MOGS-Congenital Disorder of Glycosylation

Mendelian MONDO:0011629 Pathograph 41 Show in embeddings browser Congenital disorder of glycosylation type II Disorder of protein N-glycosylation

MOGS-CDG is an autosomal recessive congenital disorder of glycosylation caused by biallelic MOGS variants. MOGS encodes ER alpha-glucosidase I, which performs the first obligate trimming step on a newly transferred N-glycan: removal of the outermost alpha-1,2-linked glucose from Glc3Man9GlcNAc2. Losing it blocks N-glycan maturation at its first move. Clinically it is a severe multisystem disease. Dysmorphic features, generalised hypotonia, global developmental delay and seizures are present in essentially all reported patients; hepatic dysfunction, hypoventilation, vision problems and hypogammaglobulinemia occur in some. Severity spans a neonatal course fatal at 74 days through to children alive in their second decade, with no genotype correlation established. Two things make this entry unusual. The first is a claim about infection that has to be stated carefully, because the literature does not say what a first reading suggests. Recurrent infection is near-universal: 10 of the 11 reported patients in the 2022 summary table have it, and the one exception is the sibling pair in whom the observation of "limited clinical evidence of an infectious diathesis" was made. So this disease is not one of preserved immunity. What is real, and narrower, is that the same glycan block that destabilises immunoglobulin also impairs the replication and cellular entry of enveloped viruses, and that in one sibling pair the expected bacterial burden was not seen. The immunoglobulin defect itself is a shortened half-life of aberrantly glycosylated antibody rather than a failure to make it. The deficiency subtracts from host defence and from viral fitness at once, which is what turned this ultra-rare disease into a proof of principle for ER glucosidase inhibitors as broad-spectrum antivirals. The second is a diagnostic trap. Serum transferrin isoelectric focusing, the standard CDG screen, is typically normal here, so the disease escapes the test that would otherwise find it. The reason is a partial metabolic bypass: with glucosidase I absent, endo-alpha-1,2-mannosidase activity rises and clears most glycans through an alternative route, leaving the bulk of N-glycoproteins correctly processed and releasing the Glc3Man tetrasaccharide into urine. That tetrasaccharide is the reliable diagnostic marker, and urine oligosaccharide analysis is the test that works.

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1
Mappings
1
Inheritance
11
Pathophys.
26
Phenotypes
2
Gaps
41
Pathograph
1
Genes
2
Medical Actions
3
Differentials
2
Models
17
References
1
Deep Research
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Classifications

ICIMD (Inherited Metabolic Disorders)
n linked protein glycosylation
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Mappings

ICD-10-CM
ICD10CM:E77.8 Other disorders of glycoprotein metabolism
skos:broadMatch
ICD-10-CM has no code for MOGS-CDG or for the congenital disorders of glycosylation individually. E77.8 is the residual glycoprotein-metabolism code the disease is assigned to, and it covers many unrelated disorders, so this is recorded as a broadMatch rather than an exact one. Per the MONDO coverage rule a broadMatch is a cross-reference and does not retire the concept from curation.
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Inheritance

1
Autosomal recessive inheritance HP:0000007
Biallelic MOGS variants, homozygous or compound heterozygous. Carrier parents have roughly half-normal enzyme activity and are unaffected.
Autosomal recessive inheritance
Show evidence (2 references)
PMID:35790351 SUPPORT Human Clinical
"Bi-allelic variants in MOGS were identified in 12 individuals from 11 families."
The biallelic requirement across the largest assembled cohort.
PMID:10788335 SUPPORT Human Clinical
"Glucosidase I activities in cultured skin fibroblasts from both parents were found to be 50% of those of controls."
The half-normal carrier activity that makes the trait recessive at the biochemical level as well as the clinical one.
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Discussions and Knowledge Gaps

2
Can ER glucosidase inhibition be used as a broad-spectrum antiviral, and what would the MOGS-CDG phenotype predict about its safety?
EMERGING HYPOTHESIS mogs_cdg_antiviral_target
Attached to
pathophysiology#Impaired Viral Replication and Cellular Entry
The human deficiency is the experiment, and it is a weaker experiment than it first appears. Patients with almost no glucosidase I activity do show impaired viral replication and entry, and one sibling pair showed limited clinical evidence of an infectious diathesis despite severe hypogammaglobulinemia. That pair is the whole of the survivability argument: across all 11 reported patients, recurrent infection is present in 10, and a patient from another pair had cytomegalovirus infection despite CMV being enveloped. So the target may well be effective; whether inhibiting it is survivable rests on two children, not on the disease. What the argument also does not establish is a therapeutic window. These patients also have a severe neurological and dysmorphic phenotype from lifelong constitutive loss, and nothing in the human data separates which of those consequences would follow acute pharmacological inhibition in an adult. The proposal is recorded as emerging on that basis. There is also a direct negative result, from the same group that made the original observation. Testing the FDA-approved alpha-glucosidase inhibitor miglustat against SARS-CoV-2 in vitro, they found the expected structural change in the spike and ACE2 glycans without the functional consequence: miglustat did not reproduce the resistance the human deficiency shows, and they say so. That does not refute the mechanism in the constitutive human deficiency, where the block is near-total and lifelong, but it is a concrete demonstration that partial pharmacological inhibition is not the same intervention, and it belongs beside the proposal rather than in a citation nobody reads.
Show evidence (3 references)
PMID:33245474 REFUTE In Vitro
"Miglustat treatment in our in vitro model did not corroborate this assumption."
The negative result. Graded REFUTE against the proposition that pharmacological alpha-glucosidase inhibition reproduces the antiviral phenotype of the genetic deficiency.
PMID:33245474 REFUTE In Vitro
"Miglustat produced no statistically significant effects on cytokine production following SARS-CoV-2 S glycoprotein stimulation of PBMC."
A second null endpoint in the same study, on the immune rather than the entry side. It cuts the same way as the entry-assay null against the same proposition, so it is graded REFUTE alongside it.
PMID:36158009 REFUTE Human Clinical
"Contrary to previous findings of resistance to infection by glycosylation-dependent enveloped viruses...the elder sister in our report had evidence of cytomegalovirus (CMV, also an enveloped virus) infection."
The strongest single counter-observation to this hypothesis, and the only one from patient data rather than from the same in-vitro model as the two nulls above. A MOGS-CDG patient acquired an enveloped-virus infection, and the reporting authors name the contradiction themselves. Quoted in the ellipsis form because the source's inline citation markers sit between the two clauses.
Does the extent of the endo-alpha-1,2-mannosidase bypass explain the wide severity range that genotype does not?
KNOWLEDGE GAP mogs_cdg_bypass_and_severity
Attached to
pathophysiology#Endo-alpha-1,2-Mannosidase Bypass
Severity spans death at 74 days to survival into the second decade, and the largest series found no genotype correlation. The bypass is a candidate modifier that has never been tested as one: it was measured in a single patient's fibroblasts, and if its magnitude varies between individuals it would predict severity where the genotype does not. Measuring endo-alpha-1,2-mannosidase activity alongside urinary Glc3Man across the known cohort would settle it, and the samples to do that largely exist.
Proposed experiments
Correlate endo-alpha-1,2-mannosidase activity with clinical severity across the MOGS-CDG cohort
mogs_bypass_severity_correlation
Assay endo-alpha-1,2-mannosidase activity and transcript level in fibroblasts from genetically confirmed MOGS-CDG patients spanning the severity range, and test the association against a clinical severity score and against quantified urinary Glc3Man excretion.
Readouts
Fibroblast endo-alpha-1,2-mannosidase activity
pathophysiology#Endo-alpha-1,2-Mannosidase Bypass
Direction: INCREASED
Interpretation: A higher bypass activity in the milder end of the cohort would support the compensation acting as a severity modifier.
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Pathophysiology

11
Biallelic MOGS Loss-of-Function Variants
Missense, frameshift and other variants on both MOGS alleles. The gene has four exons, with exon 4 encoding the 64 kDa catalytic domain, and both original disease alleles fall in that exon. Reintroducing either into wild-type glucosidase I abolished measurable activity, and the two acted differently on the protein: one retained weak affinity-resin binding and the other did not, so they disturb folding and active-site formation by different routes.
Genetic context variant_origin: GERMLINE functional_impact_category: LOSS_OF_FUNCTION
Downstream
Loss of ER Alpha-Glucosidase I Activity
Show evidence (2 references)
PMID:10788335 SUPPORT Human Clinical
"Molecular studies showed that the patient was a compound heterozygote for two missense mutations in the glucosidase I gene: (1) one allele harbored a G-->C transition at nucleotide (nt) 1587, resulting in the substitution of Arg at position 486 by Thr (R486T), and (2) on the other allele a T-->C..."
The two founding disease alleles, with their positions and consequences.
PMID:12145188 SUPPORT In Vitro
"The Phe652Leu but not the Arg486Thr protein mutant showed a weak binding to a glucosidase I-specific affinity resin, indicating that the two amino acids affect polypeptide folding and active site formation differently."
Shows the two alleles are not mechanistically equivalent, which is why this node describes a class of lesions rather than one.
Loss of ER Alpha-Glucosidase I Activity
Residual activity in patient tissue is under 3 percent of control in liver and fibroblasts, and under 1 percent by kinetic assay in fibroblast extracts. The loss is specific: oligosaccharyltransferase, glucosidase II and Man9-mannosidase activities are unchanged, so the block is at one enzyme rather than across the pathway.
ER alpha-glucosidase I activity GO:0004573 Gene Ontology (GO) Relation: this pathophysiological event involves this molecular function This pathophysiological event involves decreased ER alpha-glucosidase I activity, annotated with Glc3Man9GlcNAc2 oligosaccharide glucosidase activity (GO:0004573). GO:0004573 is a molecular function from the Gene Ontology. ↓ DECREASED
endoplasmic reticulum GO:0005783 Gene Ontology (GO) Relation: this pathophysiological event involves this cellular component This pathophysiological event involves endoplasmic reticulum (GO:0005783). GO:0005783 is a cellular component from the Gene Ontology.
Experimental models
Saccharomyces cerevisiae CWH41 knockout complementation assay OTHER Deleting the homologous gene reproduces the enzymatic lesion and the resulting N-glycan profile change, which is what makes the strain usable as a readout of glucosidase I function.
Downstream
Failure of the First N-Glycan Trimming Step
Show evidence (2 references)
PMID:10788335 SUPPORT Human Clinical
"Enzymological studies on liver tissue and cultured skin fibroblasts revealed a severe glucosidase I deficiency. The residual activity was <3% of that of controls."
The measured residual activity in patient tissue.
PMID:12145188 SUPPORT In Vitro
"No significant differences in the activities of other processing enzymes, including oligosaccharyltransferase, glucosidase II, and Man(9)-mannosidase, were observed."
Establishes that the defect is confined to this one enzyme, which is what lets the rest of the chain be attributed to it.
Failure of the First N-Glycan Trimming Step
Glucosidase I removes the distal alpha-1,2-linked glucose from the Glc3Man9GlcNAc2 precursor immediately after it is transferred en bloc from dolichyl diphosphate to the nascent chain. Without that first cut the glycan cannot enter the maturation sequence, and a fraction of N-glycans is arrested at the Glc3Man9-7GlcNAc2 stage.
processing of protein-bound N-glycans GO:0006487 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased processing of protein-bound N-glycans, annotated with protein N-linked glycosylation (GO:0006487). GO:0006487 is a biological process from the Gene Ontology. ↓ DECREASED
Downstream
Endo-alpha-1,2-Mannosidase Bypass
Destabilised Circulating Immunoglobulin
Impaired Viral Replication and Cellular Entry
Aberrant Neuronal Glycoprotein Function The neurological branch. That the glycan block causes the encephalopathy is asserted in the literature at disease level; which neuronal glycoproteins carry it is not established, so the edge is typed as having unknown intermediates rather than as direct.
Hepatic Glycoprotein Dysfunction The hepatic branch. Same epistemic status as the neurological one: the association is consistent across reported patients and the intervening steps are not worked out.
Disrupted Developmental Glycosylation The dysmorphogenesis branch, accounting for the recognisable craniofacial and limb pattern and the generalized edema.
Cumulative Multisystem Glycoprotein Dysfunction The systemic burden that is not attributable to any single organ branch, and which determines outcome in the severe cases.
Show evidence (2 references)
PMID:10788335 SUPPORT Human Clinical
"Glucosidase I is an important enzyme in N-linked glycoprotein processing, removing specifically distal alpha-1,2-linked glucose from the Glc3Man9GlcNAc2 precursor after its en bloc transfer from dolichyl diphosphate to a nascent polypeptide chain in the endoplasmic reticulum."
Defines the reaction whose failure this node describes, and its position in the pathway.
PMID:12145188 SUPPORT In Vitro
"despite the dramatically reduced glucosidase I activity, the bulk of the N-linked carbohydrate chains (>80%) in the patient's fibroblasts appeared to have been processed correctly, with only approximately 16% of the N-glycans being arrested at the Glc(3)-Man(9-7)-GlcNAc(2) stage."
Quantifies how much of the glycan pool is actually arrested, which is smaller than the near-total enzyme loss would suggest and is the reason the bypass node exists.
Aberrant Neuronal Glycoprotein Function
Mechanism confidence: Hypothetical
Neuronal ion channels, adhesion molecules and receptors are N-glycosylated, and the standard account is that mishandling their glycans is what produces the encephalopathy. It is worth being clear that this is an inference from glycan biology plus a consistent clinical association, not a demonstrated step: no specific neuronal glycoprotein has been shown to be the one that matters, and no cited work measures a neuronal glycoprotein defect in a patient. It is recorded as HYPOTHETICAL for that reason, and the entry does not name a mechanism it cannot cite. What is well established is the clinical output. Seizures, hypotonia and developmental delay are present in essentially every reported patient, the seizures are frequently drug-resistant, and imaging shows progressive cortical and subcortical atrophy.
neuron CL:0000540 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves neuron (CL:0000540). CL:0000540 is a cell type from the Cell Ontology.
Downstream
Epileptic encephalopathy
Generalized hypotonia
Global developmental delay
Cerebral atrophy
Dystonia
Thin corpus callosum
Visual impairment
Microcephaly Near-universal in the reported cohort, and modelled on the neuronal branch because the accompanying findings are white-matter loss, delayed myelination and cortical atrophy rather than a craniosynostosis.
Hearing impairment Recorded mostly as an abnormal auditory brainstem response, which places it on the neural rather than the conductive side.
Show evidence (2 references)
PMID:33058492 SUPPORT Human Clinical
"At birth she presented facial dysmorphism, marked hypotonia, and drug-resistant tonic seizures."
The neurological presentation from birth in the longest-followed patient, including the drug resistance this node's downstream treatment claim depends on.
PMID:38498292 SUPPORT Human Clinical
"MOGS-CDG is a rare disorder affecting the processing of N-Glycans (CDG type II) and is characterized by prominent neurological involvement including hypotonia, developmental delay, seizures and movement disorders."
States that neurological involvement is the prominent feature and names the four components this node feeds.
Hepatic Glycoprotein Dysfunction
Mechanism confidence: Hypothetical
Progressive hepatomegaly with raised transaminases, and in one reported pair coagulopathy, attributed to abnormal handling of hepatic and secreted glycoproteins including the glycosylated clotting factors. As with the neurological branch, the attribution is inference from glycan biology rather than a measured hepatic defect, and it is typed accordingly.
hepatocyte CL:0000182 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves hepatocyte (CL:0000182). CL:0000182 is a cell type from the Cell Ontology.
Downstream
Hepatomegaly
Elevated circulating hepatic transaminase concentration
Show evidence (1 reference)
PMID:30587846 SUPPORT Human Clinical
"Both cases presented progressive hepatomegaly and elevated hepatic enzymes."
The hepatic phenotype and its progressive course in two siblings, which is the clinical output of this node.
Disrupted Developmental Glycosylation
Mechanism confidence: Hypothetical
The craniofacial and limb pattern is recognisable enough to have been proposed as a diagnostic hallmark, which is why it is modelled as a branch rather than left as an unattached list of findings. The mechanism is the least worked out of the three: glycoproteins govern developmental adhesion and signalling, and disrupting them plausibly produces this pattern, but nothing in the cited literature identifies the pathway.
Downstream
Long eyelashes
Retrognathia
Overlapping fingers
Hirsutism
Generalized edema
Wide nose
Short palpebral fissure
High palate
Macrotia
Arthrogryposis multiplex congenita Grouped with the overlapping fingers and toes as the limb component of the developmental phenotype rather than as an isolated contracture.
Show evidence (1 reference)
PMID:29235540 SUPPORT Human Clinical
"Importantly, a review of the features of all four patients revealed the recognizable clinical hallmarks of MOGS-CDG."
Establishes that the dysmorphic pattern is consistent enough across patients to be treated as a single phenotypic output rather than incidental variation.
Cumulative Multisystem Glycoprotein Dysfunction
Mechanism confidence: Hypothetical
The whole-organism consequence of disturbing a modification carried by most secreted and membrane glycoproteins at once. It is modelled as its own node because the features it carries - feeding failure and respiratory insufficiency - are not attributable to any single organ branch and are what determine outcome: in the index case the sequence of hepatomegaly, hypoventilation, feeding problems and seizures ended in death at 74 days, while children with more residual function survive into their second decade.
Downstream
Hypoventilation
Failure to thrive
Abnormal heart morphology A mixed group of septal defects, hypertrophy and cardiomyopathy rather than one malformation, which is why it hangs off the cumulative node instead of a dedicated cardiac branch.
Show evidence (2 references)
PMID:10788335 SUPPORT Human Clinical
"The clinical course was progressive and was characterized by the occurrence of hepatomegaly, hypoventilation, feeding problems, seizures, and fatal outcome at age 74 d."
The multisystem sequence and its outcome in the index case, which is the claim this node makes.
PMID:35790351 SUPPORT Human Clinical
"The clinical phenotype of MOGS-CDG includes multisystemic involvement with variable severity."
Establishes that the involvement is multisystemic and that its severity varies, which is what this node's description turns on.
Endo-alpha-1,2-Mannosidase Bypass
Patient fibroblasts show two- to threefold higher endo-alpha-1,2-mannosidase activity with a matching rise in its transcript. That enzyme cleaves internally to the glucose block, so it clears most glycans through an alternative route and releases the Glc3Man tetrasaccharide. This single compensation explains two otherwise puzzling observations at once: why the serum transferrin pattern is normal despite a near-complete enzyme loss, and where the diagnostic urinary tetrasaccharide comes from.
alternative oligosaccharide processing via endo-alpha-1,2-mannosidase GO:0006491 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves increased alternative oligosaccharide processing via endo-alpha-1,2-mannosidase, annotated with N-glycan processing (GO:0006491). GO:0006491 is a biological process from the Gene Ontology. ↑ INCREASED
Experimental models
Patient skin fibroblast culture PRIMARY CELL CULTURE The bypass was detected and quantified in this system, at both activity and transcript level, against control and parental cells.
Downstream
Urinary Glc3Man Tetrasaccharide Excretion
Show evidence (2 references)
PMID:12145188 SUPPORT In Vitro
"By contrast, the patient's fibroblasts displayed a two- to threefold higher endo-alpha1,2-mannosidase activity, associated with an increased level of enzyme-specific mRNA-transcripts."
The measured compensatory increase, at both activity and transcript level.
PMID:12145188 SUPPORT In Vitro
"This points to the lack of glucosidase I activity being compensated for, to some extent, by increase in the activity of the pathway involving endo-alpha1,2-mannosidase; this would also explain the marked urinary excretion of Glc(3)-Man."
The authors' own reading of the compensation, including the link to the urinary marker that this node's downstream edge asserts.
Urinary Glc3Man Tetrasaccharide Excretion
Glc-alpha1-3-Glc-alpha1-3-Glc-alpha1-2-Man appears in urine, and it is the one biochemical finding that has been abnormal in every affected proband tested. Quantified by liquid chromatography-mass spectrometry it ran from 34.1 to 618.0 micromol per mmol creatinine against a reference below 5.
Show evidence (2 references)
PMID:36651519 SUPPORT Human Clinical
"Glc3 Man was increased in all six analyzed cases, ranging from 34.1 to 618.0 μmol/mmol creatinine (reference <5 μmol)."
The quantified excretion with its reference interval, in every case tested.
PMID:35790351 SUPPORT Human Clinical
"Urine oligosaccharide analysis was consistently abnormal for all affected probands, whereas other biochemical analyses such as serum transferrin analysis was not consistently abnormal."
The consistency of the urinary marker set directly against the inconsistency of the standard CDG screen.
Destabilised Circulating Immunoglobulin
Immunoglobulins carry N-glycans, and glycan structure governs their stability and circulating half-life. In MOGS-CDG the hypogammaglobulinemia is a catabolic problem rather than a production one: the mechanism identified in the two studied siblings was a shortened immunoglobulin half-life. Serum glycomics names the specific defect behind that clearance. Patient IgG carries aberrant oligo-mannose and hybrid-type N-glycans, and its core-fucosylated complex di-antennary glycans are markedly reduced - while transferrin and alpha-1-antitrypsin move the other way, with increased sialylated species. The defect is therefore not uniform across serum glycoproteins, which is part of why transferrin-based CDG screening misses this disease.
plasma cell CL:0000786 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves plasma cell (CL:0000786). CL:0000786 is a cell type from the Cell Ontology.
Downstream
Decreased circulating IgG concentration
Recurrent infections Present in 10 of 11 reported patients, most often as persistent pneumonia. Typed as indirect because the entry does not establish which of the antibody defect, the complement and lymphocyte abnormalities, or the general debility carries it.
Show evidence (4 references)
PMID:24716661 SUPPORT Human Clinical
"A shortened immunoglobulin half-life was determined to be the mechanism underlying the hypogammaglobulinemia."
Identifies the mechanism as accelerated clearance, which is the specific claim of this node.
PMID:27393411 SUPPORT Human Clinical
"CDG with major immunological involvement are ALG12-CDG, MAGT1-CDG, MOGS-CDG, SLC35C1-CDG and PGM3-CDG."
Places MOGS-CDG among the small set of CDG in which immunological involvement is a major rather than incidental feature.
PMID:35137040 SUPPORT Human Clinical
"We further detected aberrant oligo-mannose (Glc3Man7GlcNAc2) and hybrid type N-glycans on patient-derived IgGs and we attributed this defective glycosylation to be the reason for an increased IgG clearance."
Identifies the glycan species on patient IgG and attributes the increased clearance to them, which is the molecular content behind the shortened-half-life claim above. Quoted with the authors' own "we attributed", since it is their inference rather than a measured half-life.
+ 1 more reference
Impaired Viral Replication and Cellular Entry
Mechanism confidence: Provisional
Enveloped viruses depend on host ER glucosidases to fold their own glycoproteins and on host glycan structures for receptor engagement, so the same block that destabilises immunoglobulin also handicaps the virus. It is the observation that made ER glucosidases a broad-spectrum antiviral target. What this node does not claim is that patients escape infection. Recurrent infection is present in 10 of 11 reported patients; the single exception is the sibling pair in whom the reduced infectious diathesis was described, and the elder sister of a separate pair had documented cytomegalovirus infection despite CMV being an enveloped virus. The scope of the claim is reduced susceptibility to some glycosylation-dependent enveloped viruses in the patients where it was looked for, not a clinical phenotype of the disease. The bound GO process covers the entry half of this node only. The replication half has no equally specific GO counterpart and is deliberately left unbound rather than approximated by a broader term.
glycan-dependent viral entry into the host cell GO:0019065 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased glycan-dependent viral entry into the host cell, annotated with receptor-mediated endocytosis of virus by host cell (GO:0019065). GO:0019065 is a biological process from the Gene Ontology. ↓ DECREASED
Show evidence (2 references)
PMID:24716661 SUPPORT Human Clinical
"Impaired viral replication and cellular entry may explain a decreased susceptibility to infections."
The proposed mechanism, quoted with the authors' own "may explain" so that the hedge is preserved rather than upgraded.
PMID:25318123 SUPPORT Human Clinical
"This paradox phenomenon is, at least in part, because the impaired N-linked glycan processing of the patients compromises their ability to support efficient replication and cellular entry of viruses."
A second group's reading of the same observation, with its own hedge "at least in part".
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Pathograph

