ALG1-congenital disorder of glycosylation

Mendelian MONDO:0012052 Pathograph 27 Show in embeddings browser congenital disorder of glycosylation type I disorder of protein N-glycosylation

ALG1-congenital disorder of glycosylation (ALG1-CDG, formerly CDG type Ik) is a rare autosomal recessive disorder of protein N-linked glycosylation caused by biallelic pathogenic variants in ALG1. ALG1 encodes the endoplasmic reticulum beta-1,4-mannosyltransferase that adds the first of nine mannose residues to the dolichol-pyrophosphate-linked GlcNAc2 precursor, an early committed step of lipid-linked oligosaccharide assembly. Deficiency yields incomplete lipid-linked oligosaccharides, under-occupied N-glycosylation sites, and a type I congenital disorder of glycosylation with a spectrum that ranges from milder intellectual disability to lethal neonatal/infantile multisystem disease, dominated by developmental delay, epilepsy, hypotonia, microcephaly, and frequent premature death.

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1
Inheritance
7
Pathophys.
17
Phenotypes
3
Hypotheses
1
Gaps
27
Pathograph
1
Genes
2
Medical Actions
18
References
1
Deep Research
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Inheritance

1
Autosomal recessive inheritance HP:0000007
ALG1-CDG is inherited in an autosomal recessive manner, with affected individuals carrying biallelic ALG1 variants.
Autosomal recessive inheritance
Show evidence (1 reference)
PMID:26931382 SUPPORT Human Clinical
"ALG1 mutations cause a rare autosomal recessive disorder termed ALG1-CDG."
The landmark 39-patient cohort explicitly classifies ALG1-CDG as a rare autosomal recessive disorder.
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Mechanistic Hypotheses

3
Canonical ALG1-CDG Precursor Assembly and Protein Hypoglycosylation Model
canonical_alg1_cdg_model CANONICAL
Evidence balance 2 support
Biallelic ALG1 loss of function reduces ER beta-1,4-mannosyltransferase activity, blocking transfer of the first mannose onto dolichol-pyrophosphate-GlcNAc2. GlcNAc2-PP-dolichol and GlcNAc1-PP-dolichol precursors accumulate, full-sized dolichol-linked oligosaccharide synthesis is impaired, and truncated glycans are transferred to nascent proteins, producing under-occupied N-glycosylation sites and a type I transferrin pattern.
Pathograph links
ALG1 beta-1,4-mannosyltransferase deficiency -> Truncated lipid-linked oligosaccharide accumulation DIRECT Reduced ALG1 activity causes accumulation of incomplete dolichol-pyrophosphate-linked GlcNAc2 (and GlcNAc1) precursors before mannosylation.
Truncated lipid-linked oligosaccharide accumulation -> Protein hypoglycosylation INDIRECT KNOWN INTERMEDIATES Oligosaccharyltransferase-mediated transfer of incomplete precursors, together with under-occupied glycosylation sites, produces proteins bearing truncated N-glycans and a type I transferrin pattern. Intermediates: Transfer of incomplete lipid-linked oligosaccharides to nascent proteins and site under-occupancy.
Show evidence (2 references)
PMID:14973778 SUPPORT In Vitro
"indicated a severely reduced activity of the beta 1,4-mannosyltransferase, elongating GlcNAc(2)-PP-dolichol to Man(1)GlcNAc(2)-PP-dolichol at the cytosolic side of the endoplasmic reticulum."
Patient-derived biochemistry directly demonstrates the reduced beta-1,4-mannosyltransferase activity that defines the canonical model.
PMID:26931382 SUPPORT Human Clinical
"An inability to efficiently synthesize or transfer full-sized DLO results in under-occupied glycosylation sites"
The cohort describes the downstream consequence of impaired lipid-linked oligosaccharide assembly: under-occupied N-glycosylation sites.
Emerging ALG1-CDG Clinical Convergence Model
alg1_cdg_clinical_convergence_model EMERGING
Evidence balance 1 support
Protein hypoglycosylation is associated with neurological and multisystem manifestations through unresolved glycoprotein-, cell-, and tissue-specific intermediates. This group separates those clinical convergence bridges from the canonical precursor-assembly chain.
Pathograph links
Protein hypoglycosylation -> Neurodevelopmental dysfunction INDIRECT UNKNOWN INTERMEDIATES Protein hypoglycosylation is associated with the near-universal neurological burden through unresolved glycoprotein and neural-cell intermediates, independently of the provisional fibroblast-stress arm.
Protein hypoglycosylation -> Multisystem glycoprotein dysfunction INDIRECT UNKNOWN INTERMEDIATES Hypoglycosylation of many proteins is associated with the multisystem phenotype, although the responsible glycoproteins and tissue-specific intermediates remain unresolved.
Neurodevelopmental dysfunction -> Global developmental delay INDIRECT UNKNOWN INTERMEDIATES
Neurodevelopmental dysfunction -> Hypotonia INDIRECT UNKNOWN INTERMEDIATES
Neurodevelopmental dysfunction -> Seizure INDIRECT UNKNOWN INTERMEDIATES
Neurodevelopmental dysfunction -> Microcephaly INDIRECT UNKNOWN INTERMEDIATES
Neurodevelopmental dysfunction -> Intellectual disability INDIRECT UNKNOWN INTERMEDIATES
Neurodevelopmental dysfunction -> Cerebral atrophy INDIRECT UNKNOWN INTERMEDIATES
Multisystem glycoprotein dysfunction -> Strabismus INDIRECT UNKNOWN INTERMEDIATES
Multisystem glycoprotein dysfunction -> Nystagmus INDIRECT UNKNOWN INTERMEDIATES
Multisystem glycoprotein dysfunction -> Abnormal facial shape INDIRECT UNKNOWN INTERMEDIATES
Multisystem glycoprotein dysfunction -> Abnormality of blood and blood-forming tissues INDIRECT UNKNOWN INTERMEDIATES
Multisystem glycoprotein dysfunction -> Abnormality of the coagulation cascade INDIRECT UNKNOWN INTERMEDIATES
Multisystem glycoprotein dysfunction -> Hypoalbuminemia INDIRECT UNKNOWN INTERMEDIATES
Multisystem glycoprotein dysfunction -> Chronic diarrhea INDIRECT UNKNOWN INTERMEDIATES
Multisystem glycoprotein dysfunction -> Protein-losing enteropathy INDIRECT UNKNOWN INTERMEDIATES
Multisystem glycoprotein dysfunction -> Scoliosis INDIRECT UNKNOWN INTERMEDIATES
Multisystem glycoprotein dysfunction -> Sensorineural hearing impairment INDIRECT UNKNOWN INTERMEDIATES
Multisystem glycoprotein dysfunction -> Nonimmune hydrops fetalis INDIRECT UNKNOWN INTERMEDIATES
Show evidence (1 reference)
PMID:26931382 SUPPORT Human Clinical
"We also report a substantial number of patients with dysmorphic facial features 24/39 (62%), hematological defects 18/34 (53%), gastrointestinal problems 20/38 (53%), skeletal abnormalities 13/39 (33%) and hypoalbuminemia 12/39 (31%)"
The cohort supports clinical convergence but does not resolve the causal intermediates from hypoglycosylation to individual manifestations.
Emerging ALG1-CDG Fibroblast Glycoproteome and Stress Model
alg1_cdg_fibroblast_stress_model EMERGING
Evidence balance 1 support
Patient fibroblasts show broad glycoproteome disruption together with mitochondrial-protein loss and increased autophagy-related proteins. The relevance of this cellular signature to neural tissue remains provisional.
Pathograph links
Protein hypoglycosylation -> N-glycoproteome disruption DIRECT ALG1 deficiency reduces high-mannose and complex/hybrid glycopeptides across numerous proteins and increases short, incompletely mannosylated glycans on specific client proteins.
N-glycoproteome disruption -> Mitochondrial and autophagic stress INDIRECT UNKNOWN INTERMEDIATES Proteome disruption accompanies decreased mitochondrial proteins and increased autophagy-related proteins in ALG1-deficient fibroblasts.
Mitochondrial and autophagic stress -> Neurodevelopmental dysfunction INDIRECT UNKNOWN INTERMEDIATES How the fibroblast stress signature maps to neural tissue is unknown; pervasive neurological involvement makes a downstream neural-dysfunction bridge plausible but not experimentally established.
Show evidence (1 reference)
PMID:38470198 SUPPORT In Vitro
"Additionally, we observed a decrease in the expression of mitochondrial proteins and an increase in autophagy-related proteins, suggesting mitochondrial and cellular stress."
Patient-cell proteomics directly supports the emerging cellular-stress signature without establishing tissue-level clinical causality.
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Discussions and Knowledge Gaps

1
Can ALG1-specific glycan rescue or shared CDG autophagy and mitochondrial signatures be translated into a safe disease-modifying therapy?
KNOWLEDGE GAP OPEN gap_alg1_cdg_translational_therapy
Attached to
treatments#D-mannose supplementation in patient fibroblasts pathophysiology#Mitochondrial and autophagic stress
Mannose rescue is limited to selected patient fibroblasts and has no human efficacy evidence. A 2025 multi-omics study nominated shared CDG drug candidates computationally, but explicitly requires future in-vitro validation and does not establish ALG1-specific benefit.
Proposed experiments
Genotype-stratified ALG1 patient-cell rescue study
exp_alg1_genotype_stratified_therapy_screen
Test mannose and independently prioritized multi-omics candidates across ALG1 patient-derived neural and hepatic cell models representing severe and mild alleles, with glycoproteomic, mitochondrial, autophagic, and toxicity endpoints before any clinical translation.
Show evidence (1 reference)
PMID:40743674 SUPPORT Computational
"Several candidate drugs targeting these shared abnormalities emerged from integrative analysis and warrant validation in future in vitro studies."
The stated need for experimental validation motivates a genotype-stratified patient-cell study.
Posed 2026-08-04T00:00:00Z
Show evidence (1 reference)
PMID:40743674 SUPPORT Computational
"Several candidate drugs targeting these shared abnormalities emerged from integrative analysis and warrant validation in future in vitro studies."
The multi-omics analysis supplies candidate hypotheses while explicitly documenting that experimental validation remains outstanding.
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Pathophysiology

7
ALG1 beta-1,4-mannosyltransferase deficiency
Pathogenic ALG1 variants impair the ER beta-1,4-mannosyltransferase that adds the first mannose to dolichol-pyrophosphate-GlcNAc2 during lipid-linked oligosaccharide assembly.
Canonical ALG1-CDG Precursor Assembly and Protein Hypoglycosylation Model
ALG1 hgnc:18294 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves ALG1 (hgnc:18294). hgnc:18294 is a gene from the HUGO Gene Nomenclature Committee.
dolichol-linked oligosaccharide biosynthetic process GO:0006488 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased dolichol-linked oligosaccharide biosynthetic process (GO:0006488). GO:0006488 is a biological process from the Gene Ontology. ↓ DECREASED
mannosyltransferase activity GO:0000030 Gene Ontology (GO) Relation: this pathophysiological event involves this molecular function This pathophysiological event involves decreased mannosyltransferase activity (GO:0000030). GO:0000030 is a molecular function from the Gene Ontology. ↓ DECREASED
endoplasmic reticulum GO:0005783 Gene Ontology (GO) Relation: this pathophysiological event involves this cellular component This pathophysiological event involves endoplasmic reticulum (GO:0005783). GO:0005783 is a cellular component from the Gene Ontology.
Downstream
Truncated lipid-linked oligosaccharide accumulation Reduced ALG1 activity causes accumulation of incomplete dolichol-pyrophosphate-linked GlcNAc2 (and GlcNAc1) precursors before mannosylation. Canonical ALG1-CDG Precursor Assembly and Protein Hypoglycosylation Model
Show evidence (3 references)
PMID:26931382 SUPPORT Human Clinical
"ALG1 encodes a β1,4 mannosyltransferase that catalyzes the addition of the first of nine mannose moieties to form a dolichol-lipid linked oligosaccharide intermediate required for proper N-linked glycosylation."
The cohort defines the ALG1 enzymatic function whose loss underlies the disorder.
PMID:14709599 SUPPORT In Vitro
"The accumulation pattern suggested a deficiency of the ALG1 beta1,4 mannosyltransferase, which adds the first mannose residue to lipid-linked oligosaccharides."
The defining CDG-Ik report identifies deficiency of the ALG1 beta-1,4-mannosyltransferase catalysing the first mannosylation step.
PMID:38256263 SUPPORT In Vitro
"The analysis of primary skin fibroblasts from eight CDG type I patients with impaired ALG1, ALG2, and ALG11 genes, respectively, revealed a substantial reduction in the corresponding protein levels."
Targeted proteomics independently demonstrates reduced ALG1 protein in affected patient fibroblasts; it does not support a treatment claim.
Truncated lipid-linked oligosaccharide accumulation
The ALG1 enzymatic block leaves dolichol-pyrophosphate-GlcNAc2 and GlcNAc1 precursors unmannosylated, so full-sized Glc3Man9GlcNAc2 lipid-linked oligosaccharide is not efficiently assembled.
Canonical ALG1-CDG Precursor Assembly and Protein Hypoglycosylation Model
dolichol-linked oligosaccharide biosynthetic process GO:0006488 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves abnormal dolichol-linked oligosaccharide biosynthetic process (GO:0006488). GO:0006488 is a biological process from the Gene Ontology. ⚠ ABNORMAL
Downstream
Protein hypoglycosylation Oligosaccharyltransferase-mediated transfer of incomplete precursors, together with under-occupied glycosylation sites, produces proteins bearing truncated N-glycans and a type I transferrin pattern. Canonical ALG1-CDG Precursor Assembly and Protein Hypoglycosylation Model
Show evidence (1 reference)
PMID:14709599 SUPPORT In Vitro
"we have detected the accumulation of dolichylpyrophosphate-GlcNAc2 in a previously untyped CDG patient."
Independent patient biochemistry confirms accumulation of the truncated dolichol-pyrophosphate-GlcNAc2 precursor.
Protein hypoglycosylation
Transfer of incomplete ALG1-associated oligosaccharides and site under-occupancy produce hypoglycosylated glycoproteins, detectable as a type I serum transferrin pattern and, more specifically, as the ALG1-associated xeno-tetrasaccharide NeuAc-Gal-GlcNAc2.
Emerging ALG1-CDG Clinical Convergence Model Emerging ALG1-CDG Fibroblast Glycoproteome and Stress Model
protein N-linked glycosylation GO:0006487 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased protein N-linked glycosylation (GO:0006487). GO:0006487 is a biological process from the Gene Ontology. ↓ DECREASED
Downstream
N-glycoproteome disruption ALG1 deficiency reduces high-mannose and complex/hybrid glycopeptides across numerous proteins and increases short, incompletely mannosylated glycans on specific client proteins. Emerging ALG1-CDG Fibroblast Glycoproteome and Stress Model
Neurodevelopmental dysfunction Protein hypoglycosylation is associated with the near-universal neurological burden through unresolved glycoprotein and neural-cell intermediates, independently of the provisional fibroblast-stress arm. Emerging ALG1-CDG Clinical Convergence Model
Multisystem glycoprotein dysfunction Hypoglycosylation of many proteins is associated with the multisystem phenotype, although the responsible glycoproteins and tissue-specific intermediates remain unresolved. Emerging ALG1-CDG Clinical Convergence Model
Show evidence (1 reference)
PMID:26931382 SUPPORT Human Clinical
"twenty-seven were tested and all had this novel tetrasaccharide present on either serum or fibroblast glycoproteins"
The ALG1-associated xeno-tetrasaccharide, a direct readout of aberrant N-glycosylation, was present in all tested patients.
N-glycoproteome disruption
Patient fibroblasts show broad loss of high-mannose and complex/hybrid glycopeptides together with increased short oligosaccharides on client proteins including LAMP1, CD44, and integrin.
Emerging ALG1-CDG Fibroblast Glycoproteome and Stress Model
protein N-linked glycosylation GO:0006487 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves abnormal protein N-linked glycosylation (GO:0006487). GO:0006487 is a biological process from the Gene Ontology. ⚠ ABNORMAL
Downstream
Mitochondrial and autophagic stress Proteome disruption accompanies decreased mitochondrial proteins and increased autophagy-related proteins in ALG1-deficient fibroblasts. Emerging ALG1-CDG Fibroblast Glycoproteome and Stress Model
Show evidence (1 reference)
PMID:38470198 SUPPORT In Vitro
"Further, we detected an increase in several short oligosaccharides, including chitobiose (HexNAc2) trisaccharides (Hex-HexNAc2) and novel tetrasaccharides (NeuAc-Hex-HexNAc2) derived from essential proteins including LAMP1, CD44 and integrin."
Quantitative glycoproteomics identifies affected glycan classes and client proteins in three genetically distinct patient fibroblast lines.
Mitochondrial and autophagic stress
ALG1-deficient fibroblasts show reduced mitochondrial-protein expression and increased autophagy-related proteins. This is a provisional cellular consequence; its contribution to individual human manifestations remains unresolved.
Emerging ALG1-CDG Fibroblast Glycoproteome and Stress Model
autophagy GO:0006914 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves increased autophagy (GO:0006914). GO:0006914 is a biological process from the Gene Ontology. ↑ INCREASED
Downstream
Neurodevelopmental dysfunction How the fibroblast stress signature maps to neural tissue is unknown; pervasive neurological involvement makes a downstream neural-dysfunction bridge plausible but not experimentally established. Emerging ALG1-CDG Fibroblast Glycoproteome and Stress Model
Show evidence (1 reference)
PMID:38470198 SUPPORT In Vitro
"Additionally, we observed a decrease in the expression of mitochondrial proteins and an increase in autophagy-related proteins, suggesting mitochondrial and cellular stress."
The 2024 patient-fibroblast study directly supports this cellular-stress signature while leaving tissue-level clinical causality unresolved.
Neurodevelopmental dysfunction
A provisional convergence node for the near-universal neurological burden. The disease-specific glycoprotein clients and neural cell types responsible for this vulnerability remain unknown.
Emerging ALG1-CDG Clinical Convergence Model
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
Global developmental delay Emerging ALG1-CDG Clinical Convergence Model
Hypotonia Emerging ALG1-CDG Clinical Convergence Model
Seizure Emerging ALG1-CDG Clinical Convergence Model
Microcephaly Emerging ALG1-CDG Clinical Convergence Model
Intellectual disability Emerging ALG1-CDG Clinical Convergence Model
Cerebral atrophy Emerging ALG1-CDG Clinical Convergence Model
Show evidence (1 reference)
PMID:26931382 SUPPORT Human Clinical
"Patients had variable degree of neurodevelopmental deficiencies including developmental delay 37/37 (100%), hypotonia 37/39 (95%), seizures /epilepsy 36/38 (95%), microcephaly 27/37 (73%), abnormal brain imaging 25/37 (68%) which consisted primarily of cerebral or cerebellar atrophy 11/25 (44%)..."
Human clinical data support a common neurological convergence, while the node is explicitly hypothetical as a mechanistic bridge.
Multisystem glycoprotein dysfunction
A provisional whole-organism convergence node for non-neurological ALG1-CDG manifestations. The affected glycoproteins, cell types, and causal routes to individual organ findings remain unknown.
Emerging ALG1-CDG Clinical Convergence Model
protein N-linked glycosylation GO:0006487 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves abnormal protein N-linked glycosylation (GO:0006487). GO:0006487 is a biological process from the Gene Ontology. ⚠ ABNORMAL
Downstream
Strabismus Emerging ALG1-CDG Clinical Convergence Model
Nystagmus Emerging ALG1-CDG Clinical Convergence Model
Abnormal facial shape Emerging ALG1-CDG Clinical Convergence Model
Abnormality of blood and blood-forming tissues Emerging ALG1-CDG Clinical Convergence Model
Abnormality of the coagulation cascade Emerging ALG1-CDG Clinical Convergence Model
Hypoalbuminemia Emerging ALG1-CDG Clinical Convergence Model
Chronic diarrhea Emerging ALG1-CDG Clinical Convergence Model
Protein-losing enteropathy Emerging ALG1-CDG Clinical Convergence Model
Scoliosis Emerging ALG1-CDG Clinical Convergence Model
Sensorineural hearing impairment Emerging ALG1-CDG Clinical Convergence Model
Nonimmune hydrops fetalis Emerging ALG1-CDG Clinical Convergence Model
Show evidence (1 reference)
PMID:26931382 SUPPORT Human Clinical
"We also report a substantial number of patients with dysmorphic facial features 24/39 (62%), hematological defects 18/34 (53%), gastrointestinal problems 20/38 (53%), skeletal abnormalities 13/39 (33%) and hypoalbuminemia 12/39 (31%)"
The human cohort supports a multisystem convergence while leaving this node explicitly hypothetical at the mechanistic level.
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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 ALG1-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

