PMM2-Congenital Disorder of Glycosylation

MONDO:0008907 Pathograph 23 Show in embeddings browser

PMM2-CDG (historically CDG-Ia, carbohydrate-deficient glycoprotein syndrome type I, or Jaeken syndrome) is an autosomal recessive disorder of N-linked protein glycosylation caused by biallelic hypomorphic variants in PMM2. Phosphomannomutase 2 interconverts mannose-6-phosphate and mannose-1-phosphate, the committed precursor of GDP-mannose and dolichol-phosphate-mannose. Losing that step starves assembly of the dolichol-linked oligosaccharide donor, so N-glycosylation fails globally rather than for one substrate, and essentially every secreted and membrane glycoprotein is affected. The result is a multisystem disease dominated by cerebellar hypoplasia and ataxia, with coagulopathy, hepatopathy, endocrine dysfunction and a characteristic pattern of inverted nipples and abnormal subcutaneous fat distribution. It is the most common congenital disorder of glycosylation.

Ask OpenScientist

Ask a research question about PMM2-Congenital Disorder of Glycosylation. OpenScientist will conduct autonomous deep research using the Disorder Mechanisms Knowledge Base and PubMed literature (typically 10-30 minutes).

Submitting...

Do not include personal health information in your question. Questions and results are cached in your browser's local storage.

1
Inheritance
10
Pathophys.
23
Phenotypes
2
Hypotheses
2
Gaps
23
Pathograph
1
Genes
2
Variants
7
Medical Actions
2
Trials
3
Models
15
References
1
Deep Research
👪

Inheritance

1
Autosomal recessive HP:0000007
Biallelic inheritance, but with an observed recurrence risk that exceeds the Mendelian expectation in practice.
Autosomal recessive inheritance
Show evidence (1 reference)
PMID:20301289 SUPPORT Human Clinical
"however, based on outcomes of at-risk pregnancies, the risk of having an affected child is closer to 1/3 than to the expected 1/4"
The GeneReviews Genetic Counseling section records an observed segregation ratio above the 1/4 expectation, which is the figure counseling should use.
◈

Mechanistic Hypotheses

2
Precursor depletion limits oligosaccharide assembly
pmm2_precursor_depletion CANONICAL
The long-standing account: reduced PMM2 activity depletes mannose-1-phosphate and hence GDP-mannose, starving assembly of the lipid-linked oligosaccharide.
Pathograph links
Depletion of Mannose-1-Phosphate and GDP-Mannose -> Truncated Lipid-Linked Oligosaccharide Synthesis DIRECT Reduced donor supply limits assembly of the full oligosaccharide.
Substrate accumulation promotes oligosaccharide cleavage
pmm2_substrate_accumulation EMERGING
A complementary account from the zebrafish model: accumulated mannose-6-phosphate promotes cleavage of the lipid-linked oligosaccharide, reducing donor availability by a route independent of precursor supply. Suppressing mannose phosphate isomerase normalized M6P and abolished the cleavage, which is the experiment that distinguishes the two. The two are not exclusive and both may operate.
Pathograph links
Mannose-6-Phosphate Accumulation -> Truncated Lipid-Linked Oligosaccharide Synthesis DIRECT Raised M6P promotes LLO cleavage, reducing the available donor independently of precursor supply.
?

Discussions and Knowledge Gaps

2
Does underglycosylation in PMM2-CDG follow from precursor depletion, from substrate accumulation, or from both?
INTERPRETATION pmm2_two_routes_to_underglycosylation
Attached to
pathophysiology#Truncated Lipid-Linked Oligosaccharide Synthesis
The textbook account is depletion of mannose-1-phosphate and GDP-mannose. The zebrafish study could not measure either metabolite reliably, but did find that accumulated mannose-6-phosphate promotes cleavage of the lipid-linked oligosaccharide, and that suppressing M6P synthesis abolished the cleavage. Both routes converge on the same node and are not mutually exclusive; the entry models them as separate hypothesis groups so a future measurement can support one without silently retiring the other.
If the cerebellar lesion is established during development, what can any therapy started after birth be expected to achieve for it?
KNOWLEDGE GAP pmm2_developmental_window
Attached to
pathophysiology#Disrupted Cerebellar Development
The conditional mouse work locates the requirement for PMM2 in embryonic neural precursors and finds no phenotype when the enzyme is removed from mature neurons. If that transfers to humans, the structural cerebellar deficit is fixed before presentation, and post-natal therapy would be expected to act on the non-cerebellar arms of the disease rather than to reverse the hypoplasia. There is now a partial answer pointing the other way, which is why this is a gap rather than a settled limit: AAV9-PMM2 gene treatment of the Pmm2 knockout mouse reverses the cerebellar downregulation of Neurexin-2. That is a molecular readout in one protein, not a structural or behavioural rescue, so it establishes that some cerebellar molecular phenotype remains addressable after the developmental window without establishing that the hypoplasia itself is. What would settle it is a structural and functional endpoint after post-natal intervention in the same model.
⚙

Pathophysiology

10
Biallelic PMM2 Hypomorphic Variants
Two hypomorphic PMM2 alleles. Complete loss of PMM2 is embryonic lethal, so every surviving patient retains partial activity from at least one allele; this is a constraint on the genotype space rather than an incidental observation.
Downstream
Reduced Phosphomannomutase 2 Activity The variants reduce catalytic activity of the encoded enzyme.
Show evidence (1 reference)
PMID:40501776 SUPPORT Model Organism
"To overcome embryonic lethality caused by whole body knock-out of Pmm2 and mimic patient-related compound heterozygous pathogenic variants"
States the null-lethality constraint that forces every viable genotype to retain residual activity.
Reduced Phosphomannomutase 2 Activity
Cytosolic phosphomannomutase activity falls below the level needed to sustain flux from mannose-6-phosphate to mannose-1-phosphate.
phosphomannomutase activity GO:0004615 Gene Ontology (GO) Relation: this pathophysiological event involves this molecular function This pathophysiological event involves decreased phosphomannomutase activity (GO:0004615). GO:0004615 is a molecular function from the Gene Ontology. ↓ DECREASED
cytosol GO:0005829 Gene Ontology (GO) Relation: this pathophysiological event involves this cellular component This pathophysiological event involves cytosol (GO:0005829). GO:0005829 is a cellular component from the Gene Ontology.
Downstream
Depletion of Mannose-1-Phosphate and GDP-Mannose Loss of the forward reaction depletes the downstream sugar-nucleotide pool.
Mannose-6-Phosphate Accumulation Substrate upstream of the blocked step accumulates. Modeled as its own node because it turns out to do work of its own rather than being an inert marker.
Show evidence (1 reference)
PMID:22956764 SUPPORT Other
"Congenital disorder of glycosylation (PMM2-CDG) results from mutations in pmm2, which encodes the phosphomannomutase (Pmm) that converts mannose-6-phosphate (M6P) to mannose-1-phosphate (M1P)."
Background statement of the human enzymatic step, cited for the reaction rather than for the zebrafish result.
Mannose-6-Phosphate Accumulation
Substrate accumulation upstream of the enzymatic block. In the zebrafish model this is not merely a marker of the block: raised M6P promotes cleavage of the lipid-linked oligosaccharide, so accumulation contributes actively to underglycosylation alongside precursor depletion.
Substrate accumulation promotes oligosaccharide cleavage
Downstream
Truncated Lipid-Linked Oligosaccharide Synthesis Raised M6P promotes LLO cleavage, reducing the available donor independently of precursor supply. Substrate accumulation promotes oligosaccharide cleavage
Show evidence (1 reference)
PMID:22956764 SUPPORT Model Organism
"Pmm2 depletion unexpectedly caused accumulation of M6P, shown earlier to promote LLO cleavage in vitro."
Establishes the accumulation and its proposed effect on the oligosaccharide donor.
Depletion of Mannose-1-Phosphate and GDP-Mannose
The mannose-1-phosphate pool and the GDP-mannose and dolichol-phosphate-mannose derived from it fall, limiting the sugar donors for oligosaccharide assembly.
Precursor depletion limits oligosaccharide assembly
GDP-mannose biosynthetic process GO:0009298 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased GDP-mannose biosynthetic process (GO:0009298). GO:0009298 is a biological process from the Gene Ontology. ↓ DECREASED
Downstream
Truncated Lipid-Linked Oligosaccharide Synthesis Reduced donor supply limits assembly of the full oligosaccharide. Precursor depletion limits oligosaccharide assembly
Show evidence (1 reference)
PMID:22956764 SUPPORT Model Organism
"Although M1P and GDP-mannose were below reliable detection/quantification limits"
Graded PARTIAL deliberately: the depletion is the long-standing proposed mechanism, but this study reports it was not directly measurable, which is the honest state of the evidence.
Truncated Lipid-Linked Oligosaccharide Synthesis
Assembly of the dolichol-linked Glc3Man9GlcNAc2 precursor in the endoplasmic reticulum is incomplete, so the oligosaccharyltransferase complex has less full-length donor to transfer onto nascent glycoproteins.
dolichol-linked oligosaccharide biosynthetic process GO:0006488 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased dolichol-linked oligosaccharide biosynthetic process (GO:0006488). GO:0006488 is a biological process from the Gene Ontology. ↓ DECREASED
endoplasmic reticulum GO:0005783 Gene Ontology (GO) Relation: this pathophysiological event involves this cellular component This pathophysiological event involves endoplasmic reticulum (GO:0005783). GO:0005783 is a cellular component from the Gene Ontology.
Animal models
pmm2 morpholino zebrafish Zebrafish recapitulates Reproduces reduced global N-glycosylation and reduced LLO levels, and allowed the M6P-accumulation route to be separated from precursor depletion by epistasis with mannose phosphate isomerase.
Downstream
Global Protein N-Hypoglycosylation Less donor means fewer occupied sequons on nascent glycoproteins.
Show evidence (1 reference)
PMID:22956764 SUPPORT Model Organism
"Significantly, global N-linked glycosylation and LLO levels were reduced in pmm2 morphants."
Directly measures the reduction in the oligosaccharide donor.
Global Protein N-Hypoglycosylation
Occupancy of Asn-X-Ser/Thr sequons falls across the secreted and membrane glycoproteome. Because the defect is at the shared donor rather than at one transferase, the consequence is global, which is why a single enzyme deficiency produces a multisystem disease.
protein N-linked glycosylation GO:0006487 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased protein N-linked glycosylation (GO:0006487). GO:0006487 is a biological process from the Gene Ontology. ↓ DECREASED
Downstream
Disrupted Cerebellar Development The developing cerebellum is disproportionately dependent on intact N-glycosylation; the glycoproteins that mediate this are not fully identified.
Hypoglycosylation of Coagulation Regulators Antithrombin, protein C, protein S and factors IX and XI are themselves N-glycoproteins.
Hepatic Involvement Hepatocyte dysfunction with transaminase elevation and fibrosis.
Show evidence (1 reference)
PMID:20301289 SUPPORT Human Clinical
"PMM2-CDG, the most common of a group of disorders of abnormal glycosylation of N-linked oligosaccharides"
Places the disease at the level of N-linked glycosylation as a whole.
Disrupted Cerebellar Development
Cerebellar hypoplasia is established during development rather than accrued by later degeneration. Conditional mouse work localizes the requirement to embryonic neural precursors: deleting Pmm2 from post-mitotic neurons or astrocytes produces no phenotype, while deleting it from precursors reproduces the hypoplasia.
cerebellar granule cell CL:0001031 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves cerebellar granule cell (CL:0001031). CL:0001031 is a cell type from the Cell Ontology.
cerebellar granule cell differentiation GO:0021707 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased cerebellar granule cell differentiation (GO:0021707). GO:0021707 is a biological process from the Gene Ontology. ↓ DECREASED
cerebellum UBERON:0002037 Uberon multi-species anatomy ontology (UBERON) Relation: this pathophysiological event occurs in this anatomical location This pathophysiological event occurs in cerebellum (UBERON:0002037). UBERON:0002037 is an anatomical location from the Uberon multi-species anatomy ontology.
Animal models
Nestin-Cre embryonic neural precursor Pmm2 knockout mouse (eKO) Mouse recapitulates Deleting Pmm2 in embryonic neural precursors reproduces cerebellar hypoplasia, ataxia and seizures, and the glycoproteomic changes are corroborated in human post-mortem cerebellar tissue.
Post-mitotic neuronal and astrocyte Pmm2 knockout mouse (nKO, aKO) Mouse fails to recapitulate Removing PMM2 from mature neurons or astrocytes produces no detectable phenotype. This is a substantive negative result: it locates the requirement for PMM2 in development rather than in maintenance, and is the comparison that makes the embryonic-precursor model interpretable.
Downstream
Ataxia and Developmental Impairment The structural deficit produces the dominant neurological phenotype.
Show evidence (1 reference)
PMID:40501776 SUPPORT Model Organism
"These findings highlight the heightened dependency of the developing cerebellum on intact N-glycosylation, aligning with clinical observations in PMM2-CDG patients."
States the developmental dependency that makes the cerebellum the most affected structure.
Hypoglycosylation of Coagulation Regulators
Anticoagulant and procoagulant glycoproteins are simultaneously underglycosylated and lose activity, so the same patient can carry both bleeding and thrombotic risk. Antithrombin is the most consistently affected.
Show evidence (1 reference)
PMID:37224763 SUPPORT Human Clinical
"Prothrombotic and antithrombotic factor activities were frequently abnormal in PMM2-CDG patients, including AT, PC, PT, INR, and FXI."
Documents that both arms of the coagulation system are affected together, which is what makes the coagulopathy mixed rather than one-directional.
Hepatic Involvement
Hepatocyte dysfunction with transaminase elevation, hepatomegaly and, in some patients, fibrosis.
hepatocyte CL:0000182 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves hepatocyte (CL:0000182). CL:0000182 is a cell type from the Cell Ontology.
liver UBERON:0002107 Uberon multi-species anatomy ontology (UBERON) Relation: this pathophysiological event occurs in this anatomical location This pathophysiological event occurs in liver (UBERON:0002107). UBERON:0002107 is an anatomical location from the Uberon multi-species anatomy ontology.
Show evidence (1 reference)
PMID:20301289 SUPPORT Human Clinical
"cerebellar hypoplasia, and hepatopathy in infancy followed by neuropathy and retinitis pigmentosa in the first or second decade"
Places hepatopathy in the infantile course alongside the cerebellar lesion.
Ataxia and Developmental Impairment
The dominant clinical consequence: hypotonia and delay in infancy, then ataxia with intellectual disability that plateaus rather than progressing relentlessly.
Show evidence (1 reference)
PMID:20301289 SUPPORT Human Clinical
"is characterized by hypotonia, ataxia, severely delayed language and motor development, inability to walk, and IQ of 40 to 70"
Describes the childhood ataxia-intellectual disability stage.
⬡

Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.
Pathograph: causal mechanism network for PMM2-Congenital Disorder of Glycosylation Interactive directed graph showing how pathophysiology mechanisms, phenotypes, genetic factors and variants, experimental models, environmental triggers, and treatments relate through causal and linked edges.
●

