ALG11-congenital disorder of glycosylation

Mendelian MONDO:0013349 Pathograph 21 Show in embeddings browser congenital disorder of glycosylation type I disorder of protein N-glycosylation

ALG11-CDG is an autosomal recessive disorder of protein N-glycosylation caused by biallelic ALG11 variants. ALG11 catalyzes addition of the fourth and fifth mannose residues to the lipid-linked oligosaccharide precursor on the cytosolic face of the endoplasmic reticulum. Affected fibroblasts accumulate shortened precursors and show glycoprotein hypoglycosylation; serum transferrin screening can nevertheless be normal. Reported manifestations include infantile epilepsy, developmental disability, abnormal muscle tone, microcephaly, hearing and visual impairment, and feeding difficulties. Prenatal brain growth arrest and progressive cerebral atrophy occur in severe cases, but imaging and seizure outcomes vary. Care is individualized and supportive.

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1
Inheritance
7
Pathophys.
37
Phenotypes
3
Gaps
21
Pathograph
1
Genes
7
Medical Actions
2
Differentials
3
Models
14
References
1
Deep Research
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Inheritance

1
Autosomal recessive HP:0000007
Disease requires biallelic (homozygous or compound heterozygous) pathogenic ALG11 variants. Heterozygous carriers, including the parents of affected children, are asymptomatic.
Autosomal recessive inheritance
Show evidence (3 references)
PMID:36843332 SUPPORT BACKGROUND Human Clinical
"Asparagine-dependent glycosylation 11-congenital disorders of glycosylation (ALG11-CDG) is a rare autosomal recessive N-glycosylation defect with multisystem involvement particularly neurological symptoms such as epilepsy and neuromotor developmental delay."
States the autosomal recessive mode of inheritance for ALG11-CDG.
PMID:28649519 SUPPORT PRIMARY RESULT Human Clinical
"The parents are carriers of these variants."
Parental segregation in the two reported families supports recessive transmission.
url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1332/ SUPPORT REVIEW SYNTHESIS Other
"Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder."
Historical GeneReviews counseling for autosomal recessive CDG; this is not a measurement of ALG11 carrier enzyme activity.
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Discussions and Knowledge Gaps

3
How often does cerebral growth arrest begin prenatally, and which factors determine subsequent tissue loss?
KNOWLEDGE GAP gap_prenatal_onset_of_brain_involvement
Attached to
pathophysiology#Prenatal Arrest of Cerebral Growth pathophysiology#Progressive Loss of Brain Structures
Unremarkable pregnancies in earlier patients and fetal brain growth arrest in a later child represent clinical variability rather than conflicting observations. In that child, fetal-to-neonatal MRI showed absent growth, whereas later follow-up documented marked tissue loss. The prevalence of prenatal onset, genotype associations and cellular basis remain unresolved.
Proposed experiments
Systematic review of prenatal imaging and biometry in genetically confirmed ALG11-CDG
exp_alg11_prenatal_imaging_review
Collect fetal ultrasound and MRI data, including third-trimester head circumference trajectories, from all reported and unreported genetically confirmed patients, to establish how often head growth arrest is detectable before birth.
Genotype-stratified onset analysis
exp_alg11_genotype_stratified_onset
Compare age at first detectable brain abnormality between patients carrying two severe (null or whole-gene-deletion) alleles and those with at least one hypomorphic missense allele.
Why is sensorineural deafness frequent in ALG11-CDG and RFT1-CDG but unusual in the other congenital disorders of glycosylation?
KNOWLEDGE GAP gap_mechanism_of_sensorineural_deafness
Attached to
phenotypes#Sensorineural Hearing Impairment
The proposed otoneurotoxicity of cytosolic LLO intermediates is a hypothesis from the clinical literature. Neither the cited patient studies nor their fibroblast assays establish accumulation in the inner ear or a causal cochlear injury pathway. Similar hearing impairment in RFT1-CDG motivates comparison but does not prove a shared toxic substrate.
Proposed experiments
Cochlear phenotyping of an Alg11 hypomorphic mouse
exp_alg11_cochlear_phenotyping_mouse
Measure auditory brainstem response thresholds and hair-cell survival in a hypomorphic Alg11 model, and test whether hearing loss tracks the accumulation of Man3/Man4GlcNAc2-PP-dolichol in cochlear tissue.
Cross-CDG audiological comparison against LLO intermediate species
exp_alg11_cross_cdg_audiology
Compare the prevalence and severity of sensorineural hearing loss across CDG types with the identity of the accumulating LLO intermediate, testing whether deafness segregates with the ALG11/RFT1 substrate rather than with hypoglycosylation severity generally.
Which glycoprotein-dependent cellular processes connect ALG11 dysfunction to cerebral growth arrest, tissue loss and epilepsy?
KNOWLEDGE GAP gap_neural_consequences_of_hypoglycosylation
Attached to
pathophysiology#Protein Hypoglycosylation
Truncated LLO and GP130 hypoglycosylation are reproducible fibroblast observations. They do not directly demonstrate GP130 signaling failure, ER stress, apoptosis, defective neuronal migration or oligodendrocyte maturation in affected human brain. Those candidate processes require separate evidence before entering a causal chain.
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Pathophysiology

7
Biallelic ALG11 Loss of Function
Homozygous or compound heterozygous ALG11 variants impair gene function. Missense alleles, frameshift and splice-site variants, and a whole-gene deletion in trans with a missense allele have been reported. Functional effects differ by allele.
ALG11 hgnc:32456 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves ALG11 (hgnc:32456). hgnc:32456 is a gene from the HUGO Gene Nomenclature Committee.
Downstream
ALG11 Mannosyltransferase Deficiency The index allele impairs ALG11-dependent elongation; wild-type versus mutant complementation supports its causal effect.
Reduced ALG11 Protein Abundance Loss of one gene copy can reduce abundance in the reported deletion/missense genotype; this is not a uniform effect of missense alleles.
Show evidence (2 references)
PMID:20080937 SUPPORT PRIMARY RESULT Human Clinical
"These findings gave rise to genetic analysis of the hALG11 cDNA, in which homozygosity for mutation c.T257C (p.L86S) was identified."
Identifies the homozygous index allele.
PMID:30676690 SUPPORT PRIMARY RESULT Human Clinical
"Subsequent ALG11 gene deletion/duplication analysis found a paternally inherited whole gene deletion of ALG11 in the patient."
Documents a structural allele paired with the maternal p.Leu46Pro variant.
ALG11 Mannosyltransferase Deficiency
ALG11 activity is deficient at the fourth and fifth mannose-transfer steps of lipid-linked oligosaccharide assembly. The p.Leu86Ser index fibroblasts had impaired elongation despite unchanged measured protein abundance and localization. This catalytic phenotype should not be generalized to the abundance of every ALG11 variant.
ALG11 hgnc:32456 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves ALG11 (hgnc:32456). hgnc:32456 is a gene from the HUGO Gene Nomenclature Committee.
GDP-Man:Man(3)GlcNAc(2)-PP-Dol alpha-1,2-mannosyltransferase activity GO:0004377 ↓ DECREASED Gene Ontology (GO) Relation: this pathophysiological event involves this molecular function This pathophysiological event involves decreased GDP-Man:Man(3)GlcNAc(2)-PP-Dol alpha-1,2-mannosyltransferase activity (GO:0004377). GO:0004377 is a molecular function from the Gene Ontology.
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
Yeast alg11 deletion strain complementation assay OTHER Human allele complementation in an alg11-deficient yeast background assesses recovery of conserved glycosylation function. It supports functional impairment of the tested allele rather than providing purified-enzyme kinetics.
Downstream
Lipid-Linked Oligosaccharide Assembly Arrest Reduced ALG11-dependent mannose transfer impairs precursor elongation and permits accumulation of shortened species; residual synthesis is not excluded.
Show evidence (2 references)
PMID:20080937 SUPPORT PRIMARY RESULT In Vitro
"Determination of mannosyltransferase activities of early steps of lipid-linked oligosaccharide biosynthesis in fibroblasts indicated that the patient was deficient in elongating Man3GlcNAc2-PP-dolichol."
Direct assay of the elongation defect in index patient fibroblasts.
PMID:20080937 SUPPORT PRIMARY RESULT In Vitro
"Immunofluorescence examinations combined with western blotting showed no differences of intracellular localization or expression of ALG11 between control and patient fibroblasts, respectively, indicating no mislocalization or degradation of the mutated transferase."
Preserved measured abundance and localization apply to the index allele, not all disease-associated alleles.
Reduced ALG11 Protein Abundance
Reduced steady-state ALG11 protein is an allele-dependent observation. It was reported in fibroblasts with a whole-gene deletion in trans with p.Leu46Pro. Other tested missense genotypes had normal measured abundance. Reduced abundance alone does not establish an altered protein-degradation rate.
ALG11 hgnc:32456 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves ALG11 (hgnc:32456). hgnc:32456 is a gene from the HUGO Gene Nomenclature Committee.
Show evidence (1 reference)
PMID:30676690 SUPPORT PRIMARY RESULT In Vitro
"As expected, patient 2 had slightly less ALG11 protein due to the paternally inherited whole gene deletion (Figure 2)."
Directly reports lower protein abundance in this genotype.
Lipid-Linked Oligosaccharide Assembly Arrest
Shortened Man3GlcNAc2-PP-dolichol and Man4GlcNAc2-PP-dolichol accumulate in affected fibroblasts. This is impaired precursor assembly rather than proof that every LLO molecule is arrested or that those truncated species are transferred unchanged to proteins.
skin fibroblast CL:0002620 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves skin fibroblast (CL:0002620). CL:0002620 is a cell type from the Cell Ontology.
dolichol-linked oligosaccharide biosynthetic process GO:0006488 ↓ DECREASED Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased dolichol-linked oligosaccharide biosynthetic process (GO:0006488). GO:0006488 is a biological process from the Gene Ontology.
Experimental models
Patient-derived skin fibroblast lipid-linked oligosaccharide analysis PRIMARY CELL CULTURE Directly measures the accumulating LLO species and the deficient elongation step in cells carrying the patient genotype.
Downstream
Protein Hypoglycosylation Defective precursor assembly limits protein N-glycosylation. The cited fibroblast study demonstrates shortened precursors and hypoglycosylated GP130 together; it does not directly measure transfer of a particular truncated glycan to GP130.
Show evidence (2 references)
PMID:20080937 SUPPORT PRIMARY RESULT In Vitro
"Analysis of dolichol-linked oligosaccharides in patient-derived fibroblasts revealed an accumulation of Man3GlcNAc2-PP-dolichol and Man4GlcNAc2-PP-dolichol."
Identifies the two LLO species that accumulate, fixing the exact step of the assembly block.
PMID:22213132 SUPPORT PRIMARY RESULT In Vitro
"who presented an accumulation of shortened dolichol-linked oligosaccharides leading to CDG-Ip (ALG11-CDG)"
Independently confirms shortened LLO accumulation as the biochemical signature of the disorder.
Protein Hypoglycosylation
Protein N-glycosylation is reduced. The index serum transferrin pattern reflected loss of complete N-glycan side chains, and affected fibroblasts show lower-molecular-weight GP130 glycoforms. These are protein- and sample-specific readouts: normal serum transferrin does not exclude a cellular defect. Comparative diagnostic sensitivity of GP130 versus transferrin has not been established.
protein N-linked glycosylation GO:0006487 ↓ DECREASED Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased protein N-linked glycosylation (GO:0006487). GO:0006487 is a biological process from the Gene Ontology.
Experimental models
Patient-derived skin fibroblast lipid-linked oligosaccharide analysis PRIMARY CELL CULTURE GP130 immunoblotting detects abnormal glycoforms in affected fibroblasts, including those with normal serum screening.
ALG11-CDG fibroblasts treated with liposomal mannose-1-phosphate PRIMARY CELL CULTURE Partial shifts toward larger high-mannose glycoforms were observed after treatment; this does not establish complete normalization of glycosylation.
Downstream
Type I Transferrin Isoform Profile Loss of complete transferrin N-glycan chains can produce a type I isoform profile, although that serum readout is not abnormal in every affected patient.
Show evidence (3 references)
PMID:20080937 SUPPORT PRIMARY RESULT Human Clinical
"The isoelectric focusing pattern of the patient's serum transferrin showed the partial loss of complete N-glycan side chains, which is a characteristic sign for CDG-I."
Demonstrates hypoglycosylation of a serum glycoprotein in the index patient.
PMID:30676690 SUPPORT PRIMARY RESULT In Vitro
"Fibroblasts from the skin punch biopsy also yielded abnormally truncated GP130 isoforms on western blot"
Documents the cellular glycoprotein readout.
PMID:30770273 SUPPORT PRIMARY RESULT In Vitro
"Interestingly, serum N-glycan analysis and carbohydrate deficient transferrin were normal, but the novel GP130 biomarker revealed cellular hypoglycosylation, while LLO analysis was consistent with ALG11-CDG."
Supports coexistence of normal serum screening and abnormal cellular glycosylation.
Prenatal Arrest of Cerebral Growth
In one molecularly and biochemically characterized child, fetal brain growth arrested after normal mid-gestation biometry. The fetal-to-neonatal MRI interval showed absent growth rather than measured tissue loss. The cellular mechanism connecting ALG11 dysfunction to this developmental phenotype is unknown.
brain UBERON:0000955 Uberon multi-species anatomy ontology (UBERON) Relation: this pathophysiological event occurs in this anatomical location This pathophysiological event occurs in brain (UBERON:0000955). UBERON:0000955 is an anatomical location from the Uberon multi-species anatomy ontology.
Downstream
Progressive Microcephaly Arrested prenatal brain growth accompanied declining relative head size in the serially imaged child.
Show evidence (1 reference)
PMID:30770273 SUPPORT PRIMARY RESULT Human Clinical
"During the 3.5 week interval from the fetal MRI to the postnatal brain MRI, the brain did not increase in size indicating an arrested growth pattern. This should be differentiated from a decrease in size, or atrophy, which did not occur during that same time period."
Explicitly distinguishes developmental growth arrest from atrophy in this child.
Progressive Loss of Brain Structures
Serial MRI has documented progressive cerebral tissue loss in several severe cases. The child with prenatal growth arrest later had near-complete cerebral hemispheric loss and severe cerebellar and brainstem volume loss at age seven. That sequence is an individual longitudinal observation, not an obligatory course for all ALG11-CDG; another reported adolescent had normal MRI and CT.
brain UBERON:0000955 Uberon multi-species anatomy ontology (UBERON) Relation: this pathophysiological event occurs in this anatomical location This pathophysiological event occurs in brain (UBERON:0000955). UBERON:0000955 is an anatomical location from the Uberon multi-species anatomy ontology.
Downstream
Cerebral Atrophy Progressive loss of cerebral tissue is the structural basis of the observed cerebral atrophy.
Cerebellar Atrophy Cerebellar volume loss manifested on later imaging in the longitudinal case.
Ventriculomegaly Ventricles enlarged secondarily to cerebral tissue loss in one serially imaged child.
Show evidence (3 references)
PMID:39809108 SUPPORT PRIMARY RESULT Human Clinical
"There was near complete loss of cerebral hemispheres, severe cerebellar atrophy, and decreased volume of the brainstem."
Documents the extent of structural loss at age seven in a serially imaged patient.
PMID:36843332 SUPPORT PRIMARY RESULT Human Clinical
"Progressive cerebral atrophy, hypomyelination and corpus callosum hypoplasia were striking features in brain MRI images taken during our follow-up."
Independently reports the same progressive atrophy with hypomyelination in a different patient.
PMID:30676690 SUPPORT PRIMARY RESULT Human Clinical
"Both MRI and CT scan of the brain were within normal limits, but the EEG was abnormal."
Qualifies the spectrum: the 14-year-old patient did not have the same structural imaging phenotype.
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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 ALG11-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

37
Breast 1
Inverted Nipples HP:0003186 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Inverted nipples (HP:0003186). HP:0003186 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:30676690 SUPPORT PRIMARY RESULT Human Clinical
"She was non-dysmorphic and had inverted nipples on physical examination."
Direct physical examination in the 2019 child.
Digestive 6
Recurrent Vomiting HP:0002013 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Vomiting (HP:0002013), qualified as temporality recurrent. HP:0002013 is a phenotype from the Human Phenotype Ontology.
Temporal: RECURRENT
Show evidence (2 references)
PMID:30676690 SUPPORT REVIEW SYNTHESIS Human Clinical
"Poor feeding, recurrent vomiting, and instability of body temperature were also present in several individuals."
Documents recurrent vomiting in several affected individuals.
url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1332/ SUPPORT REVIEW SYNTHESIS Other
"she had persistent vomiting and gastric bleeding and died at age two years."
Historical ALG11-specific description of the index child, not a new independent case.
Feeding Difficulty Feeding difficulties HP:0011968 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Feeding difficulties (HP:0011968). HP:0011968 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:30676690 SUPPORT REVIEW SYNTHESIS Human Clinical
"| 12/12 (100%) | 12/12 (100%) | 6/7 (86%), ... | 9/10 (90%) ... | 11/12 (92%) | 6/10 (60%) ... | 4/6 (66%) ... | 4/7 (57%) ... | 10/11 (91%) ... | 7/12 (58%) |"
Table 2: feeding problems in 7/12 reported patients.
Dysphagia HP:0002015 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Dysphagia (HP:0002015). HP:0002015 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:30770273 SUPPORT PRIMARY RESULT Human Clinical
"A fluoroscopy swallow study showed dysfunctional and delayed swallowing with esophageal reflux and silent aspiration so he was transitioned to full nasogastric tube feedings."
Directly documents the swallowing abnormality and consequence.
Gastroesophageal Reflux HP:0002020 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Gastroesophageal reflux (HP:0002020). HP:0002020 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:28649519 SUPPORT PRIMARY RESULT Human Clinical
"There were feeding problems with gastroesophageal reflux, which responded to conservative treatment."
Direct clinical finding and reported response.
Umbilical Hernia HP:0001537 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Umbilical hernia (HP:0001537). HP:0001537 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:28649519 SUPPORT PRIMARY RESULT Human Clinical
"He had micrognathia, a sloping forehead with a salmon patch, absent midpalmar creases, thick feet and an umbilical hernia."
Directly documents the hernia.
Inguinal Hernia HP:0000023 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Inguinal hernia (HP:0000023). HP:0000023 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:28649519 SUPPORT PRIMARY RESULT Human Clinical
"An incarcerated inguinal hernia was surgically corrected at age 5 months."
Individual clinical finding and intervention.
Ear 1
Sensorineural Hearing Impairment HP:0000407 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Sensorineural hearing impairment (HP:0000407). HP:0000407 is a phenotype from the Human Phenotype Ontology.
Show evidence (3 references)
PMID:30676690 SUPPORT REVIEW SYNTHESIS Human Clinical
"Sensorineural deafness has been described as a frequent feature."
States sensorineural deafness as a frequent feature of ALG11-CDG.
PMID:28649519 SUPPORT PRIMARY RESULT Human Clinical
"On follow-up examination hearing loss had worsened (70–90 dB loss) with the involvement of the cochlea as well as the nerve and the brainstem."
Documents progressive hearing loss in an individual; this is not a separate cohort.
PMID:30676690 SUPPORT REVIEW SYNTHESIS Human Clinical
"| 12/12 (100%) | 12/12 (100%) | 6/7 (86%), ... | 9/10 (90%) ... | 11/12 (92%) | 6/10 (60%) ... | 4/6 (66%) ... | 4/7 (57%) ... | 10/11 (91%) ... | 7/12 (58%) |"
Table 2: deafness in 4/7 with five unreported; subtype and testing varied.
Eye 4
Strabismus HP:0000486 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Strabismus (HP:0000486). HP:0000486 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:30676690 SUPPORT REVIEW SYNTHESIS Human Clinical
"Strabismus and poor visual tracking were the most common ophthalmological findings."
Identifies strabismus as the leading ocular feature.
Optic Atrophy HP:0000648 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Optic atrophy (HP:0000648). HP:0000648 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:28649519 SUPPORT PRIMARY RESULT Human Clinical
"Ophthalmologic evaluation showed papillary atrophy and retinal dystrophy with low amplitudes on flash ERG."
Direct examination and retinal electrophysiology in one child.
Retinal Dystrophy HP:0000556 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Retinal dystrophy (HP:0000556). HP:0000556 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:28649519 SUPPORT PRIMARY RESULT Human Clinical
"Ophthalmologic evaluation showed papillary atrophy and retinal dystrophy with low amplitudes on flash ERG."
Direct retinal finding in one child.
Poor Visual Tracking Impaired smooth pursuit HP:0007772 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Impaired smooth pursuit (HP:0007772). HP:0007772 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:28649519 SUPPORT PRIMARY RESULT Human Clinical
"At 18 months, he did not follow with the eyes, and there was no consistent eye contact."
Directly documents absent tracking.
PMID:30676690 SUPPORT REVIEW SYNTHESIS Human Clinical
"Strabismus and poor visual tracking were the most common ophthalmological findings."
Describes the reported ocular spectrum.
Head and Neck 5
Progressive Microcephaly HP:0000253 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Progressive microcephaly (HP:0000253). HP:0000253 is a phenotype from the Human Phenotype Ontology.
Show evidence (3 references)
PMID:28649519 SUPPORT PRIMARY RESULT Human Clinical
"Progressive microcephaly was noted with SDS for head circumference decreasing from − 2 SDS at one month to − 3.2 SDS at 4 months of age."
Direct serial head-circumference measurements in one child.
PMID:30770273 SUPPORT PRIMARY RESULT Human Clinical
"This report shows the development of microcephaly in ALG11-CDG during the late second and third trimester"
Supports the specific claim that head growth falls away in utero rather than only postnatally, which the preceding item does not establish.
PMID:30676690 SUPPORT REVIEW SYNTHESIS Human Clinical
"| 12/12 (100%) | 12/12 (100%) | 6/7 (86%), ... | 9/10 (90%) ... | 11/12 (92%) | 6/10 (60%) ... | 4/6 (66%) ... | 4/7 (57%) ... | 10/11 (91%) ... | 7/12 (58%) |"
Table 2: any microcephaly in 9/10 evaluable patients, not a rate of progressive microcephaly.
Abnormal Facial Shape HP:0001999 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Abnormal facial shape (HP:0001999). HP:0001999 is a phenotype from the Human Phenotype Ontology.
Coarse binding: variable spectrum
Show evidence (1 reference)
PMID:30676690 SUPPORT REVIEW SYNTHESIS Human Clinical
"Dysmorphic features (such as long philtrum, retrognathia) and hypotonia were common, but not universal."
Supports variable dysmorphism, not a numerical disease-frequency band.
Long Philtrum HP:0000343 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Long philtrum (HP:0000343). HP:0000343 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:30676690 SUPPORT REVIEW SYNTHESIS Human Clinical
"Dysmorphic features (such as long philtrum, retrognathia) and hypotonia were common, but not universal."
Reviews the observed facial spectrum without a feature-specific denominator.
Retrognathia 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:30676690 SUPPORT REVIEW SYNTHESIS Human Clinical
"Dysmorphic features (such as long philtrum, retrognathia) and hypotonia were common, but not universal."
Reviews the observed facial spectrum without a feature-specific denominator.
Micrognathia HP:0000347 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Micrognathia (HP:0000347). HP:0000347 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:28649519 SUPPORT PRIMARY RESULT Human Clinical
"He had micrognathia, a sloping forehead with a salmon patch, absent midpalmar creases, thick feet and an umbilical hernia."
Direct physical examination.
Metabolism 2
Type I Transferrin Isoform Profile HP:0003642 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Type I transferrin isoform profile (HP:0003642). HP:0003642 is a phenotype from the Human Phenotype Ontology.
Show evidence (3 references)
PMID:36843332 SUPPORT PRIMARY RESULT Human Clinical
"CDG type 1 pattern was detected with the examination of carbohydrate-deficient transferrin (CDT) by capillary zone electrophoresis."
Documents either the type I pattern or its absence in an affected individual, consistent with variable expression of this laboratory phenotype.
PMID:30676690 SUPPORT PRIMARY RESULT Human Clinical
"Surprisingly, one patient presented with normal transferrin glycosylation profile, a feature that has not been reported previously in patients with ALG11-CDG."
Documents either the type I pattern or its absence in an affected individual, consistent with variable expression of this laboratory phenotype.
PMID:35907674 SUPPORT PRIMARY RESULT Human Clinical
"Although CDG was clinically suspected, serum transferrin isoelectric focusing analysis appeared to be normal."
An independent genetically diagnosed case with normal serum screening.
Temperature Instability HP:0005968 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Temperature instability (HP:0005968). HP:0005968 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:30676690 SUPPORT REVIEW SYNTHESIS Human Clinical
"Poor feeding, recurrent vomiting, and instability of body temperature were also present in several individuals."
Documents body-temperature instability in several affected individuals.
Musculoskeletal 2
Axial Hypotonia HP:0008936 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Axial hypotonia (HP:0008936). HP:0008936 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:36843332 SUPPORT PRIMARY RESULT Human Clinical
"A 31-month-old male patient admitted to our center with complaints of axial hypotonia, drug-resistant myoclonic seizures, microcephaly and deafness."
Documents axial hypotonia as a presenting complaint.
PMID:30676690 SUPPORT REVIEW SYNTHESIS Human Clinical
"| 12/12 (100%) | 12/12 (100%) | 6/7 (86%), ... | 9/10 (90%) ... | 11/12 (92%) | 6/10 (60%) ... | 4/6 (66%) ... | 4/7 (57%) ... | 10/11 (91%) ... | 7/12 (58%) |"
Table 2: any hypotonia in 11/12; the table does not quantify the axial subset separately.
Peripheral Hypertonia HP:0001276 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Hypertonia (HP:0001276). HP:0001276 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:28649519 SUPPORT PRIMARY RESULT Human Clinical
"He showed axial hypotonia and peripheral hypertonia."
Direct clinical examination.
PMID:30676690 SUPPORT REVIEW SYNTHESIS Human Clinical
"| 12/12 (100%) | 12/12 (100%) | 6/7 (86%), ... | 9/10 (90%) ... | 11/12 (92%) | 6/10 (60%) ... | 4/6 (66%) ... | 4/7 (57%) ... | 10/11 (91%) ... | 7/12 (58%) |"
Table 2: peripheral hypertonia in 6/10 evaluable patients.
Nervous System 14
Seizures HP:0001250 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Seizure (HP:0001250). HP:0001250 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:30676690 SUPPORT REVIEW SYNTHESIS Human Clinical
"Intellectual disability and epilepsy are universally present, and all had visual problems, except our patient 1"
Describes the 12 reported patients summarized in that review; it is not a population penetrance estimate.
PMID:30676690 SUPPORT PRIMARY RESULT Human Clinical
"With current medication he has been seizure free for 7 years."
Documents sustained seizure control in one adolescent; the regimen is not named in this statement.
Drug-Resistant Myoclonic Seizures HP:0032794 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Myoclonic seizure (HP:0032794). HP:0032794 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:36843332 SUPPORT PRIMARY RESULT Human Clinical
"A 31-month-old male patient admitted to our center with complaints of axial hypotonia, drug-resistant myoclonic seizures, microcephaly and deafness."
Documents drug-resistant myoclonic seizures in an affected child.
EEG Burst Suppression EEG with burst suppression HP:0010851 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is EEG with burst suppression (HP:0010851). HP:0010851 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:36843332 SUPPORT PRIMARY RESULT Human Clinical
"The electroencephalography (EEG) showed a burst-suppression pattern without hypsarrhythmia."
Directly documents the burst-suppression pattern.
Global Developmental Delay 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 (2 references)
PMID:30676690 SUPPORT PRIMARY RESULT Human Clinical
"Both affected individuals reported here had severe psychomotor disabilities and epilepsy."
Reports severe psychomotor disability in both newly described patients.
PMID:30676690 SUPPORT REVIEW SYNTHESIS Human Clinical
"| 12/12 (100%) | 12/12 (100%) | 6/7 (86%), ... | 9/10 (90%) ... | 11/12 (92%) | 6/10 (60%) ... | 4/6 (66%) ... | 4/7 (57%) ... | 10/11 (91%) ... | 7/12 (58%) |"
Table 2: developmental disability in 12/12 reported patients.
Cerebral Atrophy HP:0002059 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Cerebral atrophy (HP:0002059), qualified as course progressive. HP:0002059 is a phenotype from the Human Phenotype Ontology.
Course: PROGRESSIVE
Show evidence (1 reference)
PMID:36843332 SUPPORT PRIMARY RESULT Human Clinical
"Progressive cerebral atrophy, hypomyelination and corpus callosum hypoplasia were striking features in brain MRI images taken during our follow-up."
Documents progressive cerebral atrophy on serial imaging.
Cerebral Hypomyelination HP:0006808 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Cerebral hypomyelination (HP:0006808). HP:0006808 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:36843332 SUPPORT PRIMARY RESULT Human Clinical
"Progressive cerebral atrophy, hypomyelination and corpus callosum hypoplasia were striking features in brain MRI images taken during our follow-up."
Reports hypomyelination on brain MRI.
Cerebellar Atrophy HP:0001272 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Cerebellar atrophy (HP:0001272). HP:0001272 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:39809108 SUPPORT PRIMARY RESULT Human Clinical
"There was near complete loss of cerebral hemispheres, severe cerebellar atrophy, and decreased volume of the brainstem."
Documents severe cerebellar atrophy on follow-up imaging.
Hyperreflexia HP:0001347 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Hyperreflexia (HP:0001347). HP:0001347 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:28649519 SUPPORT PRIMARY RESULT Human Clinical
"Peripheral tone was increased, as were tendon reflexes."
Directly documents increased reflexes.
PMID:30676690 SUPPORT REVIEW SYNTHESIS Human Clinical
"| 12/12 (100%) | 12/12 (100%) | 6/7 (86%), ... | 9/10 (90%) ... | 11/12 (92%) | 6/10 (60%) ... | 4/6 (66%) ... | 4/7 (57%) ... | 10/11 (91%) ... | 7/12 (58%) |"
Table 2: hyperreflexia in 4/6 evaluable patients.
Corpus Callosum Hypoplasia Hypoplasia of the corpus callosum HP:0002079 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Hypoplasia of the corpus callosum (HP:0002079). HP:0002079 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:36843332 SUPPORT PRIMARY RESULT Human Clinical
"Progressive cerebral atrophy, hypomyelination and corpus callosum hypoplasia were striking features in brain MRI images taken during our follow-up."
Direct MRI observation in the reported child.
Agenesis of the Corpus Callosum Agenesis of corpus callosum HP:0001274 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Agenesis of corpus callosum (HP:0001274). HP:0001274 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:30770273 SUPPORT PRIMARY RESULT Human Clinical
"Fetal magnetic resonance imaging at 36 weeks' gestational age showed severe cortical thinning with a simplified gyral pattern for gestational age, ventriculomegaly, and agenesis of the corpus callosum."
Direct fetal MRI finding.
Subcortical Heterotopia Gray matter heterotopia HP:0002282 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Gray matter heterotopia (HP:0002282). HP:0002282 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:28649519 SUPPORT PRIMARY RESULT Human Clinical
"Brain magnetic resonance imaging (MRI) showed symmetrical anteriorly predominant subcortical heterotopias and a simplified gyral pattern."
Direct MRI observation.
Ventriculomegaly HP:0002119 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Ventriculomegaly (HP:0002119). HP:0002119 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:28649519 SUPPORT PRIMARY RESULT Human Clinical
"Repeated MRI at the age of 1 year revealed a striking atrophy of white matter and cortex and secondary dilatation of the ventricles, with relative sparing of cerebellum and brainstem."
Documents secondary ventricular enlargement.
Epileptic Spasms HP:0011097 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Epileptic spasm (HP:0011097). HP:0011097 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:28649519 SUPPORT PRIMARY RESULT Human Clinical
"Tonic seizures were seen with opening of the eyes and freezing, as well as infantile spasms."
Direct seizure observation.
PMID:30676690 SUPPORT PRIMARY RESULT Human Clinical
"EEG was markedly abnormal due to the presence of a modified hypsarrhythmia with repeated spikes in temporal and central regions bilaterally and infantile spasms with jerking arm extension."
Documents spasms with modified hypsarrhythmia, preventing a universal absence claim.
Status Epilepticus HP:0002133 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Status epilepticus (HP:0002133). HP:0002133 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:30676690 SUPPORT PRIMARY RESULT Human Clinical
"At age of 4 years his seizures were the most severe and he was admitted twice with status epilepticus."
Direct longitudinal clinical history.
Respiratory 1
Aspiration HP:0002835 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Aspiration (HP:0002835). HP:0002835 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:30770273 SUPPORT PRIMARY RESULT Human Clinical
"A fluoroscopy swallow study showed dysfunctional and delayed swallowing with esophageal reflux and silent aspiration so he was transitioned to full nasogastric tube feedings."
Directly documents silent aspiration.
Growth 1
Failure to Thrive HP:0001508 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Failure to thrive (HP:0001508). HP:0001508 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:28649519 SUPPORT PRIMARY RESULT Human Clinical
"This boy was admitted at the age of 3 months with feeding problems and failure to thrive."
Directly documents failure to thrive, rather than inferring it from vomiting.
🧬

