DPAGT1-congenital disorder of glycosylation

Mendelian MONDO:0011964 Pathograph 27 Show in embeddings browser congenital disorder of glycosylation type I disorder of protein N-glycosylation

DPAGT1-CDG (formerly CDG-Ij) is a rare autosomal recessive congenital disorder of N-linked glycosylation caused by biallelic hypomorphic variants in DPAGT1, which encodes UDP-GlcNAc:dolichol phosphate N-acetylglucosamine-1-phosphate transferase (GPT). GPT is an endoplasmic-reticulum-resident enzyme that catalyses the first committed step of the lipid-linked oligosaccharide (LLO) pathway on the cytoplasmic face of the ER membrane: the transfer of GlcNAc-1-phosphate from UDP-GlcNAc onto dolichol phosphate to give dolichol-PP-GlcNAc. Because nothing downstream in LLO assembly can proceed without that first sugar, reduced GPT activity limits the supply of mature dolichol-linked oligosaccharide available to the oligosaccharyltransferase and leaves glycoproteins across every tissue incompletely N-glycosylated. The laboratory signature is a type I serum transferrin isoform pattern, and the clinical picture is a severe multisystem encephalopathy. The disease requires residual enzyme activity. In the index patient GPT activity was about 10 percent of normal, and complete loss of the orthologous mouse enzyme is lethal shortly after implantation, so no human null genotype is expected to be viable. This is why every reported genotype is missense, splice-leaky, or a compound of the two, and it is the most plausible explanation for the disease's wide severity range: patients with the least residual activity die in the first years of life with intractable epilepsy, while a minority carrying milder allele combinations reach adulthood with moderate intellectual disability, epilepsy and hypotonia. Cardinal features are pronounced muscular hypotonia, medically intractable seizures, global developmental delay and intellectual disability, microcephaly, and exotropia; cataracts, joint contractures, fetal akinesia with reduced fetal movement, hypertrichosis and feeding difficulties recur across the reported cohorts. There is no disease-modifying therapy. Management is supportive, with anticonvulsants for the epilepsy and cholinesterase inhibition for the myasthenic component of the muscle weakness. Scope. This entry covers MONDO:0011964 only, the systemic encephalopathic disease. The much milder allelic DPAGT1-related limb-girdle congenital myasthenic syndrome with tubular aggregates (CMS-13) is a separate MONDO term (MONDO:0013883, OMIM:614750) and is curated in the KB's Congenital Myasthenic Syndrome entry; it is deliberately not modelled here as a subtype. See `notes` for the reasoning.

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1
Inheritance
7
Pathophys.
1
Histopath.
16
Phenotypes
3
Gaps
27
Pathograph
1
Genes
4
Variants
3
Medical Actions
2
Models
2
References
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Inheritance

1
Autosomal recessive HP:0000007
Disease requires biallelic DPAGT1 variants, homozygous or compound heterozygous, with unaffected heterozygous carrier parents. In the index family the paternal allele carried a missense change and the maternal allele a splicing defect; homozygous missense genotypes have since been reported in consanguineous families. No complete biallelic null has been described, consistent with the enzyme's essential role.
Autosomal recessive inheritance
Show evidence (2 references)
PMID:12872255 SUPPORT Human Clinical
"In vitro enzymatic analysis of microsomal fractions from the cultured cells indicated that oligosaccharyltransferase activity is normal, but the GPT activity is reduced to approximately 10% of normal levels while parents have heterozygous levels."
Documents biallelic involvement in the proband with intermediate enzyme levels in both unaffected parents, the biochemical signature of recessive inheritance.
PMID:37766827 SUPPORT Human Clinical
"It is a rare autosomal recessive disease or a milder version with congenital myasthenic syndrome known as DPAGT1-CMS."
States the mode of inheritance directly.
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Discussions and Knowledge Gaps

3
Is the boundary between DPAGT1-CDG and DPAGT1-CMS a difference of kind or only of degree, and does the myasthenic weakness of DPAGT1-CDG patients belong to this entry or to the myasthenic one?
OPEN QUESTION OPEN dpagt1_cdg_cms_boundary
Attached to
pathophysiology#Neuromuscular Transmission Impairment
DPAGT1 has two named allelic diseases with separate MONDO terms and separate OMIM entries: the systemic encephalopathy curated here (MONDO:0011964, OMIM:608093) and limb-girdle congenital myasthenic syndrome 13 with tubular aggregates (MONDO:0013883, OMIM:614750), which the KB curates in its Congenital Myasthenic Syndrome entry. This entry follows that split. But the split is not clean in the clinic: DPAGT1-CDG patients have a myasthenic component to their weakness that responds to cholinesterase inhibition, which is the DPAGT1-CMS mechanism appearing inside the CDG phenotype, and the reported severity range within DPAGT1-CDG alone spans lethal infantile encephalopathy to stable adult disease. The likeliest organising variable is residual enzyme activity rather than a categorical difference, in which case the two MONDO terms name two regions of one continuum. If the KB later adopts a convention for allelic series graded by residual activity, this pair is a candidate for a grouping that spans both terms.
Which hypoglycosylated neural glycoproteins mediate the epilepsy, developmental delay and microcephaly of DPAGT1-CDG?
KNOWLEDGE GAP OPEN dpagt1_neural_mechanism_unknown
Attached to
pathophysiology#Hypoglycosylation of Neural Glycoproteins
The neuromuscular arm of this disease has a candidate target, endplate receptor hypoglycosylation, shown for the neighbouring ALG14 subunit and supported here by the response to cholinesterase inhibition. The central nervous system arm has none. Intractable epilepsy, developmental delay and microcephaly are documented in every cohort, but no specific neural glycoprotein has been shown to be hypoglycosylated in patients and no intermediate step between the biosynthetic defect and the encephalopathy has been established. Brain imaging is not even consistent across patients. The corresponding pathophysiology node therefore asserts a tissue-scale association and is tagged with hypothetical mechanism confidence; it should not be read as a mechanism.
If the unfolded protein response is not activated in DPAGT1-CDG fibroblasts, what does the increased sensitivity to tunicamycin in those cells represent?
OPEN QUESTION OPEN dpagt1_er_stress_not_the_mechanism
Attached to
pathophysiology#Global Protein N-Hypoglycosylation
ER stress is an attractive candidate mediator for a disease of ER-resident glycan assembly, and it is active in other CDG subtypes. It was tested directly in DPAGT1-CDG patient fibroblasts and was not found: the unfolded protein response was inactive, unlike in PMM2-CDG or DPM1-CDG cells. The same cells were nonetheless more sensitive than controls to the GPT inhibitor tunicamycin. Whether that reflects a reduced reserve of the same enzyme rather than a stress-response phenotype is unresolved, and the negative result is worth recording so that ER stress is not assumed into this entry's mechanism by analogy with other CDGs.
Show evidence (1 reference)
PMID:28662078 REFUTE In Vitro
"The unfolded protein response (UPR; the response to ER stress) was found not to be active in patient-derived fibroblasts, unlike that seen in cells from patients with PMM2-CDG or DPM1-CDG."
Refutes an activated unfolded protein response as a mechanism in DPAGT1-CDG patient cells.
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Pathophysiology

7
Biallelic Hypomorphic DPAGT1 Variants
Germline variants on both DPAGT1 alleles reduce, but do not abolish, the amount of functional GPT the cell can make. Functional analysis of patient alleles shows three mechanisms: disruption of splicing, destabilisation of the protein, and failure to localise correctly to the ER membrane. Residual activity is a requirement rather than an incidental finding, because complete loss of the enzyme is not compatible with post-implantation development.
Genetic context DPAGT1 hgnc:2995 HUGO Gene Nomenclature Committee (hgnc) Relation: this genetic context concerns this gene This genetic context concerns DPAGT1 (hgnc:2995). hgnc:2995 is a gene from the HUGO Gene Nomenclature Committee. variant_origin: GERMLINE functional_impact_category: PARTIAL_LOSS_OF_FUNCTION
Homozygous or compound heterozygous germline variants, predominantly missense or leaky splice alleles. The index genotype paired a missense allele with almost no activity against a splice allele retaining about 12 percent normal mature transcript.
Animal models
Gpt (Dpagt1) null mouse Mus musculus fails to recapitulate Complete enzyme loss produces peri-implantation lethality rather than the human phenotype, which is why every viable human genotype retains partial activity.
Downstream
Reduced GlcNAc-1-Phosphotransferase Activity Fewer functional GPT molecules reach the ER membrane, so measured transferase activity in patient microsomes falls well below carrier levels.
Show evidence (2 references)
PMID:28662078 SUPPORT In Vitro
"The results obtained, together with those of bioinformatic studies, revealed these mutations to affect the splicing process, the stability of GTP, or the ability of this protein to correctly localise in the ER membrane."
Reports the molecular consequences of six patient DPAGT1 alleles, none of which is a coding null.
PMID:10536042 SUPPORT INDIRECT Model Organism
"We find that embryos homozygous for a deletion in the GPT gene complete preimplantation development and also implant in the uterine epithelium, but die shortly thereafter between days 4-5 postfertilization with cell degeneration apparent among both embryonic and extraembryonic cell types."
Complete loss of the orthologous mouse enzyme is lethal shortly after implantation, so viable human disease must retain residual activity. The inference from mouse null to the human allelic requirement is the indirect step.
Reduced GlcNAc-1-Phosphotransferase Activity
GPT catalyses the transfer of GlcNAc-1-phosphate from UDP-GlcNAc onto dolichol phosphate on the cytoplasmic face of the endoplasmic reticulum membrane, the first and committed step of lipid-linked oligosaccharide assembly. The step is not bypassable: without it none of the subsequent glycosyltransferase reactions that build the oligosaccharide precursor can take place. Oligosaccharyltransferase activity itself is normal in patient cells, which localises the lesion to the biosynthetic arm rather than to glycan transfer.
UDP-GlcNAc:dolichol phosphate N-acetylglucosamine-1-phosphate transferase activity GO:0003975 Gene Ontology (GO) Relation: this pathophysiological event involves this molecular function This pathophysiological event involves decreased UDP-GlcNAc:dolichol phosphate N-acetylglucosamine-1-phosphate transferase activity, annotated with UDP-N-acetylglucosamine-dolichyl-phosphate N-acetylglucosaminephosphotransferase activity (GO:0003975). GO:0003975 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.
Animal models
Drosophila DPAGT1 RNAi rough-eye model Drosophila melanogaster perturbs RNAi knockdown reproduces the partial enzyme deficiency of the human disease in a tractable invertebrate system, giving a scorable phenotype for chemical and genetic modifier screening.
Downstream
Impaired Lipid-Linked Oligosaccharide Assembly
Show evidence (2 references)
PMID:28662078 SUPPORT In Vitro
"UDP-N-acetylglucosamine-dolichyl-phosphate N-acetylglucosamine phosphotransferase (GPT), the protein encoded by DPAGT1, is an endoplasmic reticulum (ER)-resident protein involved in an initial step in the N-glycosylation pathway."
Identifies the enzyme, its subcellular location and its position in the pathway.
PMID:10536042 SUPPORT Other
"Without GPT activity, subsequent steps necessary in constructing the oligosaccharide precursor cannot occur."
States the non-bypassable position of this reaction in the pathway, which is why a partial deficit propagates to the whole of N-glycosylation.
Impaired Lipid-Linked Oligosaccharide Assembly
With less dolichol-PP-GlcNAc being made, the cell assembles less of the full-length dolichol-linked oligosaccharide that the oligosaccharyltransferase uses as its donor substrate. Metabolic labelling of patient fibroblasts shows the deficit directly: radiolabelled mannose is incorporated into full-length LLO at reduced rates.
dolichol-linked oligosaccharide biosynthetic process GO:0006488 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased dolichol-linked oligosaccharide biosynthetic process (GO:0006488). GO:0006488 is a biological process from the Gene Ontology. ↓ DECREASED
Endoplasmic reticulum 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
Global Protein N-Hypoglycosylation A reduced supply of donor oligosaccharide leaves a fraction of N-glycosylation sequons unoccupied on glycoproteins throughout the cell.
Show evidence (2 references)
PMID:12872255 SUPPORT In Vitro
"revealed lowered incorporation of radiolabel into full-length dolichol-linked oligosaccharides and glycoproteins"
Measures reduced flux into full-length lipid-linked oligosaccharide in patient-derived fibroblasts, which is the claim of this node.
PMID:22304930 SUPPORT Other
"CDG-Ij (DPAGT1-CDG) is caused by a defect of the human DPAGT1 (UDP-GlcNAc: Dolichol Phosphate N-Acetylglucosamine-1-Phosphotransferase), catalyzing the first step of N-linked glycosylation."
Places the enzymatic defect at the first step of the pathway whose output this node describes. Graded OTHER because the statement is the authors' framing of the disease rather than a primary measurement.
Global Protein N-Hypoglycosylation
Because N-glycosylation is a housekeeping modification applied to a large fraction of the secreted and membrane proteome, a partial deficit at a single early enzyme is felt as the simultaneous, partial malfunction of very many unrelated proteins. This is the point at which a single-enzyme biochemical lesion becomes a multisystem disease, and it is why the downstream branches below are organ-level consequences of one shared upstream defect rather than independent mechanisms.
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
Hypoglycosylation of Neural Glycoproteins The intermediate steps between reduced glycan supply and the neurodevelopmental phenotype have not been resolved; no specific neural glycoprotein has been shown to mediate them.
Neuromuscular Transmission Impairment
Fetal Akinesia Sequence
Cataract Cataract is a recurrent feature across congenital disorders of glycosylation, but the route from generalised N-hypoglycosylation to lens opacity has not been worked out in this subtype.
Show evidence (2 references)
PMID:22304930 SUPPORT Other
"Since the majority of proteins is glycosylated, a defect in a singular CDG enzyme leads to a multisytemic disease with secondary malfunction of thousands of proteins."
States the one-enzyme-to-many-proteins amplification that this node asserts. Graded OTHER because it is the authors' framing of the disease class rather than a result of their own experiment.
PMID:23249953 SUPPORT Human Clinical
"Isoelectric focusing and high-resolution mass spectrometry analyses of serum transferrin revealed glycosylation profiles that are consistent with a CDG-I defect."
Demonstrates the hypoglycosylation in a patient's circulating glycoprotein, the accessible readout of this cellular node.
Hypoglycosylation of Neural Glycoproteins
Mechanism confidence: Hypothetical
The central nervous system is the organ most conspicuously affected. Every reported cohort describes intractable epilepsy, global developmental delay or intellectual disability, and hypotonia, and imaging in individual patients has shown delayed myelination and cerebellar vermis abnormalities. Which hypoglycosylated neural glycoproteins mediate this is not known: no intermediate between the biosynthetic deficit and the encephalopathy has been established, so this node records a consistently observed tissue-level association rather than a resolved mechanism.
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
Seizure
Global developmental delay
Microcephaly
Delayed CNS myelination
Intellectual disability The cognitive outcome of the same neural hypoglycosylation that produces the seizures and developmental delay, sharing their unknown intermediate steps.
Cerebellar hypoplasia The structural brain correlate. Most scans in the largest series were read as normal, so this is a minority finding rather than a constant feature.
Show evidence (2 references)
PMID:30117111 SUPPORT Human Clinical
"Most patients have a very severe disease course, where common findings are pronounced muscular hypotonia, intractable epilepsy, global developmental delay/intellectual disability, and early death."
Establishes the consistency of the neurological picture across the largest assembled DPAGT1-CDG cohort.
PMID:23430862 SUPPORT Human Clinical
"In the index case, the brain MRI revealed delayed myelination, and there was fiber type disproportion on muscle biopsy."
Structural correlate in the brain of the second reported family.
Neuromuscular Transmission Impairment
Mechanism confidence: Provisional
Alongside the encephalopathy, DPAGT1-CDG patients have a myasthenic component to their weakness. The evidence for treating this as a transmission defect rather than as central hypotonia is therapeutic: cholinesterase inhibition improves the muscle weakness of DPAGT1-CDG patients, as it does in the allelic myasthenic syndrome. This is the same endplate vulnerability that makes milder DPAGT1 alleles present as a pure congenital myasthenic syndrome, and the same one that the KB's Congenital Myasthenic Syndrome 15 entry curates for the neighbouring ALG14 subunit.
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
Severe muscular hypotonia
Show evidence (2 references)
PMID:37766827 SUPPORT INDIRECT Human Clinical
"Cholinesterase inhibitor therapy was found to be effective in patients against muscle weakness, supporting DPAGT1 deficiency as the underlying etiology."
The response to cholinesterase inhibition is cited as validation of a neuromuscular-junction mechanism; the inference from drug response back to the mechanism it targets is the indirect step.
PMID:28662078 SUPPORT Other
"Pathogenic mutations in DPAGT1 are manifested as two possible phenotypes: congenital disorder of glycosylation DPAGT1-CDG (also known as CDG-Ij), and limb-girdle congenital myasthenic syndrome (CMS) with tubular aggregates."
Establishes that DPAGT1 deficiency can produce a neuromuscular junction disease, which is the endplate vulnerability this node invokes.
Fetal Akinesia Sequence
A subset of patients present prenatally with markedly reduced fetal movement, and the mechanical consequences of that immobility, namely joint contractures up to frank arthrogryposis multiplex congenita and polyhydramnios from impaired swallowing, dominate the neonatal picture. This is the severe end of the same weakness that appears postnatally as hypotonia, expressed early enough to deform the developing skeleton.
Downstream
Decreased fetal movement
Arthrogryposis multiplex congenita Contractures form because the fetus does not move the developing joints through their range.
Polyhydramnios Impaired fetal swallowing is part of the akinesia sequence, and is the mechanism this node's own description already names for the polyhydramnios.
Show evidence (2 references)
PMID:22786653 SUPPORT Human Clinical
"He showed severe fetal hypokinesia phenotype with decreased fetal movements and polyhydramnios."
Reports the prenatal akinesia and its obstetric consequence in a genetically confirmed patient.
PMID:26033833 SUPPORT Human Clinical
"We describe a newborn female with arthrogryposis multiplex due to fetal akinesia secondary to CDG-DPAGT1."
States the causal sequence from fetal akinesia to arthrogryposis in DPAGT1-CDG, which is the claim of this node.
✶