17
Blood 1
Abnormality of the coagulation cascade HP:0003256 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Abnormality of the coagulation cascade (HP:0003256). HP:0003256 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:22966035 SUPPORT Human Clinical
"We report on 7 patients with psychomotor delay, microcephaly, strabismus and coagulation abnormalities, seizures and abnormal fat distribution."
The phenotype-defining series reports coagulation abnormalities among core ALG1-CDG features.
Digestive 2
Chronic diarrhea OCCASIONAL HP:0002028 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Chronic diarrhea (HP:0002028). HP:0002028 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:26931382 SUPPORT Human Clinical
"chronic diarrhea (7/20) and/or PLE (5/20)"
Among patients with GI manifestations (20/38), chronic diarrhea was the most frequent (7/20).
Protein-losing enteropathy OCCASIONAL HP:0002243 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Protein-losing enteropathy (HP:0002243). HP:0002243 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:26931382 SUPPORT Human Clinical
"Specifically, gastrointestinal manifestations were most often chronic diarrhea (7/20) and/or PLE (5/20)"
Protein-losing enteropathy occurred in 5/38 patients overall (13%), which supports an OCCASIONAL frequency band.
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 (1 reference)
PMID:22966035 SUPPORT Human Clinical
"We extend the phenotypic spectrum including the first description of deafness in MT1 deficiency, and report on mildly affected patients, surviving to adulthood."
The phenotype series provides the first description of deafness in ALG1 (MT-1) deficiency.
Eye 2
Strabismus OCCASIONAL 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:26931382 SUPPORT Human Clinical
"Ocular abnormalities that mainly involved strabismus 10/27 (37%) and nystagmus 6/27 (22%) were found in 27/36 (75%)"
Strabismus occurred in 10/36 patients with ocular assessment (28% overall); 10/27 is the fraction among those who had an ocular abnormality.
Nystagmus OCCASIONAL HP:0000639 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Nystagmus (HP:0000639). HP:0000639 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:26931382 SUPPORT Human Clinical
"Ocular abnormalities that mainly involved strabismus 10/27 (37%) and nystagmus 6/27 (22%) were found in 27/36 (75%)"
Nystagmus occurred in 6/36 patients assessed overall (17%); 6/27 is the fraction among those with an ocular abnormality.
Head and Neck 2
Microcephaly FREQUENT HP:0000252 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Microcephaly (HP:0000252). HP:0000252 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:26931382 SUPPORT Human Clinical
"Patients had variable degree of neurodevelopmental deficiencies including developmental delay 37/37 (100%), hypotonia 37/39 (95%), seizures /epilepsy 36/38 (95%), microcephaly 27/37 (73%), abnormal brain imaging 25/37 (68%) which consisted primarily of cerebral or cerebellar atrophy 11/25 (44%)..."
Microcephaly was present in 27/37 (73%) of patients.
Abnormal facial shape FREQUENT HP:0001999 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Abnormal facial shape (HP:0001999). HP:0001999 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:26931382 SUPPORT Human Clinical
"dysmorphic facial features 24/39 (62%), hematological defects 18/34 (53%), gastrointestinal problems 20/38 (53%), skeletal abnormalities 13/39 (33%) and hypoalbuminemia 12/39 (31%)"
Dysmorphic facial features occurred in 24/39 (62%) of patients.
Metabolism 2
Hypoalbuminemia FREQUENT HP:0003073 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Hypoalbuminemia (HP:0003073). HP:0003073 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:26931382 SUPPORT Human Clinical
"dysmorphic facial features 24/39 (62%), hematological defects 18/34 (53%), gastrointestinal problems 20/38 (53%), skeletal abnormalities 13/39 (33%) and hypoalbuminemia 12/39 (31%) (Figure 3, Supp. Table S2). Hypoalbuminemia is noteworthy because all twelve of these individuals died at an..."
The full-text cohort supports both the 12/39 frequency reported in the preceding sentence and the poor prognosis asserted in the description; 12/39 (30.8%) maps to the FREQUENT band (30-79%).
Nonimmune hydrops fetalis HP:0001790 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Nonimmune hydrops fetalis (HP:0001790). HP:0001790 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:14973778 SUPPORT Human Clinical
"The molecular nature of a severe multisystemic disorder with a recurrent nonimmune hydrops fetalis was identified as deficiency of GDP-Man:GlcNAc(2)-PP-dolichol mannosyltransferase, the human orthologue of the yeast ALG1 gene (MIM 605907)."
The defining biochemical report describes recurrent nonimmune hydrops fetalis at the severe prenatal end of the spectrum.
Musculoskeletal 2
Hypotonia VERY_FREQUENT HP:0001252 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Hypotonia (HP:0001252). HP:0001252 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:26931382 SUPPORT Human Clinical
"Patients had variable degree of neurodevelopmental deficiencies including developmental delay 37/37 (100%), hypotonia 37/39 (95%), seizures /epilepsy 36/38 (95%), microcephaly 27/37 (73%), abnormal brain imaging 25/37 (68%) which consisted primarily of cerebral or cerebellar atrophy 11/25 (44%)..."
Hypotonia was present in 37/39 (95%) of patients.
Scoliosis OCCASIONAL HP:0002650 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Scoliosis (HP:0002650). HP:0002650 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:26931382 SUPPORT Human Clinical
"Skeletal abnormalities consisted of scoliosis (5/13), kyphosis (2/13) or joint contractures (3/13)"
Among patients with skeletal abnormalities (13/39), scoliosis was most frequent (5/13).
Nervous System 4
Global developmental delay VERY_FREQUENT HP:0001263 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Global developmental delay (HP:0001263). HP:0001263 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:26931382 SUPPORT Human Clinical
"Patients had variable degree of neurodevelopmental deficiencies including developmental delay 37/37 (100%), hypotonia 37/39 (95%), seizures /epilepsy 36/38 (95%), microcephaly 27/37 (73%), abnormal brain imaging 25/37 (68%) which consisted primarily of cerebral or cerebellar atrophy 11/25 (44%)..."
Developmental delay was present in 37/37 (100%) of evaluable patients.
Seizure VERY_FREQUENT HP:0001250 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Seizure (HP:0001250). HP:0001250 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:26931382 SUPPORT Human Clinical
"Patients had variable degree of neurodevelopmental deficiencies including developmental delay 37/37 (100%), hypotonia 37/39 (95%), seizures /epilepsy 36/38 (95%), microcephaly 27/37 (73%), abnormal brain imaging 25/37 (68%) which consisted primarily of cerebral or cerebellar atrophy 11/25 (44%)..."
Seizures/epilepsy occurred in 36/38 (95%) of patients.
Intellectual disability VERY_FREQUENT HP:0001249 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Intellectual disability (HP:0001249). HP:0001249 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:26931382 SUPPORT Human Clinical
"Patients had variable degree of neurodevelopmental deficiencies including developmental delay 37/37 (100%), hypotonia 37/39 (95%), seizures /epilepsy 36/38 (95%), microcephaly 27/37 (73%), abnormal brain imaging 25/37 (68%) which consisted primarily of cerebral or cerebellar atrophy 11/25 (44%)..."
Intellectual disability was present in 21/22 (95%) of evaluable patients.
Cerebral atrophy HP:0002059 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Cerebral atrophy (HP:0002059). HP:0002059 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:26931382 SUPPORT Human Clinical
"Patients had variable degree of neurodevelopmental deficiencies including developmental delay 37/37 (100%), hypotonia 37/39 (95%), seizures /epilepsy 36/38 (95%), microcephaly 27/37 (73%), abnormal brain imaging 25/37 (68%) which consisted primarily of cerebral or cerebellar atrophy 11/25 (44%)..."
Cerebral or cerebellar atrophy occurred in 11/37 patients overall (30%), but the publication does not separate the cerebral-specific count; therefore no cerebral-atrophy frequency band is assigned.
Other 1
Abnormality of blood and blood-forming tissues FREQUENT HP:0001871 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Abnormality of blood and blood-forming tissues (HP:0001871). HP:0001871 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:26931382 SUPPORT Human Clinical
"dysmorphic facial features 24/39 (62%), hematological defects 18/34 (53%), gastrointestinal problems 20/38 (53%), skeletal abnormalities 13/39 (33%) and hypoalbuminemia 12/39 (31%)"
Hematologic defects occurred in 18/34 patients (53%), mapping to the FREQUENT band.
🧬

Genetic Associations

1
ALG1 (Biallelic loss-of-function or hypomorphic variants)
Gene: ALG1 hgnc:18294 HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is ALG1 (hgnc:18294). hgnc:18294 is a gene from the HUGO Gene Nomenclature Committee.
Show evidence (6 references)
PMID:26931382 SUPPORT Human Clinical
"The most frequently observed mutation, in both the homozygous and compound heterozygous state (17/39, 44%) (Table 1) was c.773C>T, which encodes a known pathogenic mutation p.Ser258Leu"
The recurrent c.773C>T (p.Ser258Leu) allele was the most frequently observed ALG1 variant in the cohort.
PMID:26931382 SUPPORT Human Clinical
"All six individuals homozygous for the p.Ser258Leu mutation died within the first five months of life."
Directly supports the severe early-lethal genotype association without extrapolating it to compound heterozygotes.
PMID:34567092 SUPPORT Human Clinical
"the other carried a new uncharacterized variant (c.208 + 25G > T) causing non-functional alternative splicing that, in conjunction with the benign variant, defines the pathogenic protein effect (p.N70S_S71ins9)."
The molecular case study demonstrates a pathogenic complex allele acting through abnormal splicing.
+ 3 more references
💊

Medical Actions

2
Supportive and complication-directed management
Action: supportive careNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is supportive care (NCIT:C15747). NCIT:C15747 is a clinical intervention from the NCI Thesaurus. Ontology label: Supportive Care NCIT:C15747
No approved ALG1-specific disease-modifying therapy exists. Management is multidisciplinary and complication-directed, including antiseizure therapy, nutritional and feeding support, and surveillance/treatment of hepatic, renal, hematologic, ophthalmologic, and skeletal complications. Substrate therapies effective in some other CDGs (e.g., mannose in MPI-CDG) are not established for ALG1-CDG.
Show evidence (1 reference)
PMID:42220679 SUPPORT Human Clinical
"Supportive therapies, including physiotherapy, developmental stimulation, and nutritional management, were initiated in view of global developmental delay and hypotonia."
A recent molecularly confirmed case documents representative supportive interventions, but a single case does not establish comparative efficacy or a comprehensive management guideline.
D-mannose supplementation in patient fibroblasts
Action: experimental substrate supplementationNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is experimental substrate supplementation, annotated with Pharmacotherapy (NCIT:C15986). NCIT:C15986 is a clinical intervention from the NCI Thesaurus. Ontology label: Pharmacotherapy NCIT:C15986
Agent: D-mannose CHEBI:16024 Chemical Entities of Biological Interest (CHEBI) Relation: this treatment uses this therapeutic agent This treatment uses D-mannose (CHEBI:16024). CHEBI:16024 is a therapeutic agent from Chemical Entities of Biological Interest.
D-mannose reduced the ALG1-associated N-tetrasaccharide and increased larger N-glycans in one responsive patient-derived fibroblast line. Other ALG1 mutant lines, including homozygous p.Ser258Leu cells, did not respond, the effective in-vitro concentration may not be achievable in vivo, and no human ALG1-CDG efficacy is established; this is not a clinical recommendation.
Mechanism Target:
RESTORES Protein hypoglycosylation
Show evidence (1 reference)
PMID:26430078 SUPPORT In Vitro
"After 16 h, there was an 86% reduction of N-tetrasaccharide in ALG1-CDG cells, along with increased amounts of high-mannose and sialylated N-glycans"
Biochemical normalization in one patient fibroblast line partially supports restoration of glycosylation, without proving organism-level benefit.
Show evidence (2 references)
PMID:26430078 SUPPORT In Vitro
"After 16 h, there was an 86% reduction of N-tetrasaccharide in ALG1-CDG cells, along with increased amounts of high-mannose and sialylated N-glycans"
A patient-derived fibroblast line showed biochemical rescue, but this preclinical result does not establish clinical efficacy or generalize to all ALG1 genotypes.
PMID:26430078 SUPPORT In Vitro
"The applicability of mannose treatment for patients with ALG1-CDG remains unknown because not all the ALG1-CDG mutant cell lines respond to mannose supplementation."
The authors explicitly limit the translational scope and document genotype-dependent nonresponse.
🔬

Biochemical Markers

1
ALG1-associated xeno-tetrasaccharide NeuAc-Gal-GlcNAc2 (INCREASED)
Context: A short mannose-deprived N-glycan detected on serum transferrin and other serum or fibroblast glycoproteins; useful as a diagnostic readout but not absolutely required for diagnosis.
Pathograph Readouts
Readout Of Protein hypoglycosylation Positive Diagnostic
Detection reports transfer and Golgi processing of short ALG1-associated N-glycans downstream of incomplete lipid-linked oligosaccharide assembly.
Show evidence (1 reference)
PMID:26335155 SUPPORT Human Clinical
"This is the first time analysis of serum TF can suggest a specific CDG type I subtype and we suggest this tetrasaccharide be used in the clinic to guide the ALG1-CDG diagnostic process."
The original biomarker study supports its diagnostic readout role for ALG1-CDG while describing guidance rather than a standalone diagnosis.
Show evidence (1 reference)
PMID:26335155 SUPPORT Human Clinical
"We show mass spectrometric data combined with data from enzymatic digestions that suggest the presence of a tetrasaccharide consisting of two N-acetylglucosamines, one galactose, and one sialic acid, appearing on serum TF, is a biomarker of this particular CDG subtype."
Directly identifies the serum-transferrin glycan composition and its disease-associated biomarker interpretation.
🔬

Diagnosis

3
Serum transferrin glycoform analysis
A type I carbohydrate-deficient transferrin pattern is the usual biochemical screening clue and is not gene-specific. A normal result does not exclude ALG1-CDG, including severe disease, so molecular and orthogonal glycomic testing remain necessary when suspicion is high.
diagnostic procedure NCIT:C18020 NCI Thesaurus (NCIT)
Results: Usually a type I CDG pattern requiring etiologic follow-up; rarely normal.
Show evidence (2 references)
PMID:14973778 SUPPORT Human Clinical
"In patient-derived serum, the total amount of the glycoprotein transferrin was reduced. Moreover, a partial loss of N-glycan chains was observed, a characteristic feature of CDG type I forms."
The type I transferrin pattern is the biochemical screening result; it is not ALG1-specific.
PMID:38736633 SUPPORT Human Clinical
"Despite her severe clinical manifestations and genetic diagnosis, serum transferrin glycoform analysis was normal."
A molecularly diagnosed severe case directly demonstrates that a normal transferrin glycoform result cannot exclude ALG1-CDG.
ALG1 molecular genetic testing
Definitive diagnosis requires identification of biallelic pathogenic ALG1 variants. Testing is warranted in unsolved type I CDG with compatible features and also when glycan screening is normal but the phenotype and genomic findings remain compelling.
molecular genetic testing NCIT:C19770 NCI Thesaurus (NCIT)
Results: Biallelic pathogenic or likely pathogenic ALG1 variants confirm the diagnosis.
Show evidence (2 references)
PMID:22966035 SUPPORT Human Clinical
"We suggest testing for ALG1 mutations in unsolved CDG patients with a type 1 transferrin isoelectric focusing pattern, especially with epilepsy, severe visual loss and hemorrhagic/thrombotic events."
The phenotype series recommends ALG1 testing in unsolved type I CDG with compatible clinical features.
PMID:38736633 SUPPORT Human Clinical
"ALG1-CDG was suggested based on exome sequencing and Western blot analysis."
The severe normal-transferrin case illustrates why molecular testing and orthogonal protein/glycan assays must be integrated.
Mass-spectrometric ALG1-associated glycan profiling
Mass spectrometry can detect the ALG1-associated NeuAc-Gal-GlcNAc2 xeno-tetrasaccharide and a fucosylated N-pentasaccharide signature. These markers support subtype prioritization but do not replace biallelic variant interpretation, and the tetrasaccharide can also occur in PMM2- and MPI-CDG.
mass-spectrometric glycan profiling NCIT:C18020 NCI Thesaurus (NCIT)
Results: ALG1-associated short N-glycan signatures on serum, plasma, or fibroblast glycoproteins.
Show evidence (2 references)
PMID:26335155 SUPPORT Human Clinical
"we suggest this tetrasaccharide be used in the clinic to guide the ALG1-CDG diagnostic process."
The original study supports the tetrasaccharide as a guide to subtype selection, not a standalone molecular confirmation.
PMID:35279850 SUPPORT Human Clinical
"Glycomics profiling in patients with known defects revealed novel features such as the N-tetrasaccharide in ALG2-CDG patients and a novel fucosylated N-pentasaccharide as specific glycomarker for ALG1-CDG."
A 111-patient CDG-I glycomics cohort identifies an additional ALG1-specific fucosylated pentasaccharide signature.
📈

Progression

1
Prenatal-to-infantile multisystem spectrum
Severity ranges from milder intellectual disability to lethal neonatal or early-infantile multisystem disease; premature death is frequent, especially in the first year of life and in specific genotypes.
Show evidence (3 references)
PMID:26931382 SUPPORT Human Clinical
"Premature death occurred in 17/39 (44%) cases"
The cohort documents high premature mortality, marking the severe end of the ALG1-CDG spectrum.
PMID:14973782 SUPPORT Human Clinical
"Mutations in semiconserved regions in the corresponding gene, HMT-1 (yeast homologue, Alg1), in two patients caused drastically reduced enzyme activity, leading to a severe disease with death in early infancy."
The original CDG-Ik description links ALG1 loss of function to severe disease with death in early infancy.
PMID:35221878 SUPPORT Human Clinical
"We here present a patient with a mild phenotype of ALG1-CDG."
A molecularly diagnosed patient with a mild phenotype confirms the less severe end of the progression spectrum.
📊

Prevalence

1
European ancestry in gnomAD v2.1.1
Birth Prevalence Ultra Rare
Direct observed prevalence is not established. This is an allele-frequency-based birth-prevalence estimate rather than measured point prevalence. Within the study's all-person and European-ancestry aggregates, only PMM2-CDG exceeded one in 100,000; ancestry-specific ALG1 rates are not asserted here because they are not recoverable from the cached article text.
Show evidence (1 reference)
PMID:34447415 SUPPORT Computational
"Among assessed 27 autosomal recessive N-glycosylation disorders, the only disease with estimated birth prevalence higher than one in 100,000 was PMM2-CDG (in both, all gnomAD individuals and those with European ancestry)."
The computational study establishes the measure as estimated birth prevalence and supports an ultrarare, below-one-in-100,000 band for ALG1-CDG; it does not measure observed point prevalence.
{ }