Phenotypes

23
Blood 1
Deep Venous Thrombosis OCCASIONAL HP:0002625 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Deep venous thrombosis (HP:0002625). HP:0002625 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:20301289 SUPPORT Human Clinical
"The risk for deep venous thrombosis is increased."
States the increased thrombotic risk in the adult stage.
PMID:37224763 SUPPORT Human Clinical
"Interestingly, 16% of the cohort experienced symptoms of spontaneous bleeding and 10% had thrombosis."
Quantifies both bleeding and thrombotic events in the prospective cohort.
Digestive 1
Hepatomegaly FREQUENT HP:0002240 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Hepatomegaly (HP:0002240). HP:0002240 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:40307862 SUPPORT Human Clinical
"including brain hypoplasia, disturbed psychomotor abilities, areflexia, hypotonia, and strabismus as well as other organ involvement (hepatomegaly, tubulopathy)"
Reports hepatomegaly among the organ involvement in described patients. Graded PARTIAL because it describes specific genotypes rather than giving a cohort frequency.
Endocrine 2
Hypothyroidism FREQUENT HP:0000821 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Hypothyroidism (HP:0000821). HP:0000821 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:20301289 SUPPORT Human Clinical
"treatment of hypothyroidism, hypoglycemia, and other endocrinopathies per endocrinologist"
The GeneReviews Management section treats hypothyroidism as an expected manifestation requiring specialist management.
Hypogonadotropic Hypogonadism OCCASIONAL HP:0000044 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Hypogonadotropic hypogonadism (HP:0000044). HP:0000044 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:20301289 SUPPORT Human Clinical
"Hypogonadotropic hypogonadism and coagulopathy may occur."
States the hypogonadotropic hypogonadism of the adult stable stage.
Eye 3
Strabismus FREQUENT HP:0000486 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Strabismus (HP:0000486). HP:0000486 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:20301289 SUPPORT Human Clinical
"In the infantile multisystem presentation, infants show axial hypotonia, hyporeflexia, esotropia, and developmental delay."
Esotropia is the specific strabismus reported; curated to the general HP term because that is what the source supports at this level.
Retinitis Pigmentosa FREQUENT Rod-cone dystrophy HP:0000510 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Rod-cone dystrophy (HP:0000510), qualified as course progressive. HP:0000510 is a phenotype from the Human Phenotype Ontology.
Course: PROGRESSIVE
Show evidence (1 reference)
PMID:20301289 SUPPORT Human Clinical
"cerebellar hypoplasia, and hepatopathy in infancy followed by neuropathy and retinitis pigmentosa in the first or second decade"
Places retinitis pigmentosa in the later course of the nonfatal form.
Myopia FREQUENT HP:0000545 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Myopia (HP:0000545). HP:0000545 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:20301289 SUPPORT Human Clinical
"progressive retinitis pigmentosa and myopia are seen"
Names myopia among the adult-stage ocular findings.
Metabolism 1
Elevated Transaminases FREQUENT Elevated circulating hepatic transaminase concentration HP:0002910 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Elevated circulating hepatic transaminase concentration (HP:0002910). HP:0002910 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:20301289 SUPPORT Human Clinical
"annual AST, ALT, and albumin until normalization"
Graded PARTIAL: the surveillance recommendation implies the abnormality and its tendency to normalize, but does not state a frequency.
Musculoskeletal 3
Hypotonia VERY_FREQUENT HP:0001252 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Hypotonia (HP:0001252). HP:0001252 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:20301289 SUPPORT Human Clinical
"In the infantile multisystem presentation, infants show axial hypotonia, hyporeflexia, esotropia, and developmental delay."
Lists hypotonia among the presenting infantile features.
Joint Contractures OCCASIONAL HP:0034392 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Joint contracture (HP:0034392). HP:0034392 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:20301289 SUPPORT Human Clinical
"coagulopathy, retinitis pigmentosa, joint contractures, and skeletal deformities"
Lists joint contractures among the childhood-stage findings.
Osteoporosis FREQUENT HP:0000939 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Osteoporosis (HP:0000939). HP:0000939 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:20301289 SUPPORT Human Clinical
"thoracic and spinal deformities with osteoporosis worsen, and premature aging is observed"
States the progressive skeletal deterioration of the adult stage.
Nervous System 6
Cerebellar Hypoplasia VERY_FREQUENT HP:0001321 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Cerebellar hypoplasia (HP:0001321). HP:0001321 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:40501776 SUPPORT Other
"prominently featuring neurological deficits with nearly all patients exhibiting cerebellar hypoplasia and ataxia"
Background sentence in a mouse-model paper reciting the human frequency; graded OTHER because the sentence is a review statement, not this paper's own result.
Ataxia VERY_FREQUENT HP:0001251 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Ataxia (HP:0001251). HP:0001251 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:20301289 SUPPORT Human Clinical
"is characterized by hypotonia, ataxia, severely delayed language and motor development, inability to walk, and IQ of 40 to 70"
Names ataxia as a defining feature of the childhood stage.
Global Developmental Delay VERY_FREQUENT HP:0001263 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Global developmental delay (HP:0001263). HP:0001263 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:20301289 SUPPORT Human Clinical
"Feeding issues, vomiting, faltering growth, and developmental delay are frequently seen."
Reports developmental delay as a frequent infantile finding.
Peripheral Neuropathy FREQUENT HP:0009830 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Peripheral neuropathy (HP:0009830). HP:0009830 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:20301289 SUPPORT Human Clinical
"cerebellar hypoplasia, and hepatopathy in infancy followed by neuropathy and retinitis pigmentosa in the first or second decade"
Places neuropathy in the later course of the nonfatal neurologic form.
Seizures FREQUENT HP:0001250 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Seizure (HP:0001250). HP:0001250 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:20301289 SUPPORT Human Clinical
"other findings include seizures, stroke-like episodes or transient unilateral loss of function, coagulopathy, retinitis pigmentosa, joint contractures, and skeletal deformities"
Lists seizures among the findings of the childhood stage.
Progressive Cerebellar Atrophy FREQUENT HP:0001272 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Cerebellar atrophy (HP:0001272), qualified as course progressive. HP:0001272 is a phenotype from the Human Phenotype Ontology.
Course: PROGRESSIVE
Show evidence (1 reference)
PMID:33619652 SUPPORT Human Clinical
"Cerebellar size reduction in PMM2-CDG is thought to be the result of both hypoplasia and hypotrophy."
States that the small cerebellum reflects both a developmental deficit and subsequent tissue loss, which is why atrophy is curated separately from the congenital hypoplasia.
Growth 1
Feeding Difficulties and Faltering Growth VERY_FREQUENT Failure to thrive HP:0001508 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Failure to thrive (HP:0001508). HP:0001508 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:20301289 SUPPORT Human Clinical
"Feeding issues, vomiting, faltering growth, and developmental delay are frequently seen."
Names feeding difficulty and faltering growth as frequent findings.
Other 5
Stroke-Like Episodes OCCASIONAL HP:0002401 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Stroke-like episode (HP:0002401). HP:0002401 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:37224763 SUPPORT Human Clinical
"Stroke-like episodes (SLE) were reported in 18% of patients in our cohort."
Quantifies the frequency in a prospective cohort of 50.
Inverted Nipples FREQUENT HP:0003186 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Inverted nipples (HP:0003186). HP:0003186 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:40307862 SUPPORT Human Clinical
"Other common symptoms of PMM2-CDG are abnormal fat distribution, facial dysmorphism, inverted nipples, strabismus, coagulation and endocrine anomalies"
Lists inverted nipples among the common features in a genotype-phenotype review.
Abnormal Subcutaneous Fat Distribution FREQUENT Abnormal subcutaneous fat tissue distribution HP:0007552 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Abnormal subcutaneous fat tissue distribution (HP:0007552). HP:0007552 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:20301289 SUPPORT Human Clinical
"Subcutaneous fat may be excessive over the buttocks and suprapubic region."
Describes the distribution abnormality directly.
Antithrombin Deficiency VERY_FREQUENT Reduced antithrombin III activity HP:0001976 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Reduced antithrombin III activity (HP:0001976). HP:0001976 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:37224763 SUPPORT Human Clinical
"AT deficiency was the most common abnormality in 83.3% of patients."
Quantifies frequency in the prospective cohort.
Hyperinsulinemic Hypoglycemia OCCASIONAL
Show evidence (1 reference)
PMID:32071842 SUPPORT Human Clinical
"Hypoglycemia was specifically mentioned only in 23 of these patients (2.5%). Hyperinsulinism was identified in 10 patients (43% of all hypoglycemic patients)."
Quantifies both the rarity of hypoglycemia across 933 reviewed patients and the share of that subgroup in which hyperinsulinism was the mechanism.
🧬

Genetic Associations

1
PMM2
Gene: PMM2 hgnc:9115 HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is PMM2 (hgnc:9115). hgnc:9115 is a gene from the HUGO Gene Nomenclature Committee. relationship_type: CAUSATIVE
Variants (2)
c.422G>A (p.Arg141His) Pathogenic
The commonest allele in the disease, carried by more than 60% of patients, and the one that defines its genetic architecture. R141H has never been reported homozygous in a living patient: it is a functional null, and two nulls appear not to be compatible with live birth. Every patient therefore carries something else on the other chromosome, and it is that second allele's residual activity - not R141H - that sets where they fall on the severity spectrum. This is why the commonest genotype is a compound heterozygote rather than a homozygote, and why an allele-frequency-derived prevalence ceiling exceeds the diagnosed rate.
Functional effects
phosphomannomutase activity loss-of-function
Effectively complete loss in the homozygous state, inferred from its absence among living patients rather than from a direct assay quoted here. In trans with a hypomorph it still permits measurable residual activity, which is the basis of the enzyme-activator approach.
Show evidence (2 references)
PMID:40501776 SUPPORT Other
"R141H, a human pathogenic variant carried by more than 60% of PMM2-CDG patients"
The allele frequency among patients. Graded OTHER because it recites human epidemiology inside a mouse-model paper.
PMID:34447415 SUPPORT Computational
"the p.Arg141His variant homozygotes were not excluded although known to be embryonically lethal"
The embryonic-lethality claim this record rests on, from a reference the entry already uses in its prevalence section. It is also why an allele-frequency prevalence estimate overcounts here: the study deliberately kept homozygotes in the calculation while acknowledging they are not born.
c.357C>A (p.Phe119Leu) Pathogenic
The partial-activity allele that most often sits opposite R141H. The source that makes that pairing claim ties it to Scandinavia, where F119L is most prevalent, so R141H/F119L is reported as the commonest genotype there rather than established as the commonest worldwide. Its interest is that it is the substrate the only enzyme-directed therapy needs: an activator can raise residual activity but cannot create it, so a genotype pairing a null with a hypomorph is precisely where such a drug has something to act on. R141H/F119L fibroblasts were one of the four lines in which epalrestat was shown to raise PMM2 activity.
Functional effects
phosphomannomutase activity loss-of-function
Partial rather than complete - a hypomorph. The activity that survives is what distinguishes this allele from R141H functionally, and what the enzyme-activator approach depends on.
Show evidence (4 references)
PMID:31636082 SUPPORT In Vitro
"Epalrestat increased PMM2 enzymatic activity in four PMM2-CDG patient fibroblast lines with genotypes R141H/F119L, R141H/E139K, R141H/N216I and R141H/F183S"
Names R141H/F119L as one of the tested genotypes and reports measurable PMM2 activity in those fibroblasts, which is consistent with this allele leaving activity to raise. It is not an assay of F119L: residual activity in a compound heterozygote is a property of the pair, so this supports the hypomorph reading without measuring the allele on its own.
PMID:31636082 SUPPORT In Vitro
"PMM2 enzyme activity gains ranged from 30% to 400% over baseline, depending on genotype"
Records that the size of the response varies by genotype, which is the structured form of this entry's per-allele residual-activity claim.
PMID:40501776 SUPPORT Other
"the two most prevalent human pathogenic variants R141H (NM_000303.2:c.422G>A (p.Arg141His), ClinVar 7706) and F119L (NM_000303.2:c.357C>A (p.Phe119Leu), ClinVar 7711)"
Establishes that F119L is one of the two most prevalent pathogenic alleles, which the record previously asserted without a citation. Graded OTHER for the same reason as the sibling R141H frequency item from this paper: it recites human epidemiology inside a mouse-model study.
+ 1 more reference
💊

Medical Actions

7
Supportive and Multisystem Management
Action: Supportive CareNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Supportive Care (NCIT:C15747). NCIT:C15747 is a clinical intervention from the NCI Thesaurus. NCIT:C15747
There is no therapy that restores glycosylation. Management is organ-directed: nutritional support, seizure control, developmental therapies, and specialist management of the ocular, cardiac, endocrine and renal manifestations.
Mechanism Target:
MODULATES Ataxia and Developmental Impairment — Acts on the consequences of the cerebellar lesion rather than on the glycosylation defect.
Show evidence (2 references)
PMID:20301289 SUPPORT Human Clinical
"Symptomatic treatment for severe infantile phase in a pediatric tertiary care center."
The GeneReviews Management section frames care as symptomatic, which is the accurate description of what is available.
PMID:20301289 SUPPORT Human Clinical
"Cautious use of acetaminophen and other agents metabolized by the liver if significant liver insufficiency is present."
The GeneReviews Agents/Circumstances to Avoid line, which is a management instruction rather than a general caution and follows from the hepatic arm.
Haematological Monitoring and Perioperative Planning
Action: Supportive CareNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Supportive Care (NCIT:C15747). NCIT:C15747 is a clinical intervention from the NCI Thesaurus. NCIT:C15747
Annual assessment of bleeding and clotting parameters, with haematology input before surgery. This is the arm of management that acts on a measurable mechanistic readout rather than on symptoms.
Mechanism Target:
MODULATES Hypoglycosylation of Coagulation Regulators — Surveillance and perioperative correction address the coagulation consequences of hypoglycosylation.
Show evidence (1 reference)
PMID:20301289 SUPPORT Human Clinical
"annual assessment of bleeding and clotting parameters by a hematologist including prothrombin time, protein C, protein S, antithrombin III, factor IX, and factor XI"
The GeneReviews surveillance recommendation naming the specific factors to follow.
GLM101 (Mannose-1-Phosphate Replacement)
Action: PharmacotherapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Pharmacotherapy (NCIT:C15986). NCIT:C15986 is a clinical intervention from the NCI Thesaurus. NCIT:C15986
A liposomal mannose-1-phosphate replacement therapy that supplies the metabolite immediately downstream of the deficient enzyme, bypassing the block rather than correcting it. This is the investigational agent whose mechanism engages the pathograph most directly.
Mechanism Target:
BYPASSES Depletion of Mannose-1-Phosphate and GDP-Mannose — Delivering mannose-1-phosphate directly restores the pool the blocked enzyme cannot make, without requiring residual PMM2 activity.
Show evidence (1 reference)
clinicaltrials:NCT05549219 SUPPORT Human Clinical
"This is a Phase 2, randomized, open-label, 24-week treatment study to evaluate the potential pharmacodynamic (PD) activity, safety, tolerability, and pharmacokinetics (PK) of GLM101 in adult, adolescent, and pediatric, patients with a confirmed diagnosis of PMM2-CDG."
The registered trial establishing that this agent is under clinical evaluation in this disease, with pharmacodynamic activity as a stated endpoint.
Diazoxide for Hyperinsulinemic Hypoglycemia
Action: PharmacotherapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Pharmacotherapy (NCIT:C15986). NCIT:C15986 is a clinical intervention from the NCI Thesaurus. NCIT:C15986
Agent: diazoxide CHEBI:4495 Chemical Entities of Biological Interest (CHEBI) Relation: this treatment uses this therapeutic agent This treatment uses diazoxide (CHEBI:4495). CHEBI:4495 is a therapeutic agent from Chemical Entities of Biological Interest.
Opens the beta-cell K-ATP channel to suppress inappropriate insulin secretion. It treats a specific complication rather than the glycosylation defect, and it is the one place where an uncommon manifestation of this disease has a well-defined pharmacological answer.
Show evidence (2 references)
PMID:32071842 SUPPORT Human Clinical
"Among these 10 patients, seven were successfully treated with diazoxide."
Gives the response rate among the hyperinsulinemic subgroup.
PMID:32071842 SUPPORT Human Clinical
"However, most patients remained on therapy longer than a year to stay free of hypoglycemia."
Records that the benefit is maintenance rather than cure, which is the limit on the claim.
AAV9-PMM2 Gene Replacement (preclinical)
Action: Gene TherapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Gene Therapy (NCIT:C15238). NCIT:C15238 is a clinical intervention from the NCI Thesaurus. NCIT:C15238
Preclinical gene replacement in the Pmm2 knockout mouse. Curated because it speaks directly to this entry's own question about the developmental window: it reverses a molecular deficit in the cerebellum of the same model whose conditional knockouts locate the PMM2 requirement in development.
Mechanism Target:
RESTORES Disrupted Cerebellar Development — Restores Neurexin-2 abundance in the cerebellum of the knockout mouse. This is a molecular readout, not a behavioural or structural rescue, and the entry does not claim more.
Show evidence (1 reference)
PMID:40832321 SUPPORT Model Organism
"showed that its reduced abundance can be reversed by AAV9- PMM2 gene treatment of the Pmm2 KO mice"
Graded PARTIAL deliberately: the reversal demonstrated is of a single protein's abundance in a mouse, not of the cerebellar phenotype and not in humans.
Oral Mannose Supplementation
Action: PharmacotherapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Pharmacotherapy (NCIT:C15986). NCIT:C15986 is a clinical intervention from the NCI Thesaurus. NCIT:C15986
Agent: D-mannose CHEBI:16024 Chemical Entities of Biological Interest (CHEBI) Relation: this treatment uses this therapeutic agent This treatment uses D-mannose (CHEBI:16024). CHEBI:16024 is a therapeutic agent from Chemical Entities of Biological Interest.
Attempts to raise flux into the pathway upstream of the block. Past supplementation trials did not show clear clinical benefit. Curated because a negative result about an intuitively obvious therapy is worth recording.
Show evidence (2 references)
PMID:39236565 SUPPORT Other
"Mostly, we are only able to manage the disease symptoms rather than to address the underlying cause."
A review statement of the field's overall position, cited for the general absence of an established disease-modifying therapy rather than for mannose specifically.
PMID:35562242 SUPPORT Other
"Past mannose supplementation trials did not show clear clinical benefits"
States the negative outcome of prior mannose supplementation specifically. Graded OTHER because the sentence is a review's summary of earlier trials rather than a primary result of this paper.
Epalrestat
Action: PharmacotherapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Pharmacotherapy (NCIT:C15986). NCIT:C15986 is a clinical intervention from the NCI Thesaurus. NCIT:C15986
Agent: epalrestat CHEBI:31539 Chemical Entities of Biological Interest (CHEBI) Relation: this treatment uses this therapeutic agent This treatment uses epalrestat (CHEBI:31539). CHEBI:31539 is a therapeutic agent from Chemical Entities of Biological Interest.
An aldose reductase inhibitor, repurposed from diabetic neuropathy, that raises residual PMM enzyme activity rather than supplying a downstream metabolite. It is the one agent here that acts on the deficient enzyme step itself. Its placebo-controlled paediatric Phase III trial was terminated for futility, so the biochemical rationale below is retained as mechanism while clinical benefit is not established.
Mechanism Target:
MODULATES Reduced Phosphomannomutase 2 Activity — Raises the activity of the residual enzyme rather than bypassing it, so any benefit would depend on there being hypomorphic activity left to raise. This is a biochemical claim; the controlled trial testing whether it produces clinical benefit was stopped for futility.
Show evidence (4 references)
PMID:31636082 SUPPORT In Vitro
"Epalrestat increased PMM2 enzymatic activity in four PMM2-CDG patient fibroblast lines with genotypes R141H/F119L, R141H/E139K, R141H/N216I and R141H/F183S"
The primary result the review below was summarizing, and a much better carrier for this edge: a measurement in patient fibroblasts, in four named genotypes, rather than a secondhand statement that the effect exists.
PMID:31636082 SUPPORT In Vitro
"PMM2 enzyme activity gains ranged from 30% to 400% over baseline, depending on genotype"
Quantifies the effect and, more usefully for this entry, records that its size is genotype-dependent - which is what the MODULATES rather than RESTORES grading on this link is saying.
PMID:31636082 SUPPORT Other
"Pharmacological inhibition of aldose reductase by epalrestat may shunt glucose from the polyol pathway to glucose-1,6-bisphosphate, which is an endogenous stabilizer and coactivator of PMM2 homodimerization"
The proposed route from an aldose reductase inhibitor to phosphomannomutase activity, which is otherwise a surprising connection. Graded OTHER rather than IN_VITRO alongside the two assay results above, because the authors' own "may" marks this as the mechanism they propose, not one this paper measures.
+ 1 more reference
Show evidence (1 reference)
clinicaltrials:NCT04925960 SUPPORT Human Clinical
"designed to assess the safety, tolerability, and clinical and metabolic improvement of pediatric subjects with PMM2-CDG on oral epalrestat therapy vs. placebo"
The registered controlled trial of this agent in this disease.
🔬

Biochemical Markers

2
Serum transferrin isoform pattern (Abnormal)
Context: A type I transferrin pattern is the established screening test and the functional assay used to interpret PMM2 variants of uncertain significance. Its sensitivity is high but not complete, and two recurrent variants are enriched among false positives.
Pathograph Readouts
Readout Of Global Protein N-Hypoglycosylation Positive Diagnostic
Under-occupied glycosylation sites on transferrin report the global sequon occupancy defect.
Show evidence (1 reference)
PMID:39216211 SUPPORT Human Clinical
"The data demonstrate 94% overall test sensitivity for PMM2-CDG and importantly demonstrate two known, recurrent variants enriched in false positive cases highlighting an important limitation of the test."
Quantifies the sensitivity of this readout and names its limitation, rather than treating it as a perfect test.
Antithrombin activity (Decreased)
Context: Antithrombin is itself an N-glycoprotein, so its activity reports the glycosylation defect directly. Activity below roughly 65% marks the range in which thrombotic events occurred in the prospective cohort.
Pathograph Readouts
Readout Of Hypoglycosylation of Coagulation Regulators Negative Prognostic
Reduced activity of a glycoprotein anticoagulant reports the hypoglycosylation of the coagulation system.
Show evidence (1 reference)
PMID:37224763 SUPPORT Human Clinical
"AT activity was below 50% in 62.5% of all patients (normal range 80-130%)."
Gives the magnitude of the deficit against a stated reference interval.
🔬

Diagnosis

1
Type I transferrin isoform pattern with confirmatory PMM2 testing
Diagnosis rests on a tiered sequence rather than a single test: a type I transferrin isoform pattern establishes a disorder of N-linked glycosylation, and biallelic PMM2 variants confirm which one. Phosphomannomutase enzyme activity in leukocytes or fibroblasts is the fallback when the molecular result is uncertain, which is why the enzyme assay retains a role even in a sequencing era.
Show evidence (1 reference)
PMID:20301289 SUPPORT Human Clinical
"The diagnosis of PMM2-CDG is established in a proband with type I transferrin isoform analysis and identification of either biallelic pathogenic variants in PMM2 on molecular genetic testing or (if results of molecular genetic testing are uncertain) low levels of phosphomannomutase (PMM) enzyme activity."
The GeneReviews Diagnosis/Testing criterion, giving all three tiers and the condition under which the enzyme assay is used.
📈