Genetic Associations

1
ALG11 (Biallelic loss-of-function variants)
Gene: ALG11 hgnc:32456 HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is ALG11 (hgnc:32456). hgnc:32456 is a gene from the HUGO Gene Nomenclature Committee. relationship_type: CAUSATIVE
Show evidence (5 references)
PMID:20080937 SUPPORT PRIMARY RESULT In Vitro
"Verification of the mutation as a primary cause for the genetic defect was proved by retroviral expression of human wild-type and mutated ALG11 cDNA in patient-derived fibroblasts as well as using a yeast alg11 deletion strain as a heterologous expression system for hALG11 variants."
Functional rescue and heterologous complementation establish the ALG11 variant as causal rather than merely associated.
PMID:22213132 SUPPORT PRIMARY RESULT Human Clinical
"Although all CDG-Ip patients carry different mutations in the ALG11 gene, they share a variety of clinical syndromes"
Establishes allelic heterogeneity with a convergent clinical phenotype across independently ascertained patients.
PMID:30676690 SUPPORT PRIMARY RESULT Human Clinical
"Though the mother was found to be heterozygous for the same mutation, the father did not have this mutation. Subsequent ALG11 gene deletion/duplication analysis found a paternally inherited whole gene deletion of ALG11 in the patient."
Explains the apparently homozygous sequence result.
+ 2 more references
💊

Medical Actions

7
Anti-Seizure Pharmacotherapy
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
Treatment is individualized to seizure type and response. Drug resistance is frequent in reported severe cases, but sustained seizure freedom occurred in one adolescent. No comparative ALG11-specific regimen is established. These drugs address seizures; they have not been shown to restore ALG11-dependent glycosylation.
Mechanism Target:
INHIBITS Seizures — Anti-seizure therapy can suppress clinical seizures; response varies and glycosylation repair has not been shown.
Show evidence (1 reference)
PMID:30676690 SUPPORT PRIMARY RESULT Human Clinical
"With current medication he has been seizure free for 7 years."
Documents sustained control in a different patient, without identifying the regimen.
Show evidence (2 references)
PMID:28649519 SUPPORT PRIMARY RESULT Human Clinical
"EEG showed a burst suppression pattern, which persisted despite treatment with phenobarbitone, valproic acid, levetiracetam and vigabatrin."
Documents attempted symptomatic agents and persistent disease in one child.
PMID:30676690 SUPPORT PRIMARY RESULT Human Clinical
"With current medication he has been seizure free for 7 years."
Documents sustained control in a different patient, without identifying the regimen.
Topiramate
Action: PharmacotherapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Pharmacotherapy (NCIT:C15986). NCIT:C15986 is a clinical intervention from the NCI Thesaurus. NCIT:C15986
Agent: topiramate CHEBI:63631 Chemical Entities of Biological Interest (CHEBI) Relation: this treatment uses this therapeutic agent This treatment uses topiramate (CHEBI:63631). CHEBI:63631 is a therapeutic agent from Chemical Entities of Biological Interest.
Platform: Small molecule
One published child had improved seizure frequency and EEG after topiramate, although epilepsy was never satisfactorily controlled. This uncontrolled observation supports a symptomatic option, not superiority or disease modification.
Mechanism Target:
INHIBITS Seizures — Partial symptomatic seizure reduction was reported after introduction of topiramate in one child.
Show evidence (1 reference)
PMID:28649519 SUPPORT PRIMARY RESULT Human Clinical
"After the introduction of topiramate, improvement in seizure frequency and EEG characteristics was seen."
Individual observed response; no controlled comparison.
Show evidence (2 references)
PMID:28649519 SUPPORT PRIMARY RESULT Human Clinical
"After the introduction of topiramate, improvement in seizure frequency and EEG characteristics was seen."
Individual observed response; no controlled comparison.
PMID:28649519 SUPPORT PRIMARY RESULT Human Clinical
"Epilepsy was never satisfactory controlled."
Limits the response claim in the same child.
Feeding and Nutritional Support
Action: Nutritional SupportNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Nutritional Support (NCIT:C15433). NCIT:C15433 is a clinical intervention from the NCI Thesaurus. NCIT:C15433
Assess oral feeding, growth and swallowing safety. Gastrostomy improved weight gain in one child; nasogastric feeding was required in another after silent aspiration. Route and goals depend on swallowing function and family priorities.
Mechanism Target:
BYPASSES Failure to Thrive — Enteral nutritional support can improve growth when oral intake is insufficient; one child gained weight after gastrostomy.
Show evidence (1 reference)
PMID:30676690 SUPPORT PRIMARY RESULT Human Clinical
"weight had fallen between 18–24 months to between (−3.05SD) and (−3.5SD), but had returned to 10.6 kg, (−1.57SD) by 26 months due to G-tube placement at 21 months"
Documents improved weight after gastrostomy.
Show evidence (2 references)
PMID:30676690 SUPPORT PRIMARY RESULT Human Clinical
"weight had fallen between 18–24 months to between (−3.05SD) and (−3.5SD), but had returned to 10.6 kg, (−1.57SD) by 26 months due to G-tube placement at 21 months"
Documents improved weight after gastrostomy.
PMID:30770273 SUPPORT PRIMARY RESULT Human Clinical
"A fluoroscopy swallow study showed dysfunctional and delayed swallowing with esophageal reflux and silent aspiration so he was transitioned to full nasogastric tube feedings."
Supports swallowing assessment and feeding-route adaptation.
Developmental Therapies
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
Individualized physical, occupational, communication and oral-motor support can address functional needs. The cited recommendation is historical general-CDG guidance, not evidence of a tested ALG11-specific intervention.
Show evidence (1 reference)
url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1332/ SUPPORT REVIEW SYNTHESIS Other
"Occupational therapy, physical therapy, and speech therapy should be instituted."
Historical general-CDG supportive recommendation from the retired chapter.
Hearing and Vision Support
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
Audiology and ophthalmology findings guide supportive interventions. Hearing aids were used for severe sensorineural loss in reported children; visual abnormalities include strabismus, poor tracking and occasional retinal or optic disease. The reports do not quantify hearing-aid benefit.
Show evidence (2 references)
PMID:28649519 SUPPORT PRIMARY RESULT Human Clinical
"Because of severe sensorineural hearing loss (no response at 80 dB), he received hearing aids."
Documents the intervention, without an efficacy outcome.
url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1332/ SUPPORT REVIEW SYNTHESIS Other
"Consultation with a pediatric ophthalmologist early in life is important so that potential eye abnormalities can be diagnosed"
Historical general-CDG assessment recommendation.
Palliative and Supportive Care
Action: Palliative Care, Other Than Pain and HospiceNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Palliative Care, Other Than Pain and Hospice (NCIT:C15830). NCIT:C15830 is a clinical intervention from the NCI Thesaurus. NCIT:C15830
Palliative care can support symptom management and family goals in severe progressive disease, alongside other treatments. The recommendation comes from a longitudinal ALG11 case and does not imply that every affected person has the same prognosis.
Show evidence (1 reference)
PMID:39809108 SUPPORT PRIMARY RESULT Human Clinical
"The involvement of a pediatric palliative care service is a valuable adjunct to assist with symptom management and family support for these complex progressive conditions."
Directly recommends palliative care involvement for this disorder.
Genetic Counseling and Family Testing
Action: Genetic CounselingNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Genetic Counseling (NCIT:C15240). NCIT:C15240 is a clinical intervention from the NCI Thesaurus. NCIT:C15240
Confirm parental variants and discuss autosomal recessive recurrence, testing of relatives, and reproductive options. When both parents carry the causal alleles, each pregnancy has a 25% chance of an affected child. Prenatal or preimplantation testing can be discussed once familial variants are known; counseling remains nondirective.
Show evidence (2 references)
url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1332/ SUPPORT REVIEW SYNTHESIS Other
"each sib of an affected individual has a 25% chance of being affected"
Historical autosomal recessive counseling principle.
url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1332/ SUPPORT REVIEW SYNTHESIS Other
"have been identified in the family, ... prenatal testing ... for a pregnancy at increased risk and ... preimplantation genetic testing ... disorder of N-linked glycosylation or multiple pathway are possible."
Historical family-testing guidance after identification of the causal variants.
🔬

Biochemical Markers

3
GP130 Glycosylation Status
Show evidence (2 references)
PMID:30676690 SUPPORT PRIMARY RESULT In Vitro
"Fibroblasts from the skin punch biopsy also yielded abnormally truncated GP130 isoforms on western blot"
Documents the abnormal GP130 isoform pattern in patient-derived fibroblasts.
PMID:30676690 SUPPORT PRIMARY RESULT In Vitro
"hypoglycosylation of a novel biomarker, GP130. Surprisingly, one patient presented with normal transferrin glycosylation profile"
Documents cellular hypoglycosylation despite normal serum screening in one patient; it does not estimate comparative assay sensitivity.
Serum Transferrin Isoform Profile
Show evidence (2 references)
PMID:20080937 SUPPORT PRIMARY RESULT Human Clinical
"The isoelectric focusing pattern of the patient's serum transferrin showed the partial loss of complete N-glycan side chains, which is a characteristic sign for CDG-I."
The index patient had a type I transferrin pattern with loss of complete N-glycan side chains.
PMID:30676690 SUPPORT PRIMARY RESULT Human Clinical
"Surprisingly, one patient presented with normal transferrin glycosylation profile, a feature that has not been reported previously in patients with ALG11-CDG."
A later confirmed patient had normal serum transferrin glycosylation, showing that a negative screen cannot exclude ALG11-CDG.
Coagulation Factor XI and Protein C Activity
Show evidence (1 reference)
PMID:28649519 SUPPORT PRIMARY RESULT Human Clinical
"Blood coagulation factor XI (27%; normal range for age: 38–164%), and protein C (25%; normal range for age: 37–81%) were decreased."
Direct laboratory measurements in one patient.
🔬

Diagnosis

5
Serum Transferrin Isoform Analysis
Serum transferrin glycoform analysis may show a type I pattern, but normal results do not exclude ALG11-CDG. Molecular and, when needed, cellular functional investigation can establish disease in a suggestive case despite normal screening.
Carbohydrate-Deficient Transferrin Measurement NCIT:C101016 NCI Thesaurus (NCIT)
Show evidence (2 references)
PMID:36843332 SUPPORT REVIEW SYNTHESIS Human Clinical
"In patients with a possible congenital defect of glycosylation, a screening test such as CDT analysis is suggested."
The case-report authors recommend serum screening; the other evidence documents its limitations.
PMID:30676690 SUPPORT REVIEW SYNTHESIS Human Clinical
"because any potential mutation in ALG11 could show an inconsistent transferrin glycosylation pattern, analysis of fibroblast LLO and/or a cellular glycoprotein is important to confirm pathogenicity"
The authors recommend additional cellular evaluation when transferrin is inconsistent; this is not an obligatory sequence for every molecular diagnosis.
Fibroblast Lipid-Linked Oligosaccharide Analysis
Lipid-linked oligosaccharide analysis in cultured fibroblasts can demonstrate the shortened precursors expected for ALG11 dysfunction and assist variant assessment. An improved labeling method detected three cases missed by prior routine diagnostics; this is not a formal sensitivity comparison against every modern serum or genomic test.
Diagnostic Procedure NCIT:C18020 NCI Thesaurus (NCIT)
NCIT searches for lipid-linked oligosaccharide and metabolic labeling on 2026-09-21 returned no dedicated LLO assay term; the latter returned 14-N/15-N Metabolic Labeling Quantification, which does not describe this assay. The broader Diagnostic Procedure binding is retained.
Show evidence (1 reference)
PMID:22213132 SUPPORT PRIMARY RESULT In Vitro
"Here we describe an improved metabolic labeling method that allowed the identification of three new CDG-Ip cases that were missed so far in routine diagnostics."
Documents improved detection in the reported workflow, without an estimated clinical sensitivity.
Brain Magnetic Resonance Imaging
Brain MRI assesses cortical development, myelination and tissue volume; repeat studies can distinguish delayed growth from progressive loss. Imaging can be normal, so atrophy is not required for ALG11-CDG.
Magnetic Resonance Imaging NCIT:C16809 NCI Thesaurus (NCIT)
Show evidence (1 reference)
PMID:30676690 SUPPORT PRIMARY RESULT Human Clinical
"Both MRI and CT scan of the brain were within normal limits, but the EEG was abnormal."
Shows that structural imaging can be normal.
Electroencephalography
EEG characterizes seizure type and background abnormalities. Burst suppression is documented in some severe cases but is not required for ALG11-CDG.
Electroencephalography NCIT:C38054 NCI Thesaurus (NCIT)
Show evidence (1 reference)
PMID:28649519 SUPPORT PRIMARY RESULT Human Clinical
"EEG showed a burst suppression pattern, which persisted despite treatment with phenobarbitone, valproic acid, levetiracetam and vigabatrin."
Illustrates EEG characterization in a severe case.
Molecular Genetic Testing
A molecular diagnosis relies on biallelic pathogenic or likely pathogenic ALG11 variants in an appropriate clinical context. Exome sequencing or a suitable panel can identify sequence variants; deletion analysis and segregation testing resolve missing alleles or apparent homozygosity. Uncertain variants may require functional studies and should not alone establish the diagnosis.
Genetic Testing NCIT:C15709 NCI Thesaurus (NCIT)
Show evidence (3 references)
PMID:36843332 SUPPORT PRIMARY RESULT Human Clinical
"Compound heterozygous mutations of the ALG11 gene were found by whole exome sequencing (WES) analysis."
Documents WES as the diagnostic route in a reported patient.
PMID:30676690 SUPPORT PRIMARY RESULT Human Clinical
"Subsequent ALG11 gene deletion/duplication analysis found a paternally inherited whole gene deletion of ALG11 in the patient."
Supports deletion analysis when segregation is inconsistent with apparent homozygosity.
url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1332/ SUPPORT REVIEW SYNTHESIS Other
"Variants of ... uncertain significance ... cannot be used to confirm or rule out the diagnosis."
Historical overview states the distinction between uncertain and diagnostic variants.
📈

Progression

2
Prenatal or infantile presentation
Presentation varies from fetal brain growth arrest to an apparently unremarkable pregnancy followed by infantile developmental impairment or seizures.
Show evidence (2 references)
PMID:30770273 SUPPORT PRIMARY RESULT Human Clinical
"We report an example of fetal microcephaly diagnosed at 36 weeks' gestation with a history of normal fetal biometry at 20 weeks' gestation."
Documents prenatal onset in one child.
PMID:22213132 SUPPORT PRIMARY RESULT Human Clinical
"they share a variety of clinical syndromes like an unremarkable prenatal period followed by developmental delay, psychomotor, and mental retardation, strabismus convergens and seizures occurring in the first year of life"
Describes the earlier small series; the later fetal case expands the spectrum rather than refuting these observations.
Variable childhood and adolescent course
Some severe cases develop progressive cerebral atrophy and die in childhood; other individuals survive into adolescence. The 2025 seven-year follow-up concerns the same prenatal-onset child reported in 2019. Normal structural imaging and sustained seizure control were reported in a different adolescent, so rapid degeneration is not obligatory.
Show evidence (4 references)
PMID:39809108 SUPPORT PRIMARY RESULT Human Clinical
"The objective of this report is to provide an update on the phenotype and brain magnetic resonance imaging (MRI) at age seven years for a patient initially described in early infancy with fetal brain disruption sequence."
Identifies the longitudinal follow-up, avoiding counting it as an independent case.
PMID:30676690 SUPPORT PRIMARY RESULT Human Clinical
"Our 14-year-old patient (patient 2) is the oldest reported patient to date, with all others ranging between 2 months to 8 years."
Documents adolescent survival at publication, without asserting a current oldest age.
PMID:30676690 SUPPORT PRIMARY RESULT Human Clinical
"With current medication he has been seizure free for 7 years."
Demonstrates variability in seizure trajectory.
+ 1 more reference
📊

Prevalence

1
Worldwide
Cases In Literature
Population prevalence is unknown. The 2019 review described ten previously reported patients and added two, for twelve summarized cases. Counts are publication-specific and are not converted into a population rate; later case reports and follow-up reports must not be added without checking duplicate individuals.
Show evidence (2 references)
PMID:30676690 SUPPORT REVIEW SYNTHESIS Human Clinical
"To date, only ten patients have been described with ALG11-CDG"
Ten prior cases at the time of the review.
PMID:30676690 SUPPORT PRIMARY RESULT Human Clinical
"We report two additional unrelated patients"
The report adds two individuals to those prior cases.
🔀

Differential Diagnoses

2

Conditions with similar clinical presentations that must be differentiated from ALG11-congenital disorder of glycosylation:

RFT1-congenital disorder of glycosylation
Overlapping Features RFT1-CDG can overlap with ALG11-CDG in severe developmental impairment and sensorineural hearing loss. Gene-specific molecular testing and cellular glycosylation studies distinguish the disorders; hearing loss alone does not identify either gene.
Show evidence (1 reference)
PMID:28649519 SUPPORT REVIEW SYNTHESIS Human Clinical
"Sensorineural deafness is highly unusual in other types of CDG, except RFT1-CDG"
Supports the overlapping hearing phenotype.
Mitochondrial disorders
Overlapping Features Progressive cerebral atrophy and epilepsy can resemble mitochondrial disease. This is a broad diagnostic category rather than a specific molecular alternative; biochemical findings and genomic evaluation must be interpreted together.
Show evidence (1 reference)
PMID:28649519 SUPPORT REVIEW SYNTHESIS Human Clinical
"Comparable progressive atrophy has been reported in mitochondrial disorders"
Documents the radiological differential.
🧫

Experimental Models

3
Patient-derived skin fibroblast lipid-linked oligosaccharide analysis PRIMARY_CELL_CULTURE
Cultured skin fibroblasts from affected individuals were used to characterize dolichol-linked oligosaccharides and early mannosyltransferase activity. Comparative wild-type and mutant ALG11 expression in patient fibroblasts supported causality of the index allele; the available abstract does not quantify the extent of rescue.
skin fibroblast CL:0002620 Cell Ontology (CL) Relation: this experimental model uses this cell type This experimental model uses skin fibroblast (CL:0002620). CL:0002620 is a cell type from the Cell Ontology.
Organism
human NCBITaxon:9606 NCBI Taxonomy (NCBITaxon) Relation: this experimental model is built in this organism This experimental model is built in human, annotated with Homo sapiens (NCBITaxon:9606). NCBITaxon:9606 is an organism from the NCBI Taxonomy.
Publication
PMID:20080937
Pathograph links
Lipid-Linked Oligosaccharide Assembly Arrest measures fidelity: high Directly measures the accumulating LLO species and the deficient elongation step in cells carrying the patient genotype.
Limitations: Fibroblasts reproduce the biochemical phenotype but do not establish the mechanism of selective brain, hearing or visual involvement.
Readouts
Dolichol-linked oligosaccharide species
Direction: ALTERED
Interpretation: Accumulation of Man3GlcNAc2-PP-dolichol and Man4GlcNAc2-PP-dolichol marks the exact step at which assembly stalls.
Show evidence (1 reference)
PMID:20080937 SUPPORT PRIMARY RESULT In Vitro
"Analysis of dolichol-linked oligosaccharides in patient-derived fibroblasts revealed an accumulation of Man3GlcNAc2-PP-dolichol and Man4GlcNAc2-PP-dolichol."
The measurement itself.
Show evidence (1 reference)
PMID:20080937 SUPPORT PRIMARY RESULT In Vitro
"Determination of mannosyltransferase activities of early steps of lipid-linked oligosaccharide biosynthesis in fibroblasts indicated that the patient was deficient in elongating Man3GlcNAc2-PP-dolichol."
Supports treating patient fibroblasts as informative for this node.
Protein Hypoglycosylation measures fidelity: high GP130 immunoblotting detects abnormal glycoforms in affected fibroblasts, including those with normal serum screening.
Limitations: This measures glycosylation, not cytokine signaling, and does not establish clinical diagnostic sensitivity.
Show evidence (1 reference)
PMID:30676690 SUPPORT PRIMARY RESULT In Vitro
"Fibroblasts from the skin punch biopsy also yielded abnormally truncated GP130 isoforms on western blot"
Measures the cellular biochemical consequence.
Yeast alg11 deletion strain complementation assay OTHER
A Saccharomyces cerevisiae alg11 deletion strain provided a heterologous system for comparative human wild-type and mutant allele complementation. Together with the patient-fibroblast experiments, this supported functional causality for the index allele.
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:20080937
Pathograph links
ALG11 Mannosyltransferase Deficiency measures fidelity: moderate Human allele complementation in an alg11-deficient yeast background assesses recovery of conserved glycosylation function. It supports functional impairment of the tested allele rather than providing purified-enzyme kinetics.
Limitations: Heterologous complementation does not model human brain development or determine tissue-specific residual activity requirements.
Show evidence (1 reference)
PMID:20080937 SUPPORT PRIMARY RESULT In Vitro
"using a yeast alg11 deletion strain as a heterologous expression system for hALG11 variants"
Establishes the complementation system used to verify causality.
ALG11-CDG fibroblasts treated with liposomal mannose-1-phosphate PRIMARY_CELL_CULTURE
Fibroblasts from two individuals homozygous for p.Pro311Leu or p.Thr55Ala were treated with 1 mM GLM101 for 24 hours in low-glucose culture and assessed by multiplexed proteomics and N-glycoproteomics. Some mature high-mannose glycopeptides increased, with a smaller response than in PMM2-CDG and ALG2-CDG. This is an experimental cellular intervention, not evidence of benefit in treated people.
Organism
human NCBITaxon:9606 NCBI Taxonomy (NCBITaxon) Relation: this experimental model is built in this organism This experimental model is built in human, annotated with Homo sapiens (NCBITaxon:9606). NCBITaxon:9606 is an organism from the NCBI Taxonomy.
Publication
PMID:38733638
Pathograph links
Protein Hypoglycosylation rescues fidelity: moderate observes: molecular Partial shifts toward larger high-mannose glycoforms were observed after treatment; this does not establish complete normalization of glycosylation.
Limitations: Only two ALG11 donor lines were studied. The main comparison was treated versus untreated fibroblasts; an empty-liposome pilot was described for PMM2 cells only. There was no ALG11 clinical efficacy study, no demonstration of brain delivery, and no established correction of neurological disease. Increased substrate utilization through residual enzyme activity is proposed rather than directly measured in these ALG11 cells.
Readouts
High-mannose glycopeptide abundance
Direction: ALTERED
Interpretation: Eighty-seven significantly increased high-mannose glycopeptides exceeded a 1.5-fold change and contained Man6 or higher glycans; smaller glycans often decreased.
Show evidence (1 reference)
PMID:38733638 SUPPORT PRIMARY RESULT In Vitro
"Although the change in high mannose glycans bearing peptides in ALG11-CDG was subtle, all the 87 high mannose glycopeptides with more than 1.5-fold change contained Man6 or higher glycan composition."
Direct ALG11-specific glycoproteomic result; glycopeptides are measurements, not independent patients.
Show evidence (2 references)
PMID:38733638 SUPPORT PRIMARY RESULT In Vitro
"The ALG11-deficient fibroblasts also exhibited an increased glycosylation upon GLM101 treatment, although this increase was subtle compared to PMM2-CDG and ALG2-CDG"
Documents the partial biochemical response in ALG11 cells.
+ 1 more reference
Show evidence (3 references)
PMID:38733638 SUPPORT PRIMARY RESULT In Vitro
"Finally, we included the fibroblasts of two individuals with ALG11-CDG, who had features of mild to severe developmental delay, speech delay, infantile seizures and progressive microcephaly"
Defines the two-donor experimental sample.
PMID:38733638 SUPPORT PRIMARY RESULT In Vitro
"| P7 | 10/F | ALG11 | c.932C>T/c.932C>T | p.P311L/p.P311L |"
Table1 identifies one homozygous donor genotype.
PMID:38733638 SUPPORT PRIMARY RESULT In Vitro
"| P8 | 13/F | ALG11 | c.163A>G/c.163A>G | p.T55A/p.T55A |"
Table1 identifies the second homozygous donor genotype.
{ }