Source YAML

click to show 
name: ALG1-congenital disorder of glycosylation
creation_date: "2026-07-24T18:00:00Z"
description: >-
  ALG1-congenital disorder of glycosylation (ALG1-CDG, formerly CDG type Ik) is
  a rare autosomal recessive disorder of protein N-linked glycosylation caused
  by biallelic pathogenic variants in ALG1. ALG1 encodes the endoplasmic
  reticulum beta-1,4-mannosyltransferase that adds the first of nine mannose
  residues to the dolichol-pyrophosphate-linked GlcNAc2 precursor, an early
  committed step of lipid-linked oligosaccharide assembly. Deficiency yields
  incomplete lipid-linked oligosaccharides, under-occupied N-glycosylation
  sites, and a type I congenital disorder of glycosylation with a spectrum that
  ranges from milder intellectual disability to lethal neonatal/infantile
  multisystem disease, dominated by developmental delay, epilepsy, hypotonia,
  microcephaly, and frequent premature death.
category: Mendelian
disease_term:
  preferred_term: ALG1-congenital disorder of glycosylation
  term:
    id: MONDO:0012052
    label: ALG1-congenital disorder of glycosylation
parents:
- congenital disorder of glycosylation type I
- disorder of protein N-glycosylation
synonyms:
- ALG1-CDG
- CDG-Ik
- congenital disorder of glycosylation type Ik
- GDP-Man:GlcNAc2-PP-dolichol mannosyltransferase deficiency
references:
- reference: PMID:26931382
  title: "ALG1-CDG: Clinical and Molecular Characterization of 39 Unreported Patients."
- reference: PMID:14973778
  title: "Deficiency of GDP-Man:GlcNAc2-PP-dolichol mannosyltransferase causes congenital disorder of glycosylation type Ik."
- reference: PMID:14709599
  title: "Deficiency of the first mannosylation step in the N-glycosylation pathway causes congenital disorder of glycosylation type Ik."
- reference: PMID:14973782
  title: "Congenital disorder of glycosylation type Ik (CDG-Ik): a defect of mannosyltransferase I."
- reference: PMID:22966035
  title: "Defining the phenotype in congenital disorder of glycosylation due to ALG1 mutations."
- reference: PMID:38256263
  title: "Targeted Proteomics Reveals Quantitative Differences in Low-Abundance Glycosyltransferases of Patients with Congenital Disorders of Glycosylation."
- reference: PMID:34447415
  title: "The Estimated Prevalence of N-Linked Congenital Disorders of Glycosylation Across Various Populations Based on Allele Frequencies in General Population Databases."
- reference: PMID:26335155
  title: "Serum transferrin carrying the xeno-tetrasaccharide NeuAc-Gal-GlcNAc2 is a biomarker of ALG1-CDG."
- reference: PMID:26430078
  title: "A Novel N-Tetrasaccharide in Patients with Congenital Disorders of Glycosylation, Including Asparagine-Linked Glycosylation Protein 1, Phosphomannomutase 2, and Mannose Phosphate Isomerase Deficiencies."
- reference: PMID:34567092
  title: "ALG1-CDG Caused by Non-functional Alternative Splicing Involving a Novel Pathogenic Complex Allele."
- reference: PMID:35221878
  title: "ALG1-CDG: A Patient with a Mild Phenotype and Literature Review."
- reference: PMID:35279850
  title: "Synergistic use of glycomics and single-molecule molecular inversion probes for identification of congenital disorders of glycosylation type-1."
- reference: PMID:37204045
  title: "A novel variant in ALG1 gene associated with congenital disorder of glycosylation: A case report and short literature review."
- reference: PMID:38470198
  title: "Dysregulated proteome and N-glycoproteome in ALG1-deficient fibroblasts."
- reference: PMID:38736633
  title: "Normal transferrin glycosylation does not rule out severe ALG1 deficiency."
- reference: PMID:40743674
  title: "Predicting disease-overarching therapeutic approaches for congenital disorders of glycosylation using multi-OMICS."
- reference: PMID:41437099
  title: "Clinical and genetic characterization of congenital disorders of glycosylation in 20 Chinese patients."
- reference: PMID:42220679
  title: "Resistant Epilepsy and Developmental Delay in a Syndromic Infant: A Case of Congenital Disorder of Glycosylation Type Ik From India."
inheritance:
- name: Autosomal recessive inheritance
  inheritance_term:
    preferred_term: Autosomal recessive inheritance
    term:
      id: HP:0000007
      label: Autosomal recessive inheritance
  description: >-
    ALG1-CDG is inherited in an autosomal recessive manner, with affected
    individuals carrying biallelic ALG1 variants.
  evidence:
  - reference: PMID:26931382
    reference_title: "ALG1-CDG: Clinical and Molecular Characterization of 39 Unreported Patients."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "ALG1 mutations cause a rare autosomal recessive disorder termed ALG1-CDG."
    explanation: >-
      The landmark 39-patient cohort explicitly classifies ALG1-CDG as a rare
      autosomal recessive disorder.
prevalence:
- population: European ancestry in gnomAD v2.1.1
  measure_type: BIRTH_PREVALENCE
  prevalence_class: ULTRA_RARE
  notes: >-
    Direct observed prevalence is not established. This is an
    allele-frequency-based birth-prevalence estimate rather than measured point prevalence.
    Within the study's all-person and European-ancestry aggregates, only
    PMM2-CDG exceeded one in 100,000; ancestry-specific ALG1 rates are not
    asserted here because they are not recoverable from the cached article text.
  evidence:
  - reference: PMID:34447415
    reference_title: "The Estimated Prevalence of N-Linked Congenital Disorders of Glycosylation Across Various Populations Based on Allele Frequencies in General Population Databases."
    supports: SUPPORT
    evidence_source: COMPUTATIONAL
    snippet: "Among assessed 27 autosomal recessive N-glycosylation disorders, the only disease with estimated birth prevalence higher than one in 100,000 was PMM2-CDG (in both, all gnomAD individuals and those with European ancestry)."
    explanation: >-
      The computational study establishes the measure as estimated birth
      prevalence and supports an ultrarare, below-one-in-100,000 band for ALG1-CDG;
      it does not measure observed point prevalence.
progression:
- phase: Prenatal-to-infantile multisystem spectrum
  notes: >-
    Severity ranges from milder intellectual disability to lethal neonatal or
    early-infantile multisystem disease; premature death is frequent, especially
    in the first year of life and in specific genotypes.
  evidence:
  - reference: PMID:26931382
    reference_title: "ALG1-CDG: Clinical and Molecular Characterization of 39 Unreported Patients."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Premature death occurred in 17/39 (44%) cases"
    explanation: >-
      The cohort documents high premature mortality, marking the severe end of
      the ALG1-CDG spectrum.
  - reference: PMID:14973782
    reference_title: "Congenital disorder of glycosylation type Ik (CDG-Ik): a defect of mannosyltransferase I."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Mutations in semiconserved regions in the corresponding gene, HMT-1 (yeast homologue, Alg1), in two patients caused drastically reduced enzyme activity, leading to a severe disease with death in early infancy."
    explanation: >-
      The original CDG-Ik description links ALG1 loss of function to severe
      disease with death in early infancy.
  - reference: PMID:35221878
    reference_title: "ALG1-CDG: A Patient with a Mild Phenotype and Literature Review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We here present a patient with a mild phenotype of ALG1-CDG."
    explanation: >-
      A molecularly diagnosed patient with a mild phenotype confirms the less
      severe end of the progression spectrum.
mechanistic_hypotheses:
- hypothesis_group_id: canonical_alg1_cdg_model
  hypothesis_label: Canonical ALG1-CDG Precursor Assembly and Protein Hypoglycosylation Model
  status: CANONICAL
  description: >-
    Biallelic ALG1 loss of function reduces ER beta-1,4-mannosyltransferase
    activity, blocking transfer of the first mannose onto
    dolichol-pyrophosphate-GlcNAc2. GlcNAc2-PP-dolichol and GlcNAc1-PP-dolichol
    precursors accumulate, full-sized dolichol-linked oligosaccharide synthesis
    is impaired, and truncated glycans are transferred to nascent proteins,
    producing under-occupied N-glycosylation sites and a type I transferrin
    pattern.
  evidence:
  - reference: PMID:14973778
    reference_title: "Deficiency of GDP-Man:GlcNAc2-PP-dolichol mannosyltransferase causes congenital disorder of glycosylation type Ik."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "indicated a severely reduced activity of the beta 1,4-mannosyltransferase, elongating GlcNAc(2)-PP-dolichol to Man(1)GlcNAc(2)-PP-dolichol at the cytosolic side of the endoplasmic reticulum."
    explanation: >-
      Patient-derived biochemistry directly demonstrates the reduced
      beta-1,4-mannosyltransferase activity that defines the canonical model.
  - reference: PMID:26931382
    reference_title: "ALG1-CDG: Clinical and Molecular Characterization of 39 Unreported Patients."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "An inability to efficiently synthesize or transfer full-sized DLO results in under-occupied glycosylation sites"
    explanation: >-
      The cohort describes the downstream consequence of impaired lipid-linked
      oligosaccharide assembly: under-occupied N-glycosylation sites.
- hypothesis_group_id: alg1_cdg_clinical_convergence_model
  hypothesis_label: Emerging ALG1-CDG Clinical Convergence Model
  status: EMERGING
  description: >-
    Protein hypoglycosylation is associated with neurological and multisystem
    manifestations through unresolved glycoprotein-, cell-, and tissue-specific
    intermediates. This group separates those clinical convergence bridges from
    the canonical precursor-assembly chain.
  evidence:
  - reference: PMID:26931382
    reference_title: "ALG1-CDG: Clinical and Molecular Characterization of 39 Unreported Patients."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We also report a substantial number of patients with dysmorphic facial features 24/39 (62%), hematological defects 18/34 (53%), gastrointestinal problems 20/38 (53%), skeletal abnormalities 13/39 (33%) and hypoalbuminemia 12/39 (31%)"
    explanation: >-
      The cohort supports clinical convergence but does not resolve the causal
      intermediates from hypoglycosylation to individual manifestations.
- hypothesis_group_id: alg1_cdg_fibroblast_stress_model
  hypothesis_label: Emerging ALG1-CDG Fibroblast Glycoproteome and Stress Model
  status: EMERGING
  description: >-
    Patient fibroblasts show broad glycoproteome disruption together with
    mitochondrial-protein loss and increased autophagy-related proteins. The
    relevance of this cellular signature to neural tissue remains provisional.
  evidence:
  - reference: PMID:38470198
    reference_title: "Dysregulated proteome and N-glycoproteome in ALG1-deficient fibroblasts."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Additionally, we observed a decrease in the expression of mitochondrial proteins and an increase in autophagy-related proteins, suggesting mitochondrial and cellular stress."
    explanation: >-
      Patient-cell proteomics directly supports the emerging cellular-stress
      signature without establishing tissue-level clinical causality.
pathophysiology:
- name: ALG1 beta-1,4-mannosyltransferase deficiency
  biological_scale: MOLECULAR
  conforms_to: "congenital_disorder_of_glycosylation#ER Lipid-Linked Oligosaccharide Assembly Defect"
  description: >-
    Pathogenic ALG1 variants impair the ER beta-1,4-mannosyltransferase that
    adds the first mannose to dolichol-pyrophosphate-GlcNAc2 during lipid-linked
    oligosaccharide assembly.
  genes:
  - preferred_term: ALG1
    term:
      id: hgnc:18294
      label: ALG1
  biological_processes:
  - preferred_term: dolichol-linked oligosaccharide biosynthetic process
    modifier: DECREASED
    term:
      id: GO:0006488
      label: dolichol-linked oligosaccharide biosynthetic process
  molecular_functions:
  - preferred_term: mannosyltransferase activity
    modifier: DECREASED
    term:
      id: GO:0000030
      label: mannosyltransferase activity
  cellular_components:
  - preferred_term: endoplasmic reticulum
    term:
      id: GO:0005783
      label: endoplasmic reticulum
  evidence:
  - reference: PMID:26931382
    reference_title: "ALG1-CDG: Clinical and Molecular Characterization of 39 Unreported Patients."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "ALG1 encodes a β1,4 mannosyltransferase that catalyzes the addition of the first of nine mannose moieties to form a dolichol-lipid linked oligosaccharide intermediate required for proper N-linked glycosylation."
    explanation: >-
      The cohort defines the ALG1 enzymatic function whose loss underlies the
      disorder.
  - reference: PMID:14709599
    reference_title: "Deficiency of the first mannosylation step in the N-glycosylation pathway causes congenital disorder of glycosylation type Ik."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "The accumulation pattern suggested a deficiency of the ALG1 beta1,4 mannosyltransferase, which adds the first mannose residue to lipid-linked oligosaccharides."
    explanation: >-
      The defining CDG-Ik report identifies deficiency of the ALG1
      beta-1,4-mannosyltransferase catalysing the first mannosylation step.
  - reference: PMID:38256263
    reference_title: "Targeted Proteomics Reveals Quantitative Differences in Low-Abundance Glycosyltransferases of Patients with Congenital Disorders of Glycosylation."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "The analysis of primary skin fibroblasts from eight CDG type I patients with impaired ALG1, ALG2, and ALG11 genes, respectively, revealed a substantial reduction in the corresponding protein levels."
    explanation: >-
      Targeted proteomics independently demonstrates reduced ALG1 protein in
      affected patient fibroblasts; it does not support a treatment claim.
  downstream:
  - target: Truncated lipid-linked oligosaccharide accumulation
    description: >-
      Reduced ALG1 activity causes accumulation of incomplete
      dolichol-pyrophosphate-linked GlcNAc2 (and GlcNAc1) precursors before
      mannosylation.
    causal_link_type: DIRECT
    hypothesis_groups:
    - canonical_alg1_cdg_model
    evidence:
    - reference: PMID:14973778
      reference_title: "Deficiency of GDP-Man:GlcNAc2-PP-dolichol mannosyltransferase causes congenital disorder of glycosylation type Ik."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "an accumulation of GlcNAc(2)-PP-dolichol and GlcNAc(1)-PP-dolichol in skin fibroblasts of the patient."
      explanation: >-
        Patient fibroblast labelling directly demonstrates accumulation of the
        truncated precursors upstream of the ALG1 block.
- name: Truncated lipid-linked oligosaccharide accumulation
  biological_scale: MOLECULAR
  description: >-
    The ALG1 enzymatic block leaves dolichol-pyrophosphate-GlcNAc2 and
    GlcNAc1 precursors unmannosylated, so full-sized Glc3Man9GlcNAc2
    lipid-linked oligosaccharide is not efficiently assembled.
  biological_processes:
  - preferred_term: dolichol-linked oligosaccharide biosynthetic process
    modifier: ABNORMAL
    term:
      id: GO:0006488
      label: dolichol-linked oligosaccharide biosynthetic process
  chemical_entities:
  - preferred_term: truncated dolichol-linked oligosaccharide precursor
    modifier: ABNORMAL
    term:
      id: CHEBI:61286
      label: dolichol-linked oligosaccharide
  evidence:
  - reference: PMID:14709599
    reference_title: "Deficiency of the first mannosylation step in the N-glycosylation pathway causes congenital disorder of glycosylation type Ik."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "we have detected the accumulation of dolichylpyrophosphate-GlcNAc2 in a previously untyped CDG patient."
    explanation: >-
      Independent patient biochemistry confirms accumulation of the truncated
      dolichol-pyrophosphate-GlcNAc2 precursor.
  downstream:
  - target: Protein hypoglycosylation
    description: >-
      Oligosaccharyltransferase-mediated transfer of incomplete precursors,
      together with under-occupied glycosylation sites, produces proteins bearing
      truncated N-glycans and a type I transferrin pattern.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - Transfer of incomplete lipid-linked oligosaccharides to nascent proteins and site under-occupancy.
    hypothesis_groups:
    - canonical_alg1_cdg_model
    evidence:
    - reference: PMID:14973778
      reference_title: "Deficiency of GDP-Man:GlcNAc2-PP-dolichol mannosyltransferase causes congenital disorder of glycosylation type Ik."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "In patient-derived serum, the total amount of the glycoprotein transferrin was reduced. Moreover, a partial loss of N-glycan chains was observed, a characteristic feature of CDG type I forms."
      explanation: >-
        The patient transferrin result links the precursor lesion to protein
        hypoglycosylation with a type I pattern.
- name: Protein hypoglycosylation
  biological_scale: MOLECULAR
  conforms_to: "congenital_disorder_of_glycosylation#Protein Hypoglycosylation"
  description: >-
    Transfer of incomplete ALG1-associated oligosaccharides and site
    under-occupancy produce hypoglycosylated glycoproteins, detectable as a type
    I serum transferrin pattern and, more specifically, as the ALG1-associated
    xeno-tetrasaccharide NeuAc-Gal-GlcNAc2.
  biological_processes:
  - preferred_term: protein N-linked glycosylation
    modifier: DECREASED
    term:
      id: GO:0006487
      label: protein N-linked glycosylation
  evidence:
  - reference: PMID:26931382
    reference_title: "ALG1-CDG: Clinical and Molecular Characterization of 39 Unreported Patients."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "twenty-seven were tested and all had this novel tetrasaccharide present on either serum or fibroblast glycoproteins"
    explanation: >-
      The ALG1-associated xeno-tetrasaccharide, a direct readout of aberrant
      N-glycosylation, was present in all tested patients.
  downstream:
  - target: N-glycoproteome disruption
    description: >-
      ALG1 deficiency reduces high-mannose and complex/hybrid glycopeptides
      across numerous proteins and increases short, incompletely mannosylated
      glycans on specific client proteins.
    causal_link_type: DIRECT
    hypothesis_groups:
    - alg1_cdg_fibroblast_stress_model
    evidence:
    - reference: PMID:38470198
      reference_title: "Dysregulated proteome and N-glycoproteome in ALG1-deficient fibroblasts."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "N-glycoproteomics revealed the reduction in high-mannose and complex/hybrid glycopeptides derived from numerous proteins in patients explaining that defect in ALG1 has broad effects on glycosylation."
      explanation: >-
        Patient-derived fibroblast glycoproteomics directly demonstrates broad
        disruption of protein N-glycosylation downstream of ALG1 deficiency.
  - target: Neurodevelopmental dysfunction
    description: >-
      Protein hypoglycosylation is associated with the near-universal
      neurological burden through unresolved glycoprotein and neural-cell
      intermediates, independently of the provisional fibroblast-stress arm.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    hypothesis_groups:
    - alg1_cdg_clinical_convergence_model
    evidence:
    - reference: PMID:26931382
      reference_title: "ALG1-CDG: Clinical and Molecular Characterization of 39 Unreported Patients."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Patients had variable degree of neurodevelopmental deficiencies including developmental delay 37/37 (100%), hypotonia 37/39 (95%), seizures /epilepsy 36/38 (95%), microcephaly 27/37 (73%), abnormal brain imaging 25/37 (68%) which consisted primarily of cerebral or cerebellar atrophy 11/25 (44%) and for those who could be evaluated, intellectual disability 21/22 (95%)"
      explanation: >-
        Human data support the neurological convergence but leave the causal
        bridge from protein hypoglycosylation unresolved.
  - target: Multisystem glycoprotein dysfunction
    description: >-
      Hypoglycosylation of many proteins is associated with the multisystem
      phenotype, although the responsible glycoproteins and tissue-specific
      intermediates remain unresolved.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    hypothesis_groups:
    - alg1_cdg_clinical_convergence_model
    evidence:
    - reference: PMID:26931382
      reference_title: "ALG1-CDG: Clinical and Molecular Characterization of 39 Unreported Patients."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "We also report a substantial number of patients with dysmorphic facial features 24/39 (62%), hematological defects 18/34 (53%), gastrointestinal problems 20/38 (53%), skeletal abnormalities 13/39 (33%) and hypoalbuminemia 12/39 (31%)"
      explanation: >-
        The cohort establishes multisystem involvement downstream of ALG1
        deficiency but does not resolve the protein- or tissue-specific causal
        intermediates.
- name: N-glycoproteome disruption
  biological_scale: MOLECULAR
  description: >-
    Patient fibroblasts show broad loss of high-mannose and complex/hybrid
    glycopeptides together with increased short oligosaccharides on client
    proteins including LAMP1, CD44, and integrin.
  mechanism_confidence: PROVISIONAL
  biological_processes:
  - preferred_term: protein N-linked glycosylation
    modifier: ABNORMAL
    term:
      id: GO:0006487
      label: protein N-linked glycosylation
  evidence:
  - reference: PMID:38470198
    reference_title: "Dysregulated proteome and N-glycoproteome in ALG1-deficient fibroblasts."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Further, we detected an increase in several short oligosaccharides, including chitobiose (HexNAc2) trisaccharides (Hex-HexNAc2) and novel tetrasaccharides (NeuAc-Hex-HexNAc2) derived from essential proteins including LAMP1, CD44 and integrin."
    explanation: >-
      Quantitative glycoproteomics identifies affected glycan classes and
      client proteins in three genetically distinct patient fibroblast lines.
  downstream:
  - target: Mitochondrial and autophagic stress
    description: >-
      Proteome disruption accompanies decreased mitochondrial proteins and
      increased autophagy-related proteins in ALG1-deficient fibroblasts.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    hypothesis_groups:
    - alg1_cdg_fibroblast_stress_model
    evidence:
    - reference: PMID:38470198
      reference_title: "Dysregulated proteome and N-glycoproteome in ALG1-deficient fibroblasts."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "Additionally, we observed a decrease in the expression of mitochondrial proteins and an increase in autophagy-related proteins, suggesting mitochondrial and cellular stress."
      explanation: >-
        The patient-cell proteome supports association with mitochondrial and
        autophagic stress, but does not establish the intervening causal steps.
- name: Mitochondrial and autophagic stress
  biological_scale: CELLULAR
  description: >-
    ALG1-deficient fibroblasts show reduced mitochondrial-protein expression
    and increased autophagy-related proteins. This is a provisional cellular
    consequence; its contribution to individual human manifestations remains
    unresolved.
  mechanism_confidence: PROVISIONAL
  biological_processes:
  - preferred_term: autophagy
    modifier: INCREASED
    term:
      id: GO:0006914
      label: autophagy
  evidence:
  - reference: PMID:38470198
    reference_title: "Dysregulated proteome and N-glycoproteome in ALG1-deficient fibroblasts."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Additionally, we observed a decrease in the expression of mitochondrial proteins and an increase in autophagy-related proteins, suggesting mitochondrial and cellular stress."
    explanation: >-
      The 2024 patient-fibroblast study directly supports this cellular-stress
      signature while leaving tissue-level clinical causality unresolved.
  downstream:
  - target: Neurodevelopmental dysfunction
    description: >-
      How the fibroblast stress signature maps to neural tissue is unknown;
      pervasive neurological involvement makes a downstream neural-dysfunction
      bridge plausible but not experimentally established.
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    hypothesis_groups:
    - alg1_cdg_fibroblast_stress_model
    evidence:
    - reference: PMID:26931382
      reference_title: "ALG1-CDG: Clinical and Molecular Characterization of 39 Unreported Patients."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Patients had variable degree of neurodevelopmental deficiencies including developmental delay 37/37 (100%), hypotonia 37/39 (95%), seizures /epilepsy 36/38 (95%), microcephaly 27/37 (73%), abnormal brain imaging 25/37 (68%) which consisted primarily of cerebral or cerebellar atrophy 11/25 (44%) and for those who could be evaluated, intellectual disability 21/22 (95%)"
      explanation: >-
        The cohort establishes the neurological convergence but not the cellular
        intermediates linking glycoproteome stress to the brain phenotype.
- name: Neurodevelopmental dysfunction
  biological_scale: TISSUE
  description: >-
    A provisional convergence node for the near-universal neurological burden.
    The disease-specific glycoprotein clients and neural cell types responsible
    for this vulnerability remain unknown.
  mechanism_confidence: HYPOTHETICAL
  locations:
  - preferred_term: brain
    term:
      id: UBERON:0000955
      label: brain
  evidence:
  - reference: PMID:26931382
    reference_title: "ALG1-CDG: Clinical and Molecular Characterization of 39 Unreported Patients."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Patients had variable degree of neurodevelopmental deficiencies including developmental delay 37/37 (100%), hypotonia 37/39 (95%), seizures /epilepsy 36/38 (95%), microcephaly 27/37 (73%), abnormal brain imaging 25/37 (68%) which consisted primarily of cerebral or cerebellar atrophy 11/25 (44%) and for those who could be evaluated, intellectual disability 21/22 (95%)"
    explanation: >-
      Human clinical data support a common neurological convergence, while the
      node is explicitly hypothetical as a mechanistic bridge.
  downstream:
  - target: Global developmental delay
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    hypothesis_groups: [alg1_cdg_clinical_convergence_model]
    evidence:
    - reference: PMID:26931382
      reference_title: "ALG1-CDG: Clinical and Molecular Characterization of 39 Unreported Patients."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Patients had variable degree of neurodevelopmental deficiencies including developmental delay 37/37 (100%), hypotonia 37/39 (95%), seizures /epilepsy 36/38 (95%), microcephaly 27/37 (73%), abnormal brain imaging 25/37 (68%) which consisted primarily of cerebral or cerebellar atrophy 11/25 (44%) and for those who could be evaluated, intellectual disability 21/22 (95%)"
      explanation: The cohort supports developmental delay as a nearly universal distal manifestation.
  - target: Hypotonia
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    hypothesis_groups: [alg1_cdg_clinical_convergence_model]
    evidence:
    - reference: PMID:26931382
      reference_title: "ALG1-CDG: Clinical and Molecular Characterization of 39 Unreported Patients."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Patients had variable degree of neurodevelopmental deficiencies including developmental delay 37/37 (100%), hypotonia 37/39 (95%), seizures /epilepsy 36/38 (95%), microcephaly 27/37 (73%), abnormal brain imaging 25/37 (68%) which consisted primarily of cerebral or cerebellar atrophy 11/25 (44%) and for those who could be evaluated, intellectual disability 21/22 (95%)"
      explanation: The cohort supports hypotonia as a nearly universal distal manifestation.
  - target: Seizure
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    hypothesis_groups: [alg1_cdg_clinical_convergence_model]
    evidence:
    - reference: PMID:26931382
      reference_title: "ALG1-CDG: Clinical and Molecular Characterization of 39 Unreported Patients."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Patients had variable degree of neurodevelopmental deficiencies including developmental delay 37/37 (100%), hypotonia 37/39 (95%), seizures /epilepsy 36/38 (95%), microcephaly 27/37 (73%), abnormal brain imaging 25/37 (68%) which consisted primarily of cerebral or cerebellar atrophy 11/25 (44%) and for those who could be evaluated, intellectual disability 21/22 (95%)"
      explanation: The cohort supports seizures or epilepsy as a nearly universal distal manifestation.
  - target: Microcephaly
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    hypothesis_groups: [alg1_cdg_clinical_convergence_model]
    evidence:
    - reference: PMID:26931382
      reference_title: "ALG1-CDG: Clinical and Molecular Characterization of 39 Unreported Patients."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Patients had variable degree of neurodevelopmental deficiencies including developmental delay 37/37 (100%), hypotonia 37/39 (95%), seizures /epilepsy 36/38 (95%), microcephaly 27/37 (73%), abnormal brain imaging 25/37 (68%) which consisted primarily of cerebral or cerebellar atrophy 11/25 (44%) and for those who could be evaluated, intellectual disability 21/22 (95%)"
      explanation: The cohort supports microcephaly as a frequent distal manifestation.
  - target: Intellectual disability
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    hypothesis_groups: [alg1_cdg_clinical_convergence_model]
    evidence:
    - reference: PMID:26931382
      reference_title: "ALG1-CDG: Clinical and Molecular Characterization of 39 Unreported Patients."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Patients had variable degree of neurodevelopmental deficiencies including developmental delay 37/37 (100%), hypotonia 37/39 (95%), seizures /epilepsy 36/38 (95%), microcephaly 27/37 (73%), abnormal brain imaging 25/37 (68%) which consisted primarily of cerebral or cerebellar atrophy 11/25 (44%) and for those who could be evaluated, intellectual disability 21/22 (95%)"
      explanation: The cohort supports intellectual disability among evaluable survivors.
  - target: Cerebral atrophy
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    hypothesis_groups: [alg1_cdg_clinical_convergence_model]
    evidence:
    - reference: PMID:26931382
      reference_title: "ALG1-CDG: Clinical and Molecular Characterization of 39 Unreported Patients."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "abnormal brain imaging 25/37 (68%) which consisted primarily of cerebral or cerebellar atrophy 11/25 (44%)"
      explanation: >-
        The combined endpoint supports cerebral or cerebellar atrophy among
        abnormal scans but does not isolate the cerebral-atrophy count.
- name: Multisystem glycoprotein dysfunction
  biological_scale: ORGANISM
  conforms_to: "congenital_disorder_of_glycosylation#Multisystem Glycoprotein Dysfunction"
  description: >-
    A provisional whole-organism convergence node for non-neurological ALG1-CDG
    manifestations. The affected glycoproteins, cell types, and causal routes
    to individual organ findings remain unknown.
  mechanism_confidence: HYPOTHETICAL
  biological_processes:
  - preferred_term: protein N-linked glycosylation
    modifier: ABNORMAL
    term:
      id: GO:0006487
      label: protein N-linked glycosylation
  evidence:
  - reference: PMID:26931382
    reference_title: "ALG1-CDG: Clinical and Molecular Characterization of 39 Unreported Patients."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We also report a substantial number of patients with dysmorphic facial features 24/39 (62%), hematological defects 18/34 (53%), gastrointestinal problems 20/38 (53%), skeletal abnormalities 13/39 (33%) and hypoalbuminemia 12/39 (31%)"
    explanation: >-
      The human cohort supports a multisystem convergence while leaving this
      node explicitly hypothetical at the mechanistic level.
  downstream:
  - target: Strabismus
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    hypothesis_groups: [alg1_cdg_clinical_convergence_model]
    evidence:
    - reference: PMID:26931382
      reference_title: "ALG1-CDG: Clinical and Molecular Characterization of 39 Unreported Patients."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Ocular abnormalities that mainly involved strabismus 10/27 (37%) and nystagmus 6/27 (22%) were found in 27/36 (75%)"
      explanation: The cohort supports the manifestation but not its glycoprotein-specific causal route.
  - target: Nystagmus
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    hypothesis_groups: [alg1_cdg_clinical_convergence_model]
    evidence:
    - reference: PMID:26931382
      reference_title: "ALG1-CDG: Clinical and Molecular Characterization of 39 Unreported Patients."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Ocular abnormalities that mainly involved strabismus 10/27 (37%) and nystagmus 6/27 (22%) were found in 27/36 (75%)"
      explanation: The cohort supports the manifestation but not its glycoprotein-specific causal route.
  - target: Abnormal facial shape
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    hypothesis_groups: [alg1_cdg_clinical_convergence_model]
    evidence:
    - reference: PMID:26931382
      reference_title: "ALG1-CDG: Clinical and Molecular Characterization of 39 Unreported Patients."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "dysmorphic facial features 24/39 (62%), hematological defects 18/34 (53%), gastrointestinal problems 20/38 (53%), skeletal abnormalities 13/39 (33%) and hypoalbuminemia 12/39 (31%)"
      explanation: The cohort supports the manifestation but not its glycoprotein-specific causal route.
  - target: Abnormality of blood and blood-forming tissues
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    hypothesis_groups: [alg1_cdg_clinical_convergence_model]
    evidence:
    - reference: PMID:26931382
      reference_title: "ALG1-CDG: Clinical and Molecular Characterization of 39 Unreported Patients."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "dysmorphic facial features 24/39 (62%), hematological defects 18/34 (53%), gastrointestinal problems 20/38 (53%), skeletal abnormalities 13/39 (33%) and hypoalbuminemia 12/39 (31%)"
      explanation: The cohort supports the manifestation but not its glycoprotein-specific causal route.
  - target: Abnormality of the coagulation cascade
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    hypothesis_groups: [alg1_cdg_clinical_convergence_model]
    evidence:
    - reference: PMID:22966035
      reference_title: "Defining the phenotype in congenital disorder of glycosylation due to ALG1 mutations."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "We report on 7 patients with psychomotor delay, microcephaly, strabismus and coagulation abnormalities, seizures and abnormal fat distribution."