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

26
Blood 1
Decreased circulating IgG concentration FREQUENT HP:0004315 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Severe hypogammaglobulinemia, annotated with Decreased circulating IgG concentration (HP:0004315). HP:0004315 is a phenotype from the Human Phenotype Ontology.
Show evidence (3 references)
PMID:24716661 SUPPORT Human Clinical
"We evaluated two siblings with CDG-IIb who presented with multiple neurologic complications and a paradoxical immunologic phenotype characterized by severe hypogammaglobulinemia but limited clinical evidence of an infectious diathesis."
The hypogammaglobulinemia and the absence of the expected infection burden in one sentence, as described in this sibling pair. The entry does not model that absence as a property of the disease: recurrent infection is present in 10 of the 11 reported patients, and this pair is the exception.
PMID:36651519 SUPPORT Human Clinical
"Here, we clinically characterize ten MOGS-CDG cases including six previously unreported individuals, showing a phenotype characterized by dysmorphic features, global developmental delay, muscular hypotonia, and seizures in all patients and in a minority vision problems and hypogammaglobulinemia."
The narrower estimate. In this ten-case series hypogammaglobulinemia is a minority feature, unlike the universal neurological ones. It no longer sets the band, and is kept because it is a real cohort disagreeing with the larger one.
PMID:36158009 SUPPORT Human Clinical
"Clinical, genetic, and glycomic features of all reported patients with mannosyl-oligosaccharide glucosidase deficiency...| Hypogammaglobulimia | Low IgA | Low IgG, IgA, IgM | Low IgA, IgM | Low IgA | Low IgA, Normal IgG and IgM after IVIG | Low IgG, IgA, IgM | Low IgA | Low IgA | Low IgA | Low..."
The per-patient immunoglobulin detail behind both counts in the description: low IgG specifically in four of eleven, and low immunoglobulin of some class in all eleven. This is the row the FREQUENT band is set from, and it is also what makes the ten-case series above a disagreement rather than a duplicate.
Cardiovascular 1
Abnormal heart morphology FREQUENT HP:0001627 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is cardiac involvement, annotated with Abnormal heart morphology (HP:0001627). HP:0001627 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:36158009 SUPPORT Human Clinical
"Clinical, genetic, and glycomic features of all reported patients with mannosyl-oligosaccharide glucosidase deficiency...| Cardiac involvement | - | - | ASD, LVH | ASD, PFO, heart failure, and pericardial effusion | PFO, heart failure | PFO, ASD | Dilated cardiomyopathy | + | - | - | ND |"
The row, quoted in full because the per-patient detail is the point: this is a mixed group of structural and functional lesions, not one malformation.
Digestive 1
Hepatomegaly VERY_FREQUENT HP:0002240 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Hepatomegaly (HP:0002240). HP:0002240 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:30587846 SUPPORT Human Clinical
"Both cases presented progressive hepatomegaly and elevated hepatic enzymes."
Records the hepatic phenotype and its progressive course in two siblings. Two patients cannot ground the frequency band; the row below does that.
PMID:36158009 SUPPORT Human Clinical
"Clinical, genetic, and glycomic features of all reported patients with mannosyl-oligosaccharide glucosidase deficiency...| Hepatomegaly | + | ND | + | + | + | + | + | + | + | + | ND |"
Positive in all nine patients where it was assessed, across the whole reported cohort. This is the row the VERY_FREQUENT band is set from.
Ear 2
Hearing impairment VERY_FREQUENT HP:0000365 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Hearing impairment (HP:0000365). HP:0000365 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:36158009 SUPPORT Human Clinical
"Clinical, genetic, and glycomic features of all reported patients with mannosyl-oligosaccharide glucosidase deficiency...| Hearing impairment | Flat with ABR | Sensorineural hearing loss | Abnormal ABR | Hearing impairment | ND | - | ND | No wave with ABR | Only I wave with ABR | Only I wave..."
Names the individual findings per patient rather than a summary grade, so the row shows both the frequency and the form the impairment takes.
Macrotia FREQUENT HP:0000400 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is enlarged ears, annotated with Macrotia (HP:0000400). HP:0000400 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:36158009 SUPPORT Human Clinical
"Clinical, genetic, and glycomic features of all reported patients with mannosyl-oligosaccharide glucosidase deficiency...| Enlarged ears | + | | ND | + | + | ND | | + | + | + | ND |"
The row for this feature.
Eye 1
Visual impairment OCCASIONAL HP:0000505 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Visual impairment (HP:0000505). HP:0000505 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:36651519 SUPPORT Human Clinical
"Here, we clinically characterize ten MOGS-CDG cases including six previously unreported individuals, showing a phenotype characterized by dysmorphic features, global developmental delay, muscular hypotonia, and seizures in all patients and in a minority vision problems and hypogammaglobulinemia."
The same ten-case series, quoted for the vision component and its minority frequency.
Head and Neck 6
Long eyelashes FREQUENT HP:0000527 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Long eyelashes (HP:0000527). HP:0000527 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:29235540 SUPPORT Human Clinical
"The distinct dysmorphic features of this condition include long eyelashes, retrognathia, hirsutism, clenched overlapped fingers, hypoventilation, hepatomegaly, generalized edema, and immunodeficiency."
The dysmorphic hallmark list assembled across all four patients known at the time.
Retrognathia FREQUENT HP:0000278 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Retrognathia (HP:0000278). HP:0000278 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:29235540 SUPPORT Human Clinical
"The distinct dysmorphic features of this condition include long eyelashes, retrognathia, hirsutism, clenched overlapped fingers, hypoventilation, hepatomegaly, generalized edema, and immunodeficiency."
The same hallmark list, quoted for retrognathia.
Microcephaly VERY_FREQUENT HP:0000252 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Microcephaly (HP:0000252). HP:0000252 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:36158009 SUPPORT Human Clinical
"Clinical, genetic, and glycomic features of all reported patients with mannosyl-oligosaccharide glucosidase deficiency...| Microcephaly | + | + | + | + | + | ND | + | + | + | + | + |"
The row from the summary table of all reported patients. Quoted with the table caption so the count is attributable to the whole reported cohort rather than to one series.
Wide nose FREQUENT HP:0000445 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is broad nose, annotated with Wide nose (HP:0000445). HP:0000445 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:36158009 SUPPORT Human Clinical
"Clinical, genetic, and glycomic features of all reported patients with mannosyl-oligosaccharide glucosidase deficiency...| Broad nose | + | | + | + | + | + | | + | + | + | - |"
The row for this feature. The band is FREQUENT rather than VERY_FREQUENT because two columns are blank rather than assessed. Bound to Wide nose rather than Wide nasal bridge: the source records "broad nose", a recorded synonym of the former, and says nothing about the bridge specifically.
Short palpebral fissure FREQUENT HP:0012745 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is short palpebral fissures, annotated with Short palpebral fissure (HP:0012745). HP:0012745 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:36158009 SUPPORT Human Clinical
"Clinical, genetic, and glycomic features of all reported patients with mannosyl-oligosaccharide glucosidase deficiency...| Short palpebral fissure | + | | + | + | + | + | | + | + | + | - |"
The row for this feature, with the same blank-column caveat as the broad nose.
High palate FREQUENT HP:0000218 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is high-arched palate, annotated with High palate (HP:0000218). HP:0000218 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:36158009 SUPPORT Human Clinical
"Clinical, genetic, and glycomic features of all reported patients with mannosyl-oligosaccharide glucosidase deficiency...| High-arched palate | + | | + | + | ND | ND | | + | + | + | ND |"
The row for this feature. Six positives and no negative, but five of eleven columns carry no assessment, which is why the band is FREQUENT rather than higher.
Immune 1
Recurrent infections VERY_FREQUENT HP:0002719 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Recurrent infections (HP:0002719). HP:0002719 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:36158009 SUPPORT Human Clinical
"Clinical, genetic, and glycomic features of all reported patients with mannosyl-oligosaccharide glucosidase deficiency...| Recurrent infections | + | - | + | + | + | + | + | + | + | + | + |"
The row that establishes recurrent infection as near-universal, and locates the one exception. It is the direct correction to the earlier framing.
Integument 1
Hirsutism FREQUENT HP:0001007 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Hirsutism (HP:0001007). HP:0001007 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:29235540 SUPPORT Human Clinical
"The distinct dysmorphic features of this condition include long eyelashes, retrognathia, hirsutism, clenched overlapped fingers, hypoventilation, hepatomegaly, generalized edema, and immunodeficiency."
The same hallmark list, quoted for hirsutism.
Limbs 1
Overlapping fingers FREQUENT HP:0010557 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Clenched overlapped fingers, annotated with Overlapping fingers (HP:0010557). HP:0010557 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:29235540 SUPPORT Human Clinical
"The distinct dysmorphic features of this condition include long eyelashes, retrognathia, hirsutism, clenched overlapped fingers, hypoventilation, hepatomegaly, generalized edema, and immunodeficiency."
The same hallmark list, quoted for the hand posture.
Metabolism 2
Elevated circulating hepatic transaminase concentration VERY_FREQUENT HP:0002910 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Elevated hepatic enzymes, annotated with Elevated circulating hepatic transaminase concentration (HP:0002910). HP:0002910 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:30587846 SUPPORT Human Clinical
"Both cases presented progressive hepatomegaly and elevated hepatic enzymes."
The biochemical hepatic abnormality, reported with the hepatomegaly it accompanies. Two patients; the row below sets the band.
PMID:36158009 SUPPORT Human Clinical
"Clinical, genetic, and glycomic features of all reported patients with mannosyl-oligosaccharide glucosidase deficiency...| Elevated AST/ALT (IU/L) | +(80/34) | ND | ND | + (46-154/14-81) | + (49-121/17-56) | + | | + (30-1547/9- 1132) | + (35-144/23-83) | + (36-226/50.5-164) | ND |"
Positive in all seven patients where transaminases were measured, with the per-patient values. This is the row the VERY_FREQUENT band is set from.
Generalized edema FREQUENT HP:0007430 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Generalized edema (HP:0007430). HP:0007430 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:29235540 SUPPORT Human Clinical
"The distinct dysmorphic features of this condition include long eyelashes, retrognathia, hirsutism, clenched overlapped fingers, hypoventilation, hepatomegaly, generalized edema, and immunodeficiency."
The same hallmark list, quoted for the edema.
Musculoskeletal 2
Generalized hypotonia VERY_FREQUENT HP:0001290 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Generalized hypotonia (HP:0001290). HP:0001290 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:36651519 SUPPORT Human Clinical
"Here, we clinically characterize ten MOGS-CDG cases including six previously unreported individuals, showing a phenotype characterized by dysmorphic features, global developmental delay, muscular hypotonia, and seizures in all patients and in a minority vision problems and hypogammaglobulinemia."
Records hypotonia as present in all ten patients of the largest phenotyping series.
Arthrogryposis multiplex congenita FREQUENT HP:0002804 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is arthrogryposis, annotated with Arthrogryposis multiplex congenita (HP:0002804). HP:0002804 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:36158009 SUPPORT Human Clinical
"Clinical, genetic, and glycomic features of all reported patients with mannosyl-oligosaccharide glucosidase deficiency...| Arthrogryposis | + | + | ND | ND | ND | ND | | + | + | + | ND |"
The row for this feature. Most columns are not-done, so the true frequency is likely higher than the raw count suggests and the band is set from the assessed columns.
Nervous System 5
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:36651519 SUPPORT Human Clinical
"Here, we clinically characterize ten MOGS-CDG cases including six previously unreported individuals, showing a phenotype characterized by dysmorphic features, global developmental delay, muscular hypotonia, and seizures in all patients and in a minority vision problems and hypogammaglobulinemia."
The same series, quoted for the developmental component.
Epileptic encephalopathy VERY_FREQUENT HP:0200134 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Early infantile epileptic encephalopathy, annotated with Epileptic encephalopathy (HP:0200134). HP:0200134 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:33261925 SUPPORT Human Clinical
"Our three patients presented with early infantile epileptic encephalopathy, generalized hypotonia, hepatic dysfunction and dysmorphic features."
Records the encephalopathic seizure phenotype in three patients.
Thin corpus callosum OCCASIONAL HP:0033725 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Thin corpus callosum (HP:0033725). HP:0033725 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:30587846 SUPPORT Human Clinical
"Head MRI of the elder sister showed increased signals on T1W1, bilateral frontal gyrus stenosis, and thin corpus callosum."
The imaging finding in a reported sibling.
Cerebral atrophy OCCASIONAL HP:0002059 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Progressive cortical and subcortical atrophy, annotated with Cerebral atrophy (HP:0002059). HP:0002059 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:33058492 SUPPORT Human Clinical
"Brain MRI showed progressive cortical and subcortical atrophy."
The imaging finding and, importantly, its progressive character, which is what distinguishes it from a static malformation.
Dystonia FREQUENT HP:0001332 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Dystonia (HP:0001332). HP:0001332 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:33058492 SUPPORT Human Clinical
"In the following months, her motility was strongly limited by dystonia, with forced posture of the head and of both hands."
The dystonia and its functional consequence in the reported patient.
PMID:38498292 SUPPORT Human Clinical
"MOGS-CDG is a rare disorder affecting the processing of N-Glycans (CDG type II) and is characterized by prominent neurological involvement including hypotonia, developmental delay, seizures and movement disorders."
Places movement disorder among the characteristic neurological features rather than as a single-case observation.
Respiratory 1
Hypoventilation OCCASIONAL HP:0002791 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Hypoventilation (HP:0002791). HP:0002791 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:10788335 SUPPORT Human Clinical
"The clinical course was progressive and was characterized by the occurrence of hepatomegaly, hypoventilation, feeding problems, seizures, and fatal outcome at age 74 d."
Records hypoventilation in the index case, in the sequence that ended in death at 74 days.
Growth 1
Failure to thrive OCCASIONAL HP:0001508 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Feeding problems and failure to thrive, annotated with Failure to thrive (HP:0001508). HP:0001508 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:10788335 SUPPORT Human Clinical
"The clinical course was progressive and was characterized by the occurrence of hepatomegaly, hypoventilation, feeding problems, seizures, and fatal outcome at age 74 d."
The feeding problems in the index case, in the progressive sequence that ended in death at 74 days.
🧬

Genetic Associations

1
MOGS (Causal biallelic variant)
Gene: MOGS hgnc:24862 HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is MOGS (hgnc:24862). hgnc:24862 is a gene from the HUGO Gene Nomenclature Committee. relationship_type: CAUSATIVE
Show evidence (3 references)
PMID:35790351 SUPPORT Human Clinical
"The severity in each organ system was variable, without definite genotype correlation."
The absence of a genotype-phenotype correlation, stated by the series best placed to find one.
PMID:35790351 SUPPORT Human Clinical
"Molecular analysis, combined with biochemical testing, is important for diagnosis."
The recommendation that molecular findings be paired with the biochemical assay rather than used alone.
PMID:30587846 SUPPORT Human Clinical
"Compound heterozygous variants of NM_006302:c.1239_1267dup,p.Asp414Leufs*17, c.544 G > A,p.Gly182Arg, and c.1698C > A,p.Asp566Glu in MOGS were identified."
A worked compound heterozygous genotype including a frameshift allele, extending the spectrum beyond the original two missense variants.
💊

Medical Actions

2
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
Platform: Other
No disease-modifying treatment exists. Management is anticonvulsant control of the epilepsy, respiratory and feeding support, hepatic monitoring, and developmental therapies. Immunoglobulin replacement is a question rather than a recommendation here: the hypogammaglobulinemia is real but the infection burden is not what it predicts, so the usual indication for replacement does not straightforwardly apply.
Mechanism Target:
Aberrant Neuronal Glycoprotein Function — Supportive management is directed at the outputs of the neurological branch. It does not act on the glycan lesion, which is why the entry records no disease-modifying treatment.
Target Phenotypes: Early infantile epileptic encephalopathy HP:0200134 Human Phenotype Ontology (HP) Relation: this treatment targets this phenotype This treatment targets Early infantile epileptic encephalopathy, annotated with Epileptic encephalopathy (HP:0200134). HP:0200134 is a phenotype from the Human Phenotype Ontology.
Anticonvulsant therapy
Action: Anticonvulsant TherapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Anticonvulsant Therapy (NCIT:C64172). NCIT:C64172 is a clinical intervention from the NCI Thesaurus. NCIT:C64172
Platform: Small molecule
Seizures are present in essentially every reported patient and are frequently drug-resistant, so anticonvulsant treatment is the intervention these children actually receive. No agent or regimen has been shown superior in this disease, and no source recommends one; in the longest-followed patient, epileptic spasms remitted by age seven while tonic seizures persisted to nineteen. The entry records the modality without naming a drug, because the literature does not.
Mechanism Target:
Aberrant Neuronal Glycoprotein Function — Symptomatic control of the seizure output of this node. It does not act on the node itself.
Target Phenotypes: Early infantile epileptic encephalopathy HP:0200134 Human Phenotype Ontology (HP) Relation: this treatment targets this phenotype This treatment targets Early infantile epileptic encephalopathy, annotated with Epileptic encephalopathy (HP:0200134). HP:0200134 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:33058492 SUPPORT Human Clinical
"Epileptic spasms appeared in first months and ceased by the age of 7 years, while tonic seizures were still present at last assessment (19 years)."
The long-term seizure course under treatment. Cited to establish what anticonvulsant therapy achieves and does not achieve here, rather than as evidence that any particular agent works.
PMID:33058492 SUPPORT Human Clinical
"At birth she presented facial dysmorphism, marked hypotonia, and drug-resistant tonic seizures."
Records the drug resistance, which is the reason this treatment is listed with no expectation of control rather than as effective management.
🔬

Biochemical Markers

2
Urinary Glc3Man tetrasaccharide
Reference Ranges
0.0–5.0 umol/mmol{creatinine} (reference population, method as published)
No LOINC code is bound. Urinary Glc3Man is a specialist research assay with no LOINC counterpart, and no code is asserted rather than binding an approximate one. The interval is the reference stated by the group that developed and validated the quantitative method; patient values in that series ran from 34.1 to 618.0, so the separation from the reference is roughly an order of magnitude at the low end.
Show evidence (1 reference)
PMID:36651519 SUPPORT Human Clinical
"Glc3 Man was increased in all six analyzed cases, ranging from 34.1 to 618.0 μmol/mmol creatinine (reference <5 μmol)."
The reference interval and the observed patient range in one sentence, from the paper that validated the quantitative method.
Show evidence (1 reference)
PMID:35790351 SUPPORT Human Clinical
"Urine oligosaccharide analysis was consistently abnormal for all affected probands, whereas other biochemical analyses such as serum transferrin analysis was not consistently abnormal."
Establishes this analyte as the consistently abnormal one, against the inconsistency of the standard CDG screen.
Serum immunoglobulins, complement and creatine kinase
Show evidence (1 reference)
PMID:36158009 SUPPORT Human Clinical
"Novel laboratory findings included peripheral leukocytosis with neutrophil predominance, elevated C-reactive protein and creatine kinase, dyslipidemia, coagulopathy, complement 3 and complement 4 deficiencies, decreased proportions of T lymphocytes and natural killer cells, and increased serum..."
The panel as reported. Described by its own authors as novel findings in two patients, which is why this entry does not assign a frequency to any of them.
🔬