Histopathology

1
Fiber type disproportion on muscle biopsy
Muscle biopsy in the index case of the second reported family showed fiber type disproportion. It is recorded here as a morphological finding rather than as evidence of a specific myopathic mechanism, since a single biopsy does not establish one.
Show evidence (1 reference)
PMID:23430862 SUPPORT Human Clinical
"In the index case, the brain MRI revealed delayed myelination, and there was fiber type disproportion on muscle biopsy."
Reports the muscle-biopsy finding directly.
⬡

Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.
Pathograph: causal mechanism network for DPAGT1-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

16
Digestive 1
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:30117111 SUPPORT Human Clinical
"A number of symptoms typical for CDG, such as feeding difficulties, cataracts, hypertrichosis, hyporeflexia, joint contractures, elevated liver enzymes, and abnormal brain magnetic resonance imaging (MRI), have been described also in this subtype."
Lists feeding difficulties among the CDG-typical symptoms described in this subtype.
Eye 2
Exotropia HP:0000577 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Exotropia (HP:0000577). HP:0000577 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:12872255 SUPPORT Human Clinical
"The patient presents with severe hypotonia, medically intractable seizures, mental retardation, microcephaly, and exotropia."
Reports exotropia in the index patient.
Cataract HP:0000518 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Bilateral cataracts, annotated with Cataract (HP:0000518). HP:0000518 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:22304930 SUPPORT Human Clinical
"We report two new patients with the novel homozygous mutation, c.341C>G (A114 G), causing a severe clinical phenotype, characterized by hyperexcitability, intractable seizures, bilateral cataracts, progressive microcephaly and muscular hypotonia."
Reports bilateral cataracts in two patients.
PMID:26033833 SUPPORT Human Clinical
"At birth, the patient was evaluated for intrauterine growth restriction, bilateral cataracts, and multiple joint contractures."
Reports bilateral cataracts present at birth in a second family.
Head and Neck 1
Microcephaly FREQUENT HP:0000252 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Microcephaly (HP:0000252), qualified as course progressive. HP:0000252 is a phenotype from the Human Phenotype Ontology.
Course: PROGRESSIVE
Show evidence (2 references)
PMID:12872255 SUPPORT Human Clinical
"The patient presents with severe hypotonia, medically intractable seizures, mental retardation, microcephaly, and exotropia."
Reports microcephaly in the index patient.
PMID:22304930 SUPPORT Human Clinical
"We report two new patients with the novel homozygous mutation, c.341C>G (A114 G), causing a severe clinical phenotype, characterized by hyperexcitability, intractable seizures, bilateral cataracts, progressive microcephaly and muscular hypotonia."
Documents that the microcephaly was progressive in these two patients, which is the basis for the PROGRESSIVE clinical course.
Integument 1
Hypertrichosis HP:0000998 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Hypertrichosis (HP:0000998). HP:0000998 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:22786653 SUPPORT Human Clinical
"soft long ears, U-shaped vermilion of the upper lip, thick skin, hypertrichosis"
Lists hypertrichosis among the neonatal findings in this patient.
Metabolism 1
Elevated liver enzymes Abnormal liver enzyme activity or concentration HP:0034685 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Elevated liver enzymes, annotated with Abnormal liver enzyme activity or concentration (HP:0034685). HP:0034685 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:30117111 SUPPORT Human Clinical
"A number of symptoms typical for CDG, such as feeding difficulties, cataracts, hypertrichosis, hyporeflexia, joint contractures, elevated liver enzymes, and abnormal brain magnetic resonance imaging (MRI), have been described also in this subtype."
Lists elevated liver enzymes among the CDG-typical symptoms described in this subtype.
Musculoskeletal 2
Severe muscular hypotonia VERY_FREQUENT HP:0006829 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Severe muscular hypotonia (HP:0006829). HP:0006829 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:12872255 SUPPORT Human Clinical
"The patient presents with severe hypotonia, medically intractable seizures, mental retardation, microcephaly, and exotropia."
Reports severe hypotonia in the index patient.
PMID:23430862 SUPPORT Human Clinical
"The patients had severe hypotonia, global developmental delay, seizures, and microcephaly but no dysmorphy."
Reports severe hypotonia across the affected infants of the second reported family.
Arthrogryposis multiplex congenita HP:0002804 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Arthrogryposis multiplex congenita (HP:0002804). HP:0002804 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:26033833 SUPPORT Human Clinical
"We describe a newborn female with arthrogryposis multiplex due to fetal akinesia secondary to CDG-DPAGT1."
Reports arthrogryposis multiplex in a genetically confirmed patient.
PMID:22786653 SUPPORT Human Clinical
"moderate multiple contractures, hypotonia and severe hypokinesia, no spontaneous movements"
Reports multiple contractures with hypokinesia at birth in a second patient.
Nervous System 6
Hyporeflexia HP:0001265 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Hyporeflexia (HP:0001265). HP:0001265 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:30117111 SUPPORT Human Clinical
"A number of symptoms typical for CDG, such as feeding difficulties, cataracts, hypertrichosis, hyporeflexia, joint contractures, elevated liver enzymes, and abnormal brain magnetic resonance imaging (MRI), have been described also in this subtype."
Lists hyporeflexia among the CDG-typical symptoms described in this subtype.
Cerebellar hypoplasia HP:0001321 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Cerebellar hypoplasia (HP:0001321). HP:0001321 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:30117111 SUPPORT Human Clinical
"In 6/10 patients, the scans were considered as normal; others had findings such as global atrophy, cerebellar hypoplasia, and thin corpus callosum."
Reports cerebellar hypoplasia among the abnormal scans, alongside the majority read as normal.
Seizure VERY_FREQUENT HP:0001250 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Medically intractable seizures, annotated with Seizure (HP:0001250). HP:0001250 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:12872255 SUPPORT Human Clinical
"The patient presents with severe hypotonia, medically intractable seizures, mental retardation, microcephaly, and exotropia."
Reports intractable seizures in the index patient in whom the disease was defined.
PMID:30117111 SUPPORT Human Clinical
"Most patients have a very severe disease course, where common findings are pronounced muscular hypotonia, intractable epilepsy, global developmental delay/intellectual disability, and early death."
Supports the VERY_FREQUENT band by listing intractable epilepsy among the common findings of the largest cohort.
Intellectual disability VERY_FREQUENT 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 (1 reference)
PMID:23249953 SUPPORT Human Clinical
"Patients in the few reported DPAGT1-CDG families exhibit severe intellectual disability (ID), epilepsy, microcephaly, severe hypotonia, facial dysmorphism and structural brain anomalies."
Summarises intellectual disability as a feature of the reported families.
Global developmental delay VERY_FREQUENT HP:0001263 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Global developmental delay (HP:0001263). HP:0001263 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:23430862 SUPPORT Human Clinical
"The patients had severe hypotonia, global developmental delay, seizures, and microcephaly but no dysmorphy."
Reports global developmental delay across the affected infants of this family.
Delayed CNS myelination HP:0002188 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Delayed CNS myelination (HP:0002188). HP:0002188 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:23430862 SUPPORT Human Clinical
"In the index case, the brain MRI revealed delayed myelination, and there was fiber type disproportion on muscle biopsy."
Reports delayed myelination on imaging in the index case of this family.
PMID:26033833 SUPPORT Human Clinical
"Brain MRI showed delayed myelination and an incomplete cerebellar vermis."
Reports delayed myelination on imaging in a second patient.
Prenatal and Birth 2
Decreased fetal movement HP:0001558 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Decreased fetal movement (HP:0001558). HP:0001558 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:22786653 SUPPORT Human Clinical
"He showed severe fetal hypokinesia phenotype with decreased fetal movements and polyhydramnios."
Reports decreased fetal movements directly.
PMID:26033833 SUPPORT Human Clinical
"Pregnancy was complicated by reduced fetal movements."
Reports reduced fetal movements in a second genetically confirmed patient.
Polyhydramnios HP:0001561 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Polyhydramnios (HP:0001561). HP:0001561 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:22786653 SUPPORT Human Clinical
"He showed severe fetal hypokinesia phenotype with decreased fetal movements and polyhydramnios."
Reports polyhydramnios alongside the reduced fetal movement.
🧬