Progression

3
Infantile multisystem
Age: birth to ~3 years
Axial hypotonia, hyporeflexia, esotropia and developmental delay, with feeding difficulty and faltering growth. Two courses are distinguished: a nonfatal neurologic one, and a neurologic-multivisceral one carrying roughly 20% mortality in the first year.
Show evidence (1 reference)
PMID:20301289 SUPPORT Human Clinical
"a more severe neurologic-multivisceral course with approximately 20% mortality in the first year of life"
Gives the mortality attached to the severe infantile course.
Late-infantile and childhood ataxia-intellectual disability
Age: 3 to 10 years onward
Hypotonia, ataxia, severely delayed language and motor development, inability to walk, and IQ of 40 to 70, with seizures, stroke-like episodes, coagulopathy and retinitis pigmentosa.
Show evidence (1 reference)
PMID:20301289 SUPPORT Human Clinical
"The late-infantile and childhood ataxia–intellectual disability stage, which begins between ages three and ten years"
Defines the stage and its age of onset.
Adult stable disability
Age: adulthood
Intellectual ability stabilizes. Progressive retinitis pigmentosa and myopia, worsening thoracic and spinal deformity with osteoporosis, premature aging, and hypogonadotropic hypogonadism.
Show evidence (1 reference)
PMID:20301289 SUPPORT Human Clinical
"In the adult stable disability stage, intellectual ability is stable; peripheral neuropathy is variable, progressive retinitis pigmentosa and myopia are seen"
Characterizes the adult stage, and specifically that the cognitive trajectory plateaus rather than continuing to decline.
📊

Prevalence

4
North America and Europe
Point Prevalence 2.9 per 100,000 1–9 per 100,000
Reported as an incidence of approximately 1:35,000 in North America and Europe; normalized here to cases per 100,000.
Show evidence (1 reference)
PMID:40501776 SUPPORT Other
"PMM2-CDG has an estimated incidence of approximately 1:35,000 in North America and Europe"
Background epidemiology stated in a mouse-model paper; graded OTHER because the sentence reports human population data the paper did not generate.
Ashkenazi Jewish
Birth Prevalence 5.0 per 100,000 1–9 per 100,000
1 in 20,000, the highest of the three population estimates the study reports from gnomAD allele frequencies (it computed seven; three appear in the result sentence). An independent earlier estimate (Schollen 2000, recited in this paper's introduction) lands on the same number by a different route; it is deliberately not cited here as a second evidence item, because a coincident figure from another study is not additional support for this one. Allele-frequency-derived rather than ascertained from diagnosed cases, which is why it exceeds the observed diagnosed rate above. This entry's own null-lethality claim is one reason the two diverge: genotypes that never reach live birth are counted in an allele-based estimate and not in a clinical one.
Show evidence (1 reference)
PMID:34447415 SUPPORT Computational
"PMM2-CDG showed the highest estimated prevalence counted from 71 different pathogenic variants, and it is more prevalent in European (1 in 27,000), Ashkenazi Jewish (1 in 20,000), and admixed American populations (1 in 64,000)"
Gives all three population estimates in one sentence, including the Ashkenazi Jewish figure this record carries.
European
Birth Prevalence 3.7 per 100,000 1–9 per 100,000
1 in 27,000. Carried as its own record so the roughly three-fold spread across populations is visible in the structured data rather than only in prose; a single worldwide figure hides it. Same allele-frequency caveat as the other two. The source sentence says only "European"; the study's methods describe seven gnomAD populations of which the European one is non-Finnish, but that identification is an inference from the methods and is left out of the population field rather than asserted there.
Show evidence (1 reference)
PMID:34447415 SUPPORT Computational
"PMM2-CDG showed the highest estimated prevalence counted from 71 different pathogenic variants, and it is more prevalent in European (1 in 27,000), Ashkenazi Jewish (1 in 20,000), and admixed American populations (1 in 64,000)"
The European figure, from the same sentence that gives all three.
Admixed American
Birth Prevalence 1.6 per 100,000 1–9 per 100,000
1 in 64,000, the lowest of the three and about a third of the Ashkenazi Jewish estimate. Same allele-frequency caveat as the other two.
Show evidence (1 reference)
PMID:34447415 SUPPORT Computational
"PMM2-CDG showed the highest estimated prevalence counted from 71 different pathogenic variants, and it is more prevalent in European (1 in 27,000), Ashkenazi Jewish (1 in 20,000), and admixed American populations (1 in 64,000)"
The admixed American figure, from the same sentence that gives all three.
🔬

Clinical Trials

2
NCT05549219 PHASE_II COMPLETED
Randomized, open-label, 24-week study of intravenous GLM101 at 10, 20 and 30 mg/kg in adult, adolescent and pediatric patients with confirmed PMM2-CDG.
Show evidence (1 reference)
clinicaltrials:NCT05549219 SUPPORT Human Clinical
"The planned doses of GLM101 to be investigated are 10, 20, and 30 mg/kg."
Records the dose range under evaluation in the registered protocol.
NCT04925960 PHASE_III TERMINATED
Randomized, double-blind, placebo-controlled single-center study of oral epalrestat in pediatric PMM2-CDG, with safety, tolerability and clinical and metabolic improvement as endpoints.
Show evidence (2 references)
clinicaltrials:NCT04925960 SUPPORT Human Clinical
"This is a prospective, single-center, randomized, double-blind, placebo-controlled study designed to assess the safety, tolerability, and clinical and metabolic improvement of pediatric subjects with PMM2-CDG on oral epalrestat therapy vs. placebo."
The registered protocol record for this trial.
PMID:40501776 SUPPORT Other
"aldose reductase inhibitors are in development as novel therapeutics for PMM2-CDG, including a recent phase III clinical trial of epalrestat (NCT04925960)"
Source for the Phase III designation, which the registry record itself does not state. Graded OTHER because the sentence is contextual framing rather than a result of the mouse study it appears in.
🐁

Animal Models

3
Nestin-Cre embryonic neural precursor Pmm2 knockout mouse (eKO)
Pairs a catalytically inactive knock-in allele with a conditional null to reproduce the compound-heterozygous state while avoiding the embryonic lethality of a whole-body knockout.
Species
Mouse
Genotype
Pmm2 R137H/flox with Nestin-Cre
Publication
PMID:40501776
Pathograph links
Disrupted Cerebellar Development recapitulates fidelity: high Deleting Pmm2 in embryonic neural precursors reproduces cerebellar hypoplasia, ataxia and seizures, and the glycoproteomic changes are corroborated in human post-mortem cerebellar tissue.
Limitations: Early lethality limits study to the first weeks of life, and Nestin-Cre has ectopic renal expression, so the renal cysts in this model cannot be attributed to the cerebellar mechanism.
Readouts
Cerebellar hypoplasia and ataxic gait
Direction: DECREASED
Interpretation: Structural and behavioural correlate of the human cerebellar lesion.
Show evidence (1 reference)
PMID:40501776 SUPPORT Model Organism
"removal of PMM2 from embryonic neural precursor cells leads to cerebellar hypoplasia, ataxia, seizures, and early lethality"
Reports the phenotype produced by precursor-stage deletion.
Show evidence (1 reference)
PMID:40501776 SUPPORT Model Organism
"glycoproteomic alterations identified in our mouse model are corroborated in PMM2-CDG patient post-mortem cerebellar tissue"
Cross-validation against human tissue is what justifies treating this model as informative for the human node.
Post-mitotic neuronal and astrocyte Pmm2 knockout mouse (nKO, aKO)
Deletes Pmm2 after neurons and astrocytes are post-mitotic, testing whether ongoing glycosylation in mature cells is what the disease requires.
Species
Mouse
Genotype
Pmm2 R137H/flox with Snap25-Cre or Gfap-Cre
Publication
PMID:40501776
Pathograph links
Disrupted Cerebellar Development fails to recapitulate fidelity: low Removing PMM2 from mature neurons or astrocytes produces no detectable phenotype. This is a substantive negative result: it locates the requirement for PMM2 in development rather than in maintenance, and is the comparison that makes the embryonic-precursor model interpretable.
Limitations: A negative result in a conditional model cannot exclude a smaller maintenance requirement below the sensitivity of the assays used, and bulk-lysate enzyme assays still detect activity from non-recombined cells.
Show evidence (1 reference)
PMID:40501776 SUPPORT Model Organism
"Mice with post-mitotic loss of PMM2 from neurons or astrocytes are indistinguishable from unaffected littermates, including in a broad battery of neurological assessments."
States the negative result directly, including the breadth of testing behind it.
pmm2 morpholino zebrafish
The model in which the substrate-accumulation mechanism was identified.
Species
Zebrafish
Genotype
pmm2 morpholino knockdown
Publication
PMID:22956764
Pathograph links
Truncated Lipid-Linked Oligosaccharide Synthesis recapitulates fidelity: moderate Reproduces reduced global N-glycosylation and reduced LLO levels, and allowed the M6P-accumulation route to be separated from precursor depletion by epistasis with mannose phosphate isomerase.
Limitations: Morpholino knockdown is transient and not allele-specific, so it models loss of Pmm2 rather than the hypomorphic compound-heterozygous state patients carry.
Show evidence (1 reference)
PMID:22956764 SUPPORT Model Organism
"Suppression of the M6P-synthesizing enzyme mannose phosphate isomerase within the pmm2 background normalized M6P levels and certain aspects of the craniofacial phenotype and abrogated pmm2-dependent LLO cleavage."
The epistasis experiment that establishes M6P accumulation as causal rather than incidental.
{ }

Source YAML

click to show 
name: PMM2-Congenital Disorder of Glycosylation
description: >-
  PMM2-CDG (historically CDG-Ia, carbohydrate-deficient glycoprotein syndrome type I,
  or Jaeken syndrome) is an autosomal recessive disorder of N-linked protein
  glycosylation caused by biallelic hypomorphic variants in PMM2. Phosphomannomutase 2
  interconverts mannose-6-phosphate and mannose-1-phosphate, the committed precursor of
  GDP-mannose and dolichol-phosphate-mannose. Losing that step starves assembly of the
  dolichol-linked oligosaccharide donor, so N-glycosylation fails globally rather than
  for one substrate, and essentially every secreted and membrane glycoprotein is
  affected. The result is a multisystem disease dominated by cerebellar hypoplasia and
  ataxia, with coagulopathy, hepatopathy, endocrine dysfunction and a characteristic
  pattern of inverted nipples and abnormal subcutaneous fat distribution. It is the
  most common congenital disorder of glycosylation.
disease_term:
  preferred_term: PMM2-congenital disorder of glycosylation
  term:
    id: MONDO:0008907
    label: PMM2-congenital disorder of glycosylation
creation_date: "2026-08-27T18:45:00Z"

references:
- reference: PMID:20301289
  title: PMM2-CDG.
  tags:
  - GeneReviews
- reference: PMID:35562242
  title: Nutrition interventions in congenital disorders of glycosylation.
- reference: clinicaltrials:NCT04925960
  title: >-
    A Prospective, Randomized, Double-Blind, Placebo-Controlled, Single-Center Study of
    Oral Epalrestat Therapy in Pediatric Subjects With Phosphomannomutase 2-congenital
    Disorder of Glycosylation (PMM2-CDG)
- reference: PMID:22956764
  title: >-
    A zebrafish model of PMM2-CDG reveals altered neurogenesis and a
    substrate-accumulation mechanism for N-linked glycosylation deficiency.
- reference: PMID:31636082
  title: >-
    Repurposing the aldose reductase inhibitor and diabetic neuropathy drug epalrestat
    for the congenital disorder of glycosylation PMM2-CDG.
- reference: PMID:37224763
  title: >-
    Coagulation abnormalities in a prospective cohort of 50 patients with
    PMM2-congenital disorder of glycosylation.
- reference: PMID:39216211
  title: Sensitivity of transferrin isoform analysis for PMM2-CDG.
- reference: PMID:40307862
  title: >-
    A comprehensive update of genotype-phenotype correlations in PMM2-CDG:
    insights from molecular and structural analyses.
- reference: PMID:40501776
  title: Novel mouse model reveals neurodevelopmental origin of PMM2-CDG brain pathology.
- reference: PMID:34447415
  title: >-
    The Estimated Prevalence of N-Linked Congenital Disorders of Glycosylation
    Across Various Populations Based on Allele Frequencies in General Population
    Databases.
- reference: PMID:32071842
  title: >-
    Hypoglycemia in CDG patients due to PMM2 mutations: Follow up on
    hyperinsulinemic patients.
- reference: PMID:33619652
  title: >-
    Clinical and radiological correlates of activities of daily living in cerebellar
    atrophy caused by PMM2 mutations (PMM2-CDG).
- reference: PMID:39236565
  title: 'Treatment of congenital disorders of glycosylation: An overview.'
- reference: PMID:40832321
  title: >-
    AAV-based gene replacement reverses Neurexin-2 downregulation in the cerebellum of
    a mouse model of phosphomannomutase 2 deficiency (PMM2-CDG).
- reference: clinicaltrials:NCT05549219
  title: >-
    A Phase 2, Randomized, Open-Label, 24-Week Study to Assess the Pharmacodynamics,
    Safety, Tolerability, and Pharmacokinetics of Multiple Doses of GLM101 Administered
    Intravenously to Adult, Adolescent, and Pediatric Participants With PMM2-CDG

pathophysiology:
- name: Biallelic PMM2 Hypomorphic Variants
  biological_scale: MOLECULAR
  description: >-
    Two hypomorphic PMM2 alleles. Complete loss of PMM2 is embryonic lethal, so every
    surviving patient retains partial activity from at least one allele; this is a
    constraint on the genotype space rather than an incidental observation.
  evidence:
  - reference: PMID:40501776
    reference_title: "Novel mouse model reveals neurodevelopmental origin of PMM2-CDG brain pathology."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      To overcome embryonic lethality caused by whole body knock-out of Pmm2 and mimic
      patient-related compound heterozygous pathogenic variants
    explanation: >-
      States the null-lethality constraint that forces every viable genotype to retain
      residual activity.
  downstream:
  - target: Reduced Phosphomannomutase 2 Activity
    causal_link_type: DIRECT
    description: The variants reduce catalytic activity of the encoded enzyme.

- name: Reduced Phosphomannomutase 2 Activity
  biological_scale: MOLECULAR
  description: >-
    Cytosolic phosphomannomutase activity falls below the level needed to sustain flux
    from mannose-6-phosphate to mannose-1-phosphate.
  molecular_functions:
  - preferred_term: phosphomannomutase activity
    modifier: DECREASED
    term:
      id: GO:0004615
      label: phosphomannomutase activity
  cellular_components:
  - preferred_term: cytosol
    term:
      id: GO:0005829
      label: cytosol
  evidence:
  - reference: PMID:22956764
    reference_title: "A zebrafish model of PMM2-CDG reveals altered neurogenesis and a substrate-accumulation mechanism for N-linked glycosylation deficiency."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Congenital disorder of glycosylation (PMM2-CDG) results from mutations in pmm2,
      which encodes the phosphomannomutase (Pmm) that converts mannose-6-phosphate
      (M6P) to mannose-1-phosphate (M1P).
    explanation: >-
      Background statement of the human enzymatic step, cited for the reaction rather
      than for the zebrafish result.
  downstream:
  - target: Depletion of Mannose-1-Phosphate and GDP-Mannose
    causal_link_type: DIRECT
    description: Loss of the forward reaction depletes the downstream sugar-nucleotide pool.
  - target: Mannose-6-Phosphate Accumulation
    causal_link_type: DIRECT
    description: >-
      Substrate upstream of the blocked step accumulates. Modeled as its own node
      because it turns out to do work of its own rather than being an inert marker.

- name: Mannose-6-Phosphate Accumulation
  biological_scale: MOLECULAR
  description: >-
    Substrate accumulation upstream of the enzymatic block. In the zebrafish model this
    is not merely a marker of the block: raised M6P promotes cleavage of the
    lipid-linked oligosaccharide, so accumulation contributes actively to
    underglycosylation alongside precursor depletion.
  evidence:
  - reference: PMID:22956764
    reference_title: "A zebrafish model of PMM2-CDG reveals altered neurogenesis and a substrate-accumulation mechanism for N-linked glycosylation deficiency."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Pmm2 depletion unexpectedly caused accumulation of M6P, shown earlier to promote
      LLO cleavage in vitro.
    explanation: >-
      Establishes the accumulation and its proposed effect on the oligosaccharide
      donor.
  downstream:
  - target: Truncated Lipid-Linked Oligosaccharide Synthesis
    causal_link_type: DIRECT
    hypothesis_groups:
    - pmm2_substrate_accumulation
    description: >-
      Raised M6P promotes LLO cleavage, reducing the available donor independently of
      precursor supply.

- name: Depletion of Mannose-1-Phosphate and GDP-Mannose
  biological_scale: MOLECULAR
  description: >-
    The mannose-1-phosphate pool and the GDP-mannose and dolichol-phosphate-mannose
    derived from it fall, limiting the sugar donors for oligosaccharide assembly.
  biological_processes:
  - preferred_term: GDP-mannose biosynthetic process
    modifier: DECREASED
    term:
      id: GO:0009298
      label: GDP-mannose biosynthetic process
  evidence:
  - reference: PMID:22956764
    reference_title: "A zebrafish model of PMM2-CDG reveals altered neurogenesis and a substrate-accumulation mechanism for N-linked glycosylation deficiency."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Although M1P and GDP-mannose were below reliable detection/quantification limits
    explanation: >-
      Graded PARTIAL deliberately: the depletion is the long-standing proposed
      mechanism, but this study reports it was not directly measurable, which is the
      honest state of the evidence.
  downstream:
  - target: Truncated Lipid-Linked Oligosaccharide Synthesis
    causal_link_type: DIRECT
    hypothesis_groups:
    - pmm2_precursor_depletion
    description: Reduced donor supply limits assembly of the full oligosaccharide.

- name: Truncated Lipid-Linked Oligosaccharide Synthesis
  biological_scale: MOLECULAR
  description: >-
    Assembly of the dolichol-linked Glc3Man9GlcNAc2 precursor in the endoplasmic
    reticulum is incomplete, so the oligosaccharyltransferase complex has less
    full-length donor to transfer onto nascent glycoproteins.
  biological_processes:
  - 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
  evidence:
  - reference: PMID:22956764
    reference_title: "A zebrafish model of PMM2-CDG reveals altered neurogenesis and a substrate-accumulation mechanism for N-linked glycosylation deficiency."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Significantly, global N-linked glycosylation and LLO levels were reduced in pmm2
      morphants.
    explanation: Directly measures the reduction in the oligosaccharide donor.
  downstream:
  - target: Global Protein N-Hypoglycosylation
    causal_link_type: DIRECT
    description: Less donor means fewer occupied sequons on nascent glycoproteins.