      explanation: The case series supports the manifestation but not its glycoprotein-specific causal route.
  - target: Hypoalbuminemia
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    hypothesis_groups: [alg1_cdg_clinical_convergence_model]
    evidence:
    - reference: PMID:26931382
      reference_title: "ALG1-CDG: Clinical and Molecular Characterization of 39 Unreported Patients."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "We also report a substantial number of patients with dysmorphic facial features 24/39 (62%), hematological defects 18/34 (53%), gastrointestinal problems 20/38 (53%), skeletal abnormalities 13/39 (33%) and hypoalbuminemia 12/39 (31%)"
      explanation: The cohort supports the manifestation but not its glycoprotein-specific causal route.
  - target: Chronic diarrhea
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    hypothesis_groups: [alg1_cdg_clinical_convergence_model]
    evidence:
    - reference: PMID:26931382
      reference_title: "ALG1-CDG: Clinical and Molecular Characterization of 39 Unreported Patients."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "chronic diarrhea (7/20) and/or PLE (5/20)"
      explanation: The cohort supports the manifestation but not its glycoprotein-specific causal route.
  - target: Protein-losing enteropathy
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    hypothesis_groups: [alg1_cdg_clinical_convergence_model]
    evidence:
    - reference: PMID:26931382
      reference_title: "ALG1-CDG: Clinical and Molecular Characterization of 39 Unreported Patients."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Specifically, gastrointestinal manifestations were most often chronic diarrhea (7/20) and/or PLE (5/20)"
      explanation: The cohort supports the manifestation but not its glycoprotein-specific causal route.
  - target: Scoliosis
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    hypothesis_groups: [alg1_cdg_clinical_convergence_model]
    evidence:
    - reference: PMID:26931382
      reference_title: "ALG1-CDG: Clinical and Molecular Characterization of 39 Unreported Patients."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Skeletal abnormalities consisted of scoliosis (5/13), kyphosis (2/13) or joint contractures (3/13)"
      explanation: The cohort supports the manifestation but not its glycoprotein-specific causal route.
  - target: Sensorineural hearing impairment
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    hypothesis_groups: [alg1_cdg_clinical_convergence_model]
    evidence:
    - reference: PMID:22966035
      reference_title: "Defining the phenotype in congenital disorder of glycosylation due to ALG1 mutations."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "We extend the phenotypic spectrum including the first description of deafness in MT1 deficiency, and report on mildly affected patients, surviving to adulthood."
      explanation: The case series supports the manifestation but not its glycoprotein-specific causal route.
  - target: Nonimmune hydrops fetalis
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    hypothesis_groups: [alg1_cdg_clinical_convergence_model]
    evidence:
    - reference: PMID:14973778
      reference_title: "Deficiency of GDP-Man:GlcNAc2-PP-dolichol mannosyltransferase causes congenital disorder of glycosylation type Ik."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "The molecular nature of a severe multisystemic disorder with a recurrent nonimmune hydrops fetalis was identified as deficiency of GDP-Man:GlcNAc(2)-PP-dolichol mannosyltransferase, the human orthologue of the yeast ALG1 gene (MIM 605907)."
      explanation: The report supports the manifestation but not its glycoprotein-specific causal route.
phenotypes:
- name: Global developmental delay
  category: Nervous System
  frequency: VERY_FREQUENT
  description: >-
    Neurodevelopmental impairment is near-universal; developmental delay was
    recorded in every evaluable patient in the landmark cohort.
  phenotype_term:
    preferred_term: Global developmental delay
    term:
      id: HP:0001263
      label: Global developmental delay
  evidence:
  - reference: PMID:26931382
    reference_title: "ALG1-CDG: Clinical and Molecular Characterization of 39 Unreported Patients."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Patients had variable degree of neurodevelopmental deficiencies including developmental delay 37/37 (100%), hypotonia 37/39 (95%), seizures /epilepsy 36/38 (95%), microcephaly 27/37 (73%), abnormal brain imaging 25/37 (68%) which consisted primarily of cerebral or cerebellar atrophy 11/25 (44%) and for those who could be evaluated, intellectual disability 21/22 (95%)"
    explanation: >-
      Developmental delay was present in 37/37 (100%) of evaluable patients.
- name: Hypotonia
  category: Nervous System
  frequency: VERY_FREQUENT
  description: >-
    Central hypotonia is highly prevalent from infancy.
  phenotype_term:
    preferred_term: Hypotonia
    term:
      id: HP:0001252
      label: Hypotonia
  evidence:
  - reference: PMID:26931382
    reference_title: "ALG1-CDG: Clinical and Molecular Characterization of 39 Unreported Patients."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Patients had variable degree of neurodevelopmental deficiencies including developmental delay 37/37 (100%), hypotonia 37/39 (95%), seizures /epilepsy 36/38 (95%), microcephaly 27/37 (73%), abnormal brain imaging 25/37 (68%) which consisted primarily of cerebral or cerebellar atrophy 11/25 (44%) and for those who could be evaluated, intellectual disability 21/22 (95%)"
    explanation: >-
      Hypotonia was present in 37/39 (95%) of patients.
- name: Seizure
  category: Nervous System
  frequency: VERY_FREQUENT
  description: >-
    Seizures or epilepsy, sometimes drug-resistant, are highly prevalent.
  phenotype_term:
    preferred_term: Seizure
    term:
      id: HP:0001250
      label: Seizure
  evidence:
  - reference: PMID:26931382
    reference_title: "ALG1-CDG: Clinical and Molecular Characterization of 39 Unreported Patients."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Patients had variable degree of neurodevelopmental deficiencies including developmental delay 37/37 (100%), hypotonia 37/39 (95%), seizures /epilepsy 36/38 (95%), microcephaly 27/37 (73%), abnormal brain imaging 25/37 (68%) which consisted primarily of cerebral or cerebellar atrophy 11/25 (44%) and for those who could be evaluated, intellectual disability 21/22 (95%)"
    explanation: >-
      Seizures/epilepsy occurred in 36/38 (95%) of patients.
- name: Microcephaly
  category: Head and Neck
  frequency: FREQUENT
  description: >-
    Microcephaly is common.
  phenotype_term:
    preferred_term: Microcephaly
    term:
      id: HP:0000252
      label: Microcephaly
  evidence:
  - reference: PMID:26931382
    reference_title: "ALG1-CDG: Clinical and Molecular Characterization of 39 Unreported Patients."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Patients had variable degree of neurodevelopmental deficiencies including developmental delay 37/37 (100%), hypotonia 37/39 (95%), seizures /epilepsy 36/38 (95%), microcephaly 27/37 (73%), abnormal brain imaging 25/37 (68%) which consisted primarily of cerebral or cerebellar atrophy 11/25 (44%) and for those who could be evaluated, intellectual disability 21/22 (95%)"
    explanation: >-
      Microcephaly was present in 27/37 (73%) of patients.
- name: Intellectual disability
  category: Nervous System
  frequency: VERY_FREQUENT
  description: >-
    Intellectual disability is frequent among evaluable survivors.
  phenotype_term:
    preferred_term: Intellectual disability
    term:
      id: HP:0001249
      label: Intellectual disability
  evidence:
  - reference: PMID:26931382
    reference_title: "ALG1-CDG: Clinical and Molecular Characterization of 39 Unreported Patients."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Patients had variable degree of neurodevelopmental deficiencies including developmental delay 37/37 (100%), hypotonia 37/39 (95%), seizures /epilepsy 36/38 (95%), microcephaly 27/37 (73%), abnormal brain imaging 25/37 (68%) which consisted primarily of cerebral or cerebellar atrophy 11/25 (44%) and for those who could be evaluated, intellectual disability 21/22 (95%)"
    explanation: >-
      Intellectual disability was present in 21/22 (95%) of evaluable patients.
- name: Cerebral atrophy
  category: Nervous System
  description: >-
    Cerebral atrophy is reported, but the major cohort combines cerebral and
    cerebellar atrophy and does not provide a cerebral-specific denominator.
  phenotype_term:
    preferred_term: Cerebral atrophy
    term:
      id: HP:0002059
      label: Cerebral atrophy
  evidence:
  - reference: PMID:26931382
    reference_title: "ALG1-CDG: Clinical and Molecular Characterization of 39 Unreported Patients."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Patients had variable degree of neurodevelopmental deficiencies including developmental delay 37/37 (100%), hypotonia 37/39 (95%), seizures /epilepsy 36/38 (95%), microcephaly 27/37 (73%), abnormal brain imaging 25/37 (68%) which consisted primarily of cerebral or cerebellar atrophy 11/25 (44%) and for those who could be evaluated, intellectual disability 21/22 (95%)"
    explanation: >-
      Cerebral or cerebellar atrophy occurred in 11/37 patients overall (30%),
      but the publication does not separate the cerebral-specific count;
      therefore no cerebral-atrophy frequency band is assigned.
- name: Strabismus
  category: Eye
  frequency: OCCASIONAL
  description: >-
    Ocular abnormalities are frequent and most often involve strabismus.
  phenotype_term:
    preferred_term: Strabismus
    term:
      id: HP:0000486
      label: Strabismus
  evidence:
  - reference: PMID:26931382
    reference_title: "ALG1-CDG: Clinical and Molecular Characterization of 39 Unreported Patients."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Ocular abnormalities that mainly involved strabismus 10/27 (37%) and nystagmus 6/27 (22%) were found in 27/36 (75%)"
    explanation: >-
      Strabismus occurred in 10/36 patients with ocular assessment (28% overall);
      10/27 is the fraction among those who had an ocular abnormality.
- name: Nystagmus
  category: Eye
  frequency: OCCASIONAL
  description: >-
    Nystagmus is reported among ocular manifestations.
  phenotype_term:
    preferred_term: Nystagmus
    term:
      id: HP:0000639
      label: Nystagmus
  evidence:
  - reference: PMID:26931382
    reference_title: "ALG1-CDG: Clinical and Molecular Characterization of 39 Unreported Patients."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Ocular abnormalities that mainly involved strabismus 10/27 (37%) and nystagmus 6/27 (22%) were found in 27/36 (75%)"
    explanation: >-
      Nystagmus occurred in 6/36 patients assessed overall (17%); 6/27 is the
      fraction among those with an ocular abnormality.
- name: Abnormal facial shape
  category: Head and Neck
  frequency: FREQUENT
  description: >-
    Dysmorphic facial features are common, though no single gestalt is
    diagnostic.
  phenotype_term:
    preferred_term: Abnormal facial shape
    term:
      id: HP:0001999
      label: Abnormal facial shape
  evidence:
  - reference: PMID:26931382
    reference_title: "ALG1-CDG: Clinical and Molecular Characterization of 39 Unreported Patients."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "dysmorphic facial features 24/39 (62%), hematological defects 18/34 (53%), gastrointestinal problems 20/38 (53%), skeletal abnormalities 13/39 (33%) and hypoalbuminemia 12/39 (31%)"
    explanation: >-
      Dysmorphic facial features occurred in 24/39 (62%) of patients.
- name: Abnormality of the coagulation cascade
  category: Blood
  description: >-
    Coagulation abnormalities, including hemorrhagic and thrombotic events, are
    part of the ALG1-CDG phenotype.
  phenotype_term:
    preferred_term: Abnormality of the coagulation cascade
    term:
      id: HP:0003256
      label: Abnormality of the coagulation cascade
  evidence:
  - reference: PMID:22966035
    reference_title: "Defining the phenotype in congenital disorder of glycosylation due to ALG1 mutations."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We report on 7 patients with psychomotor delay, microcephaly, strabismus and coagulation abnormalities, seizures and abnormal fat distribution."
    explanation: >-
      The phenotype-defining series reports coagulation abnormalities among core
      ALG1-CDG features.
- name: Abnormality of blood and blood-forming tissues
  category: Blood
  frequency: FREQUENT
  description: >-
    Hematologic abnormalities affect about half of reported patients; this
    broad cohort category is retained because the source does not enumerate all
    component abnormalities in the quoted result.
  phenotype_term:
    preferred_term: Abnormality of blood and blood-forming tissues
    term:
      id: HP:0001871
      label: Abnormality of blood and blood-forming tissues
  evidence:
  - reference: PMID:26931382
    reference_title: "ALG1-CDG: Clinical and Molecular Characterization of 39 Unreported Patients."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "dysmorphic facial features 24/39 (62%), hematological defects 18/34 (53%), gastrointestinal problems 20/38 (53%), skeletal abnormalities 13/39 (33%) and hypoalbuminemia 12/39 (31%)"
    explanation: >-
      Hematologic defects occurred in 18/34 patients (53%), mapping to the
      FREQUENT band.
- name: Hypoalbuminemia
  category: Blood
  frequency: FREQUENT
  description: >-
    Hypoalbuminemia marks severe multisystem disease and was uniformly fatal in
    the cohort; it may reflect enteric or renal protein loss.
  phenotype_term:
    preferred_term: Hypoalbuminemia
    term:
      id: HP:0003073
      label: Hypoalbuminemia
  evidence:
  - reference: PMID:26931382
    reference_title: "ALG1-CDG: Clinical and Molecular Characterization of 39 Unreported Patients."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "dysmorphic facial features 24/39 (62%), hematological defects 18/34 (53%), gastrointestinal problems 20/38 (53%), skeletal abnormalities 13/39 (33%) and hypoalbuminemia 12/39 (31%) (Figure 3, Supp. Table S2). Hypoalbuminemia is noteworthy because all twelve of these individuals died at an average age of 6.75 months."
    explanation: >-
      The full-text cohort supports both the 12/39 frequency reported in the
      preceding sentence and the poor prognosis asserted in the description;
      12/39 (30.8%) maps to the FREQUENT band (30-79%).
- name: Chronic diarrhea
  category: Digestive
  frequency: OCCASIONAL
  description: >-
    Gastrointestinal problems are common; chronic diarrhea is the most frequent
    GI manifestation.
  phenotype_term:
    preferred_term: Chronic diarrhea
    term:
      id: HP:0002028
      label: Chronic diarrhea
  evidence:
  - reference: PMID:26931382
    reference_title: "ALG1-CDG: Clinical and Molecular Characterization of 39 Unreported Patients."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "chronic diarrhea (7/20) and/or PLE (5/20)"
    explanation: >-
      Among patients with GI manifestations (20/38), chronic diarrhea was the
      most frequent (7/20).
- name: Protein-losing enteropathy
  category: Digestive
  frequency: OCCASIONAL
  description: >-
    Protein-losing enteropathy is a recurrent gastrointestinal manifestation.
  phenotype_term:
    preferred_term: Protein-losing enteropathy
    term:
      id: HP:0002243
      label: Protein-losing enteropathy
  evidence:
  - reference: PMID:26931382
    reference_title: "ALG1-CDG: Clinical and Molecular Characterization of 39 Unreported Patients."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Specifically, gastrointestinal manifestations were most often chronic diarrhea (7/20) and/or PLE (5/20)"
    explanation: >-
      Protein-losing enteropathy occurred in 5/38 patients overall (13%), which
      supports an OCCASIONAL frequency band.
- name: Scoliosis
  category: Musculoskeletal
  frequency: OCCASIONAL
  description: >-
    Skeletal abnormalities occur in about one-third of patients; scoliosis is
    the most frequent skeletal finding.
  phenotype_term:
    preferred_term: Scoliosis
    term:
      id: HP:0002650
      label: Scoliosis
  evidence:
  - reference: PMID:26931382
    reference_title: "ALG1-CDG: Clinical and Molecular Characterization of 39 Unreported Patients."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Skeletal abnormalities consisted of scoliosis (5/13), kyphosis (2/13) or joint contractures (3/13)"
    explanation: >-
      Among patients with skeletal abnormalities (13/39), scoliosis was most
      frequent (5/13).
- name: Sensorineural hearing impairment
  category: Ear
  description: >-
    Deafness has been reported in ALG1-CDG, expanding the recognized phenotypic
    spectrum.
  phenotype_term:
    preferred_term: Sensorineural hearing impairment
    term:
      id: HP:0000407
      label: Sensorineural hearing impairment
  evidence:
  - reference: PMID:22966035
    reference_title: "Defining the phenotype in congenital disorder of glycosylation due to ALG1 mutations."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We extend the phenotypic spectrum including the first description of deafness in MT1 deficiency, and report on mildly affected patients, surviving to adulthood."
    explanation: >-
      The phenotype series provides the first description of deafness in ALG1
      (MT-1) deficiency.
- name: Nonimmune hydrops fetalis
  category: Prenatal and Birth
  description: >-
    A severe prenatal presentation with recurrent nonimmune hydrops fetalis has
    been described.
  phenotype_term:
    preferred_term: Nonimmune hydrops fetalis
    term:
      id: HP:0001790
      label: Nonimmune hydrops fetalis
  evidence:
  - reference: PMID:14973778
    reference_title: "Deficiency of GDP-Man:GlcNAc2-PP-dolichol mannosyltransferase causes congenital disorder of glycosylation type Ik."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The molecular nature of a severe multisystemic disorder with a recurrent nonimmune hydrops fetalis was identified as deficiency of GDP-Man:GlcNAc(2)-PP-dolichol mannosyltransferase, the human orthologue of the yeast ALG1 gene (MIM 605907)."
    explanation: >-
      The defining biochemical report describes recurrent nonimmune hydrops
      fetalis at the severe prenatal end of the spectrum.
biochemical:
- name: ALG1-associated xeno-tetrasaccharide NeuAc-Gal-GlcNAc2
  presence: INCREASED
  context: >-
    A short mannose-deprived N-glycan detected on serum transferrin and other
    serum or fibroblast glycoproteins; useful as a diagnostic readout but not
    absolutely required for diagnosis.
  readouts:
  - target: Protein hypoglycosylation
    relationship: READOUT_OF
    direction: POSITIVE
    endpoint_context: DIAGNOSTIC
    interpretation: >-
      Detection reports transfer and Golgi processing of short ALG1-associated
      N-glycans downstream of incomplete lipid-linked oligosaccharide assembly.
    evidence:
    - reference: PMID:26335155
      reference_title: "Serum transferrin carrying the xeno-tetrasaccharide NeuAc-Gal-GlcNAc2 is a biomarker of ALG1-CDG."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "This is the first time analysis of serum TF can suggest a specific CDG type I subtype and we suggest this tetrasaccharide be used in the clinic to guide the ALG1-CDG diagnostic process."
      explanation: >-
        The original biomarker study supports its diagnostic readout role for
        ALG1-CDG while describing guidance rather than a standalone diagnosis.
  evidence:
  - reference: PMID:26335155
    reference_title: "Serum transferrin carrying the xeno-tetrasaccharide NeuAc-Gal-GlcNAc2 is a biomarker of ALG1-CDG."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We show mass spectrometric data combined with data from enzymatic digestions that suggest the presence of a tetrasaccharide consisting of two N-acetylglucosamines, one galactose, and one sialic acid, appearing on serum TF, is a biomarker of this particular CDG subtype."
    explanation: >-
      Directly identifies the serum-transferrin glycan composition and its
      disease-associated biomarker interpretation.
genetic:
- name: ALG1
  association: Biallelic loss-of-function or hypomorphic variants
  features: >-
    ALG1-CDG shows broad allelic heterogeneity, including missense and
    splice-altering alleles that reduce functional ALG1 activity. The recurrent
    c.773C>T (p.Ser258Leu) allele was the most frequently observed in the major
    cohort; all six cohort patients homozygous for it died before six months.
    Complex intronic alleles can be pathogenic through non-functional
    alternative splicing, so coding-only interpretation can miss relevant
    mechanisms.
  gene_term:
    preferred_term: ALG1
    term:
      id: hgnc:18294
      label: ALG1
  evidence:
  - reference: PMID:26931382
    reference_title: "ALG1-CDG: Clinical and Molecular Characterization of 39 Unreported Patients."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The most frequently observed mutation, in both the homozygous and compound heterozygous state (17/39, 44%) (Table 1) was c.773C>T, which encodes a known pathogenic mutation p.Ser258Leu"
    explanation: >-
      The recurrent c.773C>T (p.Ser258Leu) allele was the most frequently
      observed ALG1 variant in the cohort.
  - reference: PMID:26931382
    reference_title: "ALG1-CDG: Clinical and Molecular Characterization of 39 Unreported Patients."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "All six individuals homozygous for the p.Ser258Leu mutation died within the first five months of life."
    explanation: >-
      Directly supports the severe early-lethal genotype association without
      extrapolating it to compound heterozygotes.
  - reference: PMID:34567092
    reference_title: "ALG1-CDG Caused by Non-functional Alternative Splicing Involving a Novel Pathogenic Complex Allele."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "the other carried a new uncharacterized variant (c.208 + 25G > T) causing non-functional alternative splicing that, in conjunction with the benign variant, defines the pathogenic protein effect (p.N70S_S71ins9)."
    explanation: >-
      The molecular case study demonstrates a pathogenic complex allele acting
      through abnormal splicing.
  - reference: PMID:37204045
    reference_title: "A novel variant in ALG1 gene associated with congenital disorder of glycosylation: A case report and short literature review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Clinical exome sequencing revealed the biallelic compound heterozygosity variants, a previously reported variant c.434G>A (p.G145N, paternal) and a novel variant c.314T>A (p.V105N, maternal)."
    explanation: >-
      A 2023 case expands the allelic series with a novel missense variant in
      trans with a previously reported ALG1 allele.
  - reference: PMID:41437099
    reference_title: "Clinical and genetic characterization of congenital disorders of glycosylation in 20 Chinese patients."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Additionally, variants in COG5, COG6, MOGS, DPM3, ALG1, ALG3, ALG11, SSR4 and SLC35A2 each were observed in single case."
    explanation: >-
      The 2025 Chinese CDG cohort adds a contemporary ALG1 case, while the
      abstract does not provide ALG1-specific functional evidence.
  - reference: PMID:14973778
    reference_title: "Deficiency of GDP-Man:GlcNAc2-PP-dolichol mannosyltransferase causes congenital disorder of glycosylation type Ik."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Genetic analysis of the patient's hALG1 gene identified a homozygous mutation leading to the exchange of a serine residue to leucine at position 258 in the hALG1 protein."
    explanation: >-
      The original biochemical report identified the recurrent homozygous
      p.Ser258Leu ALG1 variant.
diagnosis:
- name: Serum transferrin glycoform analysis
  description: >-
    A type I carbohydrate-deficient transferrin pattern is the usual biochemical
    screening clue and is not gene-specific. A normal result does not exclude
    ALG1-CDG, including severe disease, so molecular and orthogonal glycomic
    testing remain necessary when suspicion is high.
  diagnosis_term:
    preferred_term: diagnostic procedure
    term:
      id: NCIT:C18020
      label: Diagnostic Procedure
  results: Usually a type I CDG pattern requiring etiologic follow-up; rarely normal.
  evidence:
  - reference: PMID:14973778
    reference_title: "Deficiency of GDP-Man:GlcNAc2-PP-dolichol mannosyltransferase causes congenital disorder of glycosylation type Ik."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In patient-derived serum, the total amount of the glycoprotein transferrin was reduced. Moreover, a partial loss of N-glycan chains was observed, a characteristic feature of CDG type I forms."
    explanation: >-
      The type I transferrin pattern is the biochemical screening result; it is
      not ALG1-specific.
  - reference: PMID:38736633
    reference_title: "Normal transferrin glycosylation does not rule out severe ALG1 deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Despite her severe clinical manifestations and genetic diagnosis, serum transferrin glycoform analysis was normal."
    explanation: >-
      A molecularly diagnosed severe case directly demonstrates that a normal
      transferrin glycoform result cannot exclude ALG1-CDG.
- name: ALG1 molecular genetic testing
  description: >-
    Definitive diagnosis requires identification of biallelic pathogenic ALG1
    variants. Testing is warranted in unsolved type I CDG with compatible
    features and also when glycan screening is normal but the phenotype and
    genomic findings remain compelling.
  diagnosis_term:
    preferred_term: molecular genetic testing
    term:
      id: NCIT:C19770
      label: Molecular Analysis
  results: Biallelic pathogenic or likely pathogenic ALG1 variants confirm the diagnosis.
  evidence:
  - reference: PMID:22966035
    reference_title: "Defining the phenotype in congenital disorder of glycosylation due to ALG1 mutations."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We suggest testing for ALG1 mutations in unsolved CDG patients with a type 1 transferrin isoelectric focusing pattern, especially with epilepsy, severe visual loss and hemorrhagic/thrombotic events."
    explanation: >-
      The phenotype series recommends ALG1 testing in unsolved type I CDG with
      compatible clinical features.
  - reference: PMID:38736633
    reference_title: "Normal transferrin glycosylation does not rule out severe ALG1 deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "ALG1-CDG was suggested based on exome sequencing and Western blot analysis."
    explanation: >-
      The severe normal-transferrin case illustrates why molecular testing and
      orthogonal protein/glycan assays must be integrated.
- name: Mass-spectrometric ALG1-associated glycan profiling
  description: >-
    Mass spectrometry can detect the ALG1-associated NeuAc-Gal-GlcNAc2
    xeno-tetrasaccharide and a fucosylated N-pentasaccharide signature. These
    markers support subtype prioritization but do not replace biallelic variant
    interpretation, and the tetrasaccharide can also occur in PMM2- and MPI-CDG.
  diagnosis_term:
    preferred_term: mass-spectrometric glycan profiling
    term:
      id: NCIT:C18020
      label: Diagnostic Procedure
  results: ALG1-associated short N-glycan signatures on serum, plasma, or fibroblast glycoproteins.
  evidence:
  - reference: PMID:26335155
    reference_title: "Serum transferrin carrying the xeno-tetrasaccharide NeuAc-Gal-GlcNAc2 is a biomarker of ALG1-CDG."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "we suggest this tetrasaccharide be used in the clinic to guide the ALG1-CDG diagnostic process."
    explanation: >-
      The original study supports the tetrasaccharide as a guide to subtype
      selection, not a standalone molecular confirmation.
  - reference: PMID:35279850
    reference_title: "Synergistic use of glycomics and single-molecule molecular inversion probes for identification of congenital disorders of glycosylation type-1."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Glycomics profiling in patients with known defects revealed novel features such as the N-tetrasaccharide in ALG2-CDG patients and a novel fucosylated N-pentasaccharide as specific glycomarker for ALG1-CDG."
    explanation: >-
      A 111-patient CDG-I glycomics cohort identifies an additional
      ALG1-specific fucosylated pentasaccharide signature.
treatments:
- name: Supportive and complication-directed management
  treatment_term:
    preferred_term: supportive care
    term:
      id: NCIT:C15747
      label: Supportive Care
  description: >-
    No approved ALG1-specific disease-modifying therapy exists. Management is
    multidisciplinary and complication-directed, including antiseizure therapy,
    nutritional and feeding support, and surveillance/treatment of hepatic,
    renal, hematologic, ophthalmologic, and skeletal complications. Substrate
    therapies effective in some other CDGs (e.g., mannose in MPI-CDG) are not
    established for ALG1-CDG.
  review_notes: >-
    No ALG1-specific management guideline or therapeutic clinical trial was
    located through 2026-08-04. The examples summarize complication-directed
    practice and are not claims of disease-modifying efficacy.
  evidence:
  - reference: PMID:42220679
    reference_title: "Resistant Epilepsy and Developmental Delay in a Syndromic Infant: A Case of Congenital Disorder of Glycosylation Type Ik From India."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Supportive therapies, including physiotherapy, developmental stimulation, and nutritional management, were initiated in view of global developmental delay and hypotonia."
    explanation: >-
      A recent molecularly confirmed case documents representative supportive
      interventions, but a single case does not establish comparative efficacy
      or a comprehensive management guideline.
- name: D-mannose supplementation in patient fibroblasts
  therapeutic_modality: SMALL_MOLECULE
  treatment_term:
    preferred_term: experimental substrate supplementation
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: D-mannose
      term:
        id: CHEBI:16024
        label: D-mannose
  description: >-
    D-mannose reduced the ALG1-associated N-tetrasaccharide and increased
    larger N-glycans in one responsive patient-derived fibroblast line. Other
    ALG1 mutant lines, including homozygous p.Ser258Leu cells, did not respond,
    the effective in-vitro concentration may not be achievable in vivo, and no
    human ALG1-CDG efficacy is established; this is not a clinical
    recommendation.
  target_mechanisms:
  - target: Protein hypoglycosylation
    treatment_effect: RESTORES
    evidence:
    - reference: PMID:26430078
      reference_title: "A Novel N-Tetrasaccharide in Patients with Congenital Disorders of Glycosylation, Including Asparagine-Linked Glycosylation Protein 1, Phosphomannomutase 2, and Mannose Phosphate Isomerase Deficiencies."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "After 16 h, there was an 86% reduction of N-tetrasaccharide in ALG1-CDG cells, along with increased amounts of high-mannose and sialylated N-glycans"
      explanation: >-
        Biochemical normalization in one patient fibroblast line partially
        supports restoration of glycosylation, without proving organism-level
        benefit.
  evidence:
  - reference: PMID:26430078
    reference_title: "A Novel N-Tetrasaccharide in Patients with Congenital Disorders of Glycosylation, Including Asparagine-Linked Glycosylation Protein 1, Phosphomannomutase 2, and Mannose Phosphate Isomerase Deficiencies."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "After 16 h, there was an 86% reduction of N-tetrasaccharide in ALG1-CDG cells, along with increased amounts of high-mannose and sialylated N-glycans"
    explanation: >-
      A patient-derived fibroblast line showed biochemical rescue, but this
      preclinical result does not establish clinical efficacy or generalize to
      all ALG1 genotypes.
  - reference: PMID:26430078
    reference_title: "A Novel N-Tetrasaccharide in Patients with Congenital Disorders of Glycosylation, Including Asparagine-Linked Glycosylation Protein 1, Phosphomannomutase 2, and Mannose Phosphate Isomerase Deficiencies."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "The applicability of mannose treatment for patients with ALG1-CDG remains unknown because not all the ALG1-CDG mutant cell lines respond to mannose supplementation."
    explanation: >-
      The authors explicitly limit the translational scope and document
      genotype-dependent nonresponse.
discussions:
- discussion_id: gap_alg1_cdg_translational_therapy
  prompt: >-
    Can ALG1-specific glycan rescue or shared CDG autophagy and mitochondrial
    signatures be translated into a safe disease-modifying therapy?
  kind: KNOWLEDGE_GAP
  status: OPEN
  attaches_to:
  - treatments#D-mannose supplementation in patient fibroblasts
  - pathophysiology#Mitochondrial and autophagic stress
  rationale: >-
    Mannose rescue is limited to selected patient fibroblasts and has no human
    efficacy evidence. A 2025 multi-omics study nominated shared CDG drug
    candidates computationally, but explicitly requires future in-vitro
    validation and does not establish ALG1-specific benefit.
  proposed_experiments:
  - experiment_id: exp_alg1_genotype_stratified_therapy_screen
    name: Genotype-stratified ALG1 patient-cell rescue study
    description: >-
      Test mannose and independently prioritized multi-omics candidates across
      ALG1 patient-derived neural and hepatic cell models representing severe
      and mild alleles, with glycoproteomic, mitochondrial, autophagic, and
      toxicity endpoints before any clinical translation.
    evidence:
    - reference: PMID:40743674
      reference_title: "Predicting disease-overarching therapeutic approaches for congenital disorders of glycosylation using multi-OMICS."
      supports: SUPPORT
      evidence_source: COMPUTATIONAL
      snippet: "Several candidate drugs targeting these shared abnormalities emerged from integrative analysis and warrant validation in future in vitro studies."
      explanation: >-
        The stated need for experimental validation motivates a
        genotype-stratified patient-cell study.
  evidence:
  - reference: PMID:40743674
    reference_title: "Predicting disease-overarching therapeutic approaches for congenital disorders of glycosylation using multi-OMICS."
    supports: SUPPORT
    evidence_source: COMPUTATIONAL
    snippet: "Several candidate drugs targeting these shared abnormalities emerged from integrative analysis and warrant validation in future in vitro studies."
    explanation: >-
      The multi-omics analysis supplies candidate hypotheses while explicitly
      documenting that experimental validation remains outstanding.
  posed_date: "2026-08-04T00:00:00Z"
datasets: []
📚