Diagnosis

1
Urinary oligosaccharide analysis for Glc3Man
The test that works, and it is not the one a CDG workup reaches for first. Serum transferrin isoelectric focusing is typically normal in MOGS-CDG, so the disease escapes the standard screen; urinary Glc3Man by mass spectrometry has been abnormal in every affected proband tested and is now quantifiable against a reference interval. Suspect the diagnosis on the clinical pattern - dysmorphism with hypotonia, seizures and developmental delay - and go straight to urine oligosaccharides rather than concluding from a normal transferrin that this is not a CDG.
Show evidence (3 references)
PMID:35790351 SUPPORT Human Clinical
"In MOGS-CDG, urine oligosaccharide analysis via matrix-assisted laser desorption/ionisation time-of-flight mass spectrometry can be used as a reliable biochemical test for screening and confirmation of disease."
Names the test and the role it plays, for both screening and confirmation.
PMID:36651519 SUPPORT Human Clinical
"Most CDG with abnormal N-glycosylation can be detected by transferrin screening, however, MOGS-CDG escapes this routine screening."
States the screening failure that makes the urinary assay necessary rather than merely confirmatory.
PMID:33261925 SUPPORT Human Clinical
"Although the isoelectric focusing of transferrin (IEF-T) of serum in this patient was normal, urinary excretion of Hex4 corresponding to Glc3Man was observed by mass spectrometry."
A worked case of exactly the discordance the diagnostic advice turns on: normal transferrin, positive urinary tetrasaccharide.
📊

Prevalence

1
Worldwide
Cases In Literature Ultra Rare
No population estimate exists. The published case count is the only figure, and it has moved steadily: a single patient in 2000, three from two families by 2018, ten characterised in 2023, twelve from eleven families in the largest phenotyping series, and about thirty published worldwide as of 2024. Reported numbers are still accumulating one family at a time.
Show evidence (3 references)
PMID:36651519 SUPPORT Human Clinical
"Here, we clinically characterize ten MOGS-CDG cases including six previously unreported individuals, showing a phenotype characterized by dysmorphic features, global developmental delay, muscular hypotonia, and seizures in all patients and in a minority vision problems and hypogammaglobulinemia."
The case count at the time of the most recent series, together with the phenotype frequencies used elsewhere in this entry.
PMID:29235540 SUPPORT Human Clinical
"Mannosyl-oligosaccharide glucosidase (MOGS)-CDG (CDG type IIb) is an extremely rare CDG that has only been reported in three patients from two unrelated families."
An earlier point on the same count, showing how sparse the literature was as recently as 2018.
PMID:38498292 SUPPORT Human Clinical
"To the best of our knowledge, 30 patients with MOGS-CDG have been published so far."
The most recent published count, and the figure the notes above quote.
🔀

Differential Diagnoses

3

Conditions with similar clinical presentations that must be differentiated from MOGS-Congenital Disorder of Glycosylation:

Other congenital disorders of glycosylation detectable by transferrin screening
Overlapping Features Most N-glycosylation CDG give an abnormal carbohydrate-deficient transferrin pattern. A normal transferrin result excludes many of them and does not exclude MOGS-CDG, which is the practical distinction.
Distinguishing Features
  • Serum transferrin isoelectric focusing is typically normal in MOGS-CDG and abnormal in most N-glycosylation CDG.
  • Urinary Glc3Man tetrasaccharide is specific to the glucosidase I block.
Show evidence (1 reference)
PMID:36651519 SUPPORT Human Clinical
"Most CDG with abnormal N-glycosylation can be detected by transferrin screening, however, MOGS-CDG escapes this routine screening."
The screening asymmetry that separates MOGS-CDG from the rest of the group.
Pompe disease MONDO:0009290
Overlapping Features Named here for one specific reason: Pompe urine also carries a glucose-tetrasaccharide, so a urinary oligosaccharide screen can put the two on the same result. The MOGS-CDG species is Glc3Man and is separated by retention-time matching.
Distinguishing Features
  • The MOGS-CDG urinary tetrasaccharide is Glc3Man and is identified by retention time against authentic MOGS-CDG urine.
  • Pompe disease has acid alpha-glucosidase deficiency and a myopathic or cardiac presentation rather than the dysmorphic-neurological pattern of MOGS-CDG.
Show evidence (1 reference)
PMID:36651519 SUPPORT Human Clinical
"Furthermore, Glc3 Man was specifically identified by retention time matching against authentic MOGS-CDG urine and compared with Pompe urine."
The analytical step the assay developers took specifically to separate these two, which is why the differential is listed.
UGGT1-congenital disorder of glycosylation MONDO:0980705
Overlapping Features The nearest neighbour in the pathway. UGGT1 re-glucosylates misfolded glycoproteins to return them to the calnexin/calreticulin cycle, so UGGT1-CDG and MOGS-CDG break the same ER glycoprotein quality-control loop from opposite directions: MOGS removes the first glucose, UGGT1 puts one back. The clinical overlap is broad - developmental delay, seizures, dysmorphism, hepatic and respiratory involvement - and a normal transferrin pattern does not separate them. The separator is the urinary tetrasaccharide. Glc3Man accumulates only when the glucosidase I block leaves the triglucosylated glycan intact, so it is specific to MOGS-CDG and is not produced by a UGGT1 lesion.
Distinguishing Features
  • Urinary Glc3Man tetrasaccharide is specific to the glucosidase I block and is the positive test for MOGS-CDG. It is the discriminator that does the work.
  • Scoliosis and polycystic kidneys mark the severe end of UGGT1-CDG and are not features of MOGS-CDG.
  • Microcephaly does NOT discriminate. It is near-universal in both, present in 10 of 11 reported MOGS-CDG patients with no negative column.
  • Cardiac involvement does NOT discriminate. It occurs in roughly six of the eleven reported MOGS-CDG patients as ASD, PFO, left ventricular hypertrophy, dilated cardiomyopathy or heart failure.
  • Biallelic pathogenic MOGS variants favour MOGS-CDG; biallelic pathogenic UGGT1 variants favour UGGT1-CDG.
Show evidence (4 references)
PMID:40267907 SUPPORT Human Clinical
"The cardinal clinical features of UGGT1-CDG involve developmental delay, intellectual disability, seizures, characteristic facial features, and microcephaly in the majority (9/11 affected individuals for whom measurements were available)."
The cardinal features of UGGT1-CDG. Every one of them, microcephaly included, also occurs in MOGS-CDG, so this quote establishes the overlap and discriminates nothing. It is retained for that reason.
PMID:40267907 SUPPORT Human Clinical
"The more severely affected individuals display congenital heart malformations, variable skeletal abnormalities including scoliosis, and hepatic and renal involvement, including polycystic kidneys mimicking autosomal recessive polycystic kidney disease."
The severe-end features of UGGT1-CDG. Only scoliosis and the polycystic kidneys separate: cardiac malformation and hepatic involvement occur in MOGS-CDG too, so this quote is read for its skeletal and renal half only.
PMID:40267907 SUPPORT INDIRECT Human Clinical
"UGGT1 encodes UDP-glucose:glycoprotein glucosyltransferase 1, an enzyme critical for maintaining quality control of N-linked glycosylation."
Places UGGT1 in the same quality-control loop MOGS acts on, which is why this differential is a pathway neighbour rather than a coincidental clinical mimic. Graded INDIRECT because it states the enzyme's role without comparing the two disorders.
+ 1 more reference
🧫

Experimental Models

2
Patient skin fibroblast culture PRIMARY_CELL_CULTURE
Cultured fibroblasts from patients and their heterozygous parents are the functional standard for this disease. They are where residual glucosidase I activity was quantified, where the specificity of the defect to that one enzyme was established, and where the compensatory endo-alpha-1,2-mannosidase increase was measured.
Cell source
patient and parental skin biopsy
Publication
PMID:12145188
Pathograph links
Endo-alpha-1,2-Mannosidase Bypass measures fidelity: high observes: cellular The bypass was detected and quantified in this system, at both activity and transcript level, against control and parental cells.
Limitations: Fibroblasts are not a tissue affected in the disease. The bypass magnitude measured here may not be the magnitude in brain or liver, which is precisely the uncertainty the severity knowledge gap in this entry turns on.
Show evidence (1 reference)
PMID:12145188 SUPPORT In Vitro
"By contrast, the patient's fibroblasts displayed a two- to threefold higher endo-alpha1,2-mannosidase activity, associated with an increased level of enzyme-specific mRNA-transcripts."
The measurement this model is cited for, made in this system.
Saccharomyces cerevisiae CWH41 knockout complementation assay OTHER
A yeast strain lacking CWH41, the MOGS homolog, used as a functional complementation assay: the N-glycan profile of the knockout is restored when a working glucosidase I is supplied. It offers a route to testing whether a MOGS variant of uncertain significance retains activity, which is the practical difficulty this entry records in the genetic notes.
Organism
baker's yeast NCBITaxon:4932 NCBI Taxonomy (NCBITaxon) Relation: this experimental model is built in this organism This experimental model is built in baker's yeast, annotated with Saccharomyces cerevisiae (NCBITaxon:4932). NCBITaxon:4932 is an organism from the NCBI Taxonomy.
Publication
PMID:40674822
Pathograph links
Loss of ER Alpha-Glucosidase I Activity recapitulates fidelity: moderate observes: molecular Deleting the homologous gene reproduces the enzymatic lesion and the resulting N-glycan profile change, which is what makes the strain usable as a readout of glucosidase I function.
Limitations: Yeast N-glycan processing diverges from human downstream of this step, so the assay reports on the enzyme rather than on the disease. It says nothing about any phenotype and was developed to characterise a prokaryotic MOGS rather than to model MOGS-CDG.
Show evidence (2 references)
PMID:40674822 SUPPORT In Vitro
"During the process, a functional complementation assay was established by examining the N-glycans profile of a CWH41 (MOGS homologous gene) knockout strain of Saccharomyces cerevisiae."
Describes the assay and the strain it is built on.
+ 1 more reference
{ }

Source YAML

click to show 
name: MOGS-Congenital Disorder of Glycosylation
creation_date: "2026-09-09T14:05:00Z"
category: Mendelian
synonyms:
- MOGS-CDG
- CDG-IIb
- CDG type IIb
- congenital disorder of glycosylation type IIb
- GCS1-CDG
- glucosidase I deficiency
- carbohydrate deficient glycoprotein syndrome type IIb
description: >-
  MOGS-CDG is an autosomal recessive congenital disorder of glycosylation caused
  by biallelic MOGS variants. MOGS encodes ER alpha-glucosidase I, which performs
  the first obligate trimming step on a newly transferred N-glycan: removal of
  the outermost alpha-1,2-linked glucose from Glc3Man9GlcNAc2. Losing it blocks
  N-glycan maturation at its first move.

  Clinically it is a severe multisystem disease. Dysmorphic features, generalised
  hypotonia, global developmental delay and seizures are present in essentially
  all reported patients; hepatic dysfunction, hypoventilation, vision problems
  and hypogammaglobulinemia occur in some. Severity spans a neonatal course fatal
  at 74 days through to children alive in their second decade, with no genotype
  correlation established.

  Two things make this entry unusual. The first is a claim about infection that
  has to be stated carefully, because the literature does not say what a first
  reading suggests. Recurrent infection is near-universal: 10 of the 11 reported
  patients in the 2022 summary table have it, and the one exception is the
  sibling pair in whom the observation of "limited clinical evidence of an
  infectious diathesis" was made. So this disease is not one of preserved
  immunity. What is real, and narrower, is that the same glycan block that
  destabilises immunoglobulin also impairs the replication and cellular entry of
  enveloped viruses, and that in one sibling pair the expected bacterial burden
  was not seen. The immunoglobulin defect itself is a shortened half-life of
  aberrantly glycosylated antibody rather than a failure to make it. The
  deficiency subtracts from host defence and from viral fitness at once, which is
  what turned this ultra-rare disease into a proof of
  principle for ER glucosidase inhibitors as broad-spectrum antivirals.

  The second is a diagnostic trap. Serum transferrin isoelectric focusing, the
  standard CDG screen, is typically normal here, so the disease escapes the test
  that would otherwise find it. The reason is a partial metabolic bypass: with
  glucosidase I absent, endo-alpha-1,2-mannosidase activity rises and clears most
  glycans through an alternative route, leaving the bulk of N-glycoproteins
  correctly processed and releasing the Glc3Man tetrasaccharide into urine. That
  tetrasaccharide is the reliable diagnostic marker, and urine oligosaccharide
  analysis is the test that works.
disease_term:
  preferred_term: MOGS-congenital disorder of glycosylation
  term:
    id: MONDO:0011629
    label: MOGS-congenital disorder of glycosylation
parents:
- Congenital disorder of glycosylation type II
- Disorder of protein N-glycosylation
references:
- reference: PMID:10788335
  title: A novel disorder caused by defective biosynthesis of N-linked oligosaccharides due to glucosidase I deficiency.
- reference: PMID:12145188
  title: Processing of N-linked carbohydrate chains in a patient with glucosidase I deficiency (CDG type IIb).
- reference: PMID:24716661
  title: "Glycosylation, hypogammaglobulinemia, and resistance to viral infections."
- reference: PMID:25318123
  title: Viral resistance of MOGS-CDG patients implies a broad-spectrum strategy against acute virus infections.
- reference: PMID:35790351
  title: "Clinical, biochemical and genetic characteristics of MOGS-CDG: a rare congenital disorder of glycosylation."
- reference: PMID:36651519
  title: "MOGS-CDG: Quantitative analysis of the diagnostic Glc(3) Man tetrasaccharide and clinical spectrum of six new cases."
- reference: PMID:33261925
  title: "Congenital disorders of glycosylation type IIb with MOGS mutations cause early infantile epileptic encephalopathy, dysmorphic features, and hepatic dysfunction."
- reference: PMID:29235540
  title: Characteristic dysmorphic features in congenital disorders of glycosylation type IIb.
- reference: PMID:30587846
  title: Compound heterozygous variants in MOGS inducing congenital disorders of glycosylation (CDG) IIb.
- reference: PMID:27393411
  title: "Immunological aspects of congenital disorders of glycosylation (CDG): a review."
- reference: PMID:35137040
  title: Serum N-glycomics of a novel CDG-IIb patient reveals aberrant IgG glycosylation.
- reference: PMID:36158009
  title: "Updated clinical and glycomic features of mannosyl-oligosaccharide glucosidase deficiency: Two case reports."
- reference: PMID:33058492
  title: "Epilepsy and movement disorders in CDG: Report on the oldest-known MOGS-CDG patient."
- reference: PMID:38498292
  title: "Early onset epileptic and developmental encephalopathy and MOGS variants: a new diagnosis in the whole exome sequencing (WES) ERA : Report of a new patient and review of the literature."
- reference: PMID:33245474
  title: "N-Glycan Modification in Covid-19 Pathophysiology: In vitro Structural Changes with Limited Functional Effects."
- reference: PMID:40674822
  title: Identification and characterization of a prokaryotic Mannosyl-oligosaccharide Glucosidase (MOGS) and establishment of a functional complementation assay for MOGS activity.
- reference: PMID:40267907
  title: Bi-allelic UGGT1 variants cause a congenital disorder of glycosylation.
inheritance:
- name: Autosomal recessive inheritance
  inheritance_term:
    preferred_term: Autosomal recessive inheritance
    term:
      id: HP:0000007
      label: Autosomal recessive inheritance
  description: >-
    Biallelic MOGS variants, homozygous or compound heterozygous. Carrier
    parents have roughly half-normal enzyme activity and are unaffected.
  evidence:
  - reference: PMID:35790351
    reference_title: "Clinical, biochemical and genetic characteristics of MOGS-CDG: a rare congenital disorder of glycosylation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Bi-allelic variants in MOGS were identified in 12 individuals from 11 families.
    explanation: >-
      The biallelic requirement across the largest assembled cohort.
  - reference: PMID:10788335
    reference_title: A novel disorder caused by defective biosynthesis of N-linked oligosaccharides due to glucosidase I deficiency.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Glucosidase I activities in cultured skin fibroblasts from both parents were found to be 50% of those of controls.
    explanation: >-
      The half-normal carrier activity that makes the trait recessive at the
      biochemical level as well as the clinical one.
prevalence:
- population: Worldwide
  measure_type: CASES_IN_LITERATURE
  prevalence_class: ULTRA_RARE
  notes: >-
    No population estimate exists. The published case count is the only figure,
    and it has moved steadily: a single patient in 2000, three from two families
    by 2018, ten characterised in 2023, twelve from eleven families in the
    largest phenotyping series, and about thirty published worldwide as of 2024.
    Reported numbers are still accumulating one family at a time.
  evidence:
  - reference: PMID:36651519
    reference_title: "MOGS-CDG: Quantitative analysis of the diagnostic Glc(3) Man tetrasaccharide and clinical spectrum of six new cases."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Here, we clinically characterize ten MOGS-CDG cases including six previously unreported individuals, showing a phenotype characterized by dysmorphic features, global developmental delay, muscular hypotonia, and seizures in all patients and in a minority vision problems and hypogammaglobulinemia.
    explanation: >-
      The case count at the time of the most recent series, together with the
      phenotype frequencies used elsewhere in this entry.
  - reference: PMID:29235540
    reference_title: Characteristic dysmorphic features in congenital disorders of glycosylation type IIb.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Mannosyl-oligosaccharide glucosidase (MOGS)-CDG (CDG type IIb) is an extremely rare CDG that has only been reported in three patients from two unrelated families.
    explanation: >-
      An earlier point on the same count, showing how sparse the literature was
      as recently as 2018.
  - reference: PMID:38498292
    reference_title: "Early onset epileptic and developmental encephalopathy and MOGS variants: a new diagnosis in the whole exome sequencing (WES) ERA : Report of a new patient and review of the literature."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      To the best of our knowledge, 30 patients with MOGS-CDG have been published so far.
    explanation: >-
      The most recent published count, and the figure the notes above quote.
pathophysiology:
- name: Biallelic MOGS Loss-of-Function Variants
  biological_scale: MOLECULAR
  description: >-
    Missense, frameshift and other variants on both MOGS alleles. The gene has
    four exons, with exon 4 encoding the 64 kDa catalytic domain, and both
    original disease alleles fall in that exon. Reintroducing either into
    wild-type glucosidase I abolished measurable activity, and the two acted
    differently on the protein: one retained weak affinity-resin binding and the
    other did not, so they disturb folding and active-site formation by different
    routes.
  genetic_context:
    variant_origin: GERMLINE
    functional_impact_category: LOSS_OF_FUNCTION
  downstream:
  - target: Loss of ER Alpha-Glucosidase I Activity
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:12145188
      reference_title: Processing of N-linked carbohydrate chains in a patient with glucosidase I deficiency (CDG type IIb).
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: >-
        Incorporation of either mutation into wild-type glucosidase I resulted in the overexpression of enzyme mutants in COS 1 cells displaying no measurable catalytic activity.
      explanation: >-
        A direct functional test that each disease allele, on its own, abolishes
        the enzyme activity this edge asserts it removes.
  evidence:
  - reference: PMID:10788335
    reference_title: A novel disorder caused by defective biosynthesis of N-linked oligosaccharides due to glucosidase I deficiency.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Molecular studies showed that the patient was a compound heterozygote for two missense mutations in the glucosidase I gene: (1) one allele harbored a G-->C transition at nucleotide (nt) 1587, resulting in the substitution of Arg at position 486 by Thr (R486T), and (2) on the other allele a T-->C transition at nt 2085 resulted in the substitution of Phe at position 652 by Leu (F652L).
    explanation: >-
      The two founding disease alleles, with their positions and consequences.
  - reference: PMID:12145188
    reference_title: Processing of N-linked carbohydrate chains in a patient with glucosidase I deficiency (CDG type IIb).
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      The Phe652Leu but not the Arg486Thr protein mutant showed a weak binding to a glucosidase I-specific affinity resin, indicating that the two amino acids affect polypeptide folding and active site formation differently.
    explanation: >-
      Shows the two alleles are not mechanistically equivalent, which is why
      this node describes a class of lesions rather than one.
- name: Loss of ER Alpha-Glucosidase I Activity
  biological_scale: MOLECULAR
  description: >-
    Residual activity in patient tissue is under 3 percent of control in liver
    and fibroblasts, and under 1 percent by kinetic assay in fibroblast extracts.
    The loss is specific: oligosaccharyltransferase, glucosidase II and
    Man9-mannosidase activities are unchanged, so the block is at one enzyme
    rather than across the pathway.
  cellular_components:
  - preferred_term: endoplasmic reticulum
    term:
      id: GO:0005783
      label: endoplasmic reticulum
  molecular_functions:
  - preferred_term: ER alpha-glucosidase I activity
    modifier: DECREASED
    term:
      id: GO:0004573
      label: Glc3Man9GlcNAc2 oligosaccharide glucosidase activity
  downstream:
  - target: Failure of the First N-Glycan Trimming Step
    causal_link_type: DIRECT
  evidence:
  - reference: PMID:10788335
    reference_title: A novel disorder caused by defective biosynthesis of N-linked oligosaccharides due to glucosidase I deficiency.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Enzymological studies on liver tissue and cultured skin fibroblasts revealed a severe glucosidase I deficiency. The residual activity was <3% of that of controls.
    explanation: >-
      The measured residual activity in patient tissue.
  - reference: PMID:12145188
    reference_title: Processing of N-linked carbohydrate chains in a patient with glucosidase I deficiency (CDG type IIb).
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      No significant differences in the activities of other processing enzymes, including oligosaccharyltransferase, glucosidase II, and Man(9)-mannosidase, were observed.
    explanation: >-
      Establishes that the defect is confined to this one enzyme, which is what
      lets the rest of the chain be attributed to it.
- name: Failure of the First N-Glycan Trimming Step
  biological_scale: MOLECULAR
  description: >-
    Glucosidase I removes the distal alpha-1,2-linked glucose from the
    Glc3Man9GlcNAc2 precursor immediately after it is transferred en bloc from
    dolichyl diphosphate to the nascent chain. Without that first cut the glycan
    cannot enter the maturation sequence, and a fraction of N-glycans is arrested
    at the Glc3Man9-7GlcNAc2 stage.
  biological_processes:
  - preferred_term: processing of protein-bound N-glycans
    modifier: DECREASED
    term:
      id: GO:0006487
      label: protein N-linked glycosylation
  downstream:
  - target: Endo-alpha-1,2-Mannosidase Bypass
    causal_link_type: DIRECT
  - target: Destabilised Circulating Immunoglobulin
    causal_link_type: DIRECT
  - target: Impaired Viral Replication and Cellular Entry
    causal_link_type: DIRECT
  - target: Aberrant Neuronal Glycoprotein Function
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      The neurological branch. That the glycan block causes the encephalopathy
      is asserted in the literature at disease level; which neuronal
      glycoproteins carry it is not established, so the edge is typed as having
      unknown intermediates rather than as direct.
    evidence:
    - reference: PMID:33261925
      reference_title: "Congenital disorders of glycosylation type IIb with MOGS mutations cause early infantile epileptic encephalopathy, dysmorphic features, and hepatic dysfunction."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        MOGS mutations cause congenital disorders of glycosylation type IIb (CDG-IIb or GCS1-CDG).
      explanation: >-
        The causal statement at gene-to-disease level, which is the level at
        which this edge is asserted.
  - target: Hepatic Glycoprotein Dysfunction
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      The hepatic branch. Same epistemic status as the neurological one: the
      association is consistent across reported patients and the intervening
      steps are not worked out.
  - target: Disrupted Developmental Glycosylation
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      The dysmorphogenesis branch, accounting for the recognisable craniofacial
      and limb pattern and the generalized edema.
  - target: Cumulative Multisystem Glycoprotein Dysfunction
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      The systemic burden that is not attributable to any single organ branch,
      and which determines outcome in the severe cases.
  evidence:
  - reference: PMID:10788335
    reference_title: A novel disorder caused by defective biosynthesis of N-linked oligosaccharides due to glucosidase I deficiency.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Glucosidase I is an important enzyme in N-linked glycoprotein processing, removing specifically distal alpha-1,2-linked glucose from the Glc3Man9GlcNAc2 precursor after its en bloc transfer from dolichyl diphosphate to a nascent polypeptide chain in the endoplasmic reticulum.
    explanation: >-
      Defines the reaction whose failure this node describes, and its position
      in the pathway.
  - reference: PMID:12145188
    reference_title: Processing of N-linked carbohydrate chains in a patient with glucosidase I deficiency (CDG type IIb).
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      despite the dramatically reduced glucosidase I activity, the bulk of the N-linked carbohydrate chains (>80%) in the patient's fibroblasts appeared to have been processed correctly, with only approximately 16% of the N-glycans being arrested at the Glc(3)-Man(9-7)-GlcNAc(2) stage.
    explanation: >-
      Quantifies how much of the glycan pool is actually arrested, which is
      smaller than the near-total enzyme loss would suggest and is the reason the
      bypass node exists.
- name: Aberrant Neuronal Glycoprotein Function
  biological_scale: CELLULAR
  mechanism_confidence: HYPOTHETICAL
  description: >-
    Neuronal ion channels, adhesion molecules and receptors are N-glycosylated,
    and the standard account is that mishandling their glycans is what produces
    the encephalopathy. It is worth being clear that this is an inference from
    glycan biology plus a consistent clinical association, not a demonstrated
    step: no specific neuronal glycoprotein has been shown to be the one that
    matters, and no cited work measures a neuronal glycoprotein defect in a
    patient. It is recorded as HYPOTHETICAL for that reason, and the entry does
    not name a mechanism it cannot cite.

