemia
  category: Endocrine
  frequency: FREQUENT
  description: >-
    Hyperinsulinism accounts for more than two-thirds of hypoglycaemia in
    MPI-CDG. It responds to mannose and, when needed, to diazoxide.
  phenotype_term:
    preferred_term: Hyperinsulinemic hypoglycemia
    term:
      id: HP:0000825
      label: Hyperinsulinemic hypoglycemia
  evidence:
  - reference: PMID:32266963
    reference_title: "Consensus guideline for the diagnosis and management of mannose phosphate isomerase-congenital disorder of glycosylation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The most common cause of hypoglycaemia in these patients was hyperinsulinism (HH), which is present in more than two-third of hypoglycaemic patients.
    explanation: >-
      Hyperinsulinism in more than two-thirds of the hypoglycaemic patients.
  - reference: PMID:37124179
    reference_title: "Mannose phosphate isomerase gene mutation leads to a congenital disorder of glycosylation: A rare case report and literature review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      elevated serum transaminases (24/34), hyperinsulinemic-hypoglycemia (24/34), hypoalbuminemia (33/38)
    explanation: >-
      Hyperinsulinaemic hypoglycaemia in 24/34 assessed patients (71%) supports
      the FREQUENT band.
- name: Reduced antithrombin III activity
  category: Hematologic
  frequency: VERY_FREQUENT
  description: >-
    Antithrombin deficiency is the dominant coagulation abnormality of MPI-CDG
    and reflects hypoglycosylation of this heavily N-glycosylated inhibitor. It
    can be the diagnostic clue in an otherwise unexplained thrombophilia.
  phenotype_term:
    preferred_term: Reduced antithrombin III activity
    term:
      id: HP:0001976
      label: Reduced antithrombin III activity
  evidence:
  - reference: PMID:32266963
    reference_title: "Consensus guideline for the diagnosis and management of mannose phosphate isomerase-congenital disorder of glycosylation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Coagulopathy with typical pattern affecting both procoagulant and anticoagulant factors is reported in almost all patients, with mainly antithrombin (AT) deficiency.
    explanation: >-
      "Almost all patients" maps to the VERY_FREQUENT band (80-100%), with
      antithrombin named as the principal deficiency.
  - reference: PMID:37124179
    reference_title: "Mannose phosphate isomerase gene mutation leads to a congenital disorder of glycosylation: A rare case report and literature review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      hypoalbuminemia (33/38), prolonged coagulation (26/30), splenomegaly (13/21)
    explanation: >-
      Prolonged coagulation in 26/30 assessed patients (87%) corroborates the
      VERY_FREQUENT band for the coagulopathy of which antithrombin deficiency
      is the dominant component.
  - reference: PMID:32905087
    reference_title: "Mannose phosphate isomerase deficiency-congenital disorder of glycosylation (MPI-CDG) with cerebral venous sinus thrombosis as first and only presenting symptom: A rare but treatable cause of thrombophilia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      CDG screening should be included into the routine diagnostic work‐up in all patients presenting with unexplained coagulation disorder, especially when comprising AT deficiency.
    explanation: >-
      Reinforces antithrombin deficiency as the characteristic and
      diagnostically actionable coagulation abnormality.
- name: Reduced protein C activity
  category: Hematologic
  frequency: FREQUENT
  description: >-
    Protein C deficiency is frequently observed alongside antithrombin
    deficiency; protein S can also be reduced.
  phenotype_term:
    preferred_term: Reduced protein C activity
    term:
      id: HP:0005543
      label: Reduced protein C activity
  evidence:
  - reference: PMID:32266963
    reference_title: "Consensus guideline for the diagnosis and management of mannose phosphate isomerase-congenital disorder of glycosylation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Deficit in protein C (PC) and in factor XI (FXI) is also frequently observed, and protein S (PS) can also be decreased.
    explanation: >-
      "Frequently observed" maps to the FREQUENT band.
- name: Reduced factor XI activity
  category: Hematologic
  frequency: FREQUENT
  description: >-
    Factor XI deficiency is part of the characteristic mixed MPI-CDG
    coagulopathy and is a specific perioperative consideration, since factor XI
    concentrate and recombinant factor VIIa are not recommended because of
    thrombotic risk.
  phenotype_term:
    preferred_term: Reduced factor XI activity
    term:
      id: HP:0001929
      label: Reduced factor XI activity
  evidence:
  - reference: PMID:32266963
    reference_title: "Consensus guideline for the diagnosis and management of mannose phosphate isomerase-congenital disorder of glycosylation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Deficit in protein C (PC) and in factor XI (FXI) is also frequently observed, and protein S (PS) can also be decreased.
    explanation: >-
      "Frequently observed" maps to the FREQUENT band.
- name: Deep venous thrombosis
  category: Hematologic
  description: >-
    Thrombosis, most often deep venous thrombosis of the lower limbs, typically
    complicates intercurrent infection or dehydration and may be multiple and
    recurrent. No thrombotic events have been reported in patients maintained on
    mannose. A frequency band is omitted because the available denominators
    conflict: overt coagulation complications were the presenting feature in only
    7 of 35 patients in the consensus review, whereas thrombosis was recorded in
    12 of the 14 patients in whom the 2023 review could assess it.
  phenotype_term:
    preferred_term: Deep venous thrombosis
    term:
      id: HP:0002625
      label: Deep venous thrombosis
  evidence:
  - reference: PMID:32266963
    reference_title: "Consensus guideline for the diagnosis and management of mannose phosphate isomerase-congenital disorder of glycosylation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Thrombotic events often complicate acute infections and dehydration episodes. These are mainly deep vein thromboses of the lower extremities.
    explanation: >-
      Identifies deep venous thrombosis as the typical thrombotic event.
  - reference: PMID:37124179
    reference_title: "Mannose phosphate isomerase gene mutation leads to a congenital disorder of glycosylation: A rare case report and literature review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      portal hypertension (4/9), epilepsy (2/17), thrombosis (12/14)
    explanation: >-
      Records thrombosis in 12/14 assessed patients, the higher of the two
      conflicting denominators noted in the description.
- name: Cerebral venous sinus thrombosis
  category: Hematologic
  description: >-
    Cerebral venous sinus thrombosis is a reported thrombotic site and has been
    described as the first and only presenting symptom of MPI-CDG, requiring
    thrombectomy and decompressive surgery.
  phenotype_term:
    preferred_term: Cerebral venous sinus thrombosis
    term:
      id: HP:0033724
      label: Cerebral venous sinus thrombosis
  evidence:
  - reference: PMID:32905087
    reference_title: "Mannose phosphate isomerase deficiency-congenital disorder of glycosylation (MPI-CDG) with cerebral venous sinus thrombosis as first and only presenting symptom: A rare but treatable cause of thrombophilia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      In summary, we present the first MPI-CDG patient with severe cerebral venous sinus thrombosis as first and only symptom of disease manifestation.
    explanation: >-
      Case report documenting cerebral venous sinus thrombosis as the
      presenting event.
- name: Decreased circulating immunoglobulin concentration
  category: Immunologic
  frequency: OCCASIONAL
  description: >-
    Immunoglobulin deficiency secondary to protein-losing enteropathy, with
    reduced IgG but preserved IgA and IgM, is documented in a minority of
    patients.
  phenotype_term:
    preferred_term: Decreased circulating immunoglobulin concentration
    term:
      id: HP:0004313
      label: Decreased circulating immunoglobulin concentration
  evidence:
  - reference: PMID:32266963
    reference_title: "Consensus guideline for the diagnosis and management of mannose phosphate isomerase-congenital disorder of glycosylation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Immunoglobulin deficiency due to PLE (characteristic by decreased levels of IgG but normal levels of IgA and IgM) was described in six patients.
    explanation: >-
      Six of 35 patients (approximately 17%) maps to the OCCASIONAL band.
- name: Recurrent infections
  category: Immunologic
  description: >-
    Recurrent, sometimes unusual infections and febrile episodes with
    leucocytosis and sepsis have been described, though conventional immune
    function studies were normal in the reported cases and a primary
    MPI-specific immunodeficiency is unproven.
  phenotype_term:
    preferred_term: Recurrent infections
    term:
      id: HP:0002719
      label: Recurrent infections
  evidence:
  - reference: PMID:32266963
    reference_title: "Consensus guideline for the diagnosis and management of mannose phosphate isomerase-congenital disorder of glycosylation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      One patient suffered from high frequency of unusual and severe specific infections (HSV encephalitis, bronchiolitis obliterans, cryptosporidial diarrhoea, candidal urinary tract infection) and a high frequency of respiratory infections.
    explanation: >-
      Documents the recurrent-infection phenotype; frequency is deliberately
      omitted because only individual cases are reported.
- name: Type I transferrin isoform profile
  category: Biochemical
  frequency: VERY_FREQUENT
  description: >-
    Serum transferrin isoelectric focusing shows a CDG type I pattern in all
    clinically ascertained patients. The pattern is 100% sensitive but is
    indistinguishable from PMM2-CDG and other type I disorders, so MPI enzyme
    assay and/or MPI sequencing is required for the diagnosis.
  phenotype_term:
    preferred_term: Type I transferrin isoform profile
    term:
      id: HP:0003642
      label: Type I transferrin isoform profile
  evidence:
  - reference: PMID:32266963
    reference_title: "Consensus guideline for the diagnosis and management of mannose phosphate isomerase-congenital disorder of glycosylation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      This pattern is 100% sensitive but non-specific (eg, indistinguishable from PMM2-CDG) and it has been reported in all MPI-CDG patients except those diagnosed post-mortem on basis of symptoms and/or MPI gene analysis in parents or siblings.
    explanation: >-
      Reported in all living ascertained patients, supporting VERY_FREQUENT.
- name: Normal cognitive development
  category: Neurologic
  description: >-
    In sharp contrast with almost all other congenital disorders of
    glycosylation, intellect and psychomotor development are normal in MPI-CDG.
    Mild developmental delay was reported in only four of 35 patients in the
    consensus review and normalised in most; no patient in the 2023 review of 52
    cases had intellectual disability, and brain imaging is unremarkable.
  evidence:
  - reference: PMID:32266963
    reference_title: "Consensus guideline for the diagnosis and management of mannose phosphate isomerase-congenital disorder of glycosylation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      All the remaining patients have normal psychomotor development and intellect.
    explanation: >-
      Confirms preserved cognition in the great majority of patients. No HPO
      term is bound because HPO codes abnormalities, not preserved function.
  - reference: PMID:37124179
    reference_title: "Mannose phosphate isomerase gene mutation leads to a congenital disorder of glycosylation: A rare case report and literature review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      None of the patients was reported to have an intellectual disability (0/28).
    explanation: >-
      Zero of 28 assessed patients had intellectual disability in the expanded
      review.
  - reference: PMID:9525984
    reference_title: "Carbohydrate-deficient glycoprotein syndrome type Ib. Phosphomannose isomerase deficiency and mannose therapy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The clinical phenotype is characterized by protein-losing enteropathy, while neurological manifestations prevailing in other types of CDGS are absent.
    explanation: >-
      The founding report already noted the absence of neurological
      manifestations that dominate other CDG subtypes.
- name: Seizure
  category: Neurologic
  frequency: OCCASIONAL
  description: >-
    Seizures occur in a minority of patients and are always secondary - to
    hypoglycaemia, to cerebral thrombosis, or as an adverse effect of
    intravenous mannose. Chronic antiepileptic treatment is not required.
  phenotype_term:
    preferred_term: Seizure
    term:
      id: HP:0001250
      label: Seizure
  evidence:
  - reference: PMID:32266963
    reference_title: "Consensus guideline for the diagnosis and management of mannose phosphate isomerase-congenital disorder of glycosylation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Seizures were documented in six patients, but they were secondary in all cases and no chronical antiepileptic treatment was necessary.
    explanation: >-
      Six of 35 patients (approximately 17%) maps to the OCCASIONAL band, and
      the statement establishes that seizures are always secondary.
  - reference: PMID:37124179
    reference_title: "Mannose phosphate isomerase gene mutation leads to a congenital disorder of glycosylation: A rare case report and literature review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      portal hypertension (4/9), epilepsy (2/17), thrombosis (12/14)
    explanation: >-
      Epilepsy in 2/17 assessed patients (12%) independently supports the
      OCCASIONAL band.
- name: Enlarged kidney
  category: Renal
  frequency: OCCASIONAL
  description: >-
    Renal abnormalities - hyperechogenicity, nephromegaly, cysts and, in one
    case, mild tubular acidosis - are reported sporadically and their causal
    relationship to MPI-CDG is not established. Altered kidney function has also
    been reported in an adult on long-term mannose.
  phenotype_term:
    preferred_term: Nephromegaly
    term:
      id: HP:0000105
      label: Enlarged kidney
  evidence:
  - reference: PMID:32266963
    reference_title: "Consensus guideline for the diagnosis and management of mannose phosphate isomerase-congenital disorder of glycosylation."
    supports: PARTIAL
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Mild tubular acidosis, nephromegaly, renal cysts, and severe hypertrophic cardiomyopathy were described in sporadic cases; the connection with MPI-CDG is unclear.
    explanation: >-
      Six of 35 patients had renal findings (OCCASIONAL band), but the
      guideline explicitly states the causal connection is unclear, hence
      PARTIAL support.
genetic:
- name: MPI
  gene_term:
    preferred_term: MPI
    term:
      id: hgnc:7216
      label: MPI
  relationship_type: CAUSATIVE
  variant_origin: GERMLINE
  notes: >-
    Biallelic pathogenic variants in MPI (15q24.1), an eight-exon gene spanning
    only 5 kb, cause MPI-CDG. Missense variants predominate, consistent with
    survival requiring residual activity. Three recurrent variants - c.656G>A
    (p.Arg219Gln), c.457G>A (p.Arg152Gln) and c.884G>A (p.Arg295His) - together
    account for roughly half of reported alleles. p.Arg219Gln, the first variant
    identified, has been found homozygous in clinically asymptomatic adults,
    indicating incomplete penetrance or the action of unknown modifiers; neither
    residual enzyme activity nor carbohydrate-deficient transferrin reliably
    predicts clinical severity.
  evidence:
  - reference: PMID:10980531
    reference_title: "Genomic organization of the human phosphomannose isomerase (MPI) gene and mutation analysis in patients with congenital disorders of glycosylation type Ib (CDG-Ib)."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      CDG-Ib is caused by a deficiency of mannose-6-phosphate isomerase (synonym: phosphomannose isomerase, EC 5.3.1.8), due to mutations in the MPI gene.
    explanation: >-
      Establishes MPI as the disease gene.
  - reference: PMID:10980531
    reference_title: "Genomic organization of the human phosphomannose isomerase (MPI) gene and mutation analysis in patients with congenital disorders of glycosylation type Ib (CDG-Ib)."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The gene is composed of 8 exons and spans only 5 kb.
    explanation: >-
      Defines the genomic structure that underpins routine sequencing.
  - reference: PMID:32266963
    reference_title: "Consensus guideline for the diagnosis and management of mannose phosphate isomerase-congenital disorder of glycosylation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The most common variants are c.656G > A (p. Arg219Gln), c.457G > A (p.Arg152Gln), and c.884G > A (p.Arg295His), which all together form about one half of all alleles.
    explanation: >-
      Identifies the recurrent variants and their allelic burden.
  - reference: PMID:32266963
    reference_title: "Consensus guideline for the diagnosis and management of mannose phosphate isomerase-congenital disorder of glycosylation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Among 28 published patients with known genotype, 20 different pathogenic variants were described (summarised in Table 3) with 17 missense variants, 2 frameshift-causing variants, and 1 splicing defect.
    explanation: >-
      Characterises the variant spectrum as predominantly missense.
  - reference: PMID:24508628
    reference_title: "Asymptomatic phosphomannose isomerase deficiency (MPI-CDG) initially mistaken for excessive alcohol consumption."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The diagnosis was confirmed by sequence analysis of the MPI gene revealing a homozygous missense mutation (c.656G>A) causing replacement of arginine by glutamine (p.R219Q). However, the woman had never experienced any clinical manifestations associated with MPI-CDG.
    explanation: >-
      Documents clinically asymptomatic homozygosity for the commonest variant,
      the basis of the incomplete-penetrance claim.
biochemical:
- name: CDG type I transferrin pattern
  presence: ABNORMAL
  context: >-
    Serum or plasma transferrin isoelectric focusing (or HPLC/capillary
    electrophoresis quantifying carbohydrate-deficient transferrin) shows reduced
    tetrasialotransferrin with increased disialo- and asialotransferrin. This is
    the first-line screen but cannot distinguish MPI-CDG from PMM2-CDG or other
    type I disorders.
  biomarker_term:
    preferred_term: N-glycan
    term:
      id: CHEBI:59520
      label: N-glycan
  readouts:
  - target: Protein Hypoglycosylation
    relationship: READOUT_OF
    direction: POSITIVE
    endpoint_context: DIAGNOSTIC
    interpretation: >-
      The cathodal transferrin shift directly reports systemic N-glycosylation
      deficiency.
  evidence:
  - reference: PMID:32266963
    reference_title: "Consensus guideline for the diagnosis and management of mannose phosphate isomerase-congenital disorder of glycosylation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      MPI-CDG can be biochemically characterised by a decreased level of the major tetrasialylated transferrin (Trf) glycoform (tetrasialotransferrin) and an increase of disialotransferrin and asialotransferrin, that is, CDG type I pattern.
    explanation: >-
      Defines the biochemical signature.
  - reference: PMID:32266963
    reference_title: "Consensus guideline for the diagnosis and management of mannose phosphate isomerase-congenital disorder of glycosylation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The CDT% in MPI-CDG patients rises above 6% but often up to 40% to 50% of asialo-/and disialotransferrins.
    explanation: >-
      Quantifies the carbohydrate-deficient transferrin elevation, relevant to
      the recurring misdiagnosis as alcohol misuse.