Genetic Associations

1
DPAGT1 (DPAGT1 encodes UDP-GlcNAc:dolichol phosphate N-acetylglucosamine-1-phosphate transferase (GPT), a polytopic endoplasmic reticulum membrane protein that catalyses the first committed step of dolichol-linked oligosaccharide assembly. GPT works at the same point of the pathway as the ALG13-ALG14 heterodimer, with which it forms a multiglycosyltransferase complex that carries out the first two committed steps of asparagine-linked glycosylation; ALG14 and ALG2 are themselves disease genes, and the KB's Congenital Myasthenic Syndrome 15 entry curates the ALG14 side of the same complex. Reported DPAGT1 alleles act by disrupting splicing, destabilising the protein, or preventing its correct localisation in the ER membrane rather than by abolishing the coding sequence.)
Gene: DPAGT1 hgnc:2995 HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is DPAGT1 (hgnc:2995). hgnc:2995 is a gene from the HUGO Gene Nomenclature Committee. relationship_type: CAUSATIVE variant_origin: GERMLINE
Show evidence (2 references)
PMID:12872255 SUPPORT Human Clinical
"We have identified a novel CDG type, CDG-Ij, resulting from deficiency in UDP-GlcNAc: dolichol phosphate N-acetyl-glucosamine-1 phosphate transferase (GPT) activity encoded by DPAGT1."
Establishes DPAGT1 as the causative gene, the finding that defines this disease entity.
PMID:28662078 SUPPORT In Vitro
"The results obtained, together with those of bioinformatic studies, revealed these mutations to affect the splicing process, the stability of GTP, or the ability of this protein to correctly localise in the ER membrane."
Characterises the three routes by which reported DPAGT1 alleles reduce enzyme function, which is the basis for calling them hypomorphic rather than null.
Variants (4)
DPAGT1 c.660A>G (p.Tyr170Cys) Pathogenic
The paternal allele of the index patient. Over-expression of the mutant cDNA yields a full-length protein with essentially no transferase activity.
Show evidence (1 reference)
PMID:12872255 SUPPORT In Vitro
"The paternal allele cDNA produces a full-length protein with almost no activity when over-expressed in CHO cells."
Establishes the functional consequence of the paternal missense allele in a heterologous expression assay.
DPAGT1 index maternal splicing allele Pathogenic
The maternal allele of the index patient, which produces only a small fraction of normal mature transcript, the remainder being aberrantly spliced and frameshifted. It is the residual normal transcript from this allele that supplies the surviving enzyme activity.
Show evidence (1 reference)
PMID:12872255 SUPPORT In Vitro
"The maternal allele makes only about 12% normal mature mRNA, while the remainder shows a complex exon skipping pattern that shifts the reading frame encoding a truncated non-functional GPT protein."
Quantifies the leaky splicing that leaves residual wild-type transcript on the maternal allele.
DPAGT1 c.341C>G (p.Ala114Gly) Pathogenic
A homozygous allele in two patients with a severe phenotype of hyperexcitability, intractable seizures, bilateral cataracts, progressive microcephaly and hypotonia; both died in the first year of life.
Show evidence (1 reference)
PMID:22304930 SUPPORT Human Clinical
"We report two new patients with the novel homozygous mutation, c.341C>G (A114 G), causing a severe clinical phenotype, characterized by hyperexcitability, intractable seizures, bilateral cataracts, progressive microcephaly and muscular hypotonia."
Names the allele and the phenotype it produced in the homozygous state.
DPAGT1 c.902G>A (p.Arg301His) Pathogenic
A homozygous allele identified by homozygosity mapping in a large consanguineous family with 18 affected infants, in which the disorder was uniformly fatal.
Show evidence (1 reference)
PMID:23430862 SUPPORT Human Clinical
"Sequencing ALG9 did not reveal any mutations while analysis of DPAGT1 identified a novel homozygous mutation c.902G>A (p.R301H) in two affected infants."
Names the allele and the mapping route by which it was found.
💊

Medical Actions

3
Anticonvulsant agent therapy
Action: Anticonvulsant agent therapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Anticonvulsant agent therapy, annotated with Anticonvulsant Therapy (NCIT:C64172). NCIT:C64172 is a clinical intervention from the NCI Thesaurus. Ontology label: Anticonvulsant Therapy NCIT:C64172
Agent: anticonvulsant agent NCIT:C264 NCI Thesaurus (NCIT) Relation: this treatment uses this therapeutic agent This treatment uses anticonvulsant agent (NCIT:C264). NCIT:C264 is a therapeutic agent from the NCI Thesaurus.
Platform: Small molecule
Antiepileptic drugs are the mainstay of managing the seizures, which are typically early-onset and often refractory. This is symptomatic management: no anticonvulsant addresses the glycosylation defect, and seizure control is frequently incomplete.
Target Phenotypes: Medically intractable seizures HP:0001250 Human Phenotype Ontology (HP) Relation: this treatment targets this phenotype This treatment targets Medically intractable seizures, annotated with Seizure (HP:0001250). HP:0001250 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:37766827 SUPPORT Human Clinical
"A severe disease course with hypotonia, cataracts, skeletal deformities, resistant epilepsy, intellectual disability, global developmental delay, premature death has been described in most patients with DPAGT1-CDG."
Establishes that the epilepsy requiring this treatment is typically resistant, which is the constraint on what anticonvulsants achieve here.
Pyridostigmine
Action: PharmacotherapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Pharmacotherapy (NCIT:C15986). NCIT:C15986 is a clinical intervention from the NCI Thesaurus. NCIT:C15986
Agent: pyridostigmine CHEBI:8665 Chemical Entities of Biological Interest (CHEBI) Relation: this treatment uses this therapeutic agent This treatment uses pyridostigmine (CHEBI:8665). CHEBI:8665 is a therapeutic agent from Chemical Entities of Biological Interest.
Platform: Small molecule
An acetylcholinesterase inhibitor. It targets the myasthenic component of the weakness by prolonging acetylcholine dwell time at the endplate, and has produced measurable benefit in DPAGT1-CDG patients whose muscle weakness is prominent. It does nothing for the encephalopathy or the underlying glycosylation defect.
Mechanism Target:
MODULATES Neuromuscular Transmission Impairment — Inhibiting acetylcholinesterase increases the time acetylcholine remains in the synaptic cleft, compensating for reduced endplate signalling without restoring glycosylation.
Show evidence (1 reference)
PMID:37766827 SUPPORT Human Clinical
"We started pyridostigmine treatment in our patient with more pronounced muscle weakness, and we saw its benefit."
Reports a clinical benefit of pyridostigmine directed at the weakness this mechanism node describes.
Show evidence (1 reference)
PMID:37766827 SUPPORT Human Clinical
"Cholinesterase inhibitor therapy was found to be effective in patients against muscle weakness, supporting DPAGT1 deficiency as the underlying etiology."
States that cholinesterase inhibition is effective against the muscle weakness in these patients.
Supportive and multidisciplinary care
Action: Supportive CareNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Supportive Care (NCIT:C15747). NCIT:C15747 is a clinical intervention from the NCI Thesaurus. NCIT:C15747
There is no disease-modifying therapy for DPAGT1-CDG. Care is supportive: feeding support, respiratory management, seizure control, ophthalmological review for cataract, and orthopaedic management of contractures, with genetic counselling for the family given the recessive recurrence risk.
Show evidence (1 reference)
PMID:39466823 SUPPORT Other
"DPAGT1-CDG is a Congenital Disorder of Glycosylation (CDG) that lacks effective therapies."
States the absence of disease-modifying treatment that makes supportive care the standard of care.
🔬

Biochemical Markers

1
Serum Transferrin Isoform Profile
Show evidence (2 references)
PMID:22786653 SUPPORT Human Clinical
"Isoelectrofocusing of serum transferrin showed a type 1 pattern with increased asialo- and disialotransferrin."
Reports the type I pattern and the specific isoform shift that defines it.
PMID:26033833 SUPPORT Human Clinical
"Transferrin isoelectric focusing was suggestive of a type I congenital disorder of glycosylation."
Independent confirmation of the type I pattern in a second patient.
🔬

Diagnosis

2
Serum transferrin glycoform analysis
First-line screen. A type I transferrin pattern places the defect in lipid-linked oligosaccharide assembly or transfer and prompts sequencing; it does not name the gene.
Show evidence (1 reference)
PMID:23249953 SUPPORT Human Clinical
"Isoelectric focusing and high-resolution mass spectrometry analyses of serum transferrin revealed glycosylation profiles that are consistent with a CDG-I defect."
Shows the screen classifying a patient into the CDG-I group, which is what it is for.
Exome or genome sequencing of DPAGT1
Definitive diagnosis rests on identifying biallelic DPAGT1 variants. Broad sequencing has been the usual route since the phenotype is a nonspecific infantile epileptic encephalopathy, and homozygosity mapping served the same purpose in consanguineous families before exome sequencing was routine.
Show evidence (2 references)
PMID:23249953 SUPPORT Human Clinical
"Exome sequencing revealed a compound heterozygous missense mutation, c.85A>T (p.I29F) and c.503T>C (p.L168P), in the DPAGT1 gene."
Illustrates exome sequencing as the route to a molecular diagnosis in a patient whose phenotype was too mild to suggest the gene.
PMID:23430862 SUPPORT Human Clinical
"Homozygosity mapping identified a large block of homozygosity on chromosome 11p15.5-q25 where two known CDG-I causing genes, ALG9 and DPAGT1, are located."
Illustrates the mapping route used in a large consanguineous family.
📈

Progression

2
Severe infantile course
Age: birth to 5 years
The usual course. Onset is at or before birth with hypotonia, often reduced fetal movement and contractures, followed by early-onset intractable epilepsy and global developmental delay, with death in infancy or early childhood.
Show evidence (2 references)
PMID:23430862 SUPPORT Human Clinical
"The disorder was fatal in all affected cases and mostly in early infancy."
Documents the fatal early-infantile course in the largest single family.
PMID:22304930 SUPPORT Human Clinical
"Both our patients died within their first year of life."
Independent report of death within the first year in a second family.
Attenuated course surviving to adulthood
Age: adulthood
A minority of patients carrying milder allele combinations survive into adult life with moderate intellectual disability, epilepsy, hypotonia and behavioural problems, and a stable rather than progressive course. Two such adults were the first to show that the DPAGT1-CDG spectrum extends well beyond lethal infantile disease.
Show evidence (2 references)
PMID:23249953 SUPPORT Human Clinical
"In this study, we report a non-consanguineous family with two affected adults presenting with a relatively mild phenotype consisting of moderate ID, epilepsy, hypotonia, aggressive behavior and balance problems."
Documents the attenuated adult phenotype that defines this course.
PMID:30117111 SUPPORT Human Clinical
"We also present data on three affected females that are young adults and have a somewhat milder, stable disease."
Independent confirmation that a milder, stable adult course occurs.
📊

Prevalence

1
Worldwide
Cases In Literature Ultra Rare
Fewer than fifty patients have been reported since the disease was defined in 2003. A 2019 series counted 28 previously published patients from 10 families and added 11 more from 8 families; 18 of the earlier patients came from a single consanguineous family, so the number of independent ascertainments is smaller than the patient count suggests. No population prevalence estimate has been published.
Show evidence (1 reference)
PMID:30117111 SUPPORT Human Clinical
"Fourteen disease-causing mutations in 28 patients from 10 families have previously been reported to cause the systemic form, DPAGT1-CDG. We here report on another 11 patients from 8 families and add 10 new mutations."
Gives the published patient and family counts on which this ultra-rare classification rests.
🐁

Animal Models

2
Gpt (Dpagt1) null mouse
A germline deletion of the mouse GlcNAc-1-phosphotransferase gene. Nullizygous embryos implant but die within a day or two, before any organ that DPAGT1-CDG affects has formed. The model is therefore not a model of the human disease; its value is the negative constraint it places on human genotypes.
Species
Mus musculus
Genotype
Homozygous germline deletion of the mouse GPT (Dpagt1) gene
Genes
DPAGT1 hgnc:2995 HUGO Gene Nomenclature Committee (hgnc) Relation: this experimental model concerns this gene This experimental model concerns DPAGT1 (hgnc:2995). hgnc:2995 is a gene from the HUGO Gene Nomenclature Committee.
Publication
PMID:10536042
Pathograph links
Biallelic Hypomorphic DPAGT1 Variants fails to recapitulate fidelity: low Complete enzyme loss produces peri-implantation lethality rather than the human phenotype, which is why every viable human genotype retains partial activity.
Limitations: A homozygous null, not a hypomorph, so it models the wrong end of the allelic series: the embryos die at days 4-5 post-fertilisation, long before the nervous system, lens or neuromuscular junction exist, and no DPAGT1-CDG phenotype can be assessed in them. A hypomorphic mouse allele matching a patient genotype has not been reported.
Show evidence (1 reference)
PMID:10536042 SUPPORT Model Organism
"We find that embryos homozygous for a deletion in the GPT gene complete preimplantation development and also implant in the uterine epithelium, but die shortly thereafter between days 4-5 postfertilization with cell degeneration apparent among both embryonic and extraembryonic cell types."
Documents the lethal stage, which is what prevents this model from recapitulating the human disease.
Show evidence (1 reference)
PMID:10536042 SUPPORT Model Organism
"These results indicate that GPT function is essential in early embryogenesis and suggest that N-glycosylation is needed for the viability of cells comprising the peri-implantation stage embryo."
The authors' own conclusion that the enzyme is essential, which is the constraint this model contributes.
Drosophila DPAGT1 RNAi rough-eye model
An eye-based knockdown model in which reduced DPAGT1 expression produces a small, improperly developed eye that can be scored quantitatively. It was used for a 1,520-compound repurposing screen, which identified 42 suppressors and implicated dopamine D2 receptor signalling as a modifier of DPAGT1 deficiency. The readout is a developmental eye phenotype, not any clinical feature of DPAGT1-CDG.
Species
Drosophila melanogaster
Genotype
Eye-directed RNA interference knockdown of the Drosophila DPAGT1 orthologue
Genes
DPAGT1 hgnc:2995 HUGO Gene Nomenclature Committee (hgnc) Relation: this experimental model concerns this gene This experimental model concerns DPAGT1 (hgnc:2995). hgnc:2995 is a gene from the HUGO Gene Nomenclature Committee.
Publication
PMID:39466823
Pathograph links
Reduced GlcNAc-1-Phosphotransferase Activity perturbs fidelity: low RNAi knockdown reproduces the partial enzyme deficiency of the human disease in a tractable invertebrate system, giving a scorable phenotype for chemical and genetic modifier screening.
Limitations: An invertebrate developmental eye phenotype with no relationship to the encephalopathy, epilepsy, hypotonia or cataract of the human disease, and no measurement of glycosylation in the model itself. Hits from it are leads for mechanism, not evidence of therapeutic effect in patients.
Readouts
Drosophila eye size
Direction: RESTORED
Interpretation: Partial rescue of the small-eye phenotype by dopamine D2 receptor inhibition, the screen's principal hit.
Show evidence (1 reference)
PMID:39466823 SUPPORT Model Organism
"Notably from this screen, we found that pharmacological and genetic inhibition of the dopamine D2 receptor partially rescued the DPAGT1-CDG model."
Reports the direction of the eye-size readout on which the screen's conclusion rests.
Show evidence (1 reference)
PMID:39466823 SUPPORT Model Organism
"We used a Drosophila rough eye model of DPAGT1-CDG with an improperly developed, small eye phenotype."
Describes the model system and its readout.
{ }