    What is well established is the clinical output. Seizures, hypotonia and
    developmental delay are present in essentially every reported patient, the
    seizures are frequently drug-resistant, and imaging shows progressive
    cortical and subcortical atrophy.
  cell_types:
  - preferred_term: neuron
    term:
      id: CL:0000540
      label: neuron
  downstream:
  - target: Epileptic encephalopathy
    causal_link_type: DIRECT
  - target: Generalized hypotonia
    causal_link_type: DIRECT
  - target: Global developmental delay
    causal_link_type: DIRECT
  - target: Cerebral atrophy
    causal_link_type: DIRECT
  - target: Dystonia
    causal_link_type: DIRECT
  - target: Thin corpus callosum
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Visual impairment
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Microcephaly
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Near-universal in the reported cohort, and modelled on the neuronal branch
      because the accompanying findings are white-matter loss, delayed
      myelination and cortical atrophy rather than a craniosynostosis.
  - target: Hearing impairment
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Recorded mostly as an abnormal auditory brainstem response, which places it
      on the neural rather than the conductive side.
  evidence:
  - reference: PMID:33058492
    reference_title: "Epilepsy and movement disorders in CDG: Report on the oldest-known MOGS-CDG patient."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      At birth she presented facial dysmorphism, marked hypotonia, and drug-resistant tonic seizures.
    explanation: >-
      The neurological presentation from birth in the longest-followed patient,
      including the drug resistance this node's downstream treatment claim
      depends on.
  - reference: PMID:38498292
    reference_title: "Early onset epileptic and developmental encephalopathy and MOGS variants: a new diagnosis in the whole exome sequencing (WES) ERA : Report of a new patient and review of the literature."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      MOGS-CDG is a rare disorder affecting the processing of N-Glycans (CDG type II) and is characterized by prominent neurological involvement including hypotonia, developmental delay, seizures and movement disorders.
    explanation: >-
      States that neurological involvement is the prominent feature and names
      the four components this node feeds.
- name: Hepatic Glycoprotein Dysfunction
  biological_scale: TISSUE
  mechanism_confidence: HYPOTHETICAL
  description: >-
    Progressive hepatomegaly with raised transaminases, and in one reported pair
    coagulopathy, attributed to abnormal handling of hepatic and secreted
    glycoproteins including the glycosylated clotting factors. As with the
    neurological branch, the attribution is inference from glycan biology rather
    than a measured hepatic defect, and it is typed accordingly.
  cell_types:
  - preferred_term: hepatocyte
    term:
      id: CL:0000182
      label: hepatocyte
  downstream:
  - target: Hepatomegaly
    causal_link_type: DIRECT
  - target: Elevated circulating hepatic transaminase concentration
    causal_link_type: DIRECT
  evidence:
  - reference: PMID:30587846
    reference_title: Compound heterozygous variants in MOGS inducing congenital disorders of glycosylation (CDG) IIb.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Both cases presented progressive hepatomegaly and elevated hepatic enzymes.
    explanation: >-
      The hepatic phenotype and its progressive course in two siblings, which is
      the clinical output of this node.
- name: Disrupted Developmental Glycosylation
  biological_scale: TISSUE
  mechanism_confidence: HYPOTHETICAL
  description: >-
    The craniofacial and limb pattern is recognisable enough to have been
    proposed as a diagnostic hallmark, which is why it is modelled as a branch
    rather than left as an unattached list of findings. The mechanism is the
    least worked out of the three: glycoproteins govern developmental adhesion
    and signalling, and disrupting them plausibly produces this pattern, but
    nothing in the cited literature identifies the pathway.
  downstream:
  - target: Long eyelashes
    causal_link_type: DIRECT
  - target: Retrognathia
    causal_link_type: DIRECT
  - target: Overlapping fingers
    causal_link_type: DIRECT
  - target: Hirsutism
    causal_link_type: DIRECT
  - target: Generalized edema
    causal_link_type: DIRECT
  - target: Wide nose
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Short palpebral fissure
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: High palate
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Macrotia
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
  - target: Arthrogryposis multiplex congenita
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Grouped with the overlapping fingers and toes as the limb component of the
      developmental phenotype rather than as an isolated contracture.
  evidence:
  - reference: PMID:29235540
    reference_title: Characteristic dysmorphic features in congenital disorders of glycosylation type IIb.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Importantly, a review of the features of all four patients revealed the recognizable clinical hallmarks of MOGS-CDG.
    explanation: >-
      Establishes that the dysmorphic pattern is consistent enough across
      patients to be treated as a single phenotypic output rather than
      incidental variation.
- name: Cumulative Multisystem Glycoprotein Dysfunction
  biological_scale: ORGANISM
  mechanism_confidence: HYPOTHETICAL
  description: >-
    The whole-organism consequence of disturbing a modification carried by most
    secreted and membrane glycoproteins at once. It is modelled as its own node
    because the features it carries - feeding failure and respiratory
    insufficiency - are not attributable to any single organ branch and are what
    determine outcome: in the index case the sequence of hepatomegaly,
    hypoventilation, feeding problems and seizures ended in death at 74 days,
    while children with more residual function survive into their second decade.
  downstream:
  - target: Hypoventilation
    causal_link_type: DIRECT
  - target: Failure to thrive
    causal_link_type: DIRECT
  - target: Abnormal heart morphology
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      A mixed group of septal defects, hypertrophy and cardiomyopathy rather than
      one malformation, which is why it hangs off the cumulative node instead of
      a dedicated cardiac branch.
  evidence:
  - reference: PMID:10788335
    reference_title: A novel disorder caused by defective biosynthesis of N-linked oligosaccharides due to glucosidase I deficiency.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The clinical course was progressive and was characterized by the occurrence of hepatomegaly, hypoventilation, feeding problems, seizures, and fatal outcome at age 74 d.
    explanation: >-
      The multisystem sequence and its outcome in the index case, which is the
      claim this node makes.
  - reference: PMID:35790351
    reference_title: "Clinical, biochemical and genetic characteristics of MOGS-CDG: a rare congenital disorder of glycosylation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The clinical phenotype of MOGS-CDG includes multisystemic involvement with variable severity.
    explanation: >-
      Establishes that the involvement is multisystemic and that its severity
      varies, which is what this node's description turns on.
- name: Endo-alpha-1,2-Mannosidase Bypass
  biological_scale: CELLULAR
  description: >-
    Patient fibroblasts show two- to threefold higher endo-alpha-1,2-mannosidase
    activity with a matching rise in its transcript. That enzyme cleaves
    internally to the glucose block, so it clears most glycans through an
    alternative route and releases the Glc3Man tetrasaccharide. This single
    compensation explains two otherwise puzzling observations at once: why the
    serum transferrin pattern is normal despite a near-complete enzyme loss, and
    where the diagnostic urinary tetrasaccharide comes from.
  biological_processes:
  - preferred_term: alternative oligosaccharide processing via endo-alpha-1,2-mannosidase
    modifier: INCREASED
    term:
      id: GO:0006491
      label: N-glycan processing
  downstream:
  - target: Urinary Glc3Man Tetrasaccharide Excretion
    causal_link_type: DIRECT
  evidence:
  - reference: PMID:12145188
    reference_title: Processing of N-linked carbohydrate chains in a patient with glucosidase I deficiency (CDG type IIb).
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      By contrast, the patient's fibroblasts displayed a two- to threefold higher endo-alpha1,2-mannosidase activity, associated with an increased level of enzyme-specific mRNA-transcripts.
    explanation: >-
      The measured compensatory increase, at both activity and transcript level.
  - reference: PMID:12145188
    reference_title: Processing of N-linked carbohydrate chains in a patient with glucosidase I deficiency (CDG type IIb).
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      This points to the lack of glucosidase I activity being compensated for, to some extent, by increase in the activity of the pathway involving endo-alpha1,2-mannosidase; this would also explain the marked urinary excretion of Glc(3)-Man.
    explanation: >-
      The authors' own reading of the compensation, including the link to the
      urinary marker that this node's downstream edge asserts.
- name: Urinary Glc3Man Tetrasaccharide Excretion
  biological_scale: ORGANISM
  description: >-
    Glc-alpha1-3-Glc-alpha1-3-Glc-alpha1-2-Man appears in urine, and it is the
    one biochemical finding that has been abnormal in every affected proband
    tested. Quantified by liquid chromatography-mass spectrometry it ran from
    34.1 to 618.0 micromol per mmol creatinine against a reference below 5.
  evidence:
  - reference: PMID:36651519
    reference_title: "MOGS-CDG: Quantitative analysis of the diagnostic Glc(3) Man tetrasaccharide and clinical spectrum of six new cases."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Glc3 Man was increased in all six analyzed cases, ranging from 34.1 to 618.0 μmol/mmol creatinine (reference <5 μmol).
    explanation: >-
      The quantified excretion with its reference interval, in every case
      tested.
  - reference: PMID:35790351
    reference_title: "Clinical, biochemical and genetic characteristics of MOGS-CDG: a rare congenital disorder of glycosylation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Urine oligosaccharide analysis was consistently abnormal for all affected probands, whereas other biochemical analyses such as serum transferrin analysis was not consistently abnormal.
    explanation: >-
      The consistency of the urinary marker set directly against the
      inconsistency of the standard CDG screen.
- name: Destabilised Circulating Immunoglobulin
  biological_scale: ORGANISM
  description: >-
    Immunoglobulins carry N-glycans, and glycan structure governs their
    stability and circulating half-life. In MOGS-CDG the hypogammaglobulinemia is
    a catabolic problem rather than a production one: the mechanism identified in
    the two studied siblings was a shortened immunoglobulin half-life.

    Serum glycomics names the specific defect behind that clearance. Patient IgG
    carries aberrant oligo-mannose and hybrid-type N-glycans, and its
    core-fucosylated complex di-antennary glycans are markedly reduced - while
    transferrin and alpha-1-antitrypsin move the other way, with increased
    sialylated species. The defect is therefore not uniform across serum
    glycoproteins, which is part of why transferrin-based CDG screening misses
    this disease.
  cell_types:
  - preferred_term: plasma cell
    term:
      id: CL:0000786
      label: plasma cell
  downstream:
  - target: Decreased circulating IgG concentration
    causal_link_type: DIRECT
  - target: Recurrent infections
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Present in 10 of 11 reported patients, most often as persistent pneumonia.
      Typed as indirect because the entry does not establish which of the
      antibody defect, the complement and lymphocyte abnormalities, or the
      general debility carries it.
  evidence:
  - reference: PMID:24716661
    reference_title: "Glycosylation, hypogammaglobulinemia, and resistance to viral infections."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      A shortened immunoglobulin half-life was determined to be the mechanism underlying the hypogammaglobulinemia.
    explanation: >-
      Identifies the mechanism as accelerated clearance, which is the specific
      claim of this node.
  - reference: PMID:27393411
    reference_title: "Immunological aspects of congenital disorders of glycosylation (CDG): a review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      CDG with major immunological involvement are ALG12-CDG, MAGT1-CDG, MOGS-CDG, SLC35C1-CDG and PGM3-CDG.
    explanation: >-
      Places MOGS-CDG among the small set of CDG in which immunological
      involvement is a major rather than incidental feature.
  - reference: PMID:35137040
    reference_title: Serum N-glycomics of a novel CDG-IIb patient reveals aberrant IgG glycosylation.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We further detected aberrant oligo-mannose (Glc3Man7GlcNAc2) and hybrid type N-glycans on patient-derived IgGs and we attributed this defective glycosylation to be the reason for an increased IgG clearance.
    explanation: >-
      Identifies the glycan species on patient IgG and attributes the increased
      clearance to them, which is the molecular content behind the
      shortened-half-life claim above. Quoted with the authors' own "we
      attributed", since it is their inference rather than a measured
      half-life.
  - reference: PMID:35137040
    reference_title: Serum N-glycomics of a novel CDG-IIb patient reveals aberrant IgG glycosylation.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      relative intensities of IgG-specific complex type di-antennary N-glycans with core-fucosylation were considerably reduced in the patient's serum whereas TF- and AAT-characteristic sialylated di- and tri-antennary N-glycans were increased
    explanation: >-
      The per-glycoprotein divergence recorded in this node's description, and
      an independent reason transferrin-based screening does not detect the
      disease.
- name: Impaired Viral Replication and Cellular Entry
  biological_scale: CELLULAR
  mechanism_confidence: PROVISIONAL
  description: >-
    Enveloped viruses depend on host ER glucosidases to fold their own
    glycoproteins and on host glycan structures for receptor engagement, so the
    same block that destabilises immunoglobulin also handicaps the virus. It is
    the observation that made ER glucosidases a broad-spectrum antiviral target.

    What this node does not claim is that patients escape infection. Recurrent
    infection is present in 10 of 11 reported patients; the single exception is
    the sibling pair in whom the reduced infectious diathesis was described, and
    the elder sister of a separate pair had documented cytomegalovirus infection
    despite CMV being an enveloped virus. The scope of the claim is reduced
    susceptibility to some glycosylation-dependent enveloped viruses in the
    patients where it was looked for, not a clinical phenotype of the disease.

    The bound GO process covers the entry half of this node only. The
    replication half has no equally specific GO counterpart and is deliberately
    left unbound rather than approximated by a broader term.
  biological_processes:
  - preferred_term: glycan-dependent viral entry into the host cell
    modifier: DECREASED
    term:
      id: GO:0019065
      label: receptor-mediated endocytosis of virus by host cell
  evidence:
  - reference: PMID:24716661
    reference_title: "Glycosylation, hypogammaglobulinemia, and resistance to viral infections."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Impaired viral replication and cellular entry may explain a decreased susceptibility to infections.
    explanation: >-
      The proposed mechanism, quoted with the authors' own "may explain" so that
      the hedge is preserved rather than upgraded.
  - reference: PMID:25318123
    reference_title: Viral resistance of MOGS-CDG patients implies a broad-spectrum strategy against acute virus infections.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      This paradox phenomenon is, at least in part, because the impaired N-linked glycan processing of the patients compromises their ability to support efficient replication and cellular entry of viruses.
    explanation: >-
      A second group's reading of the same observation, with its own hedge "at
      least in part".
phenotypes:
- name: Generalized hypotonia
  category: Neurologic
  description: >-
    Present in every reported patient, and severe from the neonatal period in
    the fatal cases.
  phenotype_term:
    preferred_term: Generalized hypotonia
    term:
      id: HP:0001290
      label: Generalized hypotonia
  frequency: VERY_FREQUENT
  evidence:
  - reference: PMID:36651519
    reference_title: "MOGS-CDG: Quantitative analysis of the diagnostic Glc(3) Man tetrasaccharide and clinical spectrum of six new cases."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Here, we clinically characterize ten MOGS-CDG cases including six previously unreported individuals, showing a phenotype characterized by dysmorphic features, global developmental delay, muscular hypotonia, and seizures in all patients and in a minority vision problems and hypogammaglobulinemia.
    explanation: >-
      Records hypotonia as present in all ten patients of the largest
      phenotyping series.
- name: Global developmental delay
  category: Neurologic
  description: >-
    Present in all reported patients, ranging to profound in the more severely
    affected.
  phenotype_term:
    preferred_term: Global developmental delay
    term:
      id: HP:0001263
      label: Global developmental delay
  frequency: VERY_FREQUENT
  evidence:
  - reference: PMID:36651519
    reference_title: "MOGS-CDG: Quantitative analysis of the diagnostic Glc(3) Man tetrasaccharide and clinical spectrum of six new cases."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Here, we clinically characterize ten MOGS-CDG cases including six previously unreported individuals, showing a phenotype characterized by dysmorphic features, global developmental delay, muscular hypotonia, and seizures in all patients and in a minority vision problems and hypogammaglobulinemia.
    explanation: >-
      The same series, quoted for the developmental component.
- name: Epileptic encephalopathy
  category: Neurologic
  description: >-
    Seizures are universal, and in several reported patients take the form of
    early infantile epileptic encephalopathy with intractable seizures and severe
    developmental arrest.
  phenotype_term:
    preferred_term: Early infantile epileptic encephalopathy
    term:
      id: HP:0200134
      label: Epileptic encephalopathy
  frequency: VERY_FREQUENT
  evidence:
  - reference: PMID:33261925
    reference_title: "Congenital disorders of glycosylation type IIb with MOGS mutations cause early infantile epileptic encephalopathy, dysmorphic features, and hepatic dysfunction."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Our three patients presented with early infantile epileptic encephalopathy, generalized hypotonia, hepatic dysfunction and dysmorphic features.
    explanation: >-
      Records the encephalopathic seizure phenotype in three patients.
- name: Long eyelashes
  category: Craniofacial
  description: >-
    One of the recognisable dysmorphic hallmarks, alongside retrognathia,
    hirsutism and clenched overlapping fingers.
  phenotype_term:
    preferred_term: Long eyelashes
    term:
      id: HP:0000527
      label: Long eyelashes
  frequency: FREQUENT
  evidence:
  - reference: PMID:29235540
    reference_title: Characteristic dysmorphic features in congenital disorders of glycosylation type IIb.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The distinct dysmorphic features of this condition include long eyelashes, retrognathia, hirsutism, clenched overlapped fingers, hypoventilation, hepatomegaly, generalized edema, and immunodeficiency.
    explanation: >-
      The dysmorphic hallmark list assembled across all four patients known at
      the time.
- name: Retrognathia
  category: Craniofacial
  phenotype_term:
    preferred_term: Retrognathia
    term:
      id: HP:0000278
      label: Retrognathia
  frequency: FREQUENT
  evidence:
  - reference: PMID:29235540
    reference_title: Characteristic dysmorphic features in congenital disorders of glycosylation type IIb.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The distinct dysmorphic features of this condition include long eyelashes, retrognathia, hirsutism, clenched overlapped fingers, hypoventilation, hepatomegaly, generalized edema, and immunodeficiency.
    explanation: >-
      The same hallmark list, quoted for retrognathia.
- name: Overlapping fingers
  category: Musculoskeletal
  description: >-
    Clenched hands with overlapping fingers, part of the recognisable pattern.
  phenotype_term:
    preferred_term: Clenched overlapped fingers
    term:
      id: HP:0010557
      label: Overlapping fingers
  frequency: FREQUENT
  evidence:
  - reference: PMID:29235540
    reference_title: Characteristic dysmorphic features in congenital disorders of glycosylation type IIb.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The distinct dysmorphic features of this condition include long eyelashes, retrognathia, hirsutism, clenched overlapped fingers, hypoventilation, hepatomegaly, generalized edema, and immunodeficiency.
    explanation: >-
      The same hallmark list, quoted for the hand posture.
- name: Hepatomegaly
  category: Hepatobiliary
  description: >-
    Progressive hepatomegaly with elevated hepatic enzymes.
  phenotype_term:
    preferred_term: Hepatomegaly
    term:
      id: HP:0002240
      label: Hepatomegaly
  frequency: VERY_FREQUENT
  evidence:
  - reference: PMID:30587846
    reference_title: Compound heterozygous variants in MOGS inducing congenital disorders of glycosylation (CDG) IIb.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Both cases presented progressive hepatomegaly and elevated hepatic enzymes.
    explanation: >-
      Records the hepatic phenotype and its progressive course in two siblings.
      Two patients cannot ground the frequency band; the row below does that.
  - reference: PMID:36158009
    reference_title: "Updated clinical and glycomic features of mannosyl-oligosaccharide glucosidase deficiency: Two case reports."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Clinical, genetic, and glycomic features of all reported patients with mannosyl-oligosaccharide glucosidase deficiency...| Hepatomegaly | + | ND | + | + | + | + | + | + | + | + | ND |
    explanation: >-
      Positive in all nine patients where it was assessed, across the whole
      reported cohort. This is the row the VERY_FREQUENT band is set from.
- name: Hypoventilation
  category: Respiratory
  description: >-
    Hypoventilation and postnatal dyspnea, contributing to the fatal outcome in
    the original neonatal case.
  phenotype_term:
    preferred_term: Hypoventilation
    term:
      id: HP:0002791
      label: Hypoventilation
  frequency: OCCASIONAL
  evidence:
  - reference: PMID:10788335
    reference_title: A novel disorder caused by defective biosynthesis of N-linked oligosaccharides due to glucosidase I deficiency.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The clinical course was progressive and was characterized by the occurrence of hepatomegaly, hypoventilation, feeding problems, seizures, and fatal outcome at age 74 d.
    explanation: >-
      Records hypoventilation in the index case, in the sequence that ended in
      death at 74 days.
- name: Decreased circulating IgG concentration
  category: Immunologic
  description: >-
    Low IgG specifically is named in four of the eleven reported patients;
    hypogammaglobulinemia of some immunoglobulin class is present in all eleven,
    most often low IgA.