  notes: >-
    Transferrin protein polymorphisms, untreated galactosaemia, hereditary
    fructose intolerance, chronic alcohol misuse, liver disease and severe
    infection can all mimic the pattern; abnormal profiles should be repeated on
    an independent sample in an experienced laboratory. The pattern improves but
    rarely normalises completely on mannose.
- name: Deficient MPI enzyme activity in leukocytes or fibroblasts
  presence: ABNORMAL
  context: >-
    Spectrophotometric MPI assay in freshly isolated leukocytes or fibroblasts is
    the second-line confirmatory test, typically showing under 10% of normal
    activity; obligate carriers show intermediate values of 30-83% (median 50%).
  readouts:
  - target: Phosphomannose Isomerase Deficiency
    relationship: READOUT_OF
    direction: NEGATIVE
    endpoint_context: DIAGNOSTIC
    interpretation: >-
      Directly measures the deficient enzyme defining the disorder.
  evidence:
  - reference: PMID:32266963
    reference_title: "Consensus guideline for the diagnosis and management of mannose phosphate isomerase-congenital disorder of glycosylation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      In described MPI-CDG patients, enzyme activities were usually very deficient with activities less than 10% of normal values in both leukocytes and fibroblasts.
    explanation: >-
      Quantifies the diagnostic enzyme deficit.
  - reference: PMID:24508628
    reference_title: "Asymptomatic phosphomannose isomerase deficiency (MPI-CDG) initially mistaken for excessive alcohol consumption."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Probing for the underlying enzyme defect(s) using cultured skin fibroblasts demonstrated normal activity of phosphomannomutase, whereas the activity of phosphomannose isomerase (MPI) was reduced (0.64 mU/mg protein, reference 2.1-6.9), pointing to CDG of the MPI subtype (formerly called CDG-Ib).
    explanation: >-
      Worked example of the fibroblast enzyme assay discriminating MPI-CDG from
      PMM2-CDG.
diagnosis:
- name: Serum transferrin isoform analysis
  description: >-
    Isoelectric focusing (or HPLC/capillary electrophoresis) of serum or plasma
    transferrin is the preferred first-line screen. A CDG type I pattern is 100%
    sensitive but not specific.
  diagnosis_term:
    preferred_term: clinical laboratory procedure
    term:
      id: NCIT:C25294
      label: Laboratory Procedure
  results: CDG type I transferrin pattern with elevated carbohydrate-deficient transferrin.
  evidence:
  - reference: PMID:32266963
    reference_title: "Consensus guideline for the diagnosis and management of mannose phosphate isomerase-congenital disorder of glycosylation."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Isoelectric focusing of serum/plasma transferrin (TIEF) is the preferred technique for the sensitive routine screening of MPI-CDG.
    explanation: >-
      Consensus recommendation naming the first-line screening test.
- name: MPI enzyme activity assay
  description: >-
    Because the transferrin pattern cannot discriminate MPI-CDG from PMM2-CDG,
    confirmatory MPI enzyme measurement in freshly isolated leukocytes or
    fibroblasts is required.
  diagnosis_term:
    preferred_term: enzyme activity assay
    term:
      id: NCIT:C25294
      label: Laboratory Procedure
  results: MPI activity typically below 10% of normal.
  evidence:
  - reference: PMID:32266963
    reference_title: "Consensus guideline for the diagnosis and management of mannose phosphate isomerase-congenital disorder of glycosylation."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Since MPI deficiency cannot be discriminated from PMM2 deficiency and other CDGs type I by TIEF and other biochemical techniques, another confirmatory method (direct enzyme assay and/or MPI gene analysis) is strongly recommended for the correct diagnosis.
    explanation: >-
      States why a confirmatory enzymatic or molecular test is mandatory.
- name: MPI molecular genetic testing
  description: >-
    Sanger or next-generation sequencing of MPI (gene panel, exome or genome)
    confirms the diagnosis and enables carrier testing, prenatal diagnosis and
    genetic counselling.
  diagnosis_term:
    preferred_term: molecular genetic testing
    term:
      id: NCIT:C19770
      label: Molecular Analysis
    qualifiers:
    - predicate:
        preferred_term: has participant
        term:
          id: RO:0000057
          label: has participant
      value:
        preferred_term: MPI
        term:
          id: hgnc:7216
          label: MPI
  results: Biallelic pathogenic MPI variants.
  evidence:
  - reference: PMID:32266963
    reference_title: "Consensus guideline for the diagnosis and management of mannose phosphate isomerase-congenital disorder of glycosylation."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Molecular diagnosis is performed by Sanger or Next-Generation Sequencing: genes panel or whole exome/genome.
    explanation: >-
      Consensus recommendation for the molecular confirmation route.
  - reference: PMID:32266963
    reference_title: "Consensus guideline for the diagnosis and management of mannose phosphate isomerase-congenital disorder of glycosylation."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      The identification of disease-causing variants enables accurate prenatal diagnosis, determination of carrier status of family members, and genetic counselling.
    explanation: >-
      States the downstream reproductive and family uses of molecular
      confirmation.
treatments:
- name: Oral D-mannose supplementation
  description: >-
    Oral D-mannose is the disease-specific therapy and the reason MPI-CDG is one
    of the few treatable CDGs. Exogenous mannose is phosphorylated by hexokinase
    to mannose-6-phosphate, entering the N-glycosylation pathway downstream of
    the MPI block. The recommended dose is 150-170 mg/kg per dose, four to five
    times daily, started as soon as the diagnosis is made and continued lifelong.
    It corrects the digestive symptoms, hypoglycaemia and coagulopathy, but it
    does not treat the hepatic disease. Clinical response usually begins within a
    week while biochemical abnormalities take months to stabilise. Abdominal pain
    and diarrhoea are the main side effects. Poor compliance is associated with
    relapse.
  therapeutic_modality: SMALL_MOLECULE
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: D-mannose
      term:
        id: CHEBI:16024
        label: D-mannose
  target_mechanisms:
  - target: GDP-Mannose Depletion and Impaired Lipid-Linked Oligosaccharide Assembly
    treatment_effect: BYPASSES
    description: >-
      Dietary mannose is converted to mannose-6-phosphate by hexokinase,
      re-supplying the GDP-mannose pool without requiring MPI activity.
    evidence:
    - reference: PMID:21240668
      reference_title: "Seizures and stupor during intravenous mannose therapy in a patient with CDG syndrome type 1b (MPI-CDG)."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Dietary supplementation of mannose can reverse clinical symptoms by entering the N-glycosylation pathway downstream of MPI.
      explanation: >-
        States the bypass mechanism explicitly.
    - reference: PMID:22899857
      reference_title: "A zebrafish model of congenital disorders of glycosylation with phosphomannose isomerase deficiency reveals an early opportunity for corrective mannose supplementation."
      supports: SUPPORT
      evidence_source: OTHER
      snippet: >-
        MPI-CDG patients can be treated with oral mannose supplements, which is converted to mannose-6-phosphate through a minor complementary metabolic pathway, restoring protein glycosylation and ameliorating most symptoms, although liver disease continues to progress.
      explanation: >-
        Names the complementary metabolic pathway that bypasses the block and
        notes its hepatic limitation. Evidence source is OTHER because this is
        the paper's background statement about human patients.
  target_phenotypes:
  - preferred_term: Protein-losing enteropathy
    term:
      id: HP:0002243
      label: Protein-losing enteropathy
  - preferred_term: Hypoglycemia
    term:
      id: HP:0001943
      label: Hypoglycemia
  - preferred_term: Reduced antithrombin III activity
    term:
      id: HP:0001976
      label: Reduced antithrombin III activity
  evidence:
  - reference: PMID:9525984
    reference_title: "Carbohydrate-deficient glycoprotein syndrome type Ib. Phosphomannose isomerase deficiency and mannose therapy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Daily oral mannose administration is a successful therapy for this new type of CDG syndrome classified as CDGS type Ib.
    explanation: >-
      The founding report establishing oral mannose as effective therapy.
  - reference: PMID:32266963
    reference_title: "Consensus guideline for the diagnosis and management of mannose phosphate isomerase-congenital disorder of glycosylation."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Oral mannose is recommended treatment for digestive symptoms, coagulopathy and hypoglycaemia, although it does not treat the liver symptoms in MPI-CDG.
    explanation: >-
      Consensus recommendation delimiting exactly which disease arms respond.
  - reference: PMID:32266963
    reference_title: "Consensus guideline for the diagnosis and management of mannose phosphate isomerase-congenital disorder of glycosylation."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      The recommended mannose dose ranges from 150 to 170 mg/kg/dose four to five times daily.
    explanation: >-
      Consensus dosing recommendation.
  - reference: PMID:37124179
    reference_title: "Mannose phosphate isomerase gene mutation leads to a congenital disorder of glycosylation: A rare case report and literature review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The majority of patients (26/30) showed clinical symptoms, and laboratory results improved after oral mannose administration.
    explanation: >-
      Quantifies the treated-response rate across the published literature.
  - reference: PMID:37124179
    reference_title: "Mannose phosphate isomerase gene mutation leads to a congenital disorder of glycosylation: A rare case report and literature review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      One week after the start of mannose treatment, the vomiting and diarrhea symptoms disappeared completely and did not show any side effects.
    explanation: >-
      Documents the characteristic rapid clinical response in an index case.
  - reference: PMID:32266963
    reference_title: "Consensus guideline for the diagnosis and management of mannose phosphate isomerase-congenital disorder of glycosylation."
    supports: PARTIAL
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The main side effects of mannose were abdominal pain and diarrhoea, which were documented in 40% of patients and improved either spontaneously or with a dose adjustment.
    explanation: >-
      Documents the adverse-effect profile that qualifies the treatment
      recommendation.
  - reference: PMID:33098580
    reference_title: "Long term outcome of MPI-CDG patients on D-mannose therapy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Poor compliance with D-mannose was correlated with recurrence of diarrhea, thrombosis, and abnormal biological parameters including coagulation factors and transferrin profiles.
    explanation: >-
      Fifteen-year follow-up establishing the need for lifelong, compliant
      therapy.
  notes: >-
    Intravenous mannose is NOT recommended for stable patients and must be
    reserved for life-threatening situations in which oral intake is impossible,
    because mannose-6-phosphate accumulation can precipitate seizures, stupor
    and haemolysis. Caution is advised with mannose (and mannose-containing
    antibiotics) in pregnancy, since mannose accelerated embryonic death in
    Mpi-null mice and caused blindness in Mpi hypomorphic mice. Monitoring on
    oral therapy: unconjugated bilirubin, blood count, HbA1c and mannose levels
    every three months, targeting mannose above 20 micromol/L before a dose and
    above 100 micromol/L one hour after.
- name: Diazoxide for hyperinsulinaemic hypoglycaemia
  description: >-
    Patients with confirmed hyperinsulinism and hypoglycaemia not controlled by
    mannose and feeding measures may need diazoxide, at reported doses of
    4-15 mg/kg/day in three divided doses. Diazoxide is contraindicated in
    pregnancy.
  therapeutic_modality: SMALL_MOLECULE
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: diazoxide
      term:
        id: CHEBI:4495
        label: diazoxide
  target_phenotypes:
  - preferred_term: Hyperinsulinemic hypoglycemia
    term:
      id: HP:0000825
      label: Hyperinsulinemic hypoglycemia
  evidence:
  - reference: PMID:32266963
    reference_title: "Consensus guideline for the diagnosis and management of mannose phosphate isomerase-congenital disorder of glycosylation."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Patients with confirmed hyperinsulinaemia and hypoglycaemia might additionally need diazoxide treatment (reported doses vary from 4 to 15 mg/kg/day divided to three doses). The diazoxide is contraindicated in pregnancy.
    explanation: >-
      Consensus recommendation with dose and the pregnancy contraindication.
- name: Anticoagulation for thrombotic events
  description: >-
    Thrombosis is treated with unfractionated or low-molecular-weight heparin.
    Vitamin K antagonists require caution because of bleeding risk in the setting
    of digestive ulceration and oesophageal varices, and factor XI concentrate
    and recombinant factor VIIa are not recommended because unbalanced
    haemostasis makes thrombosis likely.
  therapeutic_modality: SMALL_MOLECULE
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: heparin
      term:
        id: CHEBI:28304
        label: heparin
  target_phenotypes:
  - preferred_term: Deep venous thrombosis
    term:
      id: HP:0002625
      label: Deep venous thrombosis
  - preferred_term: Cerebral venous sinus thrombosis
    term:
      id: HP:0033724
      label: Cerebral venous sinus thrombosis
  evidence:
  - reference: PMID:32266963
    reference_title: "Consensus guideline for the diagnosis and management of mannose phosphate isomerase-congenital disorder of glycosylation."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      In case of thrombosis, treatment by unfractionated heparin or low-molecular-weight heparin can be used.
    explanation: >-
      Consensus first-line anticoagulation recommendation.
  - reference: PMID:32266963
    reference_title: "Consensus guideline for the diagnosis and management of mannose phosphate isomerase-congenital disorder of glycosylation."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Infusion of factor XI concentrate or recombinant factor VIIa (rFVIIa) is not recommended due to the high risk of thrombotic events caused by unbalanced haemostasis.
    explanation: >-
      Records the explicit agents-to-avoid recommendation for bleeding
      management.
  - reference: PMID:32905087
    reference_title: "Mannose phosphate isomerase deficiency-congenital disorder of glycosylation (MPI-CDG) with cerebral venous sinus thrombosis as first and only presenting symptom: A rare but treatable cause of thrombophilia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Immediately after diagnosis of cerebral venous sinus thrombosis, therapy with unfractionated heparin was initiated and changed to low molecular weight heparin 2 weeks later.
    explanation: >-
      Worked clinical example of the anticoagulation strategy.
- name: Heparin for refractory protein-losing enteropathy
  description: >-
    Experimental heparin therapy has been used for severe protein-losing
    enteropathy in a patient with serious adverse reactions to mannose, on the
    rationale that heparin binds inflammatory cytokines that damage intestinal
    tight junctions. The bleeding risk in patients with coagulopathy, portal
    hypertension or varices must be weighed against the benefit; this is not
    routine disease-modifying treatment.
  therapeutic_modality: SMALL_MOLECULE
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: heparin
      term:
        id: CHEBI:28304
        label: heparin
  target_phenotypes:
  - preferred_term: Protein-losing enteropathy
    term:
      id: HP:0002243
      label: Protein-losing enteropathy
  evidence:
  - reference: PMID:32266963
    reference_title: "Consensus guideline for the diagnosis and management of mannose phosphate isomerase-congenital disorder of glycosylation."
    supports: PARTIAL
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Experimental heparin treatment of severe PLE was described in patient with serious adverse reactions after mannose.
    explanation: >-
      Single-patient experimental use, hence PARTIAL support.
- name: Liver transplantation
  description: >-
    Liver transplantation has been performed in selected patients, notably for
    hepatopulmonary syndrome secondary to portal hypertension. It restored
    exercise tolerance, pulmonary function, coagulation parameters and the
    transferrin isoelectric focusing pattern, although MPI enzyme activity and
    glycosylation of non-liver-derived glycoproteins remained deficient.
  therapeutic_modality: SURGERY
  treatment_term:
    preferred_term: Liver transplantation
    term:
      id: NCIT:C15271
      label: Liver Transplantation
  target_phenotypes:
  - preferred_term: Hepatic fibrosis
    term:
      id: HP:0001395
      label: Hepatic fibrosis
  - preferred_term: Portal hypertension
    term:
      id: HP:0001409
      label: Portal hypertension
  evidence:
  - reference: PMID:24982104
    reference_title: "Successful liver transplantation and long-term follow-up in a patient with MPI-CDG."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      After transplantation her physical exercise tolerance, pulmonary functions, and metabolic parameters became fully restored.
    explanation: >-
      Reports the first successful liver transplantation in a CDG patient.
  - reference: PMID:32266963
    reference_title: "Consensus guideline for the diagnosis and management of mannose phosphate isomerase-congenital disorder of glycosylation."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Liver transplantation has been performed in one patient and could be necessary in selected cases (such as in patients with hepatopulmonary syndrome due to portal hypertension).
    explanation: >-
      Consensus positioning of transplantation as a selected-case option.
- name: Nutritional support
  description: >-
    Severely undernourished patients with chronic diarrhoea or recurrent vomiting
    may need parenteral nutrition, nasogastric or gastrostomy feeding at
    presentation, and intravenous albumin before mannose achieves biochemical
    correction. Frequent feeds and complex dietary carbohydrate also help control
    hyperinsulinaemic hypoglycaemia.
  therapeutic_modality: OTHER
  treatment_term:
    preferred_term: nutritional support
    term:
      id: NCIT:C15433
      label: Nutritional Support
  target_phenotypes:
  - preferred_term: Failure to thrive
    term:
      id: HP:0001508
      label: Failure to thrive
  - preferred_term: Hypoalbuminemia
    term:
      id: HP:0003073
      label: Hypoalbuminemia
  evidence:
  - reference: PMID:32266963
    reference_title: "Consensus guideline for the diagnosis and management of mannose phosphate isomerase-congenital disorder of glycosylation."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      At presentation, severely undernourished patients with chronic diarrhoea or recurrent vomiting may require parenteral nutrition.
    explanation: >-
      Consensus recommendation for nutritional rescue at presentation.
  - reference: PMID:32266963
    reference_title: "Consensus guideline for the diagnosis and management of mannose phosphate isomerase-congenital disorder of glycosylation."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Hyperinsulinaemic hypoglycaemia can be also managed by frequent feedings and by adding complex carbohydrates to the diet.
    explanation: >-
      Consensus dietary management of the endocrine arm.
- name: Immunoglobulin replacement