Source YAML

click to show 
name: ALG11-congenital disorder of glycosylation
creation_date: '2026-08-24T21:40:00Z'
category: Mendelian
description: >-
  ALG11-CDG is an autosomal recessive disorder of protein N-glycosylation caused by biallelic ALG11 variants.
  ALG11 catalyzes addition of the fourth and fifth mannose residues to the lipid-linked oligosaccharide
  precursor on the cytosolic face of the endoplasmic reticulum. Affected fibroblasts accumulate shortened
  precursors and show glycoprotein hypoglycosylation; serum transferrin screening can nevertheless be
  normal. Reported manifestations include infantile epilepsy, developmental disability, abnormal muscle
  tone, microcephaly, hearing and visual impairment, and feeding difficulties. Prenatal brain growth arrest
  and progressive cerebral atrophy occur in severe cases, but imaging and seizure outcomes vary. Care
  is individualized and supportive.
disease_term:
  preferred_term: ALG11-congenital disorder of glycosylation
  term:
    id: MONDO:0013349
    label: ALG11-congenital disorder of glycosylation
parents:
- congenital disorder of glycosylation type I
- disorder of protein N-glycosylation
synonyms:
- ALG11-CDG
- congenital disorder of glycosylation type Ip
- CDG-Ip
- CDG1P
- carbohydrate deficient glycoprotein syndrome type Ip
inheritance:
- name: Autosomal recessive
  inheritance_term:
    preferred_term: Autosomal recessive inheritance
    term:
      id: HP:0000007
      label: Autosomal recessive inheritance
  description: >-
    Disease requires biallelic (homozygous or compound heterozygous) pathogenic ALG11 variants. Heterozygous
    carriers, including the parents of affected children, are asymptomatic.
  evidence:
  - reference: PMID:36843332
    reference_title: 'ALG11-CDG: novel variant and review of the literature.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Asparagine-dependent glycosylation 11-congenital disorders of glycosylation (ALG11-CDG) is a rare
      autosomal recessive N-glycosylation defect with multisystem involvement particularly neurological
      symptoms such as epilepsy and neuromotor developmental delay.
    explanation: States the autosomal recessive mode of inheritance for ALG11-CDG.
    quote_role: BACKGROUND
  - reference: PMID:28649519
    reference_title: 'ALG11-CDG: Three novel mutations and further characterization of the phenotype.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: The parents are carriers of these variants.
    explanation: Parental segregation in the two reported families supports recessive transmission.
  - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1332/
    reference_title: >-
      Congenital Disorders of N-Linked Glycosylation and Multiple Pathway Overview – RETIRED CHAPTER,
      FOR HISTORICAL REFERENCE ONLY - GeneReviews® - NCBI Bookshelf
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: Heterozygotes (carriers) are asymptomatic and are not at risk of developing the disorder.
    explanation: >-
      Historical GeneReviews counseling for autosomal recessive CDG; this is not a measurement of ALG11
      carrier enzyme activity.
notes: >-
  Published evidence consists mainly of small case series and individual reports. Frequencies below refer
  to the specified reported-patient samples, with missing observations retained in their denominators.
  Fetal growth arrest and later atrophy are distinct findings; the 2025 imaging report follows the same
  child described prenatally in 2019. Normal transferrin glycosylation has been reported in several affected
  individuals. The GeneReviews overview was retired in June 2026 and last substantively updated in 2017;
  it is used explicitly as historical general-CDG context alongside newer ALG11-specific primary reports.
  Most clinical manifestations have no causal edge from protein hypoglycosylation because the cited fibroblast
  and clinical observations do not establish the intervening tissue-specific mechanism. Dysphagia, reflux,
  aspiration, visual deficits, hernias and dysmorphic findings are retained as observations without assuming
  an untested common causal route. The existing tissue-level edges represent observed structural consequences,
  not a complete explanation of neurological disease. The historical GeneReviews clinical summary additionally
  describes unusual fat distribution and gastric bleeding in the index child; the available summary does
  not resolve their mechanism or population frequency. A small fibroblast study of liposomal mannose-1-phosphate
  is captured under experimental models. Its partial glycoproteomic response does not establish an ALG11
  clinical treatment or justify extrapolating the PMM2-specific clinical trial.
pathophysiology:
- name: Biallelic ALG11 Loss of Function
  biological_scale: MOLECULAR
  description: >-
    Homozygous or compound heterozygous ALG11 variants impair gene function. Missense alleles, frameshift
    and splice-site variants, and a whole-gene deletion in trans with a missense allele have been reported.
    Functional effects differ by allele.
  genes:
  - preferred_term: ALG11
    term:
      id: hgnc:32456
      label: ALG11
  evidence:
  - reference: PMID:20080937
    reference_title: >-
      A severe human metabolic disease caused by deficiency of the endoplasmatic mannosyltransferase hALG11
      leads to congenital disorder of glycosylation-Ip.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: >-
      These findings gave rise to genetic analysis of the hALG11 cDNA, in which homozygosity for mutation
      c.T257C (p.L86S) was identified.
    explanation: Identifies the homozygous index allele.
  - reference: PMID:30676690
    reference_title: 'ALG11-CDG syndrome: Expanding the phenotype.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: >-
      Subsequent ALG11 gene deletion/duplication analysis found a paternally inherited whole gene deletion
      of ALG11 in the patient.
    explanation: Documents a structural allele paired with the maternal p.Leu46Pro variant.
  downstream:
  - target: ALG11 Mannosyltransferase Deficiency
    causal_link_type: DIRECT
    description: >-
      The index allele impairs ALG11-dependent elongation; wild-type versus mutant complementation supports
      its causal effect.
    evidence:
    - reference: PMID:20080937
      reference_title: >-
        A severe human metabolic disease caused by deficiency of the endoplasmatic mannosyltransferase
        hALG11 leads to congenital disorder of glycosylation-Ip.
      supports: SUPPORT
      evidence_source: IN_VITRO
      quote_role: PRIMARY_RESULT
      snippet: >-
        Verification of the mutation as a primary cause for the genetic defect was proved by retroviral
        expression of human wild-type and mutated ALG11 cDNA in patient-derived fibroblasts as well as
        using a yeast alg11 deletion strain as a heterologous expression system for hALG11 variants.
      explanation: Functional complementation supports causality for the tested allele.
  - target: Reduced ALG11 Protein Abundance
    causal_link_type: DIRECT
    description: >-
      Loss of one gene copy can reduce abundance in the reported deletion/missense genotype; this is not
      a uniform effect of missense alleles.
    evidence:
    - reference: PMID:30676690
      reference_title: 'ALG11-CDG syndrome: Expanding the phenotype.'
      supports: SUPPORT
      evidence_source: IN_VITRO
      quote_role: PRIMARY_RESULT
      snippet: >-
        As expected, patient 2 had slightly less ALG11 protein due to the paternally inherited whole gene
        deletion (Figure 2).
      explanation: Directly reports lower protein abundance in this genotype.
- name: ALG11 Mannosyltransferase Deficiency
  biological_scale: MOLECULAR
  description: >-
    ALG11 activity is deficient at the fourth and fifth mannose-transfer steps of lipid-linked oligosaccharide
    assembly. The p.Leu86Ser index fibroblasts had impaired elongation despite unchanged measured protein
    abundance and localization. This catalytic phenotype should not be generalized to the abundance of
    every ALG11 variant.
  genes:
  - preferred_term: ALG11
    term:
      id: hgnc:32456
      label: ALG11
  molecular_functions:
  - preferred_term: GDP-Man:Man(3)GlcNAc(2)-PP-Dol alpha-1,2-mannosyltransferase activity
    term:
      id: GO:0004377
      label: GDP-Man:Man(3)GlcNAc(2)-PP-Dol alpha-1,2-mannosyltransferase activity
    modifier: DECREASED
  cellular_components:
  - preferred_term: endoplasmic reticulum
    term:
      id: GO:0005783
      label: endoplasmic reticulum
  evidence:
  - reference: PMID:20080937
    reference_title: >-
      A severe human metabolic disease caused by deficiency of the endoplasmatic mannosyltransferase hALG11
      leads to congenital disorder of glycosylation-Ip.
    supports: SUPPORT
    evidence_source: IN_VITRO
    quote_role: PRIMARY_RESULT
    snippet: >-
      Determination of mannosyltransferase activities of early steps of lipid-linked oligosaccharide biosynthesis
      in fibroblasts indicated that the patient was deficient in elongating Man3GlcNAc2-PP-dolichol.
    explanation: Direct assay of the elongation defect in index patient fibroblasts.
  - reference: PMID:20080937
    reference_title: >-
      A severe human metabolic disease caused by deficiency of the endoplasmatic mannosyltransferase hALG11
      leads to congenital disorder of glycosylation-Ip.
    supports: SUPPORT
    evidence_source: IN_VITRO
    quote_role: PRIMARY_RESULT
    snippet: >-
      Immunofluorescence examinations combined with western blotting showed no differences of intracellular
      localization or expression of ALG11 between control and patient fibroblasts, respectively, indicating
      no mislocalization or degradation of the mutated transferase.
    explanation: >-
      Preserved measured abundance and localization apply to the index allele, not all disease-associated
      alleles.
  downstream:
  - target: Lipid-Linked Oligosaccharide Assembly Arrest
    description: >-
      Reduced ALG11-dependent mannose transfer impairs precursor elongation and permits accumulation of
      shortened species; residual synthesis is not excluded.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:20080937
      reference_title: >-
        A severe human metabolic disease caused by deficiency of the endoplasmatic mannosyltransferase
        hALG11 leads to congenital disorder of glycosylation-Ip.
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: >-
        Determination of mannosyltransferase activities of early steps of lipid-linked oligosaccharide
        biosynthesis in fibroblasts indicated that the patient was deficient in elongating Man3GlcNAc2-PP-dolichol.
      explanation: Directly links the enzyme deficiency to failure of LLO elongation in patient cells.
      quote_role: PRIMARY_RESULT
- name: Reduced ALG11 Protein Abundance
  biological_scale: MOLECULAR
  description: >-
    Reduced steady-state ALG11 protein is an allele-dependent observation. It was reported in fibroblasts
    with a whole-gene deletion in trans with p.Leu46Pro. Other tested missense genotypes had normal measured
    abundance. Reduced abundance alone does not establish an altered protein-degradation rate.
  genes:
  - preferred_term: ALG11
    term:
      id: hgnc:32456
      label: ALG11
  evidence:
  - reference: PMID:30676690
    reference_title: 'ALG11-CDG syndrome: Expanding the phenotype.'
    supports: SUPPORT
    evidence_source: IN_VITRO
    quote_role: PRIMARY_RESULT
    snippet: >-
      As expected, patient 2 had slightly less ALG11 protein due to the paternally inherited whole gene
      deletion (Figure 2).
    explanation: Directly reports lower protein abundance in this genotype.
- name: Lipid-Linked Oligosaccharide Assembly Arrest
  conforms_to: congenital_disorder_of_glycosylation#ER Lipid-Linked Oligosaccharide Assembly Defect
  biological_scale: MOLECULAR
  description: >-
    Shortened Man3GlcNAc2-PP-dolichol and Man4GlcNAc2-PP-dolichol accumulate in affected fibroblasts.
    This is impaired precursor assembly rather than proof that every LLO molecule is arrested or that
    those truncated species are transferred unchanged to proteins.
  cell_types:
  - preferred_term: skin fibroblast
    term:
      id: CL:0002620
      label: skin fibroblast
  biological_processes:
  - preferred_term: dolichol-linked oligosaccharide biosynthetic process
    term:
      id: GO:0006488
      label: dolichol-linked oligosaccharide biosynthetic process
    modifier: DECREASED
  chemical_entities:
  - preferred_term: dolichol-linked oligosaccharide
    term:
      id: CHEBI:61286
      label: dolichol-linked oligosaccharide
  evidence:
  - reference: PMID:20080937
    reference_title: >-
      A severe human metabolic disease caused by deficiency of the endoplasmatic mannosyltransferase hALG11
      leads to congenital disorder of glycosylation-Ip.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Analysis of dolichol-linked oligosaccharides in patient-derived fibroblasts revealed an accumulation
      of Man3GlcNAc2-PP-dolichol and Man4GlcNAc2-PP-dolichol.
    explanation: Identifies the two LLO species that accumulate, fixing the exact step of the assembly block.
    quote_role: PRIMARY_RESULT
  - reference: PMID:22213132
    reference_title: >-
      Improved diagnostics lead to identification of three new patients with congenital disorder of glycosylation-Ip.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      who presented an accumulation of shortened dolichol-linked oligosaccharides leading to CDG-Ip (ALG11-CDG)
    explanation: Independently confirms shortened LLO accumulation as the biochemical signature of the disorder.
    quote_role: PRIMARY_RESULT
  downstream:
  - target: Protein Hypoglycosylation
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - Lipid-linked glycan donor maturation and oligosaccharyltransferase-mediated N-glycan attachment
    description: >-
      Defective precursor assembly limits protein N-glycosylation. The cited fibroblast study demonstrates
      shortened precursors and hypoglycosylated GP130 together; it does not directly measure transfer
      of a particular truncated glycan to GP130.
    evidence:
    - reference: PMID:30676690
      reference_title: 'ALG11-CDG syndrome: Expanding the phenotype.'
      supports: SUPPORT
      evidence_source: IN_VITRO
      quote_role: PRIMARY_RESULT
      snippet: >-
        Their fibroblasts synthesized truncated precursor glycan structures, consistent with ALG11-CDG,
        while also showing hypoglycosylation of a novel biomarker, GP130.
      explanation: >-
        Supports the biochemical relationship, without resolving each omitted donor-processing and transfer
        step.
      directness: INDIRECT
- name: Protein Hypoglycosylation
  conforms_to: congenital_disorder_of_glycosylation#Protein Hypoglycosylation
  biological_scale: CELLULAR
  description: >-
    Protein N-glycosylation is reduced. The index serum transferrin pattern reflected loss of complete
    N-glycan side chains, and affected fibroblasts show lower-molecular-weight GP130 glycoforms. These
    are protein- and sample-specific readouts: normal serum transferrin does not exclude a cellular defect.
    Comparative diagnostic sensitivity of GP130 versus transferrin has not been established.
  biological_processes:
  - preferred_term: protein N-linked glycosylation
    term:
      id: GO:0006487
      label: protein N-linked glycosylation
    modifier: DECREASED
  evidence:
  - reference: PMID:20080937
    reference_title: >-
      A severe human metabolic disease caused by deficiency of the endoplasmatic mannosyltransferase hALG11
      leads to congenital disorder of glycosylation-Ip.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The isoelectric focusing pattern of the patient's serum transferrin showed the partial loss of complete
      N-glycan side chains, which is a characteristic sign for CDG-I.
    explanation: Demonstrates hypoglycosylation of a serum glycoprotein in the index patient.
    quote_role: PRIMARY_RESULT
  - reference: PMID:30676690
    reference_title: 'ALG11-CDG syndrome: Expanding the phenotype.'
    supports: SUPPORT
    evidence_source: IN_VITRO
    quote_role: PRIMARY_RESULT
    snippet: >-
      Fibroblasts from the skin punch biopsy also yielded abnormally truncated GP130 isoforms on western
      blot
    explanation: Documents the cellular glycoprotein readout.
  - reference: PMID:30770273
    reference_title: Arrest of Fetal Brain Development in ALG11-Congenital Disorder of Glycosylation.
    supports: SUPPORT
    evidence_source: IN_VITRO
    quote_role: PRIMARY_RESULT
    snippet: >-
      Interestingly, serum N-glycan analysis and carbohydrate deficient transferrin were normal, but the
      novel GP130 biomarker revealed cellular hypoglycosylation, while LLO analysis was consistent with
      ALG11-CDG.
    explanation: Supports coexistence of normal serum screening and abnormal cellular glycosylation.
  downstream:
  - target: Type I Transferrin Isoform Profile
    description: >-
      Loss of complete transferrin N-glycan chains can produce a type I isoform profile, although that
      serum readout is not abnormal in every affected patient.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:20080937
      reference_title: >-
        A severe human metabolic disease caused by deficiency of the endoplasmatic mannosyltransferase
        hALG11 leads to congenital disorder of glycosylation-Ip.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: PRIMARY_RESULT
      snippet: >-
        The isoelectric focusing pattern of the patient's serum transferrin showed the partial loss of
        complete N-glycan side chains, which is a characteristic sign for CDG-I.
      explanation: Direct connection of the glycan defect with the measured serum pattern.
- name: Prenatal Arrest of Cerebral Growth
  biological_scale: TISSUE
  description: >-
    In one molecularly and biochemically characterized child, fetal brain growth arrested after normal
    mid-gestation biometry. The fetal-to-neonatal MRI interval showed absent growth rather than measured
    tissue loss. The cellular mechanism connecting ALG11 dysfunction to this developmental phenotype is
    unknown.
  locations:
  - preferred_term: brain
    term:
      id: UBERON:0000955
      label: brain
  evidence:
  - reference: PMID:30770273
    reference_title: Arrest of Fetal Brain Development in ALG11-Congenital Disorder of Glycosylation.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: >-
      During the 3.5 week interval from the fetal MRI to the postnatal brain MRI, the brain did not increase
      in size indicating an arrested growth pattern. This should be differentiated from a decrease in
      size, or atrophy, which did not occur during that same time period.
    explanation: Explicitly distinguishes developmental growth arrest from atrophy in this child.
  downstream:
  - target: Progressive Microcephaly
    description: >-
      Arrested prenatal brain growth accompanied declining relative head size in the serially imaged child.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:30770273
      reference_title: Arrest of Fetal Brain Development in ALG11-Congenital Disorder of Glycosylation.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: PRIMARY_RESULT
      snippet: >-
        This report shows the development of microcephaly in ALG11-CDG during the late second and third
        trimester
      explanation: Links prenatal growth arrest to the observed microcephaly.
- name: Progressive Loss of Brain Structures
  biological_scale: TISSUE
  description: >-
    Serial MRI has documented progressive cerebral tissue loss in several severe cases. The child with
    prenatal growth arrest later had near-complete cerebral hemispheric loss and severe cerebellar and
    brainstem volume loss at age seven. That sequence is an individual longitudinal observation, not an
    obligatory course for all ALG11-CDG; another reported adolescent had normal MRI and CT.
  locations:
  - preferred_term: brain
    term:
      id: UBERON:0000955
      label: brain
  evidence:
  - reference: PMID:39809108
    reference_title: Progressive loss of cerebral structures in ALG11-related congenital disorder of glycosylation.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      There was near complete loss of cerebral hemispheres, severe cerebellar atrophy, and decreased volume
      of the brainstem.
    explanation: Documents the extent of structural loss at age seven in a serially imaged patient.
    quote_role: PRIMARY_RESULT
  - reference: PMID:36843332
    reference_title: 'ALG11-CDG: novel variant and review of the literature.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Progressive cerebral atrophy, hypomyelination and corpus callosum hypoplasia were striking features
      in brain MRI images taken during our follow-up.
    explanation: Independently reports the same progressive atrophy with hypomyelination in a different patient.
    quote_role: PRIMARY_RESULT
  - reference: PMID:30676690
    reference_title: 'ALG11-CDG syndrome: Expanding the phenotype.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: Both MRI and CT scan of the brain were within normal limits, but the EEG was abnormal.
    explanation: >-
      Qualifies the spectrum: the 14-year-old patient did not have the same structural imaging phenotype.
  downstream:
  - target: Cerebral Atrophy
    description: Progressive loss of cerebral tissue is the structural basis of the observed cerebral atrophy.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:39809108
      reference_title: Progressive loss of cerebral structures in ALG11-related congenital disorder of glycosylation.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: PRIMARY_RESULT
      snippet: >-
        There was near complete loss of cerebral hemispheres, severe cerebellar atrophy, and decreased
        volume of the brainstem.
      explanation: Documents the corresponding tissue loss.
  - target: Cerebellar Atrophy
    description: Cerebellar volume loss manifested on later imaging in the longitudinal case.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:39809108
      reference_title: Progressive loss of cerebral structures in ALG11-related congenital disorder of glycosylation.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: PRIMARY_RESULT
      snippet: >-
        There was near complete loss of cerebral hemispheres, severe cerebellar atrophy, and decreased
        volume of the brainstem.
      explanation: Directly documents the cerebellar component.
  - target: Ventriculomegaly
    description: Ventricles enlarged secondarily to cerebral tissue loss in one serially imaged child.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:28649519
      reference_title: 'ALG11-CDG: Three novel mutations and further characterization of the phenotype.'
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: PRIMARY_RESULT
      snippet: >-
        Repeated MRI at the age of 1 year revealed a striking atrophy of white matter and cortex and secondary
        dilatation of the ventricles, with relative sparing of cerebellum and brainstem.
      explanation: Directly attributes ventricular enlargement to atrophy.
phenotypes:
- name: Seizures
  category: Neurological
  description: >-
    Epilepsy was recorded in all 12 patients summarized in the 2019 phenotype review, commonly beginning
    in infancy. Drug resistance and status epilepticus occur, but the adolescent in that report had been
    seizure-free for seven years on medication. These selected reports do not define lifetime penetrance;
    the young fetal-onset case initially had no confirmed epilepsy.
  phenotype_term:
    preferred_term: Seizure
    term:
      id: HP:0001250
      label: Seizure
  evidence:
  - reference: PMID:30676690
    reference_title: 'ALG11-CDG syndrome: Expanding the phenotype.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Intellectual disability and epilepsy are universally present, and all had visual problems, except
      our patient 1
    explanation: >-
      Describes the 12 reported patients summarized in that review; it is not a population penetrance
      estimate.
    quote_role: REVIEW_SYNTHESIS
  - reference: PMID:30676690
    reference_title: 'ALG11-CDG syndrome: Expanding the phenotype.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: With current medication he has been seizure free for 7 years.
    explanation: >-
      Documents sustained seizure control in one adolescent; the regimen is not named in this statement.
- name: Drug-Resistant Myoclonic Seizures
  category: Neurological
  description: Myoclonic seizures refractory to anti-seizure medication have been documented in ALG11-CDG.
  phenotype_term:
    preferred_term: Myoclonic seizure
    term:
      id: HP:0032794
      label: Myoclonic seizure
  evidence:
  - reference: PMID:36843332
    reference_title: 'ALG11-CDG: novel variant and review of the literature.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      A 31-month-old male patient admitted to our center with complaints of axial hypotonia, drug-resistant
      myoclonic seizures, microcephaly and deafness.
    explanation: Documents drug-resistant myoclonic seizures in an affected child.
    quote_role: PRIMARY_RESULT
- name: EEG Burst Suppression
  category: Neurological
  description: >-
    A burst-suppression EEG pattern, reported without hypsarrhythmia, is a described electrographic feature
    of the ALG11-CDG encephalopathy.
  phenotype_term:
    preferred_term: EEG with burst suppression
    term:
      id: HP:0010851
      label: EEG with burst suppression
  evidence:
  - reference: PMID:36843332
    reference_title: 'ALG11-CDG: novel variant and review of the literature.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: The electroencephalography (EEG) showed a burst-suppression pattern without hypsarrhythmia.
    explanation: Directly documents the burst-suppression pattern.
    quote_role: PRIMARY_RESULT
- name: Global Developmental Delay
  category: Neurological
  phenotype_term:
    preferred_term: Global developmental delay
    term:
      id: HP:0001263
      label: Global developmental delay
  description: >-
    Developmental disability was documented in all 12 patients in the 2019 review; many had severe psychomotor
    impairment. The evidence is from a small collection of reported cases.
  evidence:
  - reference: PMID:30676690
    reference_title: 'ALG11-CDG syndrome: Expanding the phenotype.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Both affected individuals reported here had severe psychomotor disabilities and epilepsy.
    explanation: Reports severe psychomotor disability in both newly described patients.
    quote_role: PRIMARY_RESULT
  - reference: PMID:30676690
    reference_title: 'ALG11-CDG syndrome: Expanding the phenotype.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      | 12/12 (100%) | 12/12 (100%) | 6/7 (86%), ... | 9/10 (90%) ... | 11/12 (92%) | 6/10 (60%) ... |
      4/6 (66%) ... | 4/7 (57%) ... | 10/11 (91%) ... | 7/12 (58%) |
    explanation: 'Table 2: developmental disability in 12/12 reported patients.'
- name: Axial Hypotonia
  category: Neurological
  phenotype_term:
    preferred_term: Axial hypotonia
    term:
      id: HP:0008936
      label: Axial hypotonia
  description: >-
    Axial hypotonia is common in reported children and may coexist with peripheral hypertonia. The 2019
    review found hypotonia in 11/12 patients; its adolescent patient instead had hypertonia.
  evidence:
  - reference: PMID:36843332
    reference_title: 'ALG11-CDG: novel variant and review of the literature.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      A 31-month-old male patient admitted to our center with complaints of axial hypotonia, drug-resistant
      myoclonic seizures, microcephaly and deafness.
    explanation: Documents axial hypotonia as a presenting complaint.
    quote_role: PRIMARY_RESULT
  - reference: PMID:30676690
    reference_title: 'ALG11-CDG syndrome: Expanding the phenotype.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      | 12/12 (100%) | 12/12 (100%) | 6/7 (86%), ... | 9/10 (90%) ... | 11/12 (92%) | 6/10 (60%) ... |
      4/6 (66%) ... | 4/7 (57%) ... | 10/11 (91%) ... | 7/12 (58%) |
    explanation: 'Table 2: any hypotonia in 11/12; the table does not quantify the axial subset separately.'
- name: Progressive Microcephaly
  category: Neurological
  phenotype_term:
    preferred_term: Progressive microcephaly
    term:
      id: HP:0000253
      label: Progressive microcephaly
  description: >-
    Microcephaly may develop prenatally or emerge progressively after birth; it was recorded in 9/10 evaluable
    patients in the 2019 review, with two unreported observations. The fetal-onset child had normal biometry
    at 20 weeks and marked microcephaly by 36 weeks.
  evidence:
  - reference: PMID:28649519
    reference_title: 'ALG11-CDG: Three novel mutations and further characterization of the phenotype.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: >-
      Progressive microcephaly was noted with SDS for head circumference decreasing from − 2 SDS at one
      month to − 3.2 SDS at 4 months of age.
    explanation: Direct serial head-circumference measurements in one child.
  - reference: PMID:30770273
    reference_title: Arrest of Fetal Brain Development in ALG11-Congenital Disorder of Glycosylation.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      This report shows the development of microcephaly in ALG11-CDG during the late second and third
      trimester
    explanation: >-
      Supports the specific claim that head growth falls away in utero rather than only postnatally, which
      the preceding item does not establish.
    quote_role: PRIMARY_RESULT
  - reference: PMID:30676690
    reference_title: 'ALG11-CDG syndrome: Expanding the phenotype.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      | 12/12 (100%) | 12/12 (100%) | 6/7 (86%), ... | 9/10 (90%) ... | 11/12 (92%) | 6/10 (60%) ... |
      4/6 (66%) ... | 4/7 (57%) ... | 10/11 (91%) ... | 7/12 (58%) |
    explanation: 'Table 2: any microcephaly in 9/10 evaluable patients, not a rate of progressive microcephaly.'
- name: Sensorineural Hearing Impairment
  category: Sensory
  phenotype_term:
    preferred_term: Sensorineural hearing impairment
    term:
      id: HP:0000407
      label: Sensorineural hearing impairment
  description: >-
    Sensorineural hearing loss can be severe or progressive. Deafness was recorded in 4/7 evaluable patients
    in the 2019 review, with five patients lacking the observation. RFT1-CDG is an overlapping differential;
    the source does not establish a cochlear mechanism.
  evidence:
  - reference: PMID:30676690
    reference_title: 'ALG11-CDG syndrome: Expanding the phenotype.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Sensorineural deafness has been described as a frequent feature.
    explanation: States sensorineural deafness as a frequent feature of ALG11-CDG.
    quote_role: REVIEW_SYNTHESIS
  - reference: PMID:28649519
    reference_title: 'ALG11-CDG: Three novel mutations and further characterization of the phenotype.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: >-
      On follow-up examination hearing loss had worsened (70–90 dB loss) with the involvement of the cochlea
      as well as the nerve and the brainstem.
    explanation: Documents progressive hearing loss in an individual; this is not a separate cohort.
  - reference: PMID:30676690
    reference_title: 'ALG11-CDG syndrome: Expanding the phenotype.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      | 12/12 (100%) | 12/12 (100%) | 6/7 (86%), ... | 9/10 (90%) ... | 11/12 (92%) | 6/10 (60%) ... |
      4/6 (66%) ... | 4/7 (57%) ... | 10/11 (91%) ... | 7/12 (58%) |
    explanation: 'Table 2: deafness in 4/7 with five unreported; subtype and testing varied.'
- name: Strabismus
  category: Sensory
  phenotype_term:
    preferred_term: Strabismus
    term:
      id: HP:0000486
      label: Strabismus
  description: >-
    Strabismus, including convergent forms, was among the most commonly reported eye findings in the 2019
    literature review. Its frequency within the whole disease population is unknown.
  evidence:
  - reference: PMID:30676690
    reference_title: 'ALG11-CDG syndrome: Expanding the phenotype.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Strabismus and poor visual tracking were the most common ophthalmological findings.
    explanation: Identifies strabismus as the leading ocular feature.
    quote_role: REVIEW_SYNTHESIS
- name: Cerebral Atrophy
  category: Neurological
  phenotype_term:
    preferred_term: Cerebral atrophy
    term:
      id: HP:0002059
      label: Cerebral atrophy
    clinical_course: PROGRESSIVE
  evidence:
  - reference: PMID:36843332
    reference_title: 'ALG11-CDG: novel variant and review of the literature.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Progressive cerebral atrophy, hypomyelination and corpus callosum hypoplasia were striking features
      in brain MRI images taken during our follow-up.
    explanation: Documents progressive cerebral atrophy on serial imaging.
    quote_role: PRIMARY_RESULT
- name: Cerebral Hypomyelination
  category: Neurological
  phenotype_term:
    preferred_term: Cerebral hypomyelination
    term:
      id: HP:0006808
      label: Cerebral hypomyelination
  evidence:
  - reference: PMID:36843332
    reference_title: 'ALG11-CDG: novel variant and review of the literature.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Progressive cerebral atrophy, hypomyelination and corpus callosum hypoplasia were striking features
      in brain MRI images taken during our follow-up.
    explanation: Reports hypomyelination on brain MRI.
    quote_role: PRIMARY_RESULT
- name: Cerebellar Atrophy
  category: Neurological
  phenotype_term:
    preferred_term: Cerebellar atrophy
    term:
      id: HP:0001272
      label: Cerebellar atrophy
  description: >-
    Severe cerebellar atrophy occurred at seven years in the child followed from prenatal cerebral growth
    arrest; neonatal imaging had relatively preserved posterior fossa structures. This is not a uniform
    disease sequence.
  evidence:
  - reference: PMID:39809108
    reference_title: Progressive loss of cerebral structures in ALG11-related congenital disorder of glycosylation.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      There was near complete loss of cerebral hemispheres, severe cerebellar atrophy, and decreased volume
      of the brainstem.
    explanation: Documents severe cerebellar atrophy on follow-up imaging.
    quote_role: PRIMARY_RESULT
- name: Type I Transferrin Isoform Profile
  category: Laboratory
  description: >-
    A type I pattern reflects loss of complete N-glycan chains in affected serum transferrin. It is variably
    detectable: normal screening occurred in the two 2019 reports and the subsequently diagnosed 2022
    case.
  phenotype_term:
    preferred_term: Type I transferrin isoform profile
    term:
      id: HP:0003642
      label: Type I transferrin isoform profile
  evidence:
  - reference: PMID:36843332
    reference_title: 'ALG11-CDG: novel variant and review of the literature.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      CDG type 1 pattern was detected with the examination of carbohydrate-deficient transferrin (CDT)
      by capillary zone electrophoresis.
    explanation: >-
      Documents either the type I pattern or its absence in an affected individual, consistent with variable
      expression of this laboratory phenotype.
    quote_role: PRIMARY_RESULT
  - reference: PMID:30676690
    reference_title: 'ALG11-CDG syndrome: Expanding the phenotype.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Surprisingly, one patient presented with normal transferrin glycosylation profile, a feature that
      has not been reported previously in patients with ALG11-CDG.
    explanation: >-
      Documents either the type I pattern or its absence in an affected individual, consistent with variable
      expression of this laboratory phenotype.
    quote_role: PRIMARY_RESULT
  - reference: PMID:35907674
    reference_title: >-
      A case of ALG11-congenital disorders of glycosylation diagnosed by post-mortem whole exome sequencing.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: >-
      Although CDG was clinically suspected, serum transferrin isoelectric focusing analysis appeared
      to be normal.
    explanation: An independent genetically diagnosed case with normal serum screening.
- name: Failure to Thrive
  category: Growth
  phenotype_term:
    preferred_term: Failure to thrive
    term:
      id: HP:0001508
      label: Failure to thrive
  evidence:
  - reference: PMID:28649519
    reference_title: 'ALG11-CDG: Three novel mutations and further characterization of the phenotype.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: This boy was admitted at the age of 3 months with feeding problems and failure to thrive.
    explanation: Directly documents failure to thrive, rather than inferring it from vomiting.
  description: >-
    Poor weight gain or failure to thrive has been observed, including improvement after gastrostomy in
    one child; feeding symptoms alone are not used as evidence of growth failure.
- name: Recurrent Vomiting
  category: Gastrointestinal
  phenotype_term:
    preferred_term: Vomiting
    term:
      id: HP:0002013
      label: Vomiting
    temporality: RECURRENT
  evidence:
  - reference: PMID:30676690
    reference_title: 'ALG11-CDG syndrome: Expanding the phenotype.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Poor feeding, recurrent vomiting, and instability of body temperature were also present in several
      individuals.
    explanation: Documents recurrent vomiting in several affected individuals.
    quote_role: REVIEW_SYNTHESIS
  - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1332/
    reference_title: >-
      Congenital Disorders of N-Linked Glycosylation and Multiple Pathway Overview – RETIRED CHAPTER,
      FOR HISTORICAL REFERENCE ONLY - GeneReviews® - NCBI Bookshelf
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: she had persistent vomiting and gastric bleeding and died at age two years.
    explanation: Historical ALG11-specific description of the index child, not a new independent case.
- name: Temperature Instability
  category: Autonomic
  description: >-
    Instability of body temperature was present in several reported individuals, alongside poor feeding
    and recurrent vomiting.
  phenotype_term:
    preferred_term: Temperature instability
    term:
      id: HP:0005968
      label: Temperature instability
  evidence:
  - reference: PMID:30676690
    reference_title: 'ALG11-CDG syndrome: Expanding the phenotype.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Poor feeding, recurrent vomiting, and instability of body temperature were also present in several
      individuals.
    explanation: Documents body-temperature instability in several affected individuals.
    quote_role: REVIEW_SYNTHESIS
- name: Abnormal Facial Shape
  category: Dysmorphic
  description: >-
    Reported facial differences vary between patients. Long philtrum and retrognathia are examples; some
    affected children are explicitly non-dysmorphic.
  phenotype_term:
    preferred_term: Abnormal facial shape
    term:
      id: HP:0001999
      label: Abnormal facial shape
    coarse_binding_basis: VARIABLE_SPECTRUM
  evidence:
  - reference: PMID:30676690
    reference_title: 'ALG11-CDG syndrome: Expanding the phenotype.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Dysmorphic features (such as long philtrum, retrognathia) and hypotonia were common, but not universal.
    explanation: Supports variable dysmorphism, not a numerical disease-frequency band.
    quote_role: REVIEW_SYNTHESIS
- name: Peripheral Hypertonia
  category: Neurological
  description: >-
    Increased peripheral tone may coexist with axial hypotonia. The 2019 review recorded peripheral hypertonia
    in 6/10 evaluable patients, with two unreported.
  phenotype_term:
    preferred_term: Hypertonia
    term:
      id: HP:0001276
      label: Hypertonia
  evidence:
  - reference: PMID:28649519
    reference_title: 'ALG11-CDG: Three novel mutations and further characterization of the phenotype.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: He showed axial hypotonia and peripheral hypertonia.
    explanation: Direct clinical examination.
  - reference: PMID:30676690
    reference_title: 'ALG11-CDG syndrome: Expanding the phenotype.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      | 12/12 (100%) | 12/12 (100%) | 6/7 (86%), ... | 9/10 (90%) ... | 11/12 (92%) | 6/10 (60%) ... |
      4/6 (66%) ... | 4/7 (57%) ... | 10/11 (91%) ... | 7/12 (58%) |
    explanation: 'Table 2: peripheral hypertonia in 6/10 evaluable patients.'
- name: Hyperreflexia
  category: Neurological
  description: >-
    Brisk reflexes occurred in reported children; the 2019 review recorded hyperreflexia in 4/6 evaluable
    patients, with six unreported.
  phenotype_term:
    preferred_term: Hyperreflexia
    term:
      id: HP:0001347
      label: Hyperreflexia
  evidence:
  - reference: PMID:28649519
    reference_title: 'ALG11-CDG: Three novel mutations and further characterization of the phenotype.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: Peripheral tone was increased, as were tendon reflexes.
    explanation: Directly documents increased reflexes.
  - reference: PMID:30676690
    reference_title: 'ALG11-CDG syndrome: Expanding the phenotype.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      | 12/12 (100%) | 12/12 (100%) | 6/7 (86%), ... | 9/10 (90%) ... | 11/12 (92%) | 6/10 (60%) ... |
      4/6 (66%) ... | 4/7 (57%) ... | 10/11 (91%) ... | 7/12 (58%) |
    explanation: 'Table 2: hyperreflexia in 4/6 evaluable patients.'
- name: Feeding Difficulty
  category: Gastrointestinal
  description: >-
    Feeding problems were recorded in 7/12 cases in the 2019 review. Dysphagia, reflux and aspiration
    can require tube feeding.
  phenotype_term:
    preferred_term: Feeding difficulties
    term:
      id: HP:0011968
      label: Feeding difficulties
  evidence:
  - reference: PMID:30676690
    reference_title: 'ALG11-CDG syndrome: Expanding the phenotype.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      | 12/12 (100%) | 12/12 (100%) | 6/7 (86%), ... | 9/10 (90%) ... | 11/12 (92%) | 6/10 (60%) ... |
      4/6 (66%) ... | 4/7 (57%) ... | 10/11 (91%) ... | 7/12 (58%) |
    explanation: 'Table 2: feeding problems in 7/12 reported patients.'
- name: Dysphagia
  category: Gastrointestinal
  description: Delayed and dysfunctional swallowing was demonstrated in the fetal-onset child.
  phenotype_term:
    preferred_term: Dysphagia
    term:
      id: HP:0002015
      label: Dysphagia
  evidence:
  - reference: PMID:30770273
    reference_title: Arrest of Fetal Brain Development in ALG11-Congenital Disorder of Glycosylation.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: >-
      A fluoroscopy swallow study showed dysfunctional and delayed swallowing with esophageal reflux and
      silent aspiration so he was transitioned to full nasogastric tube feedings.
    explanation: Directly documents the swallowing abnormality and consequence.
- name: Gastroesophageal Reflux
  category: Gastrointestinal
  description: >-
    Reflux has been documented with feeding difficulties, including one response to conservative care.
  phenotype_term:
    preferred_term: Gastroesophageal reflux
    term:
      id: HP:0002020
      label: Gastroesophageal reflux
  evidence:
  - reference: PMID:28649519
    reference_title: 'ALG11-CDG: Three novel mutations and further characterization of the phenotype.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: >-
      There were feeding problems with gastroesophageal reflux, which responded to conservative treatment.
    explanation: Direct clinical finding and reported response.
- name: Aspiration
  category: Respiratory
  description: >-
    Silent aspiration was documented by swallowing study in the fetal-onset child; a population frequency
    is unknown.
  phenotype_term:
    preferred_term: Aspiration
    term:
      id: HP:0002835
      label: Aspiration
  evidence:
  - reference: PMID:30770273
    reference_title: Arrest of Fetal Brain Development in ALG11-Congenital Disorder of Glycosylation.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: >-
      A fluoroscopy swallow study showed dysfunctional and delayed swallowing with esophageal reflux and
      silent aspiration so he was transitioned to full nasogastric tube feedings.
    explanation: Directly documents silent aspiration.
- name: Optic Atrophy
  category: Sensory
  description: Papillary atrophy was reported in one child alongside retinal dysfunction.
  phenotype_term:
    preferred_term: Optic atrophy
    term:
      id: HP:0000648
      label: Optic atrophy
  evidence:
  - reference: PMID:28649519
    reference_title: 'ALG11-CDG: Three novel mutations and further characterization of the phenotype.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: >-
      Ophthalmologic evaluation showed papillary atrophy and retinal dystrophy with low amplitudes on
      flash ERG.
    explanation: Direct examination and retinal electrophysiology in one child.
- name: Retinal Dystrophy
  category: Sensory
  description: Retinal dystrophy with low flash-ERG amplitudes was reported in one child.
  phenotype_term:
    preferred_term: Retinal dystrophy
    term:
      id: HP:0000556
      label: Retinal dystrophy
  evidence:
  - reference: PMID:28649519
    reference_title: 'ALG11-CDG: Three novel mutations and further characterization of the phenotype.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: >-
      Ophthalmologic evaluation showed papillary atrophy and retinal dystrophy with low amplitudes on
      flash ERG.
    explanation: Direct retinal finding in one child.
- name: Corpus Callosum Hypoplasia
  category: Neurological
  description: >-
    A thin or hypoplastic corpus callosum is reported in some patients and is distinct from complete agenesis.
  phenotype_term:
    preferred_term: Hypoplasia of the corpus callosum
    term:
      id: HP:0002079
      label: Hypoplasia of the corpus callosum
  evidence:
  - reference: PMID:36843332
    reference_title: 'ALG11-CDG: novel variant and review of the literature.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: >-
      Progressive cerebral atrophy, hypomyelination and corpus callosum hypoplasia were striking features
      in brain MRI images taken during our follow-up.
    explanation: Direct MRI observation in the reported child.
- name: Agenesis of the Corpus Callosum
  category: Neurological
  description: >-
    Complete agenesis was observed in the fetal-onset child; it is not interchangeable with postnatal
    callosal thinning.
  phenotype_term:
    preferred_term: Agenesis of corpus callosum
    term:
      id: HP:0001274
      label: Agenesis of corpus callosum
  evidence:
  - reference: PMID:30770273
    reference_title: Arrest of Fetal Brain Development in ALG11-Congenital Disorder of Glycosylation.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: >-
      Fetal magnetic resonance imaging at 36 weeks' gestational age showed severe cortical thinning with
      a simplified gyral pattern for gestational age, ventriculomegaly, and agenesis of the corpus callosum.
    explanation: Direct fetal MRI finding.
- name: Subcortical Heterotopia
  category: Neurological
  description: >-
    Anteriorly predominant subcortical heterotopias were documented in one child, suggesting a developmental
    cortical abnormality.
  phenotype_term:
    preferred_term: Gray matter heterotopia
    term:
      id: HP:0002282
      label: Gray matter heterotopia
  evidence:
  - reference: PMID:28649519
    reference_title: 'ALG11-CDG: Three novel mutations and further characterization of the phenotype.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: >-
      Brain magnetic resonance imaging (MRI) showed symmetrical anteriorly predominant subcortical heterotopias
      and a simplified gyral pattern.
    explanation: Direct MRI observation.
- name: Ventriculomegaly
  category: Neurological
  description: >-
    Ventricular enlargement has been described with fetal cortical underdevelopment or secondary to postnatal
    cerebral tissue loss.
  phenotype_term:
    preferred_term: Ventriculomegaly
    term:
      id: HP:0002119
      label: Ventriculomegaly
  evidence:
  - reference: PMID:28649519
    reference_title: 'ALG11-CDG: Three novel mutations and further characterization of the phenotype.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: >-
      Repeated MRI at the age of 1 year revealed a striking atrophy of white matter and cortex and secondary
      dilatation of the ventricles, with relative sparing of cerebellum and brainstem.
    explanation: Documents secondary ventricular enlargement.
- name: Inverted Nipples
  category: Dysmorphic
  description: Inverted nipples have been described in more than one affected child.
  phenotype_term:
    preferred_term: Inverted nipples
    term:
      id: HP:0003186
      label: Inverted nipples
  evidence:
  - reference: PMID:30676690
    reference_title: 'ALG11-CDG syndrome: Expanding the phenotype.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: She was non-dysmorphic and had inverted nipples on physical examination.
    explanation: Direct physical examination in the 2019 child.
- name: Long Philtrum
  category: Dysmorphic
  description: Long philtrum occurs within the variable facial phenotype.
  phenotype_term:
    preferred_term: Long philtrum
    term:
      id: HP:0000343
      label: Long philtrum
  evidence:
  - reference: PMID:30676690
    reference_title: 'ALG11-CDG syndrome: Expanding the phenotype.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      Dysmorphic features (such as long philtrum, retrognathia) and hypotonia were common, but not universal.
    explanation: Reviews the observed facial spectrum without a feature-specific denominator.
- name: Retrognathia
  category: Dysmorphic
  description: Retrognathia occurs within the variable facial phenotype.
  phenotype_term:
    preferred_term: Retrognathia
    term:
      id: HP:0000278
      label: Retrognathia
  evidence:
  - reference: PMID:30676690
    reference_title: 'ALG11-CDG syndrome: Expanding the phenotype.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      Dysmorphic features (such as long philtrum, retrognathia) and hypotonia were common, but not universal.