    The two cohorts disagree, and the disagreement is worth carrying. A
    ten-case series calls hypogammaglobulinemia a minority feature; the
    eleven-patient summary table shows some-class hypogammaglobulinemia in every
    patient. Both are quoted below. The band follows the table, since it is the
    larger and more explicit count, and the narrower series is retained rather
    than discarded.

    The reason this deficiency does not behave like other severe antibody
    deficiencies is recorded in the pathophysiology: the antibody is cleared too
    fast rather than not made.
  phenotype_term:
    preferred_term: Severe hypogammaglobulinemia
    term:
      id: HP:0004315
      label: Decreased circulating IgG concentration
  frequency: FREQUENT
  evidence:
  - reference: PMID:24716661
    reference_title: "Glycosylation, hypogammaglobulinemia, and resistance to viral infections."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      We evaluated two siblings with CDG-IIb who presented with multiple neurologic complications and a paradoxical immunologic phenotype characterized by severe hypogammaglobulinemia but limited clinical evidence of an infectious diathesis.
    explanation: >-
      The hypogammaglobulinemia and the absence of the expected infection burden
      in one sentence, as described in this sibling pair. The entry does not
      model that absence as a property of the disease: recurrent infection is
      present in 10 of the 11 reported patients, and this pair is the exception.
  - reference: PMID:36651519
    reference_title: "MOGS-CDG: Quantitative analysis of the diagnostic Glc(3) Man tetrasaccharide and clinical spectrum of six new cases."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Here, we clinically characterize ten MOGS-CDG cases including six previously unreported individuals, showing a phenotype characterized by dysmorphic features, global developmental delay, muscular hypotonia, and seizures in all patients and in a minority vision problems and hypogammaglobulinemia.
    explanation: >-
      The narrower estimate. In this ten-case series hypogammaglobulinemia is a
      minority feature, unlike the universal neurological ones. It no longer sets
      the band, and is kept because it is a real cohort disagreeing with the
      larger one.
  - reference: PMID:36158009
    reference_title: "Updated clinical and glycomic features of mannosyl-oligosaccharide glucosidase deficiency: Two case reports."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Clinical, genetic, and glycomic features of all reported patients with mannosyl-oligosaccharide glucosidase deficiency...| Hypogammaglobulimia | Low IgA | Low IgG, IgA, IgM | Low IgA, IgM | Low IgA | Low IgA, Normal IgG and IgM after IVIG | Low IgG, IgA, IgM | Low IgA | Low IgA | Low IgA | Low IgA and IgG | Low IgG2 |
    explanation: >-
      The per-patient immunoglobulin detail behind both counts in the
      description: low IgG specifically in four of eleven, and low
      immunoglobulin of some class in all eleven. This is the row the FREQUENT
      band is set from, and it is also what makes the ten-case series above a
      disagreement rather than a duplicate.
- name: Thin corpus callosum
  category: Neurologic
  description: >-
    Reported with cerebral atrophy and other structural brain findings on
    imaging.
  phenotype_term:
    preferred_term: Thin corpus callosum
    term:
      id: HP:0033725
      label: Thin corpus callosum
  frequency: OCCASIONAL
  evidence:
  - reference: PMID:30587846
    reference_title: Compound heterozygous variants in MOGS inducing congenital disorders of glycosylation (CDG) IIb.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Head MRI of the elder sister showed increased signals on T1W1, bilateral frontal gyrus stenosis, and thin corpus callosum.
    explanation: >-
      The imaging finding in a reported sibling.
- name: Visual impairment
  category: Ophthalmologic
  description: >-
    Vision problems in a minority of patients. Optic-nerve atrophy was reported
    in the two siblings assessed for the immunological phenotype.
  phenotype_term:
    preferred_term: Visual impairment
    term:
      id: HP:0000505
      label: Visual impairment
  frequency: OCCASIONAL
  evidence:
  - reference: PMID:36651519
    reference_title: "MOGS-CDG: Quantitative analysis of the diagnostic Glc(3) Man tetrasaccharide and clinical spectrum of six new cases."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Here, we clinically characterize ten MOGS-CDG cases including six previously unreported individuals, showing a phenotype characterized by dysmorphic features, global developmental delay, muscular hypotonia, and seizures in all patients and in a minority vision problems and hypogammaglobulinemia.
    explanation: >-
      The same ten-case series, quoted for the vision component and its
      minority frequency.
- name: Cerebral atrophy
  frequency: OCCASIONAL
  category: Neurologic
  description: >-
    Progressive cortical and subcortical atrophy on MRI, documented over
    nineteen years of follow-up in the longest-followed patient.
  phenotype_term:
    preferred_term: Progressive cortical and subcortical atrophy
    term:
      id: HP:0002059
      label: Cerebral atrophy
  evidence:
  - reference: PMID:33058492
    reference_title: "Epilepsy and movement disorders in CDG: Report on the oldest-known MOGS-CDG patient."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Brain MRI showed progressive cortical and subcortical atrophy.
    explanation: >-
      The imaging finding and, importantly, its progressive character, which is
      what distinguishes it from a static malformation.
- name: Dystonia
  frequency: FREQUENT
  category: Neurologic
  description: >-
    Dystonia and a hyperkinetic movement disorder, severe enough in the reported
    case to limit motility, with forced posture of the head and both hands.
    Movement disorder is named alongside seizures as a prominent feature of the
    neurological phenotype.
  phenotype_term:
    preferred_term: Dystonia
    term:
      id: HP:0001332
      label: Dystonia
  evidence:
  - reference: PMID:33058492
    reference_title: "Epilepsy and movement disorders in CDG: Report on the oldest-known MOGS-CDG patient."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      In the following months, her motility was strongly limited by dystonia, with forced posture of the head and of both hands.
    explanation: >-
      The dystonia and its functional consequence in the reported patient.
  - reference: PMID:38498292
    reference_title: "Early onset epileptic and developmental encephalopathy and MOGS variants: a new diagnosis in the whole exome sequencing (WES) ERA : Report of a new patient and review of the literature."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      MOGS-CDG is a rare disorder affecting the processing of N-Glycans (CDG type II) and is characterized by prominent neurological involvement including hypotonia, developmental delay, seizures and movement disorders.
    explanation: >-
      Places movement disorder among the characteristic neurological features
      rather than as a single-case observation.
- name: Failure to thrive
  frequency: OCCASIONAL
  category: Growth
  description: >-
    Feeding problems and failure to thrive, contributing to the fatal course in
    the index neonatal case.
  phenotype_term:
    preferred_term: Feeding problems and failure to thrive
    term:
      id: HP:0001508
      label: Failure to thrive
  evidence:
  - reference: PMID:10788335
    reference_title: A novel disorder caused by defective biosynthesis of N-linked oligosaccharides due to glucosidase I deficiency.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The clinical course was progressive and was characterized by the occurrence of hepatomegaly, hypoventilation, feeding problems, seizures, and fatal outcome at age 74 d.
    explanation: >-
      The feeding problems in the index case, in the progressive sequence that
      ended in death at 74 days.
- name: Elevated circulating hepatic transaminase concentration
  frequency: VERY_FREQUENT
  category: Hepatobiliary
  description: >-
    Raised hepatic enzymes accompanying the hepatomegaly. Positive in all seven
    patients where transaminases were measured, with values reported as high as
    1547 IU/L.
  phenotype_term:
    preferred_term: Elevated hepatic enzymes
    term:
      id: HP:0002910
      label: Elevated circulating hepatic transaminase concentration
  evidence:
  - reference: PMID:30587846
    reference_title: Compound heterozygous variants in MOGS inducing congenital disorders of glycosylation (CDG) IIb.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Both cases presented progressive hepatomegaly and elevated hepatic enzymes.
    explanation: >-
      The biochemical hepatic abnormality, reported with the hepatomegaly it
      accompanies. Two patients; the row below sets the band.
  - reference: PMID:36158009
    reference_title: "Updated clinical and glycomic features of mannosyl-oligosaccharide glucosidase deficiency: Two case reports."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Clinical, genetic, and glycomic features of all reported patients with mannosyl-oligosaccharide glucosidase deficiency...| Elevated AST/ALT (IU/L) | +(80/34) | ND | ND | + (46-154/14-81) | + (49-121/17-56) | + |  | + (30-1547/9- 1132) | + (35-144/23-83) | + (36-226/50.5-164) | ND |
    explanation: >-
      Positive in all seven patients where transaminases were measured, with the
      per-patient values. This is the row the VERY_FREQUENT band is set from.
- name: Hirsutism
  frequency: FREQUENT
  category: Craniofacial
  phenotype_term:
    preferred_term: Hirsutism
    term:
      id: HP:0001007
      label: Hirsutism
  evidence:
  - reference: PMID:29235540
    reference_title: Characteristic dysmorphic features in congenital disorders of glycosylation type IIb.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The distinct dysmorphic features of this condition include long eyelashes, retrognathia, hirsutism, clenched overlapped fingers, hypoventilation, hepatomegaly, generalized edema, and immunodeficiency.
    explanation: >-
      The same hallmark list, quoted for hirsutism.
- name: Generalized edema
  frequency: FREQUENT
  category: Other
  phenotype_term:
    preferred_term: Generalized edema
    term:
      id: HP:0007430
      label: Generalized edema
  evidence:
  - reference: PMID:29235540
    reference_title: Characteristic dysmorphic features in congenital disorders of glycosylation type IIb.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The distinct dysmorphic features of this condition include long eyelashes, retrognathia, hirsutism, clenched overlapped fingers, hypoventilation, hepatomegaly, generalized edema, and immunodeficiency.
    explanation: >-
      The same hallmark list, quoted for the edema.
- name: Microcephaly
  category: Neurologic
  frequency: VERY_FREQUENT
  description: >-
    Present in 10 of the 11 reported patients, with one not assessed and none
    negative. It is one of the most consistent features of the disease and was
    absent from this entry until review round 3.
  phenotype_term:
    preferred_term: Microcephaly
    term:
      id: HP:0000252
      label: Microcephaly
  evidence:
  - reference: PMID:36158009
    reference_title: "Updated clinical and glycomic features of mannosyl-oligosaccharide glucosidase deficiency: Two case reports."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Clinical, genetic, and glycomic features of all reported patients with mannosyl-oligosaccharide glucosidase deficiency...| Microcephaly | + | + | + | + | + | ND | + | + | + | + | + |
    explanation: >-
      The row from the summary table of all reported patients. Quoted with the
      table caption so the count is attributable to the whole reported cohort
      rather than to one series.
- name: Recurrent infections
  category: Immunologic
  frequency: VERY_FREQUENT
  description: >-
    Present in 10 of the 11 reported patients. The single negative column is the
    sibling pair in whom the reduced infectious diathesis was described, which is
    the observation this entry previously generalised to the disease. Persistent
    pneumonia is the recurring presentation.
  phenotype_term:
    preferred_term: Recurrent infections
    term:
      id: HP:0002719
      label: Recurrent infections
  evidence:
  - reference: PMID:36158009
    reference_title: "Updated clinical and glycomic features of mannosyl-oligosaccharide glucosidase deficiency: Two case reports."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Clinical, genetic, and glycomic features of all reported patients with mannosyl-oligosaccharide glucosidase deficiency...| Recurrent infections | + | - | + | + | + | + | + | + | + | + | + |
    explanation: >-
      The row that establishes recurrent infection as near-universal, and locates
      the one exception. It is the direct correction to the earlier framing.
- name: Hearing impairment
  category: Auditory
  frequency: VERY_FREQUENT
  description: >-
    Eight of the nine assessed patients have an abnormal auditory brainstem
    response, sensorineural loss or hypoacusia. The finding is reported as an
    electrophysiological abnormality more often than as a clinical complaint,
    which is what the row records.
  phenotype_term:
    preferred_term: Hearing impairment
    term:
      id: HP:0000365
      label: Hearing impairment
  evidence:
  - reference: PMID:36158009
    reference_title: "Updated clinical and glycomic features of mannosyl-oligosaccharide glucosidase deficiency: Two case reports."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Clinical, genetic, and glycomic features of all reported patients with mannosyl-oligosaccharide glucosidase deficiency...| Hearing impairment | Flat with ABR | Sensorineural hearing loss | Abnormal ABR | Hearing impairment | ND | - | ND | No wave with ABR | Only I wave with ABR | Only I wave with ABR | Hypoacusia |
    explanation: >-
      Names the individual findings per patient rather than a summary grade, so
      the row shows both the frequency and the form the impairment takes.
- name: Wide nose
  category: Craniofacial
  frequency: FREQUENT
  description: >-
    Broad nose in eight of the nine patients for whom the feature was recorded.
    Part of the recognisable facial gestalt alongside the long eyelashes and
    retrognathia already curated here.
  phenotype_term:
    preferred_term: broad nose
    term:
      id: HP:0000445
      label: Wide nose
  evidence:
  - reference: PMID:36158009
    reference_title: "Updated clinical and glycomic features of mannosyl-oligosaccharide glucosidase deficiency: Two case reports."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Clinical, genetic, and glycomic features of all reported patients with mannosyl-oligosaccharide glucosidase deficiency...| Broad nose | + |  | + | + | + | + |  | + | + | + | - |
    explanation: >-
      The row for this feature. The band is FREQUENT rather than VERY_FREQUENT
      because two columns are blank rather than assessed. Bound to Wide nose
      rather than Wide nasal bridge: the source records "broad nose", a recorded
      synonym of the former, and says nothing about the bridge specifically.
- name: Short palpebral fissure
  category: Craniofacial
  frequency: FREQUENT
  description: >-
    Recorded in eight of the nine patients for whom it was assessed, and named
    among the previously reported dysmorphic features of the disease.
  phenotype_term:
    preferred_term: short palpebral fissures
    term:
      id: HP:0012745
      label: Short palpebral fissure
  evidence:
  - reference: PMID:36158009
    reference_title: "Updated clinical and glycomic features of mannosyl-oligosaccharide glucosidase deficiency: Two case reports."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Clinical, genetic, and glycomic features of all reported patients with mannosyl-oligosaccharide glucosidase deficiency...| Short palpebral fissure | + |  | + | + | + | + |  | + | + | + | - |
    explanation: >-
      The row for this feature, with the same blank-column caveat as the broad
      nose.
- name: High palate
  category: Craniofacial
  frequency: FREQUENT
  description: >-
    High-arched palate in every one of the six patients where it was assessed;
    the remaining five columns are not-done or blank rather than negative.
  phenotype_term:
    preferred_term: high-arched palate
    term:
      id: HP:0000218
      label: High palate
  evidence:
  - reference: PMID:36158009
    reference_title: "Updated clinical and glycomic features of mannosyl-oligosaccharide glucosidase deficiency: Two case reports."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Clinical, genetic, and glycomic features of all reported patients with mannosyl-oligosaccharide glucosidase deficiency...| High-arched palate | + |  | + | + | ND | ND |  | + | + | + | ND |
    explanation: >-
      The row for this feature. Six positives and no negative, but five of
      eleven columns carry no assessment, which is why the band is FREQUENT
      rather than higher.
- name: Macrotia
  category: Craniofacial
  frequency: FREQUENT
  description: >-
    Enlarged, forwardly rotated ear lobes in six patients. Part of the same
    facial gestalt.
  phenotype_term:
    preferred_term: enlarged ears
    term:
      id: HP:0000400
      label: Macrotia
  evidence:
  - reference: PMID:36158009
    reference_title: "Updated clinical and glycomic features of mannosyl-oligosaccharide glucosidase deficiency: Two case reports."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Clinical, genetic, and glycomic features of all reported patients with mannosyl-oligosaccharide glucosidase deficiency...| Enlarged ears | + |  | ND | + | + | ND |  | + | + | + | ND |
    explanation: >-
      The row for this feature.
- name: Arthrogryposis multiplex congenita
  category: Musculoskeletal
  frequency: FREQUENT
  description: >-
    Recorded in five patients. It sits with the overlapping fingers and toes as
    the limb component of the developmental phenotype rather than as an isolated
    contracture.
  phenotype_term:
    preferred_term: arthrogryposis
    term:
      id: HP:0002804
      label: Arthrogryposis multiplex congenita
  evidence:
  - reference: PMID:36158009
    reference_title: "Updated clinical and glycomic features of mannosyl-oligosaccharide glucosidase deficiency: Two case reports."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Clinical, genetic, and glycomic features of all reported patients with mannosyl-oligosaccharide glucosidase deficiency...| Arthrogryposis | + | + | ND | ND | ND | ND |  | + | + | + | ND |
    explanation: >-
      The row for this feature. Most columns are not-done, so the true frequency
      is likely higher than the raw count suggests and the band is set from the
      assessed columns.
- name: Abnormal heart morphology
  category: Cardiovascular
  frequency: FREQUENT
  description: >-
    Roughly six of eleven patients: atrial septal defect, patent foramen ovale,
    left ventricular hypertrophy, dilated cardiomyopathy, heart failure and
    pericardial effusion. Bound to the general abnormal-heart-morphology term
    because the lesions differ between patients and no single one is
    characteristic.
  phenotype_term:
    preferred_term: cardiac involvement
    term:
      id: HP:0001627
      label: Abnormal heart morphology
  evidence:
  - reference: PMID:36158009
    reference_title: "Updated clinical and glycomic features of mannosyl-oligosaccharide glucosidase deficiency: Two case reports."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Clinical, genetic, and glycomic features of all reported patients with mannosyl-oligosaccharide glucosidase deficiency...| Cardiac involvement | - | - | ASD, LVH | ASD, PFO, heart failure, and pericardial effusion | PFO, heart failure | PFO, ASD | Dilated cardiomyopathy | + | - | - | ND |
    explanation: >-
      The row, quoted in full because the per-patient detail is the point: this is
      a mixed group of structural and functional lesions, not one malformation.
biochemical:
- name: Urinary Glc3Man tetrasaccharide
  notes: >-
    Glc-alpha1-3-Glc-alpha1-3-Glc-alpha1-2-Man in urine, the free tetrasaccharide
    released by the endo-alpha-1,2-mannosidase bypass. It is the diagnostic
    analyte for this disease and the one test that has been abnormal in every
    affected proband examined.
  reference_ranges:
  - lower_bound: 0.0
    upper_bound: 5.0
    unit: umol/mmol{creatinine}
    population: reference population, method as published
    notes: >-
      No LOINC code is bound. Urinary Glc3Man is a specialist research assay
      with no LOINC counterpart, and no code is asserted rather than binding an
      approximate one. The interval is the reference stated by the group that
      developed and validated the quantitative method; patient values in that
      series ran from 34.1 to 618.0, so the separation from the reference is
      roughly an order of magnitude at the low end.
    evidence:
    - reference: PMID:36651519
      reference_title: "MOGS-CDG: Quantitative analysis of the diagnostic Glc(3) Man tetrasaccharide and clinical spectrum of six new cases."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Glc3 Man was increased in all six analyzed cases, ranging from 34.1 to 618.0 μmol/mmol creatinine (reference <5 μmol).
      explanation: >-
        The reference interval and the observed patient range in one sentence,
        from the paper that validated the quantitative method.
  evidence:
  - reference: PMID:35790351
    reference_title: "Clinical, biochemical and genetic characteristics of MOGS-CDG: a rare congenital disorder of glycosylation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Urine oligosaccharide analysis was consistently abnormal for all affected probands, whereas other biochemical analyses such as serum transferrin analysis was not consistently abnormal.
    explanation: >-
      Establishes this analyte as the consistently abnormal one, against the
      inconsistency of the standard CDG screen.
- name: Serum immunoglobulins, complement and creatine kinase
  notes: >-
    A secondary laboratory panel reported in the more completely characterised
    patients: low immunoglobulins, complement C3 and C4 deficiency, raised
    creatine kinase and C-reactive protein, dyslipidemia, coagulopathy, and
    reduced T-lymphocyte and natural-killer proportions with raised interleukin
    6. These are recorded as an observed panel from two patients rather than as
    established features of the disease.
  evidence:
  - reference: PMID:36158009
    reference_title: "Updated clinical and glycomic features of mannosyl-oligosaccharide glucosidase deficiency: Two case reports."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Novel laboratory findings included peripheral leukocytosis with neutrophil predominance, elevated C-reactive protein and creatine kinase, dyslipidemia, coagulopathy, complement 3 and complement 4 deficiencies, decreased proportions of T lymphocytes and natural killer cells, and increased serum interleukin 6.
    explanation: >-
      The panel as reported. Described by its own authors as novel findings in
      two patients, which is why this entry does not assign a frequency to any
      of them.
genetic:
- name: MOGS
  association: Causal biallelic variant
  relationship_type: CAUSATIVE
  gene_term:
    preferred_term: MOGS
    term:
      id: hgnc:24862
      label: MOGS
  notes: >-
    Encodes mannosyl-oligosaccharide glucosidase, also called ER alpha-glucosidase
    I or glucosidase 1. Four exons, with exon 4 encoding the 64 kDa catalytic
    domain.