  description: >-
    Patients with significant hypogammaglobulinaemia secondary to
    protein-losing enteropathy should receive regular intravenous or
    subcutaneous immunoglobulin replacement.
  therapeutic_modality: OTHER
  treatment_term:
    preferred_term: immunoglobulin therapy
    term:
      id: NCIT:C62710
      label: Immunoglobulin Therapy
  target_phenotypes:
  - preferred_term: Decreased circulating immunoglobulin concentration
    term:
      id: HP:0004313
      label: Decreased circulating immunoglobulin concentration
  evidence:
  - reference: PMID:32266963
    reference_title: "Consensus guideline for the diagnosis and management of mannose phosphate isomerase-congenital disorder of glycosylation."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      IV or SC immunoglobulins should be administered regularly in patients with hypogammaglobulinaemia.
    explanation: >-
      Consensus recommendation for immunoglobulin replacement in the
      PLE-associated hypogammaglobulinaemia of MPI-CDG.
- name: Multisystem surveillance programme
  action_category: MONITORING
  description: >-
    Because the hepatic arm progresses independently of mannose and the
    coagulopathy fluctuates with intercurrent illness, the consensus guideline
    specifies scheduled surveillance rather than symptom-driven review:
    six-monthly liver chemistry (transaminases, GGT, bilirubin,
    alpha-fetoprotein, prothrombin time) plus liver ultrasound; annual
    elastography where transaminases remain elevated; annual and then at least
    three-yearly oesophageal endoscopy once portal hypertension is present, with
    echocardiography and oximetry for portopulmonary hypertension and
    hepatopulmonary syndrome; a broad annual haemostasis panel, repeated around
    infection, dehydration and any invasive procedure; albumin at a frequency
    set by the presence and severity of protein-losing enteropathy and the
    treatment response; and glucose, thyroid/IGF-axis, renal, immunoglobulin and
    nutritional review.
  treatment_term:
    preferred_term: scheduled multisystem disease surveillance
  evidence:
  - reference: PMID:32266963
    reference_title: "Consensus guideline for the diagnosis and management of mannose phosphate isomerase-congenital disorder of glycosylation."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      To the best of our knowledge, all the patients have liver involvement even at minimal stage, so the liver tests (transaminases, GGT, bilirubin, alpha-fetoprotein, prothrombin time) and liver ultrasound (in search for liver fibrosis, steatosis, ductal plate malformations, or signs of portal hypertension) should be performed every 6 months.
    explanation: >-
      Consensus hepatic surveillance schedule, justified by the near-universal
      liver involvement.
  - reference: PMID:32266963
    reference_title: "Consensus guideline for the diagnosis and management of mannose phosphate isomerase-congenital disorder of glycosylation."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Broad haemostatic study including fibrinogen, prothrombin time, partial thromboplastin time, factor VIII, factor IX, factor XI, AT, PC, and PS, complete blood count and differential should be performed at diagnosis and then annually.
    explanation: >-
      Consensus haemostasis surveillance schedule.
  - reference: PMID:32266963
    reference_title: "Consensus guideline for the diagnosis and management of mannose phosphate isomerase-congenital disorder of glycosylation."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      oesophageal endoscopy should be performed each year at the beginning of the follow-up and thereafter depending on the endoscopic findings, but at least every 3 years.
    explanation: >-
      Consensus variceal-surveillance interval for patients with portal
      hypertension.
  notes: >-
    NCIT has no clinical-action term for scheduled disease surveillance that is
    reachable from NCIT:C25218 (Clinical Intervention or Procedure) - the
    obvious candidate, NCIT:C61256 Monitoring, is not in that subtree - so
    treatment_term carries a free-text preferred_term only, per the documented
    fallback. The MONITORING action_category makes the intent machine-queryable,
    and target_phenotypes/target_mechanisms are deliberately omitted because
    surveillance does not modify pathophysiology.
- name: Hepatoprotective avoidance measures
  description: >-
    Because the hepatic lesion is irreversible and progressive and unresponsive
    to mannose, further liver injury should be actively prevented: vaccination
    against hepatitis A and B, avoidance of hepatotoxic drugs, and abstinence
    from alcohol.
  therapeutic_modality: BEHAVIORAL
  treatment_term:
    preferred_term: supportive care
    term:
      id: NCIT:C15747
      label: Supportive Care
  target_phenotypes:
  - preferred_term: Hepatic fibrosis
    term:
      id: HP:0001395
      label: Hepatic fibrosis
  evidence:
  - reference: PMID:32266963
    reference_title: "Consensus guideline for the diagnosis and management of mannose phosphate isomerase-congenital disorder of glycosylation."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      As the liver involvement in MPI-CDG is irreversible and progressive, the further liver damage should be prevented by vaccination against hepatotropic viruses (hepatitises A and B), avoidance of hepatotoxic drugs, and alcohol abstinence.
    explanation: >-
      Consensus "agents and circumstances to avoid" recommendation.
- name: Genetic counseling
  description: >-
    Identification of the causative variants supports carrier testing of family
    members, prenatal diagnosis and genetic counselling; psychological support
    for families is also recommended at the time of diagnosis.
  therapeutic_modality: BEHAVIORAL
  treatment_term:
    preferred_term: genetic counseling
    term:
      id: NCIT:C15240
      label: Genetic Counseling
  evidence:
  - reference: PMID:32266963
    reference_title: "Consensus guideline for the diagnosis and management of mannose phosphate isomerase-congenital disorder of glycosylation."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      The identification of disease-causing variants enables accurate prenatal diagnosis, determination of carrier status of family members, and genetic counselling.
    explanation: >-
      Consensus recommendation for genetic counselling following molecular
      diagnosis.
differential_diagnoses:
- name: PMM2-congenital disorder of glycosylation
  description: >-
    The commonest CDG and the closest biochemical mimic: PMM2-CDG produces an
    identical CDG type I transferrin pattern but is dominated by neurologic
    disease (developmental delay, cerebellar hypoplasia) with dysmorphism,
    inverted nipples and abnormal fat pads, none of which occur in MPI-CDG.
    Discrimination requires enzyme assay or molecular testing.
  disease_term:
    preferred_term: PMM2-congenital disorder of glycosylation
    term:
      id: MONDO:0008907
      label: PMM2-congenital disorder of glycosylation
  evidence:
  - reference: PMID:32266963
    reference_title: "Consensus guideline for the diagnosis and management of mannose phosphate isomerase-congenital disorder of glycosylation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      In contrast with PMM2-CDG, facial dysmorphia, atypical fat pads, inverted nipples, and skeletal deformities are not present in MPI-CDG patients.
    explanation: >-
      States the clinical discriminators from the principal differential.
  - reference: PMID:24508628
    reference_title: "Asymptomatic phosphomannose isomerase deficiency (MPI-CDG) initially mistaken for excessive alcohol consumption."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Probing for the underlying enzyme defect(s) using cultured skin fibroblasts demonstrated normal activity of phosphomannomutase, whereas the activity of phosphomannose isomerase (MPI) was reduced (0.64 mU/mg protein, reference 2.1-6.9), pointing to CDG of the MPI subtype (formerly called CDG-Ib).
    explanation: >-
      Demonstrates how the two are separated enzymatically.
- name: Chronic excessive alcohol consumption
  description: >-
    Elevated carbohydrate-deficient transferrin is a routine biomarker of heavy
    drinking, and asymptomatic MPI-CDG adults have been misdiagnosed as alcohol
    abusers on the basis of a markedly raised CDT. A negative
    phosphatidylethanol and the type-1 glycoform pattern point instead to CDG.
  evidence:
  - reference: PMID:24508628
    reference_title: "Asymptomatic phosphomannose isomerase deficiency (MPI-CDG) initially mistaken for excessive alcohol consumption."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      If asymptomatic MPI-CDG subjects undergo CDT screening, their highly elevated test results may be wrongly interpreted as caused by excessive alcohol consumption.
    explanation: >-
      Documents the specific diagnostic pitfall.
- name: Other causes of protein-losing enteropathy
  description: >-
    Protein-losing enteropathy has many causes - gastrointestinal infection,
    severe coeliac disease, inflammatory bowel disease, other metabolic
    disorders including ALG6-CDG, and intestinal lymphangiectasia in Noonan and
    Turner syndromes. One MPI-CDG patient was managed as Crohn disease for 13
    years before mannose produced prompt improvement.
  evidence:
  - reference: PMID:32266963
    reference_title: "Consensus guideline for the diagnosis and management of mannose phosphate isomerase-congenital disorder of glycosylation."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      MPI-CDG should be included in the differential diagnosis of patients with a PLE.
    explanation: >-
      Consensus statement positioning MPI-CDG within the protein-losing
      enteropathy differential.
- name: Congenital hepatic fibrosis in autosomal recessive polycystic kidney disease
  description: >-
    The ductal plate malformation of MPI-CDG closely resembles the hepatic
    lesion of congenital hepatic fibrosis in ARPKD, which is a key
    histopathological differential on liver biopsy.
  evidence:
  - reference: PMID:32266963
    reference_title: "Consensus guideline for the diagnosis and management of mannose phosphate isomerase-congenital disorder of glycosylation."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Bile duct involvement in MPI-CDG with ductal plate malformation is very similar to those observed in Congenital Hepatic Fibrosis in Autosomal Recessive Polycystic Kidney Disease.
    explanation: >-
      Names the histopathological mimic.
- name: Liver-predominant congenital disorders of glycosylation
  description: >-
    TMEM199-CDG, CCDC115-CDG and ATP6AP1-CDG also present with liver disease as
    the predominant symptom and belong in the differential of an abnormal
    transferrin pattern with hepatopathy.
  evidence:
  - reference: PMID:32266963
    reference_title: "Consensus guideline for the diagnosis and management of mannose phosphate isomerase-congenital disorder of glycosylation."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      including other CDGs, especially those where the liver involvement is present as a predominant symptom (TMEM199-CDG, CCDC115-CDG, and ATP6AP1-CDG).
    explanation: >-
      Names the liver-predominant CDG differentials.
animal_models:
- species: Mus musculus
  genotype: Mpi null (Mpi-/-) and Mpi hypomorphic alleles
  description: >-
    Germline ablation of mouse Mpi causes mannose-6-phosphate accumulation,
    inhibition of glycolytic enzymes, ATP depletion and embryonic lethality
    around E11.5, with growth retardation, placental hyperplasia and failed yolk
    sac vasculogenesis; mannose supplementation hastens rather than rescues
    embryonic death, so a faithful murine CDG-Ib model requires hypomorphic
    alleles. Hypomorphic mice with patient-range residual activity are largely
    normal apart from about 15% embryonic lethality, but antenatal mannose
    reduces litter size and survival to weaning and causes eye defects in about
    half of survivors. The model therefore establishes the mannose-toxicity
    mechanism but does not reproduce the human hepatic-intestinal disease.
  genes:
  - preferred_term: MPI
    term:
      id: hgnc:7216
      label: MPI
  associated_phenotypes:
  - Embryonic lethality
  - Blindness
  evidence:
  - reference: PMID:16339137
    reference_title: "Ablation of mouse phosphomannose isomerase (Mpi) causes mannose 6-phosphate accumulation, toxicity, and embryonic lethality."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Because Mpi ablation is embryonic lethal, a murine CDG-Ib model will require hypomorphic Mpi alleles.
    explanation: >-
      States the limitation of the null model for modelling the human disorder.
  - reference: PMID:24421398
    reference_title: "Mannose supplements induce embryonic lethality and blindness in phosphomannose isomerase hypomorphic mice."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      We generated viable Mpi hypomorphic mice with residual enzymatic activity comparable to that of patients, but surprisingly, these mice appeared completely normal except for modest (~15%) embryonic lethality.
    explanation: >-
      Establishes that patient-equivalent residual activity does not reproduce
      human disease in the mouse.
  - reference: PMID:24421398
    reference_title: "Mannose supplements induce embryonic lethality and blindness in phosphomannose isomerase hypomorphic mice."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      However, mannose further reduced litter size and survival to weaning by 40 and 66%, respectively. Moreover, ~50% of survivors developed eye defects beginning around midgestation.
    explanation: >-
      Documents the antenatal mannose toxicity that motivates caution in
      pregnancy.
- species: Danio rerio
  genotype: mpi morpholino knockdown (morphant, ~13% residual Mpi activity)
  description: >-
    Morpholino knockdown of zebrafish mpi to 13% residual activity - within the
    range measured in MPI-CDG patient fibroblasts - reduces lipid-linked
    oligosaccharide and N-glycan levels and produces embryonic lethality and
    multisystem abnormalities including a small liver, pericardial oedema and
    small eyes. The phenotype is rescued by mannose, but only when supplied
    before 24 hours post-fertilisation, defining a developmental window for
    correction. Transient knockdown and embryonic phenotypes do not reproduce
    chronic human portal-hypertensive disease.
  genes:
  - preferred_term: MPI
    term:
      id: hgnc:7216
      label: MPI
  associated_phenotypes:
  - Embryonic lethality
  - Small liver
  - Pericardial edema
  evidence:
  - reference: PMID:22899857
    reference_title: "A zebrafish model of congenital disorders of glycosylation with phosphomannose isomerase deficiency reveals an early opportunity for corrective mannose supplementation."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Importantly, these phenotypes could be rescued with mannose supplementation. Thus, parallel processes in fish and humans contribute to the phenotypes caused by Mpi depletion. Interestingly, mannose was only effective if provided prior to 24 hpf.
    explanation: >-
      Establishes both the mannose responsiveness and the early developmental
      window of the model.
  - reference: PMID:22899857
    reference_title: "A zebrafish model of congenital disorders of glycosylation with phosphomannose isomerase deficiency reveals an early opportunity for corrective mannose supplementation."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      We used a morpholino to block mpi mRNA translation and established a concentration that consistently yielded 13% residual Mpi enzyme activity at 4 days post-fertilization (dpf), which is within the range of MPI activity detected in fibroblasts from MPI-CDG patients.
    explanation: >-
      Documents that the knockdown was calibrated to patient-equivalent residual
      enzyme activity.
discussions:
- discussion_id: mpi_cdg_hyperinsulinism_mechanism
  kind: KNOWLEDGE_GAP
  status: OPEN
  prompt: >-
    Why does hyperinsulinaemic hypoglycaemia occur in MPI-CDG, and which
    hypoglycosylated beta-cell protein is responsible?
  attaches_to:
  - pathophysiology#Hyperinsulinaemic Hypoglycaemia
  rationale: >-
    Hyperinsulinism accounts for more than two-thirds of hypoglycaemia in
    MPI-CDG and also occurs in PGM1-CDG and PMM2-CDG, suggesting a shared
    glycosylation-dependent mechanism, but the consensus guideline states the
    cause is unknown. Hypoglycosylation of the sulfonylurea receptor SUR1 is
    proposed and altered insulin secretion has been shown in hypoglycosylated
    murine beta cells, but neither has been demonstrated in human MPI-CDG
    islets. Resolving this would clarify why mannose corrects the hypoglycaemia
    and whether beta-cell-directed therapy is ever needed beyond diazoxide.
  evidence:
  - reference: PMID:32266963
    reference_title: "Consensus guideline for the diagnosis and management of mannose phosphate isomerase-congenital disorder of glycosylation."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      However, the exact cause of HH in CDG patients is still unknown.
    explanation: >-
      The consensus panel states the mechanism is unresolved.
- discussion_id: mpi_cdg_mannose_pregnancy_model_mismatch
  kind: HUMAN_MODEL_MISMATCH
  status: OPEN
  prompt: >-
    Do the mannose-toxicity findings in Mpi mice - accelerated embryonic death
    in nulls and ocular defects with blindness in hypomorphs - predict any risk
    of oral or antenatal mannose therapy in human MPI-CDG?
  attaches_to:
  - pathophysiology#Mannose-6-Phosphate Accumulation and Energy Failure on Excess Mannose
  rationale: >-
    The direction of the mannose effect is species- and route-discordant.
    Complete Mpi ablation in mice is embryonic lethal and mannose hastens
    embryonic death; Mpi hypomorphic mice develop blindness on antenatal
    mannose. Yet in zebrafish mannose rescues the phenotype when given early,
    and in humans oral mannose is well tolerated and clearly beneficial, with
    normal pregnancies reported in treated women; human toxicity has been seen
    only with the intravenous route. Whether the murine antenatal toxicity has
    any human counterpart is unresolved and directly gates the guideline's
    cautious stance on mannose in pregnancy.
  evidence:
  - reference: PMID:24421398
    reference_title: "Mannose supplements induce embryonic lethality and blindness in phosphomannose isomerase hypomorphic mice."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      It is unknown whether mannose is harmful to human fetuses during gestation; however, mothers who are at risk for having MPI-CDG children and who consume mannose during pregnancy hoping to benefit an affected fetus in utero should be cautious.
    explanation: >-
      The authors themselves flag the translational uncertainty, which is
      exactly the mismatch recorded here.
clinical_trials:
- name: NCT03404869
  phase: PHASE_II
  status: UNKNOWN
  description: >-
    Open-label, single-group Phase 1/2 study of ORL-1M (D-mannose) in patients
    with CDG-Ib, sponsored by Orpha Labs, with an estimated enrolment of five
    participants under 18 years. The primary outcome was improvement in
    hypoglycaemia, diarrhoea and vomiting at six months and the secondary
    outcome improved serum transferrin glycosylation at 30 days. The registry
    record was last known to be recruiting and no results have been posted.
  target_phenotypes:
  - preferred_term: Hypoglycemia
    term:
      id: HP:0001943
      label: Hypoglycemia
  - preferred_term: Chronic diarrhea
    term:
      id: HP:0002028
      label: Chronic diarrhea
  - preferred_term: Episodic vomiting
    term:
      id: HP:0002572
      label: Episodic vomiting
  evidence:
  - reference: clinicaltrials:NCT03404869
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Study of ORL-1M in Patients With CDG-Ib
    explanation: >-
      The ClinicalTrials.gov record confirms a registered interventional study
      of the D-mannose product ORL-1M in CDG-Ib (MPI-CDG). Only the study title
      is available in the cached registry summary, so the detailed design
      described above is drawn from the registry record and is not quoted here.
datasets: []