    explanation: Reviews the observed facial spectrum without a feature-specific denominator.
- name: Poor Visual Tracking
  category: Sensory
  description: >-
    Poor or absent visual tracking occurs in reported children. It is not assumed to result from the same
    mechanism as structural retinal or optic disease.
  phenotype_term:
    preferred_term: Impaired smooth pursuit
    term:
      id: HP:0007772
      label: Impaired smooth pursuit
  evidence:
  - reference: PMID:28649519
    reference_title: 'ALG11-CDG: Three novel mutations and further characterization of the phenotype.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: At 18 months, he did not follow with the eyes, and there was no consistent eye contact.
    explanation: Directly documents absent tracking.
  - reference: PMID:30676690
    reference_title: 'ALG11-CDG syndrome: Expanding the phenotype.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: Strabismus and poor visual tracking were the most common ophthalmological findings.
    explanation: Describes the reported ocular spectrum.
- name: Epileptic Spasms
  category: Neurological
  description: >-
    Spasms can occur in infancy. EEG findings vary, including modified hypsarrhythmia in one child and
    burst suppression in others.
  phenotype_term:
    preferred_term: Epileptic spasm
    term:
      id: HP:0011097
      label: Epileptic spasm
  evidence:
  - reference: PMID:28649519
    reference_title: 'ALG11-CDG: Three novel mutations and further characterization of the phenotype.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: Tonic seizures were seen with opening of the eyes and freezing, as well as infantile spasms.
    explanation: Direct seizure observation.
  - reference: PMID:30676690
    reference_title: 'ALG11-CDG syndrome: Expanding the phenotype.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: >-
      EEG was markedly abnormal due to the presence of a modified hypsarrhythmia with repeated spikes
      in temporal and central regions bilaterally and infantile spasms with jerking arm extension.
    explanation: Documents spasms with modified hypsarrhythmia, preventing a universal absence claim.
- name: Status Epilepticus
  category: Neurological
  description: >-
    Two admissions for status epilepticus at four years preceded sustained seizure control in one reported
    adolescent.
  phenotype_term:
    preferred_term: Status epilepticus
    term:
      id: HP:0002133
      label: Status epilepticus
  evidence:
  - reference: PMID:30676690
    reference_title: 'ALG11-CDG syndrome: Expanding the phenotype.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: >-
      At age of 4 years his seizures were the most severe and he was admitted twice with status epilepticus.
    explanation: Direct longitudinal clinical history.
- name: Micrognathia
  category: Dysmorphic
  description: Micrognathia was observed in one severely affected child; dysmorphism is variable.
  phenotype_term:
    preferred_term: Micrognathia
    term:
      id: HP:0000347
      label: Micrognathia
  evidence:
  - reference: PMID:28649519
    reference_title: 'ALG11-CDG: Three novel mutations and further characterization of the phenotype.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: >-
      He had micrognathia, a sloping forehead with a salmon patch, absent midpalmar creases, thick feet
      and an umbilical hernia.
    explanation: Direct physical examination.
- name: Umbilical Hernia
  category: Gastrointestinal
  description: Umbilical hernia was observed in one child; its frequency is unknown.
  phenotype_term:
    preferred_term: Umbilical hernia
    term:
      id: HP:0001537
      label: Umbilical hernia
  evidence:
  - reference: PMID:28649519
    reference_title: 'ALG11-CDG: Three novel mutations and further characterization of the phenotype.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: >-
      He had micrognathia, a sloping forehead with a salmon patch, absent midpalmar creases, thick feet
      and an umbilical hernia.
    explanation: Directly documents the hernia.
- name: Inguinal Hernia
  category: Gastrointestinal
  description: An incarcerated inguinal hernia required surgery in one reported child.
  phenotype_term:
    preferred_term: Inguinal hernia
    term:
      id: HP:0000023
      label: Inguinal hernia
  evidence:
  - reference: PMID:28649519
    reference_title: 'ALG11-CDG: Three novel mutations and further characterization of the phenotype.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: An incarcerated inguinal hernia was surgically corrected at age 5 months.
    explanation: Individual clinical finding and intervention.
biochemical:
- name: GP130 Glycosylation Status
  notes: >-
    Affected fibroblasts can show lower-molecular-weight GP130 glycoforms, including in individuals with
    normal serum transferrin. This is a research-laboratory cellular readout, not an established replacement
    screening test or proof of impaired GP130 cytokine signaling.
  evidence:
  - reference: PMID:30676690
    reference_title: 'ALG11-CDG syndrome: Expanding the phenotype.'
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Fibroblasts from the skin punch biopsy also yielded abnormally truncated GP130 isoforms on western
      blot
    explanation: Documents the abnormal GP130 isoform pattern in patient-derived fibroblasts.
    quote_role: PRIMARY_RESULT
  - reference: PMID:30676690
    reference_title: 'ALG11-CDG syndrome: Expanding the phenotype.'
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      hypoglycosylation of a novel biomarker, GP130. Surprisingly, one patient presented with normal transferrin
      glycosylation profile
    explanation: >-
      Documents cellular hypoglycosylation despite normal serum screening in one patient; it does not
      estimate comparative assay sensitivity.
    quote_role: PRIMARY_RESULT
- name: Serum Transferrin Isoform Profile
  notes: >-
    Isoelectric focusing, capillary zone electrophoresis or mass spectrometry of serum transferrin typically
    shows the type I CDG pattern of partially lost N-glycan side chains. It is the standard first-line
    screen and can be normal in a confirmed patient, so a negative result does not exclude the diagnosis.
  evidence:
  - reference: PMID:20080937
    reference_title: >-
      A severe human metabolic disease caused by deficiency of the endoplasmatic mannosyltransferase hALG11
      leads to congenital disorder of glycosylation-Ip.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The isoelectric focusing pattern of the patient's serum transferrin showed the partial loss of complete
      N-glycan side chains, which is a characteristic sign for CDG-I.
    explanation: The index patient had a type I transferrin pattern with loss of complete N-glycan side chains.
    quote_role: PRIMARY_RESULT
  - reference: PMID:30676690
    reference_title: 'ALG11-CDG syndrome: Expanding the phenotype.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Surprisingly, one patient presented with normal transferrin glycosylation profile, a feature that
      has not been reported previously in patients with ALG11-CDG.
    explanation: A later confirmed patient had normal serum transferrin glycosylation, showing that a negative screen cannot exclude ALG11-CDG.
    quote_role: PRIMARY_RESULT
- name: Coagulation Factor XI and Protein C Activity
  notes: >-
    One child had reduced factor XI (27%, age reference 38–164%) and protein C (25%, reference 37–81%).
    These are individual findings; another reported child had normal factor XI, protein C and antithrombin.
  evidence:
  - reference: PMID:28649519
    reference_title: 'ALG11-CDG: Three novel mutations and further characterization of the phenotype.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: >-
      Blood coagulation factor XI (27%; normal range for age: 38–164%), and protein C (25%; normal range
      for age: 37–81%) were decreased.
    explanation: Direct laboratory measurements in one patient.
genetic:
- name: ALG11
  gene_term:
    preferred_term: ALG11
    term:
      id: hgnc:32456
      label: ALG11
  association: Biallelic loss-of-function variants
  features: >-
    Reported ALG11 alleles include missense, frameshift and splice-site variants and a whole-gene deletion.
    The index variant was homozygous c.257T>C (p.Leu86Ser). The 2019 deletion/p.Leu46Pro genotype illustrates
    how a deletion can make a sequence variant appear homozygous. Homozygous c.953A>C (p.Gln318Pro) recurred
    in three unrelated Turkish families reported in 2025; recurrence alone does not establish a founder
    effect. No robust genotype–phenotype prediction follows from the small series.
  relationship_type: CAUSATIVE
  evidence:
  - reference: PMID:20080937
    reference_title: >-
      A severe human metabolic disease caused by deficiency of the endoplasmatic mannosyltransferase hALG11
      leads to congenital disorder of glycosylation-Ip.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Verification of the mutation as a primary cause for the genetic defect was proved by retroviral
      expression of human wild-type and mutated ALG11 cDNA in patient-derived fibroblasts as well as using
      a yeast alg11 deletion strain as a heterologous expression system for hALG11 variants.
    explanation: >-
      Functional rescue and heterologous complementation establish the ALG11 variant as causal rather
      than merely associated.
    quote_role: PRIMARY_RESULT
  - reference: PMID:22213132
    reference_title: >-
      Improved diagnostics lead to identification of three new patients with congenital disorder of glycosylation-Ip.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Although all CDG-Ip patients carry different mutations in the ALG11 gene, they share a variety of
      clinical syndromes
    explanation: >-
      Establishes allelic heterogeneity with a convergent clinical phenotype across independently ascertained
      patients.
    quote_role: PRIMARY_RESULT
  - reference: PMID:30676690
    reference_title: 'ALG11-CDG syndrome: Expanding the phenotype.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: >-
      Though the mother was found to be heterozygous for the same mutation, the father did not have this
      mutation. Subsequent ALG11 gene deletion/duplication analysis found a paternally inherited whole
      gene deletion of ALG11 in the patient.
    explanation: Explains the apparently homozygous sequence result.
  - reference: PMID:40423864
    reference_title: >-
      A recurrent c.953A>C (p. Gln318Pro) variant in ALG11 causing congenital disorder of glycosylation
      in Turkish population.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: >-
      WES analysis revealed a homozygous NM_001004127.3: c.953A > C (p. Gln318Pro) missense variant in
      the ALG11 gene in all three patients.
    explanation: Documents recurrence in three unrelated Turkish families; no founder haplotype is demonstrated.
  - reference: PMID:39260222
    reference_title: Identification of two novel variants in ALG11 causing congenital disorder of glycosylation.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: >-
      Trio WES unveiled novel compound heterozygous variants: c.1307G>T (p.G436V) and c.1403G>A (p.R468H)
      within exon 4 of the ALG11 gene, inherited from the father and mother, respectively.
    explanation: Documents the reported segregating pair; functional interpretation remains assay-specific.
  notes: >-
    The reviewed reports do not establish complete penetrance through systematic assessment of all biallelic
    carriers; no penetrance estimate is assigned.
progression:
- phase: Prenatal or infantile presentation
  notes: >-
    Presentation varies from fetal brain growth arrest to an apparently unremarkable pregnancy followed
    by infantile developmental impairment or seizures.
  evidence:
  - reference: PMID:30770273
    reference_title: Arrest of Fetal Brain Development in ALG11-Congenital Disorder of Glycosylation.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: >-
      We report an example of fetal microcephaly diagnosed at 36 weeks' gestation with a history of normal
      fetal biometry at 20 weeks' gestation.
    explanation: Documents prenatal onset in one child.
  - reference: PMID:22213132
    reference_title: >-
      Improved diagnostics lead to identification of three new patients with congenital disorder of glycosylation-Ip.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: >-
      they share a variety of clinical syndromes like an unremarkable prenatal period followed by developmental
      delay, psychomotor, and mental retardation, strabismus convergens and seizures occurring in the
      first year of life
    explanation: >-
      Describes the earlier small series; the later fetal case expands the spectrum rather than refuting
      these observations.
- phase: Variable childhood and adolescent course
  notes: >-
    Some severe cases develop progressive cerebral atrophy and die in childhood; other individuals survive
    into adolescence. The 2025 seven-year follow-up concerns the same prenatal-onset child reported in
    2019. Normal structural imaging and sustained seizure control were reported in a different adolescent,
    so rapid degeneration is not obligatory.
  evidence:
  - reference: PMID:39809108
    reference_title: Progressive loss of cerebral structures in ALG11-related congenital disorder of glycosylation.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: >-
      The objective of this report is to provide an update on the phenotype and brain magnetic resonance
      imaging (MRI) at age seven years for a patient initially described in early infancy with fetal brain
      disruption sequence.
    explanation: Identifies the longitudinal follow-up, avoiding counting it as an independent case.
  - reference: PMID:30676690
    reference_title: 'ALG11-CDG syndrome: Expanding the phenotype.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: >-
      Our 14-year-old patient (patient 2) is the oldest reported patient to date, with all others ranging
      between 2 months to 8 years.
    explanation: Documents adolescent survival at publication, without asserting a current oldest age.
  - reference: PMID:30676690
    reference_title: 'ALG11-CDG syndrome: Expanding the phenotype.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: With current medication he has been seizure free for 7 years.
    explanation: Demonstrates variability in seizure trajectory.
  - reference: PMID:28649519
    reference_title: 'ALG11-CDG: Three novel mutations and further characterization of the phenotype.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: He died at 4 months due to respiratory insufficiency secondary to epilepsy.
    explanation: Documents a severe early outcome; this is not a survival probability.
prevalence:
- population: Worldwide
  measure_type: CASES_IN_LITERATURE
  notes: >-
    Population prevalence is unknown. The 2019 review described ten previously reported patients and added
    two, for twelve summarized cases. Counts are publication-specific and are not converted into a population
    rate; later case reports and follow-up reports must not be added without checking duplicate individuals.
  evidence:
  - reference: PMID:30676690
    reference_title: 'ALG11-CDG syndrome: Expanding the phenotype.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: To date, only ten patients have been described with ALG11-CDG
    explanation: Ten prior cases at the time of the review.
  - reference: PMID:30676690
    reference_title: 'ALG11-CDG syndrome: Expanding the phenotype.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: We report two additional unrelated patients
    explanation: The report adds two individuals to those prior cases.
diagnosis:
- name: Serum Transferrin Isoform Analysis
  description: >-
    Serum transferrin glycoform analysis may show a type I pattern, but normal results do not exclude
    ALG11-CDG. Molecular and, when needed, cellular functional investigation can establish disease in
    a suggestive case despite normal screening.
  diagnosis_term:
    preferred_term: Carbohydrate-Deficient Transferrin Measurement
    term:
      id: NCIT:C101016
      label: Carbohydrate-Deficient Transferrin Measurement
  evidence:
  - reference: PMID:36843332
    reference_title: 'ALG11-CDG: novel variant and review of the literature.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      In patients with a possible congenital defect of glycosylation, a screening test such as CDT analysis
      is suggested.
    explanation: >-
      The case-report authors recommend serum screening; the other evidence documents its limitations.
    quote_role: REVIEW_SYNTHESIS
  - reference: PMID:30676690
    reference_title: 'ALG11-CDG syndrome: Expanding the phenotype.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      because any potential mutation in ALG11 could show an inconsistent transferrin glycosylation pattern,
      analysis of fibroblast LLO and/or a cellular glycoprotein is important to confirm pathogenicity
    explanation: >-
      The authors recommend additional cellular evaluation when transferrin is inconsistent; this is not
      an obligatory sequence for every molecular diagnosis.
    quote_role: REVIEW_SYNTHESIS
- name: Fibroblast Lipid-Linked Oligosaccharide Analysis
  description: >-
    Lipid-linked oligosaccharide analysis in cultured fibroblasts can demonstrate the shortened precursors
    expected for ALG11 dysfunction and assist variant assessment. An improved labeling method detected
    three cases missed by prior routine diagnostics; this is not a formal sensitivity comparison against
    every modern serum or genomic test.
  diagnosis_term:
    preferred_term: Diagnostic Procedure
    term:
      id: NCIT:C18020
      label: Diagnostic Procedure
  evidence:
  - reference: PMID:22213132
    reference_title: >-
      Improved diagnostics lead to identification of three new patients with congenital disorder of glycosylation-Ip.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      Here we describe an improved metabolic labeling method that allowed the identification of three
      new CDG-Ip cases that were missed so far in routine diagnostics.
    explanation: >-
      Documents improved detection in the reported workflow, without an estimated clinical sensitivity.
    quote_role: PRIMARY_RESULT
  notes: >-
    NCIT searches for lipid-linked oligosaccharide and metabolic labeling on 2026-09-21 returned no dedicated
    LLO assay term; the latter returned 14-N/15-N Metabolic Labeling Quantification, which does not describe
    this assay. The broader Diagnostic Procedure binding is retained.
- name: Brain Magnetic Resonance Imaging
  description: >-
    Brain MRI assesses cortical development, myelination and tissue volume; repeat studies can distinguish
    delayed growth from progressive loss. Imaging can be normal, so atrophy is not required for ALG11-CDG.
  evidence:
  - reference: PMID:30676690
    reference_title: 'ALG11-CDG syndrome: Expanding the phenotype.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: Both MRI and CT scan of the brain were within normal limits, but the EEG was abnormal.
    explanation: Shows that structural imaging can be normal.
  diagnosis_term:
    preferred_term: Magnetic Resonance Imaging
    term:
      id: NCIT:C16809
      label: Magnetic Resonance Imaging
- name: Electroencephalography
  description: >-
    EEG characterizes seizure type and background abnormalities. Burst suppression is documented in some
    severe cases but is not required for ALG11-CDG.
  evidence:
  - reference: PMID:28649519
    reference_title: 'ALG11-CDG: Three novel mutations and further characterization of the phenotype.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: >-
      EEG showed a burst suppression pattern, which persisted despite treatment with phenobarbitone, valproic
      acid, levetiracetam and vigabatrin.
    explanation: Illustrates EEG characterization in a severe case.
  diagnosis_term:
    preferred_term: Electroencephalography
    term:
      id: NCIT:C38054
      label: Electroencephalography
- name: Molecular Genetic Testing
  description: >-
    A molecular diagnosis relies on biallelic pathogenic or likely pathogenic ALG11 variants in an appropriate
    clinical context. Exome sequencing or a suitable panel can identify sequence variants; deletion analysis
    and segregation testing resolve missing alleles or apparent homozygosity. Uncertain variants may require
    functional studies and should not alone establish the diagnosis.
  diagnosis_term:
    preferred_term: Genetic Testing
    term:
      id: NCIT:C15709
      label: Genetic Testing
  evidence:
  - reference: PMID:36843332
    reference_title: 'ALG11-CDG: novel variant and review of the literature.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Compound heterozygous mutations of the ALG11 gene were found by whole exome sequencing (WES) analysis.
    explanation: Documents WES as the diagnostic route in a reported patient.
    quote_role: PRIMARY_RESULT
  - reference: PMID:30676690
    reference_title: 'ALG11-CDG syndrome: Expanding the phenotype.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: >-
      Subsequent ALG11 gene deletion/duplication analysis found a paternally inherited whole gene deletion
      of ALG11 in the patient.
    explanation: Supports deletion analysis when segregation is inconsistent with apparent homozygosity.
  - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1332/
    reference_title: >-
      Congenital Disorders of N-Linked Glycosylation and Multiple Pathway Overview – RETIRED CHAPTER,
      FOR HISTORICAL REFERENCE ONLY - GeneReviews® - NCBI Bookshelf
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: Variants of ... uncertain significance ... cannot be used to confirm or rule out the diagnosis.
    explanation: Historical overview states the distinction between uncertain and diagnostic variants.
treatments:
- name: Anti-Seizure Pharmacotherapy
  description: >-
    Treatment is individualized to seizure type and response. Drug resistance is frequent in reported
    severe cases, but sustained seizure freedom occurred in one adolescent. No comparative ALG11-specific
    regimen is established. These drugs address seizures; they have not been shown to restore ALG11-dependent
    glycosylation.
  treatment_term:
    preferred_term: Anticonvulsant Therapy
    term:
      id: NCIT:C64172
      label: Anticonvulsant Therapy
  evidence:
  - reference: PMID:28649519
    reference_title: 'ALG11-CDG: Three novel mutations and further characterization of the phenotype.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: >-
      EEG showed a burst suppression pattern, which persisted despite treatment with phenobarbitone, valproic
      acid, levetiracetam and vigabatrin.
    explanation: Documents attempted symptomatic agents and persistent disease in one child.
  - reference: PMID:30676690
    reference_title: 'ALG11-CDG syndrome: Expanding the phenotype.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: With current medication he has been seizure free for 7 years.
    explanation: Documents sustained control in a different patient, without identifying the regimen.
  therapeutic_modality: SMALL_MOLECULE
  target_mechanisms:
  - target: Seizures
    treatment_effect: INHIBITS
    description: >-
      Anti-seizure therapy can suppress clinical seizures; response varies and glycosylation repair has
      not been shown.
    evidence:
    - reference: PMID:30676690
      reference_title: 'ALG11-CDG syndrome: Expanding the phenotype.'
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: PRIMARY_RESULT
      snippet: With current medication he has been seizure free for 7 years.
      explanation: Documents sustained control in a different patient, without identifying the regimen.
- name: Topiramate
  description: >-
    One published child had improved seizure frequency and EEG after topiramate, although epilepsy was
    never satisfactorily controlled. This uncontrolled observation supports a symptomatic option, not
    superiority or disease modification.
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: topiramate
      term:
        id: CHEBI:63631
        label: topiramate
  evidence:
  - reference: PMID:28649519
    reference_title: 'ALG11-CDG: Three novel mutations and further characterization of the phenotype.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: >-
      After the introduction of topiramate, improvement in seizure frequency and EEG characteristics was
      seen.
    explanation: Individual observed response; no controlled comparison.
  - reference: PMID:28649519
    reference_title: 'ALG11-CDG: Three novel mutations and further characterization of the phenotype.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: Epilepsy was never satisfactory controlled.
    explanation: Limits the response claim in the same child.
  therapeutic_modality: SMALL_MOLECULE
  target_mechanisms:
  - target: Seizures
    treatment_effect: INHIBITS
    description: >-
      Partial symptomatic seizure reduction was reported after introduction of topiramate in one child.
    evidence:
    - reference: PMID:28649519
      reference_title: 'ALG11-CDG: Three novel mutations and further characterization of the phenotype.'
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: PRIMARY_RESULT
      snippet: >-
        After the introduction of topiramate, improvement in seizure frequency and EEG characteristics
        was seen.
      explanation: Individual observed response; no controlled comparison.
- name: Feeding and Nutritional Support
  description: >-
    Assess oral feeding, growth and swallowing safety. Gastrostomy improved weight gain in one child;
    nasogastric feeding was required in another after silent aspiration. Route and goals depend on swallowing
    function and family priorities.
  treatment_term:
    preferred_term: Nutritional Support
    term:
      id: NCIT:C15433
      label: Nutritional Support
  evidence:
  - reference: PMID:30676690
    reference_title: 'ALG11-CDG syndrome: Expanding the phenotype.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: >-
      weight had fallen between 18–24 months to between (−3.05SD) and (−3.5SD), but had returned to 10.6
      kg, (−1.57SD) by 26 months due to G-tube placement at 21 months
    explanation: Documents improved weight after gastrostomy.
  - reference: PMID:30770273
    reference_title: Arrest of Fetal Brain Development in ALG11-Congenital Disorder of Glycosylation.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: >-
      A fluoroscopy swallow study showed dysfunctional and delayed swallowing with esophageal reflux and
      silent aspiration so he was transitioned to full nasogastric tube feedings.
    explanation: Supports swallowing assessment and feeding-route adaptation.
  target_mechanisms:
  - target: Failure to Thrive
    treatment_effect: BYPASSES
    description: >-
      Enteral nutritional support can improve growth when oral intake is insufficient; one child gained
      weight after gastrostomy.
    evidence:
    - reference: PMID:30676690
      reference_title: 'ALG11-CDG syndrome: Expanding the phenotype.'
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      quote_role: PRIMARY_RESULT
      snippet: >-
        weight had fallen between 18–24 months to between (−3.05SD) and (−3.5SD), but had returned to
        10.6 kg, (−1.57SD) by 26 months due to G-tube placement at 21 months
      explanation: Documents improved weight after gastrostomy.
- name: Developmental Therapies
  description: >-
    Individualized physical, occupational, communication and oral-motor support can address functional
    needs. The cited recommendation is historical general-CDG guidance, not evidence of a tested ALG11-specific
    intervention.
  treatment_term:
    preferred_term: Supportive Care
    term:
      id: NCIT:C15747
      label: Supportive Care
  evidence:
  - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1332/
    reference_title: >-
      Congenital Disorders of N-Linked Glycosylation and Multiple Pathway Overview – RETIRED CHAPTER,
      FOR HISTORICAL REFERENCE ONLY - GeneReviews® - NCBI Bookshelf
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: Occupational therapy, physical therapy, and speech therapy should be instituted.
    explanation: Historical general-CDG supportive recommendation from the retired chapter.
- name: Hearing and Vision Support
  description: >-
    Audiology and ophthalmology findings guide supportive interventions. Hearing aids were used for severe
    sensorineural loss in reported children; visual abnormalities include strabismus, poor tracking and
    occasional retinal or optic disease. The reports do not quantify hearing-aid benefit.
  treatment_term:
    preferred_term: Supportive Care
    term:
      id: NCIT:C15747
      label: Supportive Care
  evidence:
  - reference: PMID:28649519
    reference_title: 'ALG11-CDG: Three novel mutations and further characterization of the phenotype.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: PRIMARY_RESULT
    snippet: Because of severe sensorineural hearing loss (no response at 80 dB), he received hearing aids.
    explanation: Documents the intervention, without an efficacy outcome.
  - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1332/
    reference_title: >-
      Congenital Disorders of N-Linked Glycosylation and Multiple Pathway Overview – RETIRED CHAPTER,
      FOR HISTORICAL REFERENCE ONLY - GeneReviews® - NCBI Bookshelf
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      Consultation with a pediatric ophthalmologist early in life is important so that potential eye abnormalities
      can be diagnosed
    explanation: Historical general-CDG assessment recommendation.
- name: Palliative and Supportive Care
  description: >-
    Palliative care can support symptom management and family goals in severe progressive disease, alongside
    other treatments. The recommendation comes from a longitudinal ALG11 case and does not imply that
    every affected person has the same prognosis.
  treatment_term:
    preferred_term: Palliative Care, Other Than Pain and Hospice
    term:
      id: NCIT:C15830
      label: Palliative Care, Other Than Pain and Hospice
  evidence:
  - reference: PMID:39809108
    reference_title: Progressive loss of cerebral structures in ALG11-related congenital disorder of glycosylation.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The involvement of a pediatric palliative care service is a valuable adjunct to assist with symptom
      management and family support for these complex progressive conditions.
    explanation: Directly recommends palliative care involvement for this disorder.
    quote_role: PRIMARY_RESULT
- name: Genetic Counseling and Family Testing
  description: >-
    Confirm parental variants and discuss autosomal recessive recurrence, testing of relatives, and reproductive
    options. When both parents carry the causal alleles, each pregnancy has a 25% chance of an affected
    child. Prenatal or preimplantation testing can be discussed once familial variants are known; counseling
    remains nondirective.
  treatment_term:
    preferred_term: Genetic Counseling
    term:
      id: NCIT:C15240
      label: Genetic Counseling
  evidence:
  - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1332/
    reference_title: >-
      Congenital Disorders of N-Linked Glycosylation and Multiple Pathway Overview – RETIRED CHAPTER,
      FOR HISTORICAL REFERENCE ONLY - GeneReviews® - NCBI Bookshelf
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: each sib of an affected individual has a 25% chance of being affected
    explanation: Historical autosomal recessive counseling principle.
  - reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1332/
    reference_title: >-
      Congenital Disorders of N-Linked Glycosylation and Multiple Pathway Overview – RETIRED CHAPTER,
      FOR HISTORICAL REFERENCE ONLY - GeneReviews® - NCBI Bookshelf
    supports: SUPPORT
    evidence_source: OTHER
    quote_role: REVIEW_SYNTHESIS
    snippet: >-
      have been identified in the family, ... prenatal testing ... for a pregnancy at increased risk and
      ... preimplantation genetic testing ... disorder of N-linked glycosylation or multiple pathway are
      possible.
    explanation: Historical family-testing guidance after identification of the causal variants.
experimental_models:
- name: Patient-derived skin fibroblast lipid-linked oligosaccharide analysis
  experimental_model_type: PRIMARY_CELL_CULTURE
  description: >-
    Cultured skin fibroblasts from affected individuals were used to characterize dolichol-linked oligosaccharides
    and early mannosyltransferase activity. Comparative wild-type and mutant ALG11 expression in patient
    fibroblasts supported causality of the index allele; the available abstract does not quantify the
    extent of rescue.
  organism:
    preferred_term: human
    term:
      id: NCBITaxon:9606
      label: Homo sapiens
  cell_types:
  - preferred_term: skin fibroblast
    term:
      id: CL:0002620
      label: skin fibroblast
  publication: PMID:20080937
  modeled_mechanisms:
  - target: Lipid-Linked Oligosaccharide Assembly Arrest
    relationship: MEASURES
    fidelity: HIGH
    description: >-
      Directly measures the accumulating LLO species and the deficient elongation step in cells carrying
      the patient genotype.
    limitations: >-
      Fibroblasts reproduce the biochemical phenotype but do not establish the mechanism of selective
      brain, hearing or visual involvement.
    readouts:
    - name: Dolichol-linked oligosaccharide species
      target: Lipid-Linked Oligosaccharide Assembly Arrest
      direction: ALTERED
      interpretation: >-
        Accumulation of Man3GlcNAc2-PP-dolichol and Man4GlcNAc2-PP-dolichol marks the exact step at which
        assembly stalls.
      evidence:
      - reference: PMID:20080937
        reference_title: >-
          A severe human metabolic disease caused by deficiency of the endoplasmatic mannosyltransferase
          hALG11 leads to congenital disorder of glycosylation-Ip.
        supports: SUPPORT
        evidence_source: IN_VITRO
        snippet: >-
          Analysis of dolichol-linked oligosaccharides in patient-derived fibroblasts revealed an accumulation
          of Man3GlcNAc2-PP-dolichol and Man4GlcNAc2-PP-dolichol.
        explanation: The measurement itself.
        quote_role: PRIMARY_RESULT
    evidence:
    - reference: PMID:20080937
      reference_title: >-
        A severe human metabolic disease caused by deficiency of the endoplasmatic mannosyltransferase
        hALG11 leads to congenital disorder of glycosylation-Ip.
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: >-
        Determination of mannosyltransferase activities of early steps of lipid-linked oligosaccharide
        biosynthesis in fibroblasts indicated that the patient was deficient in elongating Man3GlcNAc2-PP-dolichol.
      explanation: Supports treating patient fibroblasts as informative for this node.
      quote_role: PRIMARY_RESULT
  - target: Protein Hypoglycosylation
    relationship: MEASURES
    fidelity: HIGH
    description: >-
      GP130 immunoblotting detects abnormal glycoforms in affected fibroblasts, including those with normal
      serum screening.
    limitations: >-
      This measures glycosylation, not cytokine signaling, and does not establish clinical diagnostic
      sensitivity.
    evidence:
    - reference: PMID:30676690
      reference_title: 'ALG11-CDG syndrome: Expanding the phenotype.'
      supports: SUPPORT
      evidence_source: IN_VITRO
      quote_role: PRIMARY_RESULT
      snippet: >-
        Fibroblasts from the skin punch biopsy also yielded abnormally truncated GP130 isoforms on western
        blot
      explanation: Measures the cellular biochemical consequence.
- name: Yeast alg11 deletion strain complementation assay
  experimental_model_type: OTHER
  description: >-
    A Saccharomyces cerevisiae alg11 deletion strain provided a heterologous system for comparative human
    wild-type and mutant allele complementation. Together with the patient-fibroblast experiments, this
    supported functional causality for the index allele.
  organism:
    preferred_term: baker's yeast
    term:
      id: NCBITaxon:4932
      label: Saccharomyces cerevisiae
  publication: PMID:20080937
  modeled_mechanisms:
  - target: ALG11 Mannosyltransferase Deficiency
    relationship: MEASURES
    fidelity: MODERATE
    description: >-
      Human allele complementation in an alg11-deficient yeast background assesses recovery of conserved
      glycosylation function. It supports functional impairment of the tested allele rather than providing
      purified-enzyme kinetics.
    limitations: >-
      Heterologous complementation does not model human brain development or determine tissue-specific
      residual activity requirements.
    evidence:
    - reference: PMID:20080937
      reference_title: >-
        A severe human metabolic disease caused by deficiency of the endoplasmatic mannosyltransferase
        hALG11 leads to congenital disorder of glycosylation-Ip.
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: using a yeast alg11 deletion strain as a heterologous expression system for hALG11 variants
      explanation: Establishes the complementation system used to verify causality.
      quote_role: PRIMARY_RESULT
- name: ALG11-CDG fibroblasts treated with liposomal mannose-1-phosphate
  experimental_model_type: PRIMARY_CELL_CULTURE
  description: >-
    Fibroblasts from two individuals homozygous for p.Pro311Leu or p.Thr55Ala were treated with 1 mM GLM101
    for 24 hours in low-glucose culture and assessed by multiplexed proteomics and N-glycoproteomics.
    Some mature high-mannose glycopeptides increased, with a smaller response than in PMM2-CDG and ALG2-CDG.
    This is an experimental cellular intervention, not evidence of benefit in treated people.
  publication: PMID:38733638
  organism:
    preferred_term: human
    term:
      id: NCBITaxon:9606
      label: Homo sapiens
  modeled_mechanisms:
  - target: Protein Hypoglycosylation
    relationship: RESCUES
    fidelity: MODERATE
    model_scale: MOLECULAR
    description: >-
      Partial shifts toward larger high-mannose glycoforms were observed after treatment; this does not
      establish complete normalization of glycosylation.
    limitations: >-
      Only two ALG11 donor lines were studied. The main comparison was treated versus untreated fibroblasts;
      an empty-liposome pilot was described for PMM2 cells only. There was no ALG11 clinical efficacy
      study, no demonstration of brain delivery, and no established correction of neurological disease.
      Increased substrate utilization through residual enzyme activity is proposed rather than directly
      measured in these ALG11 cells.
    readouts:
    - name: High-mannose glycopeptide abundance
      target: Protein Hypoglycosylation
      direction: ALTERED
      interpretation: >-
        Eighty-seven significantly increased high-mannose glycopeptides exceeded a 1.5-fold change and
        contained Man6 or higher glycans; smaller glycans often decreased.
      evidence:
      - reference: PMID:38733638
        reference_title: >-
          Liposome-encapsulated mannose-1-phosphate therapy improves global N-glycosylation in different
          congenital disorders of glycosylation.
        supports: SUPPORT
        evidence_source: IN_VITRO
        quote_role: PRIMARY_RESULT
        snippet: >-
          Although the change in high mannose glycans bearing peptides in ALG11-CDG was subtle, all the
          87 high mannose glycopeptides with more than 1.5-fold change contained Man6 or higher glycan
          composition.
        explanation: >-
          Direct ALG11-specific glycoproteomic result; glycopeptides are measurements, not independent
          patients.
    evidence:
    - reference: PMID:38733638
      reference_title: >-
        Liposome-encapsulated mannose-1-phosphate therapy improves global N-glycosylation in different
        congenital disorders of glycosylation.
      supports: SUPPORT
      evidence_source: IN_VITRO
      quote_role: PRIMARY_RESULT
      snippet: >-
        The ALG11-deficient fibroblasts also exhibited an increased glycosylation upon GLM101 treatment,
        although this increase was subtle compared to PMM2-CDG and ALG2-CDG
      explanation: Documents the partial biochemical response in ALG11 cells.
    - reference: PMID:38733638
      reference_title: >-
        Liposome-encapsulated mannose-1-phosphate therapy improves global N-glycosylation in different
        congenital disorders of glycosylation.
      supports: SUPPORT
      evidence_source: IN_VITRO
      quote_role: PRIMARY_RESULT
      snippet: GLM101 has not been demonstrated to cross the blood-brain barrier
      explanation: Limits translation of the cell result to neurological treatment.
  evidence:
  - reference: PMID:38733638
    reference_title: >-
      Liposome-encapsulated mannose-1-phosphate therapy improves global N-glycosylation in different congenital
      disorders of glycosylation.
    supports: SUPPORT
    evidence_source: IN_VITRO
    quote_role: PRIMARY_RESULT
    snippet: >-
      Finally, we included the fibroblasts of two individuals with ALG11-CDG, who had features of mild
      to severe developmental delay, speech delay, infantile seizures and progressive microcephaly
    explanation: Defines the two-donor experimental sample.
  - reference: PMID:38733638
    reference_title: >-
      Liposome-encapsulated mannose-1-phosphate therapy improves global N-glycosylation in different congenital
      disorders of glycosylation.
    supports: SUPPORT
    evidence_source: IN_VITRO
    quote_role: PRIMARY_RESULT
    snippet: '| P7 | 10/F | ALG11 | c.932C>T/c.932C>T | p.P311L/p.P311L |'
    explanation: Table1 identifies one homozygous donor genotype.
  - reference: PMID:38733638
    reference_title: >-
      Liposome-encapsulated mannose-1-phosphate therapy improves global N-glycosylation in different congenital
      disorders of glycosylation.
    supports: SUPPORT
    evidence_source: IN_VITRO
    quote_role: PRIMARY_RESULT
    snippet: '| P8 | 13/F | ALG11 | c.163A>G/c.163A>G | p.T55A/p.T55A |'
    explanation: Table1 identifies the second homozygous donor genotype.
discussions:
- discussion_id: gap_prenatal_onset_of_brain_involvement
  kind: KNOWLEDGE_GAP
  attaches_to:
  - pathophysiology#Prenatal Arrest of Cerebral Growth
  - pathophysiology#Progressive Loss of Brain Structures
  prompt: >-
    How often does cerebral growth arrest begin prenatally, and which factors determine subsequent tissue
    loss?
  rationale: >-
    Unremarkable pregnancies in earlier patients and fetal brain growth arrest in a later child represent
    clinical variability rather than conflicting observations. In that child, fetal-to-neonatal MRI showed
    absent growth, whereas later follow-up documented marked tissue loss. The prevalence of prenatal onset,
    genotype associations and cellular basis remain unresolved.
  proposed_experiments:
  - experiment_id: exp_alg11_prenatal_imaging_review
    name: Systematic review of prenatal imaging and biometry in genetically confirmed ALG11-CDG
    description: >-
      Collect fetal ultrasound and MRI data, including third-trimester head circumference trajectories,
      from all reported and unreported genetically confirmed patients, to establish how often head growth
      arrest is detectable before birth.
  - experiment_id: exp_alg11_genotype_stratified_onset
    name: Genotype-stratified onset analysis
    description: >-
      Compare age at first detectable brain abnormality between patients carrying two severe (null or
      whole-gene-deletion) alleles and those with at least one hypomorphic missense allele.
- discussion_id: gap_mechanism_of_sensorineural_deafness
  kind: KNOWLEDGE_GAP
  attaches_to:
  - phenotypes#Sensorineural Hearing Impairment
  prompt: >-
    Why is sensorineural deafness frequent in ALG11-CDG and RFT1-CDG but unusual in the other congenital
    disorders of glycosylation?
  rationale: >-
    The proposed otoneurotoxicity of cytosolic LLO intermediates is a hypothesis from the clinical literature.
    Neither the cited patient studies nor their fibroblast assays establish accumulation in the inner
    ear or a causal cochlear injury pathway. Similar hearing impairment in RFT1-CDG motivates comparison
    but does not prove a shared toxic substrate.
  proposed_experiments:
  - experiment_id: exp_alg11_cochlear_phenotyping_mouse
    name: Cochlear phenotyping of an Alg11 hypomorphic mouse
    description: >-
      Measure auditory brainstem response thresholds and hair-cell survival in a hypomorphic Alg11 model,
      and test whether hearing loss tracks the accumulation of Man3/Man4GlcNAc2-PP-dolichol in cochlear
      tissue.
  - experiment_id: exp_alg11_cross_cdg_audiology
    name: Cross-CDG audiological comparison against LLO intermediate species
    description: >-
      Compare the prevalence and severity of sensorineural hearing loss across CDG types with the identity
      of the accumulating LLO intermediate, testing whether deafness segregates with the ALG11/RFT1 substrate
      rather than with hypoglycosylation severity generally.
- discussion_id: gap_neural_consequences_of_hypoglycosylation
  kind: KNOWLEDGE_GAP
  attaches_to:
  - pathophysiology#Protein Hypoglycosylation
  prompt: >-
    Which glycoprotein-dependent cellular processes connect ALG11 dysfunction to cerebral growth arrest,
    tissue loss and epilepsy?
  rationale: >-
    Truncated LLO and GP130 hypoglycosylation are reproducible fibroblast observations. They do not directly
    demonstrate GP130 signaling failure, ER stress, apoptosis, defective neuronal migration or oligodendrocyte
    maturation in affected human brain. Those candidate processes require separate evidence before entering
    a causal chain.
references:
- reference: PMID:20080937
  title: >-
    A severe human metabolic disease caused by deficiency of the endoplasmatic mannosyltransferase hALG11
    leads to congenital disorder of glycosylation-Ip.
- reference: PMID:22213132
  title: >-
    Improved diagnostics lead to identification of three new patients with congenital disorder of glycosylation-Ip.
- reference: PMID:30676690
  title: 'ALG11-CDG syndrome: Expanding the phenotype.'
- reference: PMID:30770273
  title: Arrest of Fetal Brain Development in ALG11-Congenital Disorder of Glycosylation.
- reference: PMID:36843332
  title: 'ALG11-CDG: novel variant and review of the literature.'
- reference: PMID:39809108
  title: Progressive loss of cerebral structures in ALG11-related congenital disorder of glycosylation.
- reference: PMID:39260222
  title: Identification of two novel variants in ALG11 causing congenital disorder of glycosylation.
  findings:
  - statement: >-
      A 2024 compound-heterozygous p.Gly436Val/p.Arg468His report found lower ALG11 expression and GP130
      hypoglycosylation in transfected HCT116 cells. Protein stability is an interpretation supported
      by structural predictions; no direct turnover assay is described. The abstract is cached, and publisher
      main-text passages were inspected separately; the publisher prevented canonical full-text download.
- reference: PMID:28649519
  title: 'ALG11-CDG: Three novel mutations and further characterization of the phenotype.'
- reference: url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1332/
  title: >-
    Congenital Disorders of N-Linked Glycosylation and Multiple Pathway Overview – RETIRED CHAPTER, FOR
    HISTORICAL REFERENCE ONLY - GeneReviews® - NCBI Bookshelf
  tags:
  - GeneReviews
- reference: PMID:40423864
  title: >-
    A recurrent c.953A>C (p. Gln318Pro) variant in ALG11 causing congenital disorder of glycosylation
    in Turkish population.
- reference: PMID:28300031
  title: Epileptic spasms in congenital disorders of glycosylation.
  findings:
  - statement: >-
      The mixed-CDG five-patient epilepsy study includes ALG11-CDG. Its abstract does not identify which
      individual became seizure-free, so the pooled treatment outcomes are not assigned specifically to
      ALG11.
- reference: PMID:28122681
  title: Phenotypic and genotypic spectrum of congenital disorders of glycosylation type I and type II.
  findings:
  - statement: >-
      The mixed-CDG cohort includes two ALG11 patients. The abstract reports one normal transferrin result
      among six non-PMM2-CDG patients without identifying its subtype; this is not counted as a confirmed
      ALG11 normal-screen case.
- reference: PMID:35907674
  title: >-
    A case of ALG11-congenital disorders of glycosylation diagnosed by post-mortem whole exome sequencing.
- reference: PMID:38733638
  title: >-
    Liposome-encapsulated mannose-1-phosphate therapy improves global N-glycosylation in different congenital
    disorders of glycosylation.
differential_diagnoses:
- name: RFT1-congenital disorder of glycosylation
  description: >-
    RFT1-CDG can overlap with ALG11-CDG in severe developmental impairment and sensorineural hearing loss.
    Gene-specific molecular testing and cellular glycosylation studies distinguish the disorders; hearing
    loss alone does not identify either gene.
  evidence:
  - reference: PMID:28649519
    reference_title: 'ALG11-CDG: Three novel mutations and further characterization of the phenotype.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: Sensorineural deafness is highly unusual in other types of CDG, except RFT1-CDG
    explanation: Supports the overlapping hearing phenotype.
- name: Mitochondrial disorders
  description: >-
    Progressive cerebral atrophy and epilepsy can resemble mitochondrial disease. This is a broad diagnostic
    category rather than a specific molecular alternative; biochemical findings and genomic evaluation
    must be interpreted together.
  evidence:
  - reference: PMID:28649519
    reference_title: 'ALG11-CDG: Three novel mutations and further characterization of the phenotype.'
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    quote_role: REVIEW_SYNTHESIS
    snippet: Comparable progressive atrophy has been reported in mitochondrial disorders
    explanation: Documents the radiological differential.
📚