- name: Global Protein N-Hypoglycosylation
  biological_scale: CELLULAR
  description: >-
    Occupancy of Asn-X-Ser/Thr sequons falls across the secreted and membrane
    glycoproteome. Because the defect is at the shared donor rather than at one
    transferase, the consequence is global, which is why a single enzyme deficiency
    produces a multisystem disease.
  biological_processes:
  - preferred_term: protein N-linked glycosylation
    modifier: DECREASED
    term:
      id: GO:0006487
      label: protein N-linked glycosylation
  evidence:
  - reference: PMID:20301289
    reference_title: "PMM2-CDG."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      PMM2-CDG, the most common of a group of disorders of abnormal glycosylation of
      N-linked oligosaccharides
    explanation: Places the disease at the level of N-linked glycosylation as a whole.
  downstream:
  - target: Disrupted Cerebellar Development
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      The developing cerebellum is disproportionately dependent on intact
      N-glycosylation; the glycoproteins that mediate this are not fully identified.
  - target: Hypoglycosylation of Coagulation Regulators
    causal_link_type: DIRECT
    description: >-
      Antithrombin, protein C, protein S and factors IX and XI are themselves
      N-glycoproteins.
  - target: Hepatic Involvement
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Hepatocyte dysfunction with transaminase elevation and fibrosis.

- name: Disrupted Cerebellar Development
  biological_scale: TISSUE
  description: >-
    Cerebellar hypoplasia is established during development rather than accrued by
    later degeneration. Conditional mouse work localizes the requirement to embryonic
    neural precursors: deleting Pmm2 from post-mitotic neurons or astrocytes produces
    no phenotype, while deleting it from precursors reproduces the hypoplasia.
  locations:
  - preferred_term: cerebellum
    term:
      id: UBERON:0002037
      label: cerebellum
  cell_types:
  - preferred_term: cerebellar granule cell
    term:
      id: CL:0001031
      label: cerebellar granule cell
  biological_processes:
  - preferred_term: cerebellar granule cell differentiation
    modifier: DECREASED
    term:
      id: GO:0021707
      label: cerebellar granule cell differentiation
  evidence:
  - reference: PMID:40501776
    reference_title: "Novel mouse model reveals neurodevelopmental origin of PMM2-CDG brain pathology."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      These findings highlight the heightened dependency of the developing cerebellum
      on intact N-glycosylation, aligning with clinical observations in PMM2-CDG
      patients.
    explanation: >-
      States the developmental dependency that makes the cerebellum the most affected
      structure.
  downstream:
  - target: Ataxia and Developmental Impairment
    causal_link_type: DIRECT
    description: The structural deficit produces the dominant neurological phenotype.

- name: Hypoglycosylation of Coagulation Regulators
  biological_scale: ORGANISM
  description: >-
    Anticoagulant and procoagulant glycoproteins are simultaneously underglycosylated
    and lose activity, so the same patient can carry both bleeding and thrombotic risk.
    Antithrombin is the most consistently affected.
  evidence:
  - reference: PMID:37224763
    reference_title: "Coagulation abnormalities in a prospective cohort of 50 patients with PMM2-congenital disorder of glycosylation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Prothrombotic and antithrombotic factor activities were frequently abnormal in
      PMM2-CDG patients, including AT, PC, PT, INR, and FXI.
    explanation: >-
      Documents that both arms of the coagulation system are affected together, which
      is what makes the coagulopathy mixed rather than one-directional.

- name: Hepatic Involvement
  biological_scale: TISSUE
  description: >-
    Hepatocyte dysfunction with transaminase elevation, hepatomegaly and, in some
    patients, fibrosis.
  locations:
  - preferred_term: liver
    term:
      id: UBERON:0002107
      label: liver
  cell_types:
  - preferred_term: hepatocyte
    term:
      id: CL:0000182
      label: hepatocyte
  evidence:
  - reference: PMID:20301289
    reference_title: "PMM2-CDG."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      cerebellar hypoplasia, and hepatopathy in infancy followed by neuropathy and
      retinitis pigmentosa in the first or second decade
    explanation: Places hepatopathy in the infantile course alongside the cerebellar lesion.

- name: Ataxia and Developmental Impairment
  biological_scale: ORGANISM
  description: >-
    The dominant clinical consequence: hypotonia and delay in infancy, then ataxia with
    intellectual disability that plateaus rather than progressing relentlessly.
  evidence:
  - reference: PMID:20301289
    reference_title: "PMM2-CDG."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      is characterized by hypotonia, ataxia, severely delayed language and motor
      development, inability to walk, and IQ of 40 to 70
    explanation: Describes the childhood ataxia-intellectual disability stage.

mechanistic_hypotheses:
- hypothesis_group_id: pmm2_precursor_depletion
  hypothesis_label: Precursor depletion limits oligosaccharide assembly
  status: CANONICAL
  description: >-
    The long-standing account: reduced PMM2 activity depletes mannose-1-phosphate and
    hence GDP-mannose, starving assembly of the lipid-linked oligosaccharide.
- hypothesis_group_id: pmm2_substrate_accumulation
  hypothesis_label: Substrate accumulation promotes oligosaccharide cleavage
  status: EMERGING
  description: >-
    A complementary account from the zebrafish model: accumulated mannose-6-phosphate
    promotes cleavage of the lipid-linked oligosaccharide, reducing donor availability
    by a route independent of precursor supply. Suppressing mannose phosphate isomerase
    normalized M6P and abolished the cleavage, which is the experiment that
    distinguishes the two. The two are not exclusive and both may operate.

phenotypes:
- category: Neurologic
  name: Cerebellar Hypoplasia
  frequency: VERY_FREQUENT
  description: >-
    Present from birth and the most consistent structural finding, affecting the vermis
    particularly.
  phenotype_term:
    preferred_term: Cerebellar hypoplasia
    term:
      id: HP:0001321
      label: Cerebellar hypoplasia
  evidence:
  - reference: PMID:40501776
    reference_title: "Novel mouse model reveals neurodevelopmental origin of PMM2-CDG brain pathology."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      prominently featuring neurological deficits with nearly all patients exhibiting
      cerebellar hypoplasia and ataxia
    explanation: >-
      Background sentence in a mouse-model paper reciting the human frequency; graded
      OTHER because the sentence is a review statement, not this paper's own result.

- category: Neurologic
  name: Ataxia
  frequency: VERY_FREQUENT
  phenotype_term:
    preferred_term: Ataxia
    term:
      id: HP:0001251
      label: Ataxia
  evidence:
  - reference: PMID:20301289
    reference_title: "PMM2-CDG."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      is characterized by hypotonia, ataxia, severely delayed language and motor
      development, inability to walk, and IQ of 40 to 70
    explanation: Names ataxia as a defining feature of the childhood stage.

- category: Neurologic
  name: Hypotonia
  frequency: VERY_FREQUENT
  phenotype_term:
    preferred_term: Hypotonia
    term:
      id: HP:0001252
      label: Hypotonia
  evidence:
  - reference: PMID:20301289
    reference_title: "PMM2-CDG."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      In the infantile multisystem presentation, infants show axial hypotonia,
      hyporeflexia, esotropia, and developmental delay.
    explanation: Lists hypotonia among the presenting infantile features.

- category: Neurologic
  name: Global Developmental Delay
  frequency: VERY_FREQUENT
  phenotype_term:
    preferred_term: Global developmental delay
    term:
      id: HP:0001263
      label: Global developmental delay
  evidence:
  - reference: PMID:20301289
    reference_title: "PMM2-CDG."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Feeding issues, vomiting, faltering growth, and developmental delay are
      frequently seen.
    explanation: Reports developmental delay as a frequent infantile finding.

- category: Neurologic
  name: Stroke-Like Episodes
  frequency: OCCASIONAL
  description: >-
    Transient unilateral loss of function, often provoked by intercurrent illness.
  phenotype_term:
    preferred_term: Stroke-like episode
    term:
      id: HP:0002401
      label: Stroke-like episode
  evidence:
  - reference: PMID:37224763
    reference_title: "Coagulation abnormalities in a prospective cohort of 50 patients with PMM2-congenital disorder of glycosylation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Stroke-like episodes (SLE) were reported in 18% of patients in our cohort.
    explanation: Quantifies the frequency in a prospective cohort of 50.

- category: Neurologic
  name: Peripheral Neuropathy
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Peripheral neuropathy
    term:
      id: HP:0009830
      label: Peripheral neuropathy
  evidence:
  - reference: PMID:20301289
    reference_title: "PMM2-CDG."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      cerebellar hypoplasia, and hepatopathy in infancy followed by neuropathy and
      retinitis pigmentosa in the first or second decade
    explanation: Places neuropathy in the later course of the nonfatal neurologic form.

- category: Ophthalmologic
  name: Strabismus
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Strabismus
    term:
      id: HP:0000486
      label: Strabismus
  evidence:
  - reference: PMID:20301289
    reference_title: "PMM2-CDG."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      In the infantile multisystem presentation, infants show axial hypotonia,
      hyporeflexia, esotropia, and developmental delay.
    explanation: >-
      Esotropia is the specific strabismus reported; curated to the general HP term
      because that is what the source supports at this level.

- category: Dermatologic
  name: Inverted Nipples
  frequency: FREQUENT
  description: >-
    One of the two classic early external signs, alongside the abnormal fat pads.
  phenotype_term:
    preferred_term: Inverted nipples
    term:
      id: HP:0003186
      label: Inverted nipples
  evidence:
  - reference: PMID:40307862
    reference_title: "A comprehensive update of genotype-phenotype correlations in PMM2-CDG: insights from molecular and structural analyses."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Other common symptoms of PMM2-CDG are abnormal fat distribution, facial
      dysmorphism, inverted nipples, strabismus, coagulation and endocrine anomalies
    explanation: >-
      Lists inverted nipples among the common features in a genotype-phenotype review.

- category: Dermatologic
  name: Abnormal Subcutaneous Fat Distribution
  frequency: FREQUENT
  description: Excess fat over the buttocks and suprapubic region.
  phenotype_term:
    preferred_term: Abnormal subcutaneous fat tissue distribution
    term:
      id: HP:0007552
      label: Abnormal subcutaneous fat tissue distribution
  evidence:
  - reference: PMID:20301289
    reference_title: "PMM2-CDG."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Subcutaneous fat may be excessive over the buttocks and suprapubic region.
    explanation: Describes the distribution abnormality directly.

- category: Hematologic
  name: Antithrombin Deficiency
  frequency: VERY_FREQUENT
  description: >-
    The single most common laboratory abnormality, and the one that carries the
    thrombotic risk.
  phenotype_term:
    preferred_term: Reduced antithrombin III activity
    term:
      id: HP:0001976
      label: Reduced antithrombin III activity
  evidence:
  - reference: PMID:37224763
    reference_title: "Coagulation abnormalities in a prospective cohort of 50 patients with PMM2-congenital disorder of glycosylation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: AT deficiency was the most common abnormality in 83.3% of patients.
    explanation: Quantifies frequency in the prospective cohort.

- category: Hepatic
  name: Elevated Transaminases
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Elevated circulating hepatic transaminase concentration
    term:
      id: HP:0002910
      label: Elevated circulating hepatic transaminase concentration
  evidence:
  - reference: PMID:20301289
    reference_title: "PMM2-CDG."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: annual AST, ALT, and albumin until normalization
    explanation: >-
      Graded PARTIAL: the surveillance recommendation implies the abnormality and its
      tendency to normalize, but does not state a frequency.

- category: Endocrine
  name: Hyperinsulinemic Hypoglycemia
  frequency: OCCASIONAL
  description: >-
    An uncommon but specifically treatable complication, generally responsive to
    diazoxide.
  evidence:
  - reference: PMID:32071842
    reference_title: "Hypoglycemia in CDG patients due to PMM2 mutations: Follow up on hyperinsulinemic patients."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Hypoglycemia was specifically mentioned only in 23 of these patients (2.5%).
      Hyperinsulinism was identified in 10 patients (43% of all hypoglycemic patients).
    explanation: >-
      Quantifies both the rarity of hypoglycemia across 933 reviewed patients and the
      share of that subgroup in which hyperinsulinism was the mechanism.

- category: Neurologic
  name: Seizures
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Seizure
    term:
      id: HP:0001250
      label: Seizure
  evidence:
  - reference: PMID:20301289
    reference_title: "PMM2-CDG."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      other findings include seizures, stroke-like episodes or transient unilateral loss
      of function, coagulopathy, retinitis pigmentosa, joint contractures, and skeletal
      deformities
    explanation: Lists seizures among the findings of the childhood stage.

- category: Neurologic
  name: Progressive Cerebellar Atrophy
  frequency: FREQUENT
  description: >-
    Distinct from the congenital hypoplasia: the cerebellum is small at birth and then
    atrophies further.
  phenotype_term:
    preferred_term: Cerebellar atrophy
    term:
      id: HP:0001272
      label: Cerebellar atrophy
    clinical_course: PROGRESSIVE
  evidence:
  - reference: PMID:33619652
    reference_title: >-
      Clinical and radiological correlates of activities of daily living in cerebellar
      atrophy caused by PMM2 mutations (PMM2-CDG).
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Cerebellar size reduction in PMM2-CDG is thought to be the result of both
      hypoplasia and hypotrophy.
    explanation: >-
      States that the small cerebellum reflects both a developmental deficit and
      subsequent tissue loss, which is why atrophy is curated separately from the
      congenital hypoplasia.

- category: Ophthalmologic
  name: Retinitis Pigmentosa
  frequency: FREQUENT
  description: >-
    Appears in the first or second decade and progresses through adulthood.
  phenotype_term:
    preferred_term: Rod-cone dystrophy
    term:
      id: HP:0000510
      label: Rod-cone dystrophy
    clinical_course: PROGRESSIVE
  evidence:
  - reference: PMID:20301289
    reference_title: "PMM2-CDG."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      cerebellar hypoplasia, and hepatopathy in infancy followed by neuropathy and
      retinitis pigmentosa in the first or second decade
    explanation: Places retinitis pigmentosa in the later course of the nonfatal form.

- category: Gastrointestinal
  name: Feeding Difficulties and Faltering Growth
  frequency: VERY_FREQUENT
  phenotype_term:
    preferred_term: Failure to thrive
    term:
      id: HP:0001508
      label: Failure to thrive
  evidence:
  - reference: PMID:20301289
    reference_title: "PMM2-CDG."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Feeding issues, vomiting, faltering growth, and developmental delay are
      frequently seen.
    explanation: Names feeding difficulty and faltering growth as frequent findings.

- category: Endocrine
  name: Hypothyroidism
  frequency: FREQUENT
  description: >-
    Thyroid-axis glycoproteins are themselves N-glycosylated, so this is a direct
    consequence of the core defect rather than secondary organ damage.
  phenotype_term:
    preferred_term: Hypothyroidism
    term:
      id: HP:0000821
      label: Hypothyroidism
  evidence:
  - reference: PMID:20301289
    reference_title: "PMM2-CDG."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      treatment of hypothyroidism, hypoglycemia, and other endocrinopathies per
      endocrinologist
    explanation: >-
      The GeneReviews Management section treats hypothyroidism as an expected
      manifestation requiring specialist management.

- category: Hematologic
  name: Deep Venous Thrombosis
  frequency: OCCASIONAL
  description: >-
    The clinical event the antithrombin deficiency produces; reported in 10% of a
    prospective cohort, and in that series always in the context of infection.
  phenotype_term:
    preferred_term: Deep venous thrombosis
    term:
      id: HP:0002625
      label: Deep venous thrombosis
  evidence:
  - reference: PMID:20301289
    reference_title: "PMM2-CDG."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: The risk for deep venous thrombosis is increased.
    explanation: States the increased thrombotic risk in the adult stage.
  - reference: PMID:37224763
    reference_title: >-
      Coagulation abnormalities in a prospective cohort of 50 patients with
      PMM2-congenital disorder of glycosylation.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Interestingly, 16% of the cohort experienced symptoms of spontaneous bleeding and
      10% had thrombosis.
    explanation: Quantifies both bleeding and thrombotic events in the prospective cohort.

- category: Hepatic
  name: Hepatomegaly
  frequency: FREQUENT
  phenotype_term:
    preferred_term: Hepatomegaly
    term:
      id: HP:0002240
      label: Hepatomegaly
  evidence:
  - reference: PMID:40307862
    reference_title: >-
      A comprehensive update of genotype-phenotype correlations in PMM2-CDG: insights
      from molecular and structural analyses.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      including brain hypoplasia, disturbed psychomotor abilities, areflexia,
      hypotonia, and strabismus as well as other organ involvement (hepatomegaly,
      tubulopathy)
    explanation: >-
      Reports hepatomegaly among the organ involvement in described patients. Graded
      PARTIAL because it describes specific genotypes rather than giving a cohort
      frequency.

- category: Ocular
  name: Myopia
  frequency: FREQUENT
  description: >-
    Emerges in the adult stable disability stage alongside the progressive retinal
    dystrophy, and is a separate refractive problem from it.
  phenotype_term:
    preferred_term: Myopia
    term:
      id: HP:0000545
      label: Myopia
  evidence:
  - reference: PMID:20301289
    reference_title: "PMM2-CDG."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: progressive retinitis pigmentosa and myopia are seen
    explanation: Names myopia among the adult-stage ocular findings.

- category: Musculoskeletal
  name: Joint Contractures
  frequency: OCCASIONAL
  description: >-
    Reported in the late-infantile and childhood ataxia-intellectual disability stage,
    alongside skeletal deformity.
  phenotype_term:
    preferred_term: Joint contracture
    term:
      id: HP:0034392
      label: Joint contracture
  evidence:
  - reference: PMID:20301289
    reference_title: "PMM2-CDG."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      coagulopathy, retinitis pigmentosa, joint contractures, and skeletal deformities
    explanation: Lists joint contractures among the childhood-stage findings.

- category: Musculoskeletal
  name: Osteoporosis
  frequency: FREQUENT
  description: >-
    Progressive in the adult stage, in which thoracic and spinal deformity worsens with
    it. Part of the premature-aging picture of the third stage rather than a
    presenting feature.
  phenotype_term:
    preferred_term: Osteoporosis
    term:
      id: HP:0000939
      label: Osteoporosis
  evidence:
  - reference: PMID:20301289
    reference_title: "PMM2-CDG."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      thoracic and spinal deformities with osteoporosis worsen, and premature aging is
      observed
    explanation: States the progressive skeletal deterioration of the adult stage.

- category: Endocrine
  name: Hypogonadotropic Hypogonadism
  frequency: OCCASIONAL
  description: >-
    Absent or deficient secondary sexual development, reported in the adult stage:
    females may lack secondary sexual development and males may show decreased
    testicular volume.
  phenotype_term:
    preferred_term: Hypogonadotropic hypogonadism
    term:
      id: HP:0000044
      label: Hypogonadotropic hypogonadism
  evidence:
  - reference: PMID:20301289
    reference_title: "PMM2-CDG."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Hypogonadotropic hypogonadism and coagulopathy may occur.
    explanation: States the hypogonadotropic hypogonadism of the adult stable stage.

biochemical:
- name: Serum transferrin isoform pattern
  presence: Abnormal
  context: >-
    A type I transferrin pattern is the established screening test and the functional
    assay used to interpret PMM2 variants of uncertain significance. Its sensitivity is
    high but not complete, and two recurrent variants are enriched among false
    positives.
  readouts:
  - target: Global Protein N-Hypoglycosylation
    relationship: READOUT_OF
    direction: POSITIVE
    endpoint_context: DIAGNOSTIC
    interpretation: >-
      Under-occupied glycosylation sites on transferrin report the global sequon
      occupancy defect.
    evidence:
    - reference: PMID:39216211
      reference_title: "Sensitivity of transferrin isoform analysis for PMM2-CDG."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        The data demonstrate 94% overall test sensitivity for PMM2-CDG and importantly
        demonstrate two known, recurrent variants enriched in false positive cases
        highlighting an important limitation of the test.
      explanation: >-
        Quantifies the sensitivity of this readout and names its limitation, rather
        than treating it as a perfect test.

- name: Antithrombin activity
  presence: Decreased
  context: >-
    Antithrombin is itself an N-glycoprotein, so its activity reports the glycosylation
    defect directly. Activity below roughly 65% marks the range in which thrombotic
    events occurred in the prospective cohort.
  readouts:
  - target: Hypoglycosylation of Coagulation Regulators
    relationship: READOUT_OF
    direction: NEGATIVE
    endpoint_context: PROGNOSTIC
    interpretation: >-
      Reduced activity of a glycoprotein anticoagulant reports the hypoglycosylation of
      the coagulation system.
    evidence:
    - reference: PMID:37224763
      reference_title: "Coagulation abnormalities in a prospective cohort of 50 patients with PMM2-congenital disorder of glycosylation."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        AT activity was below 50% in 62.5% of all patients (normal range 80-130%).
      explanation: Gives the magnitude of the deficit against a stated reference interval.

diagnosis:
- name: Type I transferrin isoform pattern with confirmatory PMM2 testing
  description: >-
    Diagnosis rests on a tiered sequence rather than a single test: a type I transferrin
    isoform pattern establishes a disorder of N-linked glycosylation, and biallelic PMM2
    variants confirm which one. Phosphomannomutase enzyme activity in leukocytes or
    fibroblasts is the fallback when the molecular result is uncertain, which is why the
    enzyme assay retains a role even in a sequencing era.
  evidence:
  - reference: PMID:20301289
    reference_title: "PMM2-CDG."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The diagnosis of PMM2-CDG is established in a proband with type I transferrin
      isoform analysis and identification of either biallelic pathogenic variants in
      PMM2 on molecular genetic testing or (if results of molecular genetic testing are
      uncertain) low levels of phosphomannomutase (PMM) enzyme activity.
    explanation: >-
      The GeneReviews Diagnosis/Testing criterion, giving all three tiers and the
      condition under which the enzyme assay is used.

progression:
- phase: Infantile multisystem
  age_range: birth to ~3 years
  notes: >-
    Axial hypotonia, hyporeflexia, esotropia and developmental delay, with feeding
    difficulty and faltering growth. Two courses are distinguished: a nonfatal
    neurologic one, and a neurologic-multivisceral one carrying roughly 20% mortality
    in the first year.
  evidence:
  - reference: PMID:20301289
    reference_title: "PMM2-CDG."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      a more severe neurologic-multivisceral course with approximately 20% mortality in
      the first year of life
    explanation: Gives the mortality attached to the severe infantile course.
- phase: Late-infantile and childhood ataxia-intellectual disability
  age_range: 3 to 10 years onward
  notes: >-
    Hypotonia, ataxia, severely delayed language and motor development, inability to
    walk, and IQ of 40 to 70, with seizures, stroke-like episodes, coagulopathy and
    retinitis pigmentosa.
  evidence:
  - reference: PMID:20301289
    reference_title: "PMM2-CDG."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The late-infantile and childhood ataxia–intellectual disability stage, which
      begins between ages three and ten years
    explanation: Defines the stage and its age of onset.
- phase: Adult stable disability
  age_range: adulthood
  notes: >-
    Intellectual ability stabilizes. Progressive retinitis pigmentosa and myopia,
    worsening thoracic and spinal deformity with osteoporosis, premature aging, and
    hypogonadotropic hypogonadism.
  evidence:
  - reference: PMID:20301289
    reference_title: "PMM2-CDG."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      In the adult stable disability stage, intellectual ability is stable; peripheral
      neuropathy is variable, progressive retinitis pigmentosa and myopia are seen
    explanation: >-
      Characterizes the adult stage, and specifically that the cognitive trajectory
      plateaus rather than continuing to decline.

genetic:
- name: PMM2
  gene_term:
    preferred_term: PMM2
    term:
      id: hgnc:9115
      label: PMM2
  relationship_type: CAUSATIVE
  variants:
  - name: c.422G>A (p.Arg141His)
    clinical_significance: PATHOGENIC
    description: >-
      The commonest allele in the disease, carried by more than 60% of patients, and
      the one that defines its genetic architecture. R141H has never been reported
      homozygous in a living patient: it is a functional null, and two nulls appear not
      to be compatible with live birth. Every patient therefore carries something else
      on the other chromosome, and it is that second allele's residual activity - not
      R141H - that sets where they fall on the severity spectrum. This is why the
      commonest genotype is a compound heterozygote rather than a homozygote, and why
      an allele-frequency-derived prevalence ceiling exceeds the diagnosed rate.
    functional_effects:
    - function: phosphomannomutase activity
      type: loss-of-function
      description: >-
        Effectively complete loss in the homozygous state, inferred from its absence
        among living patients rather than from a direct assay quoted here. In trans
        with a hypomorph it still permits measurable residual activity, which is the
        basis of the enzyme-activator approach.
    evidence:
    - reference: PMID:40501776
      reference_title: "Novel mouse model reveals neurodevelopmental origin of PMM2-CDG brain pathology."
      supports: SUPPORT
      evidence_source: OTHER
      snippet: >-
        R141H, a human pathogenic variant carried by more than 60% of PMM2-CDG patients
      explanation: >-
        The allele frequency among patients. Graded OTHER because it recites human
        epidemiology inside a mouse-model paper.
    - reference: PMID:34447415
      reference_title: "The Estimated Prevalence of N-Linked Congenital Disorders of Glycosylation Across Various Populations Based on Allele Frequencies in General Population Databases."
      supports: SUPPORT
      evidence_source: COMPUTATIONAL
      snippet: >-
        the p.Arg141His variant homozygotes were not excluded although known to be
        embryonically lethal
      explanation: >-
        The embryonic-lethality claim this record rests on, from a reference the entry
        already uses in its prevalence section. It is also why an allele-frequency
        prevalence estimate overcounts here: the study deliberately kept homozygotes in
        the calculation while acknowledging they are not born.
  - name: c.357C>A (p.Phe119Leu)
    clinical_significance: PATHOGENIC
    description: >-
      The partial-activity allele that most often sits opposite R141H. The source that
      makes that pairing claim ties it to Scandinavia, where F119L is most prevalent, so
      R141H/F119L is reported as the commonest genotype there rather than established as
      the commonest worldwide. Its interest is that it is the
      substrate the only enzyme-directed therapy needs: an activator can raise residual
      activity but cannot create it, so a genotype pairing a null with a hypomorph is
      precisely where such a drug has something to act on. R141H/F119L fibroblasts were
      one of the four lines in which epalrestat was shown to raise PMM2 activity.
    functional_effects:
    - function: phosphomannomutase activity
      type: loss-of-function
      description: >-
        Partial rather than complete - a hypomorph. The activity that survives is what
        distinguishes this allele from R141H functionally, and what the enzyme-activator
        approach depends on.
    evidence:
    - reference: PMID:31636082
      reference_title: >-
        Repurposing the aldose reductase inhibitor and diabetic neuropathy drug
        epalrestat for the congenital disorder of glycosylation PMM2-CDG.
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: >-
        Epalrestat increased PMM2 enzymatic activity in four PMM2-CDG patient fibroblast
        lines with genotypes R141H/F119L, R141H/E139K, R141H/N216I and R141H/F183S
      explanation: >-
        Names R141H/F119L as one of the tested genotypes and reports measurable PMM2
        activity in those fibroblasts, which is consistent with this allele leaving
        activity to raise. It is not an assay of F119L: residual activity in a compound
        heterozygote is a property of the pair, so this supports the hypomorph reading
        without measuring the allele on its own.
    - reference: PMID:31636082
      reference_title: >-
        Repurposing the aldose reductase inhibitor and diabetic neuropathy drug
        epalrestat for the congenital disorder of glycosylation PMM2-CDG.
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: >-
        PMM2 enzyme activity gains ranged from 30% to 400% over baseline, depending on
        genotype
      explanation: >-
        Records that the size of the response varies by genotype, which is the
        structured form of this entry's per-allele residual-activity claim.
    - reference: PMID:40501776
      reference_title: "Novel mouse model reveals neurodevelopmental origin of PMM2-CDG brain pathology."
      supports: SUPPORT
      evidence_source: OTHER
      snippet: >-
        the two most prevalent human pathogenic variants R141H (NM_000303.2:c.422G>A
        (p.Arg141His), ClinVar 7706) and F119L (NM_000303.2:c.357C>A (p.Phe119Leu),
        ClinVar 7711)
      explanation: >-
        Establishes that F119L is one of the two most prevalent pathogenic alleles,
        which the record previously asserted without a citation. Graded OTHER for the
        same reason as the sibling R141H frequency item from this paper: it recites
        human epidemiology inside a mouse-model study.
    - reference: PMID:40307862
      reference_title: "A comprehensive update of genotype-phenotype correlations in PMM2-CDG: insights from molecular and structural analyses."
      supports: SUPPORT
      evidence_source: OTHER
      snippet: >-
        This missense mutation is more frequent in compound heterozygosity with
        p.Arg141His and is predominantly prevalent in Scandinavia
      explanation: >-
        The sentence that actually supports "most often sits opposite R141H", and the
        one that bounds it geographically. Graded OTHER rather than HUMAN_CLINICAL,
        which this paper carries elsewhere in the entry, because this particular
        sentence recites frequency and geography from three cited sources rather than
        reporting the review's own patient data.
  notes: >-
    At least one hypomorphic allele is required: biallelic complete loss of activity is
    not compatible with survival, which is why missense alleles predominate and why a
    functional null such as R141H is never seen homozygous. Per-allele residual activity
    is what places a patient on the severity spectrum; the two alleles that carry most of that
    argument, R141H and F119L, are curated as structured variants above rather than
    named only in this paragraph.

inheritance:
- name: Autosomal recessive
  inheritance_term:
    preferred_term: Autosomal recessive inheritance
    term:
      id: HP:0000007
      label: Autosomal recessive inheritance
  description: >-
    Biallelic inheritance, but with an observed recurrence risk that exceeds the
    Mendelian expectation in practice.
  evidence:
  - reference: PMID:20301289
    reference_title: "PMM2-CDG."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      however, based on outcomes of at-risk pregnancies, the risk of having an affected
      child is closer to 1/3 than to the expected 1/4
    explanation: >-
      The GeneReviews Genetic Counseling section records an observed segregation ratio
      above the 1/4 expectation, which is the figure counseling should use.

prevalence:
- population: North America and Europe
  measure_type: POINT_PREVALENCE
  prevalence_class: BAND_1_9_PER_100000
  rate_per_100000: 2.9
  notes: >-
    Reported as an incidence of approximately 1:35,000 in North America and Europe;
    normalized here to cases per 100,000.
  evidence:
  - reference: PMID:40501776
    reference_title: "Novel mouse model reveals neurodevelopmental origin of PMM2-CDG brain pathology."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      PMM2-CDG has an estimated incidence of approximately 1:35,000 in North America
      and Europe
    explanation: >-
      Background epidemiology stated in a mouse-model paper; graded OTHER because the
      sentence reports human population data the paper did not generate.

- population: Ashkenazi Jewish
  measure_type: BIRTH_PREVALENCE
  prevalence_class: BAND_1_9_PER_100000
  rate_per_100000: 5.0
  notes: >-
    1 in 20,000, the highest of the three population estimates the study reports from
    gnomAD allele frequencies (it computed seven; three appear in the result sentence). An independent earlier estimate (Schollen 2000, recited
    in this paper's introduction) lands on the same number by a different route; it is
    deliberately not cited here as a second evidence item, because a coincident figure
    from another study is not additional support for this one.

    Allele-frequency-derived rather than ascertained from diagnosed cases, which is why
    it exceeds the observed diagnosed rate above. This entry's own null-lethality claim
    is one reason the two diverge: genotypes that never reach live birth are counted in
    an allele-based estimate and not in a clinical one.
  evidence:
  - reference: PMID:34447415
    reference_title: "The Estimated Prevalence of N-Linked Congenital Disorders of Glycosylation Across Various Populations Based on Allele Frequencies in General Population Databases."
    supports: SUPPORT
    evidence_source: COMPUTATIONAL
    snippet: >-
      PMM2-CDG showed the highest estimated prevalence counted from 71 different
      pathogenic variants, and it is more prevalent in European (1 in 27,000), Ashkenazi
      Jewish (1 in 20,000), and admixed American populations (1 in 64,000)
    explanation: >-
      Gives all three population estimates in one sentence, including the Ashkenazi
      Jewish figure this record carries.

- population: European
  measure_type: BIRTH_PREVALENCE
  prevalence_class: BAND_1_9_PER_100000
  rate_per_100000: 3.7
  notes: >-
    1 in 27,000. Carried as its own record so the roughly three-fold spread across
    populations is visible in the structured data rather than only in prose; a single
    worldwide figure hides it. Same allele-frequency caveat as the other two. The source
    sentence says only "European"; the study's methods describe seven gnomAD populations
    of which the European one is non-Finnish, but that identification is an inference
    from the methods and is left out of the population field rather than asserted there.
  evidence:
  - reference: PMID:34447415
    reference_title: "The Estimated Prevalence of N-Linked Congenital Disorders of Glycosylation Across Various Populations Based on Allele Frequencies in General Population Databases."
    supports: SUPPORT
    evidence_source: COMPUTATIONAL
    snippet: >-
      PMM2-CDG showed the highest estimated prevalence counted from 71 different
      pathogenic variants, and it is more prevalent in European (1 in 27,000), Ashkenazi
      Jewish (1 in 20,000), and admixed American populations (1 in 64,000)
    explanation: >-
      The European figure, from the same sentence that gives all three.

- population: Admixed American
  measure_type: BIRTH_PREVALENCE
  prevalence_class: BAND_1_9_PER_100000
  rate_per_100000: 1.6
  notes: >-
    1 in 64,000, the lowest of the three and about a third of the Ashkenazi Jewish
    estimate. Same allele-frequency caveat as the other two.
  evidence:
  - reference: PMID:34447415
    reference_title: "The Estimated Prevalence of N-Linked Congenital Disorders of Glycosylation Across Various Populations Based on Allele Frequencies in General Population Databases."
    supports: SUPPORT
    evidence_source: COMPUTATIONAL
    snippet: >-
      PMM2-CDG showed the highest estimated prevalence counted from 71 different
      pathogenic variants, and it is more prevalent in European (1 in 27,000), Ashkenazi
      Jewish (1 in 20,000), and admixed American populations (1 in 64,000)
    explanation: >-
      The admixed American figure, from the same sentence that gives all three.

treatments:
- name: Supportive and Multisystem Management
  description: >-
    There is no therapy that restores glycosylation. Management is organ-directed:
    nutritional support, seizure control, developmental therapies, and specialist
    management of the ocular, cardiac, endocrine and renal manifestations.
  treatment_term:
    preferred_term: Supportive Care
    term:
      id: NCIT:C15747
      label: Supportive Care
  target_mechanisms:
  - target: Ataxia and Developmental Impairment
    treatment_effect: MODULATES
    description: >-
      Acts on the consequences of the cerebellar lesion rather than on the
      glycosylation defect.
  evidence:
  - reference: PMID:20301289
    reference_title: "PMM2-CDG."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Symptomatic treatment for severe infantile phase in a pediatric tertiary care
      center.
    explanation: >-
      The GeneReviews Management section frames care as symptomatic, which is the
      accurate description of what is available.
  - reference: PMID:20301289
    reference_title: "PMM2-CDG."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Cautious use of acetaminophen and other agents metabolized by the liver if
      significant liver insufficiency is present.
    explanation: >-
      The GeneReviews Agents/Circumstances to Avoid line, which is a management
      instruction rather than a general caution and follows from the hepatic arm.

- name: Haematological Monitoring and Perioperative Planning
  description: >-
    Annual assessment of bleeding and clotting parameters, with haematology input
    before surgery. This is the arm of management that acts on a measurable mechanistic
    readout rather than on symptoms.
  treatment_term:
    preferred_term: Supportive Care
    term:
      id: NCIT:C15747
      label: Supportive Care
  target_mechanisms:
  - target: Hypoglycosylation of Coagulation Regulators
    treatment_effect: MODULATES
    description: >-
      Surveillance and perioperative correction address the coagulation consequences of
      hypoglycosylation.
  evidence:
  - reference: PMID:20301289
    reference_title: "PMM2-CDG."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      annual assessment of bleeding and clotting parameters by a hematologist including
      prothrombin time, protein C, protein S, antithrombin III, factor IX, and factor XI
    explanation: >-
      The GeneReviews surveillance recommendation naming the specific factors to follow.

- name: GLM101 (Mannose-1-Phosphate Replacement)
  description: >-
    A liposomal mannose-1-phosphate replacement therapy that supplies the metabolite
    immediately downstream of the deficient enzyme, bypassing the block rather than
    correcting it. This is the investigational agent whose mechanism engages the
    pathograph most directly.
  therapeutic_modality: OTHER
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
  target_mechanisms:
  - target: Depletion of Mannose-1-Phosphate and GDP-Mannose
    treatment_effect: BYPASSES
    description: >-
      Delivering mannose-1-phosphate directly restores the pool the blocked enzyme
      cannot make, without requiring residual PMM2 activity.
    evidence:
    - reference: clinicaltrials:NCT05549219
      reference_title: >-
        A Phase 2, Randomized, Open-Label, 24-Week Study to Assess the Pharmacodynamics,
        Safety, Tolerability, and Pharmacokinetics of Multiple Doses of GLM101
        Administered Intravenously to Adult, Adolescent, and Pediatric Participants With
        PMM2-CDG
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        This is a Phase 2, randomized, open-label, 24-week treatment study to evaluate
        the potential pharmacodynamic (PD) activity, safety, tolerability, and
        pharmacokinetics (PK) of GLM101 in adult, adolescent, and pediatric, patients
        with a confirmed diagnosis of PMM2-CDG.
      explanation: >-
        The registered trial establishing that this agent is under clinical evaluation
        in this disease, with pharmacodynamic activity as a stated endpoint.
  notes: >-
    Reported Phase 2a results and the enrolment status of the Phase 2b POLAR study are
    described in press releases rather than in indexed literature, so they are not
    curated as evidence here; only the registered trial record is cited.

- name: Diazoxide for Hyperinsulinemic Hypoglycemia
  description: >-
    Opens the beta-cell K-ATP channel to suppress inappropriate insulin secretion. It
    treats a specific complication rather than the glycosylation defect, and it is the
    one place where an uncommon manifestation of this disease has a well-defined
    pharmacological answer.
  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
  evidence:
  - reference: PMID:32071842
    reference_title: >-
      Hypoglycemia in CDG patients due to PMM2 mutations: Follow up on hyperinsulinemic
      patients.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Among these 10 patients, seven were successfully treated with diazoxide.
    explanation: Gives the response rate among the hyperinsulinemic subgroup.
  - reference: PMID:32071842
    reference_title: >-
      Hypoglycemia in CDG patients due to PMM2 mutations: Follow up on hyperinsulinemic
      patients.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      However, most patients remained on therapy longer than a year to stay free of
      hypoglycemia.
    explanation: >-
      Records that the benefit is maintenance rather than cure, which is the limit on
      the claim.

- name: AAV9-PMM2 Gene Replacement (preclinical)
  description: >-
    Preclinical gene replacement in the Pmm2 knockout mouse. Curated because it speaks
    directly to this entry's own question about the developmental window: it reverses a
    molecular deficit in the cerebellum of the same model whose conditional knockouts
    locate the PMM2 requirement in development.
  therapeutic_modality: GENE_THERAPY
  treatment_term:
    preferred_term: Gene Therapy
    term:
      id: NCIT:C15238
      label: Gene Therapy
  target_mechanisms:
  - target: Disrupted Cerebellar Development
    treatment_effect: RESTORES
    description: >-
      Restores Neurexin-2 abundance in the cerebellum of the knockout mouse. This is a
      molecular readout, not a behavioural or structural rescue, and the entry does not
      claim more.
    evidence:
    - reference: PMID:40832321
      reference_title: >-
        AAV-based gene replacement reverses Neurexin-2 downregulation in the cerebellum
        of a mouse model of phosphomannomutase 2 deficiency (PMM2-CDG).
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        showed that its reduced abundance can be reversed by AAV9- PMM2 gene treatment
        of the Pmm2 KO mice
      explanation: >-
        Graded PARTIAL deliberately: the reversal demonstrated is of a single protein's
        abundance in a mouse, not of the cerebellar phenotype and not in humans.
  notes: >-
    Preclinical only. No human trial of gene replacement in PMM2-CDG is cited here.

- name: Oral Mannose Supplementation
  description: >-
    Attempts to raise flux into the pathway upstream of the block. Past supplementation
    trials did not show clear clinical benefit. Curated because a negative result about
    an intuitively obvious therapy is worth recording.
  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
  evidence:
  - reference: PMID:39236565
    reference_title: 'Treatment of congenital disorders of glycosylation: An overview.'
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Mostly, we are only able to manage the disease symptoms rather than to address
      the underlying cause.
    explanation: >-
      A review statement of the field's overall position, cited for the general absence
      of an established disease-modifying therapy rather than for mannose specifically.
  - reference: PMID:35562242
    reference_title: Nutrition interventions in congenital disorders of glycosylation.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Past mannose supplementation trials did not show clear clinical benefits
    explanation: >-
      States the negative outcome of prior mannose supplementation specifically. Graded
      OTHER because the sentence is a review's summary of earlier trials rather than a
      primary result of this paper.
  notes: >-
    Correction of hypoglycosylation in patient fibroblasts is deliberately not claimed
    here: nothing cited supports it. The primary trial reports behind the negative
    clinical result are not fetched, so the entry carries a review's summary of them,
    which is why that evidence item is graded OTHER.

- name: Epalrestat
  description: >-
    An aldose reductase inhibitor, repurposed from diabetic neuropathy, that raises
    residual PMM enzyme activity rather than supplying a downstream metabolite. It is
    the one agent here that acts on the deficient enzyme step itself. Its
    placebo-controlled paediatric Phase III trial was terminated for futility, so the
    biochemical rationale below is retained as mechanism while clinical benefit is
    not established.
  therapeutic_modality: SMALL_MOLECULE
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: epalrestat
      term:
        id: CHEBI:31539
        label: epalrestat
  target_mechanisms:
  - target: Reduced Phosphomannomutase 2 Activity
    treatment_effect: MODULATES
    description: >-
      Raises the activity of the residual enzyme rather than bypassing it, so any
      benefit would depend on there being hypomorphic activity left to raise. This is a
      biochemical claim; the controlled trial testing whether it produces clinical
      benefit was stopped for futility.
    evidence:
    - reference: PMID:31636082
      reference_title: >-
        Repurposing the aldose reductase inhibitor and diabetic neuropathy drug
        epalrestat for the congenital disorder of glycosylation PMM2-CDG.
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: >-
        Epalrestat increased PMM2 enzymatic activity in four PMM2-CDG patient fibroblast
        lines with genotypes R141H/F119L, R141H/E139K, R141H/N216I and R141H/F183S
      explanation: >-
        The primary result the review below was summarizing, and a much better carrier
        for this edge: a measurement in patient fibroblasts, in four named genotypes,
        rather than a secondhand statement that the effect exists.
    - reference: PMID:31636082
      reference_title: >-
        Repurposing the aldose reductase inhibitor and diabetic neuropathy drug
        epalrestat for the congenital disorder of glycosylation PMM2-CDG.
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: >-
        PMM2 enzyme activity gains ranged from 30% to 400% over baseline, depending on
        genotype
      explanation: >-
        Quantifies the effect and, more usefully for this entry, records that its size
        is genotype-dependent - which is what the MODULATES rather than RESTORES grading
        on this link is saying.
    - reference: PMID:31636082
      reference_title: >-
        Repurposing the aldose reductase inhibitor and diabetic neuropathy drug
        epalrestat for the congenital disorder of glycosylation PMM2-CDG.
      supports: SUPPORT
      evidence_source: OTHER
      snippet: >-
        Pharmacological inhibition of aldose reductase by epalrestat may shunt glucose
        from the polyol pathway to glucose-1,6-bisphosphate, which is an endogenous
        stabilizer and coactivator of PMM2 homodimerization
      explanation: >-
        The proposed route from an aldose reductase inhibitor to phosphomannomutase
        activity, which is otherwise a surprising connection. Graded OTHER rather than
        IN_VITRO alongside the two assay results above, because the authors' own "may"
        marks this as the mechanism they propose, not one this paper measures.
    - reference: PMID:35562242
      reference_title: Nutrition interventions in congenital disorders of glycosylation.
      supports: SUPPORT
      evidence_source: OTHER
      snippet: >-
        epalrestat (an aldose reductase enzyme inhibitor) has been reported to improve
        PMM enzyme activity levels and shown to increase protein glycosylation by
        glycoproteomic studies
      explanation: >-
        Retained below the primary source rather than removed, because it adds the
        glycoproteomic arm the fibroblast enzyme assays do not cover. Still graded
        OTHER: the sentence is a review's summary of other work.
  evidence:
  - reference: clinicaltrials:NCT04925960
    reference_title: >-
      A Prospective, Randomized, Double-Blind, Placebo-Controlled, Single-Center Study
      of Oral Epalrestat Therapy in Pediatric Subjects With Phosphomannomutase
      2-congenital Disorder of Glycosylation (PMM2-CDG)
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      designed to assess the safety, tolerability, and clinical and metabolic
      improvement of pediatric subjects with PMM2-CDG on oral epalrestat therapy vs.
      placebo
    explanation: The registered controlled trial of this agent in this disease.
  notes: >-
    The Phase III trial NCT04925960 was terminated, with "Due to futility" given as the
    reason. This is retained as a curated treatment because the enzyme-activity
    mechanism is separately evidenced and because a negative controlled result is
    informative, not because the agent is effective. The termination is recorded from
    the ClinicalTrials.gov API record (status verified 2025-09) rather than quoted as
    evidence, because the cached reference holds only the study description.
    Epalrestat is also in trial for SORD-related Charcot-Marie-Tooth disease
    (NCT05777226), where it works by lowering sorbitol rather than by raising PMM
    activity. That trial is a different disease and is deliberately not cited here.

clinical_trials:
- name: NCT05549219
  phase: PHASE_II
  status: COMPLETED
  description: >-
    Randomized, open-label, 24-week study of intravenous GLM101 at 10, 20 and 30 mg/kg
    in adult, adolescent and pediatric patients with confirmed PMM2-CDG.
  evidence:
  - reference: clinicaltrials:NCT05549219
    reference_title: >-
      A Phase 2, Randomized, Open-Label, 24-Week Study to Assess the Pharmacodynamics,
      Safety, Tolerability, and Pharmacokinetics of Multiple Doses of GLM101
      Administered Intravenously to Adult, Adolescent, and Pediatric Participants With
      PMM2-CDG
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The planned doses of GLM101 to be investigated are 10, 20, and 30 mg/kg.
    explanation: Records the dose range under evaluation in the registered protocol.
  notes: >-
    The cached reference holds only the study description, which does not state a
    recruitment status. COMPLETED was confirmed against the ClinicalTrials.gov API
    record (actual completion 2025-11-18, status verified 2025-12) and is recorded here
    rather than quoted as evidence.

- name: NCT04925960
  phase: PHASE_III
  status: TERMINATED
  description: >-
    Randomized, double-blind, placebo-controlled single-center study of oral epalrestat
    in pediatric PMM2-CDG, with safety, tolerability and clinical and metabolic
    improvement as endpoints.
  evidence:
  - reference: clinicaltrials:NCT04925960
    reference_title: >-
      A Prospective, Randomized, Double-Blind, Placebo-Controlled, Single-Center Study
      of Oral Epalrestat Therapy in Pediatric Subjects With Phosphomannomutase
      2-congenital Disorder of Glycosylation (PMM2-CDG)
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      This is a prospective, single-center, randomized, double-blind, placebo-controlled
      study designed to assess the safety, tolerability, and clinical and metabolic
      improvement of pediatric subjects with PMM2-CDG on oral epalrestat therapy vs.
      placebo.
    explanation: The registered protocol record for this trial.
  - reference: PMID:40501776
    reference_title: >-
      Novel mouse model reveals neurodevelopmental origin of PMM2-CDG brain pathology.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      aldose reductase inhibitors are in development as novel therapeutics for
      PMM2-CDG, including a recent phase III clinical trial of epalrestat (NCT04925960)
    explanation: >-
      Source for the Phase III designation, which the registry record itself does not
      state. Graded OTHER because the sentence is contextual framing rather than a
      result of the mouse study it appears in.
  notes: >-
    Terminated, with "Due to futility" given as the reason; actual completion
    2025-02-28. The cached reference holds only the study description, so the status
    and the PHASE3 designation were confirmed against the ClinicalTrials.gov API record
    (status verified 2025-09) and are recorded here rather than quoted as evidence.

animal_models:
- name: Nestin-Cre embryonic neural precursor Pmm2 knockout mouse (eKO)
  species: Mouse
  genotype: Pmm2 R137H/flox with Nestin-Cre
  publication: PMID:40501776
  description: >-
    Pairs a catalytically inactive knock-in allele with a conditional null to reproduce
    the compound-heterozygous state while avoiding the embryonic lethality of a whole-body
    knockout.
  modeled_mechanisms:
  - target: Disrupted Cerebellar Development
    relationship: RECAPITULATES
    fidelity: HIGH
    description: >-
      Deleting Pmm2 in embryonic neural precursors reproduces cerebellar hypoplasia,
      ataxia and seizures, and the glycoproteomic changes are corroborated in human
      post-mortem cerebellar tissue.
    limitations: >-
      Early lethality limits study to the first weeks of life, and Nestin-Cre has
      ectopic renal expression, so the renal cysts in this model cannot be attributed
      to the cerebellar mechanism.
    readouts:
    - name: Cerebellar hypoplasia and ataxic gait
      target: Disrupted Cerebellar Development
      direction: DECREASED
      interpretation: Structural and behavioural correlate of the human cerebellar lesion.
      evidence:
      - reference: PMID:40501776
        reference_title: "Novel mouse model reveals neurodevelopmental origin of PMM2-CDG brain pathology."
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: >-
          removal of PMM2 from embryonic neural precursor cells leads to cerebellar
          hypoplasia, ataxia, seizures, and early lethality
        explanation: Reports the phenotype produced by precursor-stage deletion.
    evidence:
    - reference: PMID:40501776
      reference_title: "Novel mouse model reveals neurodevelopmental origin of PMM2-CDG brain pathology."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        glycoproteomic alterations identified in our mouse model are corroborated in
        PMM2-CDG patient post-mortem cerebellar tissue
      explanation: >-
        Cross-validation against human tissue is what justifies treating this model as
        informative for the human node.

- name: Post-mitotic neuronal and astrocyte Pmm2 knockout mouse (nKO, aKO)
  species: Mouse
  genotype: Pmm2 R137H/flox with Snap25-Cre or Gfap-Cre
  publication: PMID:40501776
  description: >-
    Deletes Pmm2 after neurons and astrocytes are post-mitotic, testing whether ongoing
    glycosylation in mature cells is what the disease requires.
  modeled_mechanisms:
  - target: Disrupted Cerebellar Development
    relationship: FAILS_TO_RECAPITULATE
    fidelity: LOW
    description: >-
      Removing PMM2 from mature neurons or astrocytes produces no detectable phenotype.
      This is a substantive negative result: it locates the requirement for PMM2 in
      development rather than in maintenance, and is the comparison that makes the
      embryonic-precursor model interpretable.
    limitations: >-
      A negative result in a conditional model cannot exclude a smaller maintenance
      requirement below the sensitivity of the assays used, and bulk-lysate enzyme
      assays still detect activity from non-recombined cells.
    evidence:
    - reference: PMID:40501776
      reference_title: "Novel mouse model reveals neurodevelopmental origin of PMM2-CDG brain pathology."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        Mice with post-mitotic loss of PMM2 from neurons or astrocytes are
        indistinguishable from unaffected littermates, including in a broad battery of
        neurological assessments.
      explanation: >-
        States the negative result directly, including the breadth of testing behind
        it.

- name: pmm2 morpholino zebrafish
  species: Zebrafish
  genotype: pmm2 morpholino knockdown
  publication: PMID:22956764
  description: >-
    The model in which the substrate-accumulation mechanism was identified.
  modeled_mechanisms:
  - target: Truncated Lipid-Linked Oligosaccharide Synthesis
    relationship: RECAPITULATES
    fidelity: MODERATE
    description: >-
      Reproduces reduced global N-glycosylation and reduced LLO levels, and allowed the
      M6P-accumulation route to be separated from precursor depletion by epistasis with
      mannose phosphate isomerase.
    limitations: >-
      Morpholino knockdown is transient and not allele-specific, so it models loss of
      Pmm2 rather than the hypomorphic compound-heterozygous state patients carry.
    evidence:
    - reference: PMID:22956764
      reference_title: "A zebrafish model of PMM2-CDG reveals altered neurogenesis and a substrate-accumulation mechanism for N-linked glycosylation deficiency."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        Suppression of the M6P-synthesizing enzyme mannose phosphate isomerase within
        the pmm2 background normalized M6P levels and certain aspects of the
        craniofacial phenotype and abrogated pmm2-dependent LLO cleavage.
      explanation: >-
        The epistasis experiment that establishes M6P accumulation as causal rather
        than incidental.

discussions:
- discussion_id: pmm2_two_routes_to_underglycosylation
  kind: INTERPRETATION
  prompt: >-
    Does underglycosylation in PMM2-CDG follow from precursor depletion, from substrate
    accumulation, or from both?
  attaches_to:
  - pathophysiology#Truncated Lipid-Linked Oligosaccharide Synthesis
  rationale: >-
    The textbook account is depletion of mannose-1-phosphate and GDP-mannose. The
    zebrafish study could not measure either metabolite reliably, but did find that
    accumulated mannose-6-phosphate promotes cleavage of the lipid-linked
    oligosaccharide, and that suppressing M6P synthesis abolished the cleavage. Both
    routes converge on the same node and are not mutually exclusive; the entry models
    them as separate hypothesis groups so a future measurement can support one without
    silently retiring the other.

- discussion_id: pmm2_developmental_window
  kind: KNOWLEDGE_GAP
  prompt: >-
    If the cerebellar lesion is established during development, what can any therapy
    started after birth be expected to achieve for it?
  attaches_to:
  - pathophysiology#Disrupted Cerebellar Development
  rationale: >-
    The conditional mouse work locates the requirement for PMM2 in embryonic neural
    precursors and finds no phenotype when the enzyme is removed from mature neurons.
    If that transfers to humans, the structural cerebellar deficit is fixed before
    presentation, and post-natal therapy would be expected to act on the non-cerebellar
    arms of the disease rather than to reverse the hypoplasia.

    There is now a partial answer pointing the other way, which is why this is a gap
    rather than a settled limit: AAV9-PMM2 gene treatment of the Pmm2 knockout mouse
    reverses the cerebellar downregulation of Neurexin-2. That is a molecular readout in
    one protein, not a structural or behavioural rescue, so it establishes that some
    cerebellar molecular phenotype remains addressable after the developmental window
    without establishing that the hypoplasia itself is. What would settle it is a
    structural and functional endpoint after post-natal intervention in the same model.

notes: >-
  Scope and naming. This entry covers the PMM2 complementation group as a whole. The
  KB already curates thirteen other CDG entries and a Congenital_Disorders_of_Glycosylation
  grouping that does not yet list PMM2-CDG; adding this entry to that grouping's members
  is a reasonable follow-up.

  MONDO identifier. The deep-research report proposed MONDO:0015286 for this entry. That
  term is the generic "congenital disorder of glycosylation" parent and would have bound
  the entry to the whole category. The correct term is MONDO:0008907, which the stub
  already carried and whose OMIM cross-reference (212065) matches the report's own.

  Ontology corrections. Five of the twenty-seven CURIEs suggested by the research report
  were wrong and were replaced after checking each against the ontology: GO:0097502
  (mannosylation) and CL:0000643 (offered as cerebellar granule cell) are both obsolete;
  HP:0009026, offered as abnormal subcutaneous fat distribution, is Hypoplasia of
  latissimus dorsi muscle; HP:0001636, offered as pericardial effusion, is Tetralogy of
  Fallot; and HP:0001700, offered as hypertrophic cardiomyopathy, is Myocardial necrosis.
  The replacements used are GO:0006487, CL:0001031, HP:0007552, HP:0001698 and HP:0001639
  respectively, though the last two are not yet curated as phenotypes here because the
  sources consulted describe them only as subset findings without a frequency.

  GeneReviews mining. PMID:20301289 is tagged and is now mined across all four
  sections. The first version of this entry consumed Clinical Characteristics,
  Management and Genetic Counseling but not Diagnosis/Testing, while the history record
  for that session asserted all four. Review caught it. The diagnostic tiering and the
  agents-to-avoid line are curated now, and the over-claim is recorded here rather than
  quietly corrected - the same failure was caught on a previous entry in this
  repository and repeating it is worth stating.

  Evidence grading. Several quotes are taken from the mouse-model and zebrafish papers
  but state human epidemiology or human clinical features in their background sections.
  Those are graded OTHER rather than MODEL_ORGANISM, because evidence_source classifies
  what the quoted sentence reports, not which paper it sits in.
📚

References & Deep Research

References

15
PMID:20301289
PMM2-CDG.
No top-level findings curated for this source.
PMID:35562242
Nutrition interventions in congenital disorders of glycosylation.
No top-level findings curated for this source.
clinicaltrials:NCT04925960
A Prospective, Randomized, Double-Blind, Placebo-Controlled, Single-Center Study of Oral Epalrestat Therapy in Pediatric Subjects With Phosphomannomutase 2-congenital Disorder of Glycosylation (PMM2-CDG)
No top-level findings curated for this source.
PMID:22956764
A zebrafish model of PMM2-CDG reveals altered neurogenesis and a substrate-accumulation mechanism for N-linked glycosylation deficiency.
No top-level findings curated for this source.
PMID:31636082
Repurposing the aldose reductase inhibitor and diabetic neuropathy drug epalrestat for the congenital disorder of glycosylation PMM2-CDG.
No top-level findings curated for this source.
PMID:37224763
Coagulation abnormalities in a prospective cohort of 50 patients with PMM2-congenital disorder of glycosylation.
No top-level findings curated for this source.
PMID:39216211
Sensitivity of transferrin isoform analysis for PMM2-CDG.
No top-level findings curated for this source.
PMID:40307862
A comprehensive update of genotype-phenotype correlations in PMM2-CDG: insights from molecular and structural analyses.
No top-level findings curated for this source.
PMID:40501776
Novel mouse model reveals neurodevelopmental origin of PMM2-CDG brain pathology.
No top-level findings curated for this source.
PMID:34447415
The Estimated Prevalence of N-Linked Congenital Disorders of Glycosylation Across Various Populations Based on Allele Frequencies in General Population Databases.
No top-level findings curated for this source.
PMID:32071842
Hypoglycemia in CDG patients due to PMM2 mutations: Follow up on hyperinsulinemic patients.
No top-level findings curated for this source.
PMID:33619652
Clinical and radiological correlates of activities of daily living in cerebellar atrophy caused by PMM2 mutations (PMM2-CDG).
No top-level findings curated for this source.
PMID:39236565
Treatment of congenital disorders of glycosylation: An overview.
No top-level findings curated for this source.
PMID:40832321
AAV-based gene replacement reverses Neurexin-2 downregulation in the cerebellum of a mouse model of phosphomannomutase 2 deficiency (PMM2-CDG).
No top-level findings curated for this source.
clinicaltrials:NCT05549219
A Phase 2, Randomized, Open-Label, 24-Week Study to Assess the Pharmacodynamics, Safety, Tolerability, and Pharmacokinetics of Multiple Doses of GLM101 Administered Intravenously to Adult, Adolescent, and Pediatric Participants With PMM2-CDG
No top-level findings curated for this source.

Deep Research

1
Claude Code ▸
PMM2-Congenital Disorder of Glycosylation (PMM2-CDG): Comprehensive Research Report
claude-haiku-4-5-20251001, claude-sonnet-5 41 citations 2026-08-27T18:56:11.989350

PMM2-Congenital Disorder of Glycosylation (PMM2-CDG): Comprehensive Research Report

1. Disease Information

Overview

PMM2-CDG (formerly known as CDG-Ia or "carbohydrate-deficient glycoprotein syndrome type I") is an autosomal recessive inborn error of metabolism caused by biallelic pathogenic variants in PMM2, the gene encoding phosphomannomutase 2. It is the most common and best-characterized disorder of N-linked protein glycosylation in humans, accounting for roughly 60% of all diagnosed CDG cases, with more than 1,000 patients reported worldwide across >900 published cases (Frontiers in Endocrinology, 2025; Orphanet). PMM2-CDG is a multisystem disease: because essentially all secreted and membrane glycoproteins require N-glycosylation for correct folding, stability, and trafficking, defective glycosylation produces a broad, variable phenotype spanning neurological, gastrointestinal, hepatic, cardiac, renal, coagulation, endocrine, and skeletal systems.

Key Identifiers

Resource Identifier
OMIM #212065 (Congenital Disorder of Glycosylation, Type Ia)
Gene (OMIM) PMM2, 601785
Orphanet ORPHA:79318
MONDO MONDO:0015286 (PMM2-CDG)
ICD-10 E77.8 (Other disorders of glycoprotein metabolism)
ICD-11 5C56.0Y / related metabolic disorder codes
HGNC PMM2, HGNC:9115
MeSH Congenital Disorders of Glycosylation

Source: OMIM #212065; GeneReviews — PMM2-CDG

Synonyms / Alternative Names

  • CDG-Ia / CDG1A / CDGS1
  • Congenital disorder of glycosylation type Ia
  • Phosphomannomutase 2 deficiency
  • Carbohydrate-deficient glycoprotein syndrome type I (historical)
  • Jaeken syndrome (historical eponym, after Jaak Jaeken who first described the disorder in 1980)

Data Source Character

Most published information derives from aggregated case series and multicenter cohort studies (e.g., the 96-patient French cohort, the 50-patient coagulation cohort, and international registries such as the Frontiers in Congenital Disorders of Glycosylation Consortium (FCDGC) natural history study), rather than raw individual EHR mining. Orphanet and OMIM entries synthesize published cohort and case-report literature.

2. Etiology

Disease Causal Factors

PMM2-CDG is caused exclusively by biallelic (compound heterozygous or homozygous) pathogenic variants in PMM2 (chromosome 16p13.2), which encodes phosphomannomutase 2, the enzyme that isomerizes mannose-6-phosphate (M6P) to mannose-1-phosphate (M1P) — an essential precursor for GDP-mannose and dolichol-phosphate-mannose synthesis required for N-glycan assembly (GeneReviews; PMID 22956764). There is no known environmental or infectious causal pathway — this is a purely monogenic mechanistic disease.

Genetic Risk Factors

  • Causal variants: >120 pathogenic PMM2 variants have been reported (missense predominating, with fewer nonsense, splice-site, and small indel variants). Missense predominance reflects that complete loss of PMM2 activity is embryonic lethal in humans (consistent with mouse data below).
  • Most common pathogenic alleles:
  • c.422G>A (p.Arg141His / R141H) — the single most frequent PMM2-CDG allele. It has no detectable residual enzymatic activity and has never been observed in homozygosity in a living patient, implying that R141H homozygosity is embryonic/fetal lethal. gnomAD heterozygote carrier frequency is ~0.39% overall (891/224,376), rising to ~0.84% in the Finnish subpopulation (ClinVar VCV000007706).
  • c.357C>A/G (p.Phe119Leu / F119L) — retains ~25% residual enzymatic activity, likely due to impaired dimerization; among 18 Danish CDG-Ia patients, F119L together with R141H accounted for 88% of alleles.
  • The compound heterozygote genotype R141H/F119L is the most frequent genotype worldwide and is the genotype modeled in the leading mouse model (see Section 15).
  • Genotype–phenotype correlation is imperfect but broadly: genotypes combining two severe/null alleles are rarer (often embryonic lethal or very severe), while a null allele paired with a hypomorphic (partial-activity) allele like F119L is compatible with survival across the full clinical spectrum (PMC12042452, "genotype–phenotype correlations in PMM2-CDG").

Protective/Modifier Factors

No validated protective genetic variants are established. Hypomorphic alleles with higher residual PMM2 activity (vs. null alleles) act as de facto "protective" modifiers of severity in trans-heterozygotes.

Environmental Risk Factors

None established — this is a purely genetic (autosomal recessive, biallelic) disease with no known environmental, occupational, or lifestyle contributors to disease occurrence. (Environmental factors can modulate the severity of acute decompensations — e.g., febrile illness, surgery, and fasting can precipitate stroke-like episodes, bleeding, or hypoglycemic crises — but do not cause the underlying disease.)

Gene-Environment Interactions

Not a primary feature of this monogenic disorder; the closest analog is that intercurrent physiologic stress (infection, fasting, surgery) interacts with baseline coagulopathy and hypoglycemia susceptibility to precipitate acute complications.

3. Phenotypes

PMM2-CDG phenotypes span a wide severity spectrum from neonatal death to mild adult presentation. Below are phenotype categories with suggested HPO terms.

Neurological

Phenotype Frequency/Onset Suggested HPO
Cerebellar hypoplasia (present at birth, "figure-8" or "batwing" cerebellum on MRI) → progressive cerebellar atrophy Present in nearly all infants at birth; progresses HP:0001321 (Cerebellar hypoplasia), HP:0001272 (Cerebellar atrophy)
Hypotonia Common, early infancy HP:0001252
Ataxia/dysmetria/tremor Progressive, childhood onward HP:0001251 (Ataxia), HP:0001337 (Tremor)
Abnormal (esotropic/roving) eye movements, strabismus Early, frequent HP:0000486 (Strabismus), HP:0000496 (Abnormal eye movements)
Psychomotor delay / intellectual disability (mild–moderate, usually non-progressive plateau) Infancy/childhood HP:0001263, HP:0001249
Peripheral neuropathy Later childhood/adult HP:0009830
Seizures Subset HP:0001250
Stroke-like episodes (SLEs) ~18% of cohort, often provoked by febrile illness HP:0002401

Source: PMC12042452; PMC10530657 (coagulation cohort); Neurology case report on unusual eye movements.

Dysmorphic / Physical

  • Inverted/hypoplastic nipples and abnormal fat distribution/lipodystrophy (suprapubic fat pads, "orange-peel" skin over buttocks) — considered classic, near-pathognomonic early signs (HP:0003186 Inverted nipples; HP:0009026 Abnormal subcutaneous fat tissue distribution).
  • Facial dysmorphism (large ears, high forehead) — HP:0000238 etc.

Gastrointestinal/Hepatic

  • Failure to thrive, feeding difficulty/vomiting, enteropathy — HP:0001508, HP:0011968
  • Hepatomegaly, elevated transaminases, hepatic fibrosis — HP:0002240, HP:0002910
  • Recurrent pancreatitis (subset) — HP:0001733

Cardiac

  • Pericardial effusion, hypertrophic cardiomyopathy — HP:0001636, HP:0001700

Renal

  • Nephrotic-range proteinuria/renal cysts in a subset — HP:0000100

Hematologic (laboratory abnormalities)

  • Coagulopathy from hypoglycosylated clotting factors/inhibitors — see Section 6/10. Antithrombin deficiency is the single most common lab abnormality, found in 83.3% of patients, with activity <50% (normal 80–130%) in 62.5% of the cohort (PMC10530657). Also common: Factor XI deficiency, protein C deficiency, protein S and Factor IX deficiency (less common).
  • Bleeding symptoms in 16%; thrombosis in 10% of a large cohort.

Endocrine (laboratory/clinical)

  • Hypothyroidism (glycosylation-dependent TSH/thyroglobulin dysfunction)
  • Hyperinsulinemic hypoglycemia — reported in ~2.5% of a 933-patient PMM2-CDG review, with hyperinsulinism confirmed in 43% of the hypoglycemic subgroup; diazoxide-responsive in most treated cases (PMC7012739; PMC9680396)
  • Hypogonadotropic hypogonadism / abnormal FSH-LH glycoforms in females (elevated FSH from birth, later ovarian failure)
  • Growth hormone axis abnormalities (short stature) — reflecting IGFBP-3 hypoglycosylation (Frontiers Endocrinology 2025)

Phenotype Characteristics

  • Onset: Congenital/neonatal-infantile in the classic (and most common) presentation; a distinct late-onset/adult phenotype is increasingly recognized, sometimes presenting primarily with cerebellar ataxia or stroke-like episodes without the classic infantile multisystem picture (Orphanet Journal of Rare Diseases, 29 French adult patients).
  • Severity/progression: Highly variable — ranges from infants who die in the first year of life (severe multisystem/hydrops-like presentation with cardiac/renal/hepatic failure) to mildly affected adults with only ataxia and mild cognitive involvement. Three recognized natural-history stages: (1) infantile multisystem type, (2) late-infantile/childhood ataxia–intellectual disability type (ages 3–10), (3) adult stable disability type (GeneReviews).
  • Course: Neurological (cerebellar) disease is generally non-progressive after early childhood plateau in survivors, though cerebellar atrophy on imaging can progress radiographically even as clinical function stabilizes (PMC8360885, activities of daily living correlates).

Quality of Life

A cross-sectional adaptive functioning study found PMM2-CDG substantially impacts adaptive functioning across the lifespan and imposes significant parental stress, particularly around motor and communication domains (Scientific Reports, 2023, PMC10739927). A patient-reported outcomes study (Orphanet J Rare Dis, 2022) identified fatigue, gastrointestinal symptoms, and mobility/ataxia as top patient/caregiver concerns not always captured by clinician-rated instruments (OJRD 2022).

4. Genetic/Molecular Information

Causal Gene

  • PMM2 (phosphomannomutase 2), HGNC:9115, chromosome 16p13.2, OMIM *601785. Encodes a cytosolic enzyme that functions as a homodimer.

Variant Classification and Type

  • Predominantly missense variants (reflecting embryonic lethality of complete null/null genotypes); fewer nonsense, frameshift, and splice-site alleles.
  • ClinVar/ACMG classification: Both R141H and F119L are classified Pathogenic (ClinVar RCV000008145).
  • Functional consequences are predominantly hypomorphic loss-of-function — destabilizing the protein fold/reducing dimerization/catalytic efficiency rather than classic null alleles, consistent with the observation that complete biallelic null genotypes are not observed in living patients.

Allele Frequency

  • R141H heterozygote frequency in gnomAD: ~0.39% overall population, ~0.84% in Finnish subpopulation.
  • Population-based carrier-frequency modeling (using gnomAD allele frequencies across all known pathogenic PMM2 alleles) estimates a theoretical birth prevalence as high as 1:20,000, though observed/diagnosed birth prevalence is substantially lower (1:77,000–1:286,000 in some analyses; see Section 9) — a gap attributed to embryonic lethality of severe genotype combinations and underdiagnosis (PMC8383291).

Somatic vs. Germline

Exclusively germline — PMM2-CDG is a classic Mendelian recessive disorder with no somatic mosaicism subtype reported as clinically significant.

Modifier Genes

MPI (mannose phosphate isomerase) activity ratio relative to PMM2 modulates response to mannose-based therapies (the PMM2:MPI ratio determines whether supplemental mannose is shunted productively into the pathway or diverted) — this is a pharmacologically relevant "modifier" relationship rather than a classic genetic modifier locus (treatment reviews, ScienceDirect).

Chromosomal Abnormalities

Not applicable — PMM2-CDG is caused by point mutations/small indels in a single gene, not large structural/chromosomal rearrangements.

Molecular/Structural Insights

A 2025 comprehensive update integrates molecular dynamics and structural analysis of PMM2 mutant proteins to refine genotype-phenotype correlations, showing that many pathogenic variants destabilize the dimer interface or active site rather than abolishing catalysis outright (PMC12042452).

5. Environmental Information

  • Environmental/toxin factors: None causally implicated; this is a purely monogenic disease.
  • Lifestyle factors: Not causal, though diet (mannose/galactose supplementation trials) is relevant therapeutically (Section 12).
  • Infectious agents: Not causal of the underlying disease, but febrile/infectious illness is a recognized trigger of acute decompensation — stroke-like episodes, coagulopathic bleeding events, and metabolic crises are frequently precipitated by intercurrent infection (PMC10530657).

6. Mechanism / Pathophysiology

Core Molecular Defect

PMM2 catalyzes the reversible isomerization of mannose-6-phosphate (M6P) → mannose-1-phosphate (M1P) in the cytosol. M1P is the substrate for GDP-mannose pyrophosphorylase, generating GDP-mannose, which is required both directly (for cytosolic-face LLO assembly) and via conversion to dolichol-phosphate-mannose (Dol-P-Man) (for luminal-face assembly) in construction of the dolichol-linked oligosaccharide (LLO) precursor, Glc3Man9GlcNAc2-PP-Dolichol, in the endoplasmic reticulum. Deficient PMM2 activity lowers the M1P pool, causing truncated/incomplete LLO synthesis, which the oligosaccharyltransferase (OST) complex then transfers inefficiently — or not at all — onto nascent glycoproteins' Asn-X-Ser/Thr sequons (PMID 22956764; GeneReviews).

Cellular Processes / Protein Dysfunction

The resulting global hypoglycosylation compromises protein folding, ER quality control, stability, and trafficking across essentially every secreted/membrane glycoprotein — explaining the multisystem phenotype. Recent work has extended understanding to specific immune signaling pathways: hypoglycosylation impairs the TNFα–TNFR1 signaling axis, implicating aberrant cytokine signaling in PMM2-CDG immunopathology (PMC12488661, "Immunopathology in PMM2-CDG").

Suggested Ontology Terms

  • GO:0004615 (phosphomannomutase activity)
  • GO:0006487 (protein N-linked glycosylation)
  • GO:0006506 (GPI anchor biosynthetic process, related pathway)
  • GO:0097502 (mannosylation)
  • Cellular component: GO:0005783 (endoplasmic reticulum), GO:0005793 (ER-Golgi intermediate compartment)

Endocrine Mechanism

Multiple hormone-axis glycoproteins are directly affected: thyroglobulin, TSH, prolactin, FSH, LH, and IGFBP-3 are all N-glycosylated and functionally impaired by hypoglycosylation, explaining hypothyroidism, gonadal dysfunction, and growth abnormalities as direct downstream consequences of the core enzymatic defect rather than secondary organ damage (Frontiers in Endocrinology 2025).

Coagulation Mechanism

Antithrombin, protein C, protein S, and several clotting factors (XI, IX) are glycoproteins whose hypoglycosylation directly reduces their circulating activity/half-life, producing a mixed pro- and anti-thrombotic coagulopathy that can manifest as either spontaneous bleeding or thrombosis/stroke-like episodes depending on which factor imbalance predominates at a given time (de la Morena-Barrio et al., J Thromb Haemost, PMID referenced in search; PMC10530657).

Causal Chain Summary (for pathograph modeling)

  1. Biallelic PMM2 pathogenic variants → decreased phosphomannomutase 2 enzymatic activity (molecular scale; LOSS_OF_FUNCTION/GAIN... not applicable — hypomorphic)
  2. → Decreased M1P / GDP-mannose / Dol-P-Man pools (molecular)
  3. → Truncated lipid-linked oligosaccharide (LLO) synthesis (molecular)
  4. → Global protein N-hypoglycosylation (cellular)
  5. → Downstream organ-specific consequences: cerebellar granule cell/neuronal developmental disruption (neurological), hypoglycosylated coagulation factors (coagulopathy), hypoglycosylated hormone/hormone receptors (endocrinopathy), hepatocyte dysfunction (hepatic), etc.

Molecular/Omics Profiling

A 2025 mouse model study (see Section 15) using single-cell/bulk transcriptomic profiling of cerebellar tissue revealed a neurodevelopmental origin of PMM2-CDG brain pathology — i.e., cerebellar granule cell development is disrupted prenatally/perinatally rather than purely via later neurodegeneration (bioRxiv/PMC12157701, "Novel mouse model reveals neurodevelopmental origin of PMM2-CDG brain pathology").

7. Anatomical Structures Affected

Organ Level

  • Primary: Cerebellum/CNS, peripheral nerves, eyes; skin/subcutaneous fat; liver; heart; GI tract; kidney; endocrine glands (thyroid, gonads, pancreatic islets)
  • Body systems: Nervous, endocrine, digestive, cardiovascular, renal, hematologic/coagulation, integumentary, skeletal
  • Suggested UBERON: cerebellum (UBERON:0002037), liver (UBERON:0002107), heart (UBERON:0000948), kidney (UBERON:0002113), thyroid gland (UBERON:0002046)

Tissue and Cell Level

  • Cerebellar granule neurons and Purkinje cells (developmental/degenerative target)
  • Hepatocytes (fibrosis, dysfunction)
  • Vascular endothelium (coagulation factor synthesis)
  • Suggested Cell Ontology: cerebellar granule cell (CL:0000643), hepatocyte (CL:0000182)

Subcellular Level

  • Endoplasmic reticulum (site of N-glycosylation/LLO assembly) — GO:0005783
  • Cytosol (site of PMM2 enzymatic reaction) — GO:0005829
  • Golgi apparatus (downstream glycan processing) — GO:0005794

Localization

Bilateral, symmetric cerebellar hypoplasia/atrophy (not lateralized); systemic (multi-organ) involvement rather than focal.

8. Temporal Development

  • Onset: Congenital in the classic form (dysmorphic features and hypotonia apparent at or shortly after birth); a late-onset/adult-presenting phenotype exists with initial symptoms (ataxia, peripheral neuropathy) emerging in adolescence or adulthood.
  • Onset pattern: Chronic/insidious for the baseline multisystem disease, punctuated by acute stroke-like episodes, bleeding, and hypoglycemic crises that are typically provoked by infection, fasting, or surgical stress.
  • Progression / stages (per GeneReviews):
  • Infantile multisystem stage (birth–~3 years): failure to thrive, hypotonia, coagulopathy, hepatic/cardiac/renal involvement; highest mortality risk period.
  • Late-infantile/childhood ataxia–intellectual disability stage (ages 3–10): cerebellar ataxia and cognitive delay become the dominant clinical picture as acute multisystem crises recede.
  • Adult stable disability stage: chronic, largely non-progressive neurological disability (ataxia, peripheral neuropathy, mild cognitive impairment) with continued risk of episodic coagulopathic/stroke-like events.
  • Rate: Highly variable across patients — from neonatal death to stable lifelong mild disability.
  • Remission patterns: No spontaneous remission of the underlying enzymatic defect; individual acute complications (hypoglycemia, effusions) can resolve with supportive/targeted treatment.
  • Critical periods: Fetal/early neonatal period is critical for cerebellar developmental injury (per the neurodevelopmental-origin mouse data); early childhood is the period of highest risk for life-threatening multisystem crises.

9. Inheritance and Population

Epidemiology

Estimates vary substantially by methodology: - A 2025 ScienceDirect analysis calculated an incidence estimate of 1 in 33,576 for North America and Europe combined (1 in 40,375 in North America; 1 in 29,043 in Europe), predicting ~303 live births/year across both regions (ScienceDirect, "Incidence and prevalence of PMM2-CDG: Past, present, and future"). - Allele-frequency-based (gnomAD) theoretical birth prevalence estimates run as high as 1:20,000, but later empirical estimates from diagnosed cohorts are lower, 1:77,000 to 1:286,000 (PMC8383291) — the gap likely reflects embryonic lethality of severe genotypes and under-ascertainment/underdiagnosis. - Regional variation: most commonly reported/diagnosed in Denmark and other Scandinavian countries; estimated combined CDG prevalence in the Saudi population ~14/million; in Poland ~1/million.

Inheritance Pattern

Autosomal recessive. Both parents are obligate heterozygous carriers; recurrence risk is 25% per pregnancy for unaffected-carrier parents.

Penetrance / Expressivity

Full penetrance for the biochemical/glycosylation defect in biallelic carriers, but highly variable clinical expressivity — genotype only partially predicts phenotype severity, and even patients sharing the identical genotype (e.g., R141H/F119L) can show a wide range of clinical severity, implicating additional genetic/epigenetic/stochastic modifiers not yet fully characterized.

Genetic Anticipation

Not reported — not a repeat-expansion disorder.

Germline Mosaicism

Not specifically documented as a recurring feature of PMM2-CDG in the literature reviewed.

Founder Effects

R141H shows elevated carrier frequency in the Finnish population (gnomAD), consistent with a founder or drift effect in Northern European populations; the disease is disproportionately reported in Scandinavian cohorts.

Consanguinity

Increases risk in populations/families with elevated consanguinity rates, as for any autosomal recessive disorder, though PMM2-CDG is not specifically enriched in classically consanguineous populations relative to Northern European populations where it is most reported.

Carrier Frequency

Estimated from gnomAD population allele frequencies; R141H alone carrier frequency ~0.39% (general), ~0.84% (Finnish).

Sex Ratio / Age Distribution

No strong sex bias reported for disease occurrence (autosomal, so expected 1:1), though certain endocrine manifestations (hypergonadotropic hypogonadism, elevated FSH) are specifically described in affected females. Age distribution spans neonatal death through adulthood as described above.

10. Diagnostics

First-Line Biochemical Screening

  • Serum transferrin isoelectric focusing (IEF) / carbohydrate-deficient transferrin (CDT) analysis: the standard first-line screening test for N-glycosylation disorders including PMM2-CDG. PMM2-CDG produces a characteristic Type I transferrin isoform pattern (loss of entire N-glycan chains, distinguishing it from Type II patterns seen in Golgi-processing CDGs) (Mayo Clinic Labs test catalog).
  • Apolipoprotein C-III isoform analysis: used as a complementary/confirmatory first-line screen alongside transferrin isoform analysis, particularly useful in cases where transferrin results are equivocal or in liver disease (which can confound transferrin glycoform interpretation).
  • Sensitivity: a 2024 study reported 94% overall sensitivity of transferrin isoform analysis for PMM2-CDG detection (PMID 39216211) — meaning ~6% of cases could be missed by this screen alone, reinforcing the need for molecular confirmation when clinical suspicion is high despite normal/equivocal screening.

Enzyme Assay

Phosphomannomutase enzymatic activity assay in leukocytes or cultured fibroblasts, used to confirm pathogenicity when genetic variants are of uncertain significance.

Molecular Genetic Testing

  • Definitive diagnosis: identification of biallelic pathogenic/likely pathogenic PMM2 variants by sequencing (single-gene sequencing, CDG-focused gene panel, or exome/genome sequencing).
  • Recommended approach per GeneReviews: given the broad, nonspecific multisystem presentation, a metabolic/CDG gene panel or exome sequencing is often the practical first-tier molecular test alongside biochemical screening.

Imaging

  • Brain MRI: cerebellar hypoplasia at birth progressing to cerebellar atrophy — a key supportive radiological finding correlating with ataxia severity (PMC8360885).

Differential Diagnosis

Other CDG subtypes (particularly MPI-CDG/CDG-Ib, which is treatable with mannose and must be distinguished), other congenital ataxias/cerebellar hypoplasia syndromes, other causes of neonatal coagulopathy/hepatopathy, and other lipodystrophy syndromes.

Screening

No universal newborn screening program currently exists for PMM2-CDG (unlike some other IEMs); diagnosis is typically clinically triggered. Carrier screening panels for PMM2 exist commercially (e.g., Myriad Foresight Carrier Screen) for reproductive risk assessment in at-risk populations.

11. Outcome/Prognosis

Mortality

Historically, mortality in the first years of life has been reported at roughly 20% in the infantile-onset multisystem form, primarily from cardiac, hepatic, or coagulopathic/infectious complications, though outcomes have improved with modern supportive care. Long-term follow-up cohorts (e.g., the French cohort of 96 patients) demonstrate that many patients who survive the high-risk infantile period stabilize into the chronic ataxia/intellectual disability phenotype with a near-normal lifespan, though episodic life-threatening events (stroke-like episodes, severe coagulopathy) remain a lifelong risk (Genetics in Medicine, "Long-term follow-up in PMM2-CDG").

Morbidity

Chronic ataxia, peripheral neuropathy, and mild-to-moderate intellectual disability are the dominant sources of long-term morbidity and reduced adaptive functioning/quality of life, as documented in cross-sectional adaptive functioning studies (PMC10739927).

Complications

Recurrent stroke-like episodes (18% of a large cohort), spontaneous bleeding (16%), thrombosis (10%), pericardial effusion, hyperinsulinemic hypoglycemia, hypothyroidism, and hepatic fibrosis are recognized long-term/recurrent complications requiring ongoing surveillance.

Prognostic Factors

Genotype (presence of two null/severe alleles vs. a hypomorphic allele) partially correlates with severity; degree of residual PMM2 enzymatic activity is a key biochemical prognostic correlate. Early recognition and aggressive management of acute coagulopathic/metabolic crises appears to improve survival through the highest-risk infantile period.

12. Treatment

There are currently no FDA/EMA-approved disease-modifying therapies for PMM2-CDG (Frontiers search summary; EMA orphan designation EU/3/18/2047 reflects ongoing drug development, not an approved product). Management is currently supportive and symptomatic, with several investigational disease-modifying approaches in active clinical trials.

Supportive/Symptomatic Care (current standard of care)

  • Multidisciplinary management: physical/occupational/speech therapy for ataxia and developmental delay (NCIT:C15302 Physical Therapy; NCIT:C159273 Speech Therapy; NCIT:C121351 Occupational Therapy)
  • Nutritional support/feeding interventions for failure to thrive (NCIT:C15447 Dietary Intervention)
  • Coagulopathy management: fresh frozen plasma or factor/antithrombin concentrate replacement during acute bleeding, thrombotic, or peri-surgical periods
  • Diazoxide for hyperinsulinemic hypoglycemia (successful in 7/10 treated patients in one series) (NCIT:C15986 Pharmacotherapy; therapeutic_agent CHEBI diazoxide)
  • Thyroid hormone replacement for hypothyroidism (NCIT:C15986 Pharmacotherapy)
  • Cardiac monitoring/management of pericardial effusion and cardiomyopathy
  • Genetic counseling for families (NCIT:C15240)

Investigational Disease-Modifying Therapies

1. Epalrestat (repurposed aldose reductase inhibitor) — furthest along in clinical development: - Originally developed for diabetic neuropathy in Japan; repurposed by Perlara/collaborators based on the hypothesis that aldose reductase inhibition redirects glucose flux to increase mannose/GDP-mannose availability. - A Phase III, randomized, double-blind, placebo-controlled trial in pediatric PMM2-CDG patients (Mayo Clinic-led) enrolled 38 subjects, closed enrollment November 2023, and as of March 2024 all placebo subjects were permitted to cross over to open-label epalrestat at their 15-month visit (PR Newswire, March 2024; Mayo Clinic trial page). - Trial design assesses safety, tolerability, and clinical/metabolic improvement (oral, three-times-daily dosing). - Therapeutic modality: SMALL_MOLECULE; NCIT treatment_term: Pharmacotherapy (NCIT:C15986).

2. GLM101 (mannose-1-phosphate replacement therapy) — Glycomine: - A glycoprotein-based mannose-1-phosphate replacement therapy designed to bypass the deficient PMM2 enzymatic step by delivering M1P directly into cells, restoring downstream GDP-mannose/Dol-P-Man pathway flux. - Phase 1 study: NCT05549219 ("24-Week Study to Assess the PD, Safety, Tolerability, and PK of GLM101"). - Phase 2a open-label results: among 9 adult/adolescent patients, treatment produced an average 11.9-point improvement on the ICARS (International Cooperative Ataxia Rating Scale) over 24 weeks, with a favorable safety profile (no serious adverse events; only mild-moderate AEs) (BioSpace, Glycomine Phase 2 results). - Phase 2b "POLAR" trial: global, randomized, double-blind, placebo-controlled study; enrollment of 43 patients across 15 sites completed as of April 2026, with topline data expected Q4 2026 (Glycomine press release, April 2026). - Therapeutic modality: PROTEIN_REPLACEMENT (or classify as small-molecule/metabolite replacement depending on schema fit).

3. Dietary mannose supplementation: - Corrects hypoglycosylation in PMM2-deficient fibroblasts in vitro, but short-term oral/IV mannose monotherapy trials in patients have shown inconsistent/largely unsuccessful clinical results (Orphanet J Rare Dis, "Unsuccessful intravenous D-mannose treatment in PMM2-CDG"). One study found that after >1 year of dietary mannose supplementation, a majority of patients showed improved glycosylation biomarkers, suggesting a longer treatment horizon may be needed (Orphanet J Rare Dis 2020, "Dietary mannose supplementation"); efficacy is thought to depend on the individual patient's PMM2:MPI enzymatic activity ratio.

4. Pharmacological chaperones/proteostasis regulators (preclinical): - Screening identified compounds (8 candidates, 4 confirmed as functional chaperones) that increase thermal stability of destabilized/oligomerization-defective PMM2 mutant proteins and increase residual PMM enzymatic activity in cell models — proof-of-concept for a chaperone therapy strategy, not yet in clinical trials (ResearchGate, "Pharmacological Chaperoning: A Potential Treatment for PMM2-CDG").

5. AAV gene replacement therapy (preclinical): - A 2025 study in the novel Pmm2 mouse model showed AAV-based gene replacement therapy prevented and halted manifestation of abnormal neurological phenotypes when administered appropriately, providing strong preclinical proof-of-concept for gene therapy in PMM2-CDG (Gene Therapy (Nature), 2025). Therapeutic modality: GENE_THERAPY.

Treatment Algorithm

No formal consensus treatment algorithm exists beyond symptomatic/supportive management protocols and acute-crisis management guidance for coagulopathy (multicentric study on hemostasis anomalies and acute management, ScienceDirect).

13. Prevention

  • Primary prevention: Not applicable in the classic sense (no modifiable environmental cause); the main "primary prevention" lever is reproductive genetic counseling and carrier screening for at-risk couples/families, with options for prenatal diagnosis (chorionic villus sampling/amniocentesis with molecular PMM2 testing) or preimplantation genetic testing in known-carrier couples.
  • Secondary prevention: No population newborn screening program currently exists (unlike some IEMs on standard newborn screening panels); early clinical recognition based on classic phenotype (inverted nipples, abnormal fat pads, cerebellar hypoplasia, hypotonia) and prompt biochemical/molecular testing shortens diagnostic delay.
  • Tertiary prevention: Proactive multidisciplinary surveillance (coagulation panels, thyroid function, echocardiography, renal function, glucose monitoring) to catch and manage complications (thrombosis, effusions, hypoglycemia) before they become life-threatening is standard practice in specialized CDG centers.
  • Carrier screening: Commercially available (e.g., Myriad Foresight Carrier Screen) for reproductive planning.
  • Genetic counseling: Central to family management given 25% recurrence risk in each subsequent pregnancy for carrier couples.

14. Other Species / Natural Disease

PMM2-CDG is not known to occur as a naturally-occurring inherited disease in non-human species (unlike some other Mendelian disorders with veterinary counterparts in OMIA). PMM2 orthologs are broadly conserved (mouse Pmm2, zebrafish pmm2), which supports engineered animal modeling (Section 15) rather than natural disease occurrence.

15. Model Organisms

Mouse Models

  • Original hypomorphic mouse (Pmm2^R137H/F118L^): An earlier attempt at a mouse model harboring the mouse-orthologous equivalent of the human R141H/F119L compound heterozygous genotype resulted in complete embryonic lethality, making it unsuitable for postnatal disease study (HMG, Oxford Academic).
  • Viable hypomorphic model (Pmm2^R137H/F115L^): A subsequent, refined hypomorphic mouse line was generated that is viable and recapitulates multiple PMM2-CDG disease features, corresponding to the common human R141H/F119L genotype.
  • Tamoxifen-inducible conditional knockout: A newer, widely tissue-deficient Pmm2 knockout mouse (inducible) was developed and characterized to reveal distinct neurological phenotypes relevant to human PMM2-CDG.
  • 2025 novel mouse model — neurodevelopmental origin study: Demonstrated that PMM2-CDG cerebellar/brain pathology has a neurodevelopmental origin (disrupted early brain development) rather than purely progressive neurodegeneration, and the same model was used to show that AAV-based gene replacement therapy prevents/halts abnormal neurological phenotypes when given at the appropriate developmental window (PMC12157701; Gene Therapy 2025).
  • Prior hypomorphic alleles tested have historically fallen into two unhelpful extremes: too mild (no discernible phenotype) or too severe (embryonic lethal) — underscoring the difficulty of modeling a disease where complete loss-of-function is not compatible with survival.

Zebrafish Models

  • Morpholino knockdown model (pmm2 morphants): Reproduces PMM2-CDG-relevant developmental abnormalities including craniofacial defects and impaired motility linked to altered motor neurogenesis in the spinal cord; global N-glycosylation and LLO levels are reduced, directly recapitulating the human biochemical defect (PMID 22956764; Molecular Biology of the Cell). This model specifically proposed a substrate-accumulation mechanism (in addition to simple substrate deficiency) contributing to altered neurogenesis.
  • Zebrafish are noted as valuable complementary models given that >70% of human proteins (and ~82% of disease-associated human genes) have zebrafish orthologs.

Yeast Models

  • Yeast (S. cerevisiae) models of phosphomannomutase deficiency have been used to study fundamental enzymatic and structural consequences of PMM2 pathogenic variants at the cell-biology level (bioRxiv preprint, "Yeast Models Of Phosphomannomutase 2 Deficiency").

Cellular/In Vitro Models

  • HepG2 PMM2-CDG knockout cell line: A CRISPR-engineered hepatocyte-derived knockout model described as "a versatile platform for variant and therapeutic evaluation," useful for testing pharmacological chaperones and other small-molecule interventions in a human cellular context (ScienceDirect, 2024).
  • Patient-derived fibroblasts: Widely used historically for enzyme activity confirmation and mannose-supplementation proof-of-concept studies.

Model Applications and Limitations

  • Mouse and zebrafish models each recapitulate specific disease facets (neurodevelopmental/cerebellar pathology in mouse; craniofacial and motor neurogenesis defects in zebrafish) but no single model fully recapitulates the human multisystem phenotype (coagulopathy, endocrinopathy, hepatic, cardiac involvement together).
  • The species-specific difficulty in generating a viable "null/null"-equivalent model mirrors the human observation that severe biallelic null genotypes are not viable, reinforcing the mechanistic inference of embryonic lethality for complete PMM2 loss across species.

Summary Table: Suggested Ontology Bindings for KB Curation

Category Term ID
Disease PMM2-congenital disorder of glycosylation MONDO:0015286
Gene PMM2 hgnc:9115
Molecular function phosphomannomutase activity GO:0004615
Biological process protein N-linked glycosylation GO:0006487
Cellular component endoplasmic reticulum GO:0005783
Phenotype Cerebellar hypoplasia HP:0001321
Phenotype Inverted nipples HP:0003186
Phenotype Strabismus HP:0000486
Phenotype Ataxia HP:0001251
Phenotype Stroke-like episode HP:0002401
Phenotype Hypothyroidism HP:0000821
Phenotype Antithrombin III deficiency HP:0031270 (or closest match)
Anatomy Cerebellum UBERON:0002037
Anatomy Liver UBERON:0002107
Cell type Cerebellar granule cell CL:0000643
Treatment Pharmacotherapy (epalrestat, GLM101) NCIT:C15986
Treatment Gene Therapy NCIT:C15238
Treatment Physical Therapy NCIT:C15302

Sources

Reference Validation

Checked with linkml-reference-validator 0.2.1.

Outcome Count
References checked 19
Resolved 19
Unresolved (possible confabulation) 0
Unverifiable 0
References weighed for topical relevance 19
On topic 15
Off topic 0

All extracted references resolved successfully.