📚

References & Deep Research

Deep Research

1

Falcon ▸

Disease Characteristics Research Template

Edison Scientific Literature 39 citations 2026-08-01T17:15:37.072549

Question: You are an expert researcher providing comprehensive, well-cited information.

Provide detailed information focusing on: 1. Key concepts and definitions with current understanding 2. Recent developments and latest research (prioritize 2023-2024 sources) 3. Current applications and real-world implementations 4. Expert opinions and analysis from authoritative sources 5. Relevant statistics and data from recent studies

Format as a comprehensive research report with proper citations. Include URLs and publication dates where available. Always prioritize recent, authoritative sources and provide specific citations for all major claims.

Disease Characteristics Research Template

Target Disease

Disease Name: MPI-congenital disorder of glycosylation
MONDO ID: (if available)
Category: Mendelian

Research Objectives

Please provide a comprehensive research report on MPI-congenital disorder of glycosylation covering all of the disease characteristics listed below. This report will be used to populate a disease knowledge base entry. Be thorough and cite primary literature (PMID preferred) for all claims.

For each section, suggested databases/resources are listed. These are the first places you should search for information on each topic.

1. Disease Information

Search first: OMIM, Orphanet, ICD-10/ICD-11, MeSH, PubMed

What is the disease? Provide a concise overview.
What are the key identifiers? (OMIM, Orphanet, ICD-10/ICD-11, MeSH, Mondo)
What are the common synonyms and alternative names?
Is the information derived from individual patients (e.g., EHR) or aggregated disease-level resources?

2. Etiology

Disease Causal Factors: What are the primary causes? (genetic, environmental, infectious, mechanistic)
Risk Factors:

Search first: PubMed, Cochrane Library, UpToDate, clinical guidelines, ClinVar, ClinGen, GWAS Catalog, PheGenI, CTD, CDC, WHO, epidemiological databases
Genetic risk factors (causal variants, susceptibility loci, modifier genes)
Environmental risk factors (toxins, lifestyle, occupational exposures, age, sex, family history)
Protective Factors:

Search first: PubMed, Cochrane Library, clinical trial databases, GWAS Catalog, gnomAD, WHO, CDC, nutrition databases
Genetic protective factors (protective variants, modifier alleles)
Environmental protective factors (diet, lifestyle, exposures that reduce risk)
Gene-Environment Interactions: How do genetic and environmental factors interact to influence disease?

Search first: CTD, PubMed, PheGenI, GxE databases

3. Phenotypes

Search first: HPO (Human Phenotype Ontology), OMIM, Orphanet, PubMed, clinicaltrials.gov, MedDRA, SNOMED CT, DECIPHER, LOINC

For each phenotype, provide: - Phenotype type: symptoms, clinical signs, physical manifestations, behavioral changes, or laboratory abnormalities

For symptoms/signs: HPO, OMIM, Orphanet, PubMed For behavioral changes: HPO, DSM, RDoC (Research Domain Criteria), PubMed For laboratory abnormalities: LOINC, SNOMED CT, LabTests Online, PubMed - Phenotype characteristics: Search first: OMIM, Orphanet, HPO, PubMed - Age of symptom onset (neonatal, childhood, adult-onset, late-onset) - Symptom severity (mild, moderate, severe, variable) - Symptom progression (stable, progressive, episodic, fluctuating) - Frequency among affected individuals (percentage or qualitative) - Quality of life impact: Effects on daily functioning and well-being (per-phenotype when possible) Search first: EQ-5D database, SF-36, WHO QOL databases, PubMed - Suggest HPO (Human Phenotype Ontology) terms for each phenotype

4. Genetic/Molecular Information

Causal Genes: Gene mutations or chromosomal abnormalities responsible for disease (gene symbols, OMIM IDs)

Search first: OMIM, ClinVar, HGMD, Ensembl, NCBI Gene
Pathogenic Variants:
Affected genes (gene symbols, HGNC IDs) > Search first: OMIM, NCBI Gene, Ensembl, HGNC, UniProt, GeneCards
Variant classification (pathogenic, likely pathogenic, VUS per ACMG/AMP guidelines) > Search first: ClinVar, ClinGen, ACMG/AMP guidelines, VarSome
Variant type/class (missense, frameshift, nonsense, splice-site, structural)
Allele frequency in population databases > Search first: gnomAD, 1000 Genomes, ExAC, TOPMed, dbSNP
Somatic vs germline origin > Search first: COSMIC (somatic), ClinVar, ICGC, TCGA
Functional consequences (loss of function, gain of function, dominant negative)
Modifier Genes: Genes that modify disease severity or expression
Epigenetic Information: DNA methylation, histone modifications, chromatin changes affecting disease

Search first: ENCODE, Roadmap Epigenomics, MethBase, DiseaseMeth
Chromosomal Abnormalities: Large-scale genetic changes (aneuploidy, translocations, inversions)

Search first: DECIPHER, ClinVar, ECARUCA, UCSC Genome Browser

5. Environmental Information

Environmental Factors: Non-genetic contributing factors (toxins, radiation, pollution, occupational exposure)

Search first: CTD (Comparative Toxicogenomics Database), TOXNET, PubMed, EPA databases
Lifestyle Factors: Behavioral factors (smoking, diet, exercise, alcohol consumption)

Search first: CDC databases, WHO, PubMed, NHANES
Infectious Agents: If applicable, pathogens causing or triggering disease (bacteria, viruses, fungi, parasites)

Search first: NCBI Taxonomy, ViPR, BV-BRC, MicrobeDB, GIDEON

6. Mechanism / Pathophysiology

Molecular Pathways: Specific signaling cascades or biochemical pathways involved (Wnt, MAPK, mTOR, PI3K-AKT, etc.)

Search first: KEGG, Reactome, WikiPathways, PathBank, BioCyc
Cellular Processes: Cell-level mechanisms (apoptosis, autophagy, cell cycle dysregulation, inflammation, etc.)

Search first: Gene Ontology (GO), Reactome, KEGG, PubMed
Protein Dysfunction: How protein structure or function is altered (misfolding, aggregation, loss of function, gain of function)

Search first: UniProt, PDB (Protein Data Bank), InterPro, Pfam, AlphaFold
Metabolic Changes: Alterations in metabolic processes (energy metabolism, lipid metabolism, amino acid metabolism)

Search first: KEGG, BioCyc, HMDB (Human Metabolome Database), BRENDA
Immune System Involvement: Role of immune response (autoimmunity, immunodeficiency, chronic inflammation)

Search first: ImmPort, Immunome Database, IEDB, Gene Ontology
Tissue Damage Mechanisms: How tissues/ are injured (oxidative stress, ischemia, fibrosis, necrosis)

Search first: PubMed, Gene Ontology, Reactome
Biochemical Abnormalities: Specific molecular defects (enzyme deficiencies, receptor dysfunction, ion channel defects)

Search first: BRENDA, UniProt, KEGG, OMIM, PubMed
Epigenetic Changes: DNA methylation, histone modifications affecting gene expression in disease

Search first: ENCODE, Roadmap Epigenomics, MethBase, DiseaseMeth
Molecular Profiling (if available):
Transcriptomics/gene expression changes > Search first: GEO (Gene Expression Omnibus), ArrayExpress, GTEx, Human Cell Atlas, SRA
Proteomics findings > Search first: PRIDE, ProteomeXchange, Human Protein Atlas, STRING, BioGRID
Metabolomics signatures > Search first: MetaboLights, Metabolomics Workbench, HMDB, METLIN
Lipidomics alterations > Search first: LIPID MAPS, SwissLipids, LipidHome, Metabolomics Workbench
Genomic structural features > Search first: UCSC Genome Browser, Ensembl, NCBI, dbVar, DGV
Advanced Technologies (if applicable):
Single-cell analysis findings (cell-type specific mechanisms, cellular heterogeneity) > Search first: Human Cell Atlas, Single Cell Portal, GEO, CELLxGENE
Spatial transcriptomics findings > Search first: GEO, Spatial Research, Vizgen, 10x Genomics data
Multi-omics integration results > Search first: TCGA, ICGC, cBioPortal, LinkedOmics, PubMed
Functional genomics screens (CRISPR, RNAi) > Search first: DepMap, GenomeRNAi, PubMed, BioGRID ORCS

For each mechanism, describe: - The causal chain from initial trigger to clinical manifestation - Which mechanisms are upstream vs downstream - What cell types and biological processes are involved - Suggest GO terms for biological processes and CL terms for cell types

7. Anatomical Structures Affected

Organ Level:
Primary organs directly affected
Secondary organ involvement (complications, secondary effects)
Body systems involved (cardiovascular, nervous, digestive, respiratory, endocrine, etc.)

Search first: Uberon, FMA (Foundational Model of Anatomy), OMIM, HPO, ICD-11, MeSH, SNOMED CT
Tissue and Cell Level:
Specific tissue types affected (epithelial, connective, muscle, nervous)
Specific cell populations targeted (with Cell Ontology terms)

Search first: Uberon, Human Protein Atlas, Cell Ontology, Human Cell Atlas, CellMarker, PanglaoDB
Subcellular Level:
Cellular compartments involved (mitochondria, nucleus, ER, lysosomes) (with GO Cellular Component terms)

Search first: Gene Ontology (Cellular Component), UniProt, Human Protein Atlas
Localization:
Specific anatomical sites (with UBERON terms) > Search first: FMA, Uberon, NeuroNames (for brain), SNOMED CT
Lateralization (unilateral, bilateral, asymmetric) > Search first: HPO, clinical literature, imaging databases

8. Temporal Development

Onset:
Typical age of onset (congenital, pediatric, adult, geriatric)
Onset pattern (acute, subacute, chronic, insidious)

Search first: OMIM, Orphanet, HPO, PubMed
Progression:
Disease stages (early, intermediate, advanced, end-stage) > Search first: Cancer Staging Manual (AJCC), WHO classifications, PubMed
Progression rate (rapid, slow, variable)
Disease course pattern (episodic, relapsing-remitting, progressive, stable)
Disease duration (self-limited, chronic lifelong)

Search first: Disease registries, longitudinal cohort databases, natural history studies, PubMed, Orphanet, OMIM
Patterns:
Remission patterns (spontaneous, treatment-induced) > Search first: Clinical trial databases, disease registries, PubMed
Critical periods (time windows of vulnerability or opportunity for intervention) > Search first: PubMed, developmental biology databases, clinical guidelines

9. Inheritance and Population

Epidemiology:
Prevalence (cases per 100,000 at given time)
Incidence (new cases per 100,000 per year)

Search first: Orphanet, CDC, WHO, GBD (Global Burden of Disease), national registries, SEER, disease registries
For Genetic Etiology:
Inheritance pattern (AD, AR, X-linked, mitochondrial, multifactorial, polygenic) > Search first: OMIM, Orphanet, ClinVar, GTR (Genetic Testing Registry)
Penetrance (complete, incomplete, age-dependent) > Search first: ClinVar, OMIM, PubMed, ClinGen
Expressivity (variable, consistent) > Search first: OMIM, ClinVar, PubMed
Genetic anticipation (increasing severity in successive generations) > Search first: OMIM, PubMed (especially for repeat expansion disorders)
Germline mosaicism > Search first: ClinVar, OMIM, genetic counseling literature, PubMed
Founder effects (population-specific mutations) > Search first: gnomAD, population genetics databases, PubMed
Consanguinity role > Search first: OMIM, population studies, genetic counseling resources
Carrier frequency > Search first: gnomAD, carrier screening databases, GeneReviews, GTR
Population Demographics:
Affected populations (ethnic or demographic groups with higher prevalence) > Search first: gnomAD, 1000 Genomes, PAGE Study, PubMed, population registries
Geographic distribution (endemic areas, regional variation) > Search first: WHO, CDC, GBD, Orphanet, geographic epidemiology databases
Geographic distribution of specific variants
Sex ratio (male:female) > Search first: Disease registries, OMIM, PubMed, epidemiological databases
Age distribution of affected individuals > Search first: CDC, disease registries, SEER, Orphanet

10. Diagnostics

Clinical Tests:
Laboratory tests (blood, urine, tissue chemistry, specific enzyme assays) > Search first: LOINC, LabTests Online, PubMed
Biomarkers (proteins, metabolites, genetic markers, circulating biomarkers) > Search first: FDA Biomarker List, BEST (Biomarkers, EndpointS, and other Tools), PubMed
Imaging studies (X-ray, CT, MRI, PET, ultrasound) > Search first: RadLex, DICOM, Radiopaedia, imaging databases
Functional tests (pulmonary function, cardiac stress tests) > Search first: LOINC, clinical guidelines, PubMed
Electrophysiology (EEG, EMG, ECG, nerve conduction studies) > Search first: LOINC, clinical neurophysiology databases, PubMed
Biopsy findings (histopathology, immunohistochemistry) > Search first: SNOMED CT, College of American Pathologists resources, PubMed
Pathology findings (microscopic examination) > Search first: SNOMED CT, Digital Pathology databases, PubMed
Genetic Testing:

Search first: GTR (Genetic Testing Registry), GeneReviews, ClinGen
Overview of recommended genetic testing approach
Whole genome sequencing (WGS) utility > Search first: GTR, ClinVar, GEL (Genomics England), gnomAD
Whole exome sequencing (WES) utility > Search first: GTR, ClinVar, OMIM, GeneMatcher
Gene panels (which panels, which genes) > Search first: GTR, ClinVar, laboratory-specific databases
Single gene testing > Search first: GTR, ClinVar, OMIM, GeneReviews
Chromosomal microarray (CMA) > Search first: DECIPHER, ClinVar, dbVar, ECARUCA
Karyotyping > Search first: Chromosome Abnormality Database, ClinVar, cytogenetics resources
FISH > Search first: ClinVar, cytogenetics databases, PubMed
Mitochondrial DNA testing > Search first: MITOMAP, MSeqDR, ClinVar, GTR
Repeat expansion testing > Search first: GTR, ClinVar, repeat expansion databases, PubMed
Omics-Based Diagnostics (if applicable):
RNA sequencing / transcriptomics > Search first: GEO, ArrayExpress, GTEx, RNA-seq databases
Proteomics > Search first: PRIDE, ProteomeXchange, FDA Biomarker database
Metabolomics > Search first: MetaboLights, Metabolomics Workbench, HMDB
Epigenomics > Search first: GEO, ENCODE, Roadmap Epigenomics, MethBase
Liquid biopsy > Search first: COSMIC, ClinVar, liquid biopsy databases, PubMed
Clinical Criteria:
Standardized diagnostic criteria (DSM, ICD, society guidelines) > Search first: DSM-5, ICD-11, clinical society guidelines, UpToDate
Differential diagnosis (other conditions to rule out, with distinguishing features) > Search first: DynaMed, UpToDate, clinical decision support systems
Screening:
Screening methods for asymptomatic individuals (newborn screening, carrier screening, cascade screening) > Search first: ACMG recommendations, CDC newborn screening, GTR

11. Outcome/Prognosis

Survival and Mortality:
Survival rate (5-year, 10-year, overall) > Search first: SEER, cancer registries, disease-specific registries, PubMed
Life expectancy (with and without treatment if applicable) > Search first: Orphanet, disease registries, actuarial databases, PubMed
Mortality rate > Search first: CDC, WHO, GBD, national mortality databases
Disease-specific mortality (deaths directly attributable to disease) > Search first: Disease registries, CDC Wonder, GBD, PubMed
Morbidity and Function:
Morbidity (disease-related disability and health impacts) > Search first: GBD, WHO, disability databases, PubMed
Disability outcomes (long-term functional impairments) > Search first: ICF (International Classification of Functioning), disability registries
Quality of life measures (EQ-5D, SF-36, PROMIS, disease-specific tools) > Search first: EQ-5D database, SF-36, PROMIS, PubMed
Disease Course:
Complications (secondary problems: infections, organ failure, etc.) > Search first: ICD codes, disease registries, clinical databases, PubMed
Recovery potential (likelihood and extent of recovery, with vs without treatment) > Search first: Natural history studies, rehabilitation databases, PubMed
Prediction:
Prognostic factors (age, disease severity, biomarkers, treatment response) > Search first: Prognostic models databases, clinical calculators, PubMed
Prognostic biomarkers (molecular markers predicting disease course) > Search first: FDA Biomarker database, PubMed, cancer prognostic databases

12. Treatment

Pharmacotherapy:
Pharmacological treatments (drug names, drug classes, mechanisms of action) > Search first: DrugBank, RxNorm, ATC classification, DailyMed, FDA databases
Pharmacogenomics (how genetic variants affect drug metabolism, efficacy, toxicity) > Search first: PharmGKB, CPIC (Clinical Pharmacogenetics), FDA Table of PGx Biomarkers
Advanced Therapeutics:
Gene therapy (viral vectors, CRISPR, gene replacement, gene editing) > Search first: ClinicalTrials.gov, FDA gene therapy database, ASGCT resources
Cell therapy (stem cell transplant, CAR-T, cellular therapeutics) > Search first: ClinicalTrials.gov, FDA cell therapy database, FACT standards
RNA-based therapies (ASOs, siRNA, mRNA therapies) > Search first: ClinicalTrials.gov, FDA approvals, PubMed
Targeted therapies (treatments directed at specific molecular targets) > Search first: My Cancer Genome, OncoKB, ClinicalTrials.gov, FDA approvals
Immunotherapies (checkpoint inhibitors, monoclonal antibodies) > Search first: Cancer Immunotherapy Database, FDA approvals, ClinicalTrials.gov
Surgical and Interventional:
Surgical interventions (types of surgery, timing, outcomes) > Search first: CPT codes, surgical registries, clinical guidelines, PubMed
Supportive and Rehabilitative:
Supportive care (symptom management, pain control, nutrition) > Search first: Clinical guidelines, Cochrane Library, PubMed
Rehabilitation (physical therapy, occupational therapy, speech therapy) > Search first: Rehabilitation medicine databases, clinical guidelines, PubMed
Experimental:
Experimental treatments in clinical trials (with NCT identifiers if available) > Search first: ClinicalTrials.gov, EU Clinical Trials Register, WHO ICTRP
Treatment Outcomes:
Treatment response rates > Search first: Clinical trial databases, FDA reviews, systematic reviews, PubMed
Side effects and adverse events > Search first: FDA Adverse Event Reporting System (FAERS), MedWatch, PubMed
Treatment Strategy:
Treatment algorithms (clinical pathways, decision trees) > Search first: Clinical practice guidelines, NCCN Guidelines, UpToDate
Combination therapies > Search first: ClinicalTrials.gov, treatment guidelines, PubMed
Personalized medicine approaches (genotype-guided treatment) > Search first: My Cancer Genome, CIViC, PharmGKB, precision medicine databases

For each treatment, suggest NCIT (NCI Thesaurus) clinical-intervention terms where applicable.