References & Deep Research

References

14
PMID:20080937
A severe human metabolic disease caused by deficiency of the endoplasmatic mannosyltransferase hALG11 leads to congenital disorder of glycosylation-Ip.
No top-level findings curated for this source.
PMID:22213132
Improved diagnostics lead to identification of three new patients with congenital disorder of glycosylation-Ip.
No top-level findings curated for this source.
PMID:30676690
ALG11-CDG syndrome: Expanding the phenotype.
No top-level findings curated for this source.
PMID:30770273
Arrest of Fetal Brain Development in ALG11-Congenital Disorder of Glycosylation.
No top-level findings curated for this source.
PMID:36843332
ALG11-CDG: novel variant and review of the literature.
No top-level findings curated for this source.
PMID:39809108
Progressive loss of cerebral structures in ALG11-related congenital disorder of glycosylation.
No top-level findings curated for this source.
PMID:39260222
Identification of two novel variants in ALG11 causing congenital disorder of glycosylation.
1 finding
A 2024 compound-heterozygous p.Gly436Val/p.Arg468His report found lower ALG11 expression and GP130 hypoglycosylation in transfected HCT116 cells. Protein stability is an interpretation supported by structural predictions; no direct turnover assay is described. The abstract is cached, and publisher main-text passages were inspected separately; the publisher prevented canonical full-text download.
PMID:28649519
ALG11-CDG: Three novel mutations and further characterization of the phenotype.
No top-level findings curated for this source.
url:https://www.ncbi.nlm.nih.gov/sites/books/NBK1332/
Congenital Disorders of N-Linked Glycosylation and Multiple Pathway Overview – RETIRED CHAPTER, FOR HISTORICAL REFERENCE ONLY - GeneReviews® - NCBI Bookshelf
No top-level findings curated for this source.
PMID:40423864
A recurrent c.953A>C (p. Gln318Pro) variant in ALG11 causing congenital disorder of glycosylation in Turkish population.
No top-level findings curated for this source.
PMID:28300031
Epileptic spasms in congenital disorders of glycosylation.
1 finding
The mixed-CDG five-patient epilepsy study includes ALG11-CDG. Its abstract does not identify which individual became seizure-free, so the pooled treatment outcomes are not assigned specifically to ALG11.
PMID:28122681
Phenotypic and genotypic spectrum of congenital disorders of glycosylation type I and type II.
1 finding
The mixed-CDG cohort includes two ALG11 patients. The abstract reports one normal transferrin result among six non-PMM2-CDG patients without identifying its subtype; this is not counted as a confirmed ALG11 normal-screen case.
PMID:35907674
A case of ALG11-congenital disorders of glycosylation diagnosed by post-mortem whole exome sequencing.
No top-level findings curated for this source.
PMID:38733638
Liposome-encapsulated mannose-1-phosphate therapy improves global N-glycosylation in different congenital disorders 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 (3)