Source YAML

click to show 
name: DPAGT1-congenital disorder of glycosylation
creation_date: "2026-09-03T00:00:00Z"
category: Mendelian
description: >-
  DPAGT1-CDG (formerly CDG-Ij) is a rare autosomal recessive congenital disorder
  of N-linked glycosylation caused by biallelic hypomorphic variants in DPAGT1,
  which encodes UDP-GlcNAc:dolichol phosphate N-acetylglucosamine-1-phosphate
  transferase (GPT). GPT is an endoplasmic-reticulum-resident enzyme that
  catalyses the first committed step of the lipid-linked oligosaccharide (LLO)
  pathway on the cytoplasmic face of the ER membrane: the transfer of
  GlcNAc-1-phosphate from UDP-GlcNAc onto dolichol phosphate to give
  dolichol-PP-GlcNAc. Because nothing downstream in LLO assembly can proceed
  without that first sugar, reduced GPT activity limits the supply of mature
  dolichol-linked oligosaccharide available to the oligosaccharyltransferase and
  leaves glycoproteins across every tissue incompletely N-glycosylated. The
  laboratory signature is a type I serum transferrin isoform pattern, and the
  clinical picture is a severe multisystem encephalopathy.

  The disease requires residual enzyme activity. In the index patient GPT
  activity was about 10 percent of normal, and complete loss of the orthologous
  mouse enzyme is lethal shortly after implantation, so no human null genotype
  is expected to be viable. This is why every reported genotype is missense,
  splice-leaky, or a compound of the two, and it is the most plausible
  explanation for the disease's wide severity range: patients with the least
  residual activity die in the first years of life with intractable epilepsy,
  while a minority carrying milder allele combinations reach adulthood with
  moderate intellectual disability, epilepsy and hypotonia.

  Cardinal features are pronounced muscular hypotonia, medically intractable
  seizures, global developmental delay and intellectual disability,
  microcephaly, and exotropia; cataracts, joint contractures, fetal akinesia
  with reduced fetal movement, hypertrichosis and feeding difficulties recur
  across the reported cohorts. There is no disease-modifying therapy.
  Management is supportive, with anticonvulsants for the epilepsy and
  cholinesterase inhibition for the myasthenic component of the muscle
  weakness.

  Scope. This entry covers MONDO:0011964 only, the systemic encephalopathic
  disease. The much milder allelic DPAGT1-related limb-girdle congenital
  myasthenic syndrome with tubular aggregates (CMS-13) is a separate MONDO term
  (MONDO:0013883, OMIM:614750) and is curated in the KB's
  Congenital Myasthenic Syndrome entry; it is deliberately not modelled here as
  a subtype. See `notes` for the reasoning.
disease_term:
  preferred_term: DPAGT1-congenital disorder of glycosylation
  term:
    id: MONDO:0011964
    label: DPAGT1-congenital disorder of glycosylation
parents:
- congenital disorder of glycosylation type I
- disorder of protein N-glycosylation
synonyms:
- DPAGT1-CDG
- CDG-Ij
- CDG1J
- CDGIj
- congenital disorder of glycosylation type Ij
- carbohydrate deficient glycoprotein syndrome type Ij
- dolichyl-phosphate N-acetylgalactosamine phosphotransferase deficiency
inheritance:
- name: Autosomal recessive
  inheritance_term:
    preferred_term: Autosomal recessive inheritance
    term:
      id: HP:0000007
      label: Autosomal recessive inheritance
  description: >-
    Disease requires biallelic DPAGT1 variants, homozygous or compound
    heterozygous, with unaffected heterozygous carrier parents. In the index
    family the paternal allele carried a missense change and the maternal
    allele a splicing defect; homozygous missense genotypes have since been
    reported in consanguineous families. No complete biallelic null has been
    described, consistent with the enzyme's essential role.
  evidence:
  - reference: PMID:12872255
    reference_title: "Deficiency of UDP-GlcNAc:Dolichol Phosphate N-Acetylglucosamine-1
      Phosphate Transferase (DPAGT1) causes a novel congenital disorder of Glycosylation
      Type Ij."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In vitro enzymatic analysis of microsomal fractions from the cultured
      cells indicated that oligosaccharyltransferase activity is normal, but the GPT
      activity is reduced to approximately 10% of normal levels while parents have
      heterozygous levels."
    explanation: Documents biallelic involvement in the proband with intermediate
      enzyme levels in both unaffected parents, the biochemical signature of recessive
      inheritance.
  - reference: PMID:37766827
    reference_title: "DPAGT1-CDG: Report of Two New Pediatric Patients and Brief Review
      of the Literature."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "It is a rare autosomal recessive disease or a milder version with congenital
      myasthenic syndrome known as DPAGT1-CMS."
    explanation: States the mode of inheritance directly.
genetic:
- name: DPAGT1
  gene_term:
    preferred_term: DPAGT1
    term:
      id: hgnc:2995
      label: DPAGT1
  relationship_type: CAUSATIVE
  variant_origin: GERMLINE
  association: >-
    DPAGT1 encodes UDP-GlcNAc:dolichol phosphate N-acetylglucosamine-1-phosphate
    transferase (GPT), a polytopic endoplasmic reticulum membrane protein that
    catalyses the first committed step of dolichol-linked oligosaccharide
    assembly. GPT works at the same point of the pathway as the ALG13-ALG14
    heterodimer, with which it forms a multiglycosyltransferase complex that
    carries out the first two committed steps of asparagine-linked
    glycosylation; ALG14 and ALG2 are themselves disease genes, and the KB's
    Congenital Myasthenic Syndrome 15 entry curates the ALG14 side of the same
    complex. Reported DPAGT1 alleles act by disrupting splicing, destabilising
    the protein, or preventing its correct localisation in the ER membrane
    rather than by abolishing the coding sequence.
  variants:
  - name: "DPAGT1 c.660A>G (p.Tyr170Cys)"
    description: >-
      The paternal allele of the index patient. Over-expression of the mutant
      cDNA yields a full-length protein with essentially no transferase
      activity.
    clinical_significance: PATHOGENIC
    evidence:
    - reference: PMID:12872255
      reference_title: "Deficiency of UDP-GlcNAc:Dolichol Phosphate N-Acetylglucosamine-1
        Phosphate Transferase (DPAGT1) causes a novel congenital disorder of Glycosylation
        Type Ij."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "The paternal allele cDNA produces a full-length protein with almost
        no activity when over-expressed in CHO cells."
      explanation: Establishes the functional consequence of the paternal missense
        allele in a heterologous expression assay.
  - name: "DPAGT1 index maternal splicing allele"
    description: >-
      The maternal allele of the index patient, which produces only a small
      fraction of normal mature transcript, the remainder being aberrantly
      spliced and frameshifted. It is the residual normal transcript from this
      allele that supplies the surviving enzyme activity.
    clinical_significance: PATHOGENIC
    evidence:
    - reference: PMID:12872255
      reference_title: "Deficiency of UDP-GlcNAc:Dolichol Phosphate N-Acetylglucosamine-1
        Phosphate Transferase (DPAGT1) causes a novel congenital disorder of Glycosylation
        Type Ij."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "The maternal allele makes only about 12% normal mature mRNA, while
        the remainder shows a complex exon skipping pattern that shifts the reading
        frame encoding a truncated non-functional GPT protein."
      explanation: Quantifies the leaky splicing that leaves residual wild-type
        transcript on the maternal allele.
  - name: "DPAGT1 c.341C>G (p.Ala114Gly)"
    description: >-
      A homozygous allele in two patients with a severe phenotype of
      hyperexcitability, intractable seizures, bilateral cataracts, progressive
      microcephaly and hypotonia; both died in the first year of life.
    clinical_significance: PATHOGENIC
    evidence:
    - reference: PMID:22304930
      reference_title: "Congenital disorder of glycosylation type Ij (CDG-Ij, DPAGT1-CDG):
        extending the clinical and molecular spectrum of a rare disease."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "We report two new patients with the novel homozygous mutation, c.341C>G
        (A114 G), causing a severe clinical phenotype, characterized by hyperexcitability,
        intractable seizures, bilateral cataracts, progressive microcephaly and muscular
        hypotonia."
      explanation: Names the allele and the phenotype it produced in the homozygous
        state.
  - name: "DPAGT1 c.902G>A (p.Arg301His)"
    description: >-
      A homozygous allele identified by homozygosity mapping in a large
      consanguineous family with 18 affected infants, in which the disorder was
      uniformly fatal.
    clinical_significance: PATHOGENIC
    evidence:
    - reference: PMID:23430862
      reference_title: "Further Delineation of the Phenotype of Congenital Disorder
        of Glycosylation DPAGT1-CDG (CDG-Ij) Identified by Homozygosity Mapping."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Sequencing ALG9 did not reveal any mutations while analysis of DPAGT1
        identified a novel homozygous mutation c.902G>A (p.R301H) in two affected
        infants."
      explanation: Names the allele and the mapping route by which it was found.
  evidence:
  - reference: PMID:12872255
    reference_title: "Deficiency of UDP-GlcNAc:Dolichol Phosphate N-Acetylglucosamine-1
      Phosphate Transferase (DPAGT1) causes a novel congenital disorder of Glycosylation
      Type Ij."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We have identified a novel CDG type, CDG-Ij, resulting from deficiency
      in UDP-GlcNAc: dolichol phosphate N-acetyl-glucosamine-1 phosphate transferase
      (GPT) activity encoded by DPAGT1."
    explanation: Establishes DPAGT1 as the causative gene, the finding that defines
      this disease entity.
  - reference: PMID:28662078
    reference_title: "DPAGT1-CDG: Functional analysis of disease-causing pathogenic
      mutations and role of endoplasmic reticulum stress."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "The results obtained, together with those of bioinformatic studies,
      revealed these mutations to affect the splicing process, the stability of GTP,
      or the ability of this protein to correctly localise in the ER membrane."
    explanation: Characterises the three routes by which reported DPAGT1 alleles
      reduce enzyme function, which is the basis for calling them hypomorphic rather
      than null.
pathophysiology:
- name: Biallelic Hypomorphic DPAGT1 Variants
  biological_scale: MOLECULAR
  description: >-
    Germline variants on both DPAGT1 alleles reduce, but do not abolish, the
    amount of functional GPT the cell can make. Functional analysis of patient
    alleles shows three mechanisms: disruption of splicing, destabilisation of
    the protein, and failure to localise correctly to the ER membrane. Residual
    activity is a requirement rather than an incidental finding, because
    complete loss of the enzyme is not compatible with post-implantation
    development.
  genetic_context:
    genes:
    - preferred_term: DPAGT1
      term:
        id: hgnc:2995
        label: DPAGT1
    variant_origin: GERMLINE
    functional_impact_category: PARTIAL_LOSS_OF_FUNCTION
    description: >-
      Homozygous or compound heterozygous germline variants, predominantly
      missense or leaky splice alleles. The index genotype paired a missense
      allele with almost no activity against a splice allele retaining about
      12 percent normal mature transcript.
  evidence:
  - reference: PMID:28662078
    reference_title: "DPAGT1-CDG: Functional analysis of disease-causing pathogenic
      mutations and role of endoplasmic reticulum stress."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "The results obtained, together with those of bioinformatic studies,
      revealed these mutations to affect the splicing process, the stability of GTP,
      or the ability of this protein to correctly localise in the ER membrane."
    explanation: Reports the molecular consequences of six patient DPAGT1 alleles,
      none of which is a coding null.
  - reference: PMID:10536042
    reference_title: "A recessive deletion in the GlcNAc-1-phosphotransferase gene
      results in peri-implantation embryonic lethality."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    directness: INDIRECT
    snippet: "We find that embryos homozygous for a deletion in the GPT gene complete
      preimplantation development and also implant in the uterine epithelium, but
      die shortly thereafter between days 4-5 postfertilization with cell degeneration
      apparent among both embryonic and extraembryonic cell types."
    explanation: Complete loss of the orthologous mouse enzyme is lethal shortly
      after implantation, so viable human disease must retain residual activity.
      The inference from mouse null to the human allelic requirement is the indirect
      step.
  downstream:
  - target: Reduced GlcNAc-1-Phosphotransferase Activity
    causal_link_type: DIRECT
    description: >-
      Fewer functional GPT molecules reach the ER membrane, so measured
      transferase activity in patient microsomes falls well below carrier
      levels.
    evidence:
    - reference: PMID:12872255
      reference_title: "Deficiency of UDP-GlcNAc:Dolichol Phosphate N-Acetylglucosamine-1
        Phosphate Transferase (DPAGT1) causes a novel congenital disorder of Glycosylation
        Type Ij."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "In vitro enzymatic analysis of microsomal fractions from the cultured
        cells indicated that oligosaccharyltransferase activity is normal, but the
        GPT activity is reduced to approximately 10% of normal levels while parents
        have heterozygous levels."
      explanation: Directly measures the fall in transferase activity produced by
        the patient's genotype, with a gene-dosage relationship across the family.