13. Prevention

Prevention Levels:
Primary prevention (preventing disease occurrence: vaccination, risk factor modification) > Search first: CDC, WHO, USPSTF recommendations, Cochrane Library
Secondary prevention (early detection and treatment: screening programs, early intervention) > Search first: USPSTF, CDC screening guidelines, WHO
Tertiary prevention (preventing complications in those with disease) > Search first: Clinical guidelines, disease management protocols, PubMed
Immunization: Vaccine strategies (if applicable)

Search first: CDC vaccine schedules, WHO immunization, FDA vaccine database
Screening and Early Detection:
Screening programs (population-based: newborn screening, cancer screening) > Search first: CDC screening programs, USPSTF, cancer screening databases
Genetic screening (carrier screening, preimplantation genetic diagnosis, prenatal testing) > Search first: ACMG recommendations, ACOG guidelines, GTR
Risk stratification (identifying high-risk individuals for targeted prevention) > Search first: Risk prediction models, clinical calculators, PubMed
Behavioral Interventions: Lifestyle modifications to reduce risk

Search first: CDC, WHO, behavioral intervention databases, Cochrane Library
Counseling: Genetic counseling (risk assessment, family planning guidance)

Search first: NSGC resources, ACMG guidelines, GeneReviews
Public Health:
Public health interventions (sanitation, vector control, health education) > Search first: CDC, WHO, public health databases, PubMed
Environmental interventions (reducing environmental risk factors) > Search first: EPA databases, WHO environmental health, PubMed
Prophylaxis: Preventive medications or procedures

Search first: Clinical guidelines, FDA approvals, PubMed

14. Other Species / Natural Disease

Taxonomy: Species affected (with NCBI Taxon identifiers)

Search first: NCBI Taxonomy
Breed: Specific breeds affected (with VBO identifiers if applicable)

Search first: VBO (Vertebrate Breed Ontology)
Gene: Orthologous genes in other species (with NCBI Gene IDs)

Search first: NCBI Gene
Natural Disease:
Naturally occurring disease in other species (companion animals, wildlife) > Search first: OMIA (Online Mendelian Inheritance in Animals), VetCompass, PubMed
Veterinary relevance and importance in animal health > Search first: OMIA, veterinary databases, PubMed
Comparative Biology:
Comparative pathology (similarities and differences across species) > Search first: OMIA, comparative pathology databases, PubMed
Evolutionary conservation of disease mechanisms > Search first: HomoloGene, OrthoMCL, Alliance of Genome Resources
Transmission (if applicable):
Zoonotic potential > Search first: CDC zoonotic diseases, WHO zoonoses, GIDEON
Cross-species susceptibility > Search first: NCBI Taxonomy, veterinary databases, PubMed

15. Model Organisms

Model Types:
Model organism type (mammalian, invertebrate, cellular, in vitro) > Search first: Alliance of Genome Resources, model organism databases
Specific model systems (mouse, rat, zebrafish, Drosophila, C. elegans, yeast, cell lines, organoids, iPSCs) > Search first: MGI, RGD, ZFIN, FlyBase, WormBase, SGD, ATCC, Cellosaurus
Induced models (drug treatment, surgical intervention, environmental manipulation) > Search first: MGI, model organism databases, PubMed
Genetic Models:
Types available (knockout, knock-in, transgenic, conditional, humanized) > Search first: MGI, IMPC, KOMP, EuMMCR, IMSR
Model Characteristics:
Phenotype recapitulation (how well model reproduces human disease features) > Search first: Model organism databases, comparative studies, PubMed
Model limitations (aspects of human disease not captured) > Search first: Model organism databases, PubMed, review articles
Applications:
Research applications (what aspects of disease can be studied) > Search first: Model organism databases, PubMed
Resources:
Model databases > Search first: MGI, RGD, ZFIN, FlyBase, WormBase, IMSR, EMMA, MMRRC

Citation Requirements

Cite primary literature (PMID preferred) for all mechanistic and clinical claims
Prioritize recent reviews and landmark papers
Include direct quotes from abstracts where possible to support key statements
Distinguish evidence source types: human clinical, model organism, in vitro, computational

Output Format

Structure your response as a comprehensive narrative organized by the sections above. For each section, provide: - Factual content with specific details (numbers, percentages, gene names, variant nomenclature) - Ontology term suggestions (HPO, GO, CL, UBERON, CHEBI, NCIT, MONDO) where applicable - Evidence citations with PMIDs - Direct quotes from abstracts to support key claims - Clear indication when information is not available or not applicable for this disease

This report will be used to populate a disease knowledge base entry with: - Pathophysiology descriptions with causal chains - Gene/protein annotations (HGNC, GO terms) - Phenotype associations (HP terms) with frequencies - Cell type involvement (CL terms) - Anatomical locations (UBERON terms) - Chemical entities (CHEBI terms) - Treatment annotations (NCIT terms) - Evidence items with PMIDs and exact abstract quotes - Epidemiology, prognosis, diagnostic, and prevention information - Animal model descriptions with phenotype recapitulation details

MPI-congenital disorder of glycosylation (MPI-CDG): comprehensive disease-characteristics report

Executive summary

MPI-CDG is an autosomal-recessive disorder of protein N-glycosylation caused by biallelic pathogenic variants in MPI, encoding mannose-phosphate isomerase. It is clinically distinctive among CDGs: gastrointestinal disease, congenital/developmental hepatic fibrosis, hypoglycemia—often hyperinsulinemic—and mixed coagulopathy predominate, while intellectual disability and primary neurologic impairment are usually absent. Oral D-mannose bypasses the metabolic block and commonly produces rapid improvement in diarrhea, protein-losing enteropathy, hypoglycemia, and coagulation abnormalities, but it does not reliably prevent progressive liver fibrosis or portal hypertension. Evidence remains dominated by case reports, small series, expert consensus, and approximately 35–52 published patients rather than controlled trials. (lu2023mannosephosphateisomerase pages 1-2, cechova2020consensusguidelinefor pages 4-6, cechova2020consensusguidelinefor pages 1-3, cechova2020consensusguidelinefor pages 19-20)

Topic	Key facts	Ontology / IDs	Key sources
Identity / overview	MPI-congenital disorder of glycosylation (MPI-CDG) is a rare disorder of protein N-glycosylation caused by pathogenic variants in MPI; unlike many other CDGs, it is dominated by gastrointestinal, hepatic, endocrine, and coagulation manifestations, with usually no intellectual disability or major neurologic impairment. Former names include CDG-Ib, CDG type Ib, carbohydrate-deficient glycoprotein syndrome type Ib, phosphomannose isomerase deficiency / mannose phosphate isomerase deficiency, protein-losing enteropathy-hepatic fibrosis syndrome, and Saguenay-Lac Saint-Jean syndrome.	OMIM: 602579; MeSH in trial browse: “Congenital disorder of glycosylation type 1B”; suggested disease label: MPI-CDG	(cechova2020consensusguidelinefor pages 1-3, NCT03404869 chunk 1)
Inheritance / gene	Autosomal recessive disorder due to biallelic pathogenic variants in MPI on chromosome 15q. The MPI gene has 8 exons and spans ~5 kb.	Suggested gene: MPI; inheritance: AR	(cechova2020consensusguidelinefor pages 1-3, cechova2020consensusguidelinefor pages 17-19)
Core mechanism	MPI catalyzes fructose-6-phosphate ↔ mannose-6-phosphate, the first step toward GDP-mannose synthesis for N-glycosylation. MPI deficiency lowers intracellular mannose availability; in patients, endogenous mannose is insufficient, leading to protein N-hypoglycosylation. Consensus guideline notes plasma mannose is <10 μmol/L in MPI-CDG vs 50–100 μmol/L in healthy individuals; glycosylation can be normalized when serum mannose exceeds ~200 μmol/L. Excess mannose can cause Man-6-P accumulation, glycolytic inhibition, ATP depletion, and neurologic toxicity (“honeybee effect”).	Suggested GO terms: protein N-linked glycosylation, mannose metabolic process; suggested CHEBI concept: D-mannose	(cechova2020consensusguidelinefor pages 3-4)
Typical onset / course	Symptoms begin in infancy in the large majority; consensus review found 93% infantile onset with mean onset 1.2 years, but adolescent presentations and asymptomatic adults have been reported. In the 2023 review, onset ranged birth to 15 years, with 43/50 cases starting before age 2. Diagnostic delay ranged 0–30 years (median 2.15 years).	Suggested onset terms: congenital/infantile; chronic multisystem course	(cechova2020consensusguidelinefor pages 4-6, lu2023mannosephosphateisomerase pages 1-2)
Hallmark phenotypes (2023 frequencies)	2023 literature review of 52 patients reported: chronic diarrhea 41/46, vomiting 23/27, hepatomegaly 39/44, hepatic fibrosis 20/37, protein-losing enteropathy 30/36, elevated transaminases 24/34, hyperinsulinemic hypoglycemia 24/34, hypoalbuminemia 33/38, prolonged coagulation 26/30, splenomegaly 13/21, non-pitting edema 14/20, failure to thrive 13/36, portal hypertension 4/9, epilepsy 2/17, thrombosis 12/14, elevated leukocytes 5; intellectual disability 0/28.	Reliable phenotype suggestions: hepatomegaly, diarrhea, vomiting, protein-losing enteropathy, hypoglycemia, hypoalbuminemia, hepatic fibrosis, portal hypertension, thrombosis	(lu2023mannosephosphateisomerase pages 1-2, lu2023mannosephosphateisomerase pages 3-5)
Diagnostics	First-line biochemical screen: serum/plasma transferrin isoelectric focusing (TIEF) showing CDG type I pattern (decreased tetrasialotransferrin, increased disialo-/asialotransferrin); reported 100% sensitivity in described genotyped patients, but non-specific vs other CDG-I disorders. HPLC/capillary electrophoresis for CDT% also reported 100% sensitivity in described patients. Confirmation: MPI enzyme assay in fibroblasts/leukocytes or MPI gene testing; enzyme activity usually <10% of normal, though 14–21% residual activity has been reported in some severe cases. Differential diagnosis includes PMM2-CDG, galactosemia, hereditary fructose intolerance, liver disease, chronic alcohol abuse, and other causes of hypoglycemia/PLE/hepatopathy.	Suggested lab/ontology terms: transferrin IEF, carbohydrate-deficient transferrin; gene: MPI	(cechova2020consensusguidelinefor pages 16-17, cechova2020consensusguidelinefor pages 17-19, cechova2020consensusguidelinefor pages 11-13, cechova2020consensusguidelinefor pages 10-11)
First-line treatment / dose	Standard disease-specific treatment is oral D-mannose. Consensus recommended dose: 150–170 mg/kg/dose, 4–5 times daily. In the 2023 review, 26/30 treated patients improved clinically/laboratorily; symptoms in the index case resolved within 1 week. Monitoring every 3 months during oral therapy includes unconjugated bilirubin, blood count, HbA1C, and mannose levels; target mannose levels suggested as T0 >20 μmol/L and T1h >100 μmol/L.	Suggested treatment term: D-mannose; NCIT suggestion only where available concept exists for mannose	(cechova2020consensusguidelinefor pages 19-20, lu2023mannosephosphateisomerase pages 2-3, lu2023mannosephosphateisomerase pages 5-6)
Key limitation / persistent liver disease	Mannose improves many clinical and biochemical abnormalities but does not reliably halt liver disease. Consensus guideline states patients may still develop progressive liver fibrosis, likely because characteristic lesions reflect ductal plate malformation / congenital hepatic fibrosis, which do not respond to mannose. Selected severe cases may require liver transplantation, especially for portal hypertension with hepatopulmonary syndrome.	Suggested anatomy: liver; suggested pathology: hepatic fibrosis, portal hypertension	(cechova2020consensusguidelinefor pages 8-10, cechova2020consensusguidelinefor pages 6-8)
Prognosis / mortality	Consensus review of 35 patients found mortality 23.5% (8/35); all deaths occurred in infancy/early childhood at 4 months to 5 years (median 2.2 years). Causes, when known, included hepatic failure (n=2) and sepsis (n=1); many deaths occurred before diagnosis/treatment. In the 2023 review, 8/11 untreated patients died, supporting major benefit from timely diagnosis and mannose therapy.	Suggested outcome terms: mortality, hepatic failure, sepsis	(cechova2020consensusguidelinefor pages 4-6, lu2023mannosephosphateisomerase pages 5-6)
Clinical trial / implementation	NCT03404869: “Study of ORL-1M (D-mannose) in Patients With CDG-Ib,” sponsor Orpha Labs; Phase 1/2, single-group, open-label, estimated n=5; primary outcome: improvement in hypoglycemia, diarrhea and vomiting at 6 months; secondary outcome: improved serum transferrin glycosylation at 30 days. Registry overall status is currently listed UNKNOWN; last known status RECRUITING; first posted 2018-01-19.	NCT03404869	(NCT03404869 chunk 1)
Animal / experimental models	Zebrafish mpi morphants: 13% residual Mpi activity at 4 dpf, 50% embryonic lethality by 4 dpf, and multisystem abnormalities in 82% of survivors (small eyes, dysmorphic jaws, pericardial edema, small liver, curled tails); phenotypes were rescued by mannose only if given before 24 hpf. Mouse models: complete Mpi knockout is embryonic lethal; hypomorphic mice with patient-like residual activity appeared largely normal but had ~15% embryonic lethality. Mannose exposure worsened outcomes, reducing litter size and survival to weaning by 40% and 66%, respectively, and ~50% of survivors developed ocular defects/blindness, highlighting species-specific toxicity and caution in pregnancy.	Suggested model systems: Danio rerio, Mus musculus	(chu2013azebrafishmodel pages 1-2, sharma2014mannosesupplementsinduce pages 1-2, brasil2018cdgtherapiesfrom pages 3-4)

Table: This table condenses the most actionable disease-characterization points for MPI-CDG, including identity, mechanism, phenotype frequencies, diagnosis, treatment, prognosis, trial activity, and model systems. It is formatted for direct use in a disease knowledge-base entry and cites the supporting evidence contexts.

Evidence scope and recency

The most disease-specific authoritative source is the international consensus guideline by Čechová et al., accepted April 3, 2020 and published in Journal of Inherited Metabolic Disease 43:671–693, DOI 10.1002/jimd.12241. It combined a systematic review with opinions from 21 experts across nine countries; the authors emphasized that most evidence was low-level because it consisted of case reports and case series. The newest detailed synthesis retrieved was Lu et al., published April 2023 in Frontiers in Pediatrics, DOI 10.3389/fped.2023.1150367, which reviewed 52 reported patients from 17 countries. No MPI-CDG-specific 2024 natural-history cohort, randomized trial, single-cell study, or spatial-omics study was identified in the retrieved literature. (lu2023mannosephosphateisomerase pages 1-2, cechova2020consensusguidelinefor pages 3-4, cechova2020consensusguidelinefor pages 1-3)

1. Disease information

Definition and identifiers

MPI-CDG is a Mendelian disorder of protein N-glycosylation caused by deficient mannose-phosphate isomerase activity. The consensus guideline explicitly describes it as “a rare subtype of congenital disorders of protein N-glycosylation” characterized by pathogenic MPI variants and dominant gastrointestinal and hepatic involvement without the usual intellectual or neurologic impairment seen in many CDGs. (cechova2020consensusguidelinefor pages 1-3)

OMIM phenotype: 602579.
Gene: MPI, chromosome 15q; eight exons spanning approximately 5 kb.
MeSH/ClinicalTrials.gov browse term: “Congenital disorder of glycosylation type 1B,” MeSH C535740.
MONDO: A specific MONDO identifier was not verified in the retrieved source text and should therefore be resolved directly against the current MONDO release before database deposition.
Orphanet: A disease-specific ORPHA number was not verified in the retrieved evidence.
ICD-10/ICD-11: No uniquely disease-specific code was established in the retrieved sources; MPI-CDG is generally captured under broader congenital glycosylation/metabolic-disorder categories.