Review ALG11-CDG evidence, clinical variability and causal mechanisms · 2026-09-21T04:23:42Z · View source

Comprehensive review of the existing entry, all six original PMID sources, the genuine deep-research report, and additional clinical literature. Regenerated the two available 2019 full texts and consumed their main bodies and restored phenotype tables. Read the complete 2015 two-patient report and the full historical GeneReviews overview, explicitly retired in June 2026 with last substantive update in 2017. Other reports remain abstract-only after full-text retrieval attempts; a 2024 publisher indexed methods/results excerpt clarified expression-versus-protein-stability interpretation. Added primary reports from 2022, 2024 and 2025 and scoped two mixed-CDG 2017 abstracts without assigning pooled outcomes to ALG11. Corrected case-count denominators and removed unsupported population prevalence and penetrance bands. Split allele-dependent protein abundance from mannosyltransferase activity; retained measured LLO and GP130 findings but removed unestablished glycoprotein-to-brain mechanisms. Distinguished prenatal growth arrest from later tissue loss in the same longitudinal child and recorded normal imaging and prolonged seizure freedom in another individual. Expanded observed tone, feeding, visual, seizure, callosal and dysmorphic findings; added individualized nutritional, developmental, sensory, reproductive and palliative care with explicit historical/general-CDG scope. Primary topiramate evidence documents partial response without disease modification. New tissue and symptomatic treatment links are evidence-qualified; other unproved causal routes are explicitly left as gaps. GeneReviews mined for clinical, diagnostic, care and counseling context and tagged. NEC preflight passed MONDO:0013349/ALG11; deep-research term mismatches were not propagated. Authoritative schema/live-ontology validation and 124/124 evidence snippets passed, together with all 25 repository QC gates and whole-KB node-class example integrity (101 classes, 2192 examples). No other disorder consumes the regenerated references. A peer read-only mechanism/model review found no material causal blocker; its refinement to avoid over-quantifying rescue from the index abstract was incorporated.

Review round 1: consume PMID:30770273, add biochemical, prevalence and experimental models · 2026-08-24T22:28:00Z · View source

Addresses all three blocking findings and four of five suggestions from the ai4c-reviewer review on PR 9418. Finding 1: the Progressive Microcephaly description asserted in-utero growth arrest that its single evidence item did not support, so a second item from PMID:30770273 was added establishing microcephaly developing during the late second and third trimester. Finding 2: PMID:30770273 was in references and cited in prose but appeared in no evidence item despite being cached as full text; it now carries three structured evidence items across the microcephaly phenotype and the progressive brain-loss node. Finding 3: a biochemical section was added with GP130 glycosylation status and the serum transferrin isoform profile, the GP130 entry carrying the sentence in which the same patient shows GP130 hypoglycosylation and a normal transferrin profile, which is the pair that makes GP130 the more reliable readout. Suggestion 4: Temperature instability HP:0005968 added as a phenotype. Suggestion 6: the exome sequencing diagnosis entry moved from the generic NCIT:C19770 to NCIT:C101295 Whole Exome Sequencing. Suggestion 7: a prevalence record added as CASES_IN_LITERATURE with prevalence_class ULTRA_RARE and deliberately no rate_per_100000, since the only figure any cited source gives is a case count and converting it to a rate would invent a denominator. Suggestion 8: two experimental_models added, the patient fibroblast LLO analysis and the yeast alg11 deletion complementation assay, both linked by modeled_mechanisms with MEASURES relationships, fidelity, limitations, and in the fibroblast case a readout carrying its own evidence. Suggestion 5, a therapeutic_agent for the anti-seizure treatment, was not actioned and is answered on the PR: topiramate appears only in the deep-research artifact and is not quotable from any cached reference, and the reviewer flagged it as fine to leave. One correction made while checking: the reviewer's ready-to-paste snippet for PMID:30770273 contains non-breaking spaces between the gestational-age numerals and the word weeks, so it would not have verified as pasted; NBSP-free spans conveying the same fact were used instead. Revalidated: schema and terms pass, snippets rose from 43/43 to 55/55 verified, offline gates clean, zero dangling entity refs, and the one model readout target matches its link target.

Create: ALG11-congenital disorder of glycosylation · 2026-08-24T21:35:20Z · View source

New entry curated from primary literature. A Perplexity sonar-deep-research report was generated and cleared the NEC preflight against MONDO:0013349 with verdict PASS - ALG11 mentioned 130 times, no rival gene - but returned zero PMIDs in its body, so it served only as a lead-generation aid: all six references were located independently in PubMed and fetched with 'just fetch-reference'. The pathograph runs ALG11 mannosyltransferase deficiency -> LLO assembly arrest at Man3/Man4GlcNAc2-PP-dolichol -> protein hypoglycosylation -> multisystem glycoprotein dysfunction -> progressive loss of brain structures, declaring conformance to three congenital_disorder_of_glycosylation module nodes. Two judgements are recorded rather than smoothed over. First, the Type I transferrin isoform phenotype carries a REFUTE evidence item and deliberately no frequency band, because PMID:30676690 documents a genetically and biochemically confirmed patient with two rounds of normal carbohydrate-deficient transferrin. Second, the prenatal course is curated as an open KNOWLEDGE_GAP because PMID:22213132 reports an unremarkable prenatal period across four patients while PMID:30770273 documents arrest of fetal brain growth between 20 and 36 weeks. Validated with 'just validate' for schema and terms, 43/43 snippets verified against cached references, and the six offline CI gates. An initial draft used hgnc:20507 for ALG11, which is in fact H2AW; 'just validate-terms' caught the label mismatch and the identifier was corrected to hgnc:32456 against the HGNC REST API.

Perplexity ▸
ALG11-congenital disorder of glycosylation: comprehensive disease characteristics and pathophysiology
sonar-deep-research 18 citations 2026-08-24T21:19:38.573221

ALG11-congenital disorder of glycosylation: comprehensive disease characteristics and pathophysiology

ALG11-congenital disorder of glycosylation (ALG11-CDG), also known as congenital disorder of glycosylation type Ip (CDG-Ip), is a rare autosomal recessive inborn error of metabolism caused by pathogenic variants in the ALG11 gene, which encodes an endoplasmic reticulum mannosyltransferase required for the early steps of N-linked glycosylation.[2][14][16] Clinically, ALG11-CDG presents as a severe multisystem disorder dominated by neurological impairment—hypotonia, drug-resistant epilepsy (often with characteristic burst-suppression on electroencephalography), profound developmental delay, and progressive cerebral atrophy—combined with microcephaly, facial dysmorphism, failure to thrive, hearing impairment, gastrointestinal bleeding, and variable systemic features.[1][5][13] At the molecular level, ALG11 deficiency disrupts the assembly of the lipid-linked oligosaccharide precursor on the cytosolic face of the endoplasmic reticulum, resulting in truncated glycans, hypoglycosylation of serum glycoproteins such as transferrin and gp130, and widespread disturbance of glycoprotein and glycolipid function.[1][12][15] Since its first description in 2010, only a small number of individuals have been reported worldwide, but expanding case series and gene curation efforts have identified at least 14 unique pathogenic variants and revealed substantial phenotypic variability, including rare cases with normal transferrin glycosylation despite profound neurological disease.[1][10][14] The extreme rarity of ALG11-CDG, its severe course beginning in early infancy, and its mechanistic position within core glycosylation pathways make it an important model for understanding human N-glycosylation disorders, informing diagnostic strategies (including transferrin isoform analysis and exome sequencing), and shaping emerging precision approaches such as gene therapy, even though no disease-specific curative treatment is currently available.[1][5][16]

1. Disease information and conceptual overview

Definition and clinical concept

ALG11-congenital disorder of glycosylation is a Mendelian metabolic disease classified within the broader group of congenital disorders of N-linked glycosylation (CDG), specifically as a type I defect affecting the assembly of the dolichol-linked oligosaccharide precursor.[1][12][16] It is caused by biallelic loss-of-function variants in ALG11, the alpha-1,2-mannosyltransferase that catalyzes the sequential addition of the fourth and fifth mannose residues to the growing Man(_n)GlcNAc(_2)-PP-dolichol structure, a crucial intermediate in the N-glycosylation pathway.[2][12][15] OMIM describes congenital disorder of glycosylation type Ip (CDG1P) as a multisystem inborn error due to homozygous or compound heterozygous mutations in the ALG11 gene on chromosome 13q14.3, characterized by developmental delay, seizures, microcephaly, dysmorphism, and variable systemic involvement.[16] Orphanet and the MONDO rare disease ontology similarly define ALG11-CDG as a form of CDG characterized by facial dysmorphism (including microcephaly, high forehead, low posterior hairline, and strabismus), hypotonia, failure to thrive, intractable seizures, developmental delay, persistent vomiting, gastric bleeding, and additional features such as abnormal fat pads, inverted nipples, and body temperature instability.[13] Taken together, these descriptions establish ALG11-CDG as a severe, early-onset neurodevelopmental and multisystem disease rooted in a fundamental defect of protein and lipid glycosylation rather than a single-organ disorder.[1][13][16]

Historical discovery and early case descriptions

The disease was first delineated as a distinct CDG subtype by Rind and colleagues in 2010, who identified a severe human metabolic disease caused by deficiency of the endoplasmic mannosyltransferase hALG11 that led to congenital disorder of glycosylation type Ip.[14] In that landmark report, the authors used biochemical glycan analysis, radiolabeling studies, and molecular genetics to show that patient fibroblasts synthesized truncated lipid-linked oligosaccharide structures consistent with defective ALG11 activity, and they mapped causative mutations in ALG11 in affected individuals.[14] Subsequent reports expanded the phenotypic and mutational spectrum, including the 2015 study “ALG11-CDG: Three novel mutations and further characterization of the phenotype,” which summarized clinical features and variants across multiple patients and emphasized the neurological severity and multisystem involvement.[11] More recent publications, such as the 2019 phenotype expansion study and a 2023 case report by Erdal et al., have highlighted novel aspects including hypoglycosylation of the biomarker gp130, burst-suppression patterns on EEG, progressive cerebral atrophy and hypomyelination on MRI, and the existence of ALG11-CDG patients with normal transferrin glycosylation profiles.[1][5][9] These accumulating case-based observations, curated by ClinGen and other expert panels, have transformed ALG11-CDG from a single-family metabolic curiosity into a recognized though extremely rare CDG subtype with characteristic features and a defined molecular etiology.[10][12][16]

Key identifiers and ontology mapping

ALG11-CDG is catalogued in multiple disease ontologies and databases under specific identifiers that facilitate interoperability of knowledge across clinical and research systems.[2][13][16] OMIM assigns congenital disorder of glycosylation, type Ip the entry number 613661 and explicitly links it to the ALG11 gene, which has its own OMIM entry 613666.[2][16] Orphanet lists ALG11-CDG under the ORPHA code 280071 and notes its alternative designations such as CDG-Ip and CDG1P.[13][16] In SNOMED CT, the disease is mapped under code 733085004 for congenital disorder of glycosylation type Ip, reflecting harmonization with clinical terminologies used in electronic health records.[2][16] Although the precise MONDO identifier is not explicitly stated in the search results, the rarediseases.org MONDO disease summary makes clear that ALG11-congenital disorder of glycosylation has been incorporated into the MONDO ontology, ensuring linkage to related concepts such as “congenital disorder of N-linked glycosylation” and “CDG syndrome type I.”[13] At the gene level, ALG11 is registered with the HGNC-approved symbol ALG11, corresponds to NCBI Gene ID 440138 in humans, and is curated by the ClinGen gene–disease validity curation project as an autosomal recessive gene for ALG11-CDG.[2][3][6][10] These identifiers are crucial for building computable disease knowledge bases, enabling mapping to Human Phenotype Ontology (HPO), Gene Ontology (GO), Cell Ontology (CL), and anatomical ontologies such as UBERON.

Synonyms and naming conventions

The disease has accumulated multiple synonyms reflecting historical naming conventions in the CDG field, which transitioned from numerical CDG-I/II schemes to gene-based naming.[1][13][16] OMIM and Orphanet list common alternative names including “ALG11-congenital disorder of glycosylation,” “ALG11-CDG,” “CDG-Ip,” “CDG1P,” “congenital disorder of glycosylation type Ip,” “carbohydrate-deficient glycoprotein syndrome type Ip,” and “CDG syndrome type Ip.”[13][16] At the gene level, ALG11 itself has older names such as “asparagine-linked glycosylation 11 homolog (S. cerevisiae, alpha-1,2-mannosyltransferase)” and the alias “KIAA0266,” while functional descriptors emphasize its enzymatic role as “GDP-Man:Man(3)GlcNAc(2)-PP-dolichol alpha-1,2-mannosyltransferase.”[3][15] These multiple designations can cause confusion in clinical communication; therefore, contemporary practice favors the standardized designation “ALG11-CDG” for the disease and “ALG11” for the gene, with “congenital disorder of glycosylation type Ip” retained for backward compatibility with older CDG classifications.[1][13][16]

Nature of available information and evidence sources

Given the extreme rarity of ALG11-CDG, disease information is derived almost entirely from individual case reports, small case series, and aggregate reviews rather than large epidemiologic cohorts or randomized trials.[1][5][11][14] The initial description by Rind et al. involved a small number of patients characterized intensively with biochemical and genetic methods, and later publications have typically reported one or a few individuals with novel variants and detailed neuroimaging, electrophysiologic, and clinical data.[1][5][11][14] The 2015 “ALG11-CDG: three novel mutations and further characterization of the phenotype” paper and subsequent reviews synthesize these patient-level observations into disease-level summaries, but the sample size remains in the low tens, with ClinGen’s curation noting at least 14 unique variants across reported families.[10][11] Databases such as OMIM, Orphanet, and rarediseases.org aggregate these case-level data into structured disease summaries, which are then linked to ontologies (MONDO, HPO) and terminologies (SNOMED CT) for broader dissemination.[13][16] For the present report, the evidence base thus consists of primary human clinical and biochemical studies, curated gene–disease relationships, and mechanistic insights from model organisms (notably yeast ALG11), rather than population-level analytics or clinical trials.[1][10][14][15]

2. Etiology, causal factors, and risk

Genetic cause: ALG11 gene and N-linked glycosylation

The primary and essentially exclusive cause of ALG11-CDG is biallelic pathogenic variation in the ALG11 gene, which encodes a mannosyltransferase required for early steps of N-linked glycosylation in the endoplasmic reticulum.[2][6][16] OMIM states that congenital disorder of glycosylation type Ip is caused by homozygous or compound heterozygous mutation in ALG11 on chromosome 13q14, and ClinGen confirms the autosomal recessive gene–disease relationship based on multiple unrelated families with convincing segregation and functional data.[2][10][16] ALG11’s biochemical role is to use GDP-mannose (CHEBI:17478) as a donor substrate to sequentially add the fourth and fifth mannose residues to the growing Man(_n)GlcNAc(_2)-PP-dolichol lipid-linked oligosaccharide on the cytosolic face of the endoplasmic reticulum membrane.[2][12][15] The yeast ALG11 gene was shown to specify the addition of terminal mannose residues to Man(_4)GlcNAc(_2)-PP-dolichol, and deletion of ALG11 in Saccharomyces cerevisiae results in poor growth and temperature-sensitive lethality with accumulation of truncated Man(_3)GlcNAc(_2)-PP-dolichol intermediates, highlighting the essential nature of this enzymatic step.[15] In humans, loss-of-function mutations in ALG11 lead to defective assembly of the lipid-linked oligosaccharide precursor, resulting in under-glycosylated nascent glycoproteins and a CDG type I biochemical pattern characterized by abnormal sialotransferrin isoforms and hypoglycosylation of other secreted glycoproteins.[1][5][12] This core defect in N-glycosylation provides a mechanistic explanation for the multisystem involvement of ALG11-CDG, as virtually all secreted and membrane glycoproteins in the body rely on proper N-glycosylation for folding, stability, trafficking, and function.[1][12][14]

Variant spectrum and pathogenic mechanisms

At least 14 unique ALG11 variants, including missense, nonsense, frameshift, and splice-site changes, have been reported in individuals with ALG11-CDG and curated by ClinGen.[10] Rind et al. identified compound heterozygous mutations predicted to severely reduce or abolish ALG11 enzymatic activity, and their functional studies showed truncated lipid-linked oligosaccharides and reduced incorporation of mannose into glycan precursors in patient fibroblasts.[14] The 2015 ALG11-CDG study described three novel mutations and analyzed their effects on glycosylation and clinical phenotype; missense variants clustered in conserved regions of the mannosyltransferase domain and were associated with severe neurological disease and biochemical CDG type I patterns.[11] Erdal et al. reported a 31‑month‑old boy with compound heterozygous ALG11 mutations, including a novel c.476T>C missense variant, and demonstrated a CDG type I pattern on capillary zone electrophoresis of carbohydrate-deficient transferrin, supporting its pathogenicity.[5][8] ClinVar entries such as NM_001004127.3(ALG11):c.257T>C (p.Leu86Ser) classify specific single nucleotide variants as pathogenic for ALG11-congenital disorder of glycosylation, reflecting consensus interpretations according to ACMG/AMP criteria.[17] Functional consequences of these variants are consistent with loss-of-function of ALG11’s alpha-1,2-mannosyltransferase activity, resulting in truncated lipid-linked oligosaccharides and impaired N-glycosylation rather than gain-of-function, dominant-negative, or toxic protein aggregation mechanisms.[1][12][14]

Genetic risk factors, susceptibility, and modifier genes

Because ALG11-CDG is an autosomal recessive monogenic disorder, the primary genetic risk factor is carriage of one or two pathogenic ALG11 alleles, with disease manifesting in individuals who inherit bi-allelic loss-of-function variants from carrier parents.[10][16] Carriers of a single pathogenic ALG11 variant are typically asymptomatic, as half-normal ALG11 activity is sufficient for N-glycosylation, consistent with recessive inheritance and complete penetrance in homozygotes or compound heterozygotes.[10][14][16] There is currently no robust evidence for common susceptibility alleles or polygenic modifiers that predispose individuals to milder or partial ALG11-related phenotypes; the disease appears to require rare, high-effect variants that abolish or severely impair enzyme function.[10][11][14] Modifier genes influencing glycosylation flux or ER quality control might theoretically modulate disease severity—for example, variants in other glycosyltransferases, ER chaperones, or glycan-processing enzymes—but such modifiers have not been systematically identified in the small set of reported ALG11-CDG patients.[1][11][12] Consequently, genetic risk is best conceptualized in classical Mendelian terms: unaffected carriers and affected homozygotes/compound heterozygotes, with some variability in expressivity that may relate to residual enzymatic activity of specific missense alleles or to broader genetic background.[10][11][16]

Environmental and lifestyle risk factors

No specific environmental, lifestyle, infectious, or occupational risk factors have been identified that directly cause ALG11-CDG, reflecting its nature as a constitutional genetic disorder present from conception.[1][13][16] The disease arises from germline mutations in ALG11 that are present in all cells; there is no evidence for somatic ALG11 mutations causing acquired glycosylation disorders or for environmental toxins selectively targeting ALG11 in vivo.[2][6][10] Likewise, classic lifestyle variables such as smoking, diet, physical inactivity, or alcohol consumption have not been shown to alter the risk of ALG11-CDG, although these may influence general health outcomes in affected individuals as in the broader population.[13][16] The rarity of the disorder and its early pediatric presentation make it unlikely that environmental exposures in later life play a major causal role, although prenatal exposures could theoretically modulate fetal development in ALG11-mutant fetuses, a topic that remains unexplored.[1][5] Accordingly, current evidence supports the view that ALG11-CDG risk is determined almost entirely by parental carrier status and chance segregation of pathogenic alleles, rather than by modifiable environmental or lifestyle factors.[10][16]

Protective factors and gene–environment interactions

Given the fully genetic basis of ALG11-CDG and the paucity of reported cases, no definitive genetic protective variants or environmental protective factors have been documented.[10][11][14] In principle, alleles that mildly increase ALG11 expression or stability, or that upregulate compensatory glycosylation pathways, could mitigate disease severity in individuals with hypomorphic ALG11 variants, but such modifiers have not been described in human patients or animal models.[1][11] Similarly, there is no evidence that specific diets, micronutrient supplements, or pharmacologic agents can prevent disease onset in genetically affected individuals, though supportive care may influence symptom burden and complications.[1][5][13] Gene–environment interactions in ALG11-CDG therefore remain largely speculative; the causal chain begins with a germline loss-of-function ALG11 mutation, and subsequent environmental influences may only modulate secondary features such as infection risk, nutritional status, or seizure threshold rather than fundamentally altering disease risk.[5][9][13]

3. Clinical phenotype spectrum

Neurological manifestations: seizures, encephalopathy, and development

Neurological involvement is the most prominent and consistent feature of ALG11-CDG, with affected children typically presenting in infancy with hypotonia, severe developmental delay, and epilepsy.[1][5][11] Erdal et al. described a 31‑month‑old male with axial hypotonia, drug-resistant myoclonic seizures, microcephaly, and deafness; EEG showed a burst-suppression pattern, and brain MRI revealed progressive cerebral atrophy, hypomyelination, and corpus callosum hypoplasia.[5] In their abstract, the authors emphasize the neurologic focus:

“Asparagine-dependent glycosylation 11-congenital disorders of glycosylation (ALG11-CDG) is a rare autosomal recessive N-glycosylation defect with multisystem involvement particularly neurological symptoms such as epilepsy and neuromotor developmental delay.”[5][8]

The 2019 phenotype expansion study reported two unrelated patients with severe psychomotor disability and epilepsy, confirming that profound neurodevelopmental impairment and recurrent seizures are core features.[1] An epilepsy conference abstract noted that “ALG11-Congenital Disorder of Glycosylation (ALG11-CDG) is a rare inborn error of metabolism associated with epilepsy and intellectual disability” and highlighted severe infantile drug-resistant epilepsy with a characteristic burst-suppression pattern on EEG in at least two cases, with partial response to topiramate.[9] Collectively, these observations support mapping of several HPO terms to ALG11-CDG, including Seizures (HP:0001250), Myoclonic seizures (HP:0002123), Developmental delay (HP:0001263), Severe neurodevelopmental delay (HP:0011344), Hypotonia (HP:0001252), Microcephaly (HP:0000252), Intellectual disability (HP:0001249), Abnormal electroencephalogram (HP:0002353), and the more specific Burst-suppression pattern on EEG (HP:0010818). The neurologic phenotype is typically early-onset (infancy), severe, and progressive, with limited evidence for episodic or remitting courses, and it profoundly impairs quality of life by limiting motor milestones, communication, and independent functioning.[1][5][9][11]

Facial dysmorphism, growth, and sensorineural features

Facial dysmorphism and growth abnormalities constitute a second major phenotype cluster in ALG11-CDG.[1][4][13] Orphanet and the MONDO disease summary describe facial features including microcephaly, high forehead, low posterior hairline, and strabismus, along with global growth failure and failure to thrive.[13] VarSome’s disease summary for ALG11-CDG lists characteristic craniofacial features such as microcephaly, retrognathia, low anterior hairline, long philtrum, high forehead, and ocular findings such as strabismus, as well as hearing impairment and sensorineural hearing loss.[4] The 2015 ALG11-CDG study and earlier reports by Rind et al. describe microcephaly and craniofacial anomalies in most patients, often in combination with short stature and underweight, consistent with generalized growth disturbance.[11][14] Hearing impairment, including sensorineural deafness, has been reported in multiple ALG11-CDG patients; for example, Erdal’s case had deafness, and earlier CDG literature cited deafness as a novel feature in related glycosylation disorders such as RFT1-CDG.[5][11] Relevant HPO terms include Facial dysmorphism (HP:0001999), Microcephaly (HP:0000252), Retrognathia (HP:0000278), High forehead (HP:0000348), Low anterior hairline (HP:0000294), Long philtrum (HP:0000301), Strabismus (HP:0000486), Failure to thrive (HP:0001508), Short stature (HP:0004322), and Sensorineural hearing impairment (HP:0000407).[4][11][13] These phenotypes typically present in early infancy and remain stable or progressive, contributing significantly to psychosocial and functional impact, especially when combined with severe neurodevelopmental delay.[1][4][13]

Systemic and gastrointestinal manifestations

Systemic features beyond the nervous system and craniofacial region are increasingly recognized in ALG11-CDG.[1][11][13] Rarediseases.org and Orphanet note that persistent vomiting and gastric bleeding are recurrent features, suggesting gastrointestinal mucosal vulnerability or dysmotility, although specific histopathologic data are limited.[13] Additional features described include anomalies of subcutaneous fat pads, inverted nipples, and oscillation of body temperature, which resemble systemic manifestations seen in other CDG type I disorders such as PMM2-CDG.[13] The 2015 ALG11-CDG study summarized the broader phenotype across patients and reported failure to thrive, gastrointestinal problems, and fat pad anomalies as part of the multisystem pattern.[11] Some patients have had feeding difficulties requiring nutritional support, recurrent infections, and possible coagulopathy or bleeding tendencies, though systematic data on liver function, coagulation profiles, and endocrine involvement are sparse.[1][11][13] HPO terms appropriate for these systemic features include Gastrointestinal hemorrhage (HP:0002239), Vomiting (HP:0002013), Feeding difficulties in infancy (HP:0008872), Abnormal subcutaneous fat distribution (HP:0000951), Inverted nipples (HP:0006706), and Body temperature instability (HP:0005968).[11][13] These manifestations, though less universal than neurological signs, can dramatically affect quality of life by causing pain, nutritional deficits, and risk of acute complications such as gastrointestinal bleeding.[1][13]

Laboratory and imaging phenotypes

Biochemical and imaging abnormalities constitute a distinct category of ALG11-CDG phenotypes and are central to diagnosis.[1][5][11][14] A hallmark laboratory feature in many CDG type I disorders is abnormal glycosylation of serum transferrin, detectable as altered isoform patterns on isoelectric focusing or capillary electrophoresis, indicative of hyposialylated transferrin.[1][5][11] Erdal et al. reported a CDG type I pattern on capillary zone electrophoresis of carbohydrate-deficient transferrin in their ALG11-CDG patient, confirming defective N-glycosylation.[5][8] The 2019 phenotype expansion study introduced gp130 as a novel biomarker, demonstrating hypoglycosylation of gp130 in patient fibroblasts and indicating that this acute-phase glycoprotein may serve as a sensitive marker of ALG11 deficiency.[1] Surprisingly, one of their patients had a normal transferrin glycosylation profile despite typical clinical and cellular features of ALG11-CDG, underscoring that transferrin analysis is not universally abnormal and that additional biomarkers are needed.[1] Neuroimaging findings are striking: brain MRI in several patients has shown progressive cerebral atrophy, hypomyelination, and corpus callosum hypoplasia, consistent with a global neurodevelopmental and neurodegenerative process.[1][5][11] EEG abnormalities include severe background attenuation and burst-suppression patterns, which are characteristic of profound encephalopathy and have been observed in at least two ALG11-CDG patients with infantile drug-resistant epilepsy.[5][9] HPO terms capturing these laboratory and imaging phenotypes include Abnormal transferrin isoform profile (HP:0003160), Abnormal glycosylation (HP:0012348), Cerebral atrophy (HP:0002059), Hypomyelination (HP:0003429), Corpus callosum hypoplasia (HP:0002079), and Burst suppression pattern on EEG (HP:0010818).[1][5][9][11]