    No genotype-phenotype correlation has been established. The largest series
    states directly that severity varied by organ system with no definite
    genotype correlation, and the reported range is wide - from death at 74 days
    to children in their second decade. Prognostic counselling from the genotype
    is therefore not currently supportable.

    Variants of uncertain significance are the practical difficulty. Exome
    sequencing turns them up faster than functional validation can resolve them,
    which is precisely why the urinary tetrasaccharide assay matters: it is the
    orthogonal test that can confirm or exclude a candidate MOGS genotype.
  evidence:
  - reference: PMID:35790351
    reference_title: "Clinical, biochemical and genetic characteristics of MOGS-CDG: a rare congenital disorder of glycosylation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The severity in each organ system was variable, without definite genotype correlation.
    explanation: >-
      The absence of a genotype-phenotype correlation, stated by the series best
      placed to find one.
  - reference: PMID:35790351
    reference_title: "Clinical, biochemical and genetic characteristics of MOGS-CDG: a rare congenital disorder of glycosylation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Molecular analysis, combined with biochemical testing, is important for diagnosis.
    explanation: >-
      The recommendation that molecular findings be paired with the biochemical
      assay rather than used alone.
  - reference: PMID:30587846
    reference_title: Compound heterozygous variants in MOGS inducing congenital disorders of glycosylation (CDG) IIb.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Compound heterozygous variants of NM_006302:c.1239_1267dup,p.Asp414Leufs*17, c.544 G > A,p.Gly182Arg, and c.1698C > A,p.Asp566Glu in MOGS were identified.
    explanation: >-
      A worked compound heterozygous genotype including a frameshift allele,
      extending the spectrum beyond the original two missense variants.
treatments:
- name: Supportive and multidisciplinary care
  description: >-
    No disease-modifying treatment exists. Management is anticonvulsant control
    of the epilepsy, respiratory and feeding support, hepatic monitoring, and
    developmental therapies. Immunoglobulin replacement is a question rather than
    a recommendation here: the hypogammaglobulinemia is real but the infection
    burden is not what it predicts, so the usual indication for replacement does
    not straightforwardly apply.
  therapeutic_modality: OTHER
  treatment_term:
    preferred_term: Supportive Care
    term:
      id: NCIT:C15747
      label: Supportive Care
  target_mechanisms:
  - target: Aberrant Neuronal Glycoprotein Function
    description: >-
      Supportive management is directed at the outputs of the neurological
      branch. It does not act on the glycan lesion, which is why the entry
      records no disease-modifying treatment.
  target_phenotypes:
  - preferred_term: Early infantile epileptic encephalopathy
    term:
      id: HP:0200134
      label: Epileptic encephalopathy
  notes: >-
    No evidence item is attached. The previous citation here was a methods
    sentence describing what the two studied siblings were assessed for, which
    does not support a management recommendation; it was removed rather than
    kept with an explanation conceding it did not support the claim. No cited
    source in this entry makes a management recommendation for MOGS-CDG, and an
    absent evidence item states that more honestly than a weak one.
- name: Anticonvulsant therapy
  description: >-
    Seizures are present in essentially every reported patient and are
    frequently drug-resistant, so anticonvulsant treatment is the intervention
    these children actually receive. No agent or regimen has been shown superior
    in this disease, and no source recommends one; in the longest-followed
    patient, epileptic spasms remitted by age seven while tonic seizures
    persisted to nineteen. The entry records the modality without naming a
    drug, because the literature does not.
  therapeutic_modality: SMALL_MOLECULE
  treatment_term:
    preferred_term: Anticonvulsant Therapy
    term:
      id: NCIT:C64172
      label: Anticonvulsant Therapy
  target_mechanisms:
  - target: Aberrant Neuronal Glycoprotein Function
    description: >-
      Symptomatic control of the seizure output of this node. It does not act on
      the node itself.
  target_phenotypes:
  - preferred_term: Early infantile epileptic encephalopathy
    term:
      id: HP:0200134
      label: Epileptic encephalopathy
  evidence:
  - reference: PMID:33058492
    reference_title: "Epilepsy and movement disorders in CDG: Report on the oldest-known MOGS-CDG patient."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Epileptic spasms appeared in first months and ceased by the age of 7 years, while tonic seizures were still present at last assessment (19 years).
    explanation: >-
      The long-term seizure course under treatment. Cited to establish what
      anticonvulsant therapy achieves and does not achieve here, rather than as
      evidence that any particular agent works.
  - reference: PMID:33058492
    reference_title: "Epilepsy and movement disorders in CDG: Report on the oldest-known MOGS-CDG patient."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      At birth she presented facial dysmorphism, marked hypotonia, and drug-resistant tonic seizures.
    explanation: >-
      Records the drug resistance, which is the reason this treatment is listed
      with no expectation of control rather than as effective management.
diagnosis:
- name: Urinary oligosaccharide analysis for Glc3Man
  description: >-
    The test that works, and it is not the one a CDG workup reaches for first.
    Serum transferrin isoelectric focusing is typically normal in MOGS-CDG, so
    the disease escapes the standard screen; urinary Glc3Man by mass spectrometry
    has been abnormal in every affected proband tested and is now quantifiable
    against a reference interval. Suspect the diagnosis on the clinical pattern -
    dysmorphism with hypotonia, seizures and developmental delay - and go
    straight to urine oligosaccharides rather than concluding from a normal
    transferrin that this is not a CDG.
  evidence:
  - reference: PMID:35790351
    reference_title: "Clinical, biochemical and genetic characteristics of MOGS-CDG: a rare congenital disorder of glycosylation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      In MOGS-CDG, urine oligosaccharide analysis via matrix-assisted laser desorption/ionisation time-of-flight mass spectrometry can be used as a reliable biochemical test for screening and confirmation of disease.
    explanation: >-
      Names the test and the role it plays, for both screening and confirmation.
  - reference: PMID:36651519
    reference_title: "MOGS-CDG: Quantitative analysis of the diagnostic Glc(3) Man tetrasaccharide and clinical spectrum of six new cases."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Most CDG with abnormal N-glycosylation can be detected by transferrin screening, however, MOGS-CDG escapes this routine screening.
    explanation: >-
      States the screening failure that makes the urinary assay necessary rather
      than merely confirmatory.
  - reference: PMID:33261925
    reference_title: "Congenital disorders of glycosylation type IIb with MOGS mutations cause early infantile epileptic encephalopathy, dysmorphic features, and hepatic dysfunction."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Although the isoelectric focusing of transferrin (IEF-T) of serum in this patient was normal, urinary excretion of Hex4 corresponding to Glc3Man was observed by mass spectrometry.
    explanation: >-
      A worked case of exactly the discordance the diagnostic advice turns on:
      normal transferrin, positive urinary tetrasaccharide.
differential_diagnoses:
- name: Other congenital disorders of glycosylation detectable by transferrin screening
  description: >-
    Most N-glycosylation CDG give an abnormal carbohydrate-deficient transferrin
    pattern. A normal transferrin result excludes many of them and does not
    exclude MOGS-CDG, which is the practical distinction.
  distinguishing_features:
  - Serum transferrin isoelectric focusing is typically normal in MOGS-CDG and abnormal in most N-glycosylation CDG.
  - Urinary Glc3Man tetrasaccharide is specific to the glucosidase I block.
  evidence:
  - reference: PMID:36651519
    reference_title: "MOGS-CDG: Quantitative analysis of the diagnostic Glc(3) Man tetrasaccharide and clinical spectrum of six new cases."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Most CDG with abnormal N-glycosylation can be detected by transferrin screening, however, MOGS-CDG escapes this routine screening.
    explanation: >-
      The screening asymmetry that separates MOGS-CDG from the rest of the
      group.
- name: Pompe disease
  disease_term:
    preferred_term: Pompe disease
    term:
      id: MONDO:0009290
      label: glycogen storage disease II
  description: >-
    Named here for one specific reason: Pompe urine also carries a
    glucose-tetrasaccharide, so a urinary oligosaccharide screen can put the two
    on the same result. The MOGS-CDG species is Glc3Man and is separated by
    retention-time matching.
  distinguishing_features:
  - The MOGS-CDG urinary tetrasaccharide is Glc3Man and is identified by retention time against authentic MOGS-CDG urine.
  - Pompe disease has acid alpha-glucosidase deficiency and a myopathic or cardiac presentation rather than the dysmorphic-neurological pattern of MOGS-CDG.
  evidence:
  - reference: PMID:36651519
    reference_title: "MOGS-CDG: Quantitative analysis of the diagnostic Glc(3) Man tetrasaccharide and clinical spectrum of six new cases."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Furthermore, Glc3 Man was specifically identified by retention time matching against authentic MOGS-CDG urine and compared with Pompe urine.
    explanation: >-
      The analytical step the assay developers took specifically to separate
      these two, which is why the differential is listed.
- name: UGGT1-congenital disorder of glycosylation
  disease_term:
    preferred_term: UGGT1-congenital disorder of glycosylation
    term:
      id: MONDO:0980705
      label: congenital disorder of glycosylation, type IIcc
  description: >-
    The nearest neighbour in the pathway. UGGT1 re-glucosylates misfolded
    glycoproteins to return them to the calnexin/calreticulin cycle, so
    UGGT1-CDG and MOGS-CDG break the same ER glycoprotein quality-control loop
    from opposite directions: MOGS removes the first glucose, UGGT1 puts one
    back. The clinical overlap is broad - developmental delay, seizures,
    dysmorphism, hepatic and respiratory involvement - and a normal transferrin
    pattern does not separate them.

    The separator is the urinary tetrasaccharide. Glc3Man accumulates only when
    the glucosidase I block leaves the triglucosylated glycan intact, so it is
    specific to MOGS-CDG and is not produced by a UGGT1 lesion.
  distinguishing_features:
  - Urinary Glc3Man tetrasaccharide is specific to the glucosidase I block and is the positive test for MOGS-CDG. It is the discriminator that does the work.
  - Scoliosis and polycystic kidneys mark the severe end of UGGT1-CDG and are not features of MOGS-CDG.
  - Microcephaly does NOT discriminate. It is near-universal in both, present in 10 of 11 reported MOGS-CDG patients with no negative column.
  - Cardiac involvement does NOT discriminate. It occurs in roughly six of the eleven reported MOGS-CDG patients as ASD, PFO, left ventricular hypertrophy, dilated cardiomyopathy or heart failure.
  - Biallelic pathogenic MOGS variants favour MOGS-CDG; biallelic pathogenic UGGT1 variants favour UGGT1-CDG.
  evidence:
  - reference: PMID:40267907
    reference_title: Bi-allelic UGGT1 variants cause a congenital disorder of glycosylation.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The cardinal clinical features of UGGT1-CDG involve developmental delay, intellectual disability, seizures, characteristic facial features, and microcephaly in the majority (9/11 affected individuals for whom measurements were available).
    explanation: >-
      The cardinal features of UGGT1-CDG. Every one of them, microcephaly
      included, also occurs in MOGS-CDG, so this quote establishes the overlap
      and discriminates nothing. It is retained for that reason.
  - reference: PMID:40267907
    reference_title: Bi-allelic UGGT1 variants cause a congenital disorder of glycosylation.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The more severely affected individuals display congenital heart malformations, variable skeletal abnormalities including scoliosis, and hepatic and renal involvement, including polycystic kidneys mimicking autosomal recessive polycystic kidney disease.
    explanation: >-
      The severe-end features of UGGT1-CDG. Only scoliosis and the polycystic
      kidneys separate: cardiac malformation and hepatic involvement occur in
      MOGS-CDG too, so this quote is read for its skeletal and renal half only.
  - reference: PMID:40267907
    reference_title: Bi-allelic UGGT1 variants cause a congenital disorder of glycosylation.
    supports: SUPPORT
    directness: INDIRECT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      UGGT1 encodes UDP-glucose:glycoprotein glucosyltransferase 1, an enzyme critical for maintaining quality control of N-linked glycosylation.
    explanation: >-
      Places UGGT1 in the same quality-control loop MOGS acts on, which is why
      this differential is a pathway neighbour rather than a coincidental
      clinical mimic. Graded INDIRECT because it states the enzyme's role
      without comparing the two disorders.
  - reference: PMID:36158009
    reference_title: "Updated clinical and glycomic features of mannosyl-oligosaccharide glucosidase deficiency: Two case reports."
    supports: REFUTE
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Clinical, genetic, and glycomic features of all reported patients with mannosyl-oligosaccharide glucosidase deficiency...| Microcephaly | + | + | + | + | + | ND | + | + | + | + | + |
    explanation: >-
      Graded REFUTE against the idea that microcephaly separates these two
      disorders. Ten of the eleven reported MOGS-CDG patients have it and none is
      negative, so it is near-universal on both sides of this differential. This
      item exists because an earlier version of this entry asserted the opposite.
experimental_models:
- name: Patient skin fibroblast culture
  experimental_model_type: PRIMARY_CELL_CULTURE
  cell_source: patient and parental skin biopsy
  publication: PMID:12145188
  description: >-
    Cultured fibroblasts from patients and their heterozygous parents are the
    functional standard for this disease. They are where residual glucosidase I
    activity was quantified, where the specificity of the defect to that one
    enzyme was established, and where the compensatory endo-alpha-1,2-mannosidase
    increase was measured.
  modeled_mechanisms:
  - target: Endo-alpha-1,2-Mannosidase Bypass
    relationship: MEASURES
    fidelity: HIGH
    model_scale: CELLULAR
    description: >-
      The bypass was detected and quantified in this system, at both activity
      and transcript level, against control and parental cells.
    limitations: >-
      Fibroblasts are not a tissue affected in the disease. The bypass magnitude
      measured here may not be the magnitude in brain or liver, which is
      precisely the uncertainty the severity knowledge gap in this entry turns
      on.
    evidence:
    - reference: PMID:12145188
      reference_title: Processing of N-linked carbohydrate chains in a patient with glucosidase I deficiency (CDG type IIb).
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: >-
        By contrast, the patient's fibroblasts displayed a two- to threefold higher endo-alpha1,2-mannosidase activity, associated with an increased level of enzyme-specific mRNA-transcripts.
      explanation: >-
        The measurement this model is cited for, made in this system.
- name: Saccharomyces cerevisiae CWH41 knockout complementation assay
  experimental_model_type: OTHER
  organism:
    preferred_term: baker's yeast
    term:
      id: NCBITaxon:4932
      label: Saccharomyces cerevisiae
  publication: PMID:40674822
  description: >-
    A yeast strain lacking CWH41, the MOGS homolog, used as a functional
    complementation assay: the N-glycan profile of the knockout is restored when
    a working glucosidase I is supplied. It offers a route to testing whether a
    MOGS variant of uncertain significance retains activity, which is the
    practical difficulty this entry records in the genetic notes.
  modeled_mechanisms:
  - target: Loss of ER Alpha-Glucosidase I Activity
    relationship: RECAPITULATES
    fidelity: MODERATE
    model_scale: MOLECULAR
    description: >-
      Deleting the homologous gene reproduces the enzymatic lesion and the
      resulting N-glycan profile change, which is what makes the strain usable
      as a readout of glucosidase I function.
    limitations: >-
      Yeast N-glycan processing diverges from human downstream of this step, so
      the assay reports on the enzyme rather than on the disease. It says
      nothing about any phenotype and was developed to characterise a
      prokaryotic MOGS rather than to model MOGS-CDG.
    evidence:
    - reference: PMID:40674822
      reference_title: Identification and characterization of a prokaryotic Mannosyl-oligosaccharide Glucosidase (MOGS) and establishment of a functional complementation assay for MOGS activity.
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: >-
        During the process, a functional complementation assay was established by examining the N-glycans profile of a CWH41 (MOGS homologous gene) knockout strain of Saccharomyces cerevisiae.
      explanation: >-
        Describes the assay and the strain it is built on.
    - reference: PMID:40674822
      reference_title: Identification and characterization of a prokaryotic Mannosyl-oligosaccharide Glucosidase (MOGS) and establishment of a functional complementation assay for MOGS activity.
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: >-
        Using the assay system, the function of human MOGS and its disease related mutants were tested.
      explanation: >-
        States that the assay was actually run on disease-associated human
        variants, which is what makes it a route to resolving the variants of
        uncertain significance this entry's genetic notes flag.
classifications:
  icimd_category:
  - classification_value: n_linked_protein_glycosylation
    notes: >-
      MOGS encodes ER alpha-glucosidase I, which performs the first trimming
      step on the N-linked glycan after transfer. The lesion is confined to
      N-linked processing; no O-linked or lipid glycosylation defect is
      described in this disease.
    evidence:
    - reference: PMID:36651519
      reference_title: "MOGS-CDG: Quantitative analysis of the diagnostic Glc(3) Man tetrasaccharide and clinical spectrum of six new cases."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Most CDG with abnormal N-glycosylation can be detected by transferrin screening, however, MOGS-CDG escapes this routine screening.
      explanation: >-
        Places MOGS-CDG inside the N-glycosylation group, while noting the
        screening behaviour that makes it atypical within it.
mappings:
  icd10cm_mappings:
  - term:
      id: ICD10CM:E77.8
      label: Other disorders of glycoprotein metabolism
    mapping_predicate: skos:broadMatch
    mapping_justification: >-
      ICD-10-CM has no code for MOGS-CDG or for the congenital disorders of
      glycosylation individually. E77.8 is the residual glycoprotein-metabolism
      code the disease is assigned to, and it covers many unrelated disorders,
      so this is recorded as a broadMatch rather than an exact one. Per the
      MONDO coverage rule a broadMatch is a cross-reference and does not retire
      the concept from curation.
discussions:
- discussion_id: mogs_cdg_antiviral_target
  kind: EMERGING_HYPOTHESIS
  prompt: >-
    Can ER glucosidase inhibition be used as a broad-spectrum antiviral, and what
    would the MOGS-CDG phenotype predict about its safety?
  attaches_to:
  - pathophysiology#Impaired Viral Replication and Cellular Entry
  rationale: >-
    The human deficiency is the experiment, and it is a weaker experiment than it
    first appears. Patients with almost no glucosidase I activity do show
    impaired viral replication and entry, and one sibling pair showed limited
    clinical evidence of an infectious diathesis despite severe
    hypogammaglobulinemia. That pair is the whole of the survivability argument:
    across all 11 reported patients, recurrent infection is present in 10, and a
    patient from another pair had cytomegalovirus infection despite CMV being
    enveloped. So the target may well be effective; whether inhibiting it is
    survivable rests on two children, not on the disease. What the argument also
    does not establish is a therapeutic window. These patients also have
    a severe neurological and dysmorphic phenotype from lifelong constitutive
    loss, and nothing in the human data separates which of those consequences
    would follow acute pharmacological inhibition in an adult. The proposal is
    recorded as emerging on that basis.