References & Deep Research

References

18
PMID:26931382
ALG1-CDG: Clinical and Molecular Characterization of 39 Unreported Patients.
No top-level findings curated for this source.
PMID:14973778
Deficiency of GDP-Man:GlcNAc2-PP-dolichol mannosyltransferase causes congenital disorder of glycosylation type Ik.
No top-level findings curated for this source.
PMID:14709599
Deficiency of the first mannosylation step in the N-glycosylation pathway causes congenital disorder of glycosylation type Ik.
No top-level findings curated for this source.
PMID:14973782
Congenital disorder of glycosylation type Ik (CDG-Ik): a defect of mannosyltransferase I.
No top-level findings curated for this source.
PMID:22966035
Defining the phenotype in congenital disorder of glycosylation due to ALG1 mutations.
No top-level findings curated for this source.
PMID:38256263
Targeted Proteomics Reveals Quantitative Differences in Low-Abundance Glycosyltransferases of Patients with Congenital Disorders of Glycosylation.
No top-level findings curated for this source.
PMID:34447415
The Estimated Prevalence of N-Linked Congenital Disorders of Glycosylation Across Various Populations Based on Allele Frequencies in General Population Databases.
No top-level findings curated for this source.
PMID:26335155
Serum transferrin carrying the xeno-tetrasaccharide NeuAc-Gal-GlcNAc2 is a biomarker of ALG1-CDG.
No top-level findings curated for this source.
PMID:26430078
A Novel N-Tetrasaccharide in Patients with Congenital Disorders of Glycosylation, Including Asparagine-Linked Glycosylation Protein 1, Phosphomannomutase 2, and Mannose Phosphate Isomerase Deficiencies.
No top-level findings curated for this source.
PMID:34567092
ALG1-CDG Caused by Non-functional Alternative Splicing Involving a Novel Pathogenic Complex Allele.
No top-level findings curated for this source.
PMID:35221878
ALG1-CDG: A Patient with a Mild Phenotype and Literature Review.
No top-level findings curated for this source.
PMID:35279850
Synergistic use of glycomics and single-molecule molecular inversion probes for identification of congenital disorders of glycosylation type-1.
No top-level findings curated for this source.
PMID:37204045
A novel variant in ALG1 gene associated with congenital disorder of glycosylation: A case report and short literature review.
No top-level findings curated for this source.
PMID:38470198
Dysregulated proteome and N-glycoproteome in ALG1-deficient fibroblasts.
No top-level findings curated for this source.
PMID:38736633
Normal transferrin glycosylation does not rule out severe ALG1 deficiency.
No top-level findings curated for this source.
PMID:40743674
Predicting disease-overarching therapeutic approaches for congenital disorders of glycosylation using multi-OMICS.
No top-level findings curated for this source.
PMID:41437099
Clinical and genetic characterization of congenital disorders of glycosylation in 20 Chinese patients.
No top-level findings curated for this source.
PMID:42220679
Resistant Epilepsy and Developmental Delay in a Syndromic Infant: A Case of Congenital Disorder of Glycosylation Type Ik From India.
No top-level findings curated for this source.

Deep Research

1
Falcon ▸
Disease Characteristics Research Template
Edison Scientific Literature 14 citations 2026-07-24T14:58:32.887469

Question: You are an expert researcher providing comprehensive, well-cited information.

Provide detailed information focusing on: 1. Key concepts and definitions with current understanding 2. Recent developments and latest research (prioritize 2023-2024 sources) 3. Current applications and real-world implementations 4. Expert opinions and analysis from authoritative sources 5. Relevant statistics and data from recent studies

Format as a comprehensive research report with proper citations. Include URLs and publication dates where available. Always prioritize recent, authoritative sources and provide specific citations for all major claims.