Symptom onset, progression, and quality of life impact

Across reported cases, symptom onset in ALG11-CDG is consistently in the neonatal or early infantile period, reflecting the constitutional nature of the glycosylation defect.[1][5][11] Hypotonia, feeding difficulties, failure to thrive, and delayed developmental milestones often appear within the first months of life, while seizures may begin in infancy and rapidly become drug-resistant with complex EEG patterns.[5][9][11] Microcephaly may be evident at birth or emerge progressively as head growth fails to keep pace with age norms, and facial dysmorphism becomes more apparent as the child grows.[4][13] Disease progression is generally severe and either progressive or static at a low functional level; most children achieve limited motor skills and have minimal language development, with some showing progressive cerebral atrophy and worsening epilepsy.[1][5][11] Quality of life is profoundly affected, with reliance on caregivers for all activities of daily living, frequent hospitalizations for seizures or infections, and psychosocial burden on families; formal health-related quality-of-life metrics have not been reported, but the disability profile aligns with substantial impairment across EQ-5D and SF-36 domains.[1][5][13]

4. Genetic and molecular information

ALG11 gene: structure, locus, and expression

ALG11, officially designated ALG11 alpha-1,2-mannosyltransferase, is a gene with a protein product that belongs to the asparagine-linked glycosylation (ALG) family of glycosyltransferases.[2][3] The gene is located on chromosome 13q14.3, with genomic coordinates 13:52,012,398–52,033,600 on the GRCh38 assembly, and its cytogenetic location is consistently reported in OMIM and NCBI Gene.[2][6] ALG11 overlaps but is distinct from the UTP14, U3 gene, a nearby locus, indicating partial genomic complexity but separate coding sequences.[6] The ALG11 protein is a multi-pass endoplasmic reticulum membrane protein that localizes to the ER and faces the cytosolic side where it interacts with dolichol-linked oligosaccharide intermediates and GDP-mannose.[2][12][15] Although detailed human tissue expression patterns are not provided in the search results, ALG11 is expected to be ubiquitously expressed in cells capable of N-glycosylation, including hepatocytes, neurons, and secretory cells, consistent with the widespread impact of its deficiency in ALG11-CDG.[1][12][14] The gene’s HGNC-approved symbol is ALG11, and it is catalogued in Ensembl (ENSG00000253710), Reactome, and other genomic resources that link it to N-glycosylation pathways.[3][12]

Pathogenic variants: types, classification, and origin

Clinical reports and curated databases reveal a heterogeneous spectrum of ALG11 pathogenic variants, most of which arise as germline mutations in affected families.[10][11][14][17] Rind et al. identified missense and possibly truncating variants in hALG11, showing that these changes disrupt enzyme function and glycan assembly, and they provided evidence for autosomal recessive inheritance with affected siblings in consanguineous or non-consanguineous families.[14] The 2015 ALG11-CDG paper described three novel mutations, expanding the repertoire of pathogenic variants and indicating that both missense and nonsense changes across different exons can cause severe disease.[11] ClinGen’s curation notes at least 14 unique variants documented in ALG11-CDG families, including missense variants affecting conserved residues in the mannosyltransferase domain and other predicted loss-of-function alleles.[10] Erdal et al. reported compound heterozygous mutations, including a novel c.476T>C variant, and used functional data (CDG type I transferrin pattern and typical clinical features) to classify this variant as pathogenic or likely pathogenic under ACMG guidelines.[5][8] ClinVar records such as NM_001004127.3(ALG11):c.257T>C (p.Leu86Ser) show single nucleotide variants classified as pathogenic for ALG11-congenital disorder of glycosylation, supporting clinical validity.[17] All reported disease-causing variants are germline in origin, with affected individuals harboring two mutated alleles inherited from apparently healthy carrier parents; there is no evidence for somatic ALG11 variants causing acquired CDG or for dominant inheritance.[10][14][16]

Allele frequency and population distribution

Direct allele frequency data for specific ALG11 pathogenic variants are not provided in the search results, but the extreme rarity of ALG11-CDG implies that disease-causing alleles are very rare in general populations.[1][10][16] gnomAD and other population databases, although not cited directly here, typically show extremely low allele frequencies for known pathogenic ALG11 variants and may lack homozygous individuals, consistent with severe disease and likely early mortality in homozygotes.[10][14] ClinGen’s identification of at least 14 unique variants, each in one or a few families, suggests that most ALG11-CDG cases are due to private or family-specific mutations rather than common founder alleles.[10][11] Geographic and ethnic distribution patterns are not well characterized due to the small number of cases, and no founder mutations with elevated frequency in specific populations have been reported, in contrast to some other CDG types such as PMM2-CDG.[1][10][16] Carrier frequency therefore appears to be extremely low, and ALG11-CDG can be regarded as an ultra-rare autosomal recessive disease with scattered cases worldwide, largely identified via exome sequencing in children with unexplained neurodevelopmental syndromes.[5][11][16]

Functional consequences: loss of function of an ER mannosyltransferase

Functional studies in humans and yeast converge on a consistent mechanism: ALG11 pathogenic variants result in loss of alpha-1,2-mannosyltransferase activity, truncated dolichol-linked oligosaccharide intermediates, and defective N-glycosylation of nascent polypeptides.[1][12][14][15] The yeast ALG11 gene specifies addition of terminal mannose residues to Man(_3)GlcNAc(_2)-PP-dolichol; deletion of ALG11 in yeast leads to accumulation of Man(_3)GlcNAc(_2)-PP-dolichol and Man(_4)GlcNAc(_2)-PP-dolichol intermediates, poor growth, and temperature-sensitive lethality, illustrating the essential nature of this step.[15] In humans, Rind et al. showed that ALG11-deficient fibroblasts synthesize truncated precursor glycan structures, consistent with defective addition of the fourth and fifth mannose residues in the lipid-linked oligosaccharide assembly.[14] The 2019 phenotype expansion study demonstrated truncated glycan structures and hypoglycosylation of gp130 in ALG11-CDG fibroblasts, confirming that disease-causing variants result in generalized hypoglycosylation of secreted glycoproteins.[1] Reactome’s pathway entry “Defective ALG11 causes CDG-1p” describes the biochemical defect: mutations in ALG11 disrupt the N-glycosylation pathway at the step of adding mannose residues to dolichol-linked oligosaccharides, leading to CDG type Ip.[12] These findings collectively support classification of ALG11-CDG pathogenic variants as loss-of-function mutations that impair enzymatic activity rather than altering substrate specificity or conferring toxic gain-of-function.[1][12][14][15]

Modifier genes, epigenetic and chromosomal information

Although ALG11 resides in a genomic region that overlaps with UTP14, U3, no structural chromosomal abnormalities such as deletions, duplications, or translocations involving 13q14.3 have been expressly implicated in ALG11-CDG in the available reports.[6][16] Disease-causing events are point mutations or small indels within ALG11 itself rather than larger chromosomal rearrangements, and karyotyping or chromosomal microarray has not been emphasized in published cases.[5][11][14] Epigenetic modifications of ALG11, such as DNA methylation or histone marks, have not been studied in relation to ALG11-CDG, and given the primarily loss-of-function mutational mechanism, epigenetic dysregulation is unlikely to be a primary cause, although it could hypothetically modulate residual expression in some contexts.[1][12] Modifier genes have not been systematically explored; the small number of cases precludes robust genotype–phenotype correlation beyond the observation that null variants tend to associate with severe phenotypes, while missense variants might permit minimal residual activity.[11][14] As more patients are identified, future studies may investigate whether variants in other glycosylation genes, ER quality-control pathways, or neuronal survival pathways modulate disease expressivity, but current evidence remains silent on specific modifier loci.[1][11]

5. Environmental information and non-genetic contributors

The pathogenesis of ALG11-CDG is rooted in congenital genetic defects of N-glycosylation and does not depend on exogenous environmental triggers in the way that autoimmune, infectious, or toxic disorders do.[1][13][16] No studies have implicated exposure to environmental toxins, radiation, heavy metals, or industrial chemicals as etiologic factors in ALG11-CDG, and the disease presents in early childhood in the absence of such triggers, in families where parents are clinically healthy carriers.[1][5][16] Similarly, infections with specific bacterial, viral, or parasitic agents have not been linked to disease onset, although infections may precipitate decompensation or exacerbate seizures in affected children, as in many neurodevelopmental disorders.[5][9] Lifestyle factors such as diet, smoking, and alcohol use are largely irrelevant to disease risk because ALG11-CDG manifests in infancy and is determined by germline genotype; however, nutritional support and avoidance of certain exposures may be important in supportive care.[13][16] The comparative toxicogenomics and environmental epidemiology literature, while relevant to some metabolic diseases, has not reported ALG11 as a target of environmental modulation, underscoring the purely genetic nature of this condition.[2][6][12]

6. Mechanisms and pathophysiology

N-linked glycosylation pathway and the step controlled by ALG11

N-linked glycosylation is a fundamental post-translational modification in eukaryotic cells in which a preassembled oligosaccharide is transferred en bloc to asparagine residues of nascent proteins in the endoplasmic reticulum, typically on consensus sequences Asn-X-Ser/Thr.[12][15] The process begins with assembly of a lipid-linked oligosaccharide (LLO) composed of GlcNAc and mannose on a dolichol phosphate carrier embedded in the ER membrane; the initial steps occur on the cytosolic face, with subsequent steps on the luminal side.[12][15] ALG11 encodes an alpha-1,2-mannosyltransferase that uses GDP-mannose to sequentially add the fourth and fifth of the nine mannoses to the growing LLO on the outer (cytosolic) leaflet of the ER.[1][2][12] In Saccharomyces cerevisiae, Cipollo et al. showed that the yeast ALG11 gene specifies addition of the terminal mannose residues to Man(_4)GlcNAc(_2)-PP-dolichol; deletion of ALG11 caused accumulation of truncated intermediates and led to poor growth and temperature-sensitive lethality, illustrating the critical nature of this step in glycan assembly.[15] In humans, Rind et al. demonstrated that deficiency of the endoplasmic mannosyltransferase hALG11 results in incomplete LLO assembly, hypoglycosylated nascent glycoproteins, and the biochemical signature of CDG type Ip.[14] Reactome’s “Defective ALG11 causes CDG-1p” pathway succinctly captures this mechanism, linking ALG11 mutations to disruption of N-glycosylation and the downstream clinical phenotype.[12]

Cellular consequences: hypoglycosylation, ER stress, and global protein dysfunction

At the cellular level, ALG11 deficiency causes hypoglycosylation of newly synthesized proteins that ordinarily receive complex N-glycans, leading to widespread disturbance of protein folding, trafficking, and stability.[1][12][14] The truncated LLO intermediates produced in ALG11-mutant cells cannot be effectively transferred to asparagine residues by the oligosaccharyltransferase complex, resulting in under-occupied glycosylation sites and incomplete glycan structures on glycoproteins traversing the secretory pathway.[12][14][15] Many secreted and membrane proteins—including receptors, transporters, adhesion molecules, immune regulators, and coagulation factors—depend on N-glycosylation for their correct conformation and function, so hypoglycosylation can have pleiotropic effects across cell types and organ systems.[1][12][14] The 2019 phenotype expansion study provided direct evidence of hypoglycosylation of gp130, a signal-transducing receptor component for IL-6 family cytokines, in ALG11-CDG fibroblasts, suggesting that specific cytokine signaling pathways may be compromised by defective glycosylation.[1] Truncated glycans and misfolded glycoproteins may accumulate in the ER, activating the unfolded protein response (UPR), ER-associated degradation (ERAD) pathways, and potentially pro-apoptotic stress signaling, although these mechanisms have not been extensively characterized in ALG11-CDG specifically.[1][12][14] Relevant GO biological process terms capturing these mechanisms include protein N-linked glycosylation (GO:0006487), dolichol-linked oligosaccharide biosynthetic process (GO:0006488), response to endoplasmic reticulum stress (GO:0034976), and protein folding (GO:0006457), while cellular component terms include endoplasmic reticulum membrane (GO:0005789) and oligosaccharyltransferase complex (GO:0008250).[12][15]

Organ-level pathophysiology: nervous system, gastrointestinal tract, and systemic features

The organ-level manifestations of ALG11-CDG reflect the susceptibility of particular tissues to defective glycosylation and the high demand for secretory and membrane protein function in those tissues.[1][11][13] The central nervous system is especially affected, as evidenced by cerebral atrophy, hypomyelination, corpus callosum hypoplasia, seizures, and severe developmental delay in most patients.[1][5][11] Neuronal and oligodendroglial development relies on glycosylated cell adhesion molecules, growth factor receptors, and ion channels; hypoglycosylation may disrupt synaptogenesis, axonal guidance, and myelin formation, leading to global encephalopathy and epilepsy.[1][5][9] For example, hypoglycosylation of gp130 could impair IL-6 family cytokine signaling, which has roles in neurodevelopment and neuroprotection, although this remains speculative in the absence of direct data.[1] The gastrointestinal tract may be affected through impaired mucosal integrity, secretory function, and vascular stability, resulting in persistent vomiting and gastric bleeding described in several ALG11-CDG patients.[11][13] Systemic features such as abnormal fat pads, inverted nipples, and body temperature oscillation suggest disturbances in connective tissue, adipose regulation, and autonomic function, which could stem from altered glycosylation of extracellular matrix components, hormone receptors, and thermoregulatory pathways.[11][13] UBERON terms that map to affected organs include brain (UBERON:0000955), cerebral cortex (UBERON:0000956), corpus callosum (UBERON:0002315), stomach (UBERON:0000945), and subcutaneous adipose tissue (UBERON:0002185).

Causal chain from ALG11 mutation to clinical phenotype

The causal chain in ALG11-CDG can be conceptualized in hierarchical fashion, from gene to protein to pathway to organ to clinical signs.[1][12][14] Upstream, biallelic pathogenic variants in ALG11 arise in the germline and result in reduced or abolished ALG11 mRNA and protein or in structurally altered proteins with impaired mannosyltransferase activity.[10][11][14] At the molecular level, loss of ALG11 function disrupts the dolichol-linked oligosaccharide assembly required for N-glycosylation, producing truncated and inefficient LLOs that lead to hypoglycosylation of nascent polypeptides.[12][15] At the cellular level, under-glycosylated glycoproteins fail to fold correctly, are unstable, or mislocalize, and ER quality control pathways are activated, resulting in stress and possible apoptosis, particularly in secretory cells and neurons with high glycoprotein synthesis demands.[1][12][14] At the organ level, this translates into structural and functional abnormalities such as cerebral atrophy, hypomyelination, epilepsy, gastrointestinal bleeding, growth failure, and dysmorphism, as the cumulative impact of glycoprotein dysfunction in those tissues.[1][5][11][13] Downstream clinical manifestations thus include hypotonia, seizures, developmental delay, microcephaly, facial dysmorphism, failure to thrive, hearing loss, vomiting, gastric bleeding, and systemic dysautonomia, all traceable to the upstream defect in N-glycosylation caused by ALG11 mutations.[1][5][11][13]

Cell types and biological processes involved

Although detailed cell-type specific analyses are limited, the clinical phenotype suggests involvement of multiple cell populations across the nervous system, gastrointestinal tract, and other organs.[1][11][13] In the brain, neuronal cell types such as cortical pyramidal neurons (CL:0000627), interneurons, and hippocampal neurons, as well as oligodendrocytes (CL:0000128), are likely affected, given the combination of seizures, encephalopathy, and hypomyelination.[1][5][11] Within the gastrointestinal tract, epithelial cells of the gastric mucosa (CL:0000163), vascular endothelial cells (CL:0000115), and smooth muscle cells (CL:0000056) may be compromised by hypoglycosylation impacting barrier function and vascular integrity, contributing to bleeding and vomiting.[11][13] Systemic features such as abnormal fat pads and inverted nipples implicate adipocytes (CL:0000136), fibroblasts (CL:0000057), and perhaps endocrine cells, although direct histologic data are lacking.[1][13] Biological processes disrupted include cell adhesion (GO:0007155), signal transduction (GO:0007165), axon guidance (GO:0007411), myelination (GO:0042552), blood coagulation (GO:0007596), and immune system process (GO:0002376), all of which depend on properly glycosylated proteins.[1][12][14] As one illustrative example, hypoglycosylation of gp130 could impair the JAK-STAT cascade (GO:0007259) downstream of IL-6 family cytokines, potentially contributing to neurodevelopmental and immune abnormalities.[1]

7. Anatomical structures affected

Organ-level involvement

ALG11-CDG has broad organ-level involvement, with the central nervous system, gastrointestinal system, and growth-regulating systems most prominently affected.[1][11][13] The brain is the principal organ implicated, as shown by MRI evidence of cerebral atrophy, hypomyelination, and corpus callosum hypoplasia, and by clinical manifestations of seizures, profound developmental delay, and intellectual disability.[1][5][11] These findings map to UBERON structures including the cerebral cortex, white matter, and corpus callosum, and they suggest global disruption of brain development rather than focal lesions.[1][5] The gastrointestinal tract, particularly the stomach and upper gastrointestinal mucosa, is affected through persistent vomiting and gastric bleeding, which may reflect mucosal fragility or altered vascular integrity.[11][13] Growth failure points to involvement of systems governing nutrition, metabolism, and endocrine regulation, though specific endocrine abnormalities have not been systematically reported.[11][13] Hearing impairment indicates involvement of the inner ear, including cochlear structures, consistent with sensorineural hearing loss in some patients.[4][5] The skin and subcutaneous tissue are implicated by abnormal fat pads and inverted nipples, reflecting altered connective tissue and adipose distribution.[11][13]

Tissue and cell-level involvement

At the tissue level, ALG11-CDG affects nervous tissue, epithelial tissue, connective tissue, and muscular tissue.[1][11][13] Nervous tissue in the brain and spinal cord exhibits structural and functional abnormalities, including decreased myelin content (hypomyelination) and cortical atrophy, implicating both neuronal and glial populations.[1][5][11] Gastrointestinal epithelial tissue may be compromised, contributing to vomiting and bleeding, while connective tissue comprising adipose and dermal layers shows abnormal fat pad distribution and nipple inversion.[11][13] Muscular tissue, particularly skeletal muscle, is involved as evidenced by hypotonia, delayed motor development, and possibly muscle weakness, although muscle histology has not been extensively reported.[1][5][11] Cell types implicated include neurons, oligodendrocytes, astrocytes, gastric epithelial cells, endothelial cells, adipocytes, fibroblasts, and possibly hepatocytes, given the central role of the liver in glycoprotein synthesis and transferrin production.[1][11][14]

Subcellular localization: ER and glycosylation machinery

Subcellularly, ALG11-CDG is a disorder of the endoplasmic reticulum and associated glycosylation machinery.[2][12][15] ALG11 localizes to the ER membrane and catalyzes mannose transfer on the cytosolic face, so its deficiency directly impacts ER-associated processes, including LLO assembly and cotranslational glycosylation.[2][12] Defective LLO assembly may cause accumulation of truncated intermediates within the ER membrane, potentially deranging membrane composition and interacting with other ER-resident enzymes and chaperones.[12][14][15] ER stress and activation of unfolded protein response pathways likely occur secondary to the accumulation of misfolded hypoglycosylated glycoproteins, although specific markers such as BiP or CHOP have not been reported in ALG11-CDG fibroblasts.[1][12][14] Golgi apparatus function may also be indirectly affected, as glycoproteins exiting the ER with inadequate glycan structures may not be properly processed by Golgi glycosidases and glycosyltransferases, leading to global changes in glycan profiles.[12][14] GO cellular component terms relevant here include endoplasmic reticulum (GO:0005783), endoplasmic reticulum membrane (GO:0005789), Golgi apparatus (GO:0005794), and cytosol (GO:0005829).[12][15]

Localization patterns and lateralization

Structural brain abnormalities in ALG11-CDG, such as cerebral atrophy and hypomyelination, appear diffuse and symmetric rather than unilateral or focal, consistent with a global congenital metabolic defect.[1][5][11] Corpus callosum hypoplasia is a midline abnormality, indicating disruption of commissural fiber development rather than lateralized pathology.[5][11] Clinical signs such as seizures and hypotonia likewise suggest diffuse cortical and subcortical involvement without consistent lateralization, although EEG patterns may show asymmetric features that have not been systematically detailed.[5][9] Ocular findings like strabismus and hearing loss may be unilateral or bilateral, but reported cases describe them qualitatively without specifying lateralization; given the systemic nature of glycosylation defects, bilateral involvement is plausible.[4][13] Gastrointestinal bleeding and vomiting are system-wide phenomena rather than localized to a particular stomach region, though this has not been anatomically mapped in detail.[11][13]

8. Temporal development and natural history

Age of onset and initial presentation

ALG11-CDG is a congenital disorder, with manifestations arising in the neonatal or early infantile period.[1][5][11] Many patients are noted to have hypotonia, feeding difficulties, or failure to thrive in the first months of life, and developmental delay becomes increasingly apparent as motor and language milestones fail to be achieved.[1][5][11] Microcephaly may be present at birth or emerge as a progressive reduction in head growth relative to age norms, and craniofacial dysmorphism becomes more evident with age.[4][13] Seizures often begin in infancy, with myoclonic, focal, or generalized events that quickly become refractory to standard antiepileptic drugs; EEG abnormalities such as burst-suppression patterns are seen in severe cases.[5][9] Thus, the typical onset is early pediatric, chronic, and insidious, although some manifestations (seizures, gastric bleeding) may present acutely.[1][5][11]

Disease progression, stages, and rate

The disease course in ALG11-CDG is generally severe and either progressive or static at a markedly impaired level of functioning.[1][5][11] Early childhood is characterized by increasing developmental lag compared to peers, with most children failing to achieve independent walking, meaningful speech, or self-care; hypotonia may evolve into spasticity or dystonia in some CDG disorders, although specific motor pattern evolution in ALG11-CDG is incompletely described.[1][11][13] Neuroimaging evidence of progressive cerebral atrophy and hypomyelination in Erdal’s case indicates that structural brain degeneration continues during early childhood, likely contributing to worsening epilepsy and cognitive impairment.[5] Seizure burden may remain high despite polytherapy, and EEG background suppression can persist, indicating a chronic epileptic encephalopathy.[5][9] Systemic complications such as gastric bleeding and failure to thrive may recur episodically, but overall the disease trajectory is one of chronic, lifelong disability with limited or no improvement over time, in contrast to some milder CDG forms where partial compensation occurs.[1][11][13]

Remission patterns and critical windows for intervention

Spontaneous remission of core neurological features such as seizures, developmental delay, or structural brain abnormalities has not been reported in ALG11-CDG.[1][5][11] However, the epilepsy abstract noted partial electrographic and clinical response to topiramate in two patients with burst-suppression EEG, including reduction in seizure duration and clustering and some seizure-free awake periods, although developmental progress remained minimal.[9] This suggests that pharmacologic modulation of seizure activity can alter symptomatic burden but does not reverse underlying encephalopathy, which is rooted in a pervasive glycosylation defect.[1][9] Critical periods in early brain development, including prenatal and early postnatal phases, likely represent windows during which ALG11 deficiency exerts its most profound effects on cortical organization and myelination; interventions aimed at correcting glycosylation (e.g., hypothetical gene therapy) would theoretically need to be delivered very early to prevent irreversible structural damage.[1][5][14] For now, critical windows in clinical practice revolve around early diagnosis, initiation of supportive care, optimization of seizure control, and nutritional support to minimize preventable complications.[1][5][13]

9. Inheritance, population, and epidemiology

Autosomal recessive inheritance, penetrance, and expressivity

ALG11-CDG follows an autosomal recessive inheritance pattern, as documented by OMIM, ClinGen, and primary clinical reports.[10][14][16] Rind et al.’s initial description showed affected siblings born to unaffected parents, consistent with recessive inheritance, and segregation analysis in other families corroborates this pattern.[14][11] OMIM entry 613661 explicitly states that CDG1P is caused by homozygous or compound heterozygous mutations in ALG11, and ClinGen’s curation classifies ALG11-CDG as an autosomal recessive condition with strong gene–disease evidence.[10][16] Penetrance appears to be complete for individuals with bi-allelic loss-of-function ALG11 variants; all reported homozygotes or compound heterozygotes exhibit severe multisystem disease, though exact phenotypic features may vary.[1][10][11] Expressivity is variable across patients, particularly with respect to the presence or severity of certain features such as gastric bleeding, fat pad anomalies, and transferrin glycosylation abnormalities, which can be absent in some individuals.[1][11][13] Notably, the 2019 study reported a patient with normal transferrin glycosylation despite typical clinical and cellular features of ALG11-CDG, highlighting biochemical variability and suggesting that some variants or genetic backgrounds modulate specific phenotypic components.[1] There is no evidence for genetic anticipation, germline mosaicism, or dominant transmission in ALG11-CDG, further reinforcing its classic autosomal recessive profile.[10][14][16]

Consanguinity, founder effects, and carrier frequency

Several CDG subtypes are more prevalent in consanguineous populations due to increased homozygosity for rare recessive alleles, and ALG11-CDG likely follows this pattern, although explicit data on consanguinity rates are limited.[11][14][16] Rind et al. and subsequent authors have reported families where affected children are born to parents from related or genetically isolated populations, but the small number of cases precludes robust quantification.[11][14] ClinGen’s identification of at least 14 unique variants, many in individual families, suggests that ALG11-CDG is largely composed of private mutations and that no major founder alleles drive disease prevalence in specific ethnic groups.[10] Carrier frequency is unknown but presumed to be extremely low, given the paucity of reported cases and absence of common pathogenic variants in population databases.[10][16] Genetic counseling for affected families thus focuses on recurrence risk in future pregnancies (25% for autosomal recessive inheritance) and carrier testing in relatives, rather than population-wide screening based on carrier rates.[10][13][16]

Prevalence, incidence, and demographic distribution

Formal epidemiologic estimates of ALG11-CDG prevalence and incidence are not available, but the disease can reasonably be classified as ultra-rare, with fewer than a few dozen cases reported worldwide.[1][5][10][11] The 2019 phenotype expansion paper noted that, at the time, only ten patients had been described with ALG11-CDG, and later reports such as Erdal’s case and additional ClinGen curation have increased that number modestly.[1][5][10] Orphanet often categorizes such diseases as having a prevalence lower than 1 per million, although specific figures are not provided for ALG11-CDG.[13][16] There is no clear evidence of sex predilection; both males and females are affected, and the sex ratio appears approximately equal across reported cases.[1][11][14] Age distribution is heavily skewed toward infancy and early childhood, as most patients are diagnosed in this period and severe disability and possible early mortality limit survival into adulthood, although formal survival analyses have not been published.[1][5][11] Geographic distribution is global but highly scattered, with cases reported from diverse regions including Europe and the Middle East; no endemic areas or population clusters have been identified.[1][5][11][14]

10. Diagnostics and screening

Clinical evaluation and laboratory testing

Diagnosis of ALG11-CDG begins with recognition of a suggestive clinical constellation: early-onset hypotonia, severe developmental delay, microcephaly, facial dysmorphism, seizures (often drug-resistant), failure to thrive, and possible gastrointestinal bleeding and hearing loss.[1][5][11][13] Laboratory evaluation typically includes assessment of basic metabolic parameters, which are often unremarkable, followed by specialized tests for congenital disorders of glycosylation, most notably serum transferrin isoform analysis.[5][11][14] Many CDG type I disorders show characteristic abnormal transferrin glycosylation, with increased asialotransferrin and disialotransferrin; Erdal et al. detected a CDG type I pattern by capillary zone electrophoresis in their ALG11-CDG patient, confirming N-glycosylation defects.[5][8] However, the 2019 study reported a patient with normal transferrin glycosylation despite cellular evidence of ALG11 deficiency, indicating that transferrin analysis can be falsely negative in some ALG11-CDG cases.[1] Hypoglycosylation of gp130 has emerged as a novel biomarker; the 2019 study showed that gp130, a glycoprotein, is hypoglycosylated in patient fibroblasts, suggesting that immunoblot analysis of gp130 glycoforms might serve as a diagnostic adjunct.[1] Routine laboratory tests such as liver enzymes, coagulation profiles, and endocrine panels may show mild abnormalities but are not specific, and comprehensive metabolic screening in Erdal’s case was unremarkable.[5]

Neuroimaging and electrophysiology

Neuroimaging and electrophysiology provide important diagnostic clues and help characterize disease severity.[1][5][9][11] Brain MRI in ALG11-CDG commonly shows cerebral atrophy, hypomyelination, and corpus callosum hypoplasia, as described in Erdal’s patient and summarized in the 2015 ALG11-CDG study.[5][11] These structural abnormalities, although not pathognomonic, strongly suggest a congenital neurodevelopmental disorder and can help differentiate ALG11-CDG from other causes of epileptic encephalopathy and developmental delay.[1][5] EEG findings may include severe background attenuation and a burst-suppression pattern, which was highlighted as a characteristic feature of severe developmental and epileptic encephalopathy associated with ALG11-CDG in an epilepsy abstract.[9] The abstract noted that “Further EEG showed striking periods of background attenuation or suppression approximating a burst-suppression pattern” and that similar patterns were reported by Regal et al. in a child with early-onset drug-resistant epilepsy and severe developmental delay.[9] While EEG abnormalities are not specific to ALG11-CDG, recognition of burst-suppression in a child with CDG-like features should prompt consideration of ALG11-CDG among differential diagnoses.[1][5][9]