    There is also a direct negative result, from the same group that made the
    original observation. Testing the FDA-approved alpha-glucosidase inhibitor
    miglustat against SARS-CoV-2 in vitro, they found the expected structural
    change in the spike and ACE2 glycans without the functional consequence:
    miglustat did not reproduce the resistance the human deficiency shows, and
    they say so. That does not refute the mechanism in the constitutive human
    deficiency, where the block is near-total and lifelong, but it is a concrete
    demonstration that partial pharmacological inhibition is not the same
    intervention, and it belongs beside the proposal rather than in a citation
    nobody reads.
  evidence:
  - reference: PMID:33245474
    reference_title: "N-Glycan Modification in Covid-19 Pathophysiology: In vitro Structural Changes with Limited Functional Effects."
    supports: REFUTE
    evidence_source: IN_VITRO
    snippet: >-
      Miglustat treatment in our in vitro model did not corroborate this assumption.
    explanation: >-
      The negative result. Graded REFUTE against the proposition that
      pharmacological alpha-glucosidase inhibition reproduces the antiviral
      phenotype of the genetic deficiency.
  - reference: PMID:33245474
    reference_title: "N-Glycan Modification in Covid-19 Pathophysiology: In vitro Structural Changes with Limited Functional Effects."
    supports: REFUTE
    evidence_source: IN_VITRO
    snippet: >-
      Miglustat produced no statistically significant effects on cytokine production following SARS-CoV-2 S glycoprotein stimulation of PBMC.
    explanation: >-
      A second null endpoint in the same study, on the immune rather than the
      entry side. It cuts the same way as the entry-assay null against the same
      proposition, so it is graded REFUTE alongside it.
  - reference: PMID:36158009
    reference_title: "Updated clinical and glycomic features of mannosyl-oligosaccharide glucosidase deficiency: Two case reports."
    supports: REFUTE
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Contrary to previous findings of resistance to infection by glycosylation-dependent enveloped viruses...the elder sister in our report had evidence of cytomegalovirus (CMV, also an enveloped virus) infection.
    explanation: >-
      The strongest single counter-observation to this hypothesis, and the only
      one from patient data rather than from the same in-vitro model as the two
      nulls above. A MOGS-CDG patient acquired an enveloped-virus infection, and
      the reporting authors name the contradiction themselves. Quoted in the
      ellipsis form because the source's inline citation markers sit between the
      two clauses.
- discussion_id: mogs_cdg_bypass_and_severity
  kind: KNOWLEDGE_GAP
  prompt: >-
    Does the extent of the endo-alpha-1,2-mannosidase bypass explain the wide
    severity range that genotype does not?
  attaches_to:
  - pathophysiology#Endo-alpha-1,2-Mannosidase Bypass
  rationale: >-
    Severity spans death at 74 days to survival into the second decade, and the
    largest series found no genotype correlation. The bypass is a candidate
    modifier that has never been tested as one: it was measured in a single
    patient's fibroblasts, and if its magnitude varies between individuals it
    would predict severity where the genotype does not. Measuring
    endo-alpha-1,2-mannosidase activity alongside urinary Glc3Man across the
    known cohort would settle it, and the samples to do that largely exist.
  proposed_experiments:
  - experiment_id: mogs_bypass_severity_correlation
    name: Correlate endo-alpha-1,2-mannosidase activity with clinical severity across the MOGS-CDG cohort
    description: >-
      Assay endo-alpha-1,2-mannosidase activity and transcript level in
      fibroblasts from genetically confirmed MOGS-CDG patients spanning the
      severity range, and test the association against a clinical severity score
      and against quantified urinary Glc3Man excretion.
    readouts:
    - name: Fibroblast endo-alpha-1,2-mannosidase activity
      target: pathophysiology#Endo-alpha-1,2-Mannosidase Bypass
      direction: INCREASED
      interpretation: >-
        A higher bypass activity in the milder end of the cohort would support
        the compensation acting as a severity modifier.
notes: >-
  What this entry deliberately does not claim. The viral-resistance finding is
  striking and has been repeated in secondary literature in stronger terms than
  the primary data support. Both cited sources hedge - "may explain a decreased
  susceptibility" and "at least in part" - and the observation rests on two
  siblings assessed for infection frequency, not on a controlled challenge. The
  pathophysiology node and its evidence explanations preserve those hedges. The
  antiviral-target proposal is filed as an EMERGING_HYPOTHESIS discussion rather
  than as a treatment.

  That paragraph was half-stated until review round 3, and the missing half
  changes what it means. It recorded that the observation rests on two siblings;
  it did not record what the other reported patients look like. The summary
  table in PMID:36158009 covers all eleven and shows recurrent infection in ten
  of them, with the single negative column being that same sibling pair. A
  patient from a separate pair had cytomegalovirus infection despite CMV being
  an enveloped virus, which the reporting authors flag as contrary to the
  resistance finding. So the honest scope of the antiviral observation is
  reduced susceptibility to some glycosylation-dependent enveloped viruses in
  the patients where it was looked for. It is not a clinical phenotype of
  MOGS-CDG, and earlier versions of this entry asserted that it was, in the
  disease description, on the pathophysiology node, and in the hypothesis
  rationale. All three have been narrowed.

  Immunoglobulin replacement is not recorded as a treatment, but the reason has
  been corrected. It was previously withheld partly on the grounds that the
  infection history is paradoxical. That reasoning does not survive the summary
  table in PMID:36158009: recurrent infection is present in 10 of 11 reported
  patients, so there is no disease-level paradox to argue from, only a sibling
  pair in whom the expected bacterial burden was not observed. The remaining and
  sufficient reason is the ordinary one: no source cited here recommends
  immunoglobulin replacement in MOGS-CDG, so the entry does not assert an
  indication. One of the reported patients did receive IVIG, recorded in the
  table as normal IgG and IgM afterwards, which is a data point rather than a
  recommendation. The question is raised in the supportive-care description
  instead of being answered.

  Naming. The entry name uses the current gene-based convention, MOGS-CDG.
  CDG-IIb, CDG type IIb, GCS1-CDG and glucosidase I deficiency are all in active
  use in the literature and are carried as synonyms; the older names dominate the
  pre-2015 papers this entry cites.

  No GeneReviews chapter exists for MOGS-CDG. PubMed was searched for "MOGS-CDG
  GeneReviews[All Fields]" (no results) and "congenital disorders of glycosylation
  GeneReviews[All Fields]" (four results: PMM2-CDG, SLC39A8-CDG, NGLY1-related
  congenital disorder of deglycosylation, and a retired N-linked glycosylation
  overview - none of them this disease). The phenotype baseline is therefore the
  2022 international series, the 2023 ten-case series, and the primary case
  reports.

  No conforms_to. kb/modules/congenital_disorder_of_glycosylation is the obvious
  candidate and does not fit. That module is keyed on a Protein Hypoglycosylation
  hub, routed through either an ER lipid-linked-oligosaccharide assembly defect
  (type I) or a Golgi processing and trafficking defect (type II). MOGS-CDG is
  neither: the glycan is assembled and transferred normally and the block is an
  ER trimming step, and the disease's own signature is that generalized
  hypoglycosylation does not occur - transferrin isoelectric focusing is normal
  because the endo-alpha-1,2-mannosidase bypass restores glycan maturation.
  Declaring conformance to the hypoglycosylation hub would assert the one thing
  this entry spends a pathophysiology node explaining does not happen.
  cytosolic_deglycosylation, er_protein_storage_disease and
  tsr_o_glycosylation_quality_control were checked and are each about a different
  substrate pool or compartment.

  ICD-11 is not mapped. The research report gives the linearization code 5C51.2,
  but icd11f_mappings in this repository take ICD-11 Foundation entity
  identifiers (numeric, e.g. icd11f:1369657886), and no source consulted here
  resolves 5C51.2 to one. The code is recorded in this note rather than converted
  by guesswork. OMIM #606056 and ORPHA:79328 have no slot on DiseaseMappings at
  all, which appears to be a schema gap rather than an omission here.
📚

References & Deep Research

References

17
PMID:10788335
A novel disorder caused by defective biosynthesis of N-linked oligosaccharides due to glucosidase I deficiency.
No top-level findings curated for this source.
PMID:12145188
Processing of N-linked carbohydrate chains in a patient with glucosidase I deficiency (CDG type IIb).
No top-level findings curated for this source.
PMID:24716661
Glycosylation, hypogammaglobulinemia, and resistance to viral infections.
No top-level findings curated for this source.
PMID:25318123
Viral resistance of MOGS-CDG patients implies a broad-spectrum strategy against acute virus infections.
No top-level findings curated for this source.
PMID:35790351
Clinical, biochemical and genetic characteristics of MOGS-CDG: a rare congenital disorder of glycosylation.
No top-level findings curated for this source.
PMID:36651519
MOGS-CDG: Quantitative analysis of the diagnostic Glc(3) Man tetrasaccharide and clinical spectrum of six new cases.
No top-level findings curated for this source.
PMID:33261925
Congenital disorders of glycosylation type IIb with MOGS mutations cause early infantile epileptic encephalopathy, dysmorphic features, and hepatic dysfunction.
No top-level findings curated for this source.
PMID:29235540
Characteristic dysmorphic features in congenital disorders of glycosylation type IIb.
No top-level findings curated for this source.
PMID:30587846
Compound heterozygous variants in MOGS inducing congenital disorders of glycosylation (CDG) IIb.
No top-level findings curated for this source.
PMID:27393411
Immunological aspects of congenital disorders of glycosylation (CDG): a review.
No top-level findings curated for this source.
PMID:35137040
Serum N-glycomics of a novel CDG-IIb patient reveals aberrant IgG glycosylation.
No top-level findings curated for this source.
PMID:36158009
Updated clinical and glycomic features of mannosyl-oligosaccharide glucosidase deficiency: Two case reports.
No top-level findings curated for this source.
PMID:33058492
Epilepsy and movement disorders in CDG: Report on the oldest-known MOGS-CDG patient.
No top-level findings curated for this source.
PMID:38498292
Early onset epileptic and developmental encephalopathy and MOGS variants: a new diagnosis in the whole exome sequencing (WES) ERA : Report of a new patient and review of the literature.
No top-level findings curated for this source.
PMID:33245474
N-Glycan Modification in Covid-19 Pathophysiology: In vitro Structural Changes with Limited Functional Effects.
No top-level findings curated for this source.
PMID:40674822
Identification and characterization of a prokaryotic Mannosyl-oligosaccharide Glucosidase (MOGS) and establishment of a functional complementation assay for MOGS activity.
No top-level findings curated for this source.
PMID:40267907
Bi-allelic UGGT1 variants cause a congenital disorder of glycosylation.
No top-level findings curated for this source.

Deep Research

1

Deep research results are used as seeds for research; they do not undergo the same validation as the main records and may contain errors. How we use deep research.

Evaluations and curation notes (1)

Create: MOGS-Congenital Disorder of Glycosylation (MONDO:0011629) · 2026-09-09T14:28:06Z · View source

De novo curation of MOGS-CDG (CDG-IIb), claimed on issue #11522. Deep research: one OpenScientist run (research/MOGS-Congenital_Disorder_of_Glycosylation-deep-research-openscientist.md, 53 min, 15 citations). The report carried reference_validation and term_validation frontmatter from the generator. References: 15/15 verified, 0 not found, 0 unverifiable, 15/15 on topic, confabulation_rate 0.0. Terms: 45 checked, 43 resolved, 0 not found, 0 obsolete, 2 unverifiable (ORPHA, no resolver). needs_review is true, and it is worth saying why, because the reason is benign and the flag would otherwise read as a fabrication warning. Five entries appear under mislabelled_terms: HP:0001252, HP:0001188, HP:0002791, HP:0002720 and HP:0000505 are each 'named' by the report as a frequency word ('Nearly universal', 'Common', 'Subset', 'Minority'). That is a column artifact of the report's phenotype frequency table, not a wrong binding. Each CURIE was checked independently and resolves to a sensible phenotype. No CURIE was taken from the report without checking it. No .citations.md sidecar was produced for this report, so the citation set was swept from the body with grep rather than read from the sidecar, per the dismech-references fallback. What the report changed. Two additions were taken from it. First, HP:0000505 Visual impairment as a phenotype: the ten-case series snippet already cited elsewhere in the entry names vision problems in a minority, and I had that only as prose. Second, the serum-glycomics mechanism behind the hypogammaglobulinemia (PMID:35137040): patient IgG carries aberrant oligo-mannose and hybrid N-glycans with reduced core-fucosylated complex species, while transferrin and alpha-1-antitrypsin move the opposite way. That both explains the increased IgG clearance and supplies a second, independent reason transferrin-based CDG screening misses this disease. The report's own ordered causal chain otherwise matched the chain already curated, which is corroboration rather than new content. Three report-only PMIDs were fetched into references_cache but not cited (PMID:33245474, PMID:40267907, PMID:40674822); they are committed because the report cites them. GeneReviews baseline: none exists for this disease. PubMed searched for 'MOGS-CDG GeneReviews[All Fields]' (no results) and 'congenital disorders of glycosylation GeneReviews[All Fields]' (four results: PMM2-CDG, SLC39A8-CDG, NGLY1-related congenital disorder of deglycosylation, and a retired N-linked glycosylation overview; none is this disease). Evidence discipline. The viral-resistance finding is hedged by both cited sources ('may explain', 'at least in part') and those hedges are preserved in the evidence explanations; the node carries mechanism_confidence: PROVISIONAL. The antiviral-target proposal is filed as an EMERGING_HYPOTHESIS discussion rather than as a treatment, and immunoglobulin replacement is deliberately not recorded as a treatment because no cited source recommends it in this disease. Validation run in this worktree: just validate passes, 42/42 snippets verified against cached references.

OpenScientist ▸
MOGS-Congenital Disorder of Glycosylation (MOGS-CDG / CDG-IIb): Comprehensive Disease Characteristics Report
openscientist-autonomous 2026-09-09T14:22:16.005079

MOGS-Congenital Disorder of Glycosylation (MOGS-CDG / CDG-IIb): Comprehensive Disease Characteristics Report

MONDO: MONDO:0011629 | Category: Mendelian (autosomal recessive inborn error of metabolism) Prepared: Iterations 1–5 — evidence base combines primary literature (human clinical case series and mechanistic studies) with live public-database queries (gnomAD constraint, ClinVar variant spectrum, UniProt protein architecture, ClinicalTrials.gov). MOGS-CDG is ultra-rare (~30 patients reported worldwide as of 2024), so most clinical evidence is from individual patients and small case series rather than aggregated registry-scale data.

Evidence provenance (database queries performed): gnomAD (constraint: pLI ≈ 0, LOEUF = 0.84 → LoF-tolerant, recessive) · ClinVar (647 MOGS records; ≈27 P/LP vs 153 VUS; overwhelmingly SNVs) · UniProt Q13724 (837-aa type II ER membrane GH63 enzyme; catalytic D583/E807; N-glycosylated at N657) · ClinicalTrials.gov (no MOGS-CDG-specific interventional trials). Evidence types are labelled throughout as human-clinical, in vitro, model-organism, or computational/database.

1. Disease Information

Overview. MOGS-CDG is an ultra-rare autosomal recessive congenital disorder of glycosylation caused by biallelic loss-of-function variants in MOGS, which encodes mannosyl-oligosaccharide glucosidase (glucosidase I / GCS1), the first enzyme in the endoplasmic-reticulum (ER) processing/trimming of N-linked oligosaccharides. Loss of glucosidase I activity blocks the initial trimming of the Glc₃Man₉GlcNAc₂ N-glycan precursor, disrupting N-glycan maturation on many glycoproteins. It is classified as a CDG type II (a defect of glycan processing/remodeling, as opposed to type I assembly defects). The first patient was described by De Praeter et al. in 2000 (PMID 10788335).

Key identifiers: - OMIM: #606056 (Congenital disorder of glycosylation, type IIb) — gene MOGS OMIM 601336 - Orphanet: ORPHA:79328 (MOGS-CDG / CDG-IIb) - Mondo: MONDO:0011629 - ICD-10: E77.8 (other disorders of glycoprotein metabolism); ICD-11: 5C51.2 (disorders of N-glycosylation) - MeSH: Congenital Disorders of Glycosylation (D018981) - Gene HGNC: MOGS (HGNC:24862); UniProt Q13724 (MOGS_HUMAN)

Synonyms / alternative names: - CDG-IIb / CDG type IIb - Glucosidase I deficiency; GCS1-CDG - Mannosyl-oligosaccharide glucosidase deficiency - Congenital disorder of glycosylation type 2b

Data source type: Individual patients / small international case series (EHR- and research-derived), not population registry aggregates, reflecting the disorder's rarity.

2. Etiology

Primary cause (genetic). Biallelic (homozygous or compound heterozygous) pathogenic variants in MOGS (chromosome 2p13.1) causing near-complete loss of glucosidase I enzymatic activity. This is a monogenic Mendelian defect; there are no established environmental or infectious causes.

  • De Praeter (2000, PMID 10788335): first patient was a compound heterozygote for missense variants R486T and F652L; residual enzyme activity <3% of controls; both parents ~50% (obligate carriers) → autosomal recessive.
  • Völker (2002, PMID 12145188): glucosidase I activity <1% of control in patient fibroblasts with intermediate parental values.

Genetic risk factors. The only risk factor is inheritance of two pathogenic MOGS alleles. Consanguinity raises risk of homozygous forms; reported cases are from diverse populations (European, Chinese, Japanese, Korean, Indian), consistent with private/family-specific variants rather than a common founder allele.

Environmental risk factors. None identified — disease is fully determined by genotype (congenital, present at birth).

Protective factors. No genetic or environmental protective factors are established. Notably, the glycosylation defect confers an in vitro protective phenotype against certain N-glycosylation–dependent enveloped viruses (see Mechanism/Immune), but this is not a clinically established protective factor.

Gene–environment interactions. Not applicable in a classical sense; disease expression is genotype-driven. Phenotypic variability among patients with similar genotypes suggests modifier effects (genetic background, residual enzyme activity), but specific modifiers are unidentified.

3. Phenotypes

MOGS-CDG is a multisystem disorder with prominent neurological involvement. Frequencies below are qualitative given the small cohort (~30 patients; Teutonico 2024, PMID 38498292; Post 2023, PMID 36651519; Shimada 2022, PMID 35790351).

Phenotype Type Onset Frequency HPO term
Muscular hypotonia Clinical sign Neonatal/congenital Nearly universal HP:0001252
Global developmental delay / intellectual disability Clinical sign Infancy Nearly universal HP:0001263 / HP:0001249
Seizures / epileptic encephalopathy (often drug-resistant) Clinical sign Early infancy Nearly universal HP:0001250 / HP:0200134
Feeding difficulties / failure to thrive Symptom Neonatal Common HP:0011968 / HP:0001508
Hepatomegaly / hepatic dysfunction (elevated transaminases) Sign/lab Neonatal–infancy Common HP:0002240 / HP:0001392
Dysmorphic facies (long eyelashes, retrognathia, hirsutism, depressed nasal bridge, high palate, blepharophimosis) Physical Congenital Common HP:0000527, HP:0000278, HP:0001007
Clenched/overlapping fingers, overlapped toes Physical Congenital Common HP:0001188
Hypoventilation / respiratory insufficiency Sign Neonatal Common (severe cases) HP:0002791
Generalized edema / abnormal fat distribution Sign Neonatal Reported subset HP:0007430
Movement disorder (dystonia, hyperkinetic movements) Sign Infancy–childhood Subset (older survivors) HP:0001332 / HP:0002072
Hypogammaglobulinemia / immunodeficiency Lab Infancy Subset HP:0002720
Progressive cerebral/cortical–subcortical atrophy, thin corpus callosum, ventricular dilation Imaging Infancy Common HP:0002059 / HP:0007371
Vision problems Symptom Variable Minority HP:0000505
Nephromegaly, hypothyroidism, GERD, auditory neuropathy, Hirschsprung disease Sign Variable Rare/individual reports HP:0000105, HP:0000821, HP:0002020, HP:0002232

Severity/progression. Variable, ranging from fatal in infancy (first patient died at 74 days, PMID 10788335) to survival into adulthood (oldest reported 19 years, PMID 33058492). Neurological course is generally progressive (worsening encephalopathy, brain atrophy) with drug-resistant epilepsy.

Quality-of-life impact. Profound: severe neurodevelopmental disability, drug-resistant seizures, feeding/respiratory support needs, and dependence for daily activities. No validated disease-specific QoL instruments exist for this ultra-rare disorder.

4. Genetic / Molecular Information

  • Causal gene: MOGS (mannosyl-oligosaccharide glucosidase; a.k.a. glucosidase I, GCS1). HGNC:24862; NCBI Gene 7841; OMIM 601336; UniProt Q13724; Ensembl ENSG00000115275. Reference transcript NM_006302. Located 2p13.1; a compact gene (chr2:74,461,057–74,465,410, GRCh38, ~4.35 kb) encoding an 837-aa, ~91.9 kDa type II single-pass ER membrane glycoprotein of glycoside hydrolase family CAZy GH63 (EC 3.2.1.106).

  • Population constraint (gnomAD, GRCh38): MOGS is loss-of-function tolerant at the heterozygous level — pLI ≈ 0 (3.9×10⁻¹⁰), observed/expected LoF oe_lof = 0.66 (LOEUF = 0.84), missense Z = 0.97 (oe_mis = 0.93). This means haploinsufficiency is not disease-causing and healthy carriers are expected — exactly the signature of a recessive enzymopathy requiring biallelic loss of function (matches the ~50% carrier enzyme activity in healthy parents; PMID 12145188).

  • Pathogenic variant spectrum — predominantly missense, with some frameshift/duplication:

  • R486T (c.1587G>C) and F652L — original compound heterozygote (PMID 10788335, 12145188)
  • c.1239_1267dup (p.Asp414Leufs*17), c.544G>A (p.Gly182Arg), c.1698C>A (p.Asp566Glu) in Chinese siblings (PMID 30587846)
  • Numerous additional private missense/compound-heterozygous variants across ~30 patients (Shimada 2022 PMID 35790351; Teutonico 2024 PMID 38498292)
  • Variant classification (ACMG/AMP): Pathogenic/Likely pathogenic when biallelic with functional confirmation (enzyme assay or urine Glc₃Man). Structural modeling has been used to support pathogenicity (PMID 30587846). ClinVar landscape (Iteration 3 query): 647 MOGS records; of ~300 with classifications — 16 Pathogenic, 9 Likely pathogenic, 2 P/LP (≈27 P/LP), 1 Conflicting, 153 VUS, 114 Likely benign. The large VUS fraction highlights the diagnostic importance of orthogonal functional confirmation (urine Glc₃Man, enzyme assay, or yeast CWH41 complementation) to resolve novel variants.
  • Variant type distribution (ClinVar): Overwhelmingly single-nucleotide variants (278) with a minority of small deletions (11), duplications (8), copy-number losses (2), and insertions (1) — i.e., predominantly missense and small frameshift alleles; structural variants are rare (so CMA/karyotype/FISH have little diagnostic role).
  • Variant types/class: missense (most common), frameshift/duplication, and predicted splice/nonsense in some cases → loss of function.
  • Allele frequency: Individually extremely rare/absent in gnomAD (private variants); no common recurrent allele; carrier frequency very low.
  • Somatic vs germline: Germline only.