Disease Characteristics Research Template

Target Disease

  • Disease Name: ALG1-congenital disorder of glycosylation
  • MONDO ID: (if available)
  • Category: Mendelian

Research Objectives

Please provide a comprehensive research report on ALG1-congenital disorder of glycosylation covering all of the disease characteristics listed below. This report will be used to populate a disease knowledge base entry. Be thorough and cite primary literature (PMID preferred) for all claims.

For each section, suggested databases/resources are listed. These are the first places you should search for information on each topic.

1. Disease Information

Search first: OMIM, Orphanet, ICD-10/ICD-11, MeSH, PubMed

  • What is the disease? Provide a concise overview.
  • What are the key identifiers? (OMIM, Orphanet, ICD-10/ICD-11, MeSH, Mondo)
  • What are the common synonyms and alternative names?
  • Is the information derived from individual patients (e.g., EHR) or aggregated disease-level resources?

2. Etiology

  • Disease Causal Factors: What are the primary causes? (genetic, environmental, infectious, mechanistic)
  • Risk Factors:

    Search first: PubMed, Cochrane Library, UpToDate, clinical guidelines, ClinVar, ClinGen, GWAS Catalog, PheGenI, CTD, CDC, WHO, epidemiological databases

  • Genetic risk factors (causal variants, susceptibility loci, modifier genes)
  • Environmental risk factors (toxins, lifestyle, occupational exposures, age, sex, family history)
  • Protective Factors:

    Search first: PubMed, Cochrane Library, clinical trial databases, GWAS Catalog, gnomAD, WHO, CDC, nutrition databases

  • Genetic protective factors (protective variants, modifier alleles)
  • Environmental protective factors (diet, lifestyle, exposures that reduce risk)
  • Gene-Environment Interactions: How do genetic and environmental factors interact to influence disease?

    Search first: CTD, PubMed, PheGenI, GxE databases

3. Phenotypes

Search first: HPO (Human Phenotype Ontology), OMIM, Orphanet, PubMed, clinicaltrials.gov, MedDRA, SNOMED CT, DECIPHER, LOINC

For each phenotype, provide: - Phenotype type: symptoms, clinical signs, physical manifestations, behavioral changes, or laboratory abnormalities

For symptoms/signs: HPO, OMIM, Orphanet, PubMed For behavioral changes: HPO, DSM, RDoC (Research Domain Criteria), PubMed For laboratory abnormalities: LOINC, SNOMED CT, LabTests Online, PubMed - Phenotype characteristics: Search first: OMIM, Orphanet, HPO, PubMed - Age of symptom onset (neonatal, childhood, adult-onset, late-onset) - Symptom severity (mild, moderate, severe, variable) - Symptom progression (stable, progressive, episodic, fluctuating) - Frequency among affected individuals (percentage or qualitative) - Quality of life impact: Effects on daily functioning and well-being (per-phenotype when possible) Search first: EQ-5D database, SF-36, WHO QOL databases, PubMed - Suggest HPO (Human Phenotype Ontology) terms for each phenotype

4. Genetic/Molecular Information

  • Causal Genes: Gene mutations or chromosomal abnormalities responsible for disease (gene symbols, OMIM IDs)

    Search first: OMIM, ClinVar, HGMD, Ensembl, NCBI Gene

  • Pathogenic Variants:
  • Affected genes (gene symbols, HGNC IDs) > Search first: OMIM, NCBI Gene, Ensembl, HGNC, UniProt, GeneCards
  • Variant classification (pathogenic, likely pathogenic, VUS per ACMG/AMP guidelines) > Search first: ClinVar, ClinGen, ACMG/AMP guidelines, VarSome
  • Variant type/class (missense, frameshift, nonsense, splice-site, structural)
  • Allele frequency in population databases > Search first: gnomAD, 1000 Genomes, ExAC, TOPMed, dbSNP
  • Somatic vs germline origin > Search first: COSMIC (somatic), ClinVar, ICGC, TCGA
  • Functional consequences (loss of function, gain of function, dominant negative)
  • Modifier Genes: Genes that modify disease severity or expression
  • Epigenetic Information: DNA methylation, histone modifications, chromatin changes affecting disease

    Search first: ENCODE, Roadmap Epigenomics, MethBase, DiseaseMeth

  • Chromosomal Abnormalities: Large-scale genetic changes (aneuploidy, translocations, inversions)

    Search first: DECIPHER, ClinVar, ECARUCA, UCSC Genome Browser

5. Environmental Information

  • Environmental Factors: Non-genetic contributing factors (toxins, radiation, pollution, occupational exposure)

    Search first: CTD (Comparative Toxicogenomics Database), TOXNET, PubMed, EPA databases

  • Lifestyle Factors: Behavioral factors (smoking, diet, exercise, alcohol consumption)

    Search first: CDC databases, WHO, PubMed, NHANES

  • Infectious Agents: If applicable, pathogens causing or triggering disease (bacteria, viruses, fungi, parasites)

    Search first: NCBI Taxonomy, ViPR, BV-BRC, MicrobeDB, GIDEON

6. Mechanism / Pathophysiology

  • Molecular Pathways: Specific signaling cascades or biochemical pathways involved (Wnt, MAPK, mTOR, PI3K-AKT, etc.)

    Search first: KEGG, Reactome, WikiPathways, PathBank, BioCyc

  • Cellular Processes: Cell-level mechanisms (apoptosis, autophagy, cell cycle dysregulation, inflammation, etc.)

    Search first: Gene Ontology (GO), Reactome, KEGG, PubMed

  • Protein Dysfunction: How protein structure or function is altered (misfolding, aggregation, loss of function, gain of function)

    Search first: UniProt, PDB (Protein Data Bank), InterPro, Pfam, AlphaFold

  • Metabolic Changes: Alterations in metabolic processes (energy metabolism, lipid metabolism, amino acid metabolism)

    Search first: KEGG, BioCyc, HMDB (Human Metabolome Database), BRENDA

  • Immune System Involvement: Role of immune response (autoimmunity, immunodeficiency, chronic inflammation)

    Search first: ImmPort, Immunome Database, IEDB, Gene Ontology

  • Tissue Damage Mechanisms: How tissues/ are injured (oxidative stress, ischemia, fibrosis, necrosis)

    Search first: PubMed, Gene Ontology, Reactome

  • Biochemical Abnormalities: Specific molecular defects (enzyme deficiencies, receptor dysfunction, ion channel defects)

    Search first: BRENDA, UniProt, KEGG, OMIM, PubMed

  • Epigenetic Changes: DNA methylation, histone modifications affecting gene expression in disease

    Search first: ENCODE, Roadmap Epigenomics, MethBase, DiseaseMeth

  • Molecular Profiling (if available):
  • Transcriptomics/gene expression changes > Search first: GEO (Gene Expression Omnibus), ArrayExpress, GTEx, Human Cell Atlas, SRA
  • Proteomics findings > Search first: PRIDE, ProteomeXchange, Human Protein Atlas, STRING, BioGRID
  • Metabolomics signatures > Search first: MetaboLights, Metabolomics Workbench, HMDB, METLIN
  • Lipidomics alterations > Search first: LIPID MAPS, SwissLipids, LipidHome, Metabolomics Workbench
  • Genomic structural features > Search first: UCSC Genome Browser, Ensembl, NCBI, dbVar, DGV
  • Advanced Technologies (if applicable):
  • Single-cell analysis findings (cell-type specific mechanisms, cellular heterogeneity) > Search first: Human Cell Atlas, Single Cell Portal, GEO, CELLxGENE
  • Spatial transcriptomics findings > Search first: GEO, Spatial Research, Vizgen, 10x Genomics data
  • Multi-omics integration results > Search first: TCGA, ICGC, cBioPortal, LinkedOmics, PubMed
  • Functional genomics screens (CRISPR, RNAi) > Search first: DepMap, GenomeRNAi, PubMed, BioGRID ORCS

For each mechanism, describe: - The causal chain from initial trigger to clinical manifestation - Which mechanisms are upstream vs downstream - What cell types and biological processes are involved - Suggest GO terms for biological processes and CL terms for cell types

7. Anatomical Structures Affected

  • Organ Level:
  • Primary organs directly affected
  • Secondary organ involvement (complications, secondary effects)
  • Body systems involved (cardiovascular, nervous, digestive, respiratory, endocrine, etc.)

    Search first: Uberon, FMA (Foundational Model of Anatomy), OMIM, HPO, ICD-11, MeSH, SNOMED CT

  • Tissue and Cell Level:
  • Specific tissue types affected (epithelial, connective, muscle, nervous)
  • Specific cell populations targeted (with Cell Ontology terms)

    Search first: Uberon, Human Protein Atlas, Cell Ontology, Human Cell Atlas, CellMarker, PanglaoDB

  • Subcellular Level:
  • Cellular compartments involved (mitochondria, nucleus, ER, lysosomes) (with GO Cellular Component terms)

    Search first: Gene Ontology (Cellular Component), UniProt, Human Protein Atlas

  • Localization:
  • Specific anatomical sites (with UBERON terms) > Search first: FMA, Uberon, NeuroNames (for brain), SNOMED CT
  • Lateralization (unilateral, bilateral, asymmetric) > Search first: HPO, clinical literature, imaging databases

8. Temporal Development

  • Onset:
  • Typical age of onset (congenital, pediatric, adult, geriatric)
  • Onset pattern (acute, subacute, chronic, insidious)

    Search first: OMIM, Orphanet, HPO, PubMed

  • Progression:
  • Disease stages (early, intermediate, advanced, end-stage) > Search first: Cancer Staging Manual (AJCC), WHO classifications, PubMed
  • Progression rate (rapid, slow, variable)
  • Disease course pattern (episodic, relapsing-remitting, progressive, stable)
  • Disease duration (self-limited, chronic lifelong)

    Search first: Disease registries, longitudinal cohort databases, natural history studies, PubMed, Orphanet, OMIM

  • Patterns:
  • Remission patterns (spontaneous, treatment-induced) > Search first: Clinical trial databases, disease registries, PubMed
  • Critical periods (time windows of vulnerability or opportunity for intervention) > Search first: PubMed, developmental biology databases, clinical guidelines

9. Inheritance and Population

  • Epidemiology:
  • Prevalence (cases per 100,000 at given time)
  • Incidence (new cases per 100,000 per year)

    Search first: Orphanet, CDC, WHO, GBD (Global Burden of Disease), national registries, SEER, disease registries

  • For Genetic Etiology:
  • Inheritance pattern (AD, AR, X-linked, mitochondrial, multifactorial, polygenic) > Search first: OMIM, Orphanet, ClinVar, GTR (Genetic Testing Registry)
  • Penetrance (complete, incomplete, age-dependent) > Search first: ClinVar, OMIM, PubMed, ClinGen
  • Expressivity (variable, consistent) > Search first: OMIM, ClinVar, PubMed
  • Genetic anticipation (increasing severity in successive generations) > Search first: OMIM, PubMed (especially for repeat expansion disorders)
  • Germline mosaicism > Search first: ClinVar, OMIM, genetic counseling literature, PubMed
  • Founder effects (population-specific mutations) > Search first: gnomAD, population genetics databases, PubMed
  • Consanguinity role > Search first: OMIM, population studies, genetic counseling resources
  • Carrier frequency > Search first: gnomAD, carrier screening databases, GeneReviews, GTR
  • Population Demographics:
  • Affected populations (ethnic or demographic groups with higher prevalence) > Search first: gnomAD, 1000 Genomes, PAGE Study, PubMed, population registries
  • Geographic distribution (endemic areas, regional variation) > Search first: WHO, CDC, GBD, Orphanet, geographic epidemiology databases
  • Geographic distribution of specific variants
  • Sex ratio (male:female) > Search first: Disease registries, OMIM, PubMed, epidemiological databases
  • Age distribution of affected individuals > Search first: CDC, disease registries, SEER, Orphanet

10. Diagnostics

  • Clinical Tests:
  • Laboratory tests (blood, urine, tissue chemistry, specific enzyme assays) > Search first: LOINC, LabTests Online, PubMed
  • Biomarkers (proteins, metabolites, genetic markers, circulating biomarkers) > Search first: FDA Biomarker List, BEST (Biomarkers, EndpointS, and other Tools), PubMed
  • Imaging studies (X-ray, CT, MRI, PET, ultrasound) > Search first: RadLex, DICOM, Radiopaedia, imaging databases
  • Functional tests (pulmonary function, cardiac stress tests) > Search first: LOINC, clinical guidelines, PubMed
  • Electrophysiology (EEG, EMG, ECG, nerve conduction studies) > Search first: LOINC, clinical neurophysiology databases, PubMed
  • Biopsy findings (histopathology, immunohistochemistry) > Search first: SNOMED CT, College of American Pathologists resources, PubMed
  • Pathology findings (microscopic examination) > Search first: SNOMED CT, Digital Pathology databases, PubMed
  • Genetic Testing:

    Search first: GTR (Genetic Testing Registry), GeneReviews, ClinGen

  • Overview of recommended genetic testing approach
  • Whole genome sequencing (WGS) utility > Search first: GTR, ClinVar, GEL (Genomics England), gnomAD
  • Whole exome sequencing (WES) utility > Search first: GTR, ClinVar, OMIM, GeneMatcher
  • Gene panels (which panels, which genes) > Search first: GTR, ClinVar, laboratory-specific databases
  • Single gene testing > Search first: GTR, ClinVar, OMIM, GeneReviews
  • Chromosomal microarray (CMA) > Search first: DECIPHER, ClinVar, dbVar, ECARUCA
  • Karyotyping > Search first: Chromosome Abnormality Database, ClinVar, cytogenetics resources
  • FISH > Search first: ClinVar, cytogenetics databases, PubMed
  • Mitochondrial DNA testing > Search first: MITOMAP, MSeqDR, ClinVar, GTR
  • Repeat expansion testing > Search first: GTR, ClinVar, repeat expansion databases, PubMed
  • Omics-Based Diagnostics (if applicable):
  • RNA sequencing / transcriptomics > Search first: GEO, ArrayExpress, GTEx, RNA-seq databases
  • Proteomics > Search first: PRIDE, ProteomeXchange, FDA Biomarker database
  • Metabolomics > Search first: MetaboLights, Metabolomics Workbench, HMDB
  • Epigenomics > Search first: GEO, ENCODE, Roadmap Epigenomics, MethBase
  • Liquid biopsy > Search first: COSMIC, ClinVar, liquid biopsy databases, PubMed
  • Clinical Criteria:
  • Standardized diagnostic criteria (DSM, ICD, society guidelines) > Search first: DSM-5, ICD-11, clinical society guidelines, UpToDate
  • Differential diagnosis (other conditions to rule out, with distinguishing features) > Search first: DynaMed, UpToDate, clinical decision support systems
  • Screening:
  • Screening methods for asymptomatic individuals (newborn screening, carrier screening, cascade screening) > Search first: ACMG recommendations, CDC newborn screening, GTR

11. Outcome/Prognosis

  • Survival and Mortality:
  • Survival rate (5-year, 10-year, overall) > Search first: SEER, cancer registries, disease-specific registries, PubMed
  • Life expectancy (with and without treatment if applicable) > Search first: Orphanet, disease registries, actuarial databases, PubMed
  • Mortality rate > Search first: CDC, WHO, GBD, national mortality databases
  • Disease-specific mortality (deaths directly attributable to disease) > Search first: Disease registries, CDC Wonder, GBD, PubMed
  • Morbidity and Function:
  • Morbidity (disease-related disability and health impacts) > Search first: GBD, WHO, disability databases, PubMed
  • Disability outcomes (long-term functional impairments) > Search first: ICF (International Classification of Functioning), disability registries
  • Quality of life measures (EQ-5D, SF-36, PROMIS, disease-specific tools) > Search first: EQ-5D database, SF-36, PROMIS, PubMed
  • Disease Course:
  • Complications (secondary problems: infections, organ failure, etc.) > Search first: ICD codes, disease registries, clinical databases, PubMed
  • Recovery potential (likelihood and extent of recovery, with vs without treatment) > Search first: Natural history studies, rehabilitation databases, PubMed
  • Prediction:
  • Prognostic factors (age, disease severity, biomarkers, treatment response) > Search first: Prognostic models databases, clinical calculators, PubMed
  • Prognostic biomarkers (molecular markers predicting disease course) > Search first: FDA Biomarker database, PubMed, cancer prognostic databases

12. Treatment

  • Pharmacotherapy:
  • Pharmacological treatments (drug names, drug classes, mechanisms of action) > Search first: DrugBank, RxNorm, ATC classification, DailyMed, FDA databases
  • Pharmacogenomics (how genetic variants affect drug metabolism, efficacy, toxicity) > Search first: PharmGKB, CPIC (Clinical Pharmacogenetics), FDA Table of PGx Biomarkers
  • Advanced Therapeutics:
  • Gene therapy (viral vectors, CRISPR, gene replacement, gene editing) > Search first: ClinicalTrials.gov, FDA gene therapy database, ASGCT resources
  • Cell therapy (stem cell transplant, CAR-T, cellular therapeutics) > Search first: ClinicalTrials.gov, FDA cell therapy database, FACT standards
  • RNA-based therapies (ASOs, siRNA, mRNA therapies) > Search first: ClinicalTrials.gov, FDA approvals, PubMed
  • Targeted therapies (treatments directed at specific molecular targets) > Search first: My Cancer Genome, OncoKB, ClinicalTrials.gov, FDA approvals
  • Immunotherapies (checkpoint inhibitors, monoclonal antibodies) > Search first: Cancer Immunotherapy Database, FDA approvals, ClinicalTrials.gov
  • Surgical and Interventional:
  • Surgical interventions (types of surgery, timing, outcomes) > Search first: CPT codes, surgical registries, clinical guidelines, PubMed
  • Supportive and Rehabilitative:
  • Supportive care (symptom management, pain control, nutrition) > Search first: Clinical guidelines, Cochrane Library, PubMed
  • Rehabilitation (physical therapy, occupational therapy, speech therapy) > Search first: Rehabilitation medicine databases, clinical guidelines, PubMed
  • Experimental:
  • Experimental treatments in clinical trials (with NCT identifiers if available) > Search first: ClinicalTrials.gov, EU Clinical Trials Register, WHO ICTRP
  • Treatment Outcomes:
  • Treatment response rates > Search first: Clinical trial databases, FDA reviews, systematic reviews, PubMed
  • Side effects and adverse events > Search first: FDA Adverse Event Reporting System (FAERS), MedWatch, PubMed
  • Treatment Strategy:
  • Treatment algorithms (clinical pathways, decision trees) > Search first: Clinical practice guidelines, NCCN Guidelines, UpToDate
  • Combination therapies > Search first: ClinicalTrials.gov, treatment guidelines, PubMed
  • Personalized medicine approaches (genotype-guided treatment) > Search first: My Cancer Genome, CIViC, PharmGKB, precision medicine databases

For each treatment, suggest MAXO (Medical Action Ontology) terms where applicable.