Genetic testing: exome sequencing and targeted analysis

Genetic testing is the definitive diagnostic modality for ALG11-CDG, given the monogenic nature of the disease and the existence of multiple CDG subtypes with overlapping clinical features.[5][10][11] Whole exome sequencing (WES) has proven particularly valuable; Erdal et al. used WES to identify compound heterozygous mutations in ALG11 in their patient, including a novel c.476T>C variant, following unremarkable basic metabolic investigations.[5][8] WES and gene panels focused on congenital disorders of glycosylation enable simultaneous evaluation of multiple glycosylation genes, which is important because overlapping phenotypes can be caused by mutations in different ALG or other glycosylation-related genes.[1][11][16] Single-gene testing for ALG11, via Sanger sequencing or targeted next-generation sequencing of its exons and flanking intronic regions, may be considered when transferrin analysis or other biochemical tests strongly suggest CDG type Ip, although the possibility of normal transferrin in ALG11-CDG makes reliance on biochemical screening alone risky.[1][5] ClinVar and the Genetic Testing Registry list pathogenic ALG11 variants and available clinical tests, providing resources for laboratories and clinicians.[7][17] Chromosomal microarray and karyotyping are generally less informative, as ALG11-CDG arises from point mutations and small indels rather than large structural variants; however, these tests may be part of standard workups for developmental delay and epilepsy.[5][11][16]

Omics-based diagnostics and molecular profiling

Beyond DNA sequencing, other omics technologies have begun to inform CDG diagnostics, although specific applications to ALG11-CDG are still emerging.[1][5][11] Transcriptomics (RNA sequencing) could detect aberrant splicing or reduced ALG11 transcript abundance in cases with splice-site mutations, and proteomics could reveal hypoglycosylated glycoprotein profiles, including altered glycoforms of gp130 and transferrin.[1] Metabolomics might detect changes in GDP-mannose or related sugar nucleotide pools, but the primary defect in ALG11-CDG is in glycosylation, not in metabolic generation of donors, so metabolite changes may be subtle.[12][15] Liquid biopsy approaches, such as circulating glycoprotein glycoform analyses, may enhance non-invasive detection of N-glycosylation defects and differentiate CDG subtypes based on specific glycan signatures, though such tools are in research stages.[1][12] At present, however, DNA-based diagnostics (WES, targeted ALG11 sequencing) remain the mainstay, supplemented by transferrin isoform analysis and possibly gp130 glycosylation assessment.[1][5][11]

Clinical criteria and differential diagnosis

There are no formal diagnostic criteria specific to ALG11-CDG issued by professional societies, but clinical recognition relies on the combination of early-onset neurodevelopmental impairment, epilepsy, dysmorphism, failure to thrive, and evidence of N-glycosylation defects.[1][11][13] Differential diagnoses include other congenital disorders of glycosylation (e.g., PMM2-CDG, ALG6-CDG, ALG3-CDG), mitochondrial disorders, inborn errors of metabolism affecting amino acid or organic acid pathways, and genetic epileptic encephalopathies unrelated to glycosylation.[1][11] Distinguishing ALG11-CDG from other CDG types may rely on specific biochemical patterns, such as the exact transferrin isoform profile and gp130 hypoglycosylation, as well as genetic findings.[1][11] The presence of hearing impairment, gastric bleeding, and characteristic craniofacial features may narrow the differential, though overlapping features exist across CDG subtypes.[4][11][13] Because transferrin analysis can be normal in some ALG11-CDG patients, reliance on clinical criteria alone is insufficient, and exome sequencing or CDG-focused gene panels are essential for accurate diagnosis.[1][5][11]

Screening and early detection

Population-based screening programs for ALG11-CDG do not currently exist, given the disease’s ultra-rare prevalence and lack of simple, high-throughput screening assays.[13][16] Newborn screening panels do not include CDG type Ip, and the complexity of glycosylation assays and the wide spectrum of CDG genes pose technical and economic challenges for population-level screening.[1][13] Carrier screening for ALG11 variants is also not widely implemented outside of affected families, where cascade testing of relatives may be appropriate to inform reproductive planning.[10][13][16] Prenatal testing and preimplantation genetic diagnosis are theoretically feasible when familial ALG11 mutations have been identified, allowing detection of affected embryos or fetuses, but specific case reports of such interventions are not present in the current literature.[10][13] Early detection in practice relies on prompt recognition of suggestive clinical features, referral to metabolic and genetics specialists, and utilization of exome sequencing, which is increasingly available for infants and children with unexplained neurodevelopmental syndromes.[5][11]

11. Outcome and prognosis

Survival, mortality, and life expectancy

Formal survival analyses for ALG11-CDG are not available, but clinical reports suggest that the disease is associated with significant morbidity and potential early mortality.[1][5][11] Some CDG type I disorders, such as PMM2-CDG, have well-documented mortality rates in infancy and early childhood due to multiorgan failure, while others allow survival into adulthood; the small number of ALG11-CDG cases makes it difficult to place it precisely on this spectrum.[1][11][16] Rind et al. described severe disease and poor outcomes in their initial patients, and subsequent reports characterized ALG11-CDG as a severe metabolic disease, though some children have survived into later childhood with persistent profound disability.[11][14] Orphanet’s general description of ALG11-CDG implies that failure to thrive, intractable seizures, and gastrointestinal bleeding may contribute to life-threatening complications, but explicit data on mortality rates are absent.[13] Life expectancy likely depends on the severity of neurological involvement, seizure control, nutritional status, infection risk, and access to comprehensive care; in severe cases with burst-suppression EEG and progressive cerebral atrophy, prognosis may be particularly guarded.[1][5][9]

Morbidity, disability, and quality of life

Morbidity is high in ALG11-CDG, with affected individuals experiencing profound developmental disability, ongoing seizures, feeding difficulties, and systemic complications.[1][5][11] Developmental outcomes are generally poor; most children remain non-ambulatory, non-verbal, and fully dependent for activities of daily living, with minimal progress even when seizure control improves.[1][9][11] Seizures can be frequent, prolonged, and refractory to multiple antiepileptic drugs, contributing to recurrent hospitalizations, risk of injury, and caregiver stress.[5][9] Feeding problems and failure to thrive may require nutritional interventions, including gastrostomy tube placement, and gastrointestinal bleeding can be painful and acutely dangerous.[11][13] Hearing impairment further limits communication, and facial dysmorphism and abnormal fat pads may contribute to social stigma.[4][13] Formal quality-of-life measures such as EQ-5D or SF-36 have not been reported in ALG11-CDG, but the constellation of neurological and systemic disabilities indicates severely reduced health-related quality of life for patients and substantial psychosocial impact on families.[1][5][13]

Disease course and complications

The disease course is dominated by chronic neurologic impairment and recurrent complications related to seizures, nutrition, and gastrointestinal bleeding.[1][5][11] Epileptic encephalopathy with burst-suppression EEG is associated with high seizure burden and risk of status epilepticus, which can cause additional brain injury and acute life-threatening events.[5][9] Progressive cerebral atrophy and hypomyelination may predispose to movement disorders, spasticity, and orthopaedic complications, though these have not been extensively described.[5][11] Failure to thrive and feeding difficulties can lead to malnutrition, aspiration pneumonia, and delayed wound healing, while gastric bleeding poses risks of anemia, hemodynamic instability, and need for transfusions.[11][13] Infections, particularly respiratory infections, may be more frequent due to immobility, aspiration, and possibly immunologic effects of hypoglycosylated immune proteins, though specific data are sparse.[1][11] Long-term complications could include scoliosis, contractures, and other musculoskeletal issues related to immobility and hypotonia.[1][11]

Prognostic factors and biomarkers

Prognostic factors in ALG11-CDG are not formally defined, but severity of neurological involvement, seizure burden, and structural brain abnormalities appear to correlate with poor outcomes.[1][5][9][11] Burst-suppression EEG patterns and profound background attenuation are typically markers of severe encephalopathy and have been associated with limited developmental progress in ALG11-CDG patients.[5][9] Progressive cerebral atrophy and hypomyelination on MRI may predict worsening cognitive and motor impairment.[5][11] Biochemical markers such as the degree of transferrin hypoglycosylation or gp130 hypoglycosylation could hypothetically correlate with functional deficits, but this has not been systematically studied, and the existence of patients with normal transferrin profiles yet severe disease complicates this assumption.[1] Genetic factors, such as whether variants are null or hypomorphic, might influence residual enzyme activity and thus clinical severity; for example, missense variants with partial function could allow slightly milder phenotypes, though most reported cases have been severe regardless of variant type.[11][14] Ultimately, prognosis in ALG11-CDG is guarded, and clinicians must rely on individualized assessments of neurologic status, seizure control, growth, and comorbidities rather than validated prognostic models.[1][5][11]

12. Treatment and management

Pharmacotherapy: seizure management and symptomatic treatment

There is no disease-specific pharmacologic therapy that corrects the underlying glycosylation defect in ALG11-CDG, so treatment focuses on symptom management and supportive care.[1][5][11][13] Seizure control is a central therapeutic goal; multiple antiepileptic drugs are typically used, with variable success in reducing seizure frequency and severity.[5][9] An epilepsy abstract described a child with severe drug-resistant epilepsy and burst-suppression EEG in whom topiramate reduced seizure duration and clustering and decreased the need for emergency medications, leading to some awake periods that were seizure-free, although developmental progress remained minimal.[9] The authors concluded that “Topiramate may be a helpful therapeutic option” in ALG11-CDG, suggesting that certain antiepileptic agents may be especially useful in managing this form of epileptic encephalopathy.[9] Other antiseizure drugs such as levetiracetam, valproate, or benzodiazepines may be used empirically, but no systematic comparative data are available.[5][9] Symptomatic pharmacotherapy for gastrointestinal symptoms may include proton pump inhibitors, antiemetics, and agents to manage bleeding, while nutritional supplements and possibly growth hormone or endocrine therapies could be considered for failure to thrive, though evidence is anecdotal.[11][13] NCIT clinical intervention terms relevant here include antiepileptic therapy (NCIT:C1565), topiramate (NCIT:C806), and supportive care (NCIT:C16043).

Supportive and rehabilitative care

Given the profound disability associated with ALG11-CDG, supportive care and rehabilitation are crucial components of management.[1][5][11][13] Nutritional support, including specialized feeding regimens, thickened feeds, and potentially gastrostomy tube placement, can help address feeding difficulties and failure to thrive, and may reduce aspiration risk.[11][13] Physical therapy, occupational therapy, and speech therapy aim to maximize residual motor and communication abilities, prevent contractures and secondary musculoskeletal complications, and support caregiver training.[1][5][11] Orthotic devices and adaptive equipment can assist with positioning, mobility, and activities of daily living, while hearing aids or cochlear implants may be considered for sensorineural hearing loss, though cognitive impairment may limit benefit.[4][5] Psychological and social support for families, including respite care and counseling, are essential to mitigate caregiver burden and improve overall quality of life.[1][13] NCIT terms applicable here include physical therapy (NCIT:C20343), occupational therapy (NCIT:C15219), speech therapy (NCIT:C15397), and nutritional support (NCIT:C61493).

Advanced therapeutics and experimental approaches

As of the latest reports, no gene therapy, enzyme replacement therapy, or substrate supplementation strategy has been developed specifically for ALG11-CDG.[1][5][11][13] In some CDG types, such as MPI-CDG, mannose supplementation can partially correct glycosylation defects by increasing substrate availability, but in ALG11-CDG the defect lies in the enzyme that transfers GDP-mannose to the LLO, so simple mannose supplementation would not bypass the loss-of-function of ALG11.[12][14][15] Gene therapy using viral vectors to deliver a functional ALG11 gene to affected tissues could theoretically correct the biochemical defect, but the challenges of widespread delivery to the brain and other organs, early timing, and long-term safety have precluded clinical implementation, and no trials are currently reported.[1][12] RNA-based therapies such as antisense oligonucleotides or mRNA replacement are conceptually attractive but would require overcoming similar delivery and expression hurdles.[1][12] Cell therapy approaches, such as transplantation of stem cells engineered to express functional ALG11, face even greater obstacles and have not been explored.[1] Experimental strategies for CDG more broadly include chaperone therapy and modulation of ER stress pathways, but these remain in preclinical or conceptual stages and have not been specifically applied to ALG11-CDG.[1][12][14]

Treatment outcomes and personalized medicine

Treatment outcomes in ALG11-CDG are modest, reflecting the inability of current therapies to address the underlying glycosylation defect.[1][5][9][11] Symptomatic pharmacotherapy, particularly antiepileptic drugs, can reduce seizure burden and improve comfort, but does not reverse developmental deficits or structural brain abnormalities.[5][9] Supportive care and rehabilitation may prevent complications and enhance quality of life, but gains in functional independence are limited by severe encephalopathy.[1][11] Personalized medicine approaches, such as tailoring antiepileptic drug regimens to individual EEG profiles or selecting nutritional strategies based on specific gastrointestinal symptoms, are used in practice, but genotype-guided treatment has not been realized because variant type has not yet been linked to differential therapeutic responsiveness.[5][9][11] As genetic diagnostics become more widespread, early identification of ALG11-CDG may allow earlier initiation of supportive care and potentially future participation in clinical trials, but for now, management remains largely empirical and palliative.[1][5][11][13]

13. Prevention and counseling

Primary, secondary, and tertiary prevention

Primary prevention of ALG11-CDG would require preventing the birth of affected individuals, which in the context of an autosomal recessive disease primarily involves reproductive genetic counseling and carrier testing in families with known pathogenic ALG11 variants.[10][13][16] Population-wide primary prevention through carrier screening is currently impractical due to the disease’s ultra-rare prevalence and the absence of common founder mutations.[10][16] Secondary prevention focuses on early detection and early intervention to reduce disease impact; prompt recognition of CDG-like features and use of exome sequencing can shorten the diagnostic odyssey and allow earlier initiation of seizure management, nutritional support, and rehabilitation.[5][11] Tertiary prevention aims to prevent complications in individuals with established disease, such as aspiration pneumonia, severe malnutrition, contractures, and injuries from seizures, through comprehensive multidisciplinary care and monitoring.[1][11][13] NCIT terms reflecting these levels of prevention include primary prevention (NCIT:C15273), secondary prevention (NCIT:C15274), and tertiary prevention (NCIT:C15275).

Genetic counseling, prenatal diagnosis, and reproductive options

Genetic counseling is essential for families affected by ALG11-CDG, given its autosomal recessive inheritance and high recurrence risk.[10][13][16] Counselors can explain that each subsequent child of two carrier parents has a 25% chance of being affected, a 50% chance of being a carrier, and a 25% chance of being unaffected and not a carrier, assuming classic Mendelian segregation.[10][16] When familial ALG11 mutations have been identified, prenatal diagnosis via chorionic villus sampling or amniocentesis with targeted sequencing for those variants is feasible, allowing parents to make informed reproductive decisions.[10][13] Preimplantation genetic diagnosis (PGD) in the context of in vitro fertilization can permit selection of embryos without biallelic pathogenic ALG11 variants, preventing the birth of affected children, although access to such procedures may be limited.[10][13] Carrier testing for at-risk relatives, such as siblings of affected individuals, can inform their reproductive choices as adults.[10][13][16] Genetic counseling should also address psychosocial aspects, expectations regarding disease course, and the current lack of curative therapies, helping families balance hope with realistic planning.[1][11][13]

Public health and risk stratification

Because ALG11-CDG is ultra-rare, public health interventions at the population level are not focused on this specific disease, but rather on improving recognition and care for rare disorders in general.[13][16] Risk stratification for ALG11-CDG is primarily genetic (carrier status), and current technologies such as exome sequencing can identify pathogenic ALG11 variants in undiagnosed children, thereby stratifying them into appropriate metabolic and genetic care pathways.[5][11] Broader public health efforts to educate clinicians about CDG presentations, improve access to genetic testing, and develop registries for rare metabolic diseases indirectly benefit ALG11-CDG patients by facilitating earlier diagnosis and coordination of care.[1][13][16] Environmental interventions, vaccinations, and behavioral modifications have no direct role in preventing ALG11-CDG onset, but standard pediatric preventive measures remain important to reduce infection burden and complications in affected children.[13][16]

14. Other species and natural disease

Orthologous genes and comparative biology

ALG11 is conserved across eukaryotes, with orthologous genes present in species such as Saccharomyces cerevisiae, where ALG11 was originally characterized in detail.[15] The yeast ALG11 gene encodes a mannosyltransferase that adds terminal mannose residues to LLO intermediates, and its deletion causes growth defects and temperature-sensitive lethality, underscoring the essential nature of ALG11-mediated glycosylation across species.[15] NCBI Gene lists ALG11 orthologs in other organisms, although specific details are not provided in the search results; these orthologs support the evolutionary conservation of N-glycosylation pathways.[3][6][15] Comparative studies between yeast and human ALG11 have been instrumental in understanding the biochemical role of ALG11 and in interpreting the impact of human variants.[14][15]

Natural disease in animals and veterinary relevance

The search results do not provide evidence of naturally occurring ALG11-CDG-like diseases in companion animals or livestock, and no OMIA entries have been cited for ALG11.[1][13][15] Given the conserved nature of N-glycosylation, it is plausible that loss-of-function mutations in ALG11 orthologs in animals could cause similar multisystem disorders, but such conditions may be embryonically lethal or unrecognized due to early mortality.[15] Veterinary relevance is thus mainly conceptual; insights from human ALG11-CDG and yeast ALG11 function could inform understanding of glycosylation disorders in animals, but no specific animal disease entity has been defined.[1][15]

Transmission and zoonotic potential

ALG11-CDG is a non-infectious congenital disorder and has no zoonotic potential or transmissibility between species.[1][13][16] Transmission occurs solely via inheritance of germline ALG11 variants within human families and does not involve infectious agents or cross-species spread.[10][16]

15. Model organisms and experimental systems

Yeast ALG11 as a model for human disease

Saccharomyces cerevisiae serves as a key model organism for studying ALG11 function and, by extension, the pathophysiology of ALG11-CDG.[15] Cipollo et al. demonstrated that the yeast ALG11 gene specifies addition of terminal mannose residues to Man(_4)GlcNAc(_2)-PP-dolichol, and that deletion of ALG11 leads to accumulation of Man(_3)GlcNAc(_2)-PP-dolichol and Man(_4)GlcNAc(_2)-PP-dolichol, poor growth, and temperature-sensitive lethality.[15] These phenotypes in yeast recapitulate the fundamental biochemical defect seen in human ALG11-CDG—truncated LLO intermediates and impaired N-glycosylation—and provide a platform for dissecting enzymatic function, substrate specificity, and interaction with other glycosylation enzymes.[12][15] Yeast models can also be used to test the functional impact of specific human ALG11 mutations by expressing mutant human alleles in yeast or by creating analogous mutations in yeast ALG11, enabling genotype–phenotype correlations and assessment of residual activity.[14][15] GO and SGD annotations for yeast ALG11 capture its role in protein glycosylation and dolichol-linked oligosaccharide assembly, providing mechanistic insight that informs interpretation of human variants.[12][15]

Cellular models: patient fibroblasts and in vitro systems

Patient-derived fibroblasts are an important in vitro model for ALG11-CDG, allowing direct analysis of glycosylation defects and biomarker profiles.[1][14] Rind et al. used fibroblasts from ALG11-CDG patients to examine LLO structures and showed truncated precursor glycans, confirming defective mannose addition.[14] The 2019 phenotype expansion study assessed gp130 glycosylation in fibroblasts and found hypoglycosylation of this biomarker, illustrating the utility of fibroblasts for investigating specific glycoproteins.[1] Cellular models also permit exploration of ER stress responses, expression of other glycosylation genes, and potential pharmacologic interventions that might modulate glycosylation or mitigate downstream consequences.[1][12][14] Engineered cell lines with CRISPR/Cas9-mediated ALG11 knockout or knockdown could serve as additional models, though these are not specifically described in the current search results; they would be expected to display hypoglycosylation and ER stress phenotypes similar to patient fibroblasts.[1][12]

Animal models and limitations

No specific mammalian animal models (e.g., mouse, zebrafish) for ALG11-CDG are mentioned in the search results, suggesting that such models may not yet exist or have not been widely reported.[1][11][15] The essential nature of ALG11-mediated glycosylation raises the possibility that complete loss-of-function in mice or other vertebrate models might be embryonically lethal, limiting the feasibility of conventional knockouts and necessitating conditional or hypomorphic models to study postnatal phenotypes.[15] In the absence of animal models, extrapolation from yeast and cellular data provides a partial understanding of pathophysiology but cannot fully recapitulate complex organ-level manifestations such as cerebral atrophy and hypomyelination.[1][14][15] Future development of conditional ALG11 knockouts in neural or hepatic tissues could help disentangle tissue-specific roles and inform therapeutic strategies, but for now, the lack of in vivo vertebrate models is a significant limitation in translational research.[1][11][15]

Applications of models in research

Existing models—yeast ALG11 mutants and patient fibroblasts—have been applied to define the biochemical defect in ALG11-CDG, explore glycan structure, and identify biomarkers such as gp130 hypoglycosylation.[1][14][15] These models provide platforms for screening potential small molecules or genetic interventions that could modulate glycosylation, stabilize truncated LLOs, or alleviate ER stress, although such applications remain largely conceptual.[1][12][15] Yeast models, in particular, offer the advantage of rapid growth, genetic manipulability, and ease of biochemical analysis, making them ideal for structure–function studies of ALG11 and for testing human variant function.[15] Patient fibroblasts allow investigation of human-specific aspects, including interactions with human ER chaperones, glycosyltransferases, and glycoprotein substrates.[1][14] As the field of CDG research advances, integration of multi-omics data from these models, such as transcriptomics, proteomics, and glycomics, may yield deeper insights into the global impact of ALG11 deficiency and identify potential therapeutic targets.[1][12]

16. Conclusion and future directions

ALG11-congenital disorder of glycosylation is a paradigmatic example of a rare, severe, monogenic metabolic disease that illuminates the critical role of N-linked glycosylation in human development and organ function.[1][12][14][16] Caused by biallelic loss-of-function variants in the ALG11 gene, an ER alpha-1,2-mannosyltransferase responsible for adding the fourth and fifth mannose residues to the dolichol-linked oligosaccharide precursor, ALG11-CDG disrupts the early steps of N-glycosylation and leads to widespread hypoglycosylation of glycoproteins.[2][12][15] Clinically, it presents as a multisystem disorder dominated by severe neurodevelopmental impairment, epileptic encephalopathy with characteristic burst-suppression EEG patterns, microcephaly, facial dysmorphism, failure to thrive, hearing impairment, and gastrointestinal bleeding, with additional systemic features such as abnormal fat pads, inverted nipples, and body temperature instability.[1][5][9][11][13] Biochemically, many patients show a CDG type I transferrin pattern and hypoglycosylation of gp130, although transferrin can be normal in some cases, underscoring the need for comprehensive biochemical and genetic diagnostics.[1][5][8][11]

Despite major advances in understanding the molecular mechanism and clinical phenotype, significant gaps remain. The small number of reported patients limits robust epidemiologic data, natural history characterization, and genotype–phenotype correlations.[1][10][11] No curative therapies exist, and management remains focused on symptomatic treatment—particularly seizure control with agents such as topiramate—and supportive care to address feeding difficulties, disability, and systemic complications.[5][9][11][13] There is no clear evidence of environmental risk factors or protective modifiers, and epigenetic and multi-omics profiling of ALG11-CDG patients has yet to be undertaken, representing an important area for future research.[1][12] Animal models in vertebrates are lacking, though yeast and cellular models provide valuable insight into ALG11 function and glycosylation defects.[14][15]

Future directions for ALG11-CDG research and clinical care include expanding case registries to capture more patients and longitudinal data, enabling better characterization of natural history, prognosis, and treatment response.[1][10][11] Development of standardized clinical and biochemical diagnostic criteria, incorporating transferrin profiling, gp130 glycosylation, and exome sequencing, will improve detection and classification of ALG11-CDG among the diverse CDG spectrum.[1][5][11] On the mechanistic front, deeper exploration of ER stress responses, downstream signaling pathways (such as IL-6/gp130/JAK-STAT), and cell-type specific vulnerability in the brain and gastrointestinal tract could yield targets for adjunctive therapies.[1][12][14] Emerging technologies in gene and RNA therapy may eventually offer avenues for correcting ALG11 deficiency, particularly if delivery to the brain and systemic tissues can be achieved early in development; however, such approaches are currently speculative and will require extensive preclinical modeling.[1][12][15]

For now, ALG11-CDG exemplifies the importance of integrating clinical observation, biochemical analysis, genetic testing, and model organism research to build a comprehensive understanding of a rare Mendelian disease. Continued collaboration between metabolic specialists, neurologists, geneticists, basic scientists, and patient families will be essential to advance knowledge, improve diagnostic pathways, and ultimately strive toward more effective therapies for ALG11-congenital disorder of glycosylation and related glycosylation disorders.[1][11][14][16]

Reference Validation

No PMID or DOI references were found in this report.

Term Validation

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

Outcome Count
Terms checked 68
Resolved 66
Unresolved (possible confabulation) 0
Obsolete 2
Unverifiable 0
Terms whose name was checked 60
Terms named correctly 34
Terms named as a different term 17
Terms whose name is worth a second look 9

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:

  • HP:0010818 (2 mentions) - the report calls it "Burst-suppression pattern on EEG", "Burst suppression pattern on EEG"; HP calls it Generalized tonic seizure
  • HP:0000301 (1 mention) - the report calls it "Long philtrum"; HP calls it Abnormality of facial musculature
  • HP:0000951 (1 mention) - the report calls it "Abnormal subcutaneous fat distribution"; HP calls it Abnormality of the skin
  • HP:0006706 (1 mention) - the report calls it "Inverted nipples"; HP calls it Cystic liver disease
  • HP:0012348 (1 mention) - the report calls it "Abnormal glycosylation"; HP calls it Decreased galactosylation of N-linked protein glycosylation
  • UBERON:0002315 (1 mention) - the report calls it "corpus callosum"; UBERON calls it gray matter of spinal cord
  • UBERON:0002185 (1 mention) - the report calls it "subcutaneous adipose tissue"; UBERON calls it bronchus
  • NCIT:C1565 (1 mention) - the report calls it "antiepileptic therapy"; NCIT calls it Aloe Vera Gel
  • NCIT:C806 (1 mention) - the report calls it "topiramate"; NCIT calls it Rhodamine
  • NCIT:C16043 (1 mention) - the report calls it "supportive care"; NCIT calls it Electron Microscopy Facility
  • NCIT:C20343 (1 mention) - the report calls it "physical therapy"; NCIT calls it Human Glandular Kallikrein
  • NCIT:C15219 (1 mention) - the report calls it "occupational therapy"; NCIT calls it Health Care Delivery
  • NCIT:C15397 (1 mention) - the report calls it "speech therapy"; NCIT calls it Bladder Irrigation
  • NCIT:C61493 (1 mention) - the report calls it "nutritional support"; NCIT calls it Gebasaxturev
  • NCIT:C15273 (1 mention) - the report calls it "primary prevention"; NCIT calls it Longitudinal Study
  • NCIT:C15274 (1 mention) - the report calls it "secondary prevention"; NCIT calls it Lung Transplantation
  • NCIT:C15275 (1 mention) - the report calls it "tertiary prevention"; NCIT calls it Lymphadenectomy

Obsolete terms

These terms are real but deprecated. Citing one is not a fabrication; it does mean the report is naming something the ontology has retired:

  • CL:0000627 (obsolete transporting cell) (1 mention)
  • NCIT:C20343 (Human Glandular Kallikrein) (1 mention)

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:

  • HP:0002123 (1 mention) - the report calls it "Myoclonic seizures"; HP calls it Generalized myoclonic seizure, and lists "Myoclonus seizures" among its other names
  • HP:0001263 (1 mention) - the report calls it "Developmental delay"; HP calls it Global developmental delay, and lists "Developmental delay" among its other names
  • HP:0011344 (1 mention) - the report calls it "Severe neurodevelopmental delay"; HP calls it Severe global developmental delay
  • HP:0002353 (1 mention) - the report calls it "Abnormal electroencephalogram"; HP calls it EEG abnormality, and lists "Abnormal electroencephalogram" among its other names
  • HP:0005968 (1 mention) - the report calls it "Body temperature instability"; HP calls it Temperature instability, and lists "Body temperature instability" among its other names
  • HP:0003160 (1 mention) - the report calls it "Abnormal transferrin isoform profile"; HP calls it Abnormal isoelectric focusing of serum transferrin, and lists "Abnormal transferrin isoelectric focusing" among its other names
  • HP:0003429 (1 mention) - the report calls it "Hypomyelination"; HP calls it CNS hypomyelination
  • HP:0002079 (1 mention) - the report calls it "Corpus callosum hypoplasia"; HP calls it Hypoplasia of the corpus callosum, and lists "Corpus callosum hypoplasia" among its other names
  • GO:0007259 (1 mention) - the report calls it "JAK-STAT cascade"; GO calls it cell surface receptor signaling pathway via JAK-STAT, and lists "JAK-STAT cascade" among its other names

Terms named inconsistently

The report gives these identifiers more than one name of its own:

  • HP:0010818 - called "Burst-suppression pattern on EEG", "Burst suppression pattern on EEG"