- name: Reduced GlcNAc-1-Phosphotransferase Activity
  biological_scale: MOLECULAR
  description: >-
    GPT catalyses the transfer of GlcNAc-1-phosphate from UDP-GlcNAc onto
    dolichol phosphate on the cytoplasmic face of the endoplasmic reticulum
    membrane, the first and committed step of lipid-linked oligosaccharide
    assembly. The step is not bypassable: without it none of the subsequent
    glycosyltransferase reactions that build the oligosaccharide precursor can
    take place. Oligosaccharyltransferase activity itself is normal in patient
    cells, which localises the lesion to the biosynthetic arm rather than to
    glycan transfer.
  molecular_functions:
  - preferred_term: UDP-GlcNAc:dolichol phosphate N-acetylglucosamine-1-phosphate
      transferase activity
    term:
      id: GO:0003975
      label: UDP-N-acetylglucosamine-dolichyl-phosphate N-acetylglucosaminephosphotransferase
        activity
    modifier: DECREASED
  locations:
  - preferred_term: Endoplasmic reticulum membrane
    term:
      id: GO:0005789
      label: endoplasmic reticulum membrane
  evidence:
  - reference: PMID:28662078
    reference_title: "DPAGT1-CDG: Functional analysis of disease-causing pathogenic
      mutations and role of endoplasmic reticulum stress."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "UDP-N-acetylglucosamine-dolichyl-phosphate N-acetylglucosamine phosphotransferase
      (GPT), the protein encoded by DPAGT1, is an endoplasmic reticulum (ER)-resident
      protein involved in an initial step in the N-glycosylation pathway."
    explanation: Identifies the enzyme, its subcellular location and its position
      in the pathway.
  - reference: PMID:10536042
    reference_title: "A recessive deletion in the GlcNAc-1-phosphotransferase gene
      results in peri-implantation embryonic lethality."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Without GPT activity, subsequent steps necessary in constructing the
      oligosaccharide precursor cannot occur."
    explanation: States the non-bypassable position of this reaction in the pathway,
      which is why a partial deficit propagates to the whole of N-glycosylation.
  downstream:
  - target: Impaired Lipid-Linked Oligosaccharide Assembly
    causal_link_type: DIRECT

- name: Impaired Lipid-Linked Oligosaccharide Assembly
  biological_scale: MOLECULAR
  description: >-
    With less dolichol-PP-GlcNAc being made, the cell assembles less of the
    full-length dolichol-linked oligosaccharide that the
    oligosaccharyltransferase uses as its donor substrate. Metabolic labelling
    of patient fibroblasts shows the deficit directly: radiolabelled mannose is
    incorporated into full-length LLO at reduced rates.
  biological_processes:
  - preferred_term: dolichol-linked oligosaccharide biosynthetic process
    term:
      id: GO:0006488
      label: dolichol-linked oligosaccharide biosynthetic process
    modifier: DECREASED
  locations:
  - preferred_term: Endoplasmic reticulum membrane
    term:
      id: GO:0005789
      label: endoplasmic reticulum membrane
  evidence:
  - reference: PMID:12872255
    reference_title: "Deficiency of UDP-GlcNAc:Dolichol Phosphate N-Acetylglucosamine-1
      Phosphate Transferase (DPAGT1) causes a novel congenital disorder of Glycosylation
      Type Ij."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "revealed lowered incorporation of radiolabel into full-length dolichol-linked
      oligosaccharides and glycoproteins"
    explanation: Measures reduced flux into full-length lipid-linked oligosaccharide
      in patient-derived fibroblasts, which is the claim of this node.
  - reference: PMID:22304930
    reference_title: "Congenital disorder of glycosylation type Ij (CDG-Ij, DPAGT1-CDG):
      extending the clinical and molecular spectrum of a rare disease."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "CDG-Ij (DPAGT1-CDG) is caused by a defect of the human DPAGT1 (UDP-GlcNAc:
      Dolichol Phosphate N-Acetylglucosamine-1-Phosphotransferase), catalyzing the
      first step of N-linked glycosylation."
    explanation: Places the enzymatic defect at the first step of the pathway whose
      output this node describes. Graded OTHER because the statement is the authors'
      framing of the disease rather than a primary measurement.
  downstream:
  - target: Global Protein N-Hypoglycosylation
    causal_link_type: DIRECT
    description: >-
      A reduced supply of donor oligosaccharide leaves a fraction of
      N-glycosylation sequons unoccupied on glycoproteins throughout the cell.
    evidence:
    - reference: PMID:12872255
      reference_title: "Deficiency of UDP-GlcNAc:Dolichol Phosphate N-Acetylglucosamine-1
        Phosphate Transferase (DPAGT1) causes a novel congenital disorder of Glycosylation
        Type Ij."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "revealed lowered incorporation of radiolabel into full-length dolichol-linked
        oligosaccharides and glycoproteins"
      explanation: The same labelling experiment measures the deficit at both ends
        of this edge, in lipid-linked oligosaccharide and in the glycoproteins
        downstream of it.

- name: Global Protein N-Hypoglycosylation
  biological_scale: CELLULAR
  description: >-
    Because N-glycosylation is a housekeeping modification applied to a large
    fraction of the secreted and membrane proteome, a partial deficit at a
    single early enzyme is felt as the simultaneous, partial malfunction of
    very many unrelated proteins. This is the point at which a single-enzyme
    biochemical lesion becomes a multisystem disease, and it is why the
    downstream branches below are organ-level consequences of one shared
    upstream defect rather than independent mechanisms.
  biological_processes:
  - preferred_term: protein N-linked glycosylation
    term:
      id: GO:0006487
      label: protein N-linked glycosylation
    modifier: DECREASED
  evidence:
  - reference: PMID:22304930
    reference_title: "Congenital disorder of glycosylation type Ij (CDG-Ij, DPAGT1-CDG):
      extending the clinical and molecular spectrum of a rare disease."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Since the majority of proteins is glycosylated, a defect in a singular
      CDG enzyme leads to a multisytemic disease with secondary malfunction of thousands
      of proteins."
    explanation: States the one-enzyme-to-many-proteins amplification that this node
      asserts. Graded OTHER because it is the authors' framing of the disease class
      rather than a result of their own experiment.
  - reference: PMID:23249953
    reference_title: A compound heterozygous mutation in DPAGT1 results in a congenital
      disorder of glycosylation with a relatively mild phenotype.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Isoelectric focusing and high-resolution mass spectrometry analyses
      of serum transferrin revealed glycosylation profiles that are consistent with
      a CDG-I defect."
    explanation: Demonstrates the hypoglycosylation in a patient's circulating
      glycoprotein, the accessible readout of this cellular node.
  downstream:
  - target: Hypoglycosylation of Neural Glycoproteins
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      The intermediate steps between reduced glycan supply and the
      neurodevelopmental phenotype have not been resolved; no specific neural
      glycoprotein has been shown to mediate them.
  - target: Neuromuscular Transmission Impairment
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Fetal Akinesia Sequence
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Cataract
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Cataract is a recurrent feature across congenital disorders of
      glycosylation, but the route from generalised N-hypoglycosylation to lens
      opacity has not been worked out in this subtype.

- name: Hypoglycosylation of Neural Glycoproteins
  biological_scale: TISSUE
  description: >-
    The central nervous system is the organ most conspicuously affected. Every
    reported cohort describes intractable epilepsy, global developmental delay
    or intellectual disability, and hypotonia, and imaging in individual
    patients has shown delayed myelination and cerebellar vermis
    abnormalities. Which hypoglycosylated neural glycoproteins mediate this is
    not known: no intermediate between the biosynthetic deficit and the
    encephalopathy has been established, so this node records a consistently
    observed tissue-level association rather than a resolved mechanism.
  biological_processes:
  - preferred_term: protein N-linked glycosylation
    term:
      id: GO:0006487
      label: protein N-linked glycosylation
    modifier: DECREASED
  mechanism_confidence: HYPOTHETICAL
  evidence:
  - reference: PMID:30117111
    reference_title: "DPAGT1 Deficiency with Encephalopathy (DPAGT1-CDG): Clinical
      and Genetic Description of 11 New Patients."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Most patients have a very severe disease course, where common findings
      are pronounced muscular hypotonia, intractable epilepsy, global developmental
      delay/intellectual disability, and early death."
    explanation: Establishes the consistency of the neurological picture across the
      largest assembled DPAGT1-CDG cohort.
  - reference: PMID:23430862
    reference_title: "Further Delineation of the Phenotype of Congenital Disorder
      of Glycosylation DPAGT1-CDG (CDG-Ij) Identified by Homozygosity Mapping."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In the index case, the brain MRI revealed delayed myelination, and there
      was fiber type disproportion on muscle biopsy."
    explanation: Structural correlate in the brain of the second reported family.
  downstream:
  - target: Seizure
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Global developmental delay
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Microcephaly
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Delayed CNS myelination
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Intellectual disability
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      The cognitive outcome of the same neural hypoglycosylation that produces the
      seizures and developmental delay, sharing their unknown intermediate steps.
  - target: Cerebellar hypoplasia
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      The structural brain correlate. Most scans in the largest series were read
      as normal, so this is a minority finding rather than a constant feature.
    evidence:
    - reference: PMID:30117111
      reference_title: "DPAGT1 Deficiency with Encephalopathy (DPAGT1-CDG): Clinical and Genetic Description of 11 New Patients."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "In 6/10 patients, the scans were considered as normal; others had findings such as global atrophy, cerebellar hypoplasia, and thin corpus callosum."
      explanation: Reports cerebellar hypoplasia among the imaging findings, in a minority of the series.

- name: Neuromuscular Transmission Impairment
  biological_scale: TISSUE
  description: >-
    Alongside the encephalopathy, DPAGT1-CDG patients have a myasthenic
    component to their weakness. The evidence for treating this as a
    transmission defect rather than as central hypotonia is therapeutic:
    cholinesterase inhibition improves the muscle weakness of DPAGT1-CDG
    patients, as it does in the allelic myasthenic syndrome. This is the same
    endplate vulnerability that makes milder DPAGT1 alleles present as a pure
    congenital myasthenic syndrome, and the same one that the KB's Congenital
    Myasthenic Syndrome 15 entry curates for the neighbouring ALG14 subunit.
  biological_processes:
  - preferred_term: protein N-linked glycosylation
    term:
      id: GO:0006487
      label: protein N-linked glycosylation
    modifier: DECREASED
  mechanism_confidence: PROVISIONAL
  evidence:
  - reference: PMID:37766827
    reference_title: "DPAGT1-CDG: Report of Two New Pediatric Patients and Brief Review
      of the Literature."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    directness: INDIRECT
    snippet: "Cholinesterase inhibitor therapy was found to be effective in patients
      against muscle weakness, supporting DPAGT1 deficiency as the underlying etiology."
    explanation: The response to cholinesterase inhibition is cited as validation
      of a neuromuscular-junction mechanism; the inference from drug response back
      to the mechanism it targets is the indirect step.
  - reference: PMID:28662078
    reference_title: "DPAGT1-CDG: Functional analysis of disease-causing pathogenic
      mutations and role of endoplasmic reticulum stress."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Pathogenic mutations in DPAGT1 are manifested as two possible phenotypes:
      congenital disorder of glycosylation DPAGT1-CDG (also known as CDG-Ij), and
      limb-girdle congenital myasthenic syndrome (CMS) with tubular aggregates."
    explanation: Establishes that DPAGT1 deficiency can produce a neuromuscular
      junction disease, which is the endplate vulnerability this node invokes.
  downstream:
  - target: Severe muscular hypotonia
    causal_link_type: DIRECT