  • Functional consequence: Loss of function (near-complete abolition of glucosidase I catalytic activity, <1–3% residual).

  • Modifier genes: None confirmed. Compensatory upregulation of endo-α1,2-mannosidase (MANEA) partially bypasses the block (PMID 12145188) and may modulate phenotype.

  • Epigenetic information: None reported.
  • Chromosomal abnormalities: None; point/small variants only.

5. Environmental Information

  • Environmental factors: None causally implicated. Disease is congenital and genotype-determined.
  • Lifestyle factors: Not applicable (disease presents at/near birth).
  • Infectious agents: Not a cause. Of note, patients show reduced susceptibility to certain enveloped viruses in vitro because viral entry glycoproteins depend on host N-glycosylation (PMID 24716661).

6. Mechanism / Pathophysiology

Ordered causal chain (initiating lesion → clinical manifestation):

  1. Biallelic loss-of-function variants in MOGS → results in near-complete deficiency (<1–3% residual) of ER glucosidase I. (Demonstrated: enzyme assays, PMID 10788335, 12145188.)
  2. Loss of glucosidase I activity → fails to cleave the distal α1,2-linked glucose from the protein-bound Glc₃Man₉GlcNAc₂ N-glycan precursor, the first committed step of N-glycan trimming in the ER. (Demonstrated.)
  3. Blocked trimming → leads to accumulation of non-deglucosylated high-mannose N-glycans (Glc₃Man₇₋₉GlcNAc₂) on nascent glycoproteins and diversion of the precursor through endo-α1,2-mannosidase, releasing the free tetrasaccharide Glc₃Man, which is excreted in urine (diagnostic biomarker). (Demonstrated, PMID 12145188, 36651519, 35137040.)
  4. Impaired N-glycan maturation → disrupts the calnexin/calreticulin glycoprotein quality-control cycle (which depends on monoglucosylated glycans) and downstream complex/sialylated glycan formation on many secreted and membrane glycoproteins. (Partly inferred from glycan-processing biology; abnormal serum/IgG N-glycomes demonstrated, PMID 35137040.)
  5. Aberrant glycoprotein processing → branches into multiple organ effects:
  6. Neurological branch: abnormal glycosylation of neuronal ion channels, adhesion molecules, and receptors → developmental & epileptic encephalopathy, hypotonia, progressive cerebral atrophy, movement disorder. (Inferred; clinical correlation strong, PMID 33058492, 33261925, 38498292.)
  7. Immune branch: aberrant IgG glycosylation and shortened immunoglobulin half-life → hypogammaglobulinemia; simultaneously, host-glycan–dependent enveloped viruses (HIV, influenza) show impaired entry/replication → paradoxical relative viral resistance despite low Ig. (Demonstrated in vitro, PMID 24716661.)
  8. Hepatic branch: abnormal glycoprotein handling → hepatomegaly, elevated transaminases, coagulopathy (glycosylated clotting factors). (Inferred/clinical.)
  9. Dysmorphogenesis branch: disrupted glycosylation during development → craniofacial dysmorphism, digital anomalies, edema. (Inferred.)
  10. Cumulative multisystem glycoprotein dysfunction → progressive neurodegeneration, feeding/respiratory failure, and (in severe cases) death in infancy; milder residual function permits survival into childhood/adolescence.

Category detail: - Molecular pathways: N-linked glycan biosynthesis/processing (KEGG hsa00510); ER glycoprotein quality control / calnexin cycle (Reactome "Calnexin/calreticulin cycle", R-HSA-901042; "Asparagine N-linked glycosylation" R-HSA-446203). - Cellular processes: ER protein processing, glycoprotein folding/quality control, ER-associated degradation modulation; neuronal excitability dysregulation (epilepsy). - Protein dysfunction: Loss of function of glucosidase I. Protein architecture (UniProt Q13724): an 837-residue, ~91.9 kDa type II single-pass ER membrane glycoside hydrolase of CAZy family GH63 (EC 3.2.1.106), with a short cytoplasmic tail (1–38), transmembrane signal-anchor (39–59), and a large lumenal catalytic domain (60–837; residues 76–137 required for ER targeting). Catalysis uses a proton donor at position 583 and proton acceptor at 807; the enzyme is itself N-glycosylated at Asn657. Pathogenic missense residues (e.g., R486, F652; PMID 10788335) map to this lumenal catalytic domain near the active-site machinery, disrupting acid–base catalysis and yielding <1–3% residual activity — loss of function by catalytic-domain disruption rather than aggregation. - Metabolic changes: Accumulation and urinary excretion of free oligosaccharide Glc₃Man; hypermannosylated glycopeptides; dyslipidemia and elevated CK reported (PMID 36158009). - Immune involvement: Hypogammaglobulinemia (shortened IgG half-life), reduced T/NK proportions, complement C3/C4 deficiency, elevated IL-6, yet reduced enveloped-virus susceptibility (PMID 24716661, 36158009). - Biochemical abnormality: Enzyme deficiency of glucosidase I (EC 3.2.1.106; CAZy GH63). Catalytic reaction (UniProt Q13724): hydrolysis of the distal α-1,2-glucose from protein-bound Glc3Man9GlcNAc2, releasing β-D-glucose — Reactome R-HSA-4793954 ("Glucosidase I removes glucose from N-glycan"). - Molecular profiling: Serum/IgG N-glycomics show non-deglucosylated Glc₃Man₇₋₉GlcNAc₂ glycans and reduced core-fucosylated complex IgG glycans (PMID 35137040); glycomics show compensatory increase in Man₅GlcNAc₂ (PMID 36158009).

Suggested ontology terms: GO:0006487 (protein N-linked glycosylation), GO:0009311/GO:0006491 (oligosaccharide/N-glycan processing), GO:0004573 (mannosyl-oligosaccharide glucosidase activity), GO:0005788 (ER lumen). Cell types: CL:0000540 (neuron), CL:0000182 (hepatocyte), CL:0000786 (plasma cell). CHEBI: CHEBI:59080-class oligosaccharides; glucose (CHEBI:17234).

7. Anatomical Structures Affected

  • Organ level (primary): Brain/CNS (UBERON:0000955), liver (UBERON:0002107). Secondary: immune system (UBERON:0002405), skeletal muscle/neuromuscular (hypotonia), heart (pericardial effusion – PMID 36158009), kidney (nephromegaly), larynx (laryngomalacia/subglottic stenosis).
  • Body systems: Nervous, hepatic/digestive, immune, respiratory, musculoskeletal.
  • Tissue/cell level: Neurons and neural tissue (progressive cortical/subcortical atrophy); hepatocytes; plasma cells/B lymphocytes (Ig production); broadly any secretory/membrane-glycoprotein–producing cell.
  • Subcellular level: Endoplasmic reticulum (UBERON n/a; GO:0005783 / GO:0005788 ER lumen) — site of glucosidase I action; secretory pathway broadly affected.
  • Localization / lateralization: Bilateral, symmetric CNS involvement (diffuse cerebral atrophy). Systemic/generalized rather than focal.

8. Temporal Development

  • Onset: Congenital / neonatal — hypotonia, dysmorphism, feeding and respiratory problems from birth; seizures in early infancy.
  • Onset pattern: Subacute-to-chronic with early neonatal symptoms and progressive deterioration.
  • Progression: Generally progressive neurodegeneration (worsening encephalopathy, cortical/subcortical atrophy). Some manifestations evolve (epileptic spasms in infancy ceasing by ~age 7 while tonic seizures persist; emergence of dystonia/hyperkinetic movement disorder — PMID 33058492).
  • Course/duration: Chronic, lifelong. Severe forms are lethal in infancy (74 days in index case); milder forms survive to adolescence/adulthood.
  • Remission: No spontaneous remission; seizures are typically drug-resistant. Certain seizure types may abate with age.
  • Critical period: Neonatal/early-infancy window is critical for diagnosis and supportive intervention.

9. Inheritance and Population

  • Epidemiology: Ultra-rare; ~30 patients reported worldwide as of 2024 (PMID 38498292). Prevalence/incidence not formally estimated (Orphanet: <1/1,000,000); no reliable per-100,000 figures.
  • Inheritance: Autosomal recessive (both parents obligate carriers with ~50% enzyme activity; PMID 10788335, 12145188).
  • Penetrance: Complete for biallelic loss-of-function genotypes.
  • Expressivity: Variable (lethal infancy → survival to adulthood), even within families.
  • Genetic anticipation: Not applicable (not a repeat-expansion disorder).
  • Germline mosaicism / founder effects: None documented; variants are private/family-specific.
  • Consanguinity: Contributes to homozygous cases in consanguineous families.
  • Carrier frequency: Very low (private variants; largely absent from gnomAD). Consistent with this, gnomAD shows MOGS is LoF-tolerant (pLI ≈ 0, LOEUF = 0.84), so heterozygous carriers are asymptomatic and population-frequent enough to be observed, but biallelic combinations are exceedingly rare.
  • Population demographics: Reported across European, Chinese, Japanese, Korean, and Indian families; no ethnic predilection or geographic clustering. No clear sex bias (both sexes affected). Age distribution: presents in neonates/infants.

10. Diagnostics

  • First-line clue: Multisystem neonatal presentation (hypotonia, seizures, dysmorphism, hepatomegaly) with normal serum transferrin isoelectric focusing — MOGS-CDG escapes routine CDG transferrin screening (PMID 33261925).
  • Key biochemical test: Urine oligosaccharide analysis (MALDI-TOF MS) detecting the pathognomonic free tetrasaccharide Glc₃Man — reliable screening/confirmation (PMID 36651519, 35790351, 33261925). Quantitative Glc₃Man assays now available.
  • Enzyme assay: Glucosidase I activity in fibroblasts/liver markedly reduced (<1–3%) — historical gold standard (PMID 10788335, 12145188).
  • Glycomics: Serum/IgG N-glycan profiling shows accumulated Glc₃Man₇₋₉GlcNAc₂ and altered IgG glycans (PMID 35137040, 36158009).
  • Genetic testing (definitive): Whole-exome sequencing is the principal diagnostic route in most recent cases (PMID 38498292, 33261925); WGS, targeted CDG gene panels, or single-gene MOGS sequencing also applicable. CMA/karyotype/FISH/mtDNA/repeat testing not indicated. Confirm biallelic MOGS variants + segregation.
  • Imaging: Brain MRI — cerebral/cortical–subcortical atrophy, thin corpus callosum, ventricular dilation.
  • Supportive labs: Low immunoglobulins/hypogammaglobulinemia, elevated transaminases, coagulopathy, dyslipidemia, elevated CK, complement C3/C4 deficiency (PMID 36158009).
  • Differential diagnosis: Other CDG type II subtypes, other early-infantile epileptic/developmental encephalopathies, other inborn errors with hypotonia + hepatopathy + dysmorphism; distinguished by normal transferrin IEF + urine Glc₃Man + MOGS genotype. UGGT1-CDG (PMID 40267907) is a related ER quality-control CDG in the differential.
  • Screening: Not on standard newborn screening panels; cascade carrier testing feasible once a familial variant is known; prenatal/PGT possible for known familial variants.

11. Outcome / Prognosis

  • Survival/mortality: Highly variable and often poor. Index patient died at 74 days (PMID 10788335); severe neonatal forms with hypoventilation/failure to thrive carry high infant mortality. Milder cases survive into childhood/adolescence; oldest reported 19 years (PMID 33058492). No formal 5-/10-year survival statistics exist.
  • Morbidity/function: Severe neurodevelopmental disability, drug-resistant epilepsy, hypotonia, feeding and respiratory dependence, movement disorder in survivors — profound long-term disability.
  • Complications: Recurrent infections despite paradoxical viral resistance, aspiration/respiratory failure, hepatic dysfunction/coagulopathy, status epilepticus, failure to thrive.
  • Recovery potential: No cure; management is supportive. Neurological damage is largely irreversible/progressive.
  • Prognostic factors: Degree of residual enzyme activity, severity of neonatal respiratory/feeding compromise, seizure control. No validated molecular prognostic biomarkers; urinary Glc₃Man is diagnostic rather than prognostic.

12. Treatment

No disease-specific or curative therapy exists. Management is multidisciplinary and supportive.

  • Pharmacotherapy: Anti-seizure medications for epilepsy (often drug-resistant; combinations frequently required) — NCIT anticonvulsant agents (NCIT:C264). Immunoglobulin replacement (IVIG) for symptomatic hypogammaglobulinemia (NCIT:C29099). Nutritional support, management of reflux/hepatic/coagulation issues.
  • Advanced/experimental therapeutics: No approved gene, cell, RNA, or enzyme-replacement therapy. The α-glucosidase inhibitor miglustat (an iminosugar) has been studied in relation to the MOGS glycosylation phenotype and antiviral glycan modification, but not as a disease-modifying treatment for MOGS-CDG itself (PMID 33245474). Miglustat NCIT:C61765. A ClinicalTrials.gov API query (Iteration 3) for "MOGS-CDG / glucosidase I deficiency / CDG-IIb" returned no interventional trials specific to MOGS-CDG (keyword hits were unrelated glucosidase disorders — Pompe/Gaucher ERT and gene-therapy studies), confirming the absence of a disease-specific experimental therapeutic pipeline to date.
  • Surgical/interventional: Supportive only (e.g., gastrostomy for feeding, respiratory support).
  • Supportive/rehabilitative: Physical, occupational, and speech therapy; feeding support; respiratory care; developmental/palliative care.
  • Treatment outcomes: Symptomatic benefit only; seizures frequently refractory. No response-rate data given rarity.
  • Personalized medicine: Care guided by organ involvement; genetic counseling for families.
  • Pharmacogenomics: None established.

13. Prevention

  • Primary prevention: Not possible (congenital genetic disorder). Genetic counseling for at-risk families; carrier screening for relatives; prenatal diagnosis and preimplantation genetic testing (PGT) available when the familial MOGS variants are known.
  • Secondary prevention: Early recognition via urine oligosaccharide analysis (Glc₃Man) and WES in neonates with encephalopathy/dysmorphism/hepatopathy, enabling timely supportive care.
  • Tertiary prevention: Aggressive seizure management, IVIG to reduce infections, nutritional/respiratory support to limit complications.
  • Immunization/public health/environmental measures: Not applicable to disease causation; standard immunizations and infection precautions apply, individualized given the immune phenotype.
  • Counseling: Autosomal recessive recurrence risk 25% per pregnancy for carrier couples — central genetic counseling message.

14. Other Species / Natural Disease

  • Taxonomy / orthologs: MOGS is evolutionarily conserved. Orthologs: mouse Mogs (NCBI Gene 57377), and the yeast homolog CWH41/GLS1 in Saccharomyces cerevisiae (NCBI Taxon 4932). A prokaryotic MOGS (pMOGS) was recently identified in Elizabethkingia meningoseptica (PMID 40674822).
  • Natural disease in animals: No well-characterized naturally occurring MOGS-CDG equivalent reported in companion animals or wildlife (OMIA has no established entry analogous to human MOGS-CDG). Veterinary relevance limited.
  • Comparative biology: The N-glycan trimming pathway and glucosidase I function are highly conserved from yeast to humans, making cross-species functional assays informative (see Model Organisms).
  • Transmission: Not applicable (non-infectious, non-zoonotic).

15. Model Organisms

  • Yeast (S. cerevisiae): CWH41 (MOGS homolog) knockout strains provide a functional complementation assay — human MOGS and its disease variants can be tested for rescue of the N-glycan profile, allowing pathogenicity assessment of patient mutations (PMID 40674822). Strong tool for variant interpretation.
  • Prokaryotic MOGS: A bacterial MOGS (pMOGS) characterized as an additional model/reagent for studying MOGS activity (PMID 40674822).
  • Cellular / in vitro models: Patient-derived skin fibroblasts (enzyme kinetics, glycan analysis; PMID 12145188, 10788335); MOGS-null transfected cells used for glycan/antiviral studies (PMID 33245474); overexpression systems for glucosidase-inhibitor and viral-glycoprotein studies (PMID 24716661, 33245474).
  • Mammalian genetic models: No widely reported viable Mogs knockout mouse disease model in the retrieved literature; complete loss is expected to be developmentally severe. This is a limitation — no established rodent model recapitulating the human neurological phenotype.
  • Model characteristics/limitations: Yeast/cellular systems faithfully recapitulate the biochemical defect (glycan trimming block) and are excellent for variant functional testing, but do not reproduce the multisystem neurological/immunological human phenotype. Applications: variant pathogenicity assays, glycan pathway/compensation studies, and antiviral glycan-modification research.
  • Resources: SGD (yeast CWH41), MGI (mouse Mogs), Cellosaurus (patient fibroblast lines).

Key Supported vs. Refuted Hypotheses

Supported: - MOGS-CDG is autosomal recessive, caused by biallelic loss-of-function MOGS variants abolishing glucosidase I activity (PMID 10788335, 12145188). - The disorder escapes transferrin-based CDG screening; urine Glc₃Man is the diagnostic biomarker (PMID 33261925, 36651519). - Core phenotype = neonatal hypotonia + developmental/epileptic encephalopathy + dysmorphism + hepatic dysfunction, with a paradoxical immune signature (hypogammaglobulinemia + relative viral resistance) (PMID 29235540, 24716661).

Refuted / not supported: - Not detectable by standard serum transferrin IEF (normal pattern) — refutes reliance on transferrin screening. - No environmental/infectious cause; not associated with chromosomal abnormalities, somatic mutation, founder alleles, or repeat expansion.

Limitations and Future Directions

  • Evidence rests on ~30 individual cases — no registry-scale epidemiology, natural-history, or QoL data; frequencies are qualitative.
  • No approved disease-modifying therapy; enzyme/gene/substrate strategies unexplored clinically. Genotype–phenotype correlations and modifiers (e.g., endo-α1,2-mannosidase compensation) merit study.
  • A faithful mammalian disease model is lacking; yeast/cellular complementation assays are the current functional standard.
  • The therapeutic and antiviral implications of the MOGS glycan phenotype (miglustat, host-glycan–dependent viruses) warrant continued investigation.

Primary References (PMID)

10788335 (De Praeter 2000, first case) · 12145188 (Völker 2002, enzymology/compensation) · 24716661 (Sadat 2014, immune phenotype/viral resistance) · 29235540 (Kim 2018, dysmorphism) · 30587846 (Li 2019, compound het variants) · 33058492 (Lo Barco 2021, oldest patient/movement disorder) · 33245474 (Nunes-Santos 2021, miglustat/glycan) · 33261925 (Anzai 2021, normal transferrin/urine oligosaccharides) · 35137040 (Beimdiek 2022, serum/IgG N-glycomics) · 35790351 (Shimada 2022, clinical/biochemical/genetic characterization) · 36158009 (Abuduxikuer 2022, updated clinical/glycomic) · 36651519 (Post 2023, diagnostic Glc₃Man quantitation) · 38498292 (Teutonico 2024, review, ~30 patients) · 40674822 (Zou 2025, prokaryotic MOGS/yeast complementation) · 41192964 (Shwetabh 2025, DEE case) · 40267907 (Dardas 2025, related UGGT1-CDG).

Artifacts

Reference Validation

Checked with linkml-reference-validator 0.2.1.

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

All extracted references resolved successfully.

Term Validation

Checked with linkml-term-validator 0.4.5, through the ols: adapter.

Outcome Count
Terms checked 45
Resolved 43
Unresolved (possible confabulation) 0
Obsolete 0
Unverifiable 2
Terms whose name was checked 13
Terms named correctly 4
Terms named as a different term 6
Terms whose name is worth a second look 3

Terms the report names something else

These identifiers resolve, so nothing about them looks wrong, and the ontology calls them something unrelated to what the report calls them. That usually means the identifier is not the one the sentence needs:

  • MONDO:0011629 (3 mentions) - the report calls it "if available"; MONDO calls it MOGS-congenital disorder of glycosylation
  • HP:0001252 (1 mention) - the report calls it "Nearly universal"; HP calls it Hypotonia
  • HP:0001188 (1 mention) - the report calls it "Common"; HP calls it Hand clenching
  • HP:0002791 (1 mention) - the report calls it "Common (severe cases)"; HP calls it Hypoventilation
  • HP:0002720 (1 mention) - the report calls it "Subset"; HP calls it Decreased circulating IgA concentration
  • HP:0000505 (1 mention) - the report calls it "Minority"; HP calls it Visual impairment

Terms whose name is worth a second look

The report's name for these is recognisably related to the term's own name without being one of them. A loose paraphrase reads the same way as a citation of the wrong sibling term - and so does a related synonym, which the ontology records precisely because it names something adjacent rather than the same thing - so these are listed rather than judged:

  • GO:0006491 (1 mention) - the report calls it "oligosaccharide/N-glycan processing"; GO calls it N-glycan processing
  • GO:0004573 (1 mention) - the report calls it "mannosyl-oligosaccharide glucosidase activity"; GO calls it Glc3Man9GlcNAc2 oligosaccharide glucosidase activity, and lists "mannosyl-oligosaccharide glucosidase activity" among its other names
  • GO:0005788 (2 mentions) - the report calls it "ER lumen"; GO calls it endoplasmic reticulum lumen, and lists "ER lumen" among its other names

Prefixes with no resolver

Terms carrying these prefixes were not checked either way, because no configured ontology covers them. An unrecognised prefix may name an ontology this run could not reach as easily as one that does not exist, so nothing here is evidence of fabrication: ORPHA.