Synonyms include CDG-Ib, CDG1B, congenital disorder of glycosylation type Ib, carbohydrate-deficient glycoprotein syndrome type Ib, phosphomannose isomerase deficiency, mannose-phosphate isomerase deficiency, protein-losing enteropathy–hepatic fibrosis syndrome, and Saguenay–Lac-Saint-Jean syndrome. (cechova2020consensusguidelinefor pages 3-4, cechova2020consensusguidelinefor pages 1-3, NCT03404869 chunk 1)

Provenance

This entry is based on aggregated disease-level resources, published case reports/series, an international expert guideline, and a trial registry—not individual-level EHR data. The 2023 frequencies are literature-derived denominators that vary by phenotype because not every feature was assessed in every patient. (lu2023mannosephosphateisomerase pages 3-5, lu2023mannosephosphateisomerase pages 1-2)

2. Etiology, risk, protective factors, and gene–environment interaction

Primary cause

The sole established primary cause is biallelic germline loss-of-function/hypomorphic variation in MPI. MPI catalyzes fructose-6-phosphate ↔ mannose-6-phosphate; reduced activity limits mannose-6-phosphate and downstream GDP-mannose availability for lipid-linked oligosaccharide synthesis and N-glycosylation. Pathogenic alleles are predominantly missense variants, consistent with survival requiring residual activity. (cechova2020consensusguidelinefor pages 3-4, cechova2020consensusguidelinefor pages 17-19)

Genetic risk factors

Risk is highest for a child inheriting one pathogenic allele from each carrier parent. Among 28 genotyped published patients in the 2020 review, 13 were homozygous; parental consanguinity was reported for nine patients. Twenty pathogenic variants comprised 17 missense variants, two frameshift-causing variants, and one splice defect. (cechova2020consensusguidelinefor pages 17-19)

Potentially mild p.Arg219Gln homozygosity was observed in two asymptomatic adults, suggesting incomplete penetrance or substantial modifier effects. However, neither residual enzyme activity nor carbohydrate-deficient transferrin reliably predicted clinical severity, and no validated modifier gene is known. (cechova2020consensusguidelinefor pages 17-19)

Environmental and protective factors

There are no established toxins, infections, lifestyle exposures, age, or sex factors that cause MPI-CDG. Exogenous dietary mannose is protective at the biochemical level because it bypasses the endogenous MPI-dependent route. Conversely, dehydration and acute infection can precipitate hypoglycemia and destabilize the mixed coagulation defect, increasing thrombosis risk. Alcohol and hepatotoxic drugs can add secondary liver injury and should be avoided. (cechova2020consensusguidelinefor pages 8-10, cechova2020consensusguidelinefor pages 13-14)

A clinically important gene–environment interaction is dose-dependent mannose rescue versus toxicity. Therapeutic oral mannose restores substrate for glycosylation, but excessive intracellular mannose-6-phosphate can inhibit hexokinase, phosphoglucose isomerase, and glucose-6-phosphate dehydrogenase, reduce glycolytic flux, deplete ATP, and cause energy failure—the “honeybee effect.” Pregnancy exposure warrants caution because adverse developmental effects occurred in MPI-deficient mice, although comparable human teratogenicity has not been demonstrated. (cechova2020consensusguidelinefor pages 3-4, sharma2014mannosesupplementsinduce pages 1-2)

No validated protective variant, environmental prevention strategy, or lifestyle measure prevents disease occurrence in a person with a disease-causing biallelic genotype.

3. Phenotypes

Quantitative clinical spectrum

The 2023 review reported the following frequencies: chronic diarrhea 41/46 (89%); vomiting 23/27 (85%); hepatomegaly 39/44 (89%); hepatic fibrosis 20/37 (54%); protein-losing enteropathy 30/36 (83%); elevated transaminases 24/34 (71%); hyperinsulinemic hypoglycemia 24/34 (71%); hypoalbuminemia 33/38 (87%); prolonged coagulation 26/30 (87%); splenomegaly 13/21 (62%); non-pitting edema 14/20 (70%); failure to thrive 13/36 (36%); portal hypertension 4/9 (44%); epilepsy/seizures 2/17 (12%); thrombosis 12/14 (86%); and intellectual disability 0/28. These proportions may be enriched by reporting and ascertainment bias and should not be interpreted as population prevalence. (lu2023mannosephosphateisomerase pages 3-5, lu2023mannosephosphateisomerase pages 1-2)

Phenotype characterization and ontology suggestions

Chronic or cyclic diarrhea/vomiting: usually infantile, recurrent or episodic, ranging from moderate to life-threatening dehydration; often the presenting feature. Suggested HPO: Diarrhea HP:0002014, Vomiting HP:0002013. It causes recurrent admissions, feeding difficulty, and major family burden. (cechova2020consensusguidelinefor pages 8-10, cechova2020consensusguidelinefor pages 10-11)
Protein-losing enteropathy: infantile and fluctuating, causing hypoalbuminemia, edema, malnutrition, and sometimes hypogammaglobulinemia. Stool alpha-1-antitrypsin may be 3- to 20-fold elevated. Suggested HPO: Protein-losing enteropathy HP:0002243, Hypoalbuminemia HP:0003073, Edema HP:0000969. (cechova2020consensusguidelinefor pages 10-11)
Failure to thrive/growth restriction: typically secondary to enteropathy, vomiting, and hypoglycemia; approximately two-thirds in the older consensus dataset but 13/36 in the expanded 2023 review. Suggested HPO: Failure to thrive HP:0001508, Growth delay HP:0001510. (lu2023mannosephosphateisomerase pages 1-2, cechova2020consensusguidelinefor pages 10-11)
Hepatomegaly, fibrosis, and portal hypertension: chronic and potentially progressive despite therapy. Fibrosis may produce splenomegaly, thrombocytopenia, esophageal varices, hepatopulmonary syndrome, and variceal hemorrhage. Suggested HPO: Hepatomegaly HP:0002240, Hepatic fibrosis HP:0001395, Portal hypertension HP:0001409, Splenomegaly HP:0001744. (cechova2020consensusguidelinefor pages 6-8, cechova2020consensusguidelinefor pages 8-10)
Transaminase elevation: commonly 1.5–5 times the upper limit, but as high as 30–40-fold during acute decompensation; bilirubin and GGT are often normal. Suggested HPO: Elevated hepatic transaminase HP:0002910. (cechova2020consensusguidelinefor pages 6-8)
Hypoglycemia/hyperinsulinism: onset from the perinatal period through three years, mean 6.8 months in the consensus review; severity ranges from asymptomatic biochemical hypoglycemia to apnea, unresponsiveness, or seizures. Suggested HPO: Hypoglycemia HP:0001943, Hyperinsulinemic hypoglycemia HP:0000825. (cechova2020consensusguidelinefor pages 11-13)
Mixed coagulopathy: almost constant in the consensus experience; commonly low antithrombin, protein C, factor XI, and sometimes protein S. It can produce both thrombosis and bleeding in the same patient. Suggested HPO: Abnormality of coagulation HP:0001928, Thrombosis HP:0001977, and Gastrointestinal hemorrhage HP:0002239. (cechova2020consensusguidelinefor pages 11-13, cechova2020consensusguidelinefor pages 13-14)
Neurologic findings: primary neurologic disease is atypical. Mild developmental delay was reported in four cases and hypotonia in five; seizures were secondary to hypoglycemia, cerebral thrombosis, fever, or intravenous-mannose toxicity. Brain imaging was normal in ten reported patients, without cerebellar hypoplasia. Suggested HPO only when present: Global developmental delay HP:0001263, Hypotonia HP:0001252, Seizure HP:0001250. (cechova2020consensusguidelinefor pages 13-14)
Renal/cardiac/immune findings: renal echogenicity, nephromegaly, cysts, or tubular acidosis occurred sporadically; one severe patient had hypertrophic cardiomyopathy. Recurrent unusual infections and PLE-related hypogammaglobulinemia occur, but a primary MPI-specific immunodeficiency is unproven. (cechova2020consensusguidelinefor pages 14-16)

Formal EQ-5D, SF-36, PROMIS, or disease-specific quality-of-life measurements were not identified. Nonetheless, recurrent admissions, diarrhea, hypoglycemia surveillance, bleeding/thrombosis risk, and four-to-five-times-daily mannose dosing clearly affect daily function and treatment burden.

4. Genetic and molecular information

Gene and protein

MPI encodes a mainly cytosolic enzyme that can also localize to the plasma membrane. The enzyme initiates endogenous mannose production by interconverting fructose-6-phosphate and mannose-6-phosphate. The disorder results from reduced enzymatic function, not a gain-of-function or dominant-negative mechanism. (cechova2020consensusguidelinefor pages 3-4)

Variant spectrum

In the 2020 consensus dataset, three recurrent missense variants accounted for approximately half of known alleles:

c.656G>A (p.Arg219Gln): 12 alleles; 21.4%.
c.457G>A (p.Arg152Gln): 9 alleles; 16.1%.
c.884G>A (p.Arg295His): 8 alleles; 14.3%.

Other reported variants included p.Ile398Thr, p.Ser102Leu, p.Met138Thr, p.Met51Thr, p.Asp131Asn, p.Ile140Thr, p.Ala288Val, p.Gln14Pro, p.Arg56fs, p.Tyr129Cys, p.Glu156Lys, c.488-1G>C, p.Gly250Ser, p.Tyr255Cys, p.Gly281del, p.Arg418His, and p.Arg418Cys. The 2023 case added compound heterozygous c.455G>T (p.Arg152Leu), classified as likely pathogenic, and c.884G>A (p.Arg295His), classified as pathogenic. (lu2023mannosephosphateisomerase pages 2-3, cechova2020consensusguidelinefor pages 17-19)

These are constitutional germline variants. No somatic disease mechanism is established. Exact current ClinVar assertions and gnomAD allele frequencies should be retrieved variant-by-variant from live databases; the source set did not provide dependable contemporary population frequencies.

Genotype–phenotype, modifiers, and epigenetics

Clinical severity is not reliably predicted by genotype, residual enzyme activity, or CDT value. Homozygous p.Arg219Gln may be mild or asymptomatic, but this observation rests on very few adults. No validated modifier gene, epigenetic signature, repeat expansion, aneuploidy, recurrent copy-number variant, or structural chromosomal cause is established. (cechova2020consensusguidelinefor pages 17-19)

Suggested molecular ontology: GO:0006487 protein N-linked glycosylation, GO:0009298 GDP-mannose biosynthetic process where applicable, GO:0005975 carbohydrate metabolic process, and MPI enzyme activity/mannose-6-phosphate isomerase activity. Database curators should validate exact GO identifiers against the current release.

5. Environmental, lifestyle, and infectious information

MPI-CDG is not caused by pollution, radiation, occupational exposure, smoking, alcohol, diet, or infection. Acute gastrointestinal infection, poor intake, dehydration, surgery, and fasting can nevertheless trigger metabolic and hemostatic decompensation. Alcohol and hepatotoxic medications are avoidable secondary insults in a disease with progressive liver vulnerability. Hepatitis A and B vaccination is recommended to prevent additional hepatic injury. (cechova2020consensusguidelinefor pages 11-13, cechova2020consensusguidelinefor pages 8-10)

No infectious agent is etiologic, and the disease is neither contagious nor zoonotic.

6. Mechanism and pathophysiology

Upstream causal chain

Biallelic hypomorphic MPI variants reduce mannose-phosphate isomerase activity.
Conversion of fructose-6-phosphate to mannose-6-phosphate falls.
GDP-mannose and lipid-linked oligosaccharide supply become insufficient.
Nascent secretory and membrane proteins receive too few N-glycan chains.
Hypoglycosylated proteins have altered folding, stability, trafficking, secretion, or function.
Tissue-specific consequences emerge in enterocytes, hepatocytes/biliary developmental structures, pancreatic beta-cell physiology, vascular/hemostatic proteins, and endocrine transport proteins. (cechova2020consensusguidelinefor pages 3-4, chu2013azebrafishmodel pages 1-2)

Plasma mannose was reported as <10 μmol/L in MPI-CDG versus 50–100 μmol/L in controls. Serum mannose above approximately 200 μmol/L can normalize glycosylation experimentally/clinically, explaining the substrate-bypass treatment. (cechova2020consensusguidelinefor pages 3-4)

Downstream organ mechanisms

Intestine: reduced glycoproteins on enterocyte membranes and/or intestinal lymphangiectasia compromise barrier integrity, causing protein leakage, hypoalbuminemia, edema, immunoglobulin loss, and malnutrition. Suggested cells: enterocyte (CL:0000584); processes: epithelial barrier maintenance, protein absorption, glycoprotein biosynthesis. (cechova2020consensusguidelinefor pages 10-11)
Liver/biliary tract: the characteristic lesion resembles congenital hepatic fibrosis with ductal-plate configuration and von Meyenburg complexes. This likely represents a developmental malformation, explaining why fibrosis and portal hypertension can progress even after systemic biochemical rescue. Suggested cells include hepatocyte (CL:0000182) and cholangiocyte; processes include bile-duct morphogenesis, extracellular-matrix organization, and fibrosis. (cechova2020consensusguidelinefor pages 6-8, cechova2020consensusguidelinefor pages 8-10)
Pancreatic endocrine system: hyperinsulinism may reflect hypoglycosylation of membrane proteins such as SUR1, but the exact mechanism remains uncertain. In vitro murine beta-cell evidence shows that hypoglycosylation can alter insulin secretion. Suggested cell: pancreatic beta cell (CL:0000169). (cechova2020consensusguidelinefor pages 11-13)
Hemostasis: hypoglycosylation reduces abundance/stability of antithrombin, protein C, factor XI, and protein S; increased platelet aggregation may compound the imbalance. Infection, dehydration, PLE, and hepatic dysfunction further destabilize hemostasis. (cechova2020consensusguidelinefor pages 11-13, cechova2020consensusguidelinefor pages 13-14)
Endocrine transport/growth: hypoglycosylated IGFBP-3, acid-labile subunit, and thyroxine-binding globulin can contribute to growth restriction and abnormal laboratory hormone values. (cechova2020consensusguidelinefor pages 11-13, cechova2020consensusguidelinefor pages 10-11)

Subcellular and metabolic localization

MPI acts predominantly in the cytosol upstream of endoplasmic-reticulum N-glycan assembly. Relevant compartments are cytosol, ER membrane/lumen, secretory pathway, and plasma membrane. Suggested GO cellular components include cytosol and endoplasmic reticulum.

Molecular profiling and advanced technologies

Transferrin glycoform profiling is the principal disease biomarker. A 2021 longitudinal study of 32 CDG patients, including three with MPI-CDG, found that mannose in two MPI-CDG patients significantly lowered asialo-, monosialo-, and disialotransferrin while increasing tetra- and pentasialotransferrin toward reference ranges. (bogdanska2021clinicalbiochemicaland pages 1-2)

No robust MPI-CDG-specific transcriptomic, proteomic, metabolomic, lipidomic, single-cell, spatial-transcriptomic, CRISPR-screen, or integrated multi-omics signature was identified. This is an important research gap rather than evidence of absence.

7. Anatomical structures affected

Primary organs and tissues

Small intestine and gastrointestinal tract: enterocyte surface and intestinal lymphatics; UBERON suggestions: small intestine, duodenum, intestinal epithelium.
Liver and intrahepatic bile ducts: portal tracts, ductal plate, biliary structures, and hepatic vasculature; UBERON: liver UBERON:0002107 and bile duct.
Pancreatic islets: beta-cell insulin regulation; UBERON: endocrine pancreas/pancreatic islet.
Blood and vascular system: circulating glycoproteins, platelets, and venous vasculature.

Secondary involvement includes spleen from portal hypertension; esophagus through varices; lung through hepatopulmonary syndrome; brain secondary to hypoglycemia or thrombosis; kidney and heart in occasional cases. There is no characteristic lateralization. (cechova2020consensusguidelinefor pages 6-8, cechova2020consensusguidelinefor pages 11-13, cechova2020consensusguidelinefor pages 14-16, cechova2020consensusguidelinefor pages 13-14)

At the subcellular level, the initial metabolic block is cytosolic, whereas the glycan-assembly consequence is expressed in the ER/secretory pathway and on secreted or cell-surface glycoproteins.

8. Temporal development

Symptoms begin in infancy in 93% of patients in the 2020 review, with mean onset at 1.2 years. The 2023 expanded review found onset from birth to age 15 and onset before age two in 43/50. Two adolescent presentations and asymptomatic adults into their early forties demonstrate very variable expressivity. (lu2023mannosephosphateisomerase pages 1-2, cechova2020consensusguidelinefor pages 4-6)

The gastrointestinal and hypoglycemic course is often episodic, with infection, fasting, or dehydration producing exacerbations. Mannose usually improves clinical symptoms within approximately one week, while biochemical stabilization takes months. Hepatic fibrosis is chronic and can remain progressive despite correction of extrahepatic features. (cechova2020consensusguidelinefor pages 8-10, cechova2020consensusguidelinefor pages 19-20)

There is no validated staging system. Pragmatic stages are: early gastrointestinal/endocrine presentation; established multisystem disease with PLE/coagulopathy; and advanced portal-hypertensive disease with varices or hepatopulmonary syndrome. Early diagnosis is the critical therapeutic window; animal evidence also suggests developmental timing matters, but the zebrafish pre-24-hour rescue window cannot be directly extrapolated to humans. (chu2013azebrafishmodel pages 1-2)

9. Inheritance and population

MPI-CDG is autosomal recessive. For two confirmed carriers, each pregnancy has a 25% probability of an affected child, 50% probability of a carrier child, and 25% probability of inheriting neither familial pathogenic allele. Anticipation is not expected. Germline mosaicism has not emerged as a characteristic mechanism, although low residual recurrence risk from parental mosaicism cannot be excluded generically.