- name: Fetal Akinesia Sequence
  biological_scale: ORGANISM
  description: >-
    A subset of patients present prenatally with markedly reduced fetal
    movement, and the mechanical consequences of that immobility, namely joint
    contractures up to frank arthrogryposis multiplex congenita and
    polyhydramnios from impaired swallowing, dominate the neonatal picture.
    This is the severe end of the same weakness that appears postnatally as
    hypotonia, expressed early enough to deform the developing skeleton.
  evidence:
  - reference: PMID:22786653
    reference_title: "DPAGT1-CDG: report of a patient with fetal hypokinesia phenotype."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "He showed severe fetal hypokinesia phenotype with decreased fetal movements
      and polyhydramnios."
    explanation: Reports the prenatal akinesia and its obstetric consequence in a
      genetically confirmed patient.
  - reference: PMID:26033833
    reference_title: Fetal akinesia deformation sequence due to a congenital disorder
      of glycosylation.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We describe a newborn female with arthrogryposis multiplex due to fetal
      akinesia secondary to CDG-DPAGT1."
    explanation: States the causal sequence from fetal akinesia to arthrogryposis
      in DPAGT1-CDG, which is the claim of this node.
  downstream:
  - target: Decreased fetal movement
    causal_link_type: DIRECT
  - target: Arthrogryposis multiplex congenita
    causal_link_type: DIRECT
    description: >-
      Contractures form because the fetus does not move the developing joints
      through their range.
    evidence:
    - reference: PMID:26033833
      reference_title: Fetal akinesia deformation sequence due to a congenital disorder
        of glycosylation.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "We describe a newborn female with arthrogryposis multiplex due to
        fetal akinesia secondary to CDG-DPAGT1."
      explanation: Attributes the arthrogryposis specifically to the fetal akinesia
        rather than to an independent skeletal lesion.
  - target: Polyhydramnios
    causal_link_type: DIRECT
    description: >-
      Impaired fetal swallowing is part of the akinesia sequence, and is the
      mechanism this node's own description already names for the polyhydramnios.
phenotypes:
- category: Gastrointestinal
  name: Feeding difficulties
  description: >-
    Feeding difficulties recur across the reported cohorts and are the reason
    feeding support appears in the management of this disorder.
  phenotype_term:
    preferred_term: Feeding difficulties
    term:
      id: HP:0011968
      label: Feeding difficulties
  evidence:
  - reference: PMID:30117111
    reference_title: "DPAGT1 Deficiency with Encephalopathy (DPAGT1-CDG): Clinical and Genetic Description of 11 New Patients."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "A number of symptoms typical for CDG, such as feeding difficulties, cataracts, hypertrichosis, hyporeflexia, joint contractures, elevated liver enzymes, and abnormal brain magnetic resonance imaging (MRI), have been described also in this subtype."
    explanation: Lists feeding difficulties among the CDG-typical symptoms described in this subtype.
- category: Neurological
  name: Hyporeflexia
  description: >-
    Reduced tendon reflexes, consistent with the neuromuscular component of
    this disorder although not formally attributed to it in the source.
  phenotype_term:
    preferred_term: Hyporeflexia
    term:
      id: HP:0001265
      label: Hyporeflexia
  evidence:
  - reference: PMID:30117111
    reference_title: "DPAGT1 Deficiency with Encephalopathy (DPAGT1-CDG): Clinical and Genetic Description of 11 New Patients."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "A number of symptoms typical for CDG, such as feeding difficulties, cataracts, hypertrichosis, hyporeflexia, joint contractures, elevated liver enzymes, and abnormal brain magnetic resonance imaging (MRI), have been described also in this subtype."
    explanation: Lists hyporeflexia among the CDG-typical symptoms described in this subtype.
- category: Hepatic
  name: Elevated liver enzymes
  description: >-
    Biochemical hepatic involvement. The source says elevated liver enzymes
    without naming which, so the general HPO term is bound and the direction is
    carried in preferred_term; a transaminase-specific term would assert more
    than the source does.
  phenotype_term:
    preferred_term: Elevated liver enzymes
    term:
      id: HP:0034685
      label: Abnormal liver enzyme activity or concentration
  evidence:
  - reference: PMID:30117111
    reference_title: "DPAGT1 Deficiency with Encephalopathy (DPAGT1-CDG): Clinical and Genetic Description of 11 New Patients."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "A number of symptoms typical for CDG, such as feeding difficulties, cataracts, hypertrichosis, hyporeflexia, joint contractures, elevated liver enzymes, and abnormal brain magnetic resonance imaging (MRI), have been described also in this subtype."
    explanation: Lists elevated liver enzymes among the CDG-typical symptoms described in this subtype.
- category: Neurological
  name: Cerebellar hypoplasia
  description: >-
    Structural brain anomaly on MRI. Most scans in the largest series were read
    as normal, so this is a minority finding rather than a constant feature.
  phenotype_term:
    preferred_term: Cerebellar hypoplasia
    term:
      id: HP:0001321
      label: Cerebellar hypoplasia
  evidence:
  - reference: PMID:30117111
    reference_title: "DPAGT1 Deficiency with Encephalopathy (DPAGT1-CDG): Clinical and Genetic Description of 11 New Patients."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In 6/10 patients, the scans were considered as normal; others had findings such as global atrophy, cerebellar hypoplasia, and thin corpus callosum."
    explanation: Reports cerebellar hypoplasia among the abnormal scans, alongside the majority read as normal.
- category: Neurological
  name: Seizure
  description: >-
    Medically intractable seizures, usually of early onset, are among the most
    consistent and most disabling features. They were present in the index
    patient and recur across every subsequent cohort, and they remain difficult
    to control even in the patients who survive into adult life.
  phenotype_term:
    preferred_term: Medically intractable seizures
    term:
      id: HP:0001250
      label: Seizure
  frequency: VERY_FREQUENT
  evidence:
  - reference: PMID:12872255
    reference_title: "Deficiency of UDP-GlcNAc:Dolichol Phosphate N-Acetylglucosamine-1
      Phosphate Transferase (DPAGT1) causes a novel congenital disorder of Glycosylation
      Type Ij."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The patient presents with severe hypotonia, medically intractable seizures,
      mental retardation, microcephaly, and exotropia."
    explanation: Reports intractable seizures in the index patient in whom the disease
      was defined.
  - reference: PMID:30117111
    reference_title: "DPAGT1 Deficiency with Encephalopathy (DPAGT1-CDG): Clinical
      and Genetic Description of 11 New Patients."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Most patients have a very severe disease course, where common findings
      are pronounced muscular hypotonia, intractable epilepsy, global developmental
      delay/intellectual disability, and early death."
    explanation: Supports the VERY_FREQUENT band by listing intractable epilepsy
      among the common findings of the largest cohort.
- category: Neuromuscular
  name: Severe muscular hypotonia
  description: >-
    Pronounced hypotonia is present from the neonatal period and is the usual
    presenting sign. It has both a central and a neuromuscular-junction
    component, which is why cholinesterase inhibition helps some patients
    without altering the encephalopathy.
  phenotype_term:
    preferred_term: Severe muscular hypotonia
    term:
      id: HP:0006829
      label: Severe muscular hypotonia
  frequency: VERY_FREQUENT
  evidence:
  - reference: PMID:12872255
    reference_title: "Deficiency of UDP-GlcNAc:Dolichol Phosphate N-Acetylglucosamine-1
      Phosphate Transferase (DPAGT1) causes a novel congenital disorder of Glycosylation
      Type Ij."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The patient presents with severe hypotonia, medically intractable seizures,
      mental retardation, microcephaly, and exotropia."
    explanation: Reports severe hypotonia in the index patient.
  - reference: PMID:23430862
    reference_title: "Further Delineation of the Phenotype of Congenital Disorder
      of Glycosylation DPAGT1-CDG (CDG-Ij) Identified by Homozygosity Mapping."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The patients had severe hypotonia, global developmental delay, seizures,
      and microcephaly but no dysmorphy."
    explanation: Reports severe hypotonia across the affected infants of the second
      reported family.
- category: Neurological
  name: Intellectual disability
  description: >-
    All patients able to be assessed have at least moderate intellectual
    disability. The two long-surviving adults reported with a mild phenotype
    are at the moderate end; most patients are more severely affected or die
    before formal testing is possible.
  phenotype_term:
    preferred_term: Intellectual disability
    term:
      id: HP:0001249
      label: Intellectual disability
  frequency: VERY_FREQUENT
  evidence:
  - reference: PMID:23249953
    reference_title: A compound heterozygous mutation in DPAGT1 results in a congenital
      disorder of glycosylation with a relatively mild phenotype.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Patients in the few reported DPAGT1-CDG families exhibit severe intellectual
      disability (ID), epilepsy, microcephaly, severe hypotonia, facial dysmorphism
      and structural brain anomalies."
    explanation: Summarises intellectual disability as a feature of the reported
      families.
- category: Neurological
  name: Global developmental delay
  description: >-
    Developmental delay affecting all streams, evident in infancy and preceding
    any formal assessment of intellectual disability.
  phenotype_term:
    preferred_term: Global developmental delay
    term:
      id: HP:0001263
      label: Global developmental delay
  frequency: VERY_FREQUENT
  evidence:
  - reference: PMID:23430862
    reference_title: "Further Delineation of the Phenotype of Congenital Disorder
      of Glycosylation DPAGT1-CDG (CDG-Ij) Identified by Homozygosity Mapping."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The patients had severe hypotonia, global developmental delay, seizures,
      and microcephaly but no dysmorphy."
    explanation: Reports global developmental delay across the affected infants of
      this family.
- category: Neurological
  name: Microcephaly
  description: >-
    Microcephaly is a recurrent feature and has been described as progressive
    in at least one family, so it reflects impaired postnatal brain growth
    rather than a purely prenatal reduction in head size.
  phenotype_term:
    preferred_term: Microcephaly
    term:
      id: HP:0000252
      label: Microcephaly
    clinical_course: PROGRESSIVE
  frequency: FREQUENT
  evidence:
  - reference: PMID:12872255
    reference_title: "Deficiency of UDP-GlcNAc:Dolichol Phosphate N-Acetylglucosamine-1
      Phosphate Transferase (DPAGT1) causes a novel congenital disorder of Glycosylation
      Type Ij."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The patient presents with severe hypotonia, medically intractable seizures,
      mental retardation, microcephaly, and exotropia."
    explanation: Reports microcephaly in the index patient.
  - reference: PMID:22304930
    reference_title: "Congenital disorder of glycosylation type Ij (CDG-Ij, DPAGT1-CDG):
      extending the clinical and molecular spectrum of a rare disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We report two new patients with the novel homozygous mutation, c.341C>G
      (A114 G), causing a severe clinical phenotype, characterized by hyperexcitability,
      intractable seizures, bilateral cataracts, progressive microcephaly and muscular
      hypotonia."
    explanation: Documents that the microcephaly was progressive in these two
      patients, which is the basis for the PROGRESSIVE clinical course.
- category: Ophthalmological
  name: Exotropia
  description: >-
    Divergent strabismus, present in the index patient. Strabismus of one form
    or another is a recurring finding across the reported cohorts.
  phenotype_term:
    preferred_term: Exotropia
    term:
      id: HP:0000577
      label: Exotropia
  evidence:
  - reference: PMID:12872255
    reference_title: "Deficiency of UDP-GlcNAc:Dolichol Phosphate N-Acetylglucosamine-1
      Phosphate Transferase (DPAGT1) causes a novel congenital disorder of Glycosylation
      Type Ij."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The patient presents with severe hypotonia, medically intractable seizures,
      mental retardation, microcephaly, and exotropia."
    explanation: Reports exotropia in the index patient.
- category: Ophthalmological
  name: Cataract
  description: >-
    Bilateral cataracts, sometimes congenital or diagnosed in the first months
    of life. Lens opacity is one of the features that separates DPAGT1-CDG from
    the purely myasthenic DPAGT1 phenotype.
  phenotype_term:
    preferred_term: Bilateral cataracts
    term:
      id: HP:0000518
      label: Cataract
  evidence:
  - reference: PMID:22304930
    reference_title: "Congenital disorder of glycosylation type Ij (CDG-Ij, DPAGT1-CDG):
      extending the clinical and molecular spectrum of a rare disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We report two new patients with the novel homozygous mutation, c.341C>G
      (A114 G), causing a severe clinical phenotype, characterized by hyperexcitability,
      intractable seizures, bilateral cataracts, progressive microcephaly and muscular
      hypotonia."
    explanation: Reports bilateral cataracts in two patients.
  - reference: PMID:26033833
    reference_title: Fetal akinesia deformation sequence due to a congenital disorder
      of glycosylation.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "At birth, the patient was evaluated for intrauterine growth restriction,
      bilateral cataracts, and multiple joint contractures."
    explanation: Reports bilateral cataracts present at birth in a second family.
- category: Prenatal
  name: Decreased fetal movement
  description: >-
    Reduced fetal movement noted in pregnancy, in the most severely affected
    patients amounting to a fetal akinesia phenotype with polyhydramnios.
  phenotype_term:
    preferred_term: Decreased fetal movement
    term:
      id: HP:0001558
      label: Decreased fetal movement
  evidence:
  - reference: PMID:22786653
    reference_title: "DPAGT1-CDG: report of a patient with fetal hypokinesia phenotype."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "He showed severe fetal hypokinesia phenotype with decreased fetal movements
      and polyhydramnios."
    explanation: Reports decreased fetal movements directly.
  - reference: PMID:26033833
    reference_title: Fetal akinesia deformation sequence due to a congenital disorder
      of glycosylation.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Pregnancy was complicated by reduced fetal movements."
    explanation: Reports reduced fetal movements in a second genetically confirmed
      patient.
- category: Musculoskeletal
  name: Arthrogryposis multiplex congenita
  description: >-
    Multiple congenital joint contractures, in the most severe cases amounting
    to arthrogryposis multiplex congenita. This is a deformation secondary to
    fetal akinesia rather than a primary skeletal malformation.
  phenotype_term:
    preferred_term: Arthrogryposis multiplex congenita
    term:
      id: HP:0002804
      label: Arthrogryposis multiplex congenita
  evidence:
  - reference: PMID:26033833
    reference_title: Fetal akinesia deformation sequence due to a congenital disorder
      of glycosylation.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We describe a newborn female with arthrogryposis multiplex due to fetal
      akinesia secondary to CDG-DPAGT1."
    explanation: Reports arthrogryposis multiplex in a genetically confirmed patient.
  - reference: PMID:22786653
    reference_title: "DPAGT1-CDG: report of a patient with fetal hypokinesia phenotype."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "moderate multiple contractures, hypotonia and severe hypokinesia, no
      spontaneous movements"
    explanation: Reports multiple contractures with hypokinesia at birth in a second
      patient.
- category: Neurological
  name: Delayed CNS myelination
  description: >-
    Delayed myelination on brain magnetic resonance imaging. Brain imaging in
    DPAGT1-CDG is not uniform, and several reported scans were read as normal,
    so this is a finding in a subset rather than a diagnostic hallmark.
  phenotype_term:
    preferred_term: Delayed CNS myelination
    term:
      id: HP:0002188
      label: Delayed CNS myelination
  evidence:
  - reference: PMID:23430862
    reference_title: "Further Delineation of the Phenotype of Congenital Disorder
      of Glycosylation DPAGT1-CDG (CDG-Ij) Identified by Homozygosity Mapping."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In the index case, the brain MRI revealed delayed myelination, and there
      was fiber type disproportion on muscle biopsy."
    explanation: Reports delayed myelination on imaging in the index case of this
      family.
  - reference: PMID:26033833
    reference_title: Fetal akinesia deformation sequence due to a congenital disorder
      of glycosylation.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Brain MRI showed delayed myelination and an incomplete cerebellar vermis."
    explanation: Reports delayed myelination on imaging in a second patient.
- category: Prenatal
  name: Polyhydramnios
  description: >-
    Excess amniotic fluid accompanying the fetal akinesia phenotype, reflecting
    impaired fetal swallowing.
  phenotype_term:
    preferred_term: Polyhydramnios
    term:
      id: HP:0001561
      label: Polyhydramnios
  evidence:
  - reference: PMID:22786653
    reference_title: "DPAGT1-CDG: report of a patient with fetal hypokinesia phenotype."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "He showed severe fetal hypokinesia phenotype with decreased fetal movements
      and polyhydramnios."
    explanation: Reports polyhydramnios alongside the reduced fetal movement.
- category: Dermatological
  name: Hypertrichosis
  description: >-
    Excessive hair growth, one of the dysmorphic features described in
    severely affected neonates.
  phenotype_term:
    preferred_term: Hypertrichosis
    term:
      id: HP:0000998
      label: Hypertrichosis
  evidence:
  - reference: PMID:22786653
    reference_title: "DPAGT1-CDG: report of a patient with fetal hypokinesia phenotype."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "soft long ears, U-shaped vermilion of the upper lip, thick skin, hypertrichosis"
    explanation: Lists hypertrichosis among the neonatal findings in this patient.
biochemical:
- name: Serum Transferrin Isoform Profile
  notes: >-
    Isoelectric focusing, capillary electrophoresis or mass spectrometry of
    serum transferrin shows the type I CDG pattern, with increased asialo- and
    disialotransferrin from whole unoccupied N-glycosylation sites. It is the
    standard first-line screen for a disorder of lipid-linked oligosaccharide
    assembly. It does not distinguish DPAGT1-CDG from the other CDG-I subtypes;
    that requires sequencing.
  evidence:
  - reference: PMID:22786653
    reference_title: "DPAGT1-CDG: report of a patient with fetal hypokinesia phenotype."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Isoelectrofocusing of serum transferrin showed a type 1 pattern with
      increased asialo- and disialotransferrin."
    explanation: Reports the type I pattern and the specific isoform shift that
      defines it.
  - reference: PMID:26033833
    reference_title: Fetal akinesia deformation sequence due to a congenital disorder
      of glycosylation.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Transferrin isoelectric focusing was suggestive of a type I congenital
      disorder of glycosylation."
    explanation: Independent confirmation of the type I pattern in a second patient.
histopathology:
- name: Fiber type disproportion on muscle biopsy
  description: >-
    Muscle biopsy in the index case of the second reported family showed fiber
    type disproportion. It is recorded here as a morphological finding rather
    than as evidence of a specific myopathic mechanism, since a single biopsy
    does not establish one.
  evidence:
  - reference: PMID:23430862
    reference_title: "Further Delineation of the Phenotype of Congenital Disorder
      of Glycosylation DPAGT1-CDG (CDG-Ij) Identified by Homozygosity Mapping."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In the index case, the brain MRI revealed delayed myelination, and there
      was fiber type disproportion on muscle biopsy."
    explanation: Reports the muscle-biopsy finding directly.