13. Prevention

  • Prevention Levels:
  • Primary prevention (preventing disease occurrence: vaccination, risk factor modification) > Search first: CDC, WHO, USPSTF recommendations, Cochrane Library
  • Secondary prevention (early detection and treatment: screening programs, early intervention) > Search first: USPSTF, CDC screening guidelines, WHO
  • Tertiary prevention (preventing complications in those with disease) > Search first: Clinical guidelines, disease management protocols, PubMed
  • Immunization: Vaccine strategies (if applicable)

    Search first: CDC vaccine schedules, WHO immunization, FDA vaccine database

  • Screening and Early Detection:
  • Screening programs (population-based: newborn screening, cancer screening) > Search first: CDC screening programs, USPSTF, cancer screening databases
  • Genetic screening (carrier screening, preimplantation genetic diagnosis, prenatal testing) > Search first: ACMG recommendations, ACOG guidelines, GTR
  • Risk stratification (identifying high-risk individuals for targeted prevention) > Search first: Risk prediction models, clinical calculators, PubMed
  • Behavioral Interventions: Lifestyle modifications to reduce risk

    Search first: CDC, WHO, behavioral intervention databases, Cochrane Library

  • Counseling: Genetic counseling (risk assessment, family planning guidance)

    Search first: NSGC resources, ACMG guidelines, GeneReviews

  • Public Health:
  • Public health interventions (sanitation, vector control, health education) > Search first: CDC, WHO, public health databases, PubMed
  • Environmental interventions (reducing environmental risk factors) > Search first: EPA databases, WHO environmental health, PubMed
  • Prophylaxis: Preventive medications or procedures

    Search first: Clinical guidelines, FDA approvals, PubMed

14. Other Species / Natural Disease

  • Taxonomy: Species affected (with NCBI Taxon identifiers)

    Search first: NCBI Taxonomy

  • Breed: Specific breeds affected (with VBO identifiers if applicable)

    Search first: VBO (Vertebrate Breed Ontology)

  • Gene: Orthologous genes in other species (with NCBI Gene IDs)

    Search first: NCBI Gene

  • Natural Disease:
  • Naturally occurring disease in other species (companion animals, wildlife) > Search first: OMIA (Online Mendelian Inheritance in Animals), VetCompass, PubMed
  • Veterinary relevance and importance in animal health > Search first: OMIA, veterinary databases, PubMed
  • Comparative Biology:
  • Comparative pathology (similarities and differences across species) > Search first: OMIA, comparative pathology databases, PubMed
  • Evolutionary conservation of disease mechanisms > Search first: HomoloGene, OrthoMCL, Alliance of Genome Resources
  • Transmission (if applicable):
  • Zoonotic potential > Search first: CDC zoonotic diseases, WHO zoonoses, GIDEON
  • Cross-species susceptibility > Search first: NCBI Taxonomy, veterinary databases, PubMed

15. Model Organisms

  • Model Types:
  • Model organism type (mammalian, invertebrate, cellular, in vitro) > Search first: Alliance of Genome Resources, model organism databases
  • Specific model systems (mouse, rat, zebrafish, Drosophila, C. elegans, yeast, cell lines, organoids, iPSCs) > Search first: MGI, RGD, ZFIN, FlyBase, WormBase, SGD, ATCC, Cellosaurus
  • Induced models (drug treatment, surgical intervention, environmental manipulation) > Search first: MGI, model organism databases, PubMed
  • Genetic Models:
  • Types available (knockout, knock-in, transgenic, conditional, humanized) > Search first: MGI, IMPC, KOMP, EuMMCR, IMSR
  • Model Characteristics:
  • Phenotype recapitulation (how well model reproduces human disease features) > Search first: Model organism databases, comparative studies, PubMed
  • Model limitations (aspects of human disease not captured) > Search first: Model organism databases, PubMed, review articles
  • Applications:
  • Research applications (what aspects of disease can be studied) > Search first: Model organism databases, PubMed
  • Resources:
  • Model databases > Search first: MGI, RGD, ZFIN, FlyBase, WormBase, IMSR, EMMA, MMRRC

Citation Requirements

  • Cite primary literature (PMID preferred) for all mechanistic and clinical claims
  • Prioritize recent reviews and landmark papers
  • Include direct quotes from abstracts where possible to support key statements
  • Distinguish evidence source types: human clinical, model organism, in vitro, computational

Output Format

Structure your response as a comprehensive narrative organized by the sections above. For each section, provide: - Factual content with specific details (numbers, percentages, gene names, variant nomenclature) - Ontology term suggestions (HPO, GO, CL, UBERON, CHEBI, MAXO, MONDO) where applicable - Evidence citations with PMIDs - Direct quotes from abstracts to support key claims - Clear indication when information is not available or not applicable for this disease

This report will be used to populate a disease knowledge base entry with: - Pathophysiology descriptions with causal chains - Gene/protein annotations (HGNC, GO terms) - Phenotype associations (HP terms) with frequencies - Cell type involvement (CL terms) - Anatomical locations (UBERON terms) - Chemical entities (CHEBI terms) - Treatment annotations (MAXO terms) - Evidence items with PMIDs and exact abstract quotes - Epidemiology, prognosis, diagnostic, and prevention information - Animal model descriptions with phenotype recapitulation details

ALG1-congenital disorder of glycosylation (ALG1-CDG): disease-characteristics report

Executive summary

ALG1-CDG is an ultrarare, autosomal-recessive congenital disorder of protein N-glycosylation caused by biallelic pathogenic variants in ALG1, which encodes an endoplasmic-reticulum β1,4-mannosyltransferase. The enzyme adds the first mannose to the dolichol-linked oligosaccharide precursor used for N-glycosylation. Deficiency therefore produces incomplete lipid-linked glycans, under-occupancy of N-glycosylation sites, and systemic dysfunction of glycoproteins. Disease severity ranges from developmental disability to lethal neonatal/infantile multisystem disease. In the largest disease-specific cohort, developmental delay occurred in 37/37 evaluable patients, hypotonia in 37/39, seizures/epilepsy in 36/38, and premature death in 17/39. (ng2016alg1‐cdgclinicaland pages 4-6, ng2016alg1‐cdgclinicaland pages 1-3)

The most useful biochemical clue is a type-I carbohydrate-deficient transferrin pattern. A stronger ALG1-associated marker is the nonphysiologic N-linked tetrasaccharide NeuAc-Gal-GlcNAc₂, detected in all 27 tested patients in the landmark cohort. Diagnosis nevertheless requires demonstration of pathogenic biallelic ALG1 variants, ideally supported by glycan or functional evidence. There is no established disease-modifying treatment; current care is multidisciplinary and complication-directed. (ng2016alg1‐cdgclinicaland pages 1-3, ng2016alg1‐cdgclinicaland pages 6-8)

The following table summarizes high-value knowledge-base annotations.

domain high-confidence finding quantitative evidence suggested ontology terms evidence type
Disease identifiers ALG1-congenital disorder of glycosylation is a rare N-glycosylation disorder; former name CDG-Ik; disease OMIM/MIM 608540; causal gene ALG1 MIM 605907 Landmark cohort expanded known cases to 57 total by 2016 (39 new + 18 previously reported) (ng2016alg1‐cdgclinicaland pages 1-3, ng2016alg1‐cdgclinicaland pages 6-8) MONDO: not confirmed here; OMIM: 608540; MeSH/ICD not confidently established from retrieved sources; synonym: ALG1-CDG, CDG-Ik Human clinical cohort + disease literature
Gene / inheritance Caused by biallelic pathogenic variants in ALG1; inheritance is autosomal recessive 39 affected individuals from 32 unrelated families; 17 male / 22 female (ng2016alg1‐cdgclinicaland pages 4-6, ng2016alg1‐cdgclinicaland pages 1-3) ALG1 (HGNC gene symbol); autosomal recessive inheritance Human clinical genetics
Molecular function ALG1 encodes an ER-localized beta-1,4 mannosyltransferase that adds the first mannose to the growing dolichol-linked oligosaccharide in N-glycosylation First of 9 mannose residues in the DLO precursor (ng2016alg1‐cdgclinicaland pages 1-3, ng2016alg1‐cdgclinicaland pages 10-13) GO: protein N-linked glycosylation; GO cellular component: endoplasmic reticulum; CHEBI labels: GDP-mannose, dolichol-PP-GlcNAc2 Human + biochemical pathway literature
Pathomechanism ALG1 deficiency causes incomplete lipid-linked oligosaccharide synthesis, under-occupied N-glycosylation sites, and transfer of truncated glycans to proteins; NeuAc-Gal-GlcNAc2 can form after Golgi processing of truncated GlcNAc2-bearing proteins ~2–8% of purified serum transferrin carried the xeno-tetrasaccharide in prior biomarker studies cited by cohort authors; 27/27 tested ALG1-CDG patients in the 2016 cohort had the biomarker present (ng2016alg1‐cdgclinicaland pages 4-6, ng2016alg1‐cdgclinicaland pages 6-8) GO: dolichol-linked oligosaccharide biosynthetic process; GO: protein glycosylation; UBERON: blood serum Human biochemical + model-supported mechanism
Variant spectrum Broad allelic heterogeneity with many novel missense/splice variants; p.Ser258Leu is the most recurrent severe allele in available cohort data 31 potential variants identified; 26/31 (84%) novel; p.Ser258Leu present in 17/39 (44%) patients (ng2016alg1‐cdgclinicaland pages 3-4) Sequence variant classes: missense, splice-site; ACMG labels when individually assessed in later case reports Human clinical genetics
Core phenotype: developmental delay Neurodevelopmental impairment is near-universal Developmental delay 37/37 (100%) (ng2016alg1‐cdgclinicaland pages 4-6) HPO: Developmental delay (HP:0001263) Human clinical cohort
Core phenotype: hypotonia Hypotonia is highly prevalent from infancy Hypotonia 37/39 (95%) (ng2016alg1‐cdgclinicaland pages 4-6) HPO: Hypotonia (HP:0001252) Human clinical cohort
Core phenotype: seizures/epilepsy Seizures or epilepsy are highly prevalent Seizures/epilepsy 36/38 (95%) (ng2016alg1‐cdgclinicaland pages 4-6) HPO: Seizure (HP:0001250); Epilepsy (HP:0001250/label) Human clinical cohort
Core phenotype: microcephaly Microcephaly is common Microcephaly 27/37 (73%) (ng2016alg1‐cdgclinicaland pages 4-6) HPO: Microcephaly (HP:0000252) Human clinical cohort
Core phenotype: intellectual disability Intellectual disability is frequent among evaluable survivors Intellectual disability 21/22 (95%) evaluable (ng2016alg1‐cdgclinicaland pages 4-6) HPO: Intellectual disability (HP:0001249) Human clinical cohort
Neuroimaging phenotype Abnormal brain imaging is common, chiefly cerebral/cerebellar atrophy Abnormal brain imaging 25/37 (68%); cerebral or cerebellar atrophy 11/25 (44% of abnormal scans) (ng2016alg1‐cdgclinicaland pages 4-6) HPO: Abnormality of brain imaging; Cerebral atrophy (HP:0002059); Cerebellar atrophy (HP:0001272); UBERON: cerebrum, cerebellum Human clinical cohort
Ocular phenotype Ocular abnormalities are frequent Ocular abnormalities 27/36 (75%); strabismus 10/27 (37%); nystagmus 6/27 (22%) (ng2016alg1‐cdgclinicaland pages 4-6) HPO: Strabismus (HP:0000486); Nystagmus (HP:0000639); UBERON: eye Human clinical cohort
Dysmorphism Dysmorphic facial features are common 24/39 (62%) (ng2016alg1‐cdgclinicaland pages 4-6) HPO: Facial dysmorphism (label) Human clinical cohort
Hematologic involvement Hematologic defects are common but heterogeneous 18/34 (53%) (ng2016alg1‐cdgclinicaland pages 4-6) HPO: Hematologic abnormality (label); UBERON: blood Human clinical cohort
Gastrointestinal involvement GI disease is common and may include chronic diarrhea and protein-losing enteropathy GI problems 20/38 (53%); among those with GI manifestations, chronic diarrhea 7/20 and PLE 5/20 (ng2016alg1‐cdgclinicaland pages 4-6) HPO: Chronic diarrhea (HP:0002028); Protein-losing enteropathy (HP:0002242); UBERON: intestine Human clinical cohort
Skeletal involvement Skeletal abnormalities occur in about one-third 13/39 (33%); scoliosis 5/13; kyphosis 2/13; joint contractures 3/13 (ng2016alg1‐cdgclinicaland pages 4-6) HPO: Scoliosis (HP:0002650); Kyphosis (HP:0002808); Joint contracture (HP:0001371) Human clinical cohort
Hypoalbuminemia / renal-enteric severity marker Hypoalbuminemia marks severe multisystem disease and may reflect enteric or renal protein loss Hypoalbuminemia 12/39 (31%); all 12 died, mean age at death 6.75 months; within this group PLE documented in 2 and renal disease in 3 (ng2016alg1‐cdgclinicaland pages 4-6) HPO: Hypoalbuminemia (HP:0003073); Proteinuria/renal disease labels Human clinical cohort
Prognosis / mortality Mortality is high, especially in infancy and in specific genotypes Premature death 17/39 (44%); deaths before 12 months 11/17 (65%); clinical range spans mild ID to death in first weeks/2 years (ng2016alg1‐cdgclinicaland pages 4-6, ng2016alg1‐cdgclinicaland pages 1-3) HPO: Early death (label) Human clinical cohort
Genotype-phenotype correlation Homozygous p.Ser258Leu and compound heterozygous p.Gln50Arg are associated with particularly poor survival All 6 homozygous p.Ser258Leu patients died within first 5 months; 4/5 with p.Gln50Arg compound heterozygosity died at 5–28 months (ng2016alg1‐cdgclinicaland pages 4-6, ng2016alg1‐cdgclinicaland pages 3-4) Sequence variant labels; prognostic genotype annotation Human clinical cohort
Diagnostic screening Abnormal carbohydrate-deficient transferrin testing is a consistent screening clue in the major cohort, though normal transferrin can occur in some CDG and at least one later ALG1 case 39/39 in Ng cohort had at least one abnormal CDT result; methods included ESI-MS and IEF. A later long-term series reported one ALG1-CDG patient with normal transferrin IEF (ng2016alg1‐cdgclinicaland pages 4-6, ng2016alg1‐cdgclinicaland pages 1-3, bogdanska2021clinicalbiochemicaland pages 6-8) LOINC/HPO labels: abnormal transferrin glycosylation; UBERON: serum Human clinical cohort + longitudinal center experience
Diagnostic biomarker Xeno-tetrasaccharide NeuAc-Gal-GlcNAc2 is a high-value ALG1-associated biomarker useful to confirm diagnosis Detected in all 27/27 tested ALG1-CDG patients in the 2016 cohort; present on either serum or fibroblast glycoproteins; prior studies detected it on ~2–8% of purified serum transferrin (ng2016alg1‐cdgclinicaland pages 1-3, ng2016alg1‐cdgclinicaland pages 6-8) CHEBI labels: N-acetylglucosamine, galactose, sialic acid; biomarker label: NeuAc-Gal-GlcNAc2 Human biochemical biomarker
Functional confirmation Variant pathogenicity can be supported by yeast complementation rather than severity prediction Human wild-type vs missense ALG1 constructs tested in temperature-sensitive alg1-deficient yeast for growth and CPY glycosylation rescue; authors caution assay does not rank clinical severity (ng2016alg1‐cdgclinicaland pages 1-3, ng2016alg1‐cdgclinicaland pages 4-6, ng2016alg1‐cdgclinicaland pages 10-13) GO: carboxypeptidase Y glycosylation assay label; model: Saccharomyces cerevisiae Functional model assay
Recent 2024 development Targeted MRM proteomics in patient fibroblasts showed selective reduction of ALG1 protein abundance without broad compensatory changes in other ER glycosyltransferases 3 ALG1-CDG fibroblast lines, all homozygous c.773C>T p.S258L, showed substantial reduction of ALG1 protein; other GT transcript/protein levels remained largely unchanged (lin2024targetedproteomicsreveals pages 1-2, lin2024targetedproteomicsreveals pages 4-6) GO: proteomics; CL: fibroblast; protein abundance label Human primary-cell proteomics (2024)
Epidemiology Direct observed prevalence is not established; modeled birth prevalence is very low and varies by ancestry Estimated prevalence from gnomAD/ClinVar model: NFE 1:881,984; AFR 1:329,069; AMR 1:2,981,452; EAS 1:2,543,998; SAS 1:1,559,334; ASJ 1:47,656; FIN 1:4,775,806; EST 1:3,882,716 (pajusalu2021theestimatedprevalence pages 3-4) Epidemiology label; autosomal recessive rare disease Computational population estimate
Treatment status No ALG1-specific approved disease-modifying therapy was identified in retrieved evidence; management is supportive and complication-directed No relevant ALG1-specific interventional trial or supplementation efficacy study was retrieved; supportive care inferred from multisystem complications such as epilepsy, feeding/GI, infection, renal/respiratory failure (ng2016alg1‐cdgclinicaland pages 4-6, zhao2025clinicalandgenetic pages 10-11) MAXO labels: antiseizure therapy, nutritional support, infection management, respiratory support, rehabilitation (labels only) Evidence gap + real-world supportive care inference
Prevention / family planning Prevention is genetic rather than environmental: recurrence-risk counseling and reproductive testing are relevant Later case literature documents prenatal diagnosis in an ALG1 family leading to a healthy subsequent pregnancy (zhao2025clinicalandgenetic pages 10-11) Genetic counseling; prenatal diagnosis; carrier testing Human case report
Environmental factors No disease-specific environmental or infectious cause established; this is a Mendelian disorder No validated environmental triggers/protective factors found in retrieved ALG1-specific evidence Not applicable / no confident ontology term Evidence gap
Anatomical systems affected Multisystem disease with primary nervous system involvement and frequent eye, GI, hematologic, skeletal, renal, and respiratory complications Quantitative system involvement summarized above; causes of death included respiratory failure, renal failure, and infections leading to sepsis (ng2016alg1‐cdgclinicaland pages 4-6) UBERON: brain, eye, intestine, kidney, blood, skeletal system; CL labels as needed Human clinical cohort
Other species / natural disease No naturally occurring veterinary ALG1-CDG identified in retrieved evidence No specific animal natural-disease reports found NCBI Taxon: not established Evidence gap
Models / evidence gaps Available disease-relevant models are yeast and patient fibroblasts; no validated ALG1-specific vertebrate model, single-cell, spatial transcriptomic, or disease-specific multi-omics atlas was identified in retrieved evidence Yeast temperature-sensitive alg1 model and patient fibroblasts available; no relevant ALG1 clinical trials found; no single-cell/spatial studies identified (ng2016alg1‐cdgclinicaland pages 1-3, ng2016alg1‐cdgclinicaland pages 6-8, lin2024targetedproteomicsreveals pages 1-2, lin2024targetedproteomicsreveals pages 4-6) Model system labels: Saccharomyces cerevisiae, fibroblast Model organism / in vitro + evidence gap

Table: This table compiles high-confidence, disease-specific findings for ALG1-CDG across identifiers, genetics, phenotypes, mechanism, biomarkers, prognosis, epidemiology, and current evidence gaps. It is designed as a compact knowledge-base artifact with quantitative evidence and ontology-oriented annotations.

1. Disease information

Definition and nomenclature

ALG1-CDG is a congenital disorder of glycosylation affecting the assembly of the dolichol-linked precursor for protein N-glycosylation. It was formerly called congenital disorder of glycosylation type Ik, CDG-Ik, or GDP-mannose:GlcNAc₂-PP-dolichol mannosyltransferase deficiency. The landmark clinical series describes it as a rare autosomal-recessive disorder whose spectrum extends from mild intellectual disability to death in the first weeks of life. (ng2016alg1‐cdgclinicaland pages 1-3)

Identifiers supported by the retrieved literature

  • Disease: OMIM/MIM 608540.
  • Gene: ALG1, OMIM/MIM 605907; transcript used in the major cohort: NM_019109.4.
  • Former designation: CDG-Ik.
  • MONDO: ALG1-CDG is represented in MONDO, but an exact MONDO identifier was not verified in the retrieved primary literature and should be validated directly against the current MONDO release before database import.
  • Orphanet, MeSH, ICD-10, and ICD-11: no disease-specific code was established from the retrieved primary sources. In clinical coding, it may be grouped under congenital glycosylation/metabolic disorders rather than a uniquely specific ICD code.

The evidence summarized here is principally aggregated disease-level evidence from international cohorts and laboratory studies, not individual EHR-derived data. Individual case reports are used only where explicitly noted.

2. Etiology, risk, and protective factors

Causal factor

The sole established cause is germline biallelic pathogenic variation in ALG1. ALG1 encodes an ER-localized β1,4-mannosyltransferase that transfers the first of nine mannose residues onto the growing dolichol-linked oligosaccharide. The disorder is therefore a monogenic, autosomal-recessive inborn error of glycoprotein biosynthesis. (ng2016alg1‐cdgclinicaland pages 1-3)

Genetic risk

Each child of two heterozygous carriers has, per pregnancy, a 25% probability of being affected, a 50% probability of being an unaffected carrier, and a 25% probability of inheriting neither familial variant. Penetrance appears high for clearly pathogenic biallelic genotypes, but clinical expressivity is markedly variable.

The 2016 cohort identified 31 candidate disease variants, 26/31 (84%) of which were novel at that time. Twenty-two were absent from ExAC and nine occurred only at very low heterozygous frequencies. The recurrent c.773C>T (p.Ser258Leu) allele occurred in 17/39 patients. (ng2016alg1‐cdgclinicaland pages 3-4)

Environmental, lifestyle, infectious, and protective factors

No toxin, diet, lifestyle, infection, age, or sex exposure causes ALG1-CDG. Likewise, no validated protective allele, dietary factor, or gene–environment interaction has been demonstrated. Environmental events can alter complications—for example, infections may precipitate sepsis in medically fragile infants—but they do not constitute the primary etiology. Deaths in the major cohort included respiratory or renal failure and infections progressing to sepsis. (ng2016alg1‐cdgclinicaland pages 4-6)

3. Phenotypes

The best quantitative estimates come from Ng et al., published July 2016 in Human Mutation (DOI: 10.1002/humu.22983). This was a clinically ascertained cohort of 39 patients and may overrepresent severe disease. (ng2016alg1‐cdgclinicaland pages 4-6)

Neurologic and developmental phenotypes

  • Global developmental delay: 37/37, 100%; usually evident in infancy or early childhood; severity variable. Suggested HPO: HP:0001263.
  • Hypotonia: 37/39, 95%; commonly early and persistent. HPO: HP:0001252.
  • Seizures/epilepsy: 36/38, 95%; may be severe or drug-resistant. HPO: HP:0001250.
  • Intellectual disability: 21/22 evaluable patients, 95%; assessment was limited in patients who died young. HPO: HP:0001249.
  • Microcephaly: 27/37, 73%. HPO: HP:0000252.
  • Abnormal brain imaging: 25/37, 68%; cerebral or cerebellar atrophy accounted for 11/25 abnormal scans. Suggested HPO: cerebral atrophy HP:0002059; cerebellar atrophy HP:0001272. (ng2016alg1‐cdgclinicaland pages 4-6)

These findings profoundly affect quality of life: most affected children require assistance with mobility, communication, feeding, medication administration, and activities of daily living. No ALG1-specific EQ-5D, SF-36, PROMIS, or caregiver-burden study was identified.