The 2020 review included 35 patients from 30 families and described the disease as panethnic. The 2023 review found 52 patients across 17 countries. True prevalence, incidence, carrier frequency, and population-specific penetrance remain unknown. (lu2023mannosephosphateisomerase pages 1-2, cechova2020consensusguidelinefor pages 3-4, cechova2020consensusguidelinefor pages 4-6)

The 2020 sample included 18 females and nine males, with sex unspecified in eight; the authors considered the apparent 2:1 ratio likely due to small sample size rather than sex-biased biology. Consanguinity contributed to homozygosity in some families. Although “Saguenay–Lac-Saint-Jean syndrome” reflects an early regional cluster, no sufficiently quantified founder prevalence was retrieved. (cechova2020consensusguidelinefor pages 4-6, cechova2020consensusguidelinefor pages 17-19)

10. Diagnostics

When to suspect MPI-CDG

Test children or adults with combinations of recurrent/cyclic diarrhea or vomiting, PLE/hypoalbuminemia, hepatomegaly or congenital hepatic fibrosis, hyperinsulinemic hypoglycemia, unexplained prolonged coagulation, low antithrombin/protein C/factor XI, thrombosis, or portal hypertension—especially when neurodevelopment is normal. (cechova2020consensusguidelinefor pages 1-3, cechova2020consensusguidelinefor pages 11-13, cechova2020consensusguidelinefor pages 10-11)

Biochemical testing

Serum/plasma transferrin isoelectric focusing: preferred screen. The type-I pattern shows reduced tetrasialotransferrin and increased disialo- and asialotransferrin. Sensitivity was reported as 100% among described genotyped patients, but specificity is poor because PMM2-CDG and other CDG-I disorders are indistinguishable. (cechova2020consensusguidelinefor pages 14-16, cechova2020consensusguidelinefor pages 16-17)
HPLC or capillary electrophoresis/CDT%: quantitative alternatives, also reported as 100% sensitive in described cases. CDT can be 38–50% in severe disease versus 7–20% in oligo-/asymptomatic adults. (cechova2020consensusguidelinefor pages 16-17)
MPI enzyme activity: confirmatory testing in fresh leukocytes or fibroblasts. Most reported patients had <10% normal activity, although 14–21% occurred in some severe cases. Parental activity was typically intermediate, 30–83%, median 50%. (cechova2020consensusguidelinefor pages 16-17)
Molecular confirmation: sequence MPI by single-gene testing, a CDG/hypoglycemia/liver-disease panel, WES, or WGS. Sanger confirmation and parental segregation are appropriate. (cechova2020consensusguidelinefor pages 17-19)

WES diagnosed the 2023 index case and is useful for atypical disease. WGS may detect noncoding or structural alleles missed by exon-focused assays, but disease-specific diagnostic-yield data are unavailable. CMA, karyotyping, FISH, mitochondrial sequencing, and repeat-expansion testing are not routine tests because MPI-CDG is usually a small-sequence-variant disorder.

False positives and differential diagnosis

Transferrin variants, sample contamination by neuraminidase-producing microorganisms, untreated galactosemia, hereditary fructose intolerance, severe infection, chronic liver disease, and alcohol exposure can produce abnormal transferrin patterns. Repeat testing on an independent sample, neuraminidase treatment, and parental transferrin analysis can resolve some ambiguities. (cechova2020consensusguidelinefor pages 14-16, cechova2020consensusguidelinefor pages 16-17)

Clinical differentials include PMM2-CDG; PGM1-, ALG6-, TMEM199-, CCDC115-, and ATP6AP1-CDG; celiac disease; intestinal lymphangiectasia; inflammatory/infectious enteropathy; glycogen storage disease; fatty-acid oxidation disorders; galactosemia; hereditary fructose intolerance; congenital hyperinsulinism; alpha-1-antitrypsin deficiency; Wilson disease; cystic fibrosis; congenital hepatic fibrosis/ARPKD; and other metabolic liver disorders. (cechova2020consensusguidelinefor pages 6-8, cechova2020consensusguidelinefor pages 11-13, cechova2020consensusguidelinefor pages 10-11)

Surveillance after diagnosis

Consensus recommendations include liver chemistry, AFP, prothrombin time, and ultrasound every six months; annual elastography when transaminases remain elevated; annual endoscopy initially in portal hypertension and thereafter at least every three years; albumin every three months during active PLE; glucose monitoring and critical hypoglycemia samples; annual broad hemostasis testing; and annual thyroid/IGF-axis, renal, immune, developmental, and nutritional assessment as clinically indicated. (cechova2020consensusguidelinefor pages 6-8, cechova2020consensusguidelinefor pages 4-6, cechova2020consensusguidelinefor pages 11-13)

Screening

MPI-CDG is not a standard population newborn-screening condition. The Early Check trial retrieved in the search was broad expanded newborn screening and does not establish routine MPI-CDG screening. Cascade testing, carrier testing, prenatal diagnosis, and preimplantation genetic testing are feasible once familial variants are known.

11. Outcome and prognosis

In the 2020 review, mortality was 23.5% (8/35). All deaths occurred between four months and five years, median 2.2 years; known causes included hepatic failure in two and sepsis in one. Six of eight died before the disorder and mannose treatment were recognized. The 2023 review found 8/11 untreated patients died, compared with improvement in 26/30 treated patients. These uncontrolled comparisons strongly favor early treatment but are vulnerable to era, severity, and publication bias. (lu2023mannosephosphateisomerase pages 5-6, cechova2020consensusguidelinefor pages 4-6)

Survival into adulthood, normal pregnancy, and even asymptomatic adulthood are documented. No reliable five- or ten-year survival curve or life-expectancy estimate exists. Prognosis is driven by timeliness of diagnosis, severity of PLE and hypoglycemia, infection/dehydration exposure, thrombosis/bleeding, and especially progression of congenital hepatic fibrosis and portal hypertension. (cechova2020consensusguidelinefor pages 4-6, cechova2020consensusguidelinefor pages 10-11, cechova2020consensusguidelinefor pages 17-19)

Mannose offers substantial recovery potential for gastrointestinal, endocrine, and coagulation abnormalities, but established ductal-plate malformation and fibrosis may be irreversible. Formal disability and quality-of-life datasets are absent.

12. Treatment

Oral D-mannose: standard disease-specific therapy

The consensus dose is 150–170 mg/kg per dose orally four to five times daily, started as soon as diagnosis is made. Oral mannose enters a complementary pathway through hexokinase to form mannose-6-phosphate, bypassing deficient MPI. Clinical response often begins within a week; biochemical abnormalities may take months to stabilize. In the 2023 case, diarrhea and vomiting resolved completely within one week without reported adverse effects. (lu2023mannosephosphateisomerase pages 2-3, cechova2020consensusguidelinefor pages 11-13, cechova2020consensusguidelinefor pages 19-20)

Effects: regression of diarrhea, vomiting, PLE, hypoalbuminemia, hypoglycemia, and coagulopathy; improved growth and transferrin glycosylation. In the 2023 synthesis, 26/30 treated patients improved. However, abnormal transferrin profiles rarely normalize completely, and liver fibrosis may progress. (lu2023mannosephosphateisomerase pages 5-6, cechova2020consensusguidelinefor pages 8-10, cechova2020consensusguidelinefor pages 16-17, bogdanska2021clinicalbiochemicaland pages 1-2)

Monitoring: every three months, assess unconjugated bilirubin, CBC, HbA1C, and mannose. Suggested targets are trough/T0 >20 μmol/L and one-hour/T1 >100 μmol/L. Abdominal pain and diarrhea occurred in approximately 40% and usually improved spontaneously or after dose adjustment. (cechova2020consensusguidelinefor pages 19-20)

Suggested annotations: CHEBI D-mannose; NCIT intervention concept Mannose or Dietary Supplementation, subject to terminology-service validation.

Intravenous mannose

Not recommended for stable disease. It may be considered only in life-threatening situations when oral treatment is impossible, using continuous infusion up to 1 g/kg/day with individualized IV glucose. Severe hemolysis occurred in one patient and seizures/stupor in another; daily neurologic, bilirubin, CBC, and hexosuria monitoring is required. (cechova2020consensusguidelinefor pages 8-10, cechova2020consensusguidelinefor pages 19-20, cechova2020consensusguidelinefor pages 17-19)

Hypoglycemia management

Frequent feeding and complex carbohydrate supplementation are useful. Acute illness, perioperative fasting, or inability to feed requires continuous IV glucose to maintain glucose above 4 mmol/L; severe episodes target 4–6 mmol/L. Confirmed hyperinsulinism may require diazoxide 4–15 mg/kg/day in three or four divided doses. (cechova2020consensusguidelinefor pages 11-13, cechova2020consensusguidelinefor pages 8-10)

Gastrointestinal and nutritional support

Severe malnutrition may require enteral tube feeding or parenteral nutrition. Albumin infusion can bridge severe PLE with edema; the consensus table specifies 20% albumin when serum albumin is <2 g/dL. Immunoglobulin replacement may be used for significant PLE-related hypogammaglobulinemia. Experimental heparin improved PLE in one report but carries bleeding risk and is not routine disease-modifying treatment. (cechova2020consensusguidelinefor pages 8-10, cechova2020consensusguidelinefor pages 10-11)

Coagulation management

Mannose usually corrects coagulation abnormalities within weeks. Treat thrombosis with unfractionated or low-molecular-weight heparin; vitamin-K antagonists require caution in patients with ulcers or varices. Severe bleeding may require local control and fresh frozen plasma. Factor XI concentrate and recombinant factor VIIa are discouraged because of thrombosis risk. Perioperative plans should be individualized with hematology input. (cechova2020consensusguidelinefor pages 13-14)

Liver-directed treatment

Monitor and treat varices and portal-hypertensive complications according to standard hepatology practice. Liver transplantation is an option for selected patients with liver failure or portal hypertension with hepatopulmonary syndrome. In the reported transplant recipient, pulmonary function, coagulation, and transferrin IEF normalized, but extrahepatic MPI deficiency persisted. (cechova2020consensusguidelinefor pages 6-8, cechova2020consensusguidelinefor pages 8-10)

Suggested NCIT concepts include Liver Transplantation, Parenteral Nutrition, Albumin Infusion, Diazoxide, Heparin, and Glucose Infusion, with exact codes requiring current NCIT validation.

Experimental and advanced therapy

No approved gene, RNA, genome-editing, enzyme-replacement, or cell therapy was identified. NCT03404869, “Study of ORL-1M (D-mannose) in Patients With CDG-Ib,” is a Phase 1/2, open-label, single-group study with estimated enrollment of five participants younger than 18. The primary endpoint was improvement in hypoglycemia, diarrhea, and vomiting at six months; the secondary endpoint was transferrin-glycosylation improvement at 30 days. It started March 31, 2015, was first posted January 19, 2018, and is currently listed as unknown status, last known recruiting. No posted results were retrieved. Registry URL: ClinicalTrials.gov NCT03404869. (NCT03404869 chunk 1)

13. Prevention

Primary prevention of disease in an already conceived affected individual is not available because the cause is inherited. Reproductive prevention options include carrier testing for relatives, genetic counseling, prenatal diagnosis, and preimplantation genetic testing once familial variants are established.

Secondary prevention centers on early recognition and prompt mannose therapy before severe PLE, hypoglycemic brain injury, thrombosis, or irreversible portal-hypertensive complications. There is no established population newborn screen.

Tertiary prevention includes avoiding fasting and dehydration; sick-day glucose plans; rapid treatment of infection; regular liver, glucose, nutrition, and coagulation surveillance; thromboprophylaxis in appropriate high-risk settings; hepatitis A/B vaccination; alcohol abstinence; avoidance of hepatotoxic drugs; and screening/treatment of esophageal varices. (cechova2020consensusguidelinefor pages 6-8, cechova2020consensusguidelinefor pages 8-10, cechova2020consensusguidelinefor pages 13-14)

No MPI-CDG-specific vaccine, public-health sanitation measure, or environmental remediation is applicable.

14. Other species and natural disease

No naturally occurring MPI-CDG-equivalent veterinary disease in a defined companion-animal breed or wildlife population was established in the retrieved evidence. Accordingly, no VBO breed annotation is justified. There is no transmission or zoonotic potential.

The MPI pathway is evolutionarily conserved from fungi and invertebrates to fish, mice, and humans, but comparative observations such as natural mannose toxicity in honeybees are mechanistic analogies rather than homologous clinical disease. Suggested taxa for experimental evidence are Homo sapiens NCBI:9606, Mus musculus NCBI:10090, and Danio rerio NCBI:7955.

15. Model organisms and experimental systems

Mouse

Complete Mpi knockout causes embryonic death around E11.5 with placental and embryonic abnormalities; mannose cannot rescue it because toxic mannose-6-phosphate accumulates and inhibits ATP production. This model demonstrates developmental essentiality but poorly reproduces viable human hypomorphic disease. (sharma2014mannosesupplementsinduce pages 1-2, cechova2020consensusguidelinefor pages 20-21)

A patient-relevant hypomorphic mouse had near-patient residual activity and appeared mostly normal, apart from approximately 15% embryonic lethality. Providing pregnant dams 1–2% mannose reduced litter size by 40% and survival to weaning by 66%; 50% of survivors developed eye defects. Starting mannose after eye development avoided ocular toxicity. These findings support a developmental window and pregnancy caution, but the lack of human-like liver/intestinal disease and species-specific mannose sensitivity limit translational generalization. The paper was published in January 2014, FASEB Journal 28:1854–1869, DOI 10.1096/fj.13-245514. (sharma2014mannosesupplementsinduce pages 1-2)

Zebrafish

Morpholino-mediated mpi depletion generated 13% residual Mpi activity at four days post-fertilization, reduced lipid-linked oligosaccharides and N-glycans, 50% embryonic lethality, and abnormalities in 82% of surviving larvae, including small eyes, dysmorphic jaws, pericardial edema, small liver, and curled tails. Mannose rescued the phenotype only when provided before 24 hours post-fertilization. The model is useful for developmental timing, glycan biochemistry, and treatment screening, but transient morpholino knockdown and embryonic phenotypes do not reproduce chronic human portal-hypertensive disease. Published in 2013, Disease Models & Mechanisms 6:95–105, DOI 10.1242/dmm.010116. (chu2013azebrafishmodel pages 1-2)

Cellular models

Patient fibroblasts and fresh leukocytes are used for enzyme activity and mannose-rescue studies. They reproduce reduced MPI activity and glycosylation but cannot model multicellular intestinal leakage, ductal-plate malformation, portal hypertension, or whole-body hypoglycemia. No MPI-CDG iPSC, organoid, humanized mouse, or validated CRISPR knock-in model with comprehensive human phenotype recapitulation was identified.

Key expert interpretation and research priorities

The international consensus is that oral mannose is strongly indicated despite low formal evidence grades because the biochemical rationale, rapid within-patient response, long clinical experience, and untreated mortality are compelling. The most consequential misconception is that biochemical correction equals cure: MPI-CDG remains a progressive hepatic disorder in some patients because congenital ductal-plate pathology appears mannose-insensitive. (cechova2020consensusguidelinefor pages 8-10, cechova2020consensusguidelinefor pages 19-20)

Priorities for 2025-era research include an international prospective natural-history registry; validated patient-reported outcomes; current variant-level ClinVar/gnomAD curation; pharmacokinetic optimization or sustained-release mannose; pregnancy safety data; biomarkers predicting fibrosis and portal hypertension; liver/intestinal organoids; and controlled studies separating mannose-responsive systemic hypoglycosylation from mannose-resistant developmental liver pathology.

Selected direct source quotations

Čechová et al. 2020: “The manifestation of MPI-CDG is different from other CDGs as the patients suffer dominantly from gastrointestinal and hepatic involvement whereas they usually do not present intellectual disability or neurological impairment.” DOI 10.1002/jimd.12241. (cechova2020consensusguidelinefor pages 1-3)
Lu et al. 2023: after mannose initiation, “the vomiting and diarrhea symptoms disappeared completely” within one week. DOI 10.3389/fped.2023.1150367. (lu2023mannosephosphateisomerase pages 1-2)
Chu et al. 2013: mannose restored glycosylation and rescued zebrafish abnormalities, but “mannose was only effective if provided prior to 24 hpf.” DOI 10.1242/dmm.010116. (chu2013azebrafishmodel pages 1-2)
Bogdańska et al. 2021: “Mannose supplementation in MPI-CDG patients… improved patients’ clinical picture and Tf isoform profiles.” DOI 10.1186/s13023-020-01657-5. (bogdanska2021clinicalbiochemicaland pages 1-2)

Evidence caveat: Exact PMIDs were not consistently exposed in the retrieved full-text records. DOIs and registry URLs are therefore supplied where verified; PMIDs should be added through a live PubMed cross-check before final production database release.