diagnosis:
- name: Serum transferrin glycoform analysis
  description: >-
    First-line screen. A type I transferrin pattern places the defect in
    lipid-linked oligosaccharide assembly or transfer and prompts sequencing;
    it does not name the gene.
  evidence:
  - reference: PMID:23249953
    reference_title: A compound heterozygous mutation in DPAGT1 results in a congenital
      disorder of glycosylation with a relatively mild phenotype.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Isoelectric focusing and high-resolution mass spectrometry analyses
      of serum transferrin revealed glycosylation profiles that are consistent with
      a CDG-I defect."
    explanation: Shows the screen classifying a patient into the CDG-I group, which
      is what it is for.
- name: Exome or genome sequencing of DPAGT1
  description: >-
    Definitive diagnosis rests on identifying biallelic DPAGT1 variants. Broad
    sequencing has been the usual route since the phenotype is a nonspecific
    infantile epileptic encephalopathy, and homozygosity mapping served the
    same purpose in consanguineous families before exome sequencing was
    routine.
  evidence:
  - reference: PMID:23249953
    reference_title: A compound heterozygous mutation in DPAGT1 results in a congenital
      disorder of glycosylation with a relatively mild phenotype.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Exome sequencing revealed a compound heterozygous missense mutation,
      c.85A>T (p.I29F) and c.503T>C (p.L168P), in the DPAGT1 gene."
    explanation: Illustrates exome sequencing as the route to a molecular diagnosis
      in a patient whose phenotype was too mild to suggest the gene.
  - reference: PMID:23430862
    reference_title: "Further Delineation of the Phenotype of Congenital Disorder
      of Glycosylation DPAGT1-CDG (CDG-Ij) Identified by Homozygosity Mapping."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Homozygosity mapping identified a large block of homozygosity on chromosome
      11p15.5-q25 where two known CDG-I causing genes, ALG9 and DPAGT1, are located."
    explanation: Illustrates the mapping route used in a large consanguineous family.
treatments:
- name: Anticonvulsant agent therapy
  description: >-
    Antiepileptic drugs are the mainstay of managing the seizures, which are
    typically early-onset and often refractory. This is symptomatic
    management: no anticonvulsant addresses the glycosylation defect, and
    seizure control is frequently incomplete.
  therapeutic_modality: SMALL_MOLECULE
  treatment_term:
    preferred_term: Anticonvulsant agent therapy
    term:
      id: NCIT:C64172
      label: Anticonvulsant Therapy
    therapeutic_agent:
    - preferred_term: anticonvulsant agent
      term:
        id: NCIT:C264
        label: Anticonvulsant Agent
  target_phenotypes:
  - preferred_term: Medically intractable seizures
    term:
      id: HP:0001250
      label: Seizure
  evidence:
  - reference: PMID:37766827
    reference_title: "DPAGT1-CDG: Report of Two New Pediatric Patients and Brief Review
      of the Literature."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "A severe disease course with hypotonia, cataracts, skeletal deformities,
      resistant epilepsy, intellectual disability, global developmental delay, premature
      death has been described in most patients with DPAGT1-CDG."
    explanation: Establishes that the epilepsy requiring this treatment is typically
      resistant, which is the constraint on what anticonvulsants achieve here.
- name: Pyridostigmine
  description: >-
    An acetylcholinesterase inhibitor. It targets the myasthenic component of
    the weakness by prolonging acetylcholine dwell time at the endplate, and
    has produced measurable benefit in DPAGT1-CDG patients whose muscle
    weakness is prominent. It does nothing for the encephalopathy or the
    underlying glycosylation defect.
  therapeutic_modality: SMALL_MOLECULE
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: pyridostigmine
      term:
        id: CHEBI:8665
        label: Pyridostigmine
  target_mechanisms:
  - target: Neuromuscular Transmission Impairment
    treatment_effect: MODULATES
    description: >-
      Inhibiting acetylcholinesterase increases the time acetylcholine remains
      in the synaptic cleft, compensating for reduced endplate signalling
      without restoring glycosylation.
    evidence:
    - reference: PMID:37766827
      reference_title: "DPAGT1-CDG: Report of Two New Pediatric Patients and Brief
        Review of the Literature."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "We started pyridostigmine treatment in our patient with more pronounced
        muscle weakness, and we saw its benefit."
      explanation: Reports a clinical benefit of pyridostigmine directed at the
        weakness this mechanism node describes.
  evidence:
  - reference: PMID:37766827
    reference_title: "DPAGT1-CDG: Report of Two New Pediatric Patients and Brief Review
      of the Literature."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Cholinesterase inhibitor therapy was found to be effective in patients
      against muscle weakness, supporting DPAGT1 deficiency as the underlying etiology."
    explanation: States that cholinesterase inhibition is effective against the muscle
      weakness in these patients.
- name: Supportive and multidisciplinary care
  description: >-
    There is no disease-modifying therapy for DPAGT1-CDG. Care is supportive:
    feeding support, respiratory management, seizure control, ophthalmological
    review for cataract, and orthopaedic management of contractures, with
    genetic counselling for the family given the recessive recurrence risk.
  treatment_term:
    preferred_term: Supportive Care
    term:
      id: NCIT:C15747
      label: Supportive Care
  evidence:
  - reference: PMID:39466823
    reference_title: A drug repurposing screen reveals dopamine signaling as a critical
      pathway underlying potential therapeutics for the rare disease DPAGT1-CDG.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "DPAGT1-CDG is a Congenital Disorder of Glycosylation (CDG) that lacks
      effective therapies."
    explanation: States the absence of disease-modifying treatment that makes
      supportive care the standard of care.
animal_models:
- name: Gpt (Dpagt1) null mouse
  species: Mus musculus
  genotype: Homozygous germline deletion of the mouse GPT (Dpagt1) gene
  publication: PMID:10536042
  description: >-
    A germline deletion of the mouse GlcNAc-1-phosphotransferase gene.
    Nullizygous embryos implant but die within a day or two, before any organ
    that DPAGT1-CDG affects has formed. The model is therefore not a model of
    the human disease; its value is the negative constraint it places on human
    genotypes.
  genes:
  - preferred_term: DPAGT1
    term:
      id: hgnc:2995
      label: DPAGT1
  modeled_mechanisms:
  - target: Biallelic Hypomorphic DPAGT1 Variants
    relationship: FAILS_TO_RECAPITULATE
    fidelity: LOW
    description: >-
      Complete enzyme loss produces peri-implantation lethality rather than the
      human phenotype, which is why every viable human genotype retains partial
      activity.
    limitations: >-
      A homozygous null, not a hypomorph, so it models the wrong end of the
      allelic series: the embryos die at days 4-5 post-fertilisation, long
      before the nervous system, lens or neuromuscular junction exist, and no
      DPAGT1-CDG phenotype can be assessed in them. A hypomorphic mouse allele
      matching a patient genotype has not been reported.
    evidence:
    - reference: PMID:10536042
      reference_title: "A recessive deletion in the GlcNAc-1-phosphotransferase gene
        results in peri-implantation embryonic lethality."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: "We find that embryos homozygous for a deletion in the GPT gene complete
        preimplantation development and also implant in the uterine epithelium, but
        die shortly thereafter between days 4-5 postfertilization with cell degeneration
        apparent among both embryonic and extraembryonic cell types."
      explanation: Documents the lethal stage, which is what prevents this model from
        recapitulating the human disease.
  evidence:
  - reference: PMID:10536042
    reference_title: "A recessive deletion in the GlcNAc-1-phosphotransferase gene
      results in peri-implantation embryonic lethality."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "These results indicate that GPT function is essential in early embryogenesis
      and suggest that N-glycosylation is needed for the viability of cells comprising
      the peri-implantation stage embryo."
    explanation: The authors' own conclusion that the enzyme is essential, which is
      the constraint this model contributes.
- name: Drosophila DPAGT1 RNAi rough-eye model
  species: Drosophila melanogaster
  genotype: Eye-directed RNA interference knockdown of the Drosophila DPAGT1 orthologue
  publication: PMID:39466823
  description: >-
    An eye-based knockdown model in which reduced DPAGT1 expression produces a
    small, improperly developed eye that can be scored quantitatively. It was
    used for a 1,520-compound repurposing screen, which identified 42
    suppressors and implicated dopamine D2 receptor signalling as a modifier of
    DPAGT1 deficiency. The readout is a developmental eye phenotype, not any
    clinical feature of DPAGT1-CDG.
  genes:
  - preferred_term: DPAGT1
    term:
      id: hgnc:2995
      label: DPAGT1
  modeled_mechanisms:
  - target: Reduced GlcNAc-1-Phosphotransferase Activity
    relationship: PERTURBS
    fidelity: LOW
    description: >-
      RNAi knockdown reproduces the partial enzyme deficiency of the human
      disease in a tractable invertebrate system, giving a scorable phenotype
      for chemical and genetic modifier screening.
    limitations: >-
      An invertebrate developmental eye phenotype with no relationship to the
      encephalopathy, epilepsy, hypotonia or cataract of the human disease, and
      no measurement of glycosylation in the model itself. Hits from it are
      leads for mechanism, not evidence of therapeutic effect in patients.
    readouts:
    - name: Drosophila eye size
      target: Reduced GlcNAc-1-Phosphotransferase Activity
      direction: RESTORED
      interpretation: >-
        Partial rescue of the small-eye phenotype by dopamine D2 receptor
        inhibition, the screen's principal hit.
      evidence:
      - reference: PMID:39466823
        reference_title: A drug repurposing screen reveals dopamine signaling as a
          critical pathway underlying potential therapeutics for the rare disease
          DPAGT1-CDG.
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: "Notably from this screen, we found that pharmacological and genetic
          inhibition of the dopamine D2 receptor partially rescued the DPAGT1-CDG
          model."
        explanation: Reports the direction of the eye-size readout on which the
          screen's conclusion rests.
  evidence:
  - reference: PMID:39466823
    reference_title: A drug repurposing screen reveals dopamine signaling as a critical
      pathway underlying potential therapeutics for the rare disease DPAGT1-CDG.
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "We used a Drosophila rough eye model of DPAGT1-CDG with an improperly
      developed, small eye phenotype."
    explanation: Describes the model system and its readout.
prevalence:
- population: Worldwide
  measure_type: CASES_IN_LITERATURE
  prevalence_class: ULTRA_RARE
  notes: >-
    Fewer than fifty patients have been reported since the disease was defined
    in 2003. A 2019 series counted 28 previously published patients from 10
    families and added 11 more from 8 families; 18 of the earlier patients came
    from a single consanguineous family, so the number of independent
    ascertainments is smaller than the patient count suggests. No population
    prevalence estimate has been published.
  evidence:
  - reference: PMID:30117111
    reference_title: "DPAGT1 Deficiency with Encephalopathy (DPAGT1-CDG): Clinical
      and Genetic Description of 11 New Patients."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Fourteen disease-causing mutations in 28 patients from 10 families have
      previously been reported to cause the systemic form, DPAGT1-CDG. We here report
      on another 11 patients from 8 families and add 10 new mutations."
    explanation: Gives the published patient and family counts on which this
      ultra-rare classification rests.
progression:
- phase: Severe infantile course
  age_range: birth to 5 years
  notes: >-
    The usual course. Onset is at or before birth with hypotonia, often reduced
    fetal movement and contractures, followed by early-onset intractable
    epilepsy and global developmental delay, with death in infancy or early
    childhood.
  evidence:
  - reference: PMID:23430862
    reference_title: "Further Delineation of the Phenotype of Congenital Disorder
      of Glycosylation DPAGT1-CDG (CDG-Ij) Identified by Homozygosity Mapping."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The disorder was fatal in all affected cases and mostly in early infancy."
    explanation: Documents the fatal early-infantile course in the largest single
      family.
  - reference: PMID:22304930
    reference_title: "Congenital disorder of glycosylation type Ij (CDG-Ij, DPAGT1-CDG):
      extending the clinical and molecular spectrum of a rare disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Both our patients died within their first year of life."
    explanation: Independent report of death within the first year in a second
      family.
- phase: Attenuated course surviving to adulthood
  age_range: adulthood
  notes: >-
    A minority of patients carrying milder allele combinations survive into
    adult life with moderate intellectual disability, epilepsy, hypotonia and
    behavioural problems, and a stable rather than progressive course. Two such
    adults were the first to show that the DPAGT1-CDG spectrum extends well
    beyond lethal infantile disease.
  evidence:
  - reference: PMID:23249953
    reference_title: A compound heterozygous mutation in DPAGT1 results in a congenital
      disorder of glycosylation with a relatively mild phenotype.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In this study, we report a non-consanguineous family with two affected
      adults presenting with a relatively mild phenotype consisting of moderate ID,
      epilepsy, hypotonia, aggressive behavior and balance problems."
    explanation: Documents the attenuated adult phenotype that defines this course.
  - reference: PMID:30117111
    reference_title: "DPAGT1 Deficiency with Encephalopathy (DPAGT1-CDG): Clinical
      and Genetic Description of 11 New Patients."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We also present data on three affected females that are young adults
      and have a somewhat milder, stable disease."
    explanation: Independent confirmation that a milder, stable adult course occurs.
discussions:
- discussion_id: dpagt1_cdg_cms_boundary
  kind: OPEN_QUESTION
  status: OPEN
  prompt: >-
    Is the boundary between DPAGT1-CDG and DPAGT1-CMS a difference of kind or
    only of degree, and does the myasthenic weakness of DPAGT1-CDG patients
    belong to this entry or to the myasthenic one?
  attaches_to:
  - pathophysiology#Neuromuscular Transmission Impairment
  rationale: >-
    DPAGT1 has two named allelic diseases with separate MONDO terms and
    separate OMIM entries: the systemic encephalopathy curated here
    (MONDO:0011964, OMIM:608093) and limb-girdle congenital myasthenic syndrome
    13 with tubular aggregates (MONDO:0013883, OMIM:614750), which the KB
    curates in its Congenital Myasthenic Syndrome entry. This entry follows
    that split. But the split is not clean in the clinic: DPAGT1-CDG patients
    have a myasthenic component to their weakness that responds to
    cholinesterase inhibition, which is the DPAGT1-CMS mechanism appearing
    inside the CDG phenotype, and the reported severity range within
    DPAGT1-CDG alone spans lethal infantile encephalopathy to stable adult
    disease. The likeliest organising variable is residual enzyme activity
    rather than a categorical difference, in which case the two MONDO terms
    name two regions of one continuum. If the KB later adopts a convention for
    allelic series graded by residual activity, this pair is a candidate for
    a grouping that spans both terms.
- discussion_id: dpagt1_neural_mechanism_unknown
  kind: KNOWLEDGE_GAP
  status: OPEN
  prompt: >-
    Which hypoglycosylated neural glycoproteins mediate the epilepsy,
    developmental delay and microcephaly of DPAGT1-CDG?
  attaches_to:
  - pathophysiology#Hypoglycosylation of Neural Glycoproteins
  rationale: >-
    The neuromuscular arm of this disease has a candidate target, endplate
    receptor hypoglycosylation, shown for the neighbouring ALG14 subunit and
    supported here by the response to cholinesterase inhibition. The central
    nervous system arm has none. Intractable epilepsy, developmental delay and
    microcephaly are documented in every cohort, but no specific neural
    glycoprotein has been shown to be hypoglycosylated in patients and no
    intermediate step between the biosynthetic defect and the encephalopathy
    has been established. Brain imaging is not even consistent across patients.
    The corresponding pathophysiology node therefore asserts a tissue-scale
    association and is tagged with hypothetical mechanism confidence; it should
    not be read as a mechanism.
- discussion_id: dpagt1_er_stress_not_the_mechanism
  kind: OPEN_QUESTION
  status: OPEN
  prompt: >-
    If the unfolded protein response is not activated in DPAGT1-CDG
    fibroblasts, what does the increased sensitivity to tunicamycin in those
    cells represent?
  attaches_to:
  - pathophysiology#Global Protein N-Hypoglycosylation
  rationale: >-
    ER stress is an attractive candidate mediator for a disease of ER-resident
    glycan assembly, and it is active in other CDG subtypes. It was tested
    directly in DPAGT1-CDG patient fibroblasts and was not found: the unfolded
    protein response was inactive, unlike in PMM2-CDG or DPM1-CDG cells. The
    same cells were nonetheless more sensitive than controls to the GPT
    inhibitor tunicamycin. Whether that reflects a reduced reserve of the same
    enzyme rather than a stress-response phenotype is unresolved, and the
    negative result is worth recording so that ER stress is not assumed into
    this entry's mechanism by analogy with other CDGs.
  evidence:
  - reference: PMID:28662078
    reference_title: "DPAGT1-CDG: Functional analysis of disease-causing pathogenic
      mutations and role of endoplasmic reticulum stress."
    supports: REFUTE
    evidence_source: IN_VITRO
    snippet: "The unfolded protein response (UPR; the response to ER stress) was found
      not to be active in patient-derived fibroblasts, unlike that seen in cells from
      patients with PMM2-CDG or DPM1-CDG."
    explanation: Refutes an activated unfolded protein response as a mechanism in
      DPAGT1-CDG patient cells.
references:
- reference: PMID:12872255
  title: "Deficiency of UDP-GlcNAc:Dolichol Phosphate N-Acetylglucosamine-1 Phosphate
    Transferase (DPAGT1) causes a novel congenital disorder of Glycosylation Type
    Ij."
- reference: PMID:30117111
  title: "DPAGT1 Deficiency with Encephalopathy (DPAGT1-CDG): Clinical and Genetic
    Description of 11 New Patients."
notes: >-
  Entity identity. MONDO:0011964 is DPAGT1-CDG, formerly CDG-Ij, cross-referenced
  to OMIM:608093 and Orphanet:86309. MONDO's definition names hypotonia,
  intractable seizures, developmental delay, microcephaly and severe fetal
  hypokinesia, which matches the curated phenotype set here.