Ocular and craniofacial findings

Ocular abnormalities occurred in 27/36 patients (75%), including strabismus in 10/27 and nystagmus in 6/27. Suggested HPO terms are HP:0000486 and HP:0000639, respectively. Dysmorphic facial features occurred in 24/39 (62%), but no single facial gestalt is sufficiently specific for diagnosis. (ng2016alg1‐cdgclinicaland pages 4-6)

Gastrointestinal, nutritional, renal, and biochemical findings

Gastrointestinal problems occurred in 20/38 patients (53%). Within the 20 affected patients, chronic diarrhea occurred in seven and protein-losing enteropathy in five. Suggested HPO terms include chronic diarrhea HP:0002028 and protein-losing enteropathy HP:0002242. (ng2016alg1‐cdgclinicaland pages 4-6)

Hypoalbuminemia occurred in 12/39 (31%) and was a particularly adverse marker: all 12 patients died, at a mean age of 6.75 months. Two had documented protein-losing enteropathy and three had renal disease, indicating that enteric and renal protein loss can both contribute. Suggested HPO: hypoalbuminemia HP:0003073, proteinuria HP:0000093. (ng2016alg1‐cdgclinicaland pages 4-6)

Hematologic and skeletal findings

Hematologic abnormalities occurred in 18/34 patients (53%), although the cohort summary did not define one uniform defect. Skeletal abnormalities occurred in 13/39 (33%): scoliosis in 5/13, kyphosis in 2/13, and joint contractures in 3/13. Suggested HPO terms are scoliosis HP:0002650, kyphosis HP:0002808, and joint contracture HP:0001371. (ng2016alg1‐cdgclinicaland pages 4-6)

Other reported involvement

Liver dysfunction, respiratory disease, renal disease, feeding difficulty/failure to thrive, and susceptibility to serious infections have been reported variably. A later Chinese case had drug-resistant epilepsy, facial dysmorphism, abnormal liver function, and death at 14 months, illustrating continuing recognition of severe infantile disease. (zhao2025clinicalandgenetic pages 10-11)

4. Genetic and molecular information

Gene and variant mechanism

ALG1 encodes a polytopic ER membrane glycosyltransferase. Most established disease alleles are missense, splice-site, nonsense, frameshift, or small insertion/deletion variants producing absent, unstable, or catalytically impaired enzyme. Disease-causing variants are germline, not somatic. The likely unifying mechanism is loss of function or severe hypomorphism, rather than gain of function or dominant-negative activity.

Known variants in the 2016 cohort included p.Ser150Arg, p.Ser258Leu, p.Arg276Trp, p.Ser359Leu, and p.Arg438Trp, plus 26 newly reported variants. Because many variants are individually extremely rare or absent from population databases, current allele frequencies and ClinVar classifications should be checked variant-by-variant at the time of interpretation. (ng2016alg1‐cdgclinicaland pages 3-4)

A 2025 case illustrates contemporary ACMG classification: c.328C>A (p.Gln110Lys) was classified likely pathogenic and c.863-2A>G pathogenic in a compound-heterozygous child. This is supportive case evidence rather than a 2023–2024 development. (zhao2025clinicalandgenetic pages 10-11)

Genotype–phenotype relationships

  • All six patients homozygous for p.Ser258Leu died within the first five months. Two previously reported homozygotes died at two and 11 weeks.
  • Four of five patients compound heterozygous for p.Gln50Arg died between five and 28 months, irrespective of the second allele.
  • Yeast complementation can establish functional impairment but did not reliably rank human clinical severity. The authors explicitly cautioned that yeast assays should be used “as a tool for determining pathogenicity, not clinical severity.” (ng2016alg1‐cdgclinicaland pages 4-6)

No validated modifier gene, epigenetic signature, anticipation, or recurrent disease-causing chromosomal rearrangement has been established. Large deletions encompassing ALG1 are theoretically detectable but are not the characteristic mechanism.

5. Environmental information

ALG1-CDG is not an environmentally acquired, infectious, toxic, radiation-associated, occupational, or lifestyle-mediated disorder. Smoking, alcohol, exercise, or diet have no established role in disease occurrence. Nutrition and infection exposure can influence morbidity after disease onset, particularly in patients with feeding problems, protein loss, respiratory compromise, or immune vulnerability, but this represents complication modification rather than gene–environment causation.

6. Mechanism and pathophysiology

Upstream causal chain

  1. Biallelic ALG1 variants reduce ALG1 abundance, stability, GDP-mannose interaction, complex formation, or catalytic activity.
  2. The ALG1-dependent addition of the first mannose to Dol-PP-GlcNAc₂ on the cytoplasmic ER face is impaired.
  3. Full-length Glc₃Man₉GlcNAc₂ lipid-linked oligosaccharide synthesis is reduced.
  4. Nascent proteins receive too few glycans or unusually truncated glycans through the oligosaccharyltransferase complex.
  5. Aberrant glycoprotein folding, stability, trafficking, receptor function, cell adhesion, and secretion affect many tissues, producing the neurologic and systemic phenotype. (ng2016alg1‐cdgclinicaland pages 1-3, lin2024targetedproteomicsreveals pages 1-2)

The early N-glycosylation machinery includes ALG1, ALG2, and ALG11, which sequentially add five cytoplasmic-side mannoses and can form heteromeric complexes. Suggested GO concepts include protein N-linked glycosylation, dolichol-linked oligosaccharide biosynthetic process, mannosyltransferase activity, and ER membrane localization. (ng2016alg1‐cdgclinicaland pages 6-8, lin2024targetedproteomicsreveals pages 1-2)

Xeno-tetrasaccharide formation

ALG1 deficiency permits some Dol-PP-GlcNAc₂ to cross into the ER lumen and be transferred to protein. After Golgi transit, β1,4-galactosyltransferase adds galactose and an α2,6-sialyltransferase caps the structure, generating NeuAcα2,6-Galβ1,4-GlcNAcβ1,4-GlcNAc. This structure does not normally occur in mammals and is found principally in ALG1-CDG, although trace amounts may occur in PMM2-CDG and MPI-CDG. (ng2016alg1‐cdgclinicaland pages 6-8)

Cellular and tissue effects

Direct cell-type-specific causal maps remain unavailable. Neurons and developing neural circuits appear particularly vulnerable, inferred from the near-universal neurodevelopmental phenotype. Hepatocytes, intestinal epithelium, renal glomerular/tubular cells, hematopoietic cells, ocular tissues, skeletal muscle, and connective tissue are plausible affected populations because their secreted and membrane proteins depend heavily on N-glycosylation. These cell assignments are mechanistic inferences, not single-cell evidence.

Suggested CL labels include neuron, astrocyte, hepatocyte, intestinal epithelial cell, renal epithelial cell, skeletal muscle cell, fibroblast, and hematopoietic cell. Suggested GO cellular components are endoplasmic reticulum membrane, ER lumen, Golgi apparatus, and oligosaccharyltransferase complex.

Recent 2024 proteomics

A targeted multiple-reaction-monitoring study published 18 January 2024 analyzed primary fibroblasts from eight type-I CDG patients, including three ALG1-CDG lines homozygous for c.773C>T, p.Ser258Leu. It found substantial reduction of the corresponding ALG1 protein, while other measured glycosyltransferases remained largely unchanged at transcript and protein levels. The authors concluded that there is no evident compensatory “fail-safe mechanism” for these early ER glycosylation steps. DOI: 10.3390/ijms25021191. (lin2024targetedproteomicsreveals pages 1-2, lin2024targetedproteomicsreveals pages 4-6)

No ALG1-CDG-specific single-cell atlas, spatial-transcriptomic study, lipidomics profile, comprehensive metabolomics signature, CRISPR screen, or integrated multi-omics analysis was identified.

7. Anatomical structures affected

The central nervous system is the dominant organ system, particularly the cerebrum and cerebellum. Other affected structures include the eye, gastrointestinal tract, liver, kidneys, blood/hematopoietic system, skeletal system, skeletal muscle, respiratory system, and possibly heart in individual patients. (ng2016alg1‐cdgclinicaland pages 4-6)

Suggested UBERON labels include brain, cerebral cortex, cerebellum, eye, liver, small intestine, colon, kidney, blood, skeletal muscle, bone, and lung. At the subcellular level, the primary lesion is in the ER membrane, with downstream processing in the Golgi. Lateralization is not characteristic; manifestations are systemic or bilateral rather than unilateral.

8. Temporal development and natural history

ALG1-CDG is genetically present from conception. Severe cases manifest prenatally, neonatally, or in early infancy with hypotonia, feeding problems, seizures, developmental impairment, dysmorphism, protein loss, or organ dysfunction. Milder cases may first be recognized through delayed development or epilepsy.

The course is chronic and lifelong in survivors. Neurologic impairment is generally persistent; systemic complications may be episodic or progressive. There is no validated staging system or evidence for spontaneous remission. The major critical period is infancy: 11/17 deaths in the cohort occurred before 12 months, and all six p.Ser258Leu homozygotes died before five months. (ng2016alg1‐cdgclinicaland pages 4-6)

9. Inheritance and population epidemiology

Inheritance

Inheritance is autosomal recessive. The cohort’s 17 male and 22 female patients provide no evidence of sex-linked risk. Variable expressivity is clear; anticipation is not expected. Germline mosaicism is theoretically possible for any Mendelian disorder but has not emerged as a characteristic ALG1-CDG mechanism. Consanguinity increases the probability that two carriers of the same rare allele have affected offspring, but no single global founder effect is established. (ng2016alg1‐cdgclinicaland pages 4-6)

Epidemiology

No robust observed incidence or prevalence registry estimate is available. A 2021 allele-frequency model using gnomAD and ClinVar estimated birth prevalence as follows:

  • non-Finnish European: 1:881,984;
  • African/African American: 1:329,069;
  • Latino/Admixed American: 1:2,981,452;
  • East Asian: 1:2,543,998;
  • South Asian: 1:1,559,334;
  • Ashkenazi Jewish: 1:47,656;
  • Finnish: 1:4,775,806;
  • Estonian: 1:3,882,716. (pajusalu2021theestimatedprevalence pages 3-4)

These are computational estimates, not screened-population observations. They assume Hardy–Weinberg equilibrium and accurate variant classification, omit many structural/regulatory or ultra-rare variants, and may over- or underestimate viable disease genotypes. The apparently higher Ashkenazi estimate requires epidemiologic validation.

10. Diagnostics

Recommended diagnostic approach

  1. Clinical suspicion: infantile developmental delay, hypotonia, epilepsy, microcephaly, abnormal brain imaging, dysmorphism, failure to thrive, diarrhea/protein-losing enteropathy, hypoalbuminemia, liver or renal abnormalities.
  2. Biochemical screening: serum transferrin glycoform analysis by isoelectric focusing, capillary electrophoresis, HPLC, or electrospray-ionization mass spectrometry. A type-I pattern indicates deficient assembly or transfer of the lipid-linked oligosaccharide but is not gene-specific. In the 2016 cohort, all 39 patients had at least one abnormal carbohydrate-deficient transferrin result. (ng2016alg1‐cdgclinicaland pages 4-6)
  3. ALG1-associated glycan testing: mass-spectrometric detection of NeuAc-Gal-GlcNAc₂ on transferrin or total glycoproteins. It was present in all 27 tested cohort patients and on approximately 2–8% of purified transferrin in prior biomarker studies. (ng2016alg1‐cdgclinicaland pages 1-3, ng2016alg1‐cdgclinicaland pages 6-8)
  4. Molecular confirmation: identify pathogenic/likely pathogenic variants in trans by a CDG panel, exome sequencing, genome sequencing, or ALG1 sequencing with deletion/duplication analysis.
  5. Orthogonal confirmation: segregation testing, RNA analysis for splice variants, glycomics, protein abundance, or functional complementation when variant interpretation remains uncertain.

A normal transferrin result does not absolutely exclude a CDG. A 2021 long-term series reported one molecularly diagnosed ALG1-CDG patient with normal transferrin IEF; moreover, an ALG1 p.Thr64Asn VUS with normal transferrin and absent tetrasaccharide was excluded from the major cohort despite abnormal yeast assays, illustrating why biochemical, molecular, and functional data must be integrated. (ng2016alg1‐cdgclinicaland pages 6-8, bogdanska2021clinicalbiochemicaland pages 6-8)

Role of genomic methods

  • Single-gene testing: reasonable when the biochemical xeno-tetrasaccharide strongly implicates ALG1 or familial variants are known.
  • CDG/multisystem panels: efficient when transferrin indicates type-I CDG but the subtype is unclear.
  • WES/WGS: appropriate for atypical or biochemically equivocal presentations; WGS can better detect noncoding, copy-number, and structural variants.
  • CMA, karyotype, FISH, mitochondrial DNA, and repeat-expansion testing: not first-line tests for isolated suspected ALG1-CDG unless the phenotype suggests an alternative diagnosis.
  • RNA sequencing: potentially useful for splice or expression variants, but not an established routine ALG1 assay.

Baseline phenotyping after diagnosis

Reasonable assessments include neurologic examination, developmental evaluation, EEG for suspected seizures, brain MRI, ophthalmology, feeding and swallowing assessment, growth and nutrition review, serum albumin/total protein, liver enzymes, coagulation studies, CBC, urinalysis/protein quantification, renal function, and respiratory/infection review. Cardiac evaluation should be guided by symptoms and broader CDG practice.

Differential diagnosis

The principal differential includes other type-I N-glycosylation disorders—especially PMM2-CDG, MPI-CDG, ALG2-CDG, ALG6-CDG, ALG8-CDG, ALG11-CDG, DPAGT1-CDG, and defects in dolichol-linked oligosaccharide synthesis. Protein-losing enteropathy may suggest MPI-, ALG6-, or ALG8-CDG, while the NeuAc-Gal-GlcNAc₂ marker and biallelic ALG1 variants favor ALG1-CDG. (ng2016alg1‐cdgclinicaland pages 4-6, ng2016alg1‐cdgclinicaland pages 6-8)

There is no established population newborn screening program. Targeted carrier screening, cascade testing, prenatal diagnosis, and preimplantation genetic testing are possible once familial variants are known.

11. Outcome and prognosis

The best available cohort estimate is 44% premature mortality (17/39); 11/17 deaths occurred before 12 months. Causes included respiratory failure, renal failure, and infections leading to sepsis. This is not a population survival curve and likely reflects referral/ascertainment bias. No reliable 5- or 10-year survival statistic or average life expectancy is available. (ng2016alg1‐cdgclinicaland pages 4-6)

Poor prognostic indicators include homozygous p.Ser258Leu, compound heterozygosity involving p.Gln50Arg, hypoalbuminemia, protein-losing enteropathy or renal protein loss, respiratory compromise, recurrent infection/sepsis, and severe early-onset epilepsy. All 12 hypoalbuminemic patients died at a mean age of 6.75 months. (ng2016alg1‐cdgclinicaland pages 4-6)

Survivors commonly have substantial long-term neurodevelopmental disability. Recovery to normal function has not been documented as an expected outcome, although symptom control, nutrition, mobility, communication, and family quality of life may improve with intensive supportive care.

12. Treatment and real-world management

Treatment status

No approved ALG1-specific disease-modifying therapy, validated substrate supplementation, gene therapy, RNA therapy, cell therapy, or pharmacologic chaperone was identified. Mannose treatment used in MPI-CDG and galactose used in selected other CDGs should not be assumed effective for ALG1-CDG; a long-term CDG series documented biochemical improvement for MPI- and PGM1-CDG, not ALG1-CDG. (bogdanska2021clinicalbiochemicaland pages 6-8)

No ALG1-specific interventional ClinicalTrials.gov study was returned by the trial search. Thus, present treatment is supportive and individualized.

Suggested management and MAXO-oriented annotations

  • Epilepsy: standard genotype-independent antiseizure medication selection; rescue plan for prolonged seizures. Suggested MAXO: antiseizure-agent therapy, EEG monitoring.
  • Feeding/nutrition: dietitian review, texture modification, swallow study, high-calorie support, enteral feeding when necessary. Suggested MAXO: nutritional supplementation, gastrostomy placement, swallowing assessment.
  • Protein loss: monitor albumin, edema, stool/renal protein loss; treat underlying enteropathy or renal complications and provide albumin/support when clinically indicated.
  • Development: early physical, occupational, speech/communication, and feeding therapies. Suggested MAXO: physical therapy, occupational therapy, speech therapy.
  • Vision: ophthalmologic surveillance and treatment of strabismus/refractive problems.
  • Orthopedics: monitor scoliosis, kyphosis, contractures, positioning, and bone health; use bracing or surgery according to standard indications.
  • Respiratory/infectious care: airway-clearance and aspiration prevention when needed; prompt evaluation and treatment of infection; respiratory support in severe disease.
  • Renal/hepatic/hematologic care: periodic laboratory and specialist surveillance tailored to baseline abnormalities.
  • Palliative care: appropriate early in life-limiting genotypes or severe multisystem disease, alongside active treatment.

No ALG1-specific response rates, comparative treatment outcomes, or pharmacogenomic recommendations are available.

13. Prevention

Primary lifestyle prevention is not applicable because ALG1-CDG is genetic. Effective prevention options are reproductive:

  • genetic counseling and parental carrier confirmation;
  • cascade testing of at-risk relatives;
  • prenatal diagnosis by chorionic-villus sampling or amniocentesis for known familial variants;
  • preimplantation genetic testing for monogenic disease;
  • donor gametes or other family-planning alternatives.

A later case series documented prenatal diagnosis in an ALG1 family followed by a healthy subsequent pregnancy. (zhao2025clinicalandgenetic pages 10-11)

Secondary prevention consists of early molecular diagnosis and prompt management of seizures, feeding problems, protein loss, aspiration, respiratory decline, renal dysfunction, and infection. Tertiary prevention includes rehabilitation, contracture/scoliosis prevention, nutritional support, vaccination according to routine schedules, and caregiver education. No disease-specific vaccine or pharmacologic prophylaxis exists.

14. Other species and natural disease

ALG1 and the early N-glycosylation pathway are evolutionarily conserved. Nevertheless, no well-characterized naturally occurring veterinary ALG1-CDG in a companion-animal breed or wildlife species was identified. There is no zoonotic potential or cross-species transmission because this is an inherited metabolic disorder.

15. Model organisms and experimental systems

Yeast

Temperature-sensitive Saccharomyces cerevisiae alg1 mutants are the principal functional model. At restrictive temperature they accumulate Dol-PP-GlcNAc₂ and can transfer GlcNAc₂ to glycoproteins. Human ALG1 variants can be tested for rescue of yeast growth and carboxypeptidase-Y glycosylation. This assay supported pathogenicity for variants in the 2016 study, but its biochemical severity did not correlate reliably with human outcomes. (ng2016alg1‐cdgclinicaland pages 4-6, ng2016alg1‐cdgclinicaland pages 10-13)

Human cellular models

Patient-derived skin fibroblasts demonstrate abnormal glycosylation, the xeno-tetrasaccharide, and variant-dependent ALG1 protein instability. Attempts to generate a homozygous ALG1-indel human cell line by CRISPR/Cas9 failed despite targeting four exons, suggesting that complete ALG1 loss may be incompatible with cell viability. (ng2016alg1‐cdgclinicaland pages 4-6)

The 2024 MRM-proteomics assay offers a reproducible method to quantify low-abundance ER glycosyltransferases. In three p.Ser258Leu-homozygous ALG1-CDG fibroblast lines, ALG1 protein was substantially reduced without broad upregulation of other pathway enzymes. (lin2024targetedproteomicsreveals pages 1-2, lin2024targetedproteomicsreveals pages 4-6)

Vertebrate and advanced models

No validated ALG1-CDG-specific mouse, rat, zebrafish, medaka, organoid, or iPSC model with demonstrated recapitulation of the human phenotype was identified in the retrieved literature. This is a major translational gap. Patient iPSC-derived neurons, liver/intestinal organoids, and viable hypomorphic vertebrate knock-in models would be particularly valuable for defining tissue vulnerability and screening therapies.

Evidence quality and current research priorities

The strongest disease-specific evidence remains the 2016 international 39-patient cohort and associated biochemical studies. Its exact abstract states that the xeno-tetrasaccharide “was seen in all twenty-seven patients tested” and that the study “triples the number of known patients and expands the molecular and clinical correlates of this disorder.” (ng2016alg1‐cdgclinicaland pages 1-3)

Recent 2023–2024 ALG1-specific clinical research was sparse. The most substantive 2024 development was targeted proteomic confirmation that ALG1-deficient fibroblasts have reduced ALG1 protein without compensatory increases in other ER glycosyltransferases. Priorities now include prospective natural-history registries, standardized outcome measures, longitudinal glycomics, updated variant curation, disease-specific quality-of-life studies, viable vertebrate and organoid models, and preclinical testing of gene replacement, mRNA delivery, or variant-directed stabilization strategies. (lin2024targetedproteomicsreveals pages 1-2, lin2024targetedproteomicsreveals pages 4-6)

Key primary references

  1. Ng BG et al. ALG1-CDG: Clinical and molecular characterization of 39 unreported patients. Human Mutation. Published July 2016;37:653–660. DOI: 10.1002/humu.22983. (ng2016alg1‐cdgclinicaland pages 1-3)
  2. Grubenmann CE et al. Deficiency of the first mannosylation step in the N-glycosylation pathway causes CDG-Ik. Human Molecular Genetics. 2004;13:535–542. PMID 14709599. (ng2016alg1‐cdgclinicaland pages 10-13)
  3. Kranz C et al. CDG-Ik: a defect of mannosyltransferase I. American Journal of Human Genetics. 2004;74:545–551. PMID 14973782. (ng2016alg1‐cdgclinicaland pages 10-13)
  4. Schwarz M et al. Deficiency of GDP-Man:GlcNAc₂-PP-dolichol mannosyltransferase causes CDG-Ik. American Journal of Human Genetics. 2004;74:472–481. PMID 14973778. (ng2016alg1‐cdgclinicaland pages 10-13)
  5. Dupré T et al. Mannosyltransferase deficiency: five new patients and seven novel mutations. Journal of Medical Genetics. 2010;47:729–735. PMID 20679665. (ng2016alg1‐cdgclinicaland pages 10-13)
  6. Morava E et al. Defining the phenotype in congenital disorder of glycosylation due to ALG1 mutations. Pediatrics. 2012;130:e1034–e1039. PMID 22966035. (ng2016alg1‐cdgclinicaland pages 10-13)
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