References

(lu2023mannosephosphateisomerase pages 1-2): Siliang Lu, Shuheng Liang, Yi Wu, Jinyi Liu, Lin Lin, Guosheng Huang, and Huaijun Ning. Mannose phosphate isomerase gene mutation leads to a congenital disorder of glycosylation: a rare case report and literature review. Frontiers in Pediatrics, Apr 2023. URL: https://doi.org/10.3389/fped.2023.1150367, doi:10.3389/fped.2023.1150367. This article has 8 citations.
(cechova2020consensusguidelinefor pages 4-6): Anna Čechová, Ruqaiah Altassan, Delphine Borgel, Arnaud Bruneel, Joana Correia, Muriel Girard, Annie Harroche, Beata Kiec‐Wilk, Klaus Mohnike, Tiffany Pascreau, Łukasz Pawliński, Silvia Radenkovic, Sandrine Vuillaumier‐Barrot, Luis Aldamiz‐Echevarria, Maria Luz Couce, Esmeralda G. Martins, Dulce Quelhas, Eva Morava, Pascale de Lonlay, Peter Witters, and Tomáš Honzík. Consensus guideline for the diagnosis and management of mannose phosphate isomerase‐congenital disorder of glycosylation. Journal of Inherited Metabolic Disease, 43:671-693, Apr 2020. URL: https://doi.org/10.1002/jimd.12241, doi:10.1002/jimd.12241. This article has 73 citations and is from a peer-reviewed journal.
(cechova2020consensusguidelinefor pages 1-3): Anna Čechová, Ruqaiah Altassan, Delphine Borgel, Arnaud Bruneel, Joana Correia, Muriel Girard, Annie Harroche, Beata Kiec‐Wilk, Klaus Mohnike, Tiffany Pascreau, Łukasz Pawliński, Silvia Radenkovic, Sandrine Vuillaumier‐Barrot, Luis Aldamiz‐Echevarria, Maria Luz Couce, Esmeralda G. Martins, Dulce Quelhas, Eva Morava, Pascale de Lonlay, Peter Witters, and Tomáš Honzík. Consensus guideline for the diagnosis and management of mannose phosphate isomerase‐congenital disorder of glycosylation. Journal of Inherited Metabolic Disease, 43:671-693, Apr 2020. URL: https://doi.org/10.1002/jimd.12241, doi:10.1002/jimd.12241. This article has 73 citations and is from a peer-reviewed journal.
(cechova2020consensusguidelinefor pages 19-20): Anna Čechová, Ruqaiah Altassan, Delphine Borgel, Arnaud Bruneel, Joana Correia, Muriel Girard, Annie Harroche, Beata Kiec‐Wilk, Klaus Mohnike, Tiffany Pascreau, Łukasz Pawliński, Silvia Radenkovic, Sandrine Vuillaumier‐Barrot, Luis Aldamiz‐Echevarria, Maria Luz Couce, Esmeralda G. Martins, Dulce Quelhas, Eva Morava, Pascale de Lonlay, Peter Witters, and Tomáš Honzík. Consensus guideline for the diagnosis and management of mannose phosphate isomerase‐congenital disorder of glycosylation. Journal of Inherited Metabolic Disease, 43:671-693, Apr 2020. URL: https://doi.org/10.1002/jimd.12241, doi:10.1002/jimd.12241. This article has 73 citations and is from a peer-reviewed journal.
(NCT03404869 chunk 1): Study of ORL-1M (D-mannose) in Patients With CDG-Ib. Orpha Labs. 2015. ClinicalTrials.gov Identifier: NCT03404869
(cechova2020consensusguidelinefor pages 17-19): Anna Čechová, Ruqaiah Altassan, Delphine Borgel, Arnaud Bruneel, Joana Correia, Muriel Girard, Annie Harroche, Beata Kiec‐Wilk, Klaus Mohnike, Tiffany Pascreau, Łukasz Pawliński, Silvia Radenkovic, Sandrine Vuillaumier‐Barrot, Luis Aldamiz‐Echevarria, Maria Luz Couce, Esmeralda G. Martins, Dulce Quelhas, Eva Morava, Pascale de Lonlay, Peter Witters, and Tomáš Honzík. Consensus guideline for the diagnosis and management of mannose phosphate isomerase‐congenital disorder of glycosylation. Journal of Inherited Metabolic Disease, 43:671-693, Apr 2020. URL: https://doi.org/10.1002/jimd.12241, doi:10.1002/jimd.12241. This article has 73 citations and is from a peer-reviewed journal.
(cechova2020consensusguidelinefor pages 3-4): Anna Čechová, Ruqaiah Altassan, Delphine Borgel, Arnaud Bruneel, Joana Correia, Muriel Girard, Annie Harroche, Beata Kiec‐Wilk, Klaus Mohnike, Tiffany Pascreau, Łukasz Pawliński, Silvia Radenkovic, Sandrine Vuillaumier‐Barrot, Luis Aldamiz‐Echevarria, Maria Luz Couce, Esmeralda G. Martins, Dulce Quelhas, Eva Morava, Pascale de Lonlay, Peter Witters, and Tomáš Honzík. Consensus guideline for the diagnosis and management of mannose phosphate isomerase‐congenital disorder of glycosylation. Journal of Inherited Metabolic Disease, 43:671-693, Apr 2020. URL: https://doi.org/10.1002/jimd.12241, doi:10.1002/jimd.12241. This article has 73 citations and is from a peer-reviewed journal.
(lu2023mannosephosphateisomerase pages 3-5): Siliang Lu, Shuheng Liang, Yi Wu, Jinyi Liu, Lin Lin, Guosheng Huang, and Huaijun Ning. Mannose phosphate isomerase gene mutation leads to a congenital disorder of glycosylation: a rare case report and literature review. Frontiers in Pediatrics, Apr 2023. URL: https://doi.org/10.3389/fped.2023.1150367, doi:10.3389/fped.2023.1150367. This article has 8 citations.
(cechova2020consensusguidelinefor pages 16-17): Anna Čechová, Ruqaiah Altassan, Delphine Borgel, Arnaud Bruneel, Joana Correia, Muriel Girard, Annie Harroche, Beata Kiec‐Wilk, Klaus Mohnike, Tiffany Pascreau, Łukasz Pawliński, Silvia Radenkovic, Sandrine Vuillaumier‐Barrot, Luis Aldamiz‐Echevarria, Maria Luz Couce, Esmeralda G. Martins, Dulce Quelhas, Eva Morava, Pascale de Lonlay, Peter Witters, and Tomáš Honzík. Consensus guideline for the diagnosis and management of mannose phosphate isomerase‐congenital disorder of glycosylation. Journal of Inherited Metabolic Disease, 43:671-693, Apr 2020. URL: https://doi.org/10.1002/jimd.12241, doi:10.1002/jimd.12241. This article has 73 citations and is from a peer-reviewed journal.
(cechova2020consensusguidelinefor pages 11-13): Anna Čechová, Ruqaiah Altassan, Delphine Borgel, Arnaud Bruneel, Joana Correia, Muriel Girard, Annie Harroche, Beata Kiec‐Wilk, Klaus Mohnike, Tiffany Pascreau, Łukasz Pawliński, Silvia Radenkovic, Sandrine Vuillaumier‐Barrot, Luis Aldamiz‐Echevarria, Maria Luz Couce, Esmeralda G. Martins, Dulce Quelhas, Eva Morava, Pascale de Lonlay, Peter Witters, and Tomáš Honzík. Consensus guideline for the diagnosis and management of mannose phosphate isomerase‐congenital disorder of glycosylation. Journal of Inherited Metabolic Disease, 43:671-693, Apr 2020. URL: https://doi.org/10.1002/jimd.12241, doi:10.1002/jimd.12241. This article has 73 citations and is from a peer-reviewed journal.
(cechova2020consensusguidelinefor pages 10-11): Anna Čechová, Ruqaiah Altassan, Delphine Borgel, Arnaud Bruneel, Joana Correia, Muriel Girard, Annie Harroche, Beata Kiec‐Wilk, Klaus Mohnike, Tiffany Pascreau, Łukasz Pawliński, Silvia Radenkovic, Sandrine Vuillaumier‐Barrot, Luis Aldamiz‐Echevarria, Maria Luz Couce, Esmeralda G. Martins, Dulce Quelhas, Eva Morava, Pascale de Lonlay, Peter Witters, and Tomáš Honzík. Consensus guideline for the diagnosis and management of mannose phosphate isomerase‐congenital disorder of glycosylation. Journal of Inherited Metabolic Disease, 43:671-693, Apr 2020. URL: https://doi.org/10.1002/jimd.12241, doi:10.1002/jimd.12241. This article has 73 citations and is from a peer-reviewed journal.
(lu2023mannosephosphateisomerase pages 2-3): Siliang Lu, Shuheng Liang, Yi Wu, Jinyi Liu, Lin Lin, Guosheng Huang, and Huaijun Ning. Mannose phosphate isomerase gene mutation leads to a congenital disorder of glycosylation: a rare case report and literature review. Frontiers in Pediatrics, Apr 2023. URL: https://doi.org/10.3389/fped.2023.1150367, doi:10.3389/fped.2023.1150367. This article has 8 citations.
(lu2023mannosephosphateisomerase pages 5-6): Siliang Lu, Shuheng Liang, Yi Wu, Jinyi Liu, Lin Lin, Guosheng Huang, and Huaijun Ning. Mannose phosphate isomerase gene mutation leads to a congenital disorder of glycosylation: a rare case report and literature review. Frontiers in Pediatrics, Apr 2023. URL: https://doi.org/10.3389/fped.2023.1150367, doi:10.3389/fped.2023.1150367. This article has 8 citations.
(cechova2020consensusguidelinefor pages 8-10): Anna Čechová, Ruqaiah Altassan, Delphine Borgel, Arnaud Bruneel, Joana Correia, Muriel Girard, Annie Harroche, Beata Kiec‐Wilk, Klaus Mohnike, Tiffany Pascreau, Łukasz Pawliński, Silvia Radenkovic, Sandrine Vuillaumier‐Barrot, Luis Aldamiz‐Echevarria, Maria Luz Couce, Esmeralda G. Martins, Dulce Quelhas, Eva Morava, Pascale de Lonlay, Peter Witters, and Tomáš Honzík. Consensus guideline for the diagnosis and management of mannose phosphate isomerase‐congenital disorder of glycosylation. Journal of Inherited Metabolic Disease, 43:671-693, Apr 2020. URL: https://doi.org/10.1002/jimd.12241, doi:10.1002/jimd.12241. This article has 73 citations and is from a peer-reviewed journal.
(cechova2020consensusguidelinefor pages 6-8): Anna Čechová, Ruqaiah Altassan, Delphine Borgel, Arnaud Bruneel, Joana Correia, Muriel Girard, Annie Harroche, Beata Kiec‐Wilk, Klaus Mohnike, Tiffany Pascreau, Łukasz Pawliński, Silvia Radenkovic, Sandrine Vuillaumier‐Barrot, Luis Aldamiz‐Echevarria, Maria Luz Couce, Esmeralda G. Martins, Dulce Quelhas, Eva Morava, Pascale de Lonlay, Peter Witters, and Tomáš Honzík. Consensus guideline for the diagnosis and management of mannose phosphate isomerase‐congenital disorder of glycosylation. Journal of Inherited Metabolic Disease, 43:671-693, Apr 2020. URL: https://doi.org/10.1002/jimd.12241, doi:10.1002/jimd.12241. This article has 73 citations and is from a peer-reviewed journal.
(chu2013azebrafishmodel pages 1-2): Jaime Chu, Alexander Mir, Ningguo Gao, Sabrina Rosa, Christopher Monson, Vandana Sharma, Richard Steet, Hudson H. Freeze, Mark A. Lehrman, and Kirsten C. Sadler. A zebrafish model of congenital disorders of glycosylation with phosphomannose isomerase deficiency reveals an early opportunity for corrective mannose supplementation. Disease Models & Mechanisms, 6:95-105, Aug 2013. URL: https://doi.org/10.1242/dmm.010116, doi:10.1242/dmm.010116. This article has 44 citations and is from a domain leading peer-reviewed journal.
(sharma2014mannosesupplementsinduce pages 1-2): Vandana Sharma, Jonamani Nayak, Charles DeRossi, Adriana Charbono, Mie Ichikawa, Bobby G. Ng, Erika Grajales‐Esquivel, Anand Srivastava, Ling Wang, Ping He, David A. Scott, Joseph Russell, Emily Contreras, Cherise M. Guess, Stan Krajewski, Katia Del Rio‐Tsonis, and Hudson H. Freeze. Mannose supplements induce embryonic lethality and blindness in phosphomannose isomerase hypomorphic mice. The FASEB Journal, 28:1854-1869, Jan 2014. URL: https://doi.org/10.1096/fj.13-245514, doi:10.1096/fj.13-245514. This article has 39 citations.
(brasil2018cdgtherapiesfrom pages 3-4): Sandra Brasil, Carlota Pascoal, Rita Francisco, Dorinda Marques-da-Silva, Giuseppina Andreotti, Paula A. Videira, Eva Morava, Jaak Jaeken, and Vanessa Dos Reis Ferreira. Cdg therapies: from bench to bedside. International Journal of Molecular Sciences, 19:1304, Apr 2018. URL: https://doi.org/10.3390/ijms19051304, doi:10.3390/ijms19051304. This article has 120 citations.
(cechova2020consensusguidelinefor pages 13-14): Anna Čechová, Ruqaiah Altassan, Delphine Borgel, Arnaud Bruneel, Joana Correia, Muriel Girard, Annie Harroche, Beata Kiec‐Wilk, Klaus Mohnike, Tiffany Pascreau, Łukasz Pawliński, Silvia Radenkovic, Sandrine Vuillaumier‐Barrot, Luis Aldamiz‐Echevarria, Maria Luz Couce, Esmeralda G. Martins, Dulce Quelhas, Eva Morava, Pascale de Lonlay, Peter Witters, and Tomáš Honzík. Consensus guideline for the diagnosis and management of mannose phosphate isomerase‐congenital disorder of glycosylation. Journal of Inherited Metabolic Disease, 43:671-693, Apr 2020. URL: https://doi.org/10.1002/jimd.12241, doi:10.1002/jimd.12241. This article has 73 citations and is from a peer-reviewed journal.
(cechova2020consensusguidelinefor pages 14-16): Anna Čechová, Ruqaiah Altassan, Delphine Borgel, Arnaud Bruneel, Joana Correia, Muriel Girard, Annie Harroche, Beata Kiec‐Wilk, Klaus Mohnike, Tiffany Pascreau, Łukasz Pawliński, Silvia Radenkovic, Sandrine Vuillaumier‐Barrot, Luis Aldamiz‐Echevarria, Maria Luz Couce, Esmeralda G. Martins, Dulce Quelhas, Eva Morava, Pascale de Lonlay, Peter Witters, and Tomáš Honzík. Consensus guideline for the diagnosis and management of mannose phosphate isomerase‐congenital disorder of glycosylation. Journal of Inherited Metabolic Disease, 43:671-693, Apr 2020. URL: https://doi.org/10.1002/jimd.12241, doi:10.1002/jimd.12241. This article has 73 citations and is from a peer-reviewed journal.
(bogdanska2021clinicalbiochemicaland pages 1-2): Anna Bogdańska, Patryk Lipiński, Paulina Szymańska-Rożek, Aleksandra Jezela-Stanek, Dariusz Rokicki, Piotr Socha, and Anna Tylki-Szymańska. Clinical, biochemical and molecular phenotype of congenital disorders of glycosylation: long-term follow-up. Orphanet Journal of Rare Diseases, Jan 2021. URL: https://doi.org/10.1186/s13023-020-01657-5, doi:10.1186/s13023-020-01657-5. This article has 50 citations and is from a peer-reviewed journal.
(cechova2020consensusguidelinefor pages 20-21): Anna Čechová, Ruqaiah Altassan, Delphine Borgel, Arnaud Bruneel, Joana Correia, Muriel Girard, Annie Harroche, Beata Kiec‐Wilk, Klaus Mohnike, Tiffany Pascreau, Łukasz Pawliński, Silvia Radenkovic, Sandrine Vuillaumier‐Barrot, Luis Aldamiz‐Echevarria, Maria Luz Couce, Esmeralda G. Martins, Dulce Quelhas, Eva Morava, Pascale de Lonlay, Peter Witters, and Tomáš Honzík. Consensus guideline for the diagnosis and management of mannose phosphate isomerase‐congenital disorder of glycosylation. Journal of Inherited Metabolic Disease, 43:671-693, Apr 2020. URL: https://doi.org/10.1002/jimd.12241, doi:10.1002/jimd.12241. This article has 73 citations and is from a peer-reviewed journal.

Artifacts

Edison artifact artifact-00

Ask OpenScientist

OpenScientist Report

Inheritance

Discussions and Knowledge Gaps

Pathophysiology

Pathograph

Phenotypes

Genetic Associations

Medical Actions

Biochemical Markers

Differential Diagnoses

Clinical Trials

Source YAML

References & Deep Research

Deep Research

Disease Characteristics Research Template

Target Disease

Research Objectives

1. Disease Information

2. Etiology

3. Phenotypes

4. Genetic/Molecular Information

5. Environmental Information

6. Mechanism / Pathophysiology

7. Anatomical Structures Affected

8. Temporal Development

9. Inheritance and Population

10. Diagnostics

11. Outcome/Prognosis

12. Treatment

13. Prevention

14. Other Species / Natural Disease

15. Model Organisms

Citation Requirements

Output Format

MPI-congenital disorder of glycosylation (MPI-CDG): comprehensive disease-characteristics report

Executive summary

Evidence scope and recency

1. Disease information

Definition and identifiers

Provenance

2. Etiology, risk, protective factors, and gene–environment interaction

Primary cause

Genetic risk factors

Environmental and protective factors

3. Phenotypes

Quantitative clinical spectrum

Phenotype characterization and ontology suggestions

4. Genetic and molecular information

Gene and protein

Variant spectrum

Genotype–phenotype, modifiers, and epigenetics

5. Environmental, lifestyle, and infectious information

6. Mechanism and pathophysiology

Upstream causal chain

Downstream organ mechanisms

Subcellular and metabolic localization

Molecular profiling and advanced technologies

7. Anatomical structures affected

Primary organs and tissues

8. Temporal development

9. Inheritance and population

10. Diagnostics

When to suspect MPI-CDG

Biochemical testing

False positives and differential diagnosis

Surveillance after diagnosis

Screening

11. Outcome and prognosis

12. Treatment

Oral D-mannose: standard disease-specific therapy

Intravenous mannose

Hypoglycemia management

Gastrointestinal and nutritional support

Coagulation management

Liver-directed treatment

Experimental and advanced therapy

13. Prevention

14. Other species and natural disease

15. Model organisms and experimental systems