  Scope decision: DPAGT1-CDG versus DPAGT1-CMS. DPAGT1 causes two allelic
  diseases, and this entry curates only the first. The severe multisystem
  encephalopathy is MONDO:0011964 / OMIM:608093. The much milder limb-girdle
  congenital myasthenic syndrome with tubular aggregates, CMS-13, is a distinct
  MONDO term (MONDO:0013883, exact synonyms CMS13 and CMSTA2) with its own OMIM
  entry (614750), and the KB already curates it inside
  `kb/disorders/Congenital_Myasthenic_Syndrome.yaml`, where DPAGT1 is listed as
  a causative CMS gene accounting for around 10 percent of cases in one cohort.
  It is therefore NOT modelled here as a `has_subtypes` entry: doing so would
  put one MONDO disease inside another and would duplicate content that already
  exists elsewhere in the KB. This is deliberate, not an omission.

  What this entry does carry from the myasthenic side is the myasthenic
  component of DPAGT1-CDG itself, namely the pathophysiology node
  `Neuromuscular Transmission Impairment` and the pyridostigmine treatment,
  because cholinesterase inhibition demonstrably helps the muscle weakness of
  DPAGT1-CDG patients and not only of DPAGT1-CMS patients. The question of
  whether the two named diseases are really one graded continuum is recorded
  under `discussions` rather than settled here.

  Named entity confusion warning for future curators. The DPAGT1 literature is
  dominated by the myasthenic phenotype: a PubMed search for the gene returns
  many limb-girdle CMS papers, and several of the most cited DPAGT1 clinical
  papers (for example the Iranian limb-girdle CMS family, PMID:23591138) are
  about CMS-13 and not about this disease. Every reference cited in this entry
  was checked to be reporting DPAGT1-CDG rather than DPAGT1-CMS, with the
  deliberate exception of two papers that discuss both explicitly and are
  quoted only where they speak about DPAGT1-CDG or about the gene's two
  phenotypes as a pair (PMID:28662078, PMID:37766827).

  Early death is deliberately not curated as a phenotype. It is the usual
  outcome of the severe form and is recorded in `progression` and in the
  variant descriptions, but the HPO term for it (HP:0001522, Death in infancy)
  sits in the mortality/aging branch and is not a member of the schema's
  PhenotypeTerm enum, so there is no valid binding for it in `phenotypes`.

  GeneReviews. There is no current GeneReviews chapter for DPAGT1-CDG. The
  general N-linked glycosylation overview, PMID:20301507, is marked
  "RETIRED CHAPTER, FOR HISTORICAL REFERENCE ONLY" and was not used as a
  phenotype baseline. The 11-patient series (PMID:30117111) was used in its
  place as the broadest clinical baseline available.

  Relationship to the ALG14 entry. GPT works in a multiglycosyltransferase
  complex with ALG13 and ALG14 at the first committed steps of N-linked
  glycosylation. The KB's `Congenital_Myasthenic_Syndrome_15` entry curates the
  ALG14 subunit of that same complex, and this entry's account of the complex
  is consistent with it. The two diseases illustrate the same principle from
  opposite ends: ALG14 deficiency is usually a myasthenia that can extend to a
  neurodegenerative CDG, DPAGT1 deficiency is usually a CDG that carries a
  myasthenic component.

  Curation provenance. No deep-research provider report was generated for this
  entry and none is committed under research/. This was not a scoping decision:
  the drafting run was cut short, and the reference set was assembled directly
  from PubMed on DPAGT1 and CDG-Ij. The consequence is that the usual
  deep-research completeness cross-check was unavailable. A hand check against
  the committed reference caches was run instead and did find omissions, which
  have been curated: feeding difficulties, hyporeflexia, elevated liver enzymes
  and cerebellar hypoplasia, all from PMID:30117111.

  Facial dysmorphism is deliberately not curated. PMID:23249953 reports it and
  PMID:23430862 records no dysmorphy, so the reports conflict and neither is
  strong enough to settle it.

  Unattached phenotypes and why. Exotropia, hypertrichosis, feeding
  difficulties, hyporeflexia and elevated liver enzymes carry no incoming causal
  edge. Each is reported as an associated feature in a list of CDG-typical
  symptoms rather than attributed to a mechanism, and the entry's nodes do not
  reach them without inventing an intermediate. Hyporeflexia and feeding
  difficulties are the two most tempting to attach to the neuromuscular
  transmission node, and both are left alone for that reason: plausibility is
  not evidence.
📚

References & Deep Research

References

2
PMID:12872255
Deficiency of UDP-GlcNAc:Dolichol Phosphate N-Acetylglucosamine-1 Phosphate Transferase (DPAGT1) causes a novel congenital disorder of Glycosylation Type Ij.
No top-level findings curated for this source.
PMID:30117111
DPAGT1 Deficiency with Encephalopathy (DPAGT1-CDG): Clinical and Genetic Description of 11 New Patients.
No top-level findings curated for this source.