DPM2-congenital disorder of glycosylation

Mendelian MONDO:0014023 Pathograph 18 Show in embeddings browser hereditary disease

DPM2-congenital disorder of glycosylation (DPM2-CDG, CDG-Iu) is an ultra-rare autosomal recessive disorder caused by biallelic pathogenic variants in DPM2, which encodes the regulatory subunit of the endoplasmic-reticulum dolichol-phosphate-mannose (Dol-P-Man / DPM) synthase complex. Because Dol-P-Man is the obligate mannosyl donor for four distinct glycosylation pathways — N-glycan lipid-linked oligosaccharide assembly, protein O-mannosylation, C-mannosylation and GPI-anchor biosynthesis — DPM2 deficiency produces a combined glycosylation defect that simultaneously manifests as a type I congenital disorder of glycosylation and as a secondary dystroglycanopathy. The severe end of the spectrum, which defines the Orphanet/MONDO label "congenital muscular dystrophy with intellectual disability and severe epilepsy", presents at birth with severe hypotonia, elevated creatine kinase, absent psychomotor development, intractable epilepsy and progressive microcephaly, and is fatal in infancy or early childhood; later reports have expanded the phenotype to a milder, adult-viable form with intellectual disability, myopathy and hyperCKemia.

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1
Inheritance
8
Pathophys.
32
Phenotypes
3
Gaps
18
Pathograph
1
Genes
5
Variants
5
Medical Actions
4
Differentials
3
References
1
Deep Research
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Classifications

Harrison's Part
ENDOCRINOLOGY METABOLISM GENETICS ENVIRONMENT DISEASE NEUROLOGIC
ICIMD (Inherited Metabolic Disorders)
multiple glycosylation pathways
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Inheritance

1
Autosomal recessive inheritance HP:0000007
DPM2-CDG requires biallelic DPM2 variants. Reported families include compound heterozygosity for a missense plus a canonical splice-acceptor variant, homozygosity for a recurrent missense allele in two unrelated families, and homozygosity for a second missense allele in non-consanguineous Chinese siblings. Expressivity is markedly variable: reported genotypes span a neonatal-onset, infantile-lethal epileptic and myopathic encephalopathy and a mild, adult-viable intellectual-disability-plus-myopathy phenotype.
Autosomal recessive inheritance Expressivity: VARIABLE
Show evidence (2 references)
PMID:23109149 SUPPORT Human Clinical
"DNA analysis revealed mutations in DPM2, 1 of the subunits of the dolichol-phosphate-mannose (DPM) synthase; the patient in the first family is compound heterozygous for 2 mutations (c.68A>G, predicting a missense mutation p.Y23C and c.4-1G>C, a splice mutation), whereas the patients in the..."
Biallelic genotypes (compound heterozygous and homozygous) in two independent families establish autosomal recessive inheritance.
PMID:37152991 SUPPORT Human Clinical
"A homozygous mutation, c.197G>A (p.Gly66Glu) in exon 4 of DPM2 (NM_003863) was identified by whole exome sequencing (WES)."
A homozygous DPM2 variant segregating in two affected siblings of healthy parents supports recessive inheritance.
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Discussions and Knowledge Gaps

3
Is GPI-anchor biosynthesis measurably impaired in DPM2-CDG patient cells, or is this arm purely an inference from DPM synthase biochemistry?
KNOWLEDGE GAP OPEN dpm2_gpi_anchor_arm_unproven
Attached to
pathophysiology#GPI-Anchor Biosynthesis Impairment
Dol-P-Man donates mannoses to the GPI-anchor precursor, so DPM2 deficiency should impair GPI-anchor assembly, and DPM-synthase-null CHO cells do lose surface GPI-anchored proteins. But no DPM2-CDG case report has measured GPI-anchored protein display (e.g. CD59, CD55, alkaline phosphatase) in patient cells. The supporting patient data are indirect — a fibroblast lipidomic shift and congenital heart defects. This matters because a demonstrated GPI arm would place DPM2-CDG in the inherited GPI-deficiency disease class as well, with implications for expected phenotypes such as hyperphosphatasia.
Proposed experiments
Flow cytometry for GPI-anchored proteins on patient cells
exp_dpm2_gpi_flow_cytometry
Measure surface CD59 and CD55 (and FLAER binding) on DPM2-CDG patient fibroblasts or blood cells against controls, the standard assay used to establish GPI-anchor deficiency in the PIG-gene disorders.
Serum alkaline phosphatase profiling across the reported cohort
exp_dpm2_alkaline_phosphatase_cohort
Retrospectively collate alkaline phosphatase values in reported DPM2-CDG patients; hyperphosphatasia is a recognized marker of specific GPI-anchor biosynthesis defects.
Can any current animal model reproduce human DPM2-CDG, given that the published zebrafish work transiently depleted the whole DPM synthase complex rather than modeling the hypomorphic patient DPM2 alleles?
HUMAN MODEL MISMATCH OPEN dpm2_no_faithful_animal_model
Attached to
pathophysiology#Sarcolemmal Laminin Anchorage Failure pathophysiology#DPM Synthase Complex Destabilization
The zebrafish morphant study is the only in vivo model of this pathway and it recapitulates dystrophic muscle with hypoglycosylated alpha-dystroglycan — but it is a transient morpholino knockdown of dpm1/dpm2/dpm3 that causes early death, not a model of the hypomorphic missense alleles that actually cause human disease. It therefore cannot address the feature that most needs explaining: why the same pathway yields an infantile-lethal epileptic encephalopathy with one allele and an adult-viable myopathy with another. Evidence exists in a model system; its fidelity to the human allelic spectrum is the open question.
Proposed experiments
Knock-in animal models carrying patient DPM2 missense alleles
exp_dpm2_patient_allele_knockin
Generate hypomorphic knock-in alleles corresponding to p.Tyr23Cys (severe) and p.Gly66Glu (mild) rather than null alleles, and compare survival, seizure susceptibility, muscle histology and alpha-dystroglycan glycosylation between them.
Patient iPSC-derived neurons and skeletal myotubes
exp_dpm2_ipsc_neuron_myotube
Differentiate iPSC lines from severe- and mild-genotype patients into neurons and myotubes and compare Dol-P-Man levels, lipid-linked oligosaccharide profiles and alpha-dystroglycan glycosylation, to test the domain-position severity hypothesis in human cells.
Does the position of a DPM2 variant (first versus second transmembrane domain region) genuinely determine severity, or is the apparent correlation an artifact of a six-patient sample?
OPEN QUESTION OPEN dpm2_domain_position_severity
Attached to
pathophysiology#DPM Synthase Complex Destabilization
The only proposed prognostic factor in DPM2-CDG is variant position, based on a review of six patients across four families. The correlation is confounded by the fact that three of the severe patients share a single recurrent allele (p.Tyr23Cys) from two families, so the comparison is closer to allele-versus-allele than domain-versus-domain. The reporting authors explicitly note the relationship needs more study. Additional unrelated patients, or functional assays quantifying residual DPM synthase activity per allele, would resolve it.
Proposed experiments
Residual DPM synthase activity per allele
exp_dpm2_residual_activity_per_allele
Express each reported DPM2 allele in DPM2-null cells and quantify Dol-P-Man synthesis and lipid-linked oligosaccharide profiles, testing whether residual activity rather than domain position predicts clinical severity.
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Pathophysiology

8
DPM Synthase Complex Destabilization
DPM synthase is a heterotrimer of DPM1 (the catalytic subunit), DPM2 (a regulatory subunit that stabilizes DPM1 and enhances dolichol-phosphate binding) and DPM3 (which tethers DPM1 to the ER membrane). Biallelic DPM2 variants — missense alleles in either transmembrane region, a nonsense allele, or a canonical splice-acceptor allele — reduce or functionally impair DPM2, destabilizing the complex. In patient fibroblasts carrying a nonsense/missense genotype, DPM2 fell to roughly 60% of control and DPM1 protein became undetectable, showing that loss of the regulatory subunit also collapses the catalytic subunit.
Fibroblast CL:0000057 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves Fibroblast (CL:0000057). CL:0000057 is a cell type from the Cell Ontology.
DPM2 hgnc:3006 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves DPM2 (hgnc:3006). hgnc:3006 is a gene from the HUGO Gene Nomenclature Committee.
dolichol-phosphate-mannose synthase complex GO:0033185 Gene Ontology (GO) Relation: this pathophysiological event involves this protein complex This pathophysiological event involves decreased dolichol-phosphate-mannose synthase complex (GO:0033185). GO:0033185 is a protein complex from the Gene Ontology.
dolichyl-phosphate beta-D-mannosyltransferase activity GO:0004582 Gene Ontology (GO) Relation: this pathophysiological event involves this molecular function This pathophysiological event involves decreased dolichyl-phosphate beta-D-mannosyltransferase activity (GO:0004582). GO:0004582 is a molecular function from the Gene Ontology. ↓ DECREASED
endoplasmic reticulum membrane GO:0005789 Gene Ontology (GO) Relation: this pathophysiological event occurs in this anatomical location This pathophysiological event occurs in endoplasmic reticulum membrane (GO:0005789). GO:0005789 is an anatomical location from the Gene Ontology.
Downstream
Dolichol-Phosphate-Mannose Depletion
Show evidence (3 references)
PMID:33129689 SUPPORT Human Clinical
"DPMS is composed of DPM1, DPM2, and DPM3 (Figure 1). DPM1 is the catalytic subunit of DPMS while DPM2 and DPM3 have been described as regulatory and tethering subunits respectively"
Establishes the subunit architecture of the complex and DPM2's regulatory role within it.
PMID:33129689 SUPPORT In Vitro
"Patient fibroblasts showed lower DPM2 expression (~60% of control, Figure 5). No quantifiable DPM1 protein expression was detected (Figure 5A) confirming the deleterious effects of the DPM2 alleles identified by WES."
Direct demonstration in patient cells that DPM2 loss destabilizes the complex, abolishing detectable DPM1.
PMID:16280320 SUPPORT In Vitro
"DPM1 was rapidly degraded by the proteasome in the absence of DPM3."
Establishes the general principle that loss of an accessory DPM subunit destabilizes the catalytic DPM1 subunit — the mechanism observed in DPM2 patient fibroblasts.
Dolichol-Phosphate-Mannose Depletion
The destabilized complex synthesizes less dolichol-phosphate-mannose from GDP-mannose and dolichol phosphate. Dol-P-Man is flipped to the luminal face of the endoplasmic reticulum, where it serves as the sole mannosyl donor for four glycosylation pathways: lipid-linked oligosaccharide (N-glycan precursor) mannosylation, protein O-mannosylation, protein C-mannosylation, and GPI-anchor mannosylation. Depletion of this single shared donor is therefore the branch point that produces the disorder's combined CDG-plus-dystroglycanopathy phenotype.
endoplasmic reticulum membrane GO:0005789 Gene Ontology (GO) Relation: this pathophysiological event occurs in this anatomical location This pathophysiological event occurs in endoplasmic reticulum membrane (GO:0005789). GO:0005789 is an anatomical location from the Gene Ontology.
Downstream
ER Lipid-Linked Oligosaccharide Assembly Arrest
Alpha-Dystroglycan Hypo-O-Mannosylation
GPI-Anchor Biosynthesis Impairment
Show evidence (3 references)
PMID:16280320 SUPPORT In Vitro
"Dolichol-phosphate mannose (DPM) synthase is required for synthesis of the glycosylphosphatidylinositol (GPI) anchor, N-glycan precursor, protein O-mannose, and C-mannose."
Establishes that the single Dol-P-Man product feeds all four downstream glycosylation pathways, the basis for the combined defect.
PMID:18387370 SUPPORT Other
"The sugar transfer from dolichol-phosphate-sugars occurs exclusively on the luminal side of the endoplasmic reticulum and is utilized in all four glycosylation pathways."
Review evidence for the luminal topology and four-pathway usage of the dolichol-phosphate-sugar donor.
PMID:40902550 SUPPORT Other
"It is used as the membrane anchor for mono- or oligosaccharides transferred during N-glycosylation, O/C-mannosylation and glycosylphosphatidylinositol anchor biosynthesis."
Recent review confirming the shared-donor architecture that makes DPM synthase defects multi-pathway disorders.
ER Lipid-Linked Oligosaccharide Assembly Arrest
Without sufficient Dol-P-Man, the luminal mannosylation steps of lipid-linked oligosaccharide assembly stall. Patient fibroblasts accumulate the truncated intermediate Dol-PP-GlcNAc2-Man5 — precisely the species expected when the biosynthetic block lies at the first Dol-P-Man-dependent mannosyltransferase step — and truncated precursors are transferred to nascent protein, producing the type I CDG biochemical pattern on serum transferrin isoelectric focusing.
Fibroblast CL:0000057 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves Fibroblast (CL:0000057). CL:0000057 is a cell type from the Cell Ontology.
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 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
Protein Hypoglycosylation
Show evidence (2 references)
PMID:23109149 SUPPORT Human Clinical
"Metabolic investigations revealed CDG-I, pointing to a defect in protein N-glycosylation in the endoplasmic reticulum."
Places the DPM2 lesion in the ER N-glycosylation arm, i.e. the type I CDG trigger of the module.
PMID:23109149 SUPPORT In Vitro
"Analysis of lipid-linked oligosaccharides in fibroblasts showed accumulation of Dol-PP-GlcNAc(2)"
Direct biochemical demonstration of truncated lipid-linked oligosaccharide accumulation in patient fibroblasts, localizing the block to the Dol-P-Man-dependent mannosylation steps.
Alpha-Dystroglycan Hypo-O-Mannosylation
The POMT1/POMT2 O-mannosyltransferases use Dol-P-Man to initiate the O-mannosyl glycan on alpha-dystroglycan. Dol-P-Man depletion therefore truncates this glycan, so alpha-dystroglycan cannot be extended into its laminin-binding matriglycan. Muscle immunohistochemistry in DPM2-CDG patients showed deficient O-mannosylation, making DPM2-CDG a secondary dystroglycanopathy — the same arm demonstrated directly in the sister disorder DPM3-CDG.
Skeletal muscle fiber CL:0008002 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves Skeletal muscle fiber (CL:0008002). CL:0008002 is a cell type from the Cell Ontology.
protein O-linked glycosylation via mannose GO:0035269 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased protein O-linked glycosylation via mannose (GO:0035269). GO:0035269 is a biological process from the Gene Ontology. ↓ DECREASED
Downstream
Sarcolemmal Laminin Anchorage Failure
Show evidence (3 references)
PMID:23109149 SUPPORT Human Clinical
"There was clinical evidence of a muscular dystrophy-dystroglycanopathy syndrome, supported by deficient O-mannosylation by muscle immunohistochemistry."
Direct patient-tissue evidence that DPM2 deficiency causes deficient O-mannosylation in skeletal muscle.
PMID:19576565 SUPPORT Human Clinical
"Investigation of the four Dol-P-Man-dependent glycosylation pathways in the ER revealed strongly reduced O-mannosylation of alpha-dystroglycan in a muscle biopsy, thereby explaining the clinical phenotype of muscular dystrophy."
Mechanistic proof in the allelic DPM3 disorder that Dol-P-Man deficiency selectively impairs alpha-dystroglycan O-mannosylation and thereby causes muscular dystrophy.
PMID:30931530 SUPPORT Human Clinical
"In the three patients, O-mannosylation of alpha-dystroglycan (αDG) was strongly reduced"
Confirms in a second DPM-synthase-subunit cohort that skeletal-muscle alpha-dystroglycan O-mannosylation is the affected pathway.
GPI-Anchor Biosynthesis Impairment
GPI-anchor assembly requires Dol-P-Man-dependent mannosylation steps, so Dol-P-Man depletion is expected to impair GPI-anchor biosynthesis in DPM2-CDG. This arm is inferred from DPM synthase biochemistry rather than demonstrated with patient GPI-anchored-protein data; the supporting patient observations are indirect (a lipidomic shift in patient fibroblasts, and congenital heart defects of a type seen across GPI-anchor disorders). It is recorded as provisional for that reason.
Fibroblast CL:0000057 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves Fibroblast (CL:0000057). CL:0000057 is a cell type from the Cell Ontology.
GPI anchor biosynthetic process GO:0006506 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased GPI anchor biosynthetic process (GO:0006506). GO:0006506 is a biological process from the Gene Ontology. ↓ DECREASED
Downstream
Multisystem Glycoprotein Dysfunction
Show evidence (3 references)
PMID:33129689 SUPPORT In Vitro
"Given the implication of DPMS in GPI anchor synthesis, we performed lipidomics analysis in patient fibroblasts."
The authors invoke the GPI-anchor arm as the motivation for lipidomics, but the study measured lipid subclasses rather than GPI-anchored protein display, so this supports the arm only indirectly.
PMID:33129689 SUPPORT In Vitro
"We observed significant differences in lysophospholipids especially lysophosphatidylserine (LPS) and lysophosphatidic acid (LPA) (Figure 7)."
Patient-fibroblast lipidomic perturbation is consistent with, but does not by itself establish, a GPI-anchor biosynthetic defect.
PMID:16280320 SUPPORT In Vitro
"CHO2.38 cells were negative for GPI-anchored proteins, and microsomes from these cells showed no detectable DPM synthase activity, indicating that DPM3 is an essential component of this enzyme."
Cell-line evidence that abolishing DPM synthase activity abolishes surface GPI-anchored protein display, supporting the mechanistic expectation for DPM2 deficiency.
Protein Hypoglycosylation
Transfer of truncated precursors leaves many secreted and membrane client glycoproteins under-glycosylated. In DPM2-CDG this is detected clinically as a CDG type I transferrin isoelectric focusing pattern, and experimentally as reduced ICAM1, a general hypoglycosylation reporter, in cells expressing a pathogenic DPM2 allele.
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. Fibroblast CL:0000057 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves Fibroblast (CL:0000057). CL:0000057 is a cell type from the Cell Ontology.
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
Multisystem Glycoprotein Dysfunction
Show evidence (1 reference)
PMID:37152991 SUPPORT In Vitro
"In vitro functional analysis demonstrated that this variant increased the expression level of DPM2 protein and western blot revealed a significant decrease in ICAM1, a universal biomarker for hypoglycosylation in patients with CDG, suggesting abnormal N-linked glycosylation."
Functional demonstration that a pathogenic DPM2 allele causes protein hypoglycosylation, and that the mechanism is impaired function rather than reduced protein abundance for this allele.
Sarcolemmal Laminin Anchorage Failure
Hypoglycosylated alpha-dystroglycan loses its laminin-binding capacity, so the dystrophin-glycoprotein complex can no longer transmit force between the myofibre cytoskeleton and the basal lamina. The sarcolemma becomes mechanically fragile, myofibres degenerate with each contraction cycle, and creatine kinase leaks into serum — the congenital muscular dystrophy component of the disorder.
Skeletal muscle fiber CL:0008002 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves Skeletal muscle fiber (CL:0008002). CL:0008002 is a cell type from the Cell Ontology.
Downstream
Multisystem Glycoprotein Dysfunction
Show evidence (2 references)
PMID:27291147 SUPPORT Model Organism
"The resulting morphant embryos showed early death, muscle disorganization, low DPMS complex activity, and increased levels of apoptotic nuclei, together with hypoglycosylated α-DG in muscle fibers, thus recapitulating most of the characteristics seen in patients with mutations in DPMS."
Zebrafish depletion of dpm subunits reproduces the causal step from DPM synthase loss to hypoglycosylated alpha-dystroglycan and dystrophic muscle.
PMID:27291147 SUPPORT Model Organism
"Defective dolichol-phosphate mannose synthase (DPMS) complex is a rare cause of congenital muscular dystrophy associated with hypoglycosylation of alpha-dystroglycan (α-DG) in skeletal muscle."
States the causal link from DPM synthase deficiency to dystroglycan-hypoglycosylation congenital muscular dystrophy.
Multisystem Glycoprotein Dysfunction
Combined N-glycan, O-mannosyl and (inferred) GPI-anchor defects converge on a multisystem disease. In the severe form this is a neonatal neuromuscular-plus-epileptic encephalopathy with hypotonia, absent psychomotor development, intractable seizures, progressive microcephaly, liver involvement and coagulation abnormality, fatal between 7 months and 3 years. In the milder form the same lesion yields intellectual disability, myopathy with hyperCKemia, congenital heart defects and peripheral nerve involvement compatible with survival into adulthood.
Neuron CL:0000540 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves Neuron (CL:0000540). CL:0000540 is a cell type from the Cell Ontology. Skeletal muscle fiber CL:0008002 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves Skeletal muscle fiber (CL:0008002). CL:0008002 is a cell type from the Cell Ontology. 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.
Show evidence (2 references)
PMID:33129689 SUPPORT Human Clinical
"All three patients included in the report had a severe clinical presentation characterized by hypotonia, progressive muscle weakness and wasting, absent psychomotor development, intractable seizures, liver involvement, abnormal coagulation factors and early mortality (between 7 months and 3..."
Summarizes the multisystem severe-end phenotype produced by the shared hypoglycosylation lesion.
PMID:23109149 SUPPORT Human Clinical
"We describe a new CDG, due to a deficiency of DPM2. Hence, mutations have now been described in the genes for the 3 subunits of DPM: DPM1, DPM2, and DPM3, whereby DPM2-CDG links the congenital disorders of glycosylation to the congenital muscular dystrophies."
States the defining multisystem convergence of this disorder — a CDG that is simultaneously a congenital muscular dystrophy.
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Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.
Pathograph: causal mechanism network for DPM2-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.
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Phenotypes

32
Blood 1
Coagulation Abnormality Abnormality of coagulation HP:0001928 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Abnormality of coagulation (HP:0001928). HP:0001928 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:33129689 SUPPORT Human Clinical
"All three patients included in the report had a severe clinical presentation characterized by hypotonia, progressive muscle weakness and wasting, absent psychomotor development, intractable seizures, liver involvement, abnormal coagulation factors and early mortality (between 7 months and 3..."
Abnormal coagulation factors in the severe cohort.
Cardiovascular 2
Bicuspid Aortic Valve HP:0001647 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Bicuspid aortic valve (HP:0001647). HP:0001647 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:33129689 SUPPORT Human Clinical
"The patient is a 23-year-old male with truncal hypotonia, lower extremity hypertonicity, bicuspid aortic valve, aortic stenosis, intellectual disability, and generalized muscle wasting"
Names the specific valvular lesion in the single DPM2-CDG patient with cardiac involvement.
PMID:33129689 SUPPORT Human Clinical
"Additionally, he has congenital heart defects, which were previously not described in DPM2-CDG."
Explicitly reports congenital heart defects as a newly recognized DPM2-CDG feature.
Aortic Valve Stenosis HP:0001650 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Aortic valve stenosis (HP:0001650). HP:0001650 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:33129689 SUPPORT Human Clinical
"The patient is a 23-year-old male with truncal hypotonia, lower extremity hypertonicity, bicuspid aortic valve, aortic stenosis, intellectual disability, and generalized muscle wasting"
Reports aortic stenosis alongside the bicuspid valve in the same patient.
Digestive 2
Hepatomegaly 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:37152991 SUPPORT Human Clinical
"Hepatomegaly and elevation of serum transaminases"
The Table 1 hepatobiliary row for patient P3 resolves the generic "liver involvement" of the severe cohort into hepatomegaly. No frequency band is assigned: the finding is recorded for one of six patients and is NA for two others, so the denominator is not interpretable.
Feeding Difficulties HP:0011968 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Feeding difficulties (HP:0011968). HP:0011968 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:37152991 SUPPORT Human Clinical
"Feeding dif ficulties No No Yes Yes Yes No"
Table 1 feeding-difficulties row: No/No for the two Chinese siblings, Yes for P3-P5, No for P6. The ligature in the source row is reproduced verbatim rather than retyped.
Eye 2
Strabismus 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:37152991 SUPPORT Human Clinical
"She had no obvious facial abnormalities other than strabismus which had not been corrected by surgery so far."
Documents strabismus in the younger sibling.
Optic Atrophy HP:0000648 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Optic atrophy (HP:0000648). HP:0000648 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:37152991 SUPPORT Human Clinical
"Ophthalmological Strabismus No Optic atrophy No visual tracking and strabismus"
Table 1 ophthalmological row; the third column (P3) records optic atrophy. No frequency band is asserted because the row leaves P6 blank, so the denominator is not interpretable.
Head and Neck 1
Dysmorphic Features VERY_FREQUENT Abnormal facial shape HP:0001999 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Abnormal facial shape (HP:0001999). HP:0001999 is a phenotype from the Human Phenotype Ontology.
Show evidence (3 references)
PMID:37152991 SUPPORT Human Clinical
"In this study, we reported two siblings from a Chinese family with dysmorphic features, developmental delay, mild intellectual disability, hypotonia, strabismus, and increased serum creatine kinase."
Narrative statement that both mildly affected siblings had dysmorphic features.
PMID:37152991 SUPPORT Human Clinical
"Dysmorphic features Yes Yes Yes Yes Yes No"
Table 1 records dysmorphic features in 5 of the 6 published DPM2-CDG patients (83%), which is the basis for the VERY_FREQUENT band (80-99%).
PMID:33129689 SUPPORT Human Clinical
"No dysmorphic facial features were observed."
The sixth patient is the documented exception; recorded as PARTIAL so the entry does not overstate dysmorphism as universal.
Immune 1
Recurrent Infections HP:0002719 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Recurrent infections (HP:0002719), qualified as temporality recurrent. HP:0002719 is a phenotype from the Human Phenotype Ontology.
Temporal: RECURRENT
Show evidence (1 reference)
PMID:37152991 SUPPORT Human Clinical
"In addition, she had recurrent infections at the age of preschool."
Documents recurrent preschool infections in an affected sibling.
Metabolism 2
Elevated Serum Creatine Kinase VERY_FREQUENT Elevated circulating creatine kinase concentration HP:0003236 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Elevated circulating creatine kinase concentration (HP:0003236). HP:0003236 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:23109149 SUPPORT Human Clinical
"We searched for the primary defect in 3 children from 2 families with a severe neurological phenotype, including profound developmental delay, intractable epilepsy, progressive microcephaly, severe hypotonia with elevated blood creatine kinase levels, and early fatal outcome."
Elevated CK in all three severe-form patients.
PMID:37152991 SUPPORT Human Clinical
"Whole-exome sequencing (WES) was performed in a Chinese family having two siblings with a mild form of DPM2-CDG with developmental delay, mild intellectual disability, hypotonia, and increased serum creatine kinase."
Elevated CK also in the two mildly affected siblings; with elevated CK reported in all six published patients this supports the VERY_FREQUENT band.
Elevated Serum Transaminases 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:37152991 SUPPORT Human Clinical
"Hepatomegaly and elevation of serum transaminases"
Same Table 1 hepatobiliary row; recorded separately because the biochemical abnormality and the organomegaly are distinct findings. No frequency band is assigned, for the denominator reason given above.
Musculoskeletal 5
Congenital Muscular Dystrophy HP:0003560 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Muscular dystrophy (HP:0003560). HP:0003560 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:23109149 SUPPORT Human Clinical
"There was clinical evidence of a muscular dystrophy-dystroglycanopathy syndrome, supported by deficient O-mannosylation by muscle immunohistochemistry."
Establishes the congenital muscular dystrophy component with tissue-level confirmation.
Generalized Hypotonia HP:0001290 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Generalized hypotonia (HP:0001290). HP:0001290 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:23109149 SUPPORT Human Clinical
"We searched for the primary defect in 3 children from 2 families with a severe neurological phenotype, including profound developmental delay, intractable epilepsy, progressive microcephaly, severe hypotonia with elevated blood creatine kinase levels, and early fatal outcome."
Severe hypotonia is part of the index phenotype.
Hypertonia HP:0001276 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Hypertonia (HP:0001276). HP:0001276 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:33129689 SUPPORT Human Clinical
"We identified biallelic DPM2 variants in a 23-year-old male with truncal hypotonia, hypertonicity, congenital heart defects, intellectual disability, and generalized muscle wasting."
Documents hypertonicity alongside truncal hypotonia.
PMID:37152991 SUPPORT Human Clinical
"The patient was admitted to the Rehabilitation Department in Wuhan Children's Hospital due to developmental delay, mild intellectual disability, hypertonia, and strabismus at 11 years old."
Hypertonia in the younger sibling at presentation.
Skeletal Muscle Atrophy HP:0003202 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Skeletal muscle atrophy (HP:0003202). HP:0003202 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:33129689 SUPPORT Human Clinical
"We identified biallelic DPM2 variants in a 23-year-old male with truncal hypotonia, hypertonicity, congenital heart defects, intellectual disability, and generalized muscle wasting."
Generalized muscle wasting in the adult DPM2-CDG patient.
Scoliosis HP:0002650 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Scoliosis (HP:0002650). HP:0002650 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:37152991 SUPPORT Human Clinical
"Congenital contractures of the joints and scoliosis"
Same Table 1 skeletal row; curated as a separate phenotype because scoliosis and joint contracture are distinct findings.
Nervous System 10
Intractable Epilepsy Seizure HP:0001250 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Seizure (HP:0001250), qualified as temporality recurrent. HP:0001250 is a phenotype from the Human Phenotype Ontology.
Temporal: RECURRENT
Show evidence (2 references)
PMID:23109149 SUPPORT Human Clinical
"We searched for the primary defect in 3 children from 2 families with a severe neurological phenotype, including profound developmental delay, intractable epilepsy, progressive microcephaly, severe hypotonia with elevated blood creatine kinase levels, and early fatal outcome."
Intractable epilepsy is part of the index DPM2-CDG clinical description.
PMID:26453362 SUPPORT Human Clinical
"We describe a series of patients with EOEE and genetically confirmed CDG (ALG3-CDG, ALG6-CDG, DPM2-CDG, ALG1-CDG)."
DPM2-CDG is explicitly among the CDG subtypes contributing patients to this early-onset epileptic encephalopathy series.
Epileptic Spasms and Myoclonic Seizures HP:0011097 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Epileptic spasm (HP:0011097). HP:0011097 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:26453362 SUPPORT Human Clinical
"With time, patients developed recurrent and intractable seizures principally tonic-clonic seizures, infantile spasms, and myoclonic seizures."
Describes the evolving semiology for the pooled CDG epileptic encephalopathy cohort that includes DPM2-CDG; the specific attribution to DPM2-CDG patients is not itemized, hence PARTIAL.
Abnormal EEG EEG abnormality HP:0002353 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is EEG abnormality (HP:0002353). HP:0002353 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:26453362 SUPPORT Human Clinical
"Electrophysiological correlates included focal and multifocal epileptic discharges, slowed background rhythm, and generalized epileptic activity including burst suppression pattern and status epilepticus."
EEG findings for the pooled CDG epileptic encephalopathy cohort including DPM2-CDG; not itemized per subtype, hence PARTIAL.
PMID:37152991 SUPPORT Human Clinical
"Electroencephalogram examination showed that occipital background activity was slightly slower."
Documents the milder EEG abnormality at the other end of the DPM2-CDG spectrum.
Severe Global Developmental Delay HP:0011344 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Severe global developmental delay (HP:0011344). HP:0011344 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:23109149 SUPPORT Human Clinical
"We searched for the primary defect in 3 children from 2 families with a severe neurological phenotype, including profound developmental delay, intractable epilepsy, progressive microcephaly, severe hypotonia with elevated blood creatine kinase levels, and early fatal outcome."
Profound developmental delay is part of the index severe-form description.
PMID:33129689 SUPPORT Human Clinical
"Pathogenic alterations in the DPM2 gene have been previously described in patients with hypotonia, progressive muscle weakness, absent psychomotor development, intractable seizures, and early death."
Confirms absent psychomotor development in the previously reported severe cohort.
Intellectual Disability HP:0001249 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Intellectual disability (HP:0001249). HP:0001249 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:33129689 SUPPORT Human Clinical
"We identified biallelic DPM2 variants in a 23-year-old male with truncal hypotonia, hypertonicity, congenital heart defects, intellectual disability, and generalized muscle wasting."
Intellectual disability in the adult DPM2-CDG patient.
PMID:37152991 SUPPORT Human Clinical
"Whole-exome sequencing (WES) was performed in a Chinese family having two siblings with a mild form of DPM2-CDG with developmental delay, mild intellectual disability, hypotonia, and increased serum creatine kinase."
Mild intellectual disability in the two long-surviving siblings.
Peripheral Neuropathy 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:37152991 SUPPORT Human Clinical
"Electrophysiological evaluation showed slowed motor conduction velocity, longer motor latency, and decreased amplitude on the left median and ulnar nerves, but no sensory nerve action potential was detected in the median, ulnar, and sural nerves in the right lower limb, suggesting multiple..."
Direct nerve conduction evidence of peripheral neuropathy in a DPM2-CDG patient.
Cerebral White Matter Abnormality Abnormal cerebral white matter morphology HP:0002500 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Abnormal cerebral white matter morphology (HP:0002500). HP:0002500 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:37152991 SUPPORT Human Clinical
"sequence in the white matter of bilateral parietal lobes, an indication of demyelinating lesions"
MRI evidence of bilateral parietal white matter demyelinating change.
Motor Delay HP:0001270 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Motor delay (HP:0001270). HP:0001270 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:37152991 SUPPORT Human Clinical
"She showed delayed motor milestones with head control at 4 months, turning over at 7 months, and unassisted walking at 3 years old."
Documents the specific delayed motor milestones in the younger sibling.
Delayed Speech and Language Development HP:0000750 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Delayed speech and language development (HP:0000750). HP:0000750 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:37152991 SUPPORT Human Clinical
"Language development was also considerably delayed"
Documents delayed language milestones in the younger sibling.
Cerebellar Vermis Hypoplasia HP:0001320 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Cerebellar vermis hypoplasia (HP:0001320). HP:0001320 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:37152991 SUPPORT Human Clinical
"Mild cerebellar hypoplasia with severe vermis hypoplasia"
Table 1 brain-MRI row for patient P5.
Constitutional 1
Exercise Intolerance HP:0003546 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Exercise intolerance (HP:0003546). HP:0003546 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:37152991 SUPPORT Human Clinical
"She had mild intellectual disability and exercise intolerance."
Exercise intolerance in the elder sibling.
Other 5
Progressive Microcephaly HP:0000253 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Progressive microcephaly (HP:0000253), qualified as course progressive. HP:0000253 is a phenotype from the Human Phenotype Ontology.
Course: PROGRESSIVE
Show evidence (1 reference)
PMID:23109149 SUPPORT Human Clinical
"We searched for the primary defect in 3 children from 2 families with a severe neurological phenotype, including profound developmental delay, intractable epilepsy, progressive microcephaly, severe hypotonia with elevated blood creatine kinase levels, and early fatal outcome."
Progressive microcephaly is explicitly part of the index phenotype.
Achilles Tendon Contracture HP:0001771 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Achilles tendon contracture (HP:0001771). HP:0001771 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:37152991 SUPPORT Human Clinical
"She had undergone Achilles tendon lengthening procedure."
Documents the contracture requiring orthopedic surgical correction.
Liver Involvement Abnormality of the liver HP:0001392 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Abnormality of the liver (HP:0001392). HP:0001392 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:33129689 SUPPORT Human Clinical
"All three patients included in the report had a severe clinical presentation characterized by hypotonia, progressive muscle weakness and wasting, absent psychomotor development, intractable seizures, liver involvement, abnormal coagulation factors and early mortality (between 7 months and 3..."
Liver involvement in the severe cohort.
Absent Visual Tracking Absent smooth pursuit HP:0007179 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Absent visual tracking, annotated with Absent smooth pursuit (HP:0007179). HP:0007179 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:37152991 SUPPORT Human Clinical
"Ophthalmological Strabismus No Optic atrophy No visual tracking and strabismus No visual tracking"
Table 1 ophthalmological row; the P4 and P5 columns both record no visual tracking. No frequency band is asserted for the same reason as the optic atrophy item.
Congenital Joint Contractures Congenital contracture HP:0002803 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Congenital contracture (HP:0002803). HP:0002803 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:37152991 SUPPORT Human Clinical
"Congenital contractures of the joints and scoliosis"
Table 1 skeletal row for the two severe-form patients (P4, P5).
🧬

Genetic Associations

1
DPM2
Gene: DPM2 hgnc:3006 HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is DPM2 (hgnc:3006). hgnc:3006 is a gene from the HUGO Gene Nomenclature Committee. relationship_type: CAUSATIVE variant_origin: GERMLINE
Show evidence (2 references)
PMID:23109149 SUPPORT Human Clinical
"DNA analysis revealed mutations in DPM2, 1 of the subunits of the dolichol-phosphate-mannose (DPM) synthase; the patient in the first family is compound heterozygous for 2 mutations (c.68A>G, predicting a missense mutation p.Y23C and c.4-1G>C, a splice mutation), whereas the patients in the..."
Identifies DPM2 as the causal gene and lists the founding pathogenic alleles.
PMID:37152991 SUPPORT Human Clinical
"We also reviewed the 4 previously reported patients carrying homozygous or compound heterozygous variants of DMP2 gene, and found that patients with variants within the region encoding the first domain had more severe clinical symptoms than those with variants within the second domain."
Reports the domain-position genotype-severity correlation; PARTIAL because the same paper states the relationship needs more study and it rests on only six patients.
Variants (5)
NM_003863.4:c.68A>G (p.Tyr23Cys) Pathogenic
Gene: DPM2 hgnc:3006 HUGO Gene Nomenclature Committee (hgnc) Relation: this variant is in this gene This variant is in DPM2 (hgnc:3006). hgnc:3006 is a gene from the HUGO Gene Nomenclature Committee. MISSENSE VARIANT
Recurrent missense allele in the first transmembrane region, found homozygously in one Italian family and in compound heterozygosity with the c.4-1G>C splice allele in another. Associated with the severe, infantile-lethal phenotype.
Show evidence (1 reference)
PMID:23109149 SUPPORT Human Clinical
"whereas the patients in the second family are homozygous for the same missense mutation (c.68A>G, p.Y23C)."
Documents homozygosity for the recurrent p.Tyr23Cys allele.
NM_003863.4:c.4-1G>C Pathogenic
Gene: DPM2 hgnc:3006 HUGO Gene Nomenclature Committee (hgnc) Relation: this variant is in this gene This variant is in DPM2 (hgnc:3006). hgnc:3006 is a gene from the HUGO Gene Nomenclature Committee. SPLICE SITE VARIANT
Canonical splice-acceptor variant found in compound heterozygosity with p.Tyr23Cys in the first reported family.
Show evidence (1 reference)
PMID:23109149 SUPPORT Human Clinical
"the patient in the first family is compound heterozygous for 2 mutations (c.68A>G, predicting a missense mutation p.Y23C and c.4-1G>C, a splice mutation)"
Documents the splice-acceptor allele in trans with p.Tyr23Cys.
NM_003863.4:c.197G>A (p.Gly66Glu) Pathogenic
Gene: DPM2 hgnc:3006 HUGO Gene Nomenclature Committee (hgnc) Relation: this variant is in this gene This variant is in DPM2 (hgnc:3006). hgnc:3006 is a gene from the HUGO Gene Nomenclature Committee. MISSENSE VARIANT
Homozygous missense allele in the second domain region, found in two Chinese siblings with the mild phenotype. Functional testing showed increased DPM2 protein but reduced ICAM1 glycosylation, indicating impaired function rather than reduced abundance.
Show evidence (1 reference)
PMID:37152991 SUPPORT Human Clinical
"A homozygous mutation, c.197G>A (p.Gly66Glu) in exon 4 of DPM2 (NM_003863) was identified by whole exome sequencing (WES)."
Identifies the mild-phenotype allele and its zygosity.
NM_003863.4:c.139C>T (p.Arg47Ter) Pathogenic
Gene: DPM2 hgnc:3006 HUGO Gene Nomenclature Committee (hgnc) Relation: this variant is in this gene This variant is in DPM2 (hgnc:3006). hgnc:3006 is a gene from the HUGO Gene Nomenclature Committee. NONSENSE VARIANT
Nonsense allele carried in trans with p.Gly58Asp in the adult (fourth-reported) patient. Neither allele had been reported previously; patient fibroblasts showed DPM2 expression at about 60% of control with no quantifiable DPM1 protein, so the pair behaves as a hypomorphic rather than a complete-null genotype - consistent with that patient's milder-than-infantile course.
Show evidence (1 reference)
PMID:33129689 SUPPORT Human Clinical
"Whole exome sequencing (WES) identified two heterozygous alterations in the DPM2 gene (c.139C>T, p.Arg47*; c.173G>A, p.Gly58Asp) which were confirmed to be in trans by parental studies"
Identifies the nonsense allele and establishes the trans configuration by parental testing.
NM_003863.4:c.173G>A (p.Gly58Asp) Pathogenic
Gene: DPM2 hgnc:3006 HUGO Gene Nomenclature Committee (hgnc) Relation: this variant is in this gene This variant is in DPM2 (hgnc:3006). hgnc:3006 is a gene from the HUGO Gene Nomenclature Committee. MISSENSE VARIANT
Missense allele in trans with the p.Arg47Ter nonsense allele in the adult (fourth-reported) patient, predicted deleterious by multiple in-silico algorithms.
Show evidence (1 reference)
PMID:33129689 SUPPORT Human Clinical
"The p.Gly58Asp missense change is predicted to be deleterious by multiple algorithms (Mutation Taster, LRT, PolyPhen2, and SIFT)."
Documents the missense allele and its computational pathogenicity support.
💊

Medical Actions

5
Supportive and Multidisciplinary Care
Category: Therapeutic 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
No disease-modifying therapy exists for DPM2-CDG. Unlike PMM2-CDG or MPI-CDG, the lesion is in Dol-P-Man synthesis itself rather than in substrate availability, so simple mannose supplementation would not be expected to bypass the block and none has been reported. Management is symptom-directed and multidisciplinary: seizure control, orthopedic and rehabilitative care, cardiac surveillance, and nutritional support.
Show evidence (1 reference)
PMID:40902550 SUPPORT Other
"Finally, we discuss the existing biomarkers for diagnosis of these disorders and the potential for effective therapies."
The most recent review of dolichol-pathway CDG frames effective therapy as a prospect rather than an established option; PARTIAL because it does not name DPM2-CDG management specifically.
Antiseizure Pharmacotherapy
Category: Therapeutic 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
Seizures in the severe form are intractable. In the pooled CDG early-onset epileptic encephalopathy series that included DPM2-CDG patients, seizures became recurrent and drug-resistant despite antiepileptic treatment.
Target Phenotypes: Seizure HP:0001250 Human Phenotype Ontology (HP) Relation: this treatment targets this phenotype This treatment targets Seizure (HP:0001250). HP:0001250 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:26453362 SUPPORT Human Clinical
"With time, patients developed recurrent and intractable seizures principally tonic-clonic seizures, infantile spasms, and myoclonic seizures."
Documents that seizures become intractable despite antiepileptic drug treatment in this CDG cohort; PARTIAL because specific agents and per-subtype response are not reported.
Orthopedic Surgical Correction
Category: Therapeutic Action: Orthopedic Surgical ProcedureNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Orthopedic Surgical Procedure (NCIT:C16186). NCIT:C16186 is a clinical intervention from the NCI Thesaurus. NCIT:C16186
Achilles tendon lengthening was performed for equinus contracture in one patient, after which walking posture improved.
Target Phenotypes: Achilles tendon contracture HP:0001771 Human Phenotype Ontology (HP) Relation: this treatment targets this phenotype This treatment targets Achilles tendon contracture (HP:0001771). HP:0001771 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:37152991 SUPPORT Human Clinical
"She had undergone Achilles tendon lengthening procedure. Now her walking posture improved, but she still needed the help of hands to get up or down stairs."
Documents the intervention and its partial functional benefit.
Rehabilitation and Physical Therapy
Category: Therapeutic Action: Physical TherapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Physical Therapy (NCIT:C15302). NCIT:C15302 is a clinical intervention from the NCI Thesaurus. NCIT:C15302
Affected children present to rehabilitation services for motor delay, abnormal tone and gait abnormality; physical therapy is a mainstay of supportive management.
Show evidence (1 reference)
PMID:37152991 SUPPORT Human Clinical
"The patient was admitted to the Rehabilitation Department in Wuhan Children's Hospital due to developmental delay, mild intellectual disability, hypertonia, and strabismus at 11 years old."
Documents rehabilitation-service management of the motor phenotype; PARTIAL because the specific therapy protocol and its outcome are not reported.
Genetic Counseling
Category: Counseling / Informational Action: Genetic CounselingNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Genetic Counseling (NCIT:C15240). NCIT:C15240 is a clinical intervention from the NCI Thesaurus. NCIT:C15240
Autosomal recessive inheritance carries a 25% recurrence risk per pregnancy for carrier couples. Once the familial DPM2 alleles are known, carrier testing and prenatal or preimplantation diagnosis become available.
Show evidence (1 reference)
PMID:37152991 SUPPORT Human Clinical
"Sanger sequencing was used to validate the variants identified in the siblings and their parents."
Parental variant confirmation is the step that enables carrier counseling and reproductive risk assessment; PARTIAL because counseling outcomes are not themselves reported.
🔬

Biochemical Markers

3
Transferrin Isoelectric Focusing Type I Pattern (PRESENT)
Show evidence (2 references)
PMID:23109149 SUPPORT Human Clinical
"Metabolic investigations revealed CDG-I, pointing to a defect in protein N-glycosylation in the endoplasmic reticulum."
Establishes the CDG type I biochemical pattern in DPM2-CDG.
PMID:33129689 SUPPORT Human Clinical
"Laboratory studies which included POLG sequencing and whole genome microarray analysis were normal while serum transferrin isoelectric focusing (TIEF) was mildly abnormal (Figure 3)."
Shows the transferrin abnormality can be mild, an important caveat for using it as a screening test in the milder phenotype.
Lipid-Linked Oligosaccharide Accumulation (PRESENT)
Show evidence (1 reference)
PMID:23109149 SUPPORT In Vitro
"Analysis of lipid-linked oligosaccharides in fibroblasts showed accumulation of Dol-PP-GlcNAc(2)"
The truncated species accumulating in patient fibroblasts is the diagnostic biochemical fingerprint of the Dol-P-Man-dependent block.
Reduced ICAM1 as Hypoglycosylation Reporter (PRESENT)
Show evidence (1 reference)
PMID:37152991 SUPPORT In Vitro
"In vitro functional analysis demonstrated that this variant increased the expression level of DPM2 protein and western blot revealed a significant decrease in ICAM1, a universal biomarker for hypoglycosylation in patients with CDG, suggesting abnormal N-linked glycosylation."
ICAM1 reduction functions as the hypoglycosylation readout for this variant.
🔬

Diagnosis

3
DPM2 Molecular Genetic Testing (PRESENT)
Definitive diagnosis requires demonstration of biallelic DPM2 variants. Because the phenotype overlaps both the CDG and the dystroglycanopathies, exome sequencing or a combined CDG/dystroglycanopathy gene panel is the practical first-tier test; in the reported patients after the index family the diagnosis was made by whole exome sequencing.
Show evidence (1 reference)
PMID:37152991 SUPPORT Human Clinical
"A homozygous mutation, c.197G>A (p.Gly66Glu) in exon 4 of DPM2 (NM_003863) was identified by whole exome sequencing (WES)."
Exome sequencing established the molecular diagnosis in this family.
Serum Transferrin Isoelectric Focusing Screening (PRESENT)
Transferrin isoelectric focusing (or capillary zone electrophoresis) is the recommended first-line screening test in early-onset epilepsy of unknown cause, which is the presentation route for the severe DPM2-CDG phenotype. A type I pattern directs testing toward the ER N-glycosylation disorders.
Show evidence (1 reference)
PMID:26453362 SUPPORT Human Clinical
"We propose a diagnostic flowchart for the early diagnosis of CDG in patients presenting with EOEE and suggest to perform serum transferrin IEF (or capillary zone electrophoresis) as a first-line screening in early-onset epilepsy."
Establishes transferrin isoelectric focusing as the recommended screening test for the clinical presentation in which DPM2-CDG is found.
Muscle Biopsy Alpha-Dystroglycan Immunohistochemistry (PRESENT)
Muscle biopsy immunohistochemistry showing deficient alpha-dystroglycan O-mannosylation confirms the dystroglycanopathy component and, combined with a CDG type I transferrin pattern, points specifically at the DPM synthase complex rather than at an isolated dystroglycanopathy gene.
Show evidence (1 reference)
PMID:23109149 SUPPORT Human Clinical
"There was clinical evidence of a muscular dystrophy-dystroglycanopathy syndrome, supported by deficient O-mannosylation by muscle immunohistochemistry."
Muscle immunohistochemistry provided the tissue-level confirmation in the index patients.
📈

Progression

2
Severe infantile-lethal course
Age: Birth to 3 years
The severe, first-domain-variant form presents at birth and is fatal between 7 months and 3 years of age, with death attributed to severe epilepsy, muscular dystrophy and acute respiratory infections.
Show evidence (2 references)
PMID:33129689 SUPPORT Human Clinical
"All three patients included in the report had a severe clinical presentation characterized by hypotonia, progressive muscle weakness and wasting, absent psychomotor development, intractable seizures, liver involvement, abnormal coagulation factors and early mortality (between 7 months and 3..."
Documents the age range of early mortality in the severe form.
PMID:37152991 SUPPORT Human Clinical
"Until now, only four cases from three families have been reported, and three of them with the variant c.68A>G (p.Tyr23Cys) died before 3 years old due to severe epilepsy, muscular dystrophy, and acute respiratory infections"
States the causes and timing of death in the severe genotype.
Mild adult-viable course
Age: Childhood into the third decade
The milder form presents in early childhood with developmental delay and is compatible with survival into adulthood; reported patients were alive at 11, 20 and 23 years with stable intellectual disability, myopathy and hyperCKemia.
Show evidence (1 reference)
PMID:33129689 SUPPORT Human Clinical
"His clinical presentation was much less severe than that of the three previously described patients."
Establishes the milder, adult-viable end of the natural-history spectrum.
📊

Prevalence

1
Worldwide (published case reports)
Cases In Literature Ultra Rare
Six patients from four families had been reported by 2023 — three severe-form patients from two Italian families (2012), one adult male (2021), and two Chinese siblings (2023). No population prevalence or incidence rate has been established.
Show evidence (1 reference)
PMID:37152991 SUPPORT Human Clinical
"DPM2 is one subunit of a heterotrimeric complex for dolichol-phosphatemannose synthase (DPMS), a key enzyme in glycosylation, and only four patients with DPM2-CDG have been reported."
Confirms that only four patients were on record before this report added two more, establishing ultra-rare status.
🔀

Differential Diagnoses

4

Conditions with similar clinical presentations that must be differentiated from DPM2-congenital disorder of glycosylation:

DPM1-congenital disorder of glycosylation
Overlapping Features The allelic-complex disorder caused by variants in the catalytic DPM synthase subunit. Shares the CDG type I transferrin pattern, elevated CK, hypotonia and seizures.
Distinguishing Features
  • Same enzyme complex, different subunit — DPM1 is the catalytic rather than the regulatory subunit. Separation requires sequencing, since the biochemical phenotypes overlap.
Show evidence (1 reference)
PMID:23109149 SUPPORT Human Clinical
"Hence, mutations have now been described in the genes for the 3 subunits of DPM: DPM1, DPM2, and DPM3"
Establishes the three-subunit allelic series that constitutes the primary differential.
DPM3-congenital disorder of glycosylation
Overlapping Features Caused by variants in the DPM3 tethering subunit. Overlaps DPM2-CDG in combining a CDG type I pattern with alpha-dystroglycan hypo-O-mannosylation; often milder and more cardiac-predominant, with several adult-onset cases.
Distinguishing Features
  • Cardiac involvement is prominent (reported in four of six DPM3 patients), and transferrin isoelectric focusing may be normal or only mildly abnormal. Molecular testing distinguishes the subunits.
Show evidence (1 reference)
PMID:19576565 SUPPORT Human Clinical
"This mild Dol-P-Man biosynthesis defect due to DPM3 mutations is a cause for alpha-dystroglycanopathy, thereby bridging the congenital disorders of glycosylation with the dystroglycanopathies."
DPM3-CDG shares the combined CDG/dystroglycanopathy signature that defines the differential with DPM2-CDG.
MPDU1-congenital disorder of glycosylation
Overlapping Features Defect in the utilization, rather than the synthesis, of dolichol-linked mannose and glucose donors. Produces the same CDG-I-plus-dystroglycanopathy overlap space.
Distinguishing Features
  • MPDU1 affects donor utilization downstream of Dol-P-Man synthesis, whereas DPM2 affects donor synthesis. Molecular testing distinguishes them.
Show evidence (1 reference)
PMID:31741824 SUPPORT Human Clinical
"Mannose-phosphate-dolichol utilization defect 1 (MPDU1) plays a role in the utilization of DPM."
Places MPDU1 in the same Dol-P-Man axis, immediately downstream of the DPM2 lesion.
Primary alpha-dystroglycanopathies
Overlapping Features Congenital muscular dystrophies caused by variants in the dedicated alpha-dystroglycan glycosylation genes (POMT1, POMT2, POMGNT1, LARGE, FKTN, FKRP, B3GALNT2 and others), spanning Walker-Warburg syndrome and muscle-eye-brain disease.
Distinguishing Features
  • Primary dystroglycanopathies impair alpha-dystroglycan O-mannosylation without a generalized N-glycosylation defect, so serum transferrin isoelectric focusing is typically normal — the key discriminator from DPM2-CDG.
Show evidence (2 references)
PMID:28198708 SUPPORT Other
"Dystroglycanopathies are neuromuscular disorders due to abnormal glycosylation of dystroglycan which is a cell-surface glycoprotein that acts as a receptor for extracellular matrix proteins containing laminin-G domains."
Defines the primary dystroglycanopathy family that constitutes the muscular-dystrophy side of the differential.
PMID:28198708 SUPPORT Other
"Most genes code for glycosyltransferases (POMT1, POMT2, POMGNT1, LARGE, GTDC2, B4GAT1, B3GALNT2) although a minority does not (DPM1, DPM2, DPM3, DOLK, POMK, GMPPB)."
Places DPM2 explicitly within the dystroglycanopathy gene list while distinguishing it from the dedicated glycosyltransferases.
{ }

Source YAML

click to show 
name: DPM2-congenital disorder of glycosylation
creation_date: "2026-07-31T00:00:00Z"
description: >-
  DPM2-congenital disorder of glycosylation (DPM2-CDG, CDG-Iu) is an ultra-rare
  autosomal recessive disorder caused by biallelic pathogenic variants in DPM2,
  which encodes the regulatory subunit of the endoplasmic-reticulum
  dolichol-phosphate-mannose (Dol-P-Man / DPM) synthase complex. Because
  Dol-P-Man is the obligate mannosyl donor for four distinct glycosylation
  pathways — N-glycan lipid-linked oligosaccharide assembly, protein
  O-mannosylation, C-mannosylation and GPI-anchor biosynthesis — DPM2 deficiency
  produces a combined glycosylation defect that simultaneously manifests as a
  type I congenital disorder of glycosylation and as a secondary
  dystroglycanopathy. The severe end of the spectrum, which defines the
  Orphanet/MONDO label "congenital muscular dystrophy with intellectual
  disability and severe epilepsy", presents at birth with severe hypotonia,
  elevated creatine kinase, absent psychomotor development, intractable epilepsy
  and progressive microcephaly, and is fatal in infancy or early childhood; later
  reports have expanded the phenotype to a milder, adult-viable form with
  intellectual disability, myopathy and hyperCKemia.
category: Mendelian
parents:
- hereditary disease
synonyms:
- DPM2-CDG
- CDG-Iu
- CDG1U
- congenital disorder of glycosylation type Iu
- congenital muscular dystrophy with intellectual disability and severe epilepsy
- CMD with intellectual disability and severe epilepsy
- dolichyl-phosphate mannosyltransferase subunit 2 deficiency
disease_term:
  preferred_term: DPM2-congenital disorder of glycosylation
  term:
    id: MONDO:0014023
    label: congenital muscular dystrophy with intellectual disability and severe epilepsy
classifications:
  harrisons_chapter:
  - classification_value: ENDOCRINOLOGY_METABOLISM
    evidence:
    - reference: PMID:40902550
      reference_title: "Genetic disorders of dolichol synthesis and utilization."
      supports: SUPPORT
      evidence_source: OTHER
      snippet: >-
        CDG are a group of approximately 200 mostly autosomal recessive inherited
        metabolic disorders characterized by defective glycosylation of proteins
        and lipids.
      explanation: >-
        The CDG are framed as inherited metabolic disorders, placing DPM2-CDG in
        the endocrinology/metabolism Part.
  - classification_value: GENETICS_ENVIRONMENT_DISEASE
    evidence:
    - reference: PMID:40902550
      reference_title: "Genetic disorders of dolichol synthesis and utilization."
      supports: SUPPORT
      evidence_source: OTHER
      snippet: >-
        CDG are a group of approximately 200 mostly autosomal recessive inherited
        metabolic disorders characterized by defective glycosylation of proteins
        and lipids.
      explanation: >-
        Mendelian autosomal recessive inheritance is the defining axis of this
        disease group, supporting the genetics Part.
  - classification_value: NEUROLOGIC
    evidence:
    - reference: PMID:26453362
      reference_title: "Electroclinical Features of Early-Onset Epileptic Encephalopathies in Congenital Disorders of Glycosylation (CDGs)."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        CDGs are usually multisystem diseases, and in the majority of patients,
        there is an important neurological involvement comprising psychomotor
        disability, hypotonia, ataxia, seizures, stroke-like episodes, and
        peripheral neuropathy.
      explanation: >-
        Neurological involvement dominates the DPM2-CDG presentation
        (intractable epilepsy, developmental delay, microcephaly), supporting a
        secondary neurologic Part assignment.
  icimd_category:
  - classification_value: multiple_glycosylation_pathways
    notes: >-
      ICIMD (Ferreira et al. 2021, PMID:33340416): group "Disorders affecting
      multiple glycosylation pathways (dolichol metabolism, Golgi transport and
      homeostasis, sialic acid metabolism)" under category 18, "Congenital
      disorders of glycosylation". DPM2-CDG is a dolichol-metabolism defect
      whose single depleted donor (Dol-P-Man) feeds N-glycosylation,
      O-mannosylation, C-mannosylation and GPI-anchor biosynthesis, so the
      multiple-pathway group is the correct placement rather than the
      N-linked-only group.
references:
- reference: PMID:23109149
  title: "DPM2-CDG: a muscular dystrophy-dystroglycanopathy syndrome with severe epilepsy."
- reference: PMID:33129689
  title: "Expanding the clinical and metabolic phenotype of DPM2 deficient congenital disorders of glycosylation."
- reference: PMID:37152991
  title: "Identification and characterization of a new variation in DPM2 gene in two Chinese siblings with mild intellectual impairment."
inheritance:
- name: Autosomal recessive inheritance
  inheritance_term:
    preferred_term: Autosomal recessive inheritance
    term:
      id: HP:0000007
      label: Autosomal recessive inheritance
  expressivity: VARIABLE
  description: >-
    DPM2-CDG requires biallelic DPM2 variants. Reported families include
    compound heterozygosity for a missense plus a canonical splice-acceptor
    variant, homozygosity for a recurrent missense allele in two unrelated
    families, and homozygosity for a second missense allele in non-consanguineous
    Chinese siblings. Expressivity is markedly variable: reported genotypes span
    a neonatal-onset, infantile-lethal epileptic and myopathic encephalopathy and
    a mild, adult-viable intellectual-disability-plus-myopathy phenotype.
  evidence:
  - reference: PMID:23109149
    reference_title: "DPM2-CDG: a muscular dystrophy-dystroglycanopathy syndrome with severe epilepsy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      DNA analysis revealed mutations in DPM2, 1 of the subunits of the
      dolichol-phosphate-mannose (DPM) synthase; the patient in the first family
      is compound heterozygous for 2 mutations (c.68A>G, predicting a missense
      mutation p.Y23C and c.4-1G>C, a splice mutation), whereas the patients in
      the second family are homozygous for the same missense mutation (c.68A>G,
      p.Y23C).
    explanation: >-
      Biallelic genotypes (compound heterozygous and homozygous) in two
      independent families establish autosomal recessive inheritance.
  - reference: PMID:37152991
    reference_title: "Identification and characterization of a new variation in DPM2 gene in two Chinese siblings with mild intellectual impairment."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      A homozygous mutation, c.197G>A (p.Gly66Glu) in exon 4 of DPM2 (NM_003863)
      was identified by whole exome sequencing (WES).
    explanation: >-
      A homozygous DPM2 variant segregating in two affected siblings of healthy
      parents supports recessive inheritance.
pathophysiology:
- name: DPM Synthase Complex Destabilization
  biological_scale: MOLECULAR
  role: trigger
  mechanism_confidence: ESTABLISHED
  description: >-
    DPM synthase is a heterotrimer of DPM1 (the catalytic subunit), DPM2 (a
    regulatory subunit that stabilizes DPM1 and enhances dolichol-phosphate
    binding) and DPM3 (which tethers DPM1 to the ER membrane). Biallelic DPM2
    variants — missense alleles in either transmembrane region, a nonsense
    allele, or a canonical splice-acceptor allele — reduce or functionally
    impair DPM2, destabilizing the complex. In patient fibroblasts carrying a
    nonsense/missense genotype, DPM2 fell to roughly 60% of control and DPM1
    protein became undetectable, showing that loss of the regulatory subunit
    also collapses the catalytic subunit.
  genes:
  - preferred_term: DPM2
    term:
      id: hgnc:3006
      label: DPM2
  protein_complexes:
  - preferred_term: dolichol-phosphate-mannose synthase complex
    modifier: DECREASED
    term:
      id: GO:0033185
      label: dolichol-phosphate-mannose synthase complex
  molecular_functions:
  - preferred_term: dolichyl-phosphate beta-D-mannosyltransferase activity
    modifier: DECREASED
    term:
      id: GO:0004582
      label: dolichyl-phosphate beta-D-mannosyltransferase activity
  locations:
  - preferred_term: endoplasmic reticulum membrane
    term:
      id: GO:0005789
      label: endoplasmic reticulum membrane
  cell_types:
  - preferred_term: Fibroblast
    term:
      id: CL:0000057
      label: fibroblast
  evidence:
  - reference: PMID:33129689
    reference_title: "Expanding the clinical and metabolic phenotype of DPM2 deficient congenital disorders of glycosylation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      DPMS is composed of DPM1, DPM2, and DPM3 (Figure 1). DPM1 is the catalytic
      subunit of DPMS while DPM2 and DPM3 have been described as regulatory and
      tethering subunits respectively
    explanation: >-
      Establishes the subunit architecture of the complex and DPM2's regulatory
      role within it.
  - reference: PMID:33129689
    reference_title: "Expanding the clinical and metabolic phenotype of DPM2 deficient congenital disorders of glycosylation."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Patient fibroblasts showed lower DPM2 expression (~60% of control, Figure
      5). No quantifiable DPM1 protein expression was detected (Figure 5A)
      confirming the deleterious effects of the DPM2 alleles identified by WES.
    explanation: >-
      Direct demonstration in patient cells that DPM2 loss destabilizes the
      complex, abolishing detectable DPM1.
  - reference: PMID:16280320
    reference_title: "DPM1, the catalytic subunit of dolichol-phosphate mannose synthase, is tethered to and stabilized on the endoplasmic reticulum membrane by DPM3."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      DPM1 was rapidly degraded by the proteasome in the absence of DPM3.
    explanation: >-
      Establishes the general principle that loss of an accessory DPM subunit
      destabilizes the catalytic DPM1 subunit — the mechanism observed in DPM2
      patient fibroblasts.
  downstream:
  - target: Dolichol-Phosphate-Mannose Depletion
- name: Dolichol-Phosphate-Mannose Depletion
  biological_scale: MOLECULAR
  mechanism_confidence: ESTABLISHED
  description: >-
    The destabilized complex synthesizes less dolichol-phosphate-mannose from
    GDP-mannose and dolichol phosphate. Dol-P-Man is flipped to the luminal face
    of the endoplasmic reticulum, where it serves as the sole mannosyl donor for
    four glycosylation pathways: lipid-linked oligosaccharide (N-glycan
    precursor) mannosylation, protein O-mannosylation, protein C-mannosylation,
    and GPI-anchor mannosylation. Depletion of this single shared donor is
    therefore the branch point that produces the disorder's combined
    CDG-plus-dystroglycanopathy phenotype.
  chemical_entities:
  - preferred_term: dolichol phosphate mannose
    modifier: DECREASED
    term:
      id: CHEBI:17624
      label: dolichyl beta-D-mannosyl phosphate
  - preferred_term: GDP-mannose
    term:
      id: CHEBI:15820
      label: GDP-alpha-D-mannose
  locations:
  - preferred_term: endoplasmic reticulum membrane
    term:
      id: GO:0005789
      label: endoplasmic reticulum membrane
  evidence:
  - reference: PMID:16280320
    reference_title: "DPM1, the catalytic subunit of dolichol-phosphate mannose synthase, is tethered to and stabilized on the endoplasmic reticulum membrane by DPM3."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Dolichol-phosphate mannose (DPM) synthase is required for synthesis of the
      glycosylphosphatidylinositol (GPI) anchor, N-glycan precursor, protein
      O-mannose, and C-mannose.
    explanation: >-
      Establishes that the single Dol-P-Man product feeds all four downstream
      glycosylation pathways, the basis for the combined defect.
  - reference: PMID:18387370
    reference_title: "Dolichol-phosphate mannose synthase: structure, function and regulation."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      The sugar transfer from dolichol-phosphate-sugars occurs exclusively on the
      luminal side of the endoplasmic reticulum and is utilized in all four
      glycosylation pathways.
    explanation: >-
      Review evidence for the luminal topology and four-pathway usage of the
      dolichol-phosphate-sugar donor.
  - reference: PMID:40902550
    reference_title: "Genetic disorders of dolichol synthesis and utilization."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      It is used as the membrane anchor for mono- or oligosaccharides transferred
      during N-glycosylation, O/C-mannosylation and glycosylphosphatidylinositol
      anchor biosynthesis.
    explanation: >-
      Recent review confirming the shared-donor architecture that makes DPM
      synthase defects multi-pathway disorders.
  downstream:
  - target: ER Lipid-Linked Oligosaccharide Assembly Arrest
  - target: Alpha-Dystroglycan Hypo-O-Mannosylation
  - target: GPI-Anchor Biosynthesis Impairment
- name: ER Lipid-Linked Oligosaccharide Assembly Arrest
  biological_scale: MOLECULAR
  conforms_to: "congenital_disorder_of_glycosylation#ER Lipid-Linked Oligosaccharide Assembly Defect"
  mechanism_confidence: ESTABLISHED
  description: >-
    Without sufficient Dol-P-Man, the luminal mannosylation steps of
    lipid-linked oligosaccharide assembly stall. Patient fibroblasts accumulate
    the truncated intermediate Dol-PP-GlcNAc2-Man5 — precisely the species
    expected when the biosynthetic block lies at the first Dol-P-Man-dependent
    mannosyltransferase step — and truncated precursors are transferred to
    nascent protein, producing the type I CDG biochemical pattern on serum
    transferrin isoelectric focusing.
  biological_processes:
  - preferred_term: dolichol-linked oligosaccharide biosynthetic process
    modifier: DECREASED
    term:
      id: GO:0006488
      label: dolichol-linked oligosaccharide biosynthetic process
  - preferred_term: protein N-linked glycosylation
    modifier: DECREASED
    term:
      id: GO:0006487
      label: protein N-linked glycosylation
  cell_types:
  - preferred_term: Fibroblast
    term:
      id: CL:0000057
      label: fibroblast
  evidence:
  - reference: PMID:23109149
    reference_title: "DPM2-CDG: a muscular dystrophy-dystroglycanopathy syndrome with severe epilepsy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Metabolic investigations revealed CDG-I, pointing to a defect in protein
      N-glycosylation in the endoplasmic reticulum.
    explanation: >-
      Places the DPM2 lesion in the ER N-glycosylation arm, i.e. the type I CDG
      trigger of the module.
  - reference: PMID:23109149
    reference_title: "DPM2-CDG: a muscular dystrophy-dystroglycanopathy syndrome with severe epilepsy."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Analysis of lipid-linked oligosaccharides in fibroblasts showed
      accumulation of Dol-PP-GlcNAc(2)
    explanation: >-
      Direct biochemical demonstration of truncated lipid-linked oligosaccharide
      accumulation in patient fibroblasts, localizing the block to the
      Dol-P-Man-dependent mannosylation steps.
  downstream:
  - target: Protein Hypoglycosylation
- name: Alpha-Dystroglycan Hypo-O-Mannosylation
  biological_scale: MOLECULAR
  mechanism_confidence: ESTABLISHED
  description: >-
    The POMT1/POMT2 O-mannosyltransferases use Dol-P-Man to initiate the
    O-mannosyl glycan on alpha-dystroglycan. Dol-P-Man depletion therefore
    truncates this glycan, so alpha-dystroglycan cannot be extended into its
    laminin-binding matriglycan. Muscle immunohistochemistry in DPM2-CDG
    patients showed deficient O-mannosylation, making DPM2-CDG a secondary
    dystroglycanopathy — the same arm demonstrated directly in the sister
    disorder DPM3-CDG.
  biological_processes:
  - preferred_term: protein O-linked glycosylation via mannose
    modifier: DECREASED
    term:
      id: GO:0035269
      label: protein O-linked glycosylation via mannose
  cell_types:
  - preferred_term: Skeletal muscle fiber
    term:
      id: CL:0008002
      label: skeletal muscle fiber
  evidence:
  - reference: PMID:23109149
    reference_title: "DPM2-CDG: a muscular dystrophy-dystroglycanopathy syndrome with severe epilepsy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      There was clinical evidence of a muscular dystrophy-dystroglycanopathy
      syndrome, supported by deficient O-mannosylation by muscle
      immunohistochemistry.
    explanation: >-
      Direct patient-tissue evidence that DPM2 deficiency causes deficient
      O-mannosylation in skeletal muscle.
  - reference: PMID:19576565
    reference_title: "Deficiency of Dol-P-Man synthase subunit DPM3 bridges the congenital disorders of glycosylation with the dystroglycanopathies."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Investigation of the four Dol-P-Man-dependent glycosylation pathways in the
      ER revealed strongly reduced O-mannosylation of alpha-dystroglycan in a
      muscle biopsy, thereby explaining the clinical phenotype of muscular
      dystrophy.
    explanation: >-
      Mechanistic proof in the allelic DPM3 disorder that Dol-P-Man deficiency
      selectively impairs alpha-dystroglycan O-mannosylation and thereby causes
      muscular dystrophy.
  - reference: PMID:30931530
    reference_title: "Toward understanding tissue-specific symptoms in dolichol-phosphate-mannose synthesis disorders; insight from DPM3-CDG."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      In the three patients, O-mannosylation of alpha-dystroglycan (αDG) was
      strongly reduced
    explanation: >-
      Confirms in a second DPM-synthase-subunit cohort that skeletal-muscle
      alpha-dystroglycan O-mannosylation is the affected pathway.
  downstream:
  - target: Sarcolemmal Laminin Anchorage Failure
- name: GPI-Anchor Biosynthesis Impairment
  biological_scale: MOLECULAR
  mechanism_confidence: PROVISIONAL
  description: >-
    GPI-anchor assembly requires Dol-P-Man-dependent mannosylation steps, so
    Dol-P-Man depletion is expected to impair GPI-anchor biosynthesis in
    DPM2-CDG. This arm is inferred from DPM synthase biochemistry rather than
    demonstrated with patient GPI-anchored-protein data; the supporting patient
    observations are indirect (a lipidomic shift in patient fibroblasts, and
    congenital heart defects of a type seen across GPI-anchor disorders). It is
    recorded as provisional for that reason.
  biological_processes:
  - preferred_term: GPI anchor biosynthetic process
    modifier: DECREASED
    term:
      id: GO:0006506
      label: GPI anchor biosynthetic process
  cell_types:
  - preferred_term: Fibroblast
    term:
      id: CL:0000057
      label: fibroblast
  evidence:
  - reference: PMID:33129689
    reference_title: "Expanding the clinical and metabolic phenotype of DPM2 deficient congenital disorders of glycosylation."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Given the implication of DPMS in GPI anchor synthesis, we performed
      lipidomics analysis in patient fibroblasts.
    explanation: >-
      The authors invoke the GPI-anchor arm as the motivation for lipidomics, but
      the study measured lipid subclasses rather than GPI-anchored protein
      display, so this supports the arm only indirectly.
  - reference: PMID:33129689
    reference_title: "Expanding the clinical and metabolic phenotype of DPM2 deficient congenital disorders of glycosylation."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      We observed significant differences in lysophospholipids especially
      lysophosphatidylserine (LPS) and lysophosphatidic acid (LPA) (Figure 7).
    explanation: >-
      Patient-fibroblast lipidomic perturbation is consistent with, but does not
      by itself establish, a GPI-anchor biosynthetic defect.
  - reference: PMID:16280320
    reference_title: "DPM1, the catalytic subunit of dolichol-phosphate mannose synthase, is tethered to and stabilized on the endoplasmic reticulum membrane by DPM3."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      CHO2.38 cells were negative for GPI-anchored proteins, and microsomes from
      these cells showed no detectable DPM synthase activity, indicating that
      DPM3 is an essential component of this enzyme.
    explanation: >-
      Cell-line evidence that abolishing DPM synthase activity abolishes surface
      GPI-anchored protein display, supporting the mechanistic expectation for
      DPM2 deficiency.
  downstream:
  - target: Multisystem Glycoprotein Dysfunction
- name: Protein Hypoglycosylation
  biological_scale: CELLULAR
  conforms_to: "congenital_disorder_of_glycosylation#Protein Hypoglycosylation"
  mechanism_confidence: ESTABLISHED
  description: >-
    Transfer of truncated precursors leaves many secreted and membrane client
    glycoproteins under-glycosylated. In DPM2-CDG this is detected clinically as
    a CDG type I transferrin isoelectric focusing pattern, and experimentally as
    reduced ICAM1, a general hypoglycosylation reporter, in cells expressing a
    pathogenic DPM2 allele.
  biological_processes:
  - preferred_term: protein N-linked glycosylation
    modifier: DECREASED
    term:
      id: GO:0006487
      label: protein N-linked glycosylation
  cell_types:
  - preferred_term: Hepatocyte
    term:
      id: CL:0000182
      label: hepatocyte
  - preferred_term: Fibroblast
    term:
      id: CL:0000057
      label: fibroblast
  evidence:
  - reference: PMID:37152991
    reference_title: "Identification and characterization of a new variation in DPM2 gene in two Chinese siblings with mild intellectual impairment."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      In vitro functional analysis demonstrated that this variant increased the
      expression level of DPM2 protein and western blot revealed a significant
      decrease in ICAM1, a universal biomarker for hypoglycosylation in patients
      with CDG, suggesting abnormal N-linked glycosylation.
    explanation: >-
      Functional demonstration that a pathogenic DPM2 allele causes protein
      hypoglycosylation, and that the mechanism is impaired function rather than
      reduced protein abundance for this allele.
  downstream:
  - target: Multisystem Glycoprotein Dysfunction
- name: Sarcolemmal Laminin Anchorage Failure
  biological_scale: TISSUE
  mechanism_confidence: ESTABLISHED
  description: >-
    Hypoglycosylated alpha-dystroglycan loses its laminin-binding capacity, so
    the dystrophin-glycoprotein complex can no longer transmit force between the
    myofibre cytoskeleton and the basal lamina. The sarcolemma becomes
    mechanically fragile, myofibres degenerate with each contraction cycle, and
    creatine kinase leaks into serum — the congenital muscular dystrophy
    component of the disorder.
  cell_types:
  - preferred_term: Skeletal muscle fiber
    term:
      id: CL:0008002
      label: skeletal muscle fiber
  evidence:
  - reference: PMID:27291147
    reference_title: "Dolichol-phosphate mannose synthase depletion in zebrafish leads to dystrophic muscle with hypoglycosylated α-dystroglycan."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      The resulting morphant embryos showed early death, muscle disorganization,
      low DPMS complex activity, and increased levels of apoptotic nuclei,
      together with hypoglycosylated α-DG in muscle fibers, thus recapitulating
      most of the characteristics seen in patients with mutations in DPMS.
    explanation: >-
      Zebrafish depletion of dpm subunits reproduces the causal step from DPM
      synthase loss to hypoglycosylated alpha-dystroglycan and dystrophic muscle.
  - reference: PMID:27291147
    reference_title: "Dolichol-phosphate mannose synthase depletion in zebrafish leads to dystrophic muscle with hypoglycosylated α-dystroglycan."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      Defective dolichol-phosphate mannose synthase (DPMS) complex is a rare cause
      of congenital muscular dystrophy associated with hypoglycosylation of
      alpha-dystroglycan (α-DG) in skeletal muscle.
    explanation: >-
      States the causal link from DPM synthase deficiency to
      dystroglycan-hypoglycosylation congenital muscular dystrophy.
  downstream:
  - target: Multisystem Glycoprotein Dysfunction
- name: Multisystem Glycoprotein Dysfunction
  biological_scale: ORGANISM
  conforms_to: "congenital_disorder_of_glycosylation#Multisystem Glycoprotein Dysfunction"
  mechanism_confidence: ESTABLISHED
  description: >-
    Combined N-glycan, O-mannosyl and (inferred) GPI-anchor defects converge on a
    multisystem disease. In the severe form this is a neonatal
    neuromuscular-plus-epileptic encephalopathy with hypotonia, absent
    psychomotor development, intractable seizures, progressive microcephaly,
    liver involvement and coagulation abnormality, fatal between 7 months and 3
    years. In the milder form the same lesion yields intellectual disability,
    myopathy with hyperCKemia, congenital heart defects and peripheral nerve
    involvement compatible with survival into adulthood.
  cell_types:
  - preferred_term: Neuron
    term:
      id: CL:0000540
      label: neuron
  - preferred_term: Skeletal muscle fiber
    term:
      id: CL:0008002
      label: skeletal muscle fiber
  - preferred_term: Hepatocyte
    term:
      id: CL:0000182
      label: hepatocyte
  evidence:
  - reference: PMID:33129689
    reference_title: "Expanding the clinical and metabolic phenotype of DPM2 deficient congenital disorders of glycosylation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      All three patients included in the report had a severe clinical
      presentation characterized by hypotonia, progressive muscle weakness and
      wasting, absent psychomotor development, intractable seizures, liver
      involvement, abnormal coagulation factors and early mortality (between 7
      months and 3 years of age).
    explanation: >-
      Summarizes the multisystem severe-end phenotype produced by the shared
      hypoglycosylation lesion.
  - reference: PMID:23109149
    reference_title: "DPM2-CDG: a muscular dystrophy-dystroglycanopathy syndrome with severe epilepsy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We describe a new CDG, due to a deficiency of DPM2. Hence, mutations have
      now been described in the genes for the 3 subunits of DPM: DPM1, DPM2, and
      DPM3, whereby DPM2-CDG links the congenital disorders of glycosylation to
      the congenital muscular dystrophies.
    explanation: >-
      States the defining multisystem convergence of this disorder — a CDG that is
      simultaneously a congenital muscular dystrophy.
phenotypes:
- category: Neurologic
  name: Intractable Epilepsy
  description: >-
    Drug-resistant seizures are the defining neurological feature of the severe
    form and give the disorder its Orphanet name. Onset is early; semiology in
    the CDG early-onset epileptic encephalopathy series included myoclonic,
    clonic and focal seizures at onset, evolving to tonic-clonic seizures,
    infantile spasms and myoclonic seizures.
  phenotype_term:
    preferred_term: Seizure
    term:
      id: HP:0001250
      label: Seizure
    temporality: RECURRENT
  evidence:
  - reference: PMID:23109149
    reference_title: "DPM2-CDG: a muscular dystrophy-dystroglycanopathy syndrome with severe epilepsy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We searched for the primary defect in 3 children from 2 families with a
      severe neurological phenotype, including profound developmental delay,
      intractable epilepsy, progressive microcephaly, severe hypotonia with
      elevated blood creatine kinase levels, and early fatal outcome.
    explanation: >-
      Intractable epilepsy is part of the index DPM2-CDG clinical description.
  - reference: PMID:26453362
    reference_title: "Electroclinical Features of Early-Onset Epileptic Encephalopathies in Congenital Disorders of Glycosylation (CDGs)."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We describe a series of patients with EOEE and genetically confirmed CDG
      (ALG3-CDG, ALG6-CDG, DPM2-CDG, ALG1-CDG).
    explanation: >-
      DPM2-CDG is explicitly among the CDG subtypes contributing patients to this
      early-onset epileptic encephalopathy series.
- category: Neurologic
  name: Epileptic Spasms and Myoclonic Seizures
  description: >-
    Seizure semiology in the CDG early-onset epileptic encephalopathy cohort,
    which included DPM2-CDG patients, began with myoclonic, clonic and focal
    seizures and evolved to recurrent intractable tonic-clonic seizures,
    infantile spasms and myoclonic seizures.
  phenotype_term:
    preferred_term: Epileptic spasm
    term:
      id: HP:0011097
      label: Epileptic spasm
  evidence:
  - reference: PMID:26453362
    reference_title: "Electroclinical Features of Early-Onset Epileptic Encephalopathies in Congenital Disorders of Glycosylation (CDGs)."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      With time, patients developed recurrent and intractable seizures
      principally tonic-clonic seizures, infantile spasms, and myoclonic
      seizures.
    explanation: >-
      Describes the evolving semiology for the pooled CDG epileptic
      encephalopathy cohort that includes DPM2-CDG; the specific attribution to
      DPM2-CDG patients is not itemized, hence PARTIAL.
- category: Neurologic
  name: Abnormal EEG
  description: >-
    Electrophysiological correlates in the CDG early-onset epileptic
    encephalopathy cohort included focal and multifocal epileptic discharges,
    slowed background rhythm, generalized epileptic activity with burst
    suppression, and status epilepticus. In the mild sibling phenotype the EEG
    abnormality was limited to slowed occipital background activity.
  phenotype_term:
    preferred_term: EEG abnormality
    term:
      id: HP:0002353
      label: EEG abnormality
  evidence:
  - reference: PMID:26453362
    reference_title: "Electroclinical Features of Early-Onset Epileptic Encephalopathies in Congenital Disorders of Glycosylation (CDGs)."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Electrophysiological correlates included focal and multifocal epileptic
      discharges, slowed background rhythm, and generalized epileptic activity
      including burst suppression pattern and status epilepticus.
    explanation: >-
      EEG findings for the pooled CDG epileptic encephalopathy cohort including
      DPM2-CDG; not itemized per subtype, hence PARTIAL.
  - reference: PMID:37152991
    reference_title: "Identification and characterization of a new variation in DPM2 gene in two Chinese siblings with mild intellectual impairment."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Electroencephalogram examination showed that occipital background activity
      was slightly slower.
    explanation: >-
      Documents the milder EEG abnormality at the other end of the DPM2-CDG
      spectrum.
- category: Neurologic
  name: Severe Global Developmental Delay
  description: >-
    Severe-form patients showed profound developmental delay with essentially
    absent psychomotor development. Milder patients had delayed motor and
    language milestones — head control at 4 months, unassisted walking at 3
    years, first words at 4 years.
  phenotype_term:
    preferred_term: Severe global developmental delay
    term:
      id: HP:0011344
      label: Severe global developmental delay
  severity: SEVERE
  evidence:
  - reference: PMID:23109149
    reference_title: "DPM2-CDG: a muscular dystrophy-dystroglycanopathy syndrome with severe epilepsy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We searched for the primary defect in 3 children from 2 families with a
      severe neurological phenotype, including profound developmental delay,
      intractable epilepsy, progressive microcephaly, severe hypotonia with
      elevated blood creatine kinase levels, and early fatal outcome.
    explanation: >-
      Profound developmental delay is part of the index severe-form description.
  - reference: PMID:33129689
    reference_title: "Expanding the clinical and metabolic phenotype of DPM2 deficient congenital disorders of glycosylation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Pathogenic alterations in the DPM2 gene have been previously described in
      patients with hypotonia, progressive muscle weakness, absent psychomotor
      development, intractable seizures, and early death.
    explanation: >-
      Confirms absent psychomotor development in the previously reported severe
      cohort.
- category: Neurologic
  name: Intellectual Disability
  description: >-
    Intellectual disability is present across the spectrum. It is mild in the
    long-surviving patients — the Chinese siblings had mild intellectual
    disability, one unable to count to 10 at 11 years — and part of the
    adult-viable phenotype described in the fourth reported patient.
  phenotype_term:
    preferred_term: Intellectual disability
    term:
      id: HP:0001249
      label: Intellectual disability
  evidence:
  - reference: PMID:33129689
    reference_title: "Expanding the clinical and metabolic phenotype of DPM2 deficient congenital disorders of glycosylation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We identified biallelic DPM2 variants in a 23-year-old male with truncal
      hypotonia, hypertonicity, congenital heart defects, intellectual
      disability, and generalized muscle wasting.
    explanation: >-
      Intellectual disability in the adult DPM2-CDG patient.
  - reference: PMID:37152991
    reference_title: "Identification and characterization of a new variation in DPM2 gene in two Chinese siblings with mild intellectual impairment."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Whole-exome sequencing (WES) was performed in a Chinese family having two
      siblings with a mild form of DPM2-CDG with developmental delay, mild
      intellectual disability, hypotonia, and increased serum creatine kinase.
    explanation: >-
      Mild intellectual disability in the two long-surviving siblings.
- category: Neurologic
  name: Progressive Microcephaly
  description: >-
    Progressive microcephaly was documented in the severe-form patients, and
    microcephaly was also noted in the adult patient with the milder phenotype.
  phenotype_term:
    preferred_term: Progressive microcephaly
    term:
      id: HP:0000253
      label: Progressive microcephaly
    clinical_course: PROGRESSIVE
  evidence:
  - reference: PMID:23109149
    reference_title: "DPM2-CDG: a muscular dystrophy-dystroglycanopathy syndrome with severe epilepsy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We searched for the primary defect in 3 children from 2 families with a
      severe neurological phenotype, including profound developmental delay,
      intractable epilepsy, progressive microcephaly, severe hypotonia with
      elevated blood creatine kinase levels, and early fatal outcome.
    explanation: >-
      Progressive microcephaly is explicitly part of the index phenotype.
- category: Musculoskeletal
  name: Congenital Muscular Dystrophy
  description: >-
    A dystroglycanopathy-type congenital muscular dystrophy, evidenced by
    deficient alpha-dystroglycan O-mannosylation on muscle immunohistochemistry,
    with progressive muscle weakness and wasting in the severe form.
  phenotype_term:
    preferred_term: Muscular dystrophy
    term:
      id: HP:0003560
      label: Muscular dystrophy
  evidence:
  - reference: PMID:23109149
    reference_title: "DPM2-CDG: a muscular dystrophy-dystroglycanopathy syndrome with severe epilepsy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      There was clinical evidence of a muscular dystrophy-dystroglycanopathy
      syndrome, supported by deficient O-mannosylation by muscle
      immunohistochemistry.
    explanation: >-
      Establishes the congenital muscular dystrophy component with tissue-level
      confirmation.
- category: Musculoskeletal
  name: Generalized Hypotonia
  description: >-
    Severe hypotonia from birth in the severe form; truncal (axial) hypotonia,
    sometimes combined with appendicular hypertonia, in the milder form.
  phenotype_term:
    preferred_term: Generalized hypotonia
    term:
      id: HP:0001290
      label: Generalized hypotonia
  evidence:
  - reference: PMID:23109149
    reference_title: "DPM2-CDG: a muscular dystrophy-dystroglycanopathy syndrome with severe epilepsy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We searched for the primary defect in 3 children from 2 families with a
      severe neurological phenotype, including profound developmental delay,
      intractable epilepsy, progressive microcephaly, severe hypotonia with
      elevated blood creatine kinase levels, and early fatal outcome.
    explanation: >-
      Severe hypotonia is part of the index phenotype.
- category: Musculoskeletal
  name: Hypertonia
  description: >-
    Appendicular hypertonia coexisting with truncal hypotonia — a mixed tone
    abnormality — was described in the adult patient and in the younger of the
    two Chinese siblings.
  phenotype_term:
    preferred_term: Hypertonia
    term:
      id: HP:0001276
      label: Hypertonia
  evidence:
  - reference: PMID:33129689
    reference_title: "Expanding the clinical and metabolic phenotype of DPM2 deficient congenital disorders of glycosylation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We identified biallelic DPM2 variants in a 23-year-old male with truncal
      hypotonia, hypertonicity, congenital heart defects, intellectual
      disability, and generalized muscle wasting.
    explanation: >-
      Documents hypertonicity alongside truncal hypotonia.
  - reference: PMID:37152991
    reference_title: "Identification and characterization of a new variation in DPM2 gene in two Chinese siblings with mild intellectual impairment."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The patient was admitted to the Rehabilitation Department in Wuhan
      Children's Hospital due to developmental delay, mild intellectual
      disability, hypertonia, and strabismus at 11 years old.
    explanation: >-
      Hypertonia in the younger sibling at presentation.
- category: Musculoskeletal
  name: Skeletal Muscle Atrophy
  description: >-
    Generalized muscle wasting, documented in the adult patient and as
    progressive muscle weakness and wasting in the severe cohort.
  phenotype_term:
    preferred_term: Skeletal muscle atrophy
    term:
      id: HP:0003202
      label: Skeletal muscle atrophy
  evidence:
  - reference: PMID:33129689
    reference_title: "Expanding the clinical and metabolic phenotype of DPM2 deficient congenital disorders of glycosylation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We identified biallelic DPM2 variants in a 23-year-old male with truncal
      hypotonia, hypertonicity, congenital heart defects, intellectual
      disability, and generalized muscle wasting.
    explanation: >-
      Generalized muscle wasting in the adult DPM2-CDG patient.
- category: Musculoskeletal
  name: Achilles Tendon Contracture
  description: >-
    Progressive equinus/tiptoe gait requiring Achilles tendon lengthening surgery
    in the younger Chinese sibling.
  phenotype_term:
    preferred_term: Achilles tendon contracture
    term:
      id: HP:0001771
      label: Achilles tendon contracture
  evidence:
  - reference: PMID:37152991
    reference_title: "Identification and characterization of a new variation in DPM2 gene in two Chinese siblings with mild intellectual impairment."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      She had undergone Achilles tendon lengthening procedure.
    explanation: >-
      Documents the contracture requiring orthopedic surgical correction.
- category: Laboratory
  name: Elevated Serum Creatine Kinase
  description: >-
    HyperCKemia is a consistent finding across the whole phenotypic spectrum,
    reflecting the dystroglycanopathy component. Values around 2000 U/L
    (reference 20-250 U/L) were recorded in the mildly affected siblings.
  phenotype_term:
    preferred_term: Elevated circulating creatine kinase concentration
    term:
      id: HP:0003236
      label: Elevated circulating creatine kinase concentration
  frequency: VERY_FREQUENT
  diagnostic: true
  evidence:
  - reference: PMID:23109149
    reference_title: "DPM2-CDG: a muscular dystrophy-dystroglycanopathy syndrome with severe epilepsy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We searched for the primary defect in 3 children from 2 families with a
      severe neurological phenotype, including profound developmental delay,
      intractable epilepsy, progressive microcephaly, severe hypotonia with
      elevated blood creatine kinase levels, and early fatal outcome.
    explanation: >-
      Elevated CK in all three severe-form patients.
  - reference: PMID:37152991
    reference_title: "Identification and characterization of a new variation in DPM2 gene in two Chinese siblings with mild intellectual impairment."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Whole-exome sequencing (WES) was performed in a Chinese family having two
      siblings with a mild form of DPM2-CDG with developmental delay, mild
      intellectual disability, hypotonia, and increased serum creatine kinase.
    explanation: >-
      Elevated CK also in the two mildly affected siblings; with elevated CK
      reported in all six published patients this supports the VERY_FREQUENT band.
- category: Cardiovascular
  name: Bicuspid Aortic Valve
  description: >-
    The congenital heart defect reported in the adult (fourth) DPM2-CDG patient
    was a bicuspid aortic valve, explicitly noted as a phenotypic expansion not
    previously described in this disorder; cardiac involvement is well
    documented in the allelic DPM3-CDG.
  phenotype_term:
    preferred_term: Bicuspid aortic valve
    term:
      id: HP:0001647
      label: Bicuspid aortic valve
  evidence:
  - reference: PMID:33129689
    reference_title: "Expanding the clinical and metabolic phenotype of DPM2 deficient congenital disorders of glycosylation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The patient is a 23-year-old male with truncal hypotonia, lower extremity
      hypertonicity, bicuspid aortic valve, aortic stenosis, intellectual
      disability, and generalized muscle wasting
    explanation: >-
      Names the specific valvular lesion in the single DPM2-CDG patient with
      cardiac involvement.
  - reference: PMID:33129689
    reference_title: "Expanding the clinical and metabolic phenotype of DPM2 deficient congenital disorders of glycosylation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Additionally, he has congenital heart defects, which were previously not
      described in DPM2-CDG.
    explanation: >-
      Explicitly reports congenital heart defects as a newly recognized DPM2-CDG
      feature.
- category: Cardiovascular
  name: Aortic Valve Stenosis
  description: >-
    Aortic stenosis accompanied the bicuspid aortic valve in the adult DPM2-CDG
    patient - the expected haemodynamic consequence of the bicuspid valve rather
    than an independent lesion.
  phenotype_term:
    preferred_term: Aortic valve stenosis
    term:
      id: HP:0001650
      label: Aortic valve stenosis
  evidence:
  - reference: PMID:33129689
    reference_title: "Expanding the clinical and metabolic phenotype of DPM2 deficient congenital disorders of glycosylation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The patient is a 23-year-old male with truncal hypotonia, lower extremity
      hypertonicity, bicuspid aortic valve, aortic stenosis, intellectual
      disability, and generalized muscle wasting
    explanation: >-
      Reports aortic stenosis alongside the bicuspid valve in the same patient.
- category: Hepatic
  name: Liver Involvement
  description: >-
    Liver involvement was documented in the three severe-form patients. Liver
    function was normal in the mildly affected siblings, so this appears
    restricted to the severe end of the spectrum.
  phenotype_term:
    preferred_term: Abnormality of the liver
    term:
      id: HP:0001392
      label: Abnormality of the liver
  evidence:
  - reference: PMID:33129689
    reference_title: "Expanding the clinical and metabolic phenotype of DPM2 deficient congenital disorders of glycosylation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      All three patients included in the report had a severe clinical
      presentation characterized by hypotonia, progressive muscle weakness and
      wasting, absent psychomotor development, intractable seizures, liver
      involvement, abnormal coagulation factors and early mortality (between 7
      months and 3 years of age).
    explanation: >-
      Liver involvement in the severe cohort.
- category: Hepatic
  name: Hepatomegaly
  description: >-
    The liver involvement of the severe form is specified as hepatomegaly in the
    one severe-form patient (P3) for whom the hepatobiliary phenotype was
    itemized; it was not assessed in the two siblings who died earliest and was
    absent in the mildly affected patients.
  phenotype_term:
    preferred_term: Hepatomegaly
    term:
      id: HP:0002240
      label: Hepatomegaly
  evidence:
  - reference: PMID:37152991
    reference_title: "Identification and characterization of a new variation in DPM2 gene in two Chinese siblings with mild intellectual impairment."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Hepatomegaly and elevation of serum transaminases
    explanation: >-
      The Table 1 hepatobiliary row for patient P3 resolves the generic "liver
      involvement" of the severe cohort into hepatomegaly. No frequency band is
      assigned: the finding is recorded for one of six patients and is NA for
      two others, so the denominator is not interpretable.
- category: Laboratory
  name: Elevated Serum Transaminases
  description: >-
    Elevation of serum transaminases accompanied the hepatomegaly in the severe
    form, indicating hepatocellular involvement rather than isolated
    organomegaly.
  phenotype_term:
    preferred_term: Elevated circulating hepatic transaminase concentration
    term:
      id: HP:0002910
      label: Elevated circulating hepatic transaminase concentration
  evidence:
  - reference: PMID:37152991
    reference_title: "Identification and characterization of a new variation in DPM2 gene in two Chinese siblings with mild intellectual impairment."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Hepatomegaly and elevation of serum transaminases
    explanation: >-
      Same Table 1 hepatobiliary row; recorded separately because the
      biochemical abnormality and the organomegaly are distinct findings. No
      frequency band is assigned, for the denominator reason given above.
- category: Hematologic
  name: Coagulation Abnormality
  description: >-
    Abnormal coagulation factors were reported in the severe cohort — a recurrent
    CDG feature attributable to hypoglycosylation of coagulation glycoproteins.
  phenotype_term:
    preferred_term: Abnormality of coagulation
    term:
      id: HP:0001928
      label: Abnormality of coagulation
  evidence:
  - reference: PMID:33129689
    reference_title: "Expanding the clinical and metabolic phenotype of DPM2 deficient congenital disorders of glycosylation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      All three patients included in the report had a severe clinical
      presentation characterized by hypotonia, progressive muscle weakness and
      wasting, absent psychomotor development, intractable seizures, liver
      involvement, abnormal coagulation factors and early mortality (between 7
      months and 3 years of age).
    explanation: >-
      Abnormal coagulation factors in the severe cohort.
- category: Gastrointestinal
  name: Feeding Difficulties
  description: >-
    Feeding difficulties affected the three severely affected Italian patients
    (P3, P4, P5) and neither Chinese sibling nor the Indian patient, giving 3/6
    in Table 1. Like the other severe-end features, this tracks disease severity
    rather than being a constant feature of DPM2-CDG.
  phenotype_term:
    preferred_term: Feeding difficulties
    term:
      id: HP:0011968
      label: Feeding difficulties
  evidence:
  - reference: PMID:37152991
    reference_title: "Identification and characterization of a new variation in DPM2 gene in two Chinese siblings with mild intellectual impairment."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Feeding dif ficulties No No Yes Yes Yes No
    explanation: >-
      Table 1 feeding-difficulties row: No/No for the two Chinese siblings,
      Yes for P3-P5, No for P6. The ligature in the source row is reproduced
      verbatim rather than retyped.
- category: Ophthalmologic
  name: Strabismus
  description: >-
    Strabismus was present in both Chinese siblings and remained uncorrected in
    the younger sibling.
  phenotype_term:
    preferred_term: Strabismus
    term:
      id: HP:0000486
      label: Strabismus
  evidence:
  - reference: PMID:37152991
    reference_title: "Identification and characterization of a new variation in DPM2 gene in two Chinese siblings with mild intellectual impairment."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      She had no obvious facial abnormalities other than strabismus which had not
      been corrected by surgery so far.
    explanation: >-
      Documents strabismus in the younger sibling.
- category: Ophthalmologic
  name: Optic Atrophy
  description: >-
    Optic atrophy was recorded in one of the three severely affected Italian
    patients (P3) in the Table 1 ophthalmological row. It is not reported in the
    two mildly affected Chinese siblings, so it segregates with the severe end of
    the spectrum rather than being a constant feature.
  phenotype_term:
    preferred_term: Optic atrophy
    term:
      id: HP:0000648
      label: Optic atrophy
  evidence:
  - reference: PMID:37152991
    reference_title: "Identification and characterization of a new variation in DPM2 gene in two Chinese siblings with mild intellectual impairment."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Ophthalmological Strabismus No Optic atrophy No visual tracking and
      strabismus
    explanation: >-
      Table 1 ophthalmological row; the third column (P3) records optic atrophy.
      No frequency band is asserted because the row leaves P6 blank, so the
      denominator is not interpretable.
- category: Ophthalmologic
  name: Absent Visual Tracking
  description: >-
    Two of the three severely affected Italian patients (P4, P5) failed to track
    visually.
  phenotype_term:
    preferred_term: Absent visual tracking
    term:
      id: HP:0007179
      label: Absent smooth pursuit
  evidence:
  - reference: PMID:37152991
    reference_title: "Identification and characterization of a new variation in DPM2 gene in two Chinese siblings with mild intellectual impairment."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Ophthalmological Strabismus No Optic atrophy No visual tracking and
      strabismus No visual tracking
    explanation: >-
      Table 1 ophthalmological row; the P4 and P5 columns both record no visual
      tracking. No frequency band is asserted for the same reason as the optic
      atrophy item.
- category: Neurologic
  name: Peripheral Neuropathy
  description: >-
    Nerve conduction studies in the younger Chinese sibling showed slowed motor
    conduction velocity, prolonged motor latency and reduced amplitude, with
    absent sensory nerve action potentials, indicating multiple peripheral nerve
    injury with both axonal and demyelinating features.
  phenotype_term:
    preferred_term: Peripheral neuropathy
    term:
      id: HP:0009830
      label: Peripheral neuropathy
  evidence:
  - reference: PMID:37152991
    reference_title: "Identification and characterization of a new variation in DPM2 gene in two Chinese siblings with mild intellectual impairment."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Electrophysiological evaluation showed slowed motor conduction velocity,
      longer motor latency, and decreased amplitude on the left median and ulnar
      nerves, but no sensory nerve action potential was detected in the median,
      ulnar, and sural nerves in the right lower limb, suggesting multiple
      peripheral nerve injury
    explanation: >-
      Direct nerve conduction evidence of peripheral neuropathy in a DPM2-CDG
      patient.
- category: Neurologic
  name: Cerebral White Matter Abnormality
  description: >-
    Brain MRI in the younger Chinese sibling showed bilateral parietal
    white-matter signal abnormality interpreted as demyelinating lesions.
  phenotype_term:
    preferred_term: Abnormal cerebral white matter morphology
    term:
      id: HP:0002500
      label: Abnormal cerebral white matter morphology
  evidence:
  - reference: PMID:37152991
    reference_title: "Identification and characterization of a new variation in DPM2 gene in two Chinese siblings with mild intellectual impairment."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      sequence in the white matter of bilateral parietal lobes, an indication of
      demyelinating lesions
    explanation: >-
      MRI evidence of bilateral parietal white matter demyelinating change.
- category: Immunologic
  name: Recurrent Infections
  description: >-
    Both Chinese siblings had recurrent infections during the preschool years.
    Acute respiratory infection also contributed to death in the severe cohort.
    Recurrent infection is a recognized consequence of immune-glycoprotein
    hypoglycosylation across the CDG.
  phenotype_term:
    preferred_term: Recurrent infections
    term:
      id: HP:0002719
      label: Recurrent infections
    temporality: RECURRENT
  evidence:
  - reference: PMID:37152991
    reference_title: "Identification and characterization of a new variation in DPM2 gene in two Chinese siblings with mild intellectual impairment."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      In addition, she had recurrent infections at the age of preschool.
    explanation: >-
      Documents recurrent preschool infections in an affected sibling.
- category: Musculoskeletal
  name: Exercise Intolerance
  description: >-
    Exercise intolerance was reported in the elder Chinese sibling, consistent
    with the underlying myopathy.
  phenotype_term:
    preferred_term: Exercise intolerance
    term:
      id: HP:0003546
      label: Exercise intolerance
  evidence:
  - reference: PMID:37152991
    reference_title: "Identification and characterization of a new variation in DPM2 gene in two Chinese siblings with mild intellectual impairment."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      She had mild intellectual disability and exercise intolerance.
    explanation: >-
      Exercise intolerance in the elder sibling.
- category: Neurologic
  name: Motor Delay
  description: >-
    Motor milestones were delayed in the mildly affected siblings — head control
    at 4 months, turning over at 7 months, unassisted walking at 3 years — and
    language development was also considerably delayed.
  phenotype_term:
    preferred_term: Motor delay
    term:
      id: HP:0001270
      label: Motor delay
  evidence:
  - reference: PMID:37152991
    reference_title: "Identification and characterization of a new variation in DPM2 gene in two Chinese siblings with mild intellectual impairment."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      She showed delayed motor milestones with head control at 4 months, turning
      over at 7 months, and unassisted walking at 3 years old.
    explanation: >-
      Documents the specific delayed motor milestones in the younger sibling.
- category: Neurologic
  name: Delayed Speech and Language Development
  description: >-
    Language development was considerably delayed in the mildly affected siblings,
    with first words at 4 years, persistently poor expressive vocabulary and mild
    dysarthria.
  phenotype_term:
    preferred_term: Delayed speech and language development
    term:
      id: HP:0000750
      label: Delayed speech and language development
  evidence:
  - reference: PMID:37152991
    reference_title: "Identification and characterization of a new variation in DPM2 gene in two Chinese siblings with mild intellectual impairment."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Language development was also considerably delayed
    explanation: >-
      Documents delayed language milestones in the younger sibling.
- category: Craniofacial
  name: Dysmorphic Features
  description: >-
    Dysmorphic features are present across both ends of the DPM2-CDG severity
    spectrum - in the two mildly affected Chinese siblings and in the three
    severe-form Italian patients - and are recorded in 5 of the 6 patients
    reported to date. The single exception is the adult (fourth-reported)
    patient, in whom facial dysmorphism was explicitly looked for and not
    found, so this is a frequent but not obligate feature. The published
    reports do not itemize the individual facial features, so no more specific
    HPO term than the parent can be justified.
  phenotype_term:
    preferred_term: Abnormal facial shape
    term:
      id: HP:0001999
      label: Abnormal facial shape
  frequency: VERY_FREQUENT
  evidence:
  - reference: PMID:37152991
    reference_title: "Identification and characterization of a new variation in DPM2 gene in two Chinese siblings with mild intellectual impairment."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      In this study, we reported two siblings from a Chinese family with
      dysmorphic features, developmental delay, mild intellectual disability,
      hypotonia, strabismus, and increased serum creatine kinase.
    explanation: >-
      Narrative statement that both mildly affected siblings had dysmorphic
      features.
  - reference: PMID:37152991
    reference_title: "Identification and characterization of a new variation in DPM2 gene in two Chinese siblings with mild intellectual impairment."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Dysmorphic features Yes Yes Yes Yes Yes No
    explanation: >-
      Table 1 records dysmorphic features in 5 of the 6 published DPM2-CDG
      patients (83%), which is the basis for the VERY_FREQUENT band (80-99%).
  - reference: PMID:33129689
    reference_title: "Expanding the clinical and metabolic phenotype of DPM2 deficient congenital disorders of glycosylation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      No dysmorphic facial features were observed.
    explanation: >-
      The sixth patient is the documented exception; recorded as PARTIAL so the
      entry does not overstate dysmorphism as universal.
- category: Musculoskeletal
  name: Congenital Joint Contractures
  description: >-
    Two of the three severe-form patients had congenital contractures of the
    joints, a presenting arthrogryposis-like feature distinct from the acquired
    Achilles tendon contracture seen later in the mildly affected sibling.
  phenotype_term:
    preferred_term: Congenital contracture
    term:
      id: HP:0002803
      label: Congenital contracture
  evidence:
  - reference: PMID:37152991
    reference_title: "Identification and characterization of a new variation in DPM2 gene in two Chinese siblings with mild intellectual impairment."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Congenital contractures of the joints and scoliosis
    explanation: >-
      Table 1 skeletal row for the two severe-form patients (P4, P5).
- category: Musculoskeletal
  name: Scoliosis
  description: >-
    Scoliosis accompanied the congenital joint contractures in the same two
    severe-form patients, consistent with the axial weakness of the
    dystroglycanopathy component.
  phenotype_term:
    preferred_term: Scoliosis
    term:
      id: HP:0002650
      label: Scoliosis
  evidence:
  - reference: PMID:37152991
    reference_title: "Identification and characterization of a new variation in DPM2 gene in two Chinese siblings with mild intellectual impairment."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Congenital contractures of the joints and scoliosis
    explanation: >-
      Same Table 1 skeletal row; curated as a separate phenotype because
      scoliosis and joint contracture are distinct findings.
- category: Neurologic
  name: Cerebellar Vermis Hypoplasia
  description: >-
    Brain MRI in one severe-form patient showed cerebellar hypoplasia with
    severe vermis hypoplasia. This is a distinct imaging phenotype from the
    supratentorial white-matter loss described in the other severe patient and
    from the parietal white-matter signal abnormality in the mild siblings, and
    is a recognized posterior-fossa signature of the dystroglycanopathies.
  phenotype_term:
    preferred_term: Cerebellar vermis hypoplasia
    term:
      id: HP:0001320
      label: Cerebellar vermis hypoplasia
  evidence:
  - reference: PMID:37152991
    reference_title: "Identification and characterization of a new variation in DPM2 gene in two Chinese siblings with mild intellectual impairment."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Mild cerebellar hypoplasia with severe vermis hypoplasia
    explanation: >-
      Table 1 brain-MRI row for patient P5.
progression:
- phase: Severe infantile-lethal course
  age_range: Birth to 3 years
  notes: >-
    The severe, first-domain-variant form presents at birth and is fatal between
    7 months and 3 years of age, with death attributed to severe epilepsy,
    muscular dystrophy and acute respiratory infections.
  evidence:
  - reference: PMID:33129689
    reference_title: "Expanding the clinical and metabolic phenotype of DPM2 deficient congenital disorders of glycosylation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      All three patients included in the report had a severe clinical
      presentation characterized by hypotonia, progressive muscle weakness and
      wasting, absent psychomotor development, intractable seizures, liver
      involvement, abnormal coagulation factors and early mortality (between 7
      months and 3 years of age).
    explanation: >-
      Documents the age range of early mortality in the severe form.
  - reference: PMID:37152991
    reference_title: "Identification and characterization of a new variation in DPM2 gene in two Chinese siblings with mild intellectual impairment."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Until now, only four cases from three families have been reported, and three
      of them with the variant c.68A>G (p.Tyr23Cys) died before 3 years old due to
      severe epilepsy, muscular dystrophy, and acute respiratory infections
    explanation: >-
      States the causes and timing of death in the severe genotype.
- phase: Mild adult-viable course
  age_range: Childhood into the third decade
  notes: >-
    The milder form presents in early childhood with developmental delay and is
    compatible with survival into adulthood; reported patients were alive at 11,
    20 and 23 years with stable intellectual disability, myopathy and hyperCKemia.
  evidence:
  - reference: PMID:33129689
    reference_title: "Expanding the clinical and metabolic phenotype of DPM2 deficient congenital disorders of glycosylation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      His clinical presentation was much less severe than that of the three
      previously described patients.
    explanation: >-
      Establishes the milder, adult-viable end of the natural-history spectrum.
biochemical:
- name: Transferrin Isoelectric Focusing Type I Pattern
  notes: >-
    Serum transferrin isoelectric focusing shows a type I CDG pattern (cathodic
    shift from whole missing N-glycans), the classic first-line CDG screening
    test. In DPM2-CDG the abnormality can be subtle: it was described as only
    mildly abnormal in the adult patient.
  presence: PRESENT
  evidence:
  - reference: PMID:23109149
    reference_title: "DPM2-CDG: a muscular dystrophy-dystroglycanopathy syndrome with severe epilepsy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Metabolic investigations revealed CDG-I, pointing to a defect in protein
      N-glycosylation in the endoplasmic reticulum.
    explanation: >-
      Establishes the CDG type I biochemical pattern in DPM2-CDG.
  - reference: PMID:33129689
    reference_title: "Expanding the clinical and metabolic phenotype of DPM2 deficient congenital disorders of glycosylation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Laboratory studies which included POLG sequencing and whole genome
      microarray analysis were normal while serum transferrin isoelectric focusing
      (TIEF) was mildly abnormal (Figure 3).
    explanation: >-
      Shows the transferrin abnormality can be mild, an important caveat for using
      it as a screening test in the milder phenotype.
- name: Lipid-Linked Oligosaccharide Accumulation
  notes: >-
    Analysis of lipid-linked oligosaccharides in patient fibroblasts shows
    accumulation of the truncated intermediate Dol-PP-GlcNAc2-Man5, the species
    expected when the block lies at the first Dol-P-Man-dependent
    mannosyltransferase step of assembly. This is the biochemical signature that
    localizes the defect to the DPM pathway.
  presence: PRESENT
  cell_types:
  - preferred_term: Fibroblast
    term:
      id: CL:0000057
      label: fibroblast
  evidence:
  - reference: PMID:23109149
    reference_title: "DPM2-CDG: a muscular dystrophy-dystroglycanopathy syndrome with severe epilepsy."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Analysis of lipid-linked oligosaccharides in fibroblasts showed accumulation
      of Dol-PP-GlcNAc(2)
    explanation: >-
      The truncated species accumulating in patient fibroblasts is the diagnostic
      biochemical fingerprint of the Dol-P-Man-dependent block.
- name: Reduced ICAM1 as Hypoglycosylation Reporter
  notes: >-
    ICAM1 was used as a general cellular hypoglycosylation readout. Expression of
    the p.Gly66Glu DPM2 allele produced a significant decrease in ICAM1,
    confirming abnormal N-linked glycosylation despite increased DPM2 protein
    levels for this allele.
  presence: PRESENT
  evidence:
  - reference: PMID:37152991
    reference_title: "Identification and characterization of a new variation in DPM2 gene in two Chinese siblings with mild intellectual impairment."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      In vitro functional analysis demonstrated that this variant increased the
      expression level of DPM2 protein and western blot revealed a significant
      decrease in ICAM1, a universal biomarker for hypoglycosylation in patients
      with CDG, suggesting abnormal N-linked glycosylation.
    explanation: >-
      ICAM1 reduction functions as the hypoglycosylation readout for this variant.
genetic:
- name: DPM2
  gene_term:
    preferred_term: DPM2
    term:
      id: hgnc:3006
      label: DPM2
  relationship_type: CAUSATIVE
  variant_origin: GERMLINE
  presence: PRESENT
  frequency: All reported patients (biallelic in every case)
  notes: >-
    DPM2 (9q34.11) encodes the 84-amino-acid, two-transmembrane regulatory
    subunit of DPM synthase. Reported pathogenic alleles are missense
    (p.Tyr23Cys, p.Gly58Asp, p.Gly66Glu), nonsense (p.Arg47Ter) and a canonical
    splice-acceptor variant (c.4-1G>C), all germline and biallelic. Variant
    position appears to track with severity: alleles in the region encoding the
    first domain associate with the severe, early-lethal phenotype, while
    second-domain alleles associate with the milder phenotype — a correlation the
    reporting authors themselves flag as needing more data.
  evidence:
  - reference: PMID:23109149
    reference_title: "DPM2-CDG: a muscular dystrophy-dystroglycanopathy syndrome with severe epilepsy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      DNA analysis revealed mutations in DPM2, 1 of the subunits of the
      dolichol-phosphate-mannose (DPM) synthase; the patient in the first family
      is compound heterozygous for 2 mutations (c.68A>G, predicting a missense
      mutation p.Y23C and c.4-1G>C, a splice mutation), whereas the patients in
      the second family are homozygous for the same missense mutation (c.68A>G,
      p.Y23C).
    explanation: >-
      Identifies DPM2 as the causal gene and lists the founding pathogenic
      alleles.
  - reference: PMID:37152991
    reference_title: "Identification and characterization of a new variation in DPM2 gene in two Chinese siblings with mild intellectual impairment."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We also reviewed the 4 previously reported patients carrying homozygous or
      compound heterozygous variants of DMP2 gene, and found that patients with
      variants within the region encoding the first domain had more severe
      clinical symptoms than those with variants within the second domain.
    explanation: >-
      Reports the domain-position genotype-severity correlation; PARTIAL because
      the same paper states the relationship needs more study and it rests on only
      six patients.
  variants:
  - name: "NM_003863.4:c.68A>G (p.Tyr23Cys)"
    description: >-
      Recurrent missense allele in the first transmembrane region, found
      homozygously in one Italian family and in compound heterozygosity with the
      c.4-1G>C splice allele in another. Associated with the severe,
      infantile-lethal phenotype.
    type: MISSENSE_VARIANT
    clinical_significance: PATHOGENIC
    gene:
      preferred_term: DPM2
      term:
        id: hgnc:3006
        label: DPM2
    evidence:
    - reference: PMID:23109149
      reference_title: "DPM2-CDG: a muscular dystrophy-dystroglycanopathy syndrome with severe epilepsy."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        whereas the patients in the second family are homozygous for the same
        missense mutation (c.68A>G, p.Y23C).
      explanation: >-
        Documents homozygosity for the recurrent p.Tyr23Cys allele.
  - name: "NM_003863.4:c.4-1G>C"
    description: >-
      Canonical splice-acceptor variant found in compound heterozygosity with
      p.Tyr23Cys in the first reported family.
    type: SPLICE_SITE_VARIANT
    clinical_significance: PATHOGENIC
    gene:
      preferred_term: DPM2
      term:
        id: hgnc:3006
        label: DPM2
    evidence:
    - reference: PMID:23109149
      reference_title: "DPM2-CDG: a muscular dystrophy-dystroglycanopathy syndrome with severe epilepsy."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        the patient in the first family is compound heterozygous for 2 mutations
        (c.68A>G, predicting a missense mutation p.Y23C and c.4-1G>C, a splice
        mutation)
      explanation: >-
        Documents the splice-acceptor allele in trans with p.Tyr23Cys.
  - name: "NM_003863.4:c.197G>A (p.Gly66Glu)"
    description: >-
      Homozygous missense allele in the second domain region, found in two Chinese
      siblings with the mild phenotype. Functional testing showed increased DPM2
      protein but reduced ICAM1 glycosylation, indicating impaired function rather
      than reduced abundance.
    type: MISSENSE_VARIANT
    clinical_significance: PATHOGENIC
    gene:
      preferred_term: DPM2
      term:
        id: hgnc:3006
        label: DPM2
    evidence:
    - reference: PMID:37152991
      reference_title: "Identification and characterization of a new variation in DPM2 gene in two Chinese siblings with mild intellectual impairment."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        A homozygous mutation, c.197G>A (p.Gly66Glu) in exon 4 of DPM2 (NM_003863)
        was identified by whole exome sequencing (WES).
      explanation: >-
        Identifies the mild-phenotype allele and its zygosity.
  - name: "NM_003863.4:c.139C>T (p.Arg47Ter)"
    description: >-
      Nonsense allele carried in trans with p.Gly58Asp in the adult
      (fourth-reported) patient. Neither allele had been reported previously;
      patient fibroblasts showed DPM2 expression at about 60% of control with no
      quantifiable DPM1 protein, so the pair behaves as a hypomorphic rather
      than a complete-null genotype - consistent with that patient's
      milder-than-infantile course.
    type: NONSENSE_VARIANT
    clinical_significance: PATHOGENIC
    gene:
      preferred_term: DPM2
      term:
        id: hgnc:3006
        label: DPM2
    evidence:
    - reference: PMID:33129689
      reference_title: "Expanding the clinical and metabolic phenotype of DPM2 deficient congenital disorders of glycosylation."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Whole exome sequencing (WES) identified two heterozygous alterations in
        the DPM2 gene (c.139C>T, p.Arg47*; c.173G>A, p.Gly58Asp) which were
        confirmed to be in trans by parental studies
      explanation: >-
        Identifies the nonsense allele and establishes the trans configuration by
        parental testing.
  - name: "NM_003863.4:c.173G>A (p.Gly58Asp)"
    description: >-
      Missense allele in trans with the p.Arg47Ter nonsense allele in the adult
      (fourth-reported) patient, predicted deleterious by multiple in-silico
      algorithms.
    type: MISSENSE_VARIANT
    clinical_significance: PATHOGENIC
    gene:
      preferred_term: DPM2
      term:
        id: hgnc:3006
        label: DPM2
    evidence:
    - reference: PMID:33129689
      reference_title: "Expanding the clinical and metabolic phenotype of DPM2 deficient congenital disorders of glycosylation."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        The p.Gly58Asp missense change is predicted to be deleterious by
        multiple algorithms (Mutation Taster, LRT, PolyPhen2, and SIFT).
      explanation: >-
        Documents the missense allele and its computational pathogenicity
        support.
prevalence:
- population: Worldwide (published case reports)
  measure_type: CASES_IN_LITERATURE
  prevalence_class: ULTRA_RARE
  notes: >-
    Six patients from four families had been reported by 2023 — three severe-form
    patients from two Italian families (2012), one adult male (2021), and two
    Chinese siblings (2023). No population prevalence or incidence rate has been
    established.
  evidence:
  - reference: PMID:37152991
    reference_title: "Identification and characterization of a new variation in DPM2 gene in two Chinese siblings with mild intellectual impairment."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      DPM2 is one subunit of a heterotrimeric complex for dolichol-phosphatemannose
      synthase (DPMS), a key enzyme in glycosylation, and only four patients with
      DPM2-CDG have been reported.
    explanation: >-
      Confirms that only four patients were on record before this report added two
      more, establishing ultra-rare status.
diagnosis:
- name: DPM2 Molecular Genetic Testing
  description: >-
    Definitive diagnosis requires demonstration of biallelic DPM2 variants.
    Because the phenotype overlaps both the CDG and the dystroglycanopathies,
    exome sequencing or a combined CDG/dystroglycanopathy gene panel is the
    practical first-tier test; in the reported patients after the index family the
    diagnosis was made by whole exome sequencing.
  presence: PRESENT
  evidence:
  - reference: PMID:37152991
    reference_title: "Identification and characterization of a new variation in DPM2 gene in two Chinese siblings with mild intellectual impairment."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      A homozygous mutation, c.197G>A (p.Gly66Glu) in exon 4 of DPM2 (NM_003863)
      was identified by whole exome sequencing (WES).
    explanation: >-
      Exome sequencing established the molecular diagnosis in this family.
- name: Serum Transferrin Isoelectric Focusing Screening
  description: >-
    Transferrin isoelectric focusing (or capillary zone electrophoresis) is the
    recommended first-line screening test in early-onset epilepsy of unknown
    cause, which is the presentation route for the severe DPM2-CDG phenotype. A
    type I pattern directs testing toward the ER N-glycosylation disorders.
  presence: PRESENT
  evidence:
  - reference: PMID:26453362
    reference_title: "Electroclinical Features of Early-Onset Epileptic Encephalopathies in Congenital Disorders of Glycosylation (CDGs)."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We propose a diagnostic flowchart for the early diagnosis of CDG in patients
      presenting with EOEE and suggest to perform serum transferrin IEF (or
      capillary zone electrophoresis) as a first-line screening in early-onset
      epilepsy.
    explanation: >-
      Establishes transferrin isoelectric focusing as the recommended screening
      test for the clinical presentation in which DPM2-CDG is found.
- name: Muscle Biopsy Alpha-Dystroglycan Immunohistochemistry
  description: >-
    Muscle biopsy immunohistochemistry showing deficient alpha-dystroglycan
    O-mannosylation confirms the dystroglycanopathy component and, combined with a
    CDG type I transferrin pattern, points specifically at the DPM synthase
    complex rather than at an isolated dystroglycanopathy gene.
  presence: PRESENT
  evidence:
  - reference: PMID:23109149
    reference_title: "DPM2-CDG: a muscular dystrophy-dystroglycanopathy syndrome with severe epilepsy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      There was clinical evidence of a muscular dystrophy-dystroglycanopathy
      syndrome, supported by deficient O-mannosylation by muscle
      immunohistochemistry.
    explanation: >-
      Muscle immunohistochemistry provided the tissue-level confirmation in the
      index patients.
treatments:
- name: Supportive and Multidisciplinary Care
  description: >-
    No disease-modifying therapy exists for DPM2-CDG. Unlike PMM2-CDG or MPI-CDG,
    the lesion is in Dol-P-Man synthesis itself rather than in substrate
    availability, so simple mannose supplementation would not be expected to
    bypass the block and none has been reported. Management is symptom-directed
    and multidisciplinary: seizure control, orthopedic and rehabilitative care,
    cardiac surveillance, and nutritional support.
  action_category: THERAPEUTIC
  therapeutic_modality: OTHER
  treatment_term:
    preferred_term: Supportive Care
    term:
      id: NCIT:C15747
      label: Supportive Care
  evidence:
  - reference: PMID:40902550
    reference_title: "Genetic disorders of dolichol synthesis and utilization."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Finally, we discuss the existing biomarkers for diagnosis of these disorders
      and the potential for effective therapies.
    explanation: >-
      The most recent review of dolichol-pathway CDG frames effective therapy as a
      prospect rather than an established option; PARTIAL because it does not name
      DPM2-CDG management specifically.
  notes: >-
    No DPM2-CDG-specific clinical trial or targeted therapy was identified in the
    literature or on ClinicalTrials.gov.
- name: Antiseizure Pharmacotherapy
  description: >-
    Seizures in the severe form are intractable. In the pooled CDG early-onset
    epileptic encephalopathy series that included DPM2-CDG patients, seizures
    became recurrent and drug-resistant despite antiepileptic treatment.
  action_category: THERAPEUTIC
  therapeutic_modality: SMALL_MOLECULE
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
  target_phenotypes:
  - preferred_term: Seizure
    term:
      id: HP:0001250
      label: Seizure
  evidence:
  - reference: PMID:26453362
    reference_title: "Electroclinical Features of Early-Onset Epileptic Encephalopathies in Congenital Disorders of Glycosylation (CDGs)."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      With time, patients developed recurrent and intractable seizures principally
      tonic-clonic seizures, infantile spasms, and myoclonic seizures.
    explanation: >-
      Documents that seizures become intractable despite antiepileptic drug
      treatment in this CDG cohort; PARTIAL because specific agents and
      per-subtype response are not reported.
- name: Orthopedic Surgical Correction
  description: >-
    Achilles tendon lengthening was performed for equinus contracture in one
    patient, after which walking posture improved.
  action_category: THERAPEUTIC
  therapeutic_modality: SURGERY
  treatment_term:
    preferred_term: Orthopedic Surgical Procedure
    term:
      id: NCIT:C16186
      label: Orthopedic Surgical Procedure
  target_phenotypes:
  - preferred_term: Achilles tendon contracture
    term:
      id: HP:0001771
      label: Achilles tendon contracture
  evidence:
  - reference: PMID:37152991
    reference_title: "Identification and characterization of a new variation in DPM2 gene in two Chinese siblings with mild intellectual impairment."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      She had undergone Achilles tendon lengthening procedure. Now her walking
      posture improved, but she still needed the help of hands to get up or down
      stairs.
    explanation: >-
      Documents the intervention and its partial functional benefit.
- name: Rehabilitation and Physical Therapy
  description: >-
    Affected children present to rehabilitation services for motor delay,
    abnormal tone and gait abnormality; physical therapy is a mainstay of
    supportive management.
  action_category: THERAPEUTIC
  therapeutic_modality: BEHAVIORAL
  treatment_term:
    preferred_term: Physical Therapy
    term:
      id: NCIT:C15302
      label: Physical Therapy
  evidence:
  - reference: PMID:37152991
    reference_title: "Identification and characterization of a new variation in DPM2 gene in two Chinese siblings with mild intellectual impairment."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The patient was admitted to the Rehabilitation Department in Wuhan
      Children's Hospital due to developmental delay, mild intellectual
      disability, hypertonia, and strabismus at 11 years old.
    explanation: >-
      Documents rehabilitation-service management of the motor phenotype; PARTIAL
      because the specific therapy protocol and its outcome are not reported.
- name: Genetic Counseling
  description: >-
    Autosomal recessive inheritance carries a 25% recurrence risk per pregnancy
    for carrier couples. Once the familial DPM2 alleles are known, carrier testing
    and prenatal or preimplantation diagnosis become available.
  action_category: COUNSELING_INFORMATIONAL
  therapeutic_modality: OTHER
  treatment_term:
    preferred_term: Genetic Counseling
    term:
      id: NCIT:C15240
      label: Genetic Counseling
  evidence:
  - reference: PMID:37152991
    reference_title: "Identification and characterization of a new variation in DPM2 gene in two Chinese siblings with mild intellectual impairment."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Sanger sequencing was used to validate the variants identified in the
      siblings and their parents.
    explanation: >-
      Parental variant confirmation is the step that enables carrier counseling
      and reproductive risk assessment; PARTIAL because counseling outcomes are
      not themselves reported.
differential_diagnoses:
- name: DPM1-congenital disorder of glycosylation
  description: >-
    The allelic-complex disorder caused by variants in the catalytic DPM synthase
    subunit. Shares the CDG type I transferrin pattern, elevated CK, hypotonia and
    seizures.
  distinguishing_features:
  - >-
    Same enzyme complex, different subunit — DPM1 is the catalytic rather than the
    regulatory subunit. Separation requires sequencing, since the biochemical
    phenotypes overlap.
  evidence:
  - reference: PMID:23109149
    reference_title: "DPM2-CDG: a muscular dystrophy-dystroglycanopathy syndrome with severe epilepsy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Hence, mutations have now been described in the genes for the 3 subunits of
      DPM: DPM1, DPM2, and DPM3
    explanation: >-
      Establishes the three-subunit allelic series that constitutes the primary
      differential.
- name: DPM3-congenital disorder of glycosylation
  description: >-
    Caused by variants in the DPM3 tethering subunit. Overlaps DPM2-CDG in
    combining a CDG type I pattern with alpha-dystroglycan hypo-O-mannosylation;
    often milder and more cardiac-predominant, with several adult-onset cases.
  distinguishing_features:
  - >-
    Cardiac involvement is prominent (reported in four of six DPM3 patients), and
    transferrin isoelectric focusing may be normal or only mildly abnormal.
    Molecular testing distinguishes the subunits.
  evidence:
  - reference: PMID:19576565
    reference_title: "Deficiency of Dol-P-Man synthase subunit DPM3 bridges the congenital disorders of glycosylation with the dystroglycanopathies."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      This mild Dol-P-Man biosynthesis defect due to DPM3 mutations is a cause for
      alpha-dystroglycanopathy, thereby bridging the congenital disorders of
      glycosylation with the dystroglycanopathies.
    explanation: >-
      DPM3-CDG shares the combined CDG/dystroglycanopathy signature that defines
      the differential with DPM2-CDG.
- name: MPDU1-congenital disorder of glycosylation
  description: >-
    Defect in the utilization, rather than the synthesis, of dolichol-linked
    mannose and glucose donors. Produces the same CDG-I-plus-dystroglycanopathy
    overlap space.
  distinguishing_features:
  - >-
    MPDU1 affects donor utilization downstream of Dol-P-Man synthesis, whereas
    DPM2 affects donor synthesis. Molecular testing distinguishes them.
  evidence:
  - reference: PMID:31741824
    reference_title: "A mutation in mannose-phosphate-dolichol utilization defect 1 reveals clinical symptoms of congenital disorders of glycosylation type I and dystroglycanopathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Mannose-phosphate-dolichol utilization defect 1 (MPDU1) plays a role in the
      utilization of DPM.
    explanation: >-
      Places MPDU1 in the same Dol-P-Man axis, immediately downstream of the DPM2
      lesion.
- name: Primary alpha-dystroglycanopathies
  description: >-
    Congenital muscular dystrophies caused by variants in the dedicated
    alpha-dystroglycan glycosylation genes (POMT1, POMT2, POMGNT1, LARGE, FKTN,
    FKRP, B3GALNT2 and others), spanning Walker-Warburg syndrome and
    muscle-eye-brain disease.
  distinguishing_features:
  - >-
    Primary dystroglycanopathies impair alpha-dystroglycan O-mannosylation without
    a generalized N-glycosylation defect, so serum transferrin isoelectric
    focusing is typically normal — the key discriminator from DPM2-CDG.
  evidence:
  - reference: PMID:28198708
    reference_title: "Dystroglycanopathies: About Numerous Genes Involved in Glycosylation of One Single Glycoprotein."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Dystroglycanopathies are neuromuscular disorders due to abnormal
      glycosylation of dystroglycan which is a cell-surface glycoprotein that acts
      as a receptor for extracellular matrix proteins containing laminin-G
      domains.
    explanation: >-
      Defines the primary dystroglycanopathy family that constitutes the
      muscular-dystrophy side of the differential.
  - reference: PMID:28198708
    reference_title: "Dystroglycanopathies: About Numerous Genes Involved in Glycosylation of One Single Glycoprotein."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Most genes code for glycosyltransferases (POMT1, POMT2, POMGNT1, LARGE,
      GTDC2, B4GAT1, B3GALNT2) although a minority does not (DPM1, DPM2, DPM3,
      DOLK, POMK, GMPPB).
    explanation: >-
      Places DPM2 explicitly within the dystroglycanopathy gene list while
      distinguishing it from the dedicated glycosyltransferases.
discussions:
- discussion_id: dpm2_gpi_anchor_arm_unproven
  kind: KNOWLEDGE_GAP
  status: OPEN
  prompt: >-
    Is GPI-anchor biosynthesis measurably impaired in DPM2-CDG patient cells, or
    is this arm purely an inference from DPM synthase biochemistry?
  attaches_to:
  - "pathophysiology#GPI-Anchor Biosynthesis Impairment"
  rationale: >-
    Dol-P-Man donates mannoses to the GPI-anchor precursor, so DPM2 deficiency
    should impair GPI-anchor assembly, and DPM-synthase-null CHO cells do lose
    surface GPI-anchored proteins. But no DPM2-CDG case report has measured
    GPI-anchored protein display (e.g. CD59, CD55, alkaline phosphatase) in
    patient cells. The supporting patient data are indirect — a fibroblast
    lipidomic shift and congenital heart defects. This matters because a
    demonstrated GPI arm would place DPM2-CDG in the inherited GPI-deficiency
    disease class as well, with implications for expected phenotypes such as
    hyperphosphatasia.
  proposed_experiments:
  - experiment_id: exp_dpm2_gpi_flow_cytometry
    name: Flow cytometry for GPI-anchored proteins on patient cells
    description: >-
      Measure surface CD59 and CD55 (and FLAER binding) on DPM2-CDG patient
      fibroblasts or blood cells against controls, the standard assay used to
      establish GPI-anchor deficiency in the PIG-gene disorders.
  - experiment_id: exp_dpm2_alkaline_phosphatase_cohort
    name: Serum alkaline phosphatase profiling across the reported cohort
    description: >-
      Retrospectively collate alkaline phosphatase values in reported DPM2-CDG
      patients; hyperphosphatasia is a recognized marker of specific GPI-anchor
      biosynthesis defects.
- discussion_id: dpm2_no_faithful_animal_model
  kind: HUMAN_MODEL_MISMATCH
  status: OPEN
  prompt: >-
    Can any current animal model reproduce human DPM2-CDG, given that the
    published zebrafish work transiently depleted the whole DPM synthase complex
    rather than modeling the hypomorphic patient DPM2 alleles?
  attaches_to:
  - "pathophysiology#Sarcolemmal Laminin Anchorage Failure"
  - "pathophysiology#DPM Synthase Complex Destabilization"
  rationale: >-
    The zebrafish morphant study is the only in vivo model of this pathway and it
    recapitulates dystrophic muscle with hypoglycosylated alpha-dystroglycan — but
    it is a transient morpholino knockdown of dpm1/dpm2/dpm3 that causes early
    death, not a model of the hypomorphic missense alleles that actually cause
    human disease. It therefore cannot address the feature that most needs
    explaining: why the same pathway yields an infantile-lethal epileptic
    encephalopathy with one allele and an adult-viable myopathy with another.
    Evidence exists in a model system; its fidelity to the human allelic spectrum
    is the open question.
  proposed_experiments:
  - experiment_id: exp_dpm2_patient_allele_knockin
    name: Knock-in animal models carrying patient DPM2 missense alleles
    description: >-
      Generate hypomorphic knock-in alleles corresponding to p.Tyr23Cys (severe)
      and p.Gly66Glu (mild) rather than null alleles, and compare survival,
      seizure susceptibility, muscle histology and alpha-dystroglycan
      glycosylation between them.
  - experiment_id: exp_dpm2_ipsc_neuron_myotube
    name: Patient iPSC-derived neurons and skeletal myotubes
    description: >-
      Differentiate iPSC lines from severe- and mild-genotype patients into
      neurons and myotubes and compare Dol-P-Man levels, lipid-linked
      oligosaccharide profiles and alpha-dystroglycan glycosylation, to test the
      domain-position severity hypothesis in human cells.
- discussion_id: dpm2_domain_position_severity
  kind: OPEN_QUESTION
  status: OPEN
  prompt: >-
    Does the position of a DPM2 variant (first versus second transmembrane domain
    region) genuinely determine severity, or is the apparent correlation an
    artifact of a six-patient sample?
  attaches_to:
  - "pathophysiology#DPM Synthase Complex Destabilization"
  rationale: >-
    The only proposed prognostic factor in DPM2-CDG is variant position, based on
    a review of six patients across four families. The correlation is confounded
    by the fact that three of the severe patients share a single recurrent allele
    (p.Tyr23Cys) from two families, so the comparison is closer to
    allele-versus-allele than domain-versus-domain. The reporting authors
    explicitly note the relationship needs more study. Additional unrelated
    patients, or functional assays quantifying residual DPM synthase activity per
    allele, would resolve it.
  proposed_experiments:
  - experiment_id: exp_dpm2_residual_activity_per_allele
    name: Residual DPM synthase activity per allele
    description: >-
      Express each reported DPM2 allele in DPM2-null cells and quantify Dol-P-Man
      synthesis and lipid-linked oligosaccharide profiles, testing whether
      residual activity rather than domain position predicts clinical severity.
notes: >-
  Naming: this entry follows the gene-anchored convention used by the sibling CDG
  entries in this knowledge base (MPDU1-, ALG9-, COG1-congenital disorder of
  glycosylation). The MONDO/Orphanet label "congenital muscular dystrophy with
  intellectual disability and severe epilepsy" is retained as the bound
  disease_term label and as a synonym. That clinical label describes only the
  severe end of the spectrum; the disorder as now understood also has a mild,
  adult-viable form.

  Scope note on the shared DPM-synthase mechanism: DPM1-, DPM2- and DPM3-CDG share
  the same trigger-to-consequence chain (subunit loss, complex destabilization,
  Dol-P-Man depletion, four-pathway glycosylation failure). That is a candidate
  for a future mechanism module; until one exists the chain is curated in full on
  this entry, and conformance is declared against the existing
  congenital_disorder_of_glycosylation module for the shared CDG arm only.

  Early mortality in the severe form is recorded under progression rather than as
  a phenotype because the corresponding HPO term (HP:0001522, Death in infancy)
  sits outside the Phenotypic abnormality subtree that phenotype_term binds to.

  No GeneReviews chapter exists for DPM2-CDG. A PubMed search returned only the
  retired historical overview chapter "Congenital Disorders of N-Linked
  Glycosylation and Multiple Pathway Overview" (PMID:20301507), which is marked
  for historical reference only and is therefore not used as a phenotype baseline
  here.
📚

References & Deep Research

References

3
PMID:23109149
DPM2-CDG: a muscular dystrophy-dystroglycanopathy syndrome with severe epilepsy.
No top-level findings curated for this source.
PMID:33129689
Expanding the clinical and metabolic phenotype of DPM2 deficient congenital disorders of glycosylation.
No top-level findings curated for this source.
PMID:37152991
Identification and characterization of a new variation in DPM2 gene in two Chinese siblings with mild intellectual impairment.
No top-level findings curated for this source.

Deep Research

1
Claude Code ▸
I have enough primary-source material now to compile the full report.
claude-haiku-4-5-20251001, claude-sonnet-5 2026-07-31T23:50:18.089373

I have enough primary-source material now to compile the full report.

Comprehensive Research Report: DPM2-Congenital Disorder of Glycosylation (DPM2-CDG)

1. Disease Information

Overview. DPM2-CDG (also designated CDG type Iu, CDG1U) is an autosomal recessive congenital disorder of glycosylation caused by biallelic pathogenic variants in DPM2, which encodes the regulatory subunit of the heterotrimeric dolichol-phosphate-mannose (Dol-P-Man/DPM) synthase complex. Because Dol-P-Man is the mannose donor for N-linked glycosylation, O-mannosylation of α-dystroglycan, protein C-mannosylation, and GPI-anchor biosynthesis, DPM2 deficiency produces a combined glycosylation defect that bridges the classic CDGs with the secondary dystroglycanopathies (congenital muscular dystrophies caused by hypoglycosylation of α-dystroglycan). It was the first disorder shown to link CDG-I biochemistry directly to a dystroglycanopathy phenotype, following earlier descriptions of DPM1-CDG and DPM3-CDG (Barone et al., Ann Neurol 2012, PMID:23109149).

Key identifiers: - OMIM (phenotype): #615042 — Congenital Disorder of Glycosylation, Type Iu (CDG1U) - OMIM (gene): 603564 — DOLICHYL-PHOSPHATE MANNOSYLTRANSFERASE 2, REGULATORY SUBUNIT; DPM2 - Gene: DPM2; HGNC: HGNC:3006; Cytogenetic location: 9q34.11 - Orphanet: ORPHA:329178 — "Congenital muscular dystrophy with intellectual disability and severe epilepsy" (the DPM2-CDG Orphanet entry) - Inheritance: Autosomal recessive - Suggested MONDO term:* a DPM2-CDG-specific MONDO ID should be confirmed directly via the Monarch/MONDO API before curation (not independently verified in this research pass — flag for OAK lookup, e.g., uv run runoak -i sqlite:obo:mondo search "DPM2-CDG").

Synonyms/alternative names: CDG1U; CDG-Iu; DPM2-CDG; Dolichyl-phosphate mannosyltransferase subunit 2 deficiency; Congenital disorder of glycosylation, type Iu; (historically grouped clinically with) muscular dystrophy-dystroglycanopathy.

Evidence basis. Essentially all available information derives from individual published patient case reports/case series (n≈6–8 patients worldwide across 4 publications spanning 2012–2023) rather than aggregated registries — this is one of the rarest known CDGs, so curation should rely on primary case reports rather than population-level resources.

2. Etiology

Disease causal factor: Biallelic (homozygous or compound heterozygous) loss-of-function/hypomorphic variants in DPM2 (9q34.11), encoding the 84-amino-acid regulatory/stabilizing subunit of the ER-membrane-embedded DPM synthase complex. This is a purely monogenic, autosomal recessive Mendelian disease — no environmental or infectious causal factors are described.

Genetic risk factors — reported pathogenic variants: | Variant(s) | Zygosity | Family/Patients | Reference | |---|---|---|---| | c.68A>G, p.Tyr23Cys (missense, TM domain 1) | Homozygous | 2 unrelated Italian patients (P4, P5) | Barone 2012, PMID:23109149 | | c.68A>G (p.Tyr23Cys) + c.4-1G>C (splice) | Compound heterozygous | 1 Italian patient (P3) | Barone 2012, PMID:23109149 | | c.139C>T, p.Arg47Ter (nonsense) + c.173G>A, p.Gly58Asp (missense) | Compound heterozygous | 1 Indian, 23-year-old male | Radenkovic et al. 2021, PMID:33129689 | | c.197G>A, p.Gly66Glu (missense, TM domain 2) | Homozygous | 2 Chinese siblings | PMID:37152991 (PMC10154465) |

Genotype–phenotype correlation: Variants localizing to the first transmembrane/domain region (e.g., p.Tyr23Cys) associate with the severe, early-lethal phenotype; variants in the second domain region (p.Gly66Glu) or the Arg47Ter/Gly58Asp combination associate with a milder, longer-surviving phenotype — "patients with variants within the region encoding the first domain had more severe clinical symptoms than those with variants within the second domain" (PMC10154465).

Population/allele-frequency risk factors: No specific ClinVar/gnomAD population enrichment or founder-effect data were identified for DPM2 variants; the G66E and Y23C alleles are absent from gnomAD/1000 Genomes/ClinVar, consistent with extreme rarity rather than population-specific founder alleles. No consanguinity data beyond standard AR expectation were specifically reported in the search results retrieved.

Protective factors: None identified — no protective variant or environmental modifier literature exists for this ultra-rare monogenic disorder.

Gene-environment interactions: Not applicable/not reported; this is a fully genetically determined enzymatic deficiency with no known environmental modifiers.

3. Phenotypes

DPM2-CDG spans a severe, early-lethal end (Barone et al. 2012) and a mild, long-survival end (Radenkovic et al. 2021; the Chinese sibling report) — genuine phenotypic heterogeneity rather than a single stereotyped presentation.

Severe end-of-spectrum (3 patients, 2 Italian families; onset at birth): - Profound/severe developmental delay, absent psychomotor development — HP:0012758 (Motor delay), HP:0001263 (Global developmental delay) - Intractable/treatment-resistant epilepsy, described as "severe epilepsy" — HP:0001250 (Seizure), HP:0002373 (Febrile/other- consider HP:0011097 for epileptic spasms if applicable) - Progressive microcephaly — HP:0000252 - Severe hypotonia — HP:0001252 - Elevated blood creatine kinase — HP:0003236 (Elevated CK) - Mild cerebellar hypoplasia in one patient — HP:0007360 - Early fatal outcome: deaths at 3 years, 16 months, and 7 months of age - Muscle biopsy: deficient O-mannosylation of α-dystroglycan on immunohistochemistry, consistent with dystroglycanopathy-type congenital muscular dystrophy — HP:0003198 (Myopathy), HP:0009046 (Diffusely decreased α-dystroglycan immunostaining, if precise term available)

Mild end-of-spectrum (23-year-old Indian male, PMID:33129689): - Truncal hypotonia and hypertonicity (mixed tone abnormality) — HP:0001252 / HP:0001276 - Congenital heart defects — HP:0001627 - Intellectual disability (mild-moderate) — HP:0001249 - Generalized muscle wasting — HP:0003202 - Alive at 23 years — markedly better survival than the severe cohort

Mild end-of-spectrum (2 Chinese sisters, PMID:37152991, ages 11 and 20 years): - Motor and language developmental delay (delayed head control to 4 months, walking at 3 years in one) — HP:0001270 - Mild intellectual disability — HP:0001256 - Hypotonia (elder sibling) / hypertonia (younger sibling) — mixed tone findings - Strabismus — HP:0000486 - Recurrent infections in preschool years — HP:0002719 - Exercise intolerance — HP:0003546 - Markedly elevated CK (2097 and 2022 U/L; reference 20–250) and CK-MB elevation — HP:0003236 - Peripheral nerve involvement: slowed motor nerve conduction velocity, prolonged motor latency — HP:0003431 - Brain MRI: demyelinating lesions in bilateral parietal white matter — HP:0002500 (or HP:0032131) - EEG: mildly slowed occipital background — HP:0011182 - Orthopedic sequela requiring Achilles tendon lengthening (contracture) — HP:0001371

Severity/progression: Bimodal — either a rapidly progressive, fatal infantile neuromuscular/epileptic encephalopathy, or a stable/slowly progressive congenital myopathy-intellectual disability phenotype persisting into adulthood. No formal QOL instrument (EQ-5D/SF-36) data were located for this disorder given its extreme rarity; QOL impact can be inferred as substantial in the severe form (early death, no psychomotor development) and moderate in the mild form (chronic disability, preserved survival to adulthood).

4. Genetic/Molecular Information

Causal gene: DPM2 (HGNC:3006; OMIM *603564; chr9q34.11). Encodes an 84-amino-acid, two-transmembrane-domain ER integral membrane protein.

Variant classes reported: missense (p.Tyr23Cys, p.Gly58Asp, p.Gly66Glu), nonsense (p.Arg47Ter), and a canonical splice-acceptor variant (c.4-1G>C). All are germline, biallelic, loss-of-function or hypomorphic — no somatic DPM2 variants are described (not a cancer-associated gene in this context).

Functional consequences: - Reduced DPM2 protein expression in patient fibroblasts (compound heterozygous R47X/G58D case), with secondary reduction of DPM1 protein — loss-of-function/destabilization of the complex. - Conversely, the G66E variant, when overexpressed in HCT116 cells, showed increased DPM2 mRNA and protein but still produced a functional glycosylation defect (significant decrease in ICAM1, "a universal biomarker for hypoglycosylation in patients with CDG") — indicating the pathogenic mechanism is not simply reduced protein abundance but impaired function/regulatory activity, without altering ER subcellular localization. - Net biochemical consequence in all cases: reduced Dol-P-Man synthesis → defective N-glycan precursor assembly (CDG type I biochemical pattern), deficient O-mannosylation of α-dystroglycan, and (mechanistically expected, per GPI-pathway biology) defective GPI-anchor mannosylation.

Allele frequency: All reported pathogenic DPM2 alleles are absent or near-absent from gnomAD/1000 Genomes/ClinVar population databases, consistent with an ultra-rare AR disease.

Modifier genes: None specifically documented; genotype-driven severity (TM domain 1 vs. domain 2 location) functions as the main documented "modifier" of phenotype, as above.

Chromosomal abnormalities: None reported; DPM2-CDG is due to sequence-level variants, not structural/copy-number changes.

Epigenetic information: No DPM2-CDG-specific methylation/histone data were identified.

Suggested HGNC/ontology binding for curation: hgnc:3006 (lowercase per dismech convention), gene symbol DPM2.

5. Environmental Information

No environmental, lifestyle, or infectious contributing factors are described for DPM2-CDG — it is a purely monogenic enzymatic-deficiency disorder. (Infections were reported as a consequence — "recurrent infections during preschool years" in one sibling case — rather than a cause, plausibly reflecting immune-glycoprotein hypoglycosylation, a recognized theme across CDGs broadly; see immunological-involvement-in-CDG literature, PMC7408855, for the general mechanism, though not DPM2-specific.)

6. Mechanism / Pathophysiology

Causal chain (upstream → downstream):

  1. Molecular lesion: Biallelic DPM2 variants (missense/nonsense/splice) → loss or dysfunction of the DPM2 regulatory subunit.
  2. Complex destabilization: DPM synthase is a heterotrimer — DPM1 (catalytic, cytoplasmic-facing), DPM2 (ER membrane, stabilizes DPM1's correct ER localization and enhances dolichol-phosphate binding to DPM1), and DPM3 (tethers/stabilizes DPM1 at the ER membrane). Loss of DPM2 function destabilizes DPM1 localization/expression and impairs dolichol-phosphate binding.
  3. Enzymatic consequence: Reduced synthesis of dolichol-phosphate-mannose (Dol-P-Man) from GDP-mannose + dolichol-phosphate in the ER membrane (GO:0004582, dolichyl-phosphate beta-D-mannosyltransferase activity; the complex itself localizes to GO:0005789, endoplasmic reticulum membrane).
  4. Multi-pathway mannose-donor deficiency (Dol-P-Man is required by four distinct downstream pathways):
  5. N-linked glycosylation: impaired mannosylation of the dolichol-linked oligosaccharide (LLO) precursor in the ER lumen → truncated/hypoglycosylated LLO → hypoglycosylated glycoproteins (CDG type I biochemical signature). Lipid-linked oligosaccharide analysis in patient fibroblasts showed accumulation of the truncated intermediate Dol-PP-GlcNAc₂Man₅ (Barone et al. 2012), diagnostic of a defect at/after the Dol-P-Man-dependent mannosylation steps of LLO assembly.
  6. O-mannosylation of α-dystroglycan: loss of Dol-P-Man-dependent O-mannosyl transfer onto α-dystroglycan (POMT1/POMT2-catalyzed step) → hypoglycosylated α-dystroglycan → loss of its laminin-binding function in the extracellular matrix → secondary dystroglycanopathy with muscular dystrophy features (confirmed by reduced α-dystroglycan immunostaining on muscle biopsy in the Barone cohort).
  7. Protein C-mannosylation (e.g., of thrombospondin repeats) — also Dol-P-Man-dependent, mechanistically implicated though not specifically assayed in these patients.
  8. GPI-anchor biosynthesis: Dol-P-Man is required for mannosylation steps of the GPI-anchor precursor in the ER; DPM2-deficient cells accumulate GPI intermediates lacking mannose, and GPI-anchored proteins such as alkaline phosphatase are degraded/mis-processed rather than properly surface-expressed — mechanistically linking DPM2-CDG to the broader GPI-anchor-deficiency (CDG type II/IV) disease class.
  9. Cellular/tissue consequence: Combined N-glycan and O-mannosylation/GPI defects → skeletal muscle membrane fragility and impaired laminin-dystroglycan-ECM linkage (myopathy/elevated CK), CNS glycoprotein/glycolipid dysfunction (developmental delay, seizures, white-matter/demyelinating change, cerebellar hypoplasia), and generalized hypoglycosylation of serum glycoproteins (abnormal transferrin isoelectric focusing pattern, CDG type I).
  10. Downstream systemic consequence: In the Radenkovic et al. (2021) glycomics/lipidomics study, secondary alterations in phospholipid and sphingolipid metabolism were identified, suggesting broader downstream metabolic perturbation beyond glycoprotein synthesis alone.

Suggested ontology terms for pathophysiology nodes: - GO (molecular function): GO:0004582 (dolichyl-phosphate beta-D-mannosyltransferase activity) - GO (biological process): GO:0006486 (protein glycosylation), GO:0035269 (protein O-linked mannosylation), GO:0006506 (GPI anchor biosynthetic process), GO:0009101 (glycoprotein biosynthetic process) - GO (cellular component): GO:0005789 (endoplasmic reticulum membrane), GO:0033185 (dolichol-phosphate-mannose synthase complex, if present in current GO) - CL (cell types): CL:0000188 (skeletal muscle cell/myocyte), CL:0000540 (neuron) — reflecting the two principal affected tissues - UBERON: UBERON:0001134 (skeletal muscle tissue), UBERON:0000955 (brain)

Molecular/omics profiling available: Lipid-linked oligosaccharide (LLO) profiling (Barone 2012); glycomics + lipidomics (phospholipid/sphingolipid) profiling (Radenkovic 2021); targeted transcript/protein overexpression functional assay with ICAM1 as a glycosylation reporter (PMC10154465). No published single-cell, spatial transcriptomic, or CRISPR functional-genomics screen specific to DPM2-CDG was identified.

7. Anatomical Structures Affected

Organ level: - Primary: Skeletal muscle (dystroglycanopathy-type myopathy), central nervous system (developmental delay, epilepsy, structural brain abnormality) - Secondary/variable: Cardiovascular system (congenital heart defects in the mild-phenotype adult patient), peripheral nervous system (demyelinating peripheral neuropathy in the Chinese sibling case), craniofacial (dysmorphic features, micrognathia, malocclusion in the severe Barone cohort), musculoskeletal (congenital joint contractures, scoliosis, strabismus/ocular findings) - Body systems involved: musculoskeletal, nervous (central and peripheral), cardiovascular, ophthalmologic

Tissue/cell level: - Skeletal myofibers (CL:0000188/CL:0000737) — dystrophic changes, hypoglycosylated α-dystroglycan on the sarcolemma - Neurons and white-matter oligodendrocyte-myelin unit (demyelinating lesions reported) — CL:0000128 (oligodendrocyte) - Cerebellar tissue (hypoplasia in one Italian patient)

Subcellular level: - Endoplasmic reticulum (site of DPM synthase complex and Dol-P-Man synthesis) — GO:0005789 - ER lumen (site of LLO assembly and N-glycan precursor mannosylation) - Plasma membrane (site of hypoglycosylated α-dystroglycan and deficient GPI-anchored protein display)

Localization/laterality: Bilateral/symmetric involvement is described (e.g., bilateral parietal white-matter demyelination); no lateralized/asymmetric pattern reported.

8. Temporal Development

Onset: Congenital in essentially all reported cases — severe cases present at birth (hypotonia, dysmorphism, joint contractures); milder cases present in early childhood with developmental/motor/language delay (walking delayed to 3 years in one sibling), later diagnosed retrospectively in adulthood.

Onset pattern: Insidious/chronic developmental presentation in the mild phenotype; acute/severe neonatal presentation with rapid multisystem involvement in the severe phenotype.

Progression: - Severe phenotype: Rapidly progressive, fatal — deaths at 7 months, 16 months, and 3 years of age; intractable epilepsy and progressive microcephaly documented. - Mild phenotype: Stable-to-slowly progressive chronic course; patients survive into the third decade of life (23-year-old male; 20-year-old sibling) with persistent but non-fatal disability (intellectual disability, myopathy, exercise intolerance).

Disease duration: Lifelong/chronic in survivors; the disease is not self-limited.

Patterns: No remission pattern is described (this is a structural enzymatic deficiency, not an episodic/relapsing-remitting disease). No specific "critical period" intervention window has been established given the absence of disease-modifying therapy.

9. Inheritance and Population

Epidemiology: DPM2-CDG is ultra-rare — only approximately 6–8 patients have been reported in the peer-reviewed literature worldwide as of the most recent identified report (2023): 3 from 2 Italian families (Barone 2012), 1 Indian adult male (Radenkovic 2021), and 2 Chinese sisters (2023). No formal prevalence/incidence rate (cases per 100,000) has been established or published; combined N-linked CDG prevalence across ~27 disorders has been estimated around 1 in 22,000 in European populations, but DPM2-CDG specifically is far rarer than the more common subtypes (e.g., PMM2-CDG).

Inheritance pattern: Autosomal recessive (biallelic variants required in all reported cases — either homozygous or compound heterozygous).

Penetrance: Full penetrance is implied by all reported biallelic carriers being clinically affected (no unaffected biallelic carriers reported), though the sample size is too small for formal penetrance estimation.

Expressivity: Markedly variable expressivity — this is the disease's most notable population-genetics feature, spanning neonatal-lethal to adult-viable mild phenotypes, correlating with variant location (TM domain 1 vs domain 2/other).

Genetic anticipation: Not applicable (not a repeat-expansion disorder).

Founder effects/consanguinity: Not explicitly documented in the retrieved literature; the 2 Italian families with the same p.Tyr23Cys variant (one homozygous in 2 patients) could suggest a possible regional founder allele, but this has not been formally established.

Carrier frequency: Not established; consistent with allele absence from gnomAD.

Population demographics: Cases reported from Italy, India, and China — no evidence of a specific ethnic/geographic predisposition; likely reflects ascertainment/publication bias rather than a true geographic pattern for an ultra-rare AR disease.

Sex ratio: Reported cases include both sexes — 2 males + 1 female of unspecified sex noted in the severe Italian cohort description ("affected boys" is mentioned for 2 of the 3 severe patients), 1 male (Indian adult), 2 females (Chinese siblings) — no clear sex bias is apparent, consistent with autosomal inheritance.

Age distribution: Bimodal — infantile deaths (7–36 months) in the severe subgroup vs. surviving pediatric/adult patients (11, 20, 23 years) in the mild subgroup.

10. Diagnostics

Laboratory tests: - Serum creatine kinase (CK): Markedly elevated in all reported patients (up to ~2000 U/L; reference range 20–250 U/L) — reflects the myopathic/dystroglycanopathy component. - Transferrin isoelectric focusing (IEF): Shows a CDG type I pattern (cathodic shift due to under-sialylated, hypoglycosylated N-glycans from incomplete LLO assembly) — the classic first-line CDG screening test (gold standard per general CDG diagnostic literature). - Lipid-linked oligosaccharide (LLO) analysis in cultured fibroblasts: Diagnostic biochemical signature — accumulation of the truncated intermediate Dol-PP-GlcNAc₂Man₅, localizing the biosynthetic block to the Dol-P-Man-dependent mannosylation steps. - ICAM1 expression assay: Used as a functional glycosylation biomarker in one functional-variant study (decreased with pathogenic DPM2 variant expression).

Biomarkers: Elevated CK (muscle-specific); abnormal transferrin glycoform pattern (glycosylation-specific); reduced ICAM1 as an experimental hypoglycosylation reporter.

Imaging: Brain MRI — cerebellar hypoplasia (severe cases); demyelinating white-matter lesions, bilateral parietal distribution (mild case).

Electrophysiology: EEG — epileptiform/slowed background activity; nerve conduction studies — slowed motor conduction velocity and prolonged motor latency (peripheral neuropathy component in at least one mild-phenotype patient).

Biopsy/histopathology findings: Skeletal muscle biopsy immunohistochemistry demonstrating deficient O-mannosylation of α-dystroglycan — the confirmatory tissue-level test linking the biochemical CDG-I finding to the dystroglycanopathy phenotype.

Genetic testing: Confirmatory diagnosis requires DPM2 sequencing (single-gene test, CDG gene panel, or exome/genome sequencing given the extreme rarity and phenotypic overlap with other CDG-I subtypes and dystroglycanopathies). Given the phenotypic and biochemical overlap with DPM1-CDG and DPM3-CDG, a CDG/dystroglycanopathy gene panel approach (covering DPM1, DPM2, DPM3, POMT1/2, POMGNT1/2, FKTN, FKRP, LARGE1, B3GALNT2, etc.) is the pragmatic first-tier test; single-gene DPM2 testing is appropriate when biochemical/biopsy findings (combined CDG-I pattern + dystroglycan hypoglycosylation) point specifically to the DPM synthase complex.

Differential diagnosis: Other DPM-synthase-complex CDGs (DPM1-CDG, DPM3-CDG — allelic-complex disorders with overlapping combined CDG-I/dystroglycanopathy biochemistry); other secondary dystroglycanopathies (POMT1/2-, POMGNT1/2-, FKTN-, FKRP-, LARGE1-, B3GALNT2-related congenital muscular dystrophies, e.g., Walker-Warburg syndrome/muscle-eye-brain disease spectrum); other CDG type I disorders (PMM2-CDG, ALG-family CDGs) presenting with elevated CK and developmental delay; GPI-anchor-deficiency disorders (PIGA, PIGV, PIGO, etc.) given the shared GPI-mannosylation defect.

Screening: No population/newborn screening program exists for this ultra-rare disorder; diagnosis is case-by-case, typically prompted by a combination of unexplained developmental delay/epilepsy/hypotonia with elevated CK, triggering CDG biochemical screening (transferrin IEF) followed by molecular confirmation.

11. Outcome/Prognosis

Survival/mortality: Bimodal, variant-dependent: - Severe phenotype (TM-domain-1 variants, e.g., p.Tyr23Cys): Uniformly fatal in infancy/early childhood — reported deaths at 7 months, 16 months, and 3 years. - Mild phenotype (other variants): Survival into adulthood documented (23-year-old male alive at report; siblings aged 11 and 20 alive at report) — no mortality reported in this subgroup.

No formal actuarial life-expectancy or population-level mortality-rate data exist given the rarity of the disease.

Morbidity/function: In survivors — chronic intellectual disability (mild-moderate), myopathy/generalized muscle wasting, exercise intolerance, orthopedic complications (contractures requiring surgical correction), and in one case peripheral neuropathy. No standardized QOL instrument data identified.

Complications: Intractable epilepsy (severe form); congenital heart defects (mild-form adult patient); recurrent infections (childhood, mild-form siblings) — plausibly reflecting broader hypoglycosylation of immune glycoproteins, consistent with general CDG immunological literature, though not specifically studied in DPM2-CDG.

Prognostic factors: The single most important documented prognostic factor is variant location within the DPM2 protein — first transmembrane-domain variants (p.Tyr23Cys) predict a severe/lethal course, while variants outside this region (p.Gly66Glu; p.Arg47Ter/p.Gly58Asp) predict a milder, longer-surviving course. No molecular biomarker (beyond genotype) has been validated as prognostic.

Recovery potential: None — this is a fixed enzymatic/structural deficiency with a progressive-to-stable neuromuscular course; there is no disease-modifying treatment altering the underlying trajectory.

12. Treatment

Pharmacotherapy: No DPM2-CDG-specific or DPM-synthase-complex-targeted pharmacological therapy exists. Unlike PMM2-CDG (where oral D-mannose and D-galactose supplementation have shown biochemical/clinical benefit in some patients — Ligezka et al., PMC8359111; PMC7510076) or MPI-CDG (mannose-responsive) and SLC35C1-CDG/PIGM-CDG/PGM1-CDG (which have specific targeted therapies per the general CDG treatment literature), DPM2-CDG has no established substrate-supplementation or targeted therapy — the defect is upstream at the level of Dol-P-Man synthesis itself (regulatory subunit dysfunction), not substrate availability, so simple mannose supplementation would not be expected to bypass the enzymatic block. This is an important curation distinction from PMM2-CDG. - NCIT suggestion for generic management: NCIT:C15747 (Supportive Care)

Symptomatic/supportive management (documented in case reports): - Anti-seizure medication for intractable epilepsy in the severe phenotype (specific agents not detailed in retrieved abstracts) — NCIT:C15986 (Pharmacotherapy) - Orthopedic surgical correction — Achilles tendon lengthening for contracture in one sibling — NCIT:C15329 (Surgical Procedure) / NCIT:C16186 (Orthopedic Surgical Procedure) - Physical therapy / rehabilitative management for hypotonia/motor delay — NCIT:C15302 (Physical Therapy) - Nutritional/growth support (implied for failure to thrive in severe neonatal presentations) — NCIT:C15447 (Dietary Intervention) - Cardiac management for congenital heart defects in the mild adult phenotype — cardiology follow-up/surgical repair as indicated

Advanced/experimental therapeutics: No gene therapy, cell therapy, RNA-based therapy, or clinical trial specific to DPM2-CDG was identified (no ClinicalTrials.gov entries located in this search). Given the extreme rarity (<10 published patients), a dedicated interventional trial is unlikely to exist.

Genetic counseling: Recommended given autosomal recessive inheritance and 25% recurrence risk per pregnancy for carrier parents — NCIT:C15240 (Genetic Counseling).

Treatment strategy: Management is multidisciplinary and purely supportive/symptom-directed (neurology for seizures, orthopedics for contractures/scoliosis, cardiology as needed, physical/occupational therapy, nutritional support) — no disease-modifying or curative approach currently exists.

13. Prevention

Primary prevention: None available (no environmental risk factor to modify; a purely genetic AR disease).

Secondary prevention/screening: No population or newborn screening program exists. In families with a known proband, carrier testing and prenatal/preimplantation genetic diagnosis are the applicable prevention strategies once the familial DPM2 variants are identified — standard for any AR Mendelian disorder with 25% recurrence risk.

Genetic counseling: Central preventive/family-planning tool — informing carrier parents of recurrence risk and reproductive options (prenatal diagnosis, PGD/IVF) — NCIT:C15240.

Tertiary prevention: Anticipatory multidisciplinary surveillance (seizure monitoring/management, orthopedic monitoring for contractures/scoliosis, cardiac surveillance, developmental/rehabilitative support) to reduce complications in affected individuals, particularly in the milder, longer-surviving phenotype.

Immunization/public health/prophylaxis: No disease-specific vaccination, public-health, or prophylactic-medication strategy is described.

14. Other Species / Natural Disease

Taxonomy: No naturally occurring DPM2-deficient disease has been reported in non-human species (companion animals, wildlife) — this appears to be a human-only reported clinical entity; no OMIA (Online Mendelian Inheritance in Animals) entry was identified in this search.

Orthologous gene: Mouse Dpm2 (MGI:1330238) is the confirmed ortholog; used exclusively for laboratory knockout modeling (see Model Organisms below), not for natural/spontaneous veterinary disease.

Comparative biology: The DPM synthase complex (DPM1/DPM2/DPM3) is evolutionarily conserved from yeast to humans — a functional DPM2 homolog exists in Saccharomyces cerevisiae (Yil102c-A, PMC7728079), underscoring deep conservation of Dol-P-Man biosynthesis machinery across eukaryotes and validating yeast as a tool for functional variant characterization (as used for the related PMM2-CDG disorder, though not yet specifically published for DPM2 variants in the retrieved literature).

Zoonotic potential/transmission: Not applicable — this is a non-infectious, purely genetic disorder.

15. Model Organisms

Mouse: - Constitutive Dpm2 knockout is homozygous embryonic/perinatal lethal — "Knockout of the mouse homolog of human DPM2 is homozygous-lethal (defined as absence of homozygous mice after screening of at least 28 pups before weaning)" (per IMPC/MGI data referenced in search results, MGI:1330238). This parallels the embryonic lethality seen in other dystroglycanopathy-pathway mouse knockouts (e.g., Pomt1, due to the essential placental role of dystroglycan in rodents), and implies that conditional/tissue-specific knockout strategies would be required to model postnatal DPM2-CDG phenotypes in mice — no such conditional model was identified in the retrieved literature specifically for Dpm2.

Zebrafish: - No DPM2-specific zebrafish model was identified in this search. However, zebrafish are an actively used and validated platform for the broader dystroglycanopathy gene class (e.g., pomt1 loss-of-function zebrafish recapitulate α-dystroglycan hypoglycosylation and dystroglycanopathy phenotypes, PMID:38272461/PMC11000664; fkrp-deficient zebrafish, PMID:18477595) — representing a model-system gap worth flagging for a HUMAN_MODEL_MISMATCH-type discussion if curated in dismech, since DPM2 itself lacks a published zebrafish disease model despite the pathway being well-modeled in zebrafish for sibling genes.

Yeast: - Saccharomyces cerevisiae Yil102c-A functions as a DPM2 homolog and has been used to functionally characterize the yeast DPM synthase regulatory subunit (PMC7728079) — a potential future functional-variant-testing platform analogous to the yeast complementation assays already published for PMM2-CDG variant classification (bioRxiv 414862).

Cell-based/in vitro models: - Patient-derived dermal fibroblasts — used for LLO profiling (Barone 2012) and glycomics/lipidomics (Radenkovic 2021); these directly recapitulate the biochemical CDG-I defect and reduced DPM1/DPM2 protein expression. - HCT116 cell line transfection/overexpression assays — used to functionally characterize the p.Gly66Glu variant's effect on DPM2 mRNA/protein expression and on the ICAM1 hypoglycosylation reporter (PMC10154465) — this is the most direct functional-genomics tool currently published for DPM2 variant interpretation.

Model limitations: No model currently recapitulates the full clinical spectrum (severe neonatal-lethal epileptic-myopathic phenotype vs. mild adult-viable phenotype) in vivo; the mouse constitutive-knockout lethality precludes whole-animal phenotypic study without a conditional allele, and no such conditional/hypomorphic mouse model was identified in this search.

Summary for Knowledge-Base Curation

DPM2-CDG is an ultra-rare (≤10 published patients), autosomal recessive, allelic-series disorder (alongside DPM1-CDG and DPM3-CDG) of the dolichol-phosphate-mannose synthase complex, causally unifying CDG type I (N-glycosylation/LLO defect) and secondary dystroglycanopathy (α-dystroglycan O-mannosylation defect) mechanisms with a probable but unconfirmed GPI-anchor biosynthesis contribution. The clearest curatable causal chain is: DPM2 biallelic variant → DPM synthase complex destabilization → Dol-P-Man deficiency → parallel failure of (a) N-glycan LLO assembly, (b) α-dystroglycan O-mannosylation, and (c) GPI-anchor mannosylation → combined CDG-I biochemistry + dystroglycanopathy-type myopathy + neurodevelopmental phenotype, with variant location within DPM2 (TM domain 1 vs. domain 2) as the key documented genotype-severity modifier distinguishing the fatal-infantile from mild-adult-viable ends of the phenotypic spectrum. Treatment is entirely supportive; no targeted or disease-modifying therapy (including simple mannose supplementation, unlike PMM2-CDG) has been established. This entry is a strong candidate for conforms_to linkage to the lysosomal_substrate_accumulation-adjacent glycosylation-defect pattern conceptually, and more directly overlaps mechanistically with any future dismech module capturing the shared DPM1/DPM2/DPM3 "dolichol-phosphate-mannose synthesis disorder" pattern (cf. PMID:30931530, "Toward understanding tissue-specific symptoms in dolichol-phosphate-mannose synthesis disorders; insight from DPM3-CDG") — worth checking whether such a module already exists or should be proposed given the shared trigger→consequence chain across all three DPM subunit deficiencies.

Primary literature cited (PMIDs): 23109149 (Barone et al. 2012, Ann Neurol — first DPM2-CDG description, 3 patients); 33129689 (Radenkovic et al. 2021, Mol Genet Metab — 23-year-old mild phenotype, glycomics/lipidomics); 37152991 (2023 — Chinese siblings, novel p.Gly66Glu variant, ICAM1 functional assay); 16280320 and related DPM1/DPM3 stabilization mechanism papers; 30931530 (DPM3-CDG tissue-specificity review, mechanistically relevant); 38272461/PMID for zebrafish pomt1 dystroglycanopathy model (pathway-analogous, not DPM2-specific).

Notable evidence gaps requiring KNOWLEDGE_GAP/HUMAN_MODEL_MISMATCH flags if curated: (1) no confirmed MONDO ID verified in this pass — requires OAK lookup before entry creation; (2) no DPM2-specific animal model recapitulating the human phenotype exists (mouse knockout is embryonic lethal; no zebrafish model published), a clear HUMAN_MODEL_MISMATCH candidate; (3) GPI-anchor pathway involvement is mechanistically inferred from DPM-synthase biochemistry but not directly demonstrated with patient GPI-anchored-protein/ALP data in the DPM2-CDG case reports themselves (unlike PMM2-CDG, where this has been directly studied per PMC4016514) — treat as an extrapolated/inferred edge rather than direct